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Organic Reactions VOLUME III EDITORIAL BOARD ROGER ADAMS, Editor-in-Chief WERNER E. BACHMANN JOHN R. JOHNSON LOUIS F. FIESER H. R. SNYDER ASSOCIATE EDITORS MARVIN CARMACK PETER A. S. SMITH H. E. CARTER C. M. SUTER W. E. HANFORD EVERETT S. WALLIS CHARLES C. PRICE HANS WOLFF JOHN L. WOOD NEW YORK JOHN WILEY & SONS, INC. LONDON: CHAPMAN & HALL, LIMITED COPYRIGHT, 1946 BY ROQEE ADAMS All Rights Reserved This book or any part thereof must not be reproduced in any form without the written permission of the publisher. THIRD PRINTING, AUGUST, 1947 PRINTED IN THE UNITED STATES OP AMERICA PREFACE TO THE SERIES In the course of nearly every program of research in organic chemistry the investigator finds it necessary to Use several of the better-known synthetic reactions. To discover the optimum conditions for the appli- cation of even the most familiar one to a compound not previously subjected to the reaction often requires an extensive search of the litera- ture; even then a series of experiments may be necessary. When the results of the investigation are published, the synthesis, which may have required months of work, is usually described without comment. The background of knowledge and experience gained in the literature search and experimentation is "thus lost to those who subsequently have occa- sion to apply the general method. The student of preparative organic , chemistry faces similar difficulties. The textbooks and laboratory manuals furnish numerous examples of the application of various syn- theses, but only rarely do they convey an accurate conception of the scope and usefulness of the processes. For many years American organic chemists have discussed these problems. The plan of compiling critical discussions of the more impor- tant reactions thus was evolved. The volumes of Organic Reactions are collections of about twelve, chapters, each devoted to a single reac- tion, or a definite phase of a reaction, of wide applicability. The authors have had experience with the processes surveyed. The subjects are presented from the preparative viewpoint, and particular attention is given to limitations, interfering influences, effects of structure, and the selection of experimental techniques. Each chapter includes sev- eral detailed procedures illustrating the significant modifications of the method. Most of these procedures have been found satisfactory by the author or one of the editors, but unlike those in Organic Syn- theses they have not been subjected to careful testing in two or more laboratories. When all known examples of the reaction are not men- tioned in the text, tables are given to list compounds which have been prepared by or subjected to the reaction. Every effort has been made to include in the tables all such compounds and references; however, because of the very nature of the reactions discussed and their frequent use as one of the several steps of syntheses in which not all of the inter- mediates have been isolated, some instances may well have been missed. v vi PEEFACE TO THE SERIES Nevertheless, the investigator will be able to use the tables and their accompanying bibliographies in place of most or all of the literature search so often required. Because of the systematic arrangement of the material in the chapters and the entries in the tables, users of the books will be able to find infor- mation desired by reference to the table of contents of the appropriate chapter. In the interest of economy the entries in the indices have been kept to a minimum, and, in particular, the compounds listed in the tables are not repeated in the indices. The success of this publication, which will appear periodically in volumes of about twelve chapters, depends upon the cooperation of organic chemists and their willingness to devote time and effort to the preparation of the chapters. They have manifested their interest already by the almost unanimous acceptance of invitations to contribute to the work. The editors will welcome their continued interest' and their suggestions for improvements in Organic Reactions. CONTENTS CHAPTER PAGE 1. THE ALKYLATION OF AROMATIC COMPOUNDS BY THE FBIEDEL-CRAFTS METHOD¡ªCharles C. Price 1 2. THE WILLGERODT REACTION¡ªMarvin Carmack and M. A. Spielman ... 83 3. PREPARATION OF KETENES AND KETENE DIMERS¡ªW. E. Hanford and John C. Sauer 108 4. DIRECT SULFONATION OF AROMATIC HYDROCARBONS AND THEIR HALOGEN , DERIVATIVES¡ªC. M. Suter and Arthur W. Western 141 5. AZLACTONES¡ªH. E. Carter 198 6. SUBSTITUTION AND ADDITION REACTIONS OF THIOCTANOGEN¡ªJohn L. Wood 240 7. THE HOFMANN REACTION¡ªEverett S. Wallis and John F. Lane 267 8. THE SCHMIDT REACTION¡ªHans Wolff 307 9. THE CURTIUS REACTION¡ªPeter A. S. Smith 337 INDEX 451 vu SUBJECTS OF PREVIOUS VOLUMES VOLUME AcETOACETIC ESTEE CONDENSATION AND RELATED REACTIONS I ALIPHATIC FLUORINE COMPOUNDS II AMINATION OF HETEROCYCLIC BASES ARNDT-EISTERT REACTION AROMATIC ARSONIC AND ARSINIC ACIDS II BlAETLS II BUCHERER REACTION , I CANNIZZARO REACTION II CHLOROMETHYLATION OF AROMATIC COMPOUNDS I CLAISBN REARRANGEMENT . , I CLEMMENSEN REDUCTION I CYCLIC KETONES II ELBS REACTION FRIES REACTION JACOBSEN REACTION I MANNICH REACTION ....'. I PERIODIC ACID OXIDATION I PERKIN REACTION AND RELATED REACTIONS I REDUCTION WITH ALUMINUM ALKOXIDBS I REFORMATSKY REACTION I REPLACEMENT OF AROMATIC PRIMARY AMINO GROUP BY HYDROGEN II RESOLUTION OF ALCOHOLS I CHAPTER 1 THE ALKYLATION OF AROMATIC COMPOUNDS BY THE FRIEDEL-CRAFTS METHOD CHARLES C. PRICE University of Illinois CONTENTS PAGE INTBODUCTION 2 SCOPE AND LIMITATIONS Activity of Catalysts Alkylating Agents 4 Aromatic Compounds 5 Rearrangements of Alkyl Groups 6 Orientation in Alkylation ; 8 Identification 10 Related Reactions 2 Limitations 3 Other Methods of Alkylation 14 EXPERIMENTAL DIRECTIONS 6 ' Selection of Experimental Conditions 16 Triethylbenzene 16 <-Butylbenzene 7 |8-Cyclohexylnaphthalene 8 2,4,6-Triisopropylphenol 8 TABULATION OF EXPERIMENTAL RESULTS . 19 TABLE I. Reaction of Benzene with Aluminum Chloride 21 II. Alkylation of.Benzene 22 III. Alkylation of Halogenated Benzene Deriratives 44 IV. Alkylation of Toluene 45 V. Alkylation of Various Alkylbenzenes 48 VI. Alkylation of Tetralin 52 VII. Alkylation of Naphthalene . . 53 VIII. Alkylation of Miscellaneous Polynuclear Aromatic Compounds ... 56 IX: Alkylation of Phenol 8 X. Alkylation of Various Phenols and Phenolic Ethers 65 XL Alkylation of Polyhydric Phenols 69 ' XII. Alkylation of Miscellaneous Aldehydes, Acids, and Quinones .... 72 XIII. Alkylation of Aniline 73 ? XIV. Alkylation of Miscellaneous Aromatic Amines 74 XV. Alkylation of Heterocyclic Aromatic Compounds 6 1 2 ORGANIC REACTIONS INTRODUCTION Since the discovery by Friedel and Crafts' that aluminum chloride catalyzes the condensation of alkyl and acyl halides with various aromatic compounds to effect substitution of an alkyl or acyl group for one or more hydrogen atoms of the aromatic compound, this reaction has been greatly extended in scope with respect to alkylating or acylat- ing agents and catalysts. The use of aluminum chloride as a catalyst for such condensations has been considered in detail by Thomas,2 and certain aspects of the reaction have been treated in an earlier volume of this series.3 The present discussion is limited to the direct introduction of alkyl, cycloalkyl, or aralkyl residues containing no functional groups into various aromatic compounds under the influence of such catalysts as AICI3, FeCl3, SbCl5, BF3, ZnCl2, TiCl4, HF, H2SO4, H3PO4, and P2O5. The alkylating agents include olefins, highly strained cycloparaffins, polyalkylbenzenes, alkyl halides, alcohols, ethers, and esters of organic and inorganic acids. The aromatic compound may be a hydrocarbon, an aryl chloride or bromide, a mono- or poly-hydric phenol or its ether, an aromatic amine, an aldehyde, an acid, a quinone, or certain derivatives of heterocyclic aromatic compounds such as furfural or thiophene. The Friedel-Crafts process is frequently the most useful method for the introduction of an alkyl group. The reaction is capable of many prac- tical applications, and a large number of patents have appeared on the preparation of alkyl derivatives of various aromatic compounds such as xylene,4 naphthalene, and phenols. Patents have covered the utiliza- tion of such alkylating agents as the olefins derived from cracking, the mixtures prepared by chlorination of petroleum fractions,6 and various naturally occurring waxy esters.6 The most important application is the synthesis of ethylbenzene from ethylene and benzene. SCOPE AND LIMITATIONS Activity of Catalysts. Very little work has been done on the direct comparison of the relative efficacy of the catalysts used in the Friedel- 1 Friedel and Crafts, Compt. rend., 84, 1392, 14S0 (1877). 2 Thomas, "Anhydrous Aluminum Chloride in Organic Chemistry," American Chem- ioal Society Monograph 87, Reinhold Publishing Corp., New York, N. Y., 1941.8 (a) Blatt, Organic Reactions, I, "The Fries Rearrangement"; (6) Fuson, ibid., "Chloro- methylation of Aromatic Compounds."" * Akt.-Ges. f. Anilinf., Ger. pat., 184,230 [Chem. Zentr., II, 366 (1907)]. 'Thomas (to Sharpies Solvents Corp.), U. S. pat., 2,072,061 [C. A., 31, 2613 (1937)]. Wiggins, Hunter, and Nash. J. Inst. Petroleum, 26, 129 (1940). ?Robinson (to National Aniline and Chemical Co.), V. S. pat., 2,061,593 [C. A., 31, 785 (1937)]. FRIEDEL-CRAFTS METHOD 3 Crafts reaction. The catalytic activity for various metal chlorides in the condensation of toluene with acetyl chloride 7 is in the order A1C13 > SbCl6 > FeCl3 > TeCl2 > SnCl4 > TiCl4 > TeCl4 > BiCl3 > ZnCl2. The effect of catalysts for the Friedel-Crafts reaction in promoting the racemization of a-phenylethyl chloride,8 which should parallel their effect in catalyzing alkylation,9 is in the order SbCls > SnCU > BCI3 > ZnCl2 > HgCl2. O6X15 V CHCl + MClx *± CH+[MClx+i]-. / CH3 CH3 Hydrogen chloride, lithium chloride, and tetramethylammonium chlo- ride are ineffective as catalysts for both racemization and alkylation. ^ No direct comparison of the acidic catalysts has been made, although the order appears to be HF > H2SO4 > P2C>5 > H3PO4. In general, a direct comparison of the metal halides with the acids is limited by the fact that the activity varies to some extent with the alkylating agent selected. Sulfuric and phosphoric acids are usually more effective for olefins or alcohols than for alkyl halides. For example, allyl chloride and allyl alcohol condense principally at the double bond in the presence of sulfuric acid,10 whereas in the presence of boron fluoride,11 ferric chlo- ride,12 or zinc chlorideI2 these substances react chiefly to form the allyl derivative. Aluminum chloride causes condensation at both functional 'groups.12 It is of interest to note that in several instances the effect of a catalyst such as aluminum chloride or boron fluoride is enhanced by the presence of an acidic "assistant." Alkylation by olefins with aluminum chloride as a catalyst is favored by the presence of anhydrous hydrogen chlo- ride,13 and the condensation of primary alcohols with benzene using boron fluoride is possible only with the aid of an assistant such as phosr phoric anhydride, benzenesulfonic acid, or sulfuric acid.14 It has been found also that chlorides of tin, silicon, or titanium increase the catalytic activity of aluminum chloride, whereas ferric chloride decreases the 7 Dermer, Wilson, Johnson, and Dermer, /. Am. Chem. Soc., 63, 2881 (1941). 'Bodendorf and Bohme, Ann., 516, 1 (1935). 'Price, Chem. Revs., 29,37.(1941): > 10 Iruffault, Compt. rend., 202, 1286 (1936); see also Niederl, Smith, and McGreal, J. Am. Chem. Soc, 53, 3390 (1931); Smith and Niederl, ibid., 66,4151 (1933). 11 McKenna and Sowa, /. Am. Chem. Soc, 59, 470 (1937). ...." Niaetzesou and Isacescu, Ber., 66, 1100 (1933). 13 Berry and Reid, J. Am. Chem. Soc, 49, 3142 (1927). "Toussaint and Hennion, J. Am. Chem. Soc, 62, 1145 (194Q), .. ?? . : ORGANIC REACTIONS activity.16 Limited amounts of water frequently increase the effective- ness of boron fluoride or hydrogen fluoride. Alkylating Agents. The ease of alkylation by means of a reagent RX is dependent not only on the nature of X but also on the structure of the group R. Structural factors in the alkyl group promoting the po- larization of RX in the sense R+X~ facilitate alkylation.16 RX + Cat -> R+(X-Cat)- Thus, with halides, alcohols, ethers, and esters, alkylation proceeds most readily for tertiary or benzyl types, less readily for secondary types, still less readily for primary types, and least readily for methyl.17 It is therefore generally necessary to use increasingly vigorous catalysts or conditions to introduce the alkyl groups in the above sequence. For example, reactive halides like benzyl chloride will' react with benzene in the presence of traces of such a weak catalyst as zinc chloride, whereas an inert halide like methyl chloride requires a considerable quantity of a powerful catalyst such as aluminum chloride. The relative reactivity of the alkyl halides is also conditioned by the halogen atom. For aluminum chloride-catalyzed alkylations with either n-butyl or <-butyl halides,18 the order of activity is F > Cl > Br > I.1* This same order of reactivity has been found for hydrogen fluoride- catalyzed alkylation of benzene with cyclohexyl and s-octyl halides.20 The order of reactivity of the halides is thus the reverse of the normal order. Of the wide variety of alkylating agents which have been reported, the alkyl halides, olefins, and alcohols are by far the most useful. Aluminum chloride is an effective catalyst for all three classes. With halides and olefins, it is required in only catalytic amounts; but with alcohols con- 15 Ott and Brugger, Z. Elektrochem., 46, 105 (1940). 18 For reviews summarizing the evidence on the mechanism of the Friedel-Crafts reac- tion see Calloway, Chem. Revs., 17, 327 (1935); Nightingale, ibid., 25, 329 (1939); Price, ibid., 29, 37 (1941). 17 This same order of activity holds for the ease of migration and displacement of alkyl groups already attached to the aromatic nucleus. 18 Calloway, J. Am. Chem. Soc., 59, 1474 (1937). 18 Calloway (see reference 18) made the interesting observation that the ease of acylation with acyl halides is in the reverse order. "> Simons and Bassler, J. Am. Chem. Soc., 63,88(5 (1941). FRIEDEL-CRAFTS METHOD 5 siderably larger quantities are necessary because of the reaction of the aluminum chloride with the alcohol. (See the article by Norris and Sturgis cited on p. 8, reference 30.) C2HB0H + A1C1, > C2H6OH-A1C13 C2H6C1 + A1OC1 -^ C2HBOAiCl2 + HC1 Although boron fluoride or hydrogen fluoride will catalyze alkylation by means of alkyl halides, these catalysts are much more effective and useful with olefins or alcohols. Reactions carried out with either of these catalysts are distinguished by the lack of colored and resinous by- products which so generally accompany the use of aluminum chloride. Ethers and esters have not been widely applied in syntheses by the Friedel-Crafts reaction, chiefly because they offer no particular ad- vantage over the alcohols. In fact, with esters of organic acids and aluminum chloride as catalyst, a disadvantage is the simultaneous acylation. which may occur. However, the synthesis of toluene in 60% yield from benzene, methyl sulfate, and aluminum chloride represents the most successful procedure for the monomethylation of benzene (see p. 22). The use of cyclopropane as an alkylating agent has yielded n-propyl- benzene in 65% yield (see references 26 and 36 on p. 8), but other syn- theses, such as the preparation from n-propyl alcohol in 52% yield (see references 26 and 27, p. 8), are probably of more practical appli- cation. CH2 Aromatic Compounds. One characteristic feature of alkylation by the Friedel-Crafts procedure is that alkyl substituents in the aromatic ring markedly increase the ease of alkylation. Thus, there is a general tendency for the formation of considerable amounts of polyalkyl de- rivatives. An interesting observation in this connection is that the structure of the alkyl group is an important factor regulating the maximum number of alkyl groups which can be introduced into the benzene ring by the Friedel-Crafts method. (See reference 36, p. 8.) Although all six of the hydrogen atoms of benzene can be replaced by methyl, ethyl, or n-propyl groups, only four can be replaced by isopropyl groups, and, 6' ORGANIC REACTIONS although three have been replaced by ¡ê-butyI groups, the usual and principal product in this instance is the p-di-i-butyl derivative. C2H6 CH(CH3)2 C(CH3)3 (CH3)2CH C(CH3)3 The effect of a hydroxyl or an alkoxyl group on the ease of alkylation is complex. In some instances, the effect appears to be an activation. For example, although nitrobenzene has not been alkylated, o-nitro- anisole has been converted into the isopropyl derivative in good yield. j>CH(CH3)2 O2N ~ (84%) The normal activating influence of the hydroxyl or alkoxyl group is counterbalanced by the tendency for the catalyst to coordinate with the oxygen atom. F C6H6¡ªO: + B:F -? C6HB¡ª0¡ª>BF3 CH3 F CH3 This process not only decreases the activity of the catalyst but also tends to nullify the activating effect of the oxygen atom. This general effect is still more pronounced for aromatic amines, so that alkylation of these substances has found only very limited application. Rearrangements of Alkyl Groups. One factor involved in alkylation by the Friedel-Crafts method which has led to many conflicting and erroneous reports in the literature is the tendency for rearrangements of the alkyl group to occur during alkylation. The exact nature of the influence involved in these rearrangements is still not entirely clear. In general, the tendency of the rearrangements is in the direction: primary ¡ª> secondary ¡ª> tertiary. Usually the rearrangements involve only the migration of hydrogen atoms in the alkyl group rather than a rearrange- ment of ,the carbon skeleton. The first observation of such a rearrangement was made by Gus- tavson21 only a year after the announcement of the Friedel-Crafts reaction. He found that w-propyl and isopropyl bromides react with 21 Gustavson, Ber., 11, 1251 (1878). FRIEDEL-CRAFTS METHOD 7 benzene in the presence of aluminum chloride to form the same sub- stance, isopropylbenzene (cumene). "The discovery that n-propyl bromide is isomerized to isopropyl bromide in the presence of alum- inum chloride offers an explanation for this observation.22 CeHe -f- w-C3H7Br> C6H6 + MO-C3H7B: n-C3H7Br WO-C3H7C6H6 tso-C3H7Br Since such rearrangements may be represented as occurring by inter- mediate formation of an olefin, it has been suggested that olefins are involved as intermediates in the alkylations.11' n w-C3H7Br -^-> [C3H6] -^-> wo-C3H7C6H8 I Aids 'lHBr tso-C3H7Br The general theory of molecular rearrangements as outlined by Whit- more 23<I offers an alternative explanation of the isomerizations of alkyl groups during alkylation.9 CH3CH2CH2C1 + AlClg =± CH3CH2CH-+A1C14'i (CH3)2CH+ CH3 It is by no means necessary to suppose that an olefin is formed as an intermediate in all alkylations. For example, benzyl alcohol and benz- hydrol are particularly effective alkylating agents, but the intermediate formation of an olefin is impossible. Furthermore, under many condi- tions alkylation may proceed without rearrangement. It has been found that n.-propyl chloride in ike cold will react with benzene in the presence 2S Kekul6 and Sohrotter, Bull. soc. chim., [2] 34, 485 (1879). 23 MoKenna and Sowa, J. Am. Chem. Soc., 59,1204 (1937). 2sa Whitmore, J. Am. Chem. Soc., 54, 3274 (1932). 8 ORGANIC REACTIONS of aluminum chloride to give chiefly n-propylbenzene whereas at higher temperatures the product is chiefay isopropylbenzene.24'26'26 The catalyst may also influence the fate of the alkyl group. Normal alcohols, for example, usually alkylate without rearrangemerft in the presence of aluminum chloride,26'27'28 but rearrangement does occur when sulfuric acid 26> 29 or boron fluoride u> w is used as a catalyst. Under vigorous conditions changes even more extensive than isomeri- zation of the alkyl group can occur. Although benzene is alkylated normally in good yield with t-butyl alcohol and aluminum chloride at 30°, the products at 80-95° are toluene, ethylbenzene, and isopropyl- benzene.30 Alkylation with 2,4,4- or 2,3,3-trimethyl-2-pentanol can proceed to yield both normal and degraded alkylation products, the extent of degradation increasing with temperature.31 The alkylation of methyl 2-furoate proceeds normally at the active 5-position, but the alkylation of methyl 5-bromo-2-furoate at the inactive 4-position pro- ceeds with .degradation of all alkyl groups with more than four carbon atoms to give the 4-<-butyl derivative in every case.32' M Treatment of paraffin hydrocarbons with benzene in the presence of aluminum chloride leads to the formation of various alkylbenzenes by degradation of the paraffin, a reaction which has been termed "destructive alkylation." M Orientation in Alkylation. An additional factor complicating the use- fulness of Friedel-Crafts alkylations is the orientation involved in the introduction of more than one alkyl group.35'36 It was discovered at an early date that alkylation with aluminum chloride and alkyl halides yields considerable proportions of m-dialkylbenzenes, as well as the expected o- and p-isomers. The relative extent of normal and abnormal orientation has been found to be a function of the conditions of alkyla- tion. In general, the more vigorous the conditions with respect to the activity of the catalyst or the alkylating agent or the severity of the time and temperature factors, the greater is the tendency for the forma- ** Heise, Ber., 24, 7^8 (1891). 86 Konowalow, J. Buss. Phys.-Chem. Soc., 27, 457 (1895). 26 Ipatieff, Pines, and Schmerling, J. Org. Chem., 5, 253 (1940). "Tsukervanik and Vikhrova, J. Gen. Chem. U.S.S.R., 7, 632 (1937) [C. A., 31, 5779 (1937)]. 28 Bowden, J. Am. Chem. Soc, 60, 645 (1938). M Meyer and Bernhauer, Monatsh., 53 and 54, 721 (1929). 30 Norris and Sturgis, /. Am. Chem. Soc., 61, 1413 (1939). 11 Huston, Guile, Sculati, and Wasson, J. Org. Chem., 6, 252 (1941). 82 Gilman and BuHner, J. Am. Chem. Soc, 57, 909 (1935). "Gilman and Turok, J. Am. Chem. Soc, 61, 473 (1939). 84 Grosse, Mavity, and Ipatieff, J. Org. Chem., 3, 137 (1938). 36 See Ingold, Lapworth, Rothstein, and Ward, J. Chem. Soc, 1931, 1959; Bird and Ingold, ibid., 1938, 918. 3? Grosse and Ipatieff, J. Org. Chem., 2, 447 (1937). FRIEDEL-CBAFTS METHOD 9 tion of the abnormal m-derivatives. Thus, alkylation catalyzed by aluminum chloride, the most active catalyst, leads to large proportions of m-dialkylbenzenes, particularly with large amounts of catalyst at high temperatures or for long reaction times. Alkylations catalyzed with boron fluoride, sulfuric acid, ferric chloride, and most other cata- lysts yield chiefly the normal p-dialkylbenzenes. CH3 CH3 BX ROH BF, Naphthalene likewise yields two dialkyl derivatives; the principal dialkylation product from the reaction of naphthalene and cyclohex- anol or cyclohexene with aluminum chloride as the catalyst has been shown to be 2,6-dicyclohexylnaphthalene,36<I but from cyclohexanol and boron fluoride, 1,4-dicyclohexylnaphthalene is obtained.36* + CHuOH A1C1, A similar situation obtains in the trialkylation of benzene, the 1,2,4- trialkyl derivative being formed only under mild conditions, the 1,3,5- isomer under more vigorous conditions.37 It has been shown that the 1,2,4-trialkyl derivatives will, in many instances, rearrange to the 1,3,5- isomer under the influence of aluminum chloride.38'39'40-41-42 3'a Price and Tomisek, J. Am. Chern. Soc., 65, 439 (1943). 866 Price, Shafer, Huber, and Bernstein, J. Org. Chem., 7, 517 (1942). 87 Norris and Kubinstein, /. Am. Chem. Soc, 61, 1163 (1939). 88 Baddeley and Kenner, J. Chem. Soc, 1935, 303. 89 Nightingale and Smith, J. Am. Chem. Soc, 61, 101 (1939). 40 Smith and Perry, J. Am. Chem. Soc, 61, 1411 (1939). 41 Nightingale and Carton, J. Am. Chem. Soc, 62, 280 (1940). 41 Nightingale, Taylor, and Smelser, J. Am. Chem. Soc, 63, 258 (1941). 10 ORGANIC REACTIONS Even in the alkylation of phenols and aromatic halides similar effects on orientation have been observed. Thus, the ethylation of phenol with ethanol and aluminum chloride yields the o- and p-derivatives,43 whereas with ethyl ether as the alkylating agent at a higher temperature 3,5- diethylphenol ** is obtained. Alkylation of chlorobenzene with ethanol and aluminum chloride at 80-90° yields p-chloroethylbenzene,46 but with ethylene at 100°, the principal product is the m-isomer.46 C2H5 Since alkylation by the Friedel-Crafts reaction has been demon- strated to be a reversible reaction,47'48'49 it has been suggested that the various anomalous orientations can be explained on this basis. Jacob- sen 60 was the first of many s?. *i. ?. ? to' point out that normal alkyla- tion to form the 1,2,4-trialkyl derivative, followed by loss of the alkyl group in the 1-position, might account for the anomalous formation of m- dialkyl derivatives. Identification. The many possibilities for the formation of isomeric or anomalous products due to rearrangement, unusual orientation, or degradation of alkyl groups during the Friedel-Crafts reaction, coupled with the fact that the products are usually liquids, difficult to separate and identify, frequently necessitate particular care in establishing the structure and the purity of the products.64 The most effective method 43 Tsukervanik and Nazarova, J. Gen. Chem. U.S.S.R., 7, 623 (1937) [C. A. 31, 5778 (1937)]. 44 Jannasch and Rathjen, Ber., 32, 2391 (1899). 45 Tsukervanik, J. Gen. Chem. U.S.S.R., 8, 1512 (1938) [C. A., 33, 4587 (1939)]. 48 Istrati, Ann. chim., [6] 6, 395 (1885). 47 Boedtker, Bull. soc. chim., [3] 35, 834 (1906). 48 Boedtker and Halse, Bull. soc. chim., [4] 19, 447 (1916). 49 Woodward, Boreherdt, and Fuson,.J. Am. Chem. Soc, 56, 2103 (1934). 60 Jacobsen, Ber., 18, 342 (1885). 61 Anschiitz, Ann., 235, 177 (1886); Moyle and Smith, J. Org. Chem., 2, 114 (1937). ?-Schorger, J. Am. Chem. Soc., 39, 2671 (1917). 68 Price and Ciskowski, J. Am. Chem. Soc., 60, 2499 (1938). "See Marvel and Himel, /. Am. Chem. Soc, 62, 1550 (1940), who found that the aluminum chloride-catalyzed condensation of cyclohexyl chloride with bromobenzene yielded a mixture of all three bromocyclohexylbenzenes. FRIEDEL-CRAFTS METHOD 11 of establishing the orientation of the alkyl groups is oxidation to the corresponding aromatic acids. This is sometimes difficult for the tertiary groups, particularly (-butyl; for example, Jthe oxidation of p-di-¡ê-butyl- benzene with chromic acid yields 2,5-di-t-butylbenzoquinone as the principal product.66 0 (CH3) and (CH3)3C The structure of the side chain may be established by a synthesis that leaves no doubt about the structure of the product. Alkylbenzenes containing primary alkyl groups may be prepared by Clemmensen reduction of an aryl allsyl ketone,89'66 and those containing secondary groups by reaction of an aryl alkyl ketone with a Grignard reagent followed by dehydration and reduction.67 A primary alkyl group at- tached to a benzene ring can be distinguished from a secondary or ter- tiary group by bromination in the presence of aluminum bromide; all hydrogen atoms and secondary or tertiary alkyl groups attached to a benzene ring are replaced by bromine under these conditions,-whereas primary alkyl groups are not affected.68 wo-C3xi7CfiIi5 ^ CfiBrg ~r~ &0"C3H7Br ~p 5HBr n-C3H7C6H6 5Br' > n-C3H7C6Br6 + 5HBr AlBr8 Identification of alkylated benzenes can be accomplished to some degree by the physical properties, more definitely by preparation of a solid derivative such as a sulfonamide,29-69-eo a diacetamino deriva- tive,600 or a picrate.63'59 66 Boedtker, Bull. soc chim., [3] 31, 969 (1904). 66 Gilman and Turck, J. Am. Chem. Soc, 61, 478 (1939); Martin, Organic Reactions, I, "The Clemmensen Reduction." 67 Klages, Ber., 35, 3509 (1902). 68 Bodroux, Ann. chim,., [10] 11, 511 (1929); Hennion, J. Am. Chem. Soc., 66, 1801 (1944). 69 Shriner and Fuson, "Identification of Organic Compounds," John Wiley & Sons, New York, 2nd ed., 1940. 60 Huntress and Autenrieth, J. Am. Chem. Soc, 63, 3446 (1941). ma Ipatieff and Schmerling, J. Am. Chem. Soc, 59,1056 (1937) ; 60,1476 (1938); see also reference 42. 12 ORGANIC REACTIONS Related Reactions. Many compounds containing more than one carbon-halogen or carbon-oxygen bond, although beyond the scope of this chapter (see p. 4), undergo stepwise reaction with aromatic compounds to form, as intermediates, alkylating agents of the type under consideration. For example, methylene chloride reacts with benzene in the presence of aluminum chloride to yield diphenylmethane, presumably through the intermediate formation of benzyl chloride.36 Other examples are noted in the following equations. C6H6 + CH2C12 C6H6 + CH2O 2C6H6 + CHCI3 C6H6 + C6H6CHO C6H6 + CH2C1CH2C1 C6H6 + CH2 CH2 0 [C6H6CH2C1] [C6H6CH2OH] [(C6H6)2CHC1] [(C6H6)2CHOH] [C6H6CH2CH2C1] ^> C6HBCH2CH2C6H6 AIC13 AIC/I3 (C6H6)2CH2 (C6H6)2CH2 (C6H6)3CH (C6H6)3CH?i [C6HBCH2CH2OH] ^% C6H5CH2CH2C6H561'?2 AICI3 The reactions of aldehydes and ketones with phenols have been investi- gated extensively. If the two groups in a molecule capable of condensing with the aro- matic ring are properly situated, the reaction may yield a cyclic product, a process which has been termed "cyclialkylation." 63 The condensations of halides, alcohols, and unsaturated compounds containing a variety of other functional groups have been carried out 61 Schaarschmidt, Hermann, and Szemzo, Ber., 58, 1914 (1925). 42 Theimer, Abstracts, Division of Organic Chemistry, 99th Meeting of the American Chemical Society, Cincinnati, Ohio, April, 1940, p. 42. Matui, J. Soc. Chem. Ind. Japan, 44, No. 2, 88 (1941). 63 Bruson and Kroeger, J. Am. Chem. Soc, 62, 36 (1940). FRIEDEL-CRAFTS METHOD 13 successfully. Thus, nitrobenzyl alcohols and halides M condense in the normal manner, and the addition of a variety of aromatic compounds to the double bonds in unsaturated ketones such as benzalacetophenone49 or, unsaturated acids such as cinnamic 66 or oleic acids 66 has been reported. Limitations. Two important factors which govern the application of the Friedel-Crafts reaction are the activity of the aromatic compound and the activity of the alkylating agent and catalyst. Thus if the alkylating agent and catalyst are very reactive and the aromatic sub- strate is relatively inert, extensive degradationso'31> 32> 3S or polymeriza- tion 67 of the alkylating agent may occur. If the aromatic substrate is very reactive toward the catalyst and the alkylating agent is relatively inert, decomposition of the aromatic compound may take precedence over alkylation. For example, naphthalene reacts in the presence of aluminum chloride to form binaphthyls 68 and tetralin is degraded to AlCls 2C,0H8 > H2 + (C10H7)s benzene and a mixture of octahydroanthracene and octahydrophe- nanthrene through the intermediate formation of ^-(4-phenylbutyl)- tetralin.69 Methylation of naphthalene and tetralin therefore can be accom- plished only in very poor yields. Similarly such reactive heterocyclic aromatic substances as furan and thiophene.have not been alkylated successfully by the Friedel-Crafts method. Deactivation of the furan nucleus by the carboxyl group of furoic acid, however, makes alkylation by the Friedel-Crafts procedure feasible and useful (see Table XV, p. 76). 61 Staedel, Ann., 283, 157 (1895). M Liebermann and Hartmann, Bee., 25, 957 (1892). 66 Stirton and Peterson, Ind. Eng. Ckem., 31, 856 (1939). 67 Truffault, Compt. rend., 202, 1286 (1936). 68 Homer, J. Chem. Soc, 91, 1108 (1907). ?? Barbot, Bvtt. soc. chim., [i] 47, 1314 (1930). 14 ORGANIC REACTIONS The alkylation of anisole under the vigorous conditions necessary to introduce an isopropyl group (aluminum chloride at 120-140°) leads to extensive demethylation.43 Alkylation of phenol under many condi- C6HBOCH3 + C3H7ok -^> C3H7C6H4OCH3 and C3H7C6H4OB 140 tions may produce ethers as well as nuclear alkylation products.91 Both C6H6OH + C3H6 -> C3H7C6H4OH, C6H6OC3H7 and Cs formation and splitting of ethers seems to be minimized by the use of hydrogen fluoride as the catalyst for alkylation of phenol or its ethers. Aluminum chloride has been used as a catalyst for the alkylation of phenols or of acids, but it should be noted that these reagents frequently react vigorously to yield aluminum salts of the phenols or acids. For this reason boron fluoride, hydrogen fluoride, and sulfuric acid generally have been used as catalysts for alkylation of such substances. C6H6OH + A1C18 -> C6H6OA1C12 + HC1 ArCO2H + AlClg -> ArCO2AlCl2 + HC1 The reaction of bromo compounds is complicated by the possibility of migration of the aromatically bound bromine atom in the presence of aluminum chloride.64'70 Thus appreciable quantities of p-dibromo- benzene are produced in aluminum chloride-catalyzed alkylations of bromobenzene. C6HBBr + RC1 A'C1' > RC6H4Br and p-C6H4Br2 Recently, alkylation of a few aromatic aldehydes and acids has also been accomplished successfully.32' 71 Nitrobenzene is not alkylated under Friedel-Crafts conditions; it is converted slowly to 0- and p-chloroaniline in the presence of isobutyl chloride and aluminum chloride.72 Other Methods of Alkylation. A useful method for the preparation of certain alkylated phenols is that devised by Claisen 73 and extended by a number of investigators.74'76-76'77 The nuclear alkylation of phenols is accomplished by treating the sodium phenoxide with an active halide of 70 Copisarow, J. Chem. Soc., 119, 442 (1921). 71 Calcott, 'Tinker, and Weinmayr, J. Am. Chem. Soc., 61, 1010 (1939). 72 Gilman, Burtner, Calloway, and Turck, J. Am. Chem. Soc., 57, 907 (1935). 73 Claisen, Ann., 442, 220 (1925); Ber., 58, 275 (1925); 59, 2344 (1926). "Schorigin, Ber., 58, 2033 (1925); 59, 2506 (1926); Busch, Z. angew. Chem., 38, 1145 (1925); Ber., 60, 2243 (1927); van Alphen, Eec. trav. chim., 46, 287, 799 (1927). 76 Huston and Houk, J. Am. Chem. Soc., 54, 1506 (1932). 78 Huston and Lewis, /. Am. Chem. Soc, 53, 2379 (1931). 77 Huston, Swartout, and Wardwell, J. Am. Chem. Soc., 52, 4484 (1930). FRIEDEL-CRAFTS METHOD 15 the allyl or benzyl type (or even i-butyl chloride 78) in an inert solvent such as toluene. The alkylation of phenols by this procedure supple- ments the Friedel-Crafts method since the products by the Claisen method are practically always the o-isomers whereas Friedel-Crafts alkylation usually yields the p-isomer.73'75> 76-77 Another method for the preparation of alkylated phenols, also due to Claisen, is the re- arrangement of phenyl ethers, a reaction which is considered in detail in another chapter.78" One or two useful indirect methods have been reported for the intro- duction of methyl groups. Nuclear methylation of phenols has been accomplished by the condensation of phenols with formaldehyde and secondary amines,79 followed by hydrogenation of the intermediate benzylamine.79" (H) ArOH + CH2O + R2NH -* R2NCH2Ar0H ¡ª->? R2NH + CHgArOH A successful preparation of 1,2,3-trimethylbenzene (not available by the Friedel-Crafts method) has been accomplished by use of the Tif- feneau rearrangement which occurs during the reaction of benzyl-type Grignard reagents with formaldehyde.80 CH2MgX CH3 CH3 + CH2O -> C A number of polyalkylbenzene derivatives not directly available by the Friedel-Crafts procedure may be prepared by application of the Jacobsen rearrangement.80" The alkylation of aromatic nitro compounds and of quinones has been accomplished by means of the radicals liberated by the decomposition of tetravalent lead salts of organic acids or of acyl peroxides, or by the electrolysis of sodium salts of organic acids.80*1 CH3 78 Lewis, J. Am. Chem. Soc., 83, 329 (1903). 78a Tarbell, Organic Reactions, II, "The Claisen Rearrangement." n Blicke, Organic Reactions, I, "The Mannich Reaction." na Caldwell and Thompson, J. Am. Chem. Soc., 61, 2345 (1939). 80 Smith and Spillane, J. Am. Chem. Soc., 62, 2643 (1940). SOa Smith, Organic Reactions, I, "The Jacobsen Reaction," 806 Fieser and Chang, J. Am. Chem. Soc., 64, 2043 (1942); Fieser, Clapp, and Daudt, ibid., 2052; Fieser and Oxford, Md., 2060. 16 ORGANIC REACTIONS 0 0 EXPERIMENTAL DIRECTIONS 81 Selection of Experimental Conditions. An examination of the tables will suggest the most favorable experimental conditions for many par- ticular alkylations. A few generalizations are evident. Owing to the activation of the aromatic nucleus by the alkyl group, maximum con- version to the monoalkyl derivative is favored by the presence of a large excess of the aromatic compound. To increase further the overall con- version to the monoalkyl derivative, the polyalkylated material from one run may be recovered and added to the next. Because of mobility of the alkyl groups, some are removed to another aromatic nucleus by this process. The polyalkylated material thus actually may serve as the alkylating agent.48 Orientation in di- or trialkylation may be regulated by controlling the vigor of the reaction. Relatively mild catalysts, such as boron fluoride (with an alcohol), hydrogen fluoride (with an olefin), or ferric chloride (with an alkyl halide), may lead almost exclusively to p-dialky- lation or 1,2,4-trialkylation. Under more vigorous conditions, as with excess aluminum chloride at elevated temperatures, the m-dialkyl or sym-trialkyl derivative predominates. The quantity of catalyst necessary may vary considerably. Only catalytic amounts of aluminum chloride are required when olefins or alkyl halides are the alkylating agents. ? With alcohols or their deriva- tives, much larger amounts of catalyst are required, owing to inactiva- tion by reaction with the alcohol or with the water formed during the reaction. With hydrogen fluoride it is universal practice to use a large excess of catalyst, so much so that it is actually the solvent medium for the reaction. 1. sym-Trieihylbenzene.w A 5-1. three-necked flask surrounded by a ? 81 Since an excellent preparation utilizing sulfuric acid, that of cyclohexylbenzene from cyclohexene and benzene, has been described in detail in Organic Syntheses {Coll. Vol, 2, 151, John Wiley & Sons, New York, 1943), no experimental directions illustrating the technique employed with this useful catalyst have been included in this section. 82 This is essentially the procedure of Norris and Rubinstein (reference 37). Norris and Ingraham [/. Am. Chem. Spc., 60, 1421 (1938)] have prepared the same compound in 65-70% yield with ethanol as the alkylating agent. In this case, a considerably larger ratio of aluminum chloride is required. FRIEDEL-CRAFTS METHOD 17 ? tub of ice-salt mixture is fitted with (1) an efficient stirrer sealed with a mercury seal or a tight-fitting piece of rubber pressure tubing lubri- cated with mineral oil (not glycerol), (2) a long reflux condenser with a glass outlet tube leading to a hood or an efficient apparatus for absorb- ing hydrogen halide, (3) a thermometer well (containing ethanol), and (4) a 500-cc. separatory funnel. Four pounds w (1815 g., 6.8 moles) of anhydrous,aluminum chloride is added to the flask and is moistened with 750-1000 cc. of dry ethyl bromide. The stirrer is started, and, when the temperature reaches ¡ª 10°, addition of dry benzene (530 g., 604 cc, 6.8 moles) through the separatory funnel is carried out at such a rate that the temperature stays below ¡ª5° (about two and a quarter hours is necessary). The rapid current of hydrogen halide evolved carries some of the ethyl bromide out through the condenser. After the benzene has been added the remainder of a total of 2425 g. (1695 cc, 21.8 moles) of ethyl bromide is added over a period of about one and a quarter hours. The ice is then removed from the cooling bath and stirring is continued overnight while the mixture gradually warms to room temperature. The bath is then removed and stirring is con- tinued for another twenty-four hours, when evolution of hydrogen halide has ceased. The reaction mixture is poured into a large separatory funnel from which it is added, in a fine stream and with vigorous stirring, to 10 kg. of ice and 300 cc. of concentrated hydrochloric acid in a large crock. This operation should be performed in a good hood. When hydrolysis is complete, the major portion of the lower water layer is removed by siphoning and the reaction mixture is filtered to remove a black solid which impedes. separation of the layers during washing. The organic layer is then separated and washed with dilute hydrochloric acid, twice with water, with 5% aqueous sodium hydroxide, and twice with water. After drying over calcium chloride, the product is distilled through an efficient fractionating column. The triethylbenzene (943-962 g., 86- 87%) boils at 72.5-75°/3 mm. or 215-216°/760 mm.; nf>° 1.4955- 1.4968.84 2. trButylbenzene.** A mixture of 105 g. (1.35 moles) of benzene and 88 This preparation may be run as efficiently on a much smaller scale, if desired. 84 Norria and Ingraham (reference 82) give directions for further purification of the sjfln-triethylbenzene by means of sulfonation; b.p. 214.8° (75S.1 mm.); njj'1 1.4956. 85 These directions are those of Nightingale, Taylor, and Smelser (reference 42). A smaller yield (50-55%) is obtained with aluminum chloride as a catalyst (Fieser, "Experiments in Organic Chemistry," 2nd ed.. D. C. Heath and Co., New York, 1941, p. 179). The same situation holds for f-butyl alcohol, ferric chloride giving better yields than aluminum chlo- ride [Potts and Dodson, J. Am. Chem. Soc., 61, 2553 (1939)]. 18 ORGANIC REACTIONS t 12 g. (0.07 mole) of anhydrous ferric chloride (in a flask fitted with a con- denser and a trap to absorb hydrogen chloride 86°) is cooled to 10°, and 25 g. (0.27 mole) of i-butyl chloride is added. As the mixture is slowly warmed to about 25°, evolution of hydrogen chloride proceeds smoothly. When the evolution of hydrogen chloride ceases, the reaction mixture is washed with dilute hydrochloric acid and with water, dried, and frac- tionally distilled. The Z-butylbenzene (29 g., 80%) boils at 167-170°. 3. fi-Cyclohexylnaphthalene.*6 Boron fluoride 87 is passed through an empty 250-cc. suction filter flask (as a safety trap) and is then bubbled through a suspension of 50 g. (0.39 mole) of naphthalene in 40 cc. (38 g., 0.47 mole) of cyclohexanol in a 500-cc. flask at room temperature 87° until two liquid layers separate in the reaction mixture (fifteen to thirty minutes).88 The reaction flask is fitted with an outlet tube 89 leading to the top of a vertical meter-long glass tube through which a stream of water is passed; this apparatus serves to absorb the excess boron fluoride. After standing for about an hour, the reaction mixture is separated and the upper layer washed 90 with dilute alkali and with water. After drying, the mixture is fractionally distilled under diminished pressure in a modified Claisen flask, 52 g. (63%) of /?-cyclohexylnaphthalene (b.p. 190-195715 mm.; nf? 1.5973; d¡êg 1.020) is obtained. The product may be characterized by preparation of the picrate,59 m.p. 1OO0.63-B8 4. %,4,6-Triisopropylphenol.91 About 800 g. of liquid hydrogen 860 Org. Syntheses, Coll. Vol. 2, 4, John Wiley & Sons, New York, 1943. 88 These directions are based on the general procedure described by McKenna and Sowa (reference 11) for benzene and adapted to naphthalene by Price and Ciskowski (refer- ence 53). It is useful for alkylation by means of secondary, tertiary, and benzyl-type alco- hols. Toussaint and Hennion (reference 14) have found that by addition of an "assistant," such as phosphoric anhydride or benzenesulfonic acid, the procedure may be extended to many primary alcohols. 87 Cylinders of the compressed gas can be purchased from the Harshaw Chemical Co., Cleveland, Ohio. 870 If the reaction mixture is cooled to 0°, the boron fluoride dissolves without reacting until finally the reaction occurs with nearly explosive violence. 88 Glass apparatus is satisfactory although it has been found that, after repeated use, Pyrex flasks used for the condensation become appreciably etched. 89 As much as possible of the tubing for handling boron fluoride should be glass, since rubber soon hardens on contact with the gas. 80 Occasionally, naphthalene may crystallize during the washing. If so, it should be separated by nitration. 91 These are the directions of Calcott, Tinker, and Weinmayr (reference 71). Hydrogen fluoride appears to be particularly suitable for nuclear alkylation of phenols and amines, since there was no detectable alkylation of the hydroxyl or amino group, a side reaction which occurs to an appreciable extent with such catalysts as aluminum chloride (see ref- erence 43) and boron fluoride [Sowa, Hinton, and Nieuwland, J. Am. Chem. Soc, 64, 3694 (1932)]. FRIEDEL-CRAFTS METHOD 19 fluoride w is placed in a 2- to 3-1. copper, stainless steel, or nickel vessel (such as a beaker made of the metal) which is thoroughly cooled with an ice or ice-salt bath. The reaction vessel should be fitted with a cover perforated for a mechanical stirrer, a thermometer well, and an opening for the addition of reagents. The reaction mixture is kept below 8° while a solution of 140 g. (1.49 moles) of phenol in 515 cc. (405 g., 6.75 moles) of isopropyl alcohol is added from a separatory funnel over a period of three hours. The reaction mixture is then allowed to stand in a hood at room temperature for sixteen hours, after which time it is poured onto a large excess of ice (in a Pyrex beaker). Benzene is added; the organic layer is separated and washed with water, with dilute sodium bicarbonate, and again with water. The mixture is then dried and, after evaporation of the benzene, distilled under diminished pressure. 2,4,6- Triisopropylphenol (310 g., 95%) boils at 125°/7 mm. TABULATION OF EXPERIMENTAL RESULTS The summary of experimental results of the alkylation of various aromatic compounds has been divided into tables on the basis of the aromatic compound alkylated. These tables summarize the reagents and catalysts used for the various alkylations and, when available, such details as moles of reactants, solvent, temperature, time of reaction, products, and yields. In each table the alkylations have been arranged in order according to the increasing number of carbon atoms in the alkyl group. These groups are further subdivided in order on the basis of decreasing number of hydrogen atoms; thus, examples of the introduction of the allyl group follow those of the propyl, and examples of the introduction of the cyclo- hexyl group follow those of the hexyl. For the introduction of any par- ticular alkyl group, the arrangement is based on the alkylating agent. Hydrocarbons, such as olefins, are first, then alkyl halides, followed by alcohols and finally alcohol derivatives, such as ethers and esters of organic and inorganic acids. 92 Since hydrogen fluoride boils at 20°, the liquid can be very readily withdrawn from cooled inverted cylinders with a length of copper tubing leading from the valve of the oylinder to a copper beaker or flask immersed in an ice bath. If the liquid is kept cold (10° or below), it can be handled quite easily. The reactions should be carried out in a hood, however, and all handling of the liquid should be done with long, heavy rubber gloves as a precaution against accidental contact with the liquid. TABLE I REACTION OF BENZENE WITH ALUMINUM CHLO&IDE Moles of Benzene 10 25 Catalyst (moles) AlCls (0.6) AICI3¡ªHC1 (¡ª) AlBr3 (3) Temperature, °C. 125 Warm 20 Time 24 hr. 20 weeks Products (% Yield) Ethylbenzene (1.6%), biphenyl (0.8%) Methylphenylcyclopentane, diphenylcyclohexane (m.p. 170°) Phenylcyclohexane (21 g.), biphenyl (1.5 g.), di- phenylcyclohexane (2.0 g.) Reference * 200, 163 181 335 * References 93-350 appear on pp. 78-82. TABLE II AliKYLATION OF BENZENE toto Moles of Benzene 1 0.5 0.4 ¡ª 6 0.25 1 8 5 0.8 10 ¡ª Alkylating Agent (moles) Methyl chloride (¡ª) Methyl bromide (0.5) Methyl bromide (1.2) Methyl iodide Methyl alcohol (1) Methyl chloroformate (0.1) Methyl formate (3) Methyl sulfate (0.25) Ethylene (10) Ethylene (¡ª) Ethylene (18.8) Ethylene (¡ª) Catalyst (moles) A1C13 (0.3) A1C13(O.1) AICI3 (0.8) I2 (trace) A1C13 (2) AICI3 (0.1) AICI3 (5) Aids (0.36) AICI3 (0.4) * 1 AICI3 (0.5) P2O6 (0.3) H3PO4 (-) Tem- perature, °C. 80 100 -40 250 90-95 0-80 25-95 25-70 70-90 80 250 300 . Time, hours (unless noted otherwise) _ ¡ª- ¡ª 4-8 9 1 ¡ª 2 48-72 3-4 ¡ª 12 Products (% Yield) Toluene, xylenes, trimethylbenzenes, durene, penta- and hexa-methyl- benzenes Xylene (plus toluene) 1,2,4-Trimethylbenzene (50%) Toluene Toluene (21%) Toluene (20%), m-xylene (20%) Mesitylene (46%) Toluene (60%) Ethylbenzene (34%, 60%), diethyl- benzenes (20%), triethylbenzenes (10%) sj/m-Triethylbenzene (70%) Ethylbenzene (18.4%), diethylben- zenes (40%), triethylbenzenes (20%), hexaethylbenzene (3%) Ethylbenzene, diethylbenzenes, tri- ethylbenzenes Reference * 164 164 37 277 30 231 261 214 107, 252 167, 252,141 244,67 204,67 oI Q o GO 2 3 ¡ª 8 ¡ª 13 1 6 11.3 11.3 11.3 1 1 25 65 8 8 ¡ª Ethylene (¡ª) Ethylene (0.9) Ethylene (¡ª) Polyethylbenzenes (ca. 1) Ethyl chloride Ethyl chloride Ethyl chloride (1.5) Ethyl chloride (3) Ethyl chloride (1) Ethyl chloride (28) Ethyl chloride (35) Ethyl chloride (40) Ethyl bromide (3) Ethyl bromide (1) Ethyl bromide (10) Ethyl bromide (4.4) Ethyl bromide (2) Ethyl bromide (2) Ethyl bromide (¡ª) H2SO4 (1) (-) BF3 t (0.15) BFjr-H2O (0.25) A1CU (-) A1C13(O.1) A1C13 (-) AICI3 (¡ª) AlCl3(0.1) AICI3 (2) AKHgMO.l) AlClj,(1.5) A1CI3(1.5) AICI3 (1.5) AICI3 (2) AlCU(O.l) A1C13(1.1) AICI3 (0.8) Al¡ªHC1 (0.1) Al¡ªHgCl2 (0.2) Aids (-) 10-20 20-25 ¡ª 80 ¡ª ¡ª 100 25-50 25 70-75 70-75 75-80 0-25 25 7-25 80 25-80 0-25 ¡ª - 8 ¡ª 5 ¡ª ¡ª ¡ª 24 18 12 12 16 24 48-72 ¡ª ¡ª 48-2 3-48 ¡ª Ethylbenzene (5%) Ethylbenzene (60%)* Hexaethylbenzene (56-59%) Ethylbenzene (80%) Hexaethylbenzene (43%) sym- and asj/m-Triethylbenzenes Ethylbenzene (50%) sj/m-Triethylbenzene (85%) Ethylbenzene (76%) 1,3,5-and 1,2,4-Triethylbenzene (67%, 0 . 1; 1,2,4,5- and 1,2,3,5-Tetraethylbenzene (52%, 1 : 1), pentaethylbenzene (14%) 1,2,4,5- and 1,2,3,5-Tetraethylbenzene (13%, 1 : 1), pentaethylbenzene (39%), hexaethylbenzene (15%) si/m-Triethylbenzene (85-90%) Ethylbenzene (33%) Ethylbenzene (52%), polyethylben- zenes (ca. 15%) Ethylbenzene (83%) Ethylbenzene (70%) Ethylbenzene (53%) m- and p-Diethylbenzenes 341 199 222 274,48 95,334 219 290 37 347 312 312 312 37 293 274 119 275 275 96, 161, 329 3 CO § * References 93-350 appear on pp. 78-;82. t When the BF3 is omitted, no alkylation occurs (198, 341). TABLE II¡ªContinued AliKYLATION OF BENZENE Moles of Benzene ¡ª 1.3 0.1 1.6 0.4 ¡ª 3.0 2 4 2 1 Alkylating Agent (moles) Ethyl bromide (¡ª) Ethyl bromide (¡ª) Ethyl iodide (0.5) Ethanol (0.1) Ethanol (0.3) Ethanol (1.0) Ethyl ether (¡ª) Ethyl ether (0.5) Ethyl ether (1) Ethyl ether (1) Ethyl formate (0.45) Ethyl formate (1) Catalyst (moles) Aid, (-) A1CU (-) AlCl3of A1I3(¡ª) ZnCl2(0.15) A1C13 (0.6) A1C13(1.5) AlClg (¡ª) A1C13 (1.0) BF3 (1) ZnCl2 (1) A1C13 (0.67) BF3 (1) Tem- perature, °C. 100 Cold ¡ª 300 120-130 80 ¡ª 25-120 150 180 80 ¡ª Time, hours (unless noted otherwise) ¡ª? ¡ª ¡ª 10 3 ¡ª? 48 3 12 5 ¡ª Products (% Yield) 1,2,3,4-Tetraethylbenzene, t hexa- ethylbenzene 1,2,4,5-Tetraethylbenzene,t 1,2,3,4- tetraethylbenzene, pentaethylben- zene Ethylbenzene, polyethylbenzenes Ethylbenzene (poor yield) Ethylbenzene (49%), m-diethylben- zene, diethylbiphenyl, and diethyl- terphenyl sj/m-Triethylbenzene (65-70%) Hexaethylbenzene (50%) Ethylbenzene (36%) Ethylbenzene (25%), p-diethylben- zene (20%) Ethylbenzene Ethylbenzene (63%)? diethylbenzene (13%) Ethylbenzene (6%) Reference * 166 211 164 171 27,30 82 212 30 264 108 234 23 2o I I 1 ¡ª 0.3 8 2 3 ¡ª ? ¡ª 8 3 2 8 2.3 1 1.1 1.1 ¡ª ¡ª 5 ¡ª 1 Ethyl formate (3) Ethyl chloroformate (¡ª) Ethyl chloroformate (0.2) Ethyl carbonate (0.5) Ethyl acetate (0.45) Ethyl acetate (0.25) Ethyl acetate (¡ª) Ethyl chloroacetate (¡ª) Ethyl sulfate (0.5) Ethyl sulfate (0.125) Ethyl p-toluenesulfonate (0.15) Ethyl orthosilicate (0.25) ? Cyclopropane (1) Cyclopropane (1) Cyclopropane (0.4) Cyclopropane (0.6) Cyclopropane (¡ª) Propylene (¡ª) Propylene (23) Propylene (¡ª) Propylene (0.75) A1CU (5) A1C13 (-) AICI3 (0.1) AICI3 (0.72) AlClg (0.67) A1C1S (0.3) AlCls (-) AICI3 (-) AlCU (0.72) AICI3 (0.3) AICI3 (0.2) AICI3 (0.72) AICI3¡ªHC1 (0.06) AICI3¡ªHC1 (0.06) H2SO4 (0.4) HjSOi (80%) (3.0) HF(-) HF(-) HF(25) FeCl3 (0.3) A1C13 (0.1) 0-95 Cold 0-80 25-70 80 80 0-25 80 0-70 80 80 25-70 0-5 25-30 2 65 0 0 20 25 80 ¡ª ¡ª ¡ª. 30 5 1 25 ¡ª. 2 1 2 20 5 3 1 5 ¡ª ¡ª 24 ¡ª ¡ª si/m-Triethylbenzene (50%) Ethylbenzene, polyethylbenzene p-Diethylbenzene (40%) Ethylbenzene (56%) Ethylbenzene (45%), p-ethylaeeto- phenone (23%) Ethylbenzene (60%) Ethylbenzene (12-18.5%), m-diethyl- benzene (30-50%),. triethylben- zene (8-18%) Ethylbenzene Ethylbenzene (71%) Ethylbenzene (80%) Ethylbenzene (64%) Ethylbenzene (53%) n-Propylbenzene (65%) n-Propylbenzene (30%), di-n-propyF- benzene (20%) n-Propylbenzene (10%) Cumene (58%) n-Propylbenzene (42%), dipropylben- zene (20%) Cumene (84%) 1,2,4,5-Tetraisopropylbenzene (77%) Cumene (91%) Cumene (40%), ra-di- and s^m-triiso- propylbenzenes 261 164, 279 231 214 217, 234,261 28 261 164, 279 214 28 139 214 26; 36 36 36 206 26 307 71,303 71 272 13 4 2 0 * References 93-350 appear on pp. 78-82. t Products isolated through treatment with concentrated sulfuric acid, suggesting possibility of a Jacobsen rearrangement (211). to TABLE II¡ªContinued ALKYLATION OF BENZENE Moles of Benzene 10 2 * ¡ª 2 2 - 9.0 13 2 2 6 1 0.7 ¡ª Alkylating Agent (moles) ? ' Propylene (¡ª) Propylene (7) Propylene (3) Propylene (¡ª) Propylene (1.5) Propylene (1.5) Polyisopropylbenzenes (65 g.) Cymene (0.75) w-Propyl chloride (1) n-Propyl chloride (1) n-Propyl chloride (1) n-Propyl chloride (3) n-Propyl bromide (0.4) n-Propyl bromide (¡ª) Catalyst (moles) Prffe-H^PO* (-) H2SO4 (96%) (3) H#O?(96%)(1.5) H2SO4.(96%) (-) H2SO4(1) H2SO4 (1) (-) BF3(0.15) AICI3 (0.1) AICI3 (0.03) AICI3 (0.08) AICI3 (0.08) Al(Hg),(0.1) AICI3 (1) A1Q3 (0.07) Aid, (-) Tem- perature, °C. 80 10 10 ¡ª 4 4 80 80 -6 35 25 -10 -2 Below 0 Time, hours (unless noted otherwise) 2 2 ¡ª 2 2 6 10 5 5 18 ¡ª 5 ¡ª Products (% Yield) Cumene Cumene (78%), p-diisopropylbenr zenes (18%) Cumene (32%), p-diisopropylbenzene (33%), triisopropylbenzene (12%), 1,2,4,5-tetraisopropylbenzene (2%) 1,2,4,5-Tetraisopropylbenzene (35%) Cumene (35%), p-diisopropylbenzene (18%) Cumene (50%), p-diisopropylbenzene (30%), 1,2,4-triisopropylbenzene Cumene (65 g.) Toluene (80%), cumene (85-90%) n- and Isopropylbenzenes (41%; 3 : 2) ra- and Isopropylbenzenes (48%; 2 : 3) n- and Isopropylbenzenes (67%; 1 : 3) sym-Triisopropylbenzene f (90%) n-Propylbenzene (30%) n-Propylbenzene (30%) Reference * . 67 * 198 198 222 341 341, 310 48 48 26 26 347 180 24 - 25 I o 3 o ¡ª 1.0 _ 1.6 1 2 1 3 2 1 3 ¡ª 4. 6 1 0.01 ¡ª 0.7 n-Propyl bromide (¡ª) n-Propyl bromide (0.5) n-Propyl alcohol (¡ª) n-Propyl alcohol (0.5) n-Propyl alcohol (1) n-Propyl alcohol (0.5) n-Propyl formate (1) n-Iropyl formate (0.25) n-Propyl acetate (0.45) n-Propyl sulfate (1) n-Propyl sulfite (0.125) Isopropyl chloride (¡ª) Isopropyl chloride (1) Isopropyl chloride (1) Isopropyl chloride (3) Isopropyl chloride (0.12) Isopropyl bromide (¡ª) Isopropyl alcohol (0.7) HF(¡ª) AlBr3 (¡ª) H2SO4 (80%) (¡ª) A1C13 (0.7) BF3 (1) BFj¡ªP2O6 (0.5) BF3 (0.8) AICI3 (0.2) AICI3 (0.67) BF3 (0.1) - AICI3 (0.2) AICI3 (-) Al¡ªHC1 (0.1) Al(Hg),(0.1) AICI3 (1) AIQ3 (o.oi) AlBr3 (¡ª) H2SO4 (80%) (6) 80 ¡ª 65 110 60 80 ¡ª 25-60 80 ¡ª 25-60 ¡ª 25 25 -10 25 ¡ª 65 ¡ª ¡ª ¡ª 10 9 3 ¡ª 8 5 ¡ª 8~ ¡ª 18 18 ¡ª ¡ª ¡ª 3-4 Isopropylbenzene (42%), n-propyl- benzene (6%) Cumene (30%) Cumene (45%), p-diisopropylbenzene, 1,2,4-triisopropylbenzene n-Propylbenzene (52%), m-di-n-pro- pylbenzene (37%) Cumene (20%), p-diisopropylbenzene (20%) Cumene (60%), p-diisopropylbenzene (13%) . Cumene (30%), p-diisopropylbenzene (30%) n-Propylbenzene (60%) Propylbenzene (32%), p-propylaceto- phenone Cumene (40%), p-diisopropylbenzene (25%) n-Propylbenzene (66%) Cumene, m- and o-diisopropylben- zenes Cumene (66%) Cumene (83%) sym-Triisopropylbenzene (90%) t 1,2,4,5-Tetraisopropylbenzene (10%) Cumene Cumene (65%) 304 21 26,29 26,27 11 14 23 28 234 23 28 300,323 275 347 180 334 21 29 * References 93-350 appear on pp. 78-82. t Proceeds through the fonnation of an intermediate crystalline complex, Al2Cl?-2Ci5H2(HCl (180). TABLE II¡ªContinued ALKYLATION OF BENZENE Moles of Benzene 2-5 7.5 1 2 7 2 7 2 Alkylating Agent (moles) Isopropyl alcohol (1.0) Isopropyl alcohol (15) Isopropyl alcohol (1) Isopropyl alcohol (0.5) Isopropyl alcohol (1) Isopropyl ether (1) Isopropyl ether (1) Isopropyl phenyl ether (1) Catalyst (moles) A1C13 (0.5) H28O4 (80%) (65) BF3 (0.7) BFs¡ªP2O5 (0.5) HF(-) BF3 (¡ª) HF(¡ª) BF3 (-) Tem- perature, °C. 30 65 25 80 ¡ª ¡ª ¡ª -?- Time, hours (unless noted otherwise) 24 5 12 ¡ª ¡ª ¡ª ¡ª ¡ª Products (% Yield) Cumene (25%) Cumene (8%), p-diisopropylbenzene (22%) 1,2,4-triisopropylbenzene (8%), 1,2,4,5-tetraisopropylbenzene Cumene (20%), p-diisopropylbenzene (20%) Cumene (40%), p-diisopropylbenzene (20%) Cumene (22%), p-diisopropylbenzene (14%), 1,2,3-triisopropylbenzene (26%), 1,2,4,5-tetraisopropyl- benzene (28%) Cumene (25%), p-diisopropylbenzene (20%) Cumene (26%), p-diisopropylbenzene (24%), 1,2,4-triisopropylbenzene (25%), 1,2,4,5-tetraisopropylben- zene (8%) Cumene (25%), p-diisopropylbenzene (10%) Reference * 30,195 29, 218 11 14 306 264 306 264 1 I 1 1 3 ¡ª 1 8 1 2 ¡ª 3 .¡ª 1 ¡ª 3 ¡ª ¡ª ¡ª Isopropyl acetate (1) Isopropyl acetate (1) Isopropyl acetate (0.25) Isopropyl acetate (¡ª) Isopropyl trichloroacetate (1) Isopropyl sulfate (0.5) Isopropyl sulfate (1) AUyl chloride (0.7) Allyl chloride (¡ª) AUyl chloride (0.6) AUyl chloride (¡ª) Allyl alcohol (1) AUyl alcohol (¡ª) Trimethylene bromide (0.45) Isopropylidene chloride (¡ª) 1-Butene (¡ª) Isobutylene (¡ª) BF3 (1) - BF3 (1) A1CU (0.3) HF{-) BF3 (0.3) AlCU (0.72) BF3 (0.05) A1C13(O.15) A1CU(-) FeCUorZnCl2(0.1) H2SO4 (-) BF3 (-) HF(-) A1C13 (0.25) AlCU (-) HJSSO, (96%) (¡ª) P2OB (-) ¡ª ¡ª 80 80 ¡ª 0-70 ¡ª ¡ª ¡ª 25 ¡ª ¡ª ¡ª 60-100 ¡ª ? ¡ª 200-240 ¡ª ¡ª 1 ¡ª ¡ª 2 ¡ª ¡ª ¡ª ¡ª ¡ª ¡ª ¡ª ¡ª ¡ª ¡ª 2 Cumene (15%), p-diisopropylbenzene (10%) Cumene (15%), p-diisopropylbenzene (10%) Cumene (68%) Cumene (53%), acetophenone, p-iso- propylacetophenone Cumene (30%), p-diisopropylbenzene (25%) Cumene (44%) Cumene (35%), p-diisopropylbenzene (25%) n-Propylbenzene t (50%?) Isopropylbenzene,t 1,2-diphenylpro- pane 2'-Chloro-n-propylbenjsene (30%), 1,2-diphenylpropane 2'-Chloroisopropylbenzene AUylbenzene (8%) AUylbenzene (11-20%), 1,2-diphenyl- propane (8-12%) n-Propylbenzene (35%) 1,3-diptenyl- propane (20%) Isopropylbenzene s-Butylbenzene, p-di-?-butylbenzene t-Butylbenzene (50%), p-di-4-butyl- benzene (15%) 23 23 28 309 23 214 23 12, 339, 340 302, 340 12 67 11 305 125 302 198 244 O o * References 93-350 appear on pp. 78-82. t Bodroux (125) found that 1,2-diphenylpropane decomposed under the influence of aluminum chloride, yielding a mixture of n- and isopropylbemenee. TABLE II¡ªContinued ALKYLATION OF BENZENE ??§ Moles of Benzene 2 ¡ª 0.1 4 8 6 6 ¡ª 1 2 1 3 __ 2 Alkylating Agent (moles) Isobutylene (2.5) Isobutylene (¡ª) Isobutylene (¡ª) n-Butyl fluoride (0.1) ra-Butyl chloride (0.8) n-Butyl chloride (1.6) n-Butyl chloride (0.5) n-Butyl chloride (1) n-Butyl alcohol (¡ª) n-Butyl alcohol (1) n-Butyl alcohol (0.5) n-Butyl formate (1) n-Butyl formate (0.25) n-Butyl acetate (¡ª?) n-Butyl acetate (0.45) Catalyst (moles) HssSO4(96%)(1.5) HF(-) FeCla (0.3) A1C13(O.1) A1C13 (0.6) Al¡ªHgCl2 (0.3) Al¡ªHgCl2(0.1) Al(Hg),(0.1) H2SO4 (80%) (-) BF3 (1) BF3¡ªP2O6 (0.5) BF3 (1) Aicu (a. 3) HP(¡ª) AICI3 (0.67) Tem- perature, ?c. 15 0 25 ¡ª 0 0 80 25 70 60 80 80 40-75 80 80 Time, hours (unless noted otherwise) 1.2 ¡ª ¡ª ¡ª 48 48 ¡ª 18 ¡ª 9 ¡ª 5 6 ' ¡ª 5 Products (% Yield) <-Butylbenzene (7%), p-di-f-butylben- zene (77%), tri-t-butylbenzene (8%) i-Butylbenzene (44%), p-di-t-butyl- benzene (41%) t-Butylbenzene (89%) MButylbenzene (10%) s-Butylbenzene (50%) n- and s-Butylbenzenes (62%) s-Butylbenzene (80%) s-Butylbenzene (36%), n-butylben- zene s-Butylbenzene, p-di-s-butylbenzene s-Butylbenzene (35%), p-di-s-butyl- benzene (25%) s-Butylbenzene (75%), p-di-s-butyl- benzene (5-10%) s-Butylbenzene (30%), p-di-s-butyl- benzene (30%) s-Butylbenzene (73%) s-Butylbenzene (60%) Butylbenzene (32%), p-butylaceto- phenone (9%) Reference * 198, 222 303 272 18 287 151 151 347 29 11 14 23 28 309 234 I 3 3 3 3 3 3 3 3 2.67 27 8 6 2-5 1 2 1.3 0.75 0.75 0.75 0.75 n-Butyl propionate (0.25) w-Butyl isobutyrate (0.25) n-Butyl valerate (0.25) n-Butyl 2-ethylvalerate (0.25) n-Butyl benzoate (0.25) n-Butyl stearate (0.25) n-Butyl oxalate (0.125) n-Butyl sulfite (0.125) n-Butyl sulfate (0.17) n-Butyl chlorosulfonate (3) n-Butyl phosphate (1) s-Butyl chloride (0.9) s-Butyl chloride (1) s-Butyl alcohol (¡ª) s-Butyl alcohol (1.0) s-Butyl alcohol (1) s-Butyl alcohol (0.5) d-g-Butyl alcohol (0.32) d-s-Butyl alcohol (0.32) Z-s-Butyl alcohol (0.16) ks-Butyl alcohol (0.16) Z-*-Butyl alcohol (0.16) alcohol (0.16) AICI3 (0.3) AlCljj (0.3) A1CU (0.3) AICI3 (0.3) AICI3 (0.3) AICI3 (0.3) A1CU (0.3) AICI3 (0.3) AICI3 (0.24) AICI3 (6) BF8 (1) Al¡ªHgCl2(0.15) (80%) (¡ª) A1Q3 (0.5) BF3 (0.7) BFa¡ªP2O6 (0.5) AICI3 (0.3) BF3 (0.2) H3PO4 (0.78) H2SO4(0.18) BFa HF (1.62) 40-75 40-75 40-75 40-75 40-75 40-75 80 80 0-30 0-5 0 25 70 30 25 0-25 25 70 50 20 16 6 6 6 6 6 6 1 1 20 3 18 _ 24 12 12 18 2 3 12 5 s-Butylbenzene (92%) s-Butylbenzene (73%) s-Butylbenzene (85%) s-Butylbenzene (78%) s-Butylbenzene (80%) s-Butylbenzene (40%) s-Butylbenzene (55%) s-Butylbenzene (41%) Butylbenzene (44%) s-Butylbenzene (19%), ra-di-s-butyl- benzene (27.%), chlorobenzene (11%) s-Butylbenzene (8%), p-di-8-butyl benzene (20%) s-Butylbenzene (82%) (-Butylbenzene (60%) s-Butylbenzene, p-di-s-butylbenzene s-Butylbenzene (25, 60%) s-Butylbenzene (25, 50%), p-di-s- butylbenzene (20%, 12%) s-Butylbenzene (45%), p-di-s-butyl benzene (13%) d^s-Butylbenzene (50%) Z-s-Butylbenzene (48%) (99.5% race- mized) d-s-Butylbenzene (12%) (^?s-Butylbenzene (37%), di-s-butyl- benzene (40%) d-s-Butylbenzene (51%) J-s-Butylbenzene (30%), di-s-butyl- benzene (27%) 28 28 28 28 28 28 28 28 214 111 23 151 347 29 195, 273 11, 14, 273 14 273 273, 351 351 351 351 351 § CO * References 93-350 appear on pp. 78-82. TABLE II¡ªContinued ALKYLATTON OF BENZENE Coto Moles of Benzene i i ¡ª ¡ª. 12 8 0.08 13 0.2 1 1 Alkylating Agent (moles) s-Butyl formate (1) s-Butyl acetate (1) s-Butyl isobmtyrate (¡ª) Isobutyl chloride (0.5) Isobutyl chloride (3.3) Isobutyl chloride (1.1) Isobutyl alcohol (0.1) Isobutyl alcohol (2) Isobutyl alcohol (0.2) Isobutyl alcohol (1) Isobutyl formate (1) Catalyst (moles) BF3 (1) BF3 (0.9) HF(¡ª) AICI3 (-) A1C13(2.2) . A1C13 '0.7) ZnCl2(0.15) H2SO4¡ªSO3(30%) (1 kg.) H2SO4 (70%-80%) (5) BF3 (0.7) BF3 (1) Tem- perature, °C. ¡ª 80 ¡ª 0 4 260-270 0 70 ¡ª ¡ª Time, hours (unless noted otherwise) ¡ª ?¡ª : 48 48 48-72 0.7-0.8 4 ¡ª ¡ª - Products (% Yield) s-Butylftenzene (20.%), p-di-s-butyl- benzene (15%) s-Butylbenzene (25%), p-di-s-butyl- benzene (15%) s-Butylbenzene (56%) <-Butylbenzene t (55%) ?-Butylbenzene f (60%) t-Butylbenzene | (70%) p-di-t-butyl- benzene and tri-<-butylbenzene, m.p. 128° iso- and t-Butylbenzenes <-Butylbenzene (50%), p-di-?-butyl- benzene (40%) ^?Butylbenzene (70%), p-di-<-butyl- benzene <-Butylbenzene (12%), p-di-t-butyl- benzene (10%) t-Butylbenzene (25%), p-di-t-butyl- benzene (30%) Reference * 23 23 309 25, 175 287 295 171, 296 326 29 11 23 > ¡ª ¡ª 3 2 ¡ª 1.3 6 ¡ª 2-5 ¡ª 1 ¡ª 5 ¡ª 1.63 0.7 0.5 0.7 6 Isobutyl chloroformate (¡ª) Isobutyl chloroformate (¡ª) Isobutyl acetate (0.25) {-Butyl chloride (0.6) {-Butyl chloride (¡ª) (-Butyl chloride (0.3) (-Butyl chloride (1) (-Butyl alcohol (¡ª) (-Butyl alcohol (1.0) (-Butyl alcohol (¡ª) (-Butyl alcohol (1) (-Butyl alcohol (¡ª) {-Butyl alcohol (1) (-Butyl acetate (¡ª) 2,2,4-Trimethylpentane (1.40) 2,2,4-Trimethylpentane (0.5) 2,2,3-Trimethylpentane (0.25) p-Di-¡ê-butylbenzene (0.025) p-Di-t-butylbenzene (0.25) A1C13 (¡ª) A1C13 (¡ª) AICI3 (0.2) AICI3 (0.4) HF (¡ª) FeCl3 (0.08) Al(Hg)j; (0.1) H2SO4 (70-80%) AICI3 (0.5) AlCls (¡ª) BF3 (0.3) HF(-) FeClg (1) HF(-) * AICI3¡ªHC1 (0.07) H3PO4(0.15) AICI3¡ªHC1 (0.03) AICI3 (0.002) FeCl8 (0.2) 0 Warm 25-60 0 0 25 25 70 30 80-95 25 ¡ª 25 80 25-50 450 80-90 ¡ª 83 ¡ª ¡ª 8 48 ¡ª ¡ª. 18, ¡ª 24 8 12 ¡ª , ¡ª 16 4 6 11 ¡ª 4 (-Butylbenzene p-Di-(-butylbenzene (28 %), tri-(-butyl- benzene (15%) (m.p. 128°) {-Butylbenzene (33%) (-Butylbenzene (60%) (-Butylbenzene (10%), p-di-(-butyl- benzene (60%) (-Butylbenzene (80%) (-Butylbenzene (75%) {-Butylbenzene, p-di-(-butylbenzene (-Butylbenzene (67%, 84%) Toluene, ethylbenzene, cumene (-Butylbenzene (25%), di-(-butylben- zene (25%) {-Butylbenzene (40%), p-di-t-butyl- benzene (50%) {-Butylbenzene (82%) {-Butylbenzene (72%), acetophen- one (-Butylbenzene (35%), di-^butylben-zenes (25%), isobutane (70%) {-Butylbenzene (20%) (-Butylbenzene (15%) (-Butylbenzene (90%) {-Butylbenzene (85%) 231 231 28 287 304 42 347 29 30, 195 30 11 306 85 309 176 201 34 48 197 * References 93-350 appear on pp. 78-82. t Boedtker (128) has reported that t-butylbeniene prepared from isobutyl chloride may be contaminated with MO- and s-butylbenzenes. Io o CO CO TABLE II¡ªContinued ALKYLATTON OP BENZENE CO f Moles of Benzene 2 2 3.0 2 2 2 2 1.3 1.3 0.4 5 0.5 Alkylating Agent (moles) p-Di-f-butyl benzene (0.5) p-Di-t-butyl benzene (0.5) Poly-t-butyl benzenes (22 g.) p-?-Butyl phenol (0.5) 2-p-Hydroxyphenyl-2,4,4-tri- methylpentane (0.5) 2-p-Hydroxyphenyl-2,4,4-tri- methylpentane (0.5) Isobutylene bromide (0.35) n-Pentane (0.7) Isopentane (0.7) 1-Pentene (0.3) 2-Pentehe (¡ª) 3-Methyl-l-butene (3) 3-MethyU-butene (0.25) Catalyst (moles) Hi!SO4(1.5) H3PO4 (2) AICI3 (0.03) AICI3 (0.67) AICI3 (0.67) AICI3 (0.67) AlCl3(0.15) AICI3¡ªHQ (0.06) AlCU¡ªHCl (0.06) H2SO4(96%)(0.6) HF(-) H2SO4(96%)(1.8) AICI3¡ªHO (0.08) Tem- perature, ? °c. 50 300 ¡ª. 80 25 80 0-100 175 175 5 0 5 5 Time, hours (unless noted otherwise) 5 6 ¡ª 8 12 days 8 1.5 8 8 1.2 2 1.7 Products (% Yield) ? t-Butylbenzene (31%), pn!-butylben- zenesulfonic acid (25%) t-Butylbenzene (23%) f-Butylbenzene (5 g.) t-Butylbenzene, phenol i-Butylbenzene (50%) <-Butylbenzene (70%) Isobutylbenzene (25%), 1,2-diphenyl- 2-methylpropane (30%) Toluene (10%), ethylbenzene (25%) Toluene (10%), ethylbenzene (25%) 2- and 3-Phenylpentanes (65%; ca. 6.1) s-Amylbenzenes (47%)<-Amylbenzene (20%), di-t-amylben- zene(56%) 3-Methyl-2-phenylbutane (12%) Reference * 197 197 48 311 311 311 126 34 34 26 303 205 26 o b H 5 CD 2.3 1.2 0.3 1.5 0.5 4* ? 2 0.8 2 7.5 2-5 2-5 2 Trimethylethylene (3) Trimethylethylene (¡ª) Amylene (0.7) Amylene (¡ª) Methylcyclobutane (0.4) Methylcyclobutane (0.15) Cyclopentane (0.7) n-Amyl alcohol (0.3) n-Amyl alcohol (0.5) n-Amyl ether (1) Isoamyl chloride (¡ª) Isoamyl chloride (1.6) Isoamyl chloride (¡ª) Isoamyl chloride (¡ª) Isoamyl bromide (¡ª) Isoamyl alcohol (0.8) Isoamyl ether (1) oct-Amyl chloride (aD = 0.11°) (2) 2-Pentanol (1.0) 3-Methyl-2-butanol (1.0) <-Amyl chloride (0.2) H2SO4(96%)(1.8) HF(-) A1C13 (0.2) H2SO4 (¡ª) HjSO* (0.9) AlClj¡ªHC1 (0.01) AICI3¡ªHQ (0.07) H2SO4 (80%) (7) BFS¡ªP2O5 (0.5) BF3 (-) AlCU (-) A1C13(1.4) AICI3 (-) AICI3 (-) AICI3 (-) H2SO4 (80%) (6) BF, (-) AlCU (0.4) AICI3 (0.5) AICI3 (0.5) AlCls(O.l) 5 0 80 2 25 150 70 80 150 0 0or80 65 150 30 30 0 2 ¡ª ¡ª 2.5 22 8 6 3 48 5 3 24 24 <-Amylbenzene (18%), di-<-amylben- zene (50%) i-Amylbenzene (21%), p-di-<-amyl- benzene (60%) t-Amylbenzene (20%) Amyl-, di-, and tri-amylbenzenes J-Amylbenzene (2%) Amylbenzenes (25% isoamylbenzene + isomers) Amylbenzenes, cyclopentylbenzene (8%) 2- and 3-Phenylpentanes (60%; ca. 3:2) s-Amylbenzene (85%5 s-Amylbenzene (20%) <-Amylbenzene <-Amylbenzene (20%) Isoamylbenzene, 2-phenyl-3-methyl- butane, fr-amylbenzene t-Amylbenzene (70%) <-Amylbenzene i-Amylbenzene (36%) t-Amylbenzene (10%) <-Amylbenzene, diamylbenzene 2-Phenylpentane (25%) 3-Methyl-2-phenylbutane (25%) <-Amylbenzene (40%) 205 303 149 198 206 36 36 26 14 264 164 287 228 170 98 26 264 101 195 195 149, 287 O 8 * References 93-350 appear on pp. 78-82. CO TABLE II¡ªContinued AliKYliATIOK OF BENZENE CO a Moles of Benzene ¡ª 7 e.2 0.25 1.0 6 2 ¡ª 1.3 1.3 0.6 1-2 , 1 1 1 1 Alkylating Agent (moles) i-Amyl chloride (¡ª) f-Amyl bromide (¡ª) t-Amyl alcohol (1) / Neopentyl chloride (0.15) Neopentyl alcohol (0.25) Neopentyl alcohol (0.25) p-Di-t-amylbenzene (0.25) p-i-Amylphenol (0.5) Cyclopentyl chloride (¡ª) Cyclobutylcarbinol (0.3) Cyclobutylcarbinol (0.3) n-Hexane (0.6) n-Hexane (0.6) 1-Hexene (1) 3-Hexene (0.66) 3-Hexene (0.66) 3-Hexene (0.05) Catalyst (moles) HF(¡ª) AICI3 (¡ª)HF(¡ª) A1C13 (0.04) HJ3O? (80%) (3) A1C13 (0.33) FeCl3 (0.25) AlQs (0.67) A1C13 (¡ª) A1Q3 (0.2) AICI3 (0.2) HsPO4 (0.2) A1C13¡ªHC1 (0.06) H2SO4(0.1) HF-(¡ª) HgBOiFi (¡ª) H2SO4 (-) Tem- perature, °C. 0 ¡ª ¡ª 0 65 80 80 25 15 25 75-80 450 175 25 ¡ª? ¡ª ¡ª Time, hours (unless noted otherwise) ¡ª ¡ª ¡ª 6 8 5 12 days 3 24 ¡ª 10 8 ¡ª. ¡ª ¡ª ¡ª Products (% Yield) <-Amylbenzene (42%), p-di-¡ê-amyl- benzene (22%) <-Amylbenzene ^?Amylbenzene (40%), di-t-amylben- zene (50%) 2-Methyl-3-phenylbutane (24%) <-Amylbenzene (30%) Neopentylbenzene (9%) <-Amylbenzene (70%) i-Amylbenzene, phenol Cyclopentylbenzehe (47%) Benzylcyclobutane t (29%) Benzylcyclobutane f (21%) Cumene (15%), butylbenzene (10%) Toluene (10%), ethylbenzene (25%) 2-Phenylhexane (50%) 3-Phenylhexane (59%) 3-Phenylhexane (24%) 3-Phenylhexane (50%) Reference * 304 98 306 270 .270 *270 197 311 349 194 194 201 334 134 315 315 315 I 3-s 1 10 10 4 (Excess) 4.5 1.3 0.7 1.0 1 1 1.7 10 10 3-Hexene (3.0) 2-Chloro-2-methylpentane (1) 2-Methyl-2-pentanol (¡ª) 3-Chloro-3-methylpentane (1) 3-Methyl-2-pentanol (¡ª) 2,3-Dimethyl-2-butanol (¡ª) Cyclohexene (4) Cyclohexene (1) Cyclohexene (1.5) Cyclohexene (¡ª) Cyclohexyl chloride (0.4) Cyclohexanol (0.6) Cyclohexanol (0.4) Cyclohefxanol (1) Cyclohexyl acetate (1) Cyclopentylcarbinol (0.4) 3-Chloro-2-methylhexane (1) 3-Chloro-3-ethylpentane (1) HF (¡ª) AlClg (0.2) A1C13 (-) A1C13(O.2) A1CU (-) AlCls (-) AICI3 (0.4) H2SO4 (1) AICI3 (0.45) HF(-) A1CU (0.05) HjSO4 (80%) (6) A1CU (0.25) BF3 (0.7) BF3 (0.3) AlCls, (0.2) A1CU (0.2) AICI3 (0.2) 25-55 ¡ª 25 0 5-25 70 80 75-80 ¡ª 0.5 3 ¡ª ¡ª 2 ¡ª p-Dihexylbenzene (41%) 2-Phenyl-2-methylpentane (50%) 2-Phenyl-2-methylpentane (50%) 3-Phenyl-3-methylpentane 3-Phenyl-3-methylpentane 2,3-Dimethyl-2-phenylbutane Cyclohexylbenzene (10%) Cyclohexylbenzene (70%), p-dicyclo- hexylbenzene (25%) Cyclohexylbenzene (70%), diphenyl- cyclohexane (m.p. 169-170°) Cyclohexylbenzene (62%) Cyclohexylbenzene (50-60%), m-di- cyclohexylbenzene and p-diphenyl- cyclohexane Cyclohexylbenzene (50%), dicyclo- hexylbenzene Cyclohexylbenzene (62%), p- and m- dicyclohexylbenzenes, sj/m-tricyclo- hexylbenzene Cyclohexylbenzene (35%), p-dicyclo- hexylbenzene (25%) Cyclohexylbenzene (25%), p-dicyclo- hexylbenzene (12%) Benzylcyclopentane f (45%) 3-Methyl-3-phenylhexane (40%) 3-Ethyl-3-phenylpentane 315 291 195 291 195 195 13 67, 81, 350 58, 350 S O303 W 232, 246 v 29 320 11 23 194 182 291 1 * References 93-350 appear on pp. 78-82.t No proof was offered that rearrangemenrearrangement of the alkyl group had not occurred. CO TABLE II¡ªContinued ALKTLATION OF BENZENE Co oo Moles of Benzene 10 1.3 2.6 2.5 ¡ª 1.6 0.5 0.8 0.8 0.5 0.9 4.5 Alkylating Agent (moles) 2,4-Dimethyl-2-chloropen- tane (1) 1,1-Dichloroheptane (0.1) 1,1-Dichloroheptane (0.3) 3-Methylcyclohexene (0.7) 3-Methylcyclohexyl chloride Cyclohexylcarbinol (0.3) Benzyl chloride (0.08) Benzyl chloride (0.25) Benzyl chloride (0.2) Benzyl chloride (0.08) Benzyl chloride (0.8) Benzyl chloride (0.4) Catalyst (moles) AICI3 (0.2) AICI3 (0.1) AICI3 (0.05) AICI3 (0.25) AICI3 (¡ª) AICI3 (0.2) ZnCh (0.8) Zn (0.4) Ti (0.1) AICI3 (0.04) A1C13(O.15) Al¡ªHC1 (0.1) Tem- perature, °C. 40-50 25-30 25 ¡ª 75-80 80 80 90 ¡ª 7 25 Time, hours (unless noted otherwise) 4 48 3 ¡ª 12 3 10 ¡ª ¡ª 18 Products (% Yield) 2,4-Dimethyl-2-phenylpentane n-Heptylbenzene, 1,1-diphenylhep- tane (3:1) n-Heptylbenzene, 1,1-diphenylhep- tane (1 : 2.5) Methylphenylcyclohexane (33%), di- (methylcyclohexyl)-benzene 3-Methyl-l-phenylcyclohexane Benzylcyclohexane f (7%) Diphenylmethane (30%) Diphenylmethane (15%) toluene Diphenylmethane (30%) Diphenylmethane (45%) Diphenylmethane (80%), p- and 0- dibenzylbenzene Diphenylmethane (63%) Reference * 291 100, 230 100, 230 58 233 194 164 164, 343 297 164 274 275 I QI s ht 4.5 0.7 ¡ª 3 4 2 ¡ª 2 0.5 9 ¡ª 2 2 2.5 0.3 1 ¡ª 4 ¡ª Benzyl chloride (0.4) Benzyl chloride (0.25) Benzyl chloride (¡ª) Benzyl chloride (0.1) Benzyl chloride (0.2) Benzyl chloride (0.2) Benzyl chloride (¡ª) Benzyl chloride (0.5) Benzyl chloride (0.1) Benzyl alcohol (¡ª) Benzyl alcohol (¡ª) Benzyl alcohol (0.15) Benzyl alcohol (0.15) Benzyl alcohol (0.5) Benzyl alcohol (0.2) Benzyl alcohol (1) Benzyl methyl ether (¡ª) Benzyl methyl ether (0.2) Benzyl ethyl ether (0.15) Al¡ªHgCU(0.1) Al(Hg)x (0.5 g.) SnCL, (¡ª) Ag2SO4 or CH2(SOsAg)2 (0.05) T1C13(O.1) TiCl4(0.15) HF(¡ª) NaCl-AlCl3(0.15) TeO2 (0.06) HF(-) H2SO4¡ªHOAc (¡ª) P2O6(0.2) AlCl3(0.1) A1CU (0.3) HjSCU (70%) (4) BF3 (6.7) SnCU (¡ª) TICI3 (0.1) P2O5(0.15) 0 25 100 ¡ª 80 80 80 ¡ª 15-20 80 ¡ª Cold 25 25 30-35 40 ¡ª ¡ª 80 80 3- 48 ¡ª ¡ª 4 ¡ª ¡ª .¡ª 2 72 ¡ª ¡ª? 48 48 120 3 ¡ª ¡ª ¡ª ¡ª Diphenylmethane (60%) Diphenylmethane (35%) Diphenylmethane (35%) Diphenylmethane (50%) Diphenylmethane, p- and m-dibenzyl- benzene Diphenylmethane (40%) p- and m- dibenzylbenzene (8%, and9%, resp.) Diphenylmethane (56%) Diphenylmethane (50%) Diphenylmethane (40%) Diphenylmethane (65-70%) Diphenylmethane Diphenylmethane (30%) Diphenylmethane (50%) Diphenylmethane (55%), p- and o-di- benzylbenzenes, anthracene Diphenylmethane (40-50%), p-diben- . zylbenzene Diphenylmethane (15%), p-dibenzyl- benzene (20%) Diphenylmethane Diphenylmethane, p- and m-dibenzyl- benzene Diphenylmethane (40%) 275 190 346 292 217 316' 305 263 158 306 250 258 258 192 29 11 346 217 251,258 iH U2 o ? References 93-350 appear on pp. 78-82. t No proof was offered that rearrangement of the alkyl group had not occurred. CO CO TABLE II¡ªContinued AliKYIATION OF BENZENE Moles of Benzene 2 0.7 4 2 4 3.3 ¡ª 2 ¡ª ¡ª ¡ª ¡ª ¡ª 8 2.5 Alkylating Agent (moles) Benzyl ethyl ether (0.4) Benzyl ethyl ether (0.4) Benzyl ethyl ether (0.5) Benzyl ethyl ether (1) Benzyl n-propyl ether (1) Benzyl n-propyl ether (1) Benzyl isoamyl ether (¡ª?) Benzyl ether (1) Benzyl ether (¡ª) Benzyl acetate (¡ª) Benzyl benzoate (¡ª) Benzyl benzoate (¡ª) Octene (¡ª) n-Octyl alcohol (1) 2-Methyl-2-heptanol (0.5) Catalyst (moles) SnCU (0.2) A1C13 (0.3) TiCU (0.25) BF3 (-) BF3 (0.5) BF3 (1) SnCU (¡ª) BF3 (¡ª) HF(¡ª) HF(¡ª) SnCU (¡ª) A1C13 (¡ª) H2SO4 (¡ª) BF3¡ªP2O5 (1) AICI3 (0.25) Tem- perature, °C. 45 ¡ª ¡ª 80-90 80-90 ¡ª ¡ª ? ¡ª 80 ¡ª ¡ª ¡ª 80 25 Time, hours (unless noted otherwise) ¡ª 1 ¡ª 2 2 ¡ª ¡ª ¡ª ¡ª ¡ª ¡ª ¡ª ¡ª ¡ª Products (% Yield) Diphenylmethane (25%), p- and m- dibenzylbenzenes Diphenylmethane (15%) Diphenylmethane (55%), p- and m- dibenzylbenzenes (25%) Diphenylmethane (20%) Diphenylmethane (33%) Diphenylmethane (46%), cumene (11%) Diphenylmethane Diphenylmethane (15%), dibenzyl- benzenes (20%), etc. Diphenylmethane (65-70%) Diphenylmethane (75%) Diphenylmethane, p-dibenzylbenzene Diphenylmethane, p-dibenzylbenzene Octyl- and dioctyl-benzene s-Octylbenzene (79%) 2-Methyl-2-phenylheptane (24) Reference * 346 192, 217 316 264 255 255 346 264 306 309 346 217 198 14 31 o 1 CD 10 2.5 2.5 10 10 2.5 2.5 2.5 2.5 4 4 5 0.4 0.4 10 10 4-Chloro-4-methylheptane (1) 2,3-Dimethyl-2-hexanol (0.5) 2,4-Dimethyl-2-hexanol (0.5) 2-Chloro-2,5-dimethylhexane (1) 3-Chloro-3-ethylhexane (1) 3-Ethyl-2-methyl-2-pentanol (0.-5) 2,3,3-Trimethyl-2-pentanol (0.5) 2,4,4-Trimethyl-2-pentanol (0.5) 2,4,4-Trimethyl-2-pentanol (0.5) Styrene (0.25) 0-Phenylethyl chloride (0.25) a-Phenylethyl bromide (¡ª) a-Phenylethyl alcohol (1) m-Xylyl chloride (4) m-Xylyl chloride (4) o-Xylyl chloride (¡ª) Nonene (¡ª) 4-Chloro-4-ethylheptane (1) 3-Chloro-3,6-dimethylheptane (1) A1C13 (0.2) AICI3 (0.25) AICI3 (0.25) AICI3 (0.2) AICI3 (0.2) AICI3 (0.25) AICI3 (0.25) AICI3 (0.25) AICI3 (0.25) AICI3 (0.01) AICI3 (0.02) Zn(¡ª) AICI3 (0.5) AICI3 (0.02) AICI3 (0.02) Zn(-) H2SO4 (¡ª) AICI3 (0.2) AICI3 (0.2) 10 25 10 -15 -15 10 25 25 10 80 Cold ¡ª ¡ª ¡ª ¡ª ¡ª ¡ª ¡ª 45 8 days 0.1-0.2 1 1 1 1 ? 4-Methyl-4-phenylheptane (70%) 2,3-Dimethyl-2^phenylhexane (20%) 2,4-Dimethyl-2-phenylhexane (25%) 2,5-Dimethyl-2-phenylhexane 3-Ethyl-3-phenylhexane (50%) 3-Ethyl-2-methyl-2-phenylpentane (18%) 2,3,3-Trimethyl-2-phenylpentane (4%), t-butylbenzene (9%) 2,4,4-Trimethyl-2-phenylpentane (22%), i-butylbenzene (18%) 2,4,4-Trimethyl-2-phenylpentane (10%), t-butylbenzene (42%) 1,1-Diphenylethane (5%) (mainly polystyrene) 1,2-Diphenylethane (85%) 1,1-Diphenylethane 1,1-Diphenylethane (65%), ethyl- benzene (4%), diphenylmethane m-Benzyltoluene (55%) m-Benzyltoluene (45%) o-Benzyltoluene Nonyl- and dinonyl-benzenes 4-Ethyl-4-phenylheptane (75%) 3,6-Dimethyl-3-phenylheptane (50%) 182 31 31 182 182 31 ' 31 31 31 259, 288 259 276 193 294 294 110 198 181 182 d I * References 93-350 appear on pp. 78-82. TABLE II¡ªContinued ALKYLATION OF BENZENE to Moles of Benzene 10 5 ¡ª 10 10 1.2 ¡ª 10 ¡ª ¡ª 4 Alkylating Agent (moles) 3-Chloro-3-ethyl-5-methylhex- ane (1) a-Phenylpropanol (1) Allylbenzene (¡ª?) 4-Chloro-4-n-propylheptane (1) 4-Chloro-2,4,6-trimethylhep- tane (1) Menthene (0.3) Menthyl chloride (¡ª) 4-Chloro-4-n-propyl-2- methylheptane (1) 5-Phenyl-l-chloropentane (¡ª) Dodecene (¡ª) n-Dodecyl alcohol (0.5) Catalyst (moles) A1C13 (0.2) AlCU (0.5) HF(¡ª) A1C13 (0.2) AICI3 (0.2) AICI3 (0.15) A1C13 (¡ª) AICI3 (0.2) A1C13(-) H2SO4 (-) BF3¡ªP2O5 (0.5) Tem- perature, °C. " 10 ¡ª ¡ª ¡ª 25 ¡ª ¡ª ¡ª ¡ª 80 Time, hours (unless noted otherwise) 12 days ¡ª ¡ª ¡ª 3 ¡ª ¡ª ¡ª ¡ª. ¡ª? Products (% Yield) 3-Ethyl-5-methyl-3-phenylhexane (45%) 1,1-Diphenylpropane (40%), n-pro- pylbenzene (12%), diphenylmeth- ane (4%) 1,2-Diphenylpropane (63%) 4-Phenyl-4-n-propylheptane (45%) (plus didecylbenzene) 2,4,6-Trimethyl-4-phenylheptane (65%) Menthylbenzene (22%) Menthylbenzene 2-Methyl-4-phenyl-4-n-propylheptane (50%) Cyclopentylbenzene, 1,5-diphenylpen- tane Dodecyl- and didodecylbenzenes s-Dodecylbenzene (33%) Reference * 181 ? 193 305 182 182 58 25 182 132 198 14 1 8 i 03 2 10 1.1 10 ¡ª 0.7 5 0.7 0.7 0.5 ¡ª 10 ¡ª 10 ?¡ª ¡ª n-Dodecyl alcohol (0.5) 5-Chloro-2,5,8-trimethylno- nane (1) 1-Phenylcyclohexene (0.25) 5-Chloro-2,8-<Iimethyl-5- ethylnonane (1) Benzhydryl chloride (0.1) Benzhydrol (0.02) Benzhydrol (1) Benzhydryl ether (0.01) Benzhydryl acetate (0.03) 9-Chlorofluorene (0.03) 9-Hydroxyfluorene (0.06) 5-Chloro-2,8-dimethyl-5-n- propylnonane p-Methylbenzhydrol (¡ª) 5-Chloro-2,8-dimethyl-5-iso- butylnonane (1) Di-p-xylylcarbinol (¡ª) n-Octadecyl bromide (¡ª) BF3¡ªCeHsSOsH (0.5) AICI3 (0.2) A1C13(O.1) A1C13 (0.2) AICI3 (¡ª) P2O6 (0.05) AICI3 (1) P2O6 (0.04) H2SO4¡ªHOAc (0.02) A1C13(O.1) PsO5-(0.1) AICI3 (0.2) P2O5 (¡ª) AICI3 (0.2) P2O6 (-) AICI3 (¡ª) 80 ¡ª 25 ¡ª 50 0 10 0 0 80 140-150 ¡ª 130-150 ¡ª 140 ¡ª ¡ª ¡ª 3 ¡ª ¡ª 48 72 48 48 3 5 ¡ª 2-3 " ¡ª 4 ¡ª s-Dodecylbenzene (45%) 2,5,8-Trimethyl-5-phenylnonane (70%) Diphenylcyclohexane (20%) 5-Ethyl-2,8-dimethyl-5-phenylnonane (60%) Diphenylmethane (35%), triphenyl- methane (2%), triphenylmethyl chloride (30%) Triphenylmethane (70%) Triphenylmethane (70%), diphenyl- methane (1%) Triphenylmethane (60%) Triphenylmethane (40%) 9-Phenylfluorene 9-Phenylfluorene 2,8-Dimethyl-5-phenyl-5-n-propylno- nane (80%) . Diphenyl-p-tolylmethane 5-Isobutyl-2,8-dimethyl-5-phenylno- nane 2,5,2',5'-Tetramethyltriphenylmeth- ane n-Octadecylbenzene (50%) 14 182 58 182 130 258 193 258 251 333 185 182 156 182 146 56 * References 93-350 appear on pp. 78-82. TABLE III ALKYLATION OF HALOGENATED BENZENE DERIVATIVES Aromatic Compound (moles) Alkylating Agent (moles) Catalyst(moles) AICI3 (1) AlCUtO.l) AICI3 (1) H2SO4 (80%) (-) A1C13 (1)AICI3 (0.4) AlClad.5) AICI3 (0.2)AlCls(O.l) AICI3 (0.6) AICI3 (0.2) HF(¡ª)A1C1 3(O.1)AICI3 (0.2) AICI3 (0.1) AICI3 (2) AICI3 (0.2) AICI3 (0.6) Tem- perature, °C. 100 100 80-90 70 80-9080-90 80-90 80-90 100 80-90 80-90 ¡ª 25 100 100 0-25 25 25 Time, hours ¡ª 2-3 ¡ª 2-32-3 2-3 2-3 2-3 2-3 ¡ª ¡ª 12 . 24 48-72 12 Products (% Yield) Eefer-ence * Chlorobenzene (5) Chlorobenzene (5)Chlorobenzene (1) Chlorobenzene (l) Chlorobenzene (1)Chlorobenzene (1) Chlorobenzene (1.4)Chlorobenzene (1) Chlorobenzene (3.5)Chlorobenzene (1) Chlorobenzene (l)Chlorobenzene (1) Chlorobenzene (1.5)o-Dichlorobenzene (0.7) Bromobenzene (2.5)Bromobenzene (1) Bromobenzene (15) Bromobenzene (7.5) Ethylene (¡ª) Ethyl bromide (2) Ethyl alcohol (0.6) . Isopropyl alcohol (¡ª) Isopropyl alcohol (1)?-Butyl alcohol (0.5) Isobutyl alcohol (1.0)?-Butyl alcohol (0.5) Isoamyl chloride (0.6)Isoamyl alcohol (0.5) i-Amyl alcohol (0.5)3-Hexene (0.66) Cyclohexyl chloride (0.5)Methyl chloride (¡ª) Ethyl bromide (2) Ethyl bromide (2) Isoamyl chloride (1)Cyclohexyl chloride (2.5) o-, TO-, and p-Chloroethylbenzenes(2 : 3 : 1), chlorodiethylbenzenes, etc.. p-Chloroethylbenzene p-Chloroethylbenzene (40%) p-Chlorocumene (75%) p-Chlorocumene (62%)p-s-Butylchlorobenzene (50%) p-t-Butylchlorobenzene (30%)p-f-Butylchlorobenzene (65%) p-<-Amylchlorobenzenep-<-Amylchlorobenzene (35%) p- arid TO-i-Amylchlorobenzene (50%)2-(p-Chlorophenyl)hexane (25%) p-Cyelohexylehlorobenzene (70%)Hexamethylbenzene, trichloromesit- yleneo-, and p-Bromoethylbenzenes sym-Triethylbenzene, p-dibromoben- zene p-J-Amylbromobenzeneo-, m-, and p-Cyclohexylbromoben- zene (65%), p-dibromobenzene 46 29045 29 45 4545 45 17045 45 315246 165 165 290 348 170 54, 135,246 OS ? C pi5 >? ^5 WOT , GO * References 93-350 appear on pp. 78-82. TABLE IV ALKYLATION OF TOLUENE Molespf. . Toluene 30 60 3.5 1.5 1.5 1.9 1.9 2.5 0.2 0.6 3 0.5 0.9 0.25 79.4 ¡ª 0.9 ¡ª 5 Alkylating Agent (moles) Methyl chloride (¡ª) Methyl chloride (¡ª) Methyl chloride (¡ª) Methyl chloride (0.4) Methyl chloride (0.4) Methyl bromide (0.6) Methyl bromide (0.6)Methyl alcohol (1) Methyl chloroformate (0.2) Ethylene (¡ª) Ethylene (3)Ethyl bromide (1.0) Ethanol (0.5) Ethyl chloroformate (0.2) Propylene (2) Propylene (16.6)Propylene (¡ª) Propyl alcohol (0.5) Isopropyl chloride (¡ª?) Isopropyl iodide (0.6) Catalyst (moles) AlCls (10) AICI3 (20) Aids Aids Aids Aids Ald3 0.55)1.5) 1.5)0.9) 0.9)Ald 3 (2)Aids (0.15) Ald3 (0.5) Aids (0.2)Ald 3 (1.0)Aids (0.75) Aids (0.1) Aids (0.5) PsO? (0.3)H 2SO4 (¡ª)Ald 3 (0.7) Aids (-)Aids (0.3) Tem-perature, °C. 80 80 93-95 0 100 0 95 100 80 80-90 80 -10 140 25-80 80 150 15 125 ¡ª. 80-100 lime, hours ¡ª ¡ª 2 0.1 1 ¡ª 3 0.25 3-4 ¡ª 18 8 . ¡ª ¡ª¡ª 4 ¡ª ¡ª Products (% Yield) m-Xylene and p-xylene (20 : 1), pseu- documene and mesitylene (5 : 1),durene and isodurene o-Xylene and m- and p-xylenes), pseudocumene, mesityleneDurene (30%) 0-, m- and p-Xylenes (5:3:2) TO- and o-Xylenes (50 : 1) 0-, m- and p-Xylenes (2:1:1)TO-, p- and o-Xylenes (10 : 1 : 1) Mesitylene (53%) p-Xylene, pseudocumene 3,5-Diethyltoluene (good yield) Ethyltoluene (35%)3,5-Diethyltoluene (78%) m- and p-Ethyltoluene (74%), diethyl-toluene (20%) 3,4-Diethyltoluene (35%) p-Cymene (50%) p-Cymene (50%)p-Cymene (50%) m- and p-Propyltoluene (85%), dipro- pyltoluenes (10%)TO-Cymene m-Cymene (75%) Reference * 94 50, t 209 117 37 37 37 3730,82 231 167 1337 27 231 13 244198, 310 27 301, 302 215 * References 93-350 appear on pp. 7&-S2.t Jaoobsen [reference 50, p. 342 (footnote 1)] points out that the aluminum chloride-catalyzed decomposition of pseudocumene (I) to m-xylene (II) suggests that (I) is an intermediate in the formation of II by the methylation of toluene, as reported by Ador and Rilliet (94). en TABLE IV¡ªContinued AlKYLATION OF TOLTJENB O5 Moles of Toluene 0.4 0.9 4.35 1.4 0.05 54 ¡ª 1 ¡ª 11 0.05 ¡ª ¡ª 1 ¡ª 1.4 1.4 '¡ª 5.5 Alkylating Agent (moles) Isopropyl alcohol (0.4) 2,2,4-Trimethylpentane (0.6)Diisobutylene (2) n-Butyl chloride (0.25) n-Butyl alcohol (0.08) ra-Butyl chlorosulfonate (6) s-Butyl alcohol (¡ª) Isobutyl chloride (1) Isobutyl chloride (¡ª)Isobutyl alcohol (3.3) Isobutyl alcohol (0.05) Isobutyl alcohol (¡ª) Isobutyl chloroformate (¡ª) <-Butyl chloride (1)i-Butyl chloride (¡ª) ¡ê-Butyl chloride (0.25) <-Butyl chloride (0.25) <-Butyl chloride (¡ª) Amylene (3) Catalyst (moles) H2SO4 (80%) (5) AICI3¡ªHC1 (0.04) HF(5) A1C13(O.1) ZnCl2 (0.15) AICI3 (12) H2SO4 (80%) (¡ª) FeCla (¡ª) AICI3 (-)H 2SO4¡ªSO3 (25%)(1kg.) ZnCl2 (0.15) H2SO4 (80%) (¡ª) AICI3 (-) FeCl3 (-)AICI3 (-) AICI3 (0.1) FeCl3 or AICI3¡ª C6H6NO2(0.1)HF(-) A1C13 (0.2) Tem- perature, °C. 70 80-90 0-5 0 300 0 70 ¡ª. ?¡ª 25 300 70 ¡ª ¡ª.0-100 0 0 0 25-100 Time, hours _ 8 20 5 24 3 ¡ª ¡ª. ¡ª 0.7-0.8 24 ¡ª ¡ª ¡ª? 5 5 ¡ª ¡ª Products (% Yield) p-Cymene (35%), diisopropyltoluene m-?-Butyltoluene (34%) p-t-Butyltoluene (77%), di-?-butyltol- uene (19%)m- and p-s-Butyltoluenes (75 : 25, 46%)Butyltoluene m-s-Butyltoluene (32%), p-s-butyltol- uene (20%), o-chlorotoluene (22%),p-chlorotoluene (6%) p-s-Butyltoluene p-?-Butyltoluene (30%) m- and p-t-Butyltoluenesp-*-Butyltoluene (60%) Butyltoluene p-<-Butyltoluene p-e-Butyltoluene (25%) p-?-Butyltoluene (50%)m-t-Butyltoluene, <-butylbenzene and 3,5-dimethyl-i-butylbenzenem- and p-?-Butyltoluene (62 : 38, f AGO/ \*0 /o) TO- and p-<-Butyltoluene (67 : 33, t70-75%) p-t-Butyltoluene (75%) m-t-Amyltoluene (45%) Reference * 29, 218 177 71 298 171 111 29 121 227326 171 29 231 121 114 298 298 304 150 I I ¡ª ¡ª1.0 5 ¡ª¡ª ¡ª¡ª 2 ¡ª ¡ª 2.5 1 ¡ª ¡ª 5 ¡ª ¡ª ¡ª ¡ª ¡ª aci-Amyl chloride (¡ª) Isoamyl chloride (¡ª) Amyl chloroformate (¡ª)3-Hexene (0.66) Cyclohexene (1.5) Cyclohexene (¡ª)Cyclohexyl fluoridet (¡ª) Cyclohexyl chloride J (¡ª)Cyclohexyl chloride (¡ª) Cyclohexanol (0.75) Cyclohexanol (¡ª) Benzyl chloride (¡ª) Benzyl chloride (0.1) Benzyl chloride (0.2) Benzyl chloride (3) Benzyl ethyl ether (¡ª) Benzyl alcohol (0.4) 1-Octene (¡ª)2-Fluorooctane § (¡ª) 2-Octanol (¡ª) Styrene (0.4) a-Phenylethyl bromide (¡ª) Bornyl chloride (¡ª) Benzhydrol (¡ª) Benzhydrol (¡ª) 9-Hydroxyfluorene (¡ª) A1C13 (-) A1CU (-) A1CU (¡ª)HF(¡ª) AICI3 (0.45) HF(¡ª)HF (¡ª) or BFa HF(¡ª)AICI3 (-) AlCls (0.6) HF(¡ª) AICI3 (-) AlCHg), (0.02) Ti(0.1) Zn(-) P2OB (-) H2SO4 (70%) (15) HF(¡ª)HF.(¡ª) HF(¡ª) H2SO4 (-) Zn(-) Aid, (-) P2O5 (-) SnCU (¡ª) P2O5 (-) ¡ª ¡ª ¡ª ¡ª 25 00 ¡ª¡ª 80 ¡ª ¡ª 90 100 40 ¡ª¡ª ¡ª ¡ª ?¡ª. 10-40 ¡ª ¡ª 110 ¡ª ¡ª ¡ª¡ª 3 ¡ª¡ª ¡ª¡ª 2 ¡ª ¡ª 10 ¡ª ?¡ª ¡ª¡ª ¡ª .¡ª ¡ª ¡ª ¡ª ?¡ª m-i-Amyltoluene m-J-Amyltoluene p-Amyltoluene (30%)3-(p-Tolyl)-hexane (63%) Cyclohexyltoluene (40%) p-Cyclohexyltoluene (74%)p-Cyclohexyltoluene (76%) p-Cyclohexyltoluene (8%)m- and p-Cyclohexyltoluene m- and p-Cyclohexyltoluene (72%), 3,5-dicyclohexyltoluene (18%)p-Cyclohexyltoluene (45%) Benzyltoluene, dibenzyltoluene, 2,7-dimethylanthracene Benzyltoluene, dimethylanthracene p-Benzyltoluene (35%), 2,4-dibenzyl-toluene (30%) 0- and p-Benzyltoluenes (total yield¡ª ACC7 \?K>%) p-Benzyltoluenep-Benzyltoluene, anthracene p-Oetyltoluene (73%)p-Octyltoluene (13%) p-Octyltoluene (42%) 1-Phenyl-l-tolylethane (65%) 1-Phenyl-l-p-tolylethane m- and p-Bomyltoluene Diphenyl-p-tolylmethane Diphenyl-p-tolyhnethane 9-p-Tolylfluorene (good yield) 150 150 231315 58 2020,351 20 .233 320 20 164 190 297 344 251 29 2020 20 229 109 213 156 122 185 * f a HO S 3 ISH 1 ?References 93-350 appear on pp. 7S-82.t The ratio of isomers was determined by sulf onation with concentrated sulfuric acid. Since Ipatieff and Corson (197) have demonstrated that a (-butyl group will migrate under these conditions, this proof cannot be considered entirely adequate.% Cyclohexyl bromide and iodide failed to react under these conditions (20, 351). ( 2-Chloro- and 2-bromo-octane failed to react under similar conditions (20). TABLE V ALKYLATION OF VABIOTTS ALKYLBENZENES Aromatic Com- pound (moles) o-Chloro toluene (U.A) Ethylbenzene (3) Ethylbenzene (2) Ethylbenzene (¡ª) Ethylbenzene (2) Ethylbenzene (¡ª) o-Xylene (¡ª) o-Xylene (¡ª) o-Xylene (0.4) o-Xylene (¡ª) o-Xylene (¡ª) m-Xylene (¡ª) TO-Xylene (2)m-Xylene (30) m-Xylene (¡ª) m-Xylene (0.3) m-Xylene (2) TO-Xylene (1) TO-Xylene (¡ª?) TO-Xylene (1) Alkylating Agent (moles) S-Butyl alcohol (0.25) n-Propyl bromide (4) i-Butyl chloride (0.45) <-Butyl chloride (¡ª) Benzyl chloride (25) a-Phenylethylbromide (¡ª)Methylchloride (¡ª) Benzyl alcohol (¡ª) Styrene (0.15) 3-Chloro-l-phenylpro- pane ^¡ª)Benzhydrol (¡ª) Methyl chloride (¡ª) Methylchloride (1.8)Methyl chloride (¡ª) ~ Methyl iodide (¡ª) Ethylene (¡ª) Ethyl bromide (2) Ethyl bromide (1) Ethyl chloroformate Cyclopropane (0.5) Catalyst(moles) A1C13(O.1) AlCla (0.4) FeCl3 (0.03) AICI3 (CS2) (-) Zn(¡ª) Zn (¡ª) AICI3 (-) H2SO4 (70%) (-) H2SO4 (0.2) , AICI3 (¡ª) P2OB (-) AICI3 (¡ª) AICI3 (4)AICI3 (7.5) Is (trace) AICI3 (0.2) AICI3 (0.4) AICI3 (2) Aids (¡ª) A1C13 (0.03) Tem- perature,°C. 80-90 25 -10 -10 ¡ª ¡ª 80 40 Cold ¡ª . 140 80 100 80-90 250 ' ¡ª 40 0 ¡ª 0-15 Time,hours 2-3 192 48 ¡ª ¡ª ¡ª ¡ª ¡ª 4 ¡ª 1 100 4-8 1.5 48 ¡ª ¡ª ¡ª Products (% Yield) 2-Chloro-x-t-butyltoluene (45%) m- and p-Ethylisopropylbenzenes (10% each)Ethyl-?-butylbenzene (100%) Ethyl-i-butylbenzene (low yield), t-bntjl- benzene, t-butyltoluene, etc.p-Ethyldiphenylmethane (35%) 1-Phenyl-l-p-ethylphenylethane Pseudocumene 3,4-Dimethyldiphenylmethane, 1-methyl- all ijLLTilCcIlc 1-Phenyl-l-o-xylylethane (70%)l-Phenyl-3-o-xylylpropane (60%) 3,4-Dimethyltriphenylmethane Pseudocumene and mesitylene (4:1) Mesitylene (65%)Tetramethylbenzenes (50%), durene, (15%), pentamethylbenzene (18%),hexamethylbenzene Pseudocumene and mesitylene 5-Ethyl-l,3-dimethylbenzene (50%) 5-Ethyl-l,3-dimethylbenzene, 4-ethyl-l,3- dimethylbenzene (total yield¡ª35%)5-Ethyl-l,3-dimethylbenzene f (45%) 5-Ethyl-l,3-dimethylbenzene (25%) 4-n-Propyl-ro-xylene (40%) Refer- ence* ' :¡ª 45 118 114 114 330 276 209^.284 29 229 133 188 209, 284 37 265 277 167 318 37 231 41 m-Xylenem-Xylene m-Xylenem-Xylene m-Xylenem-Xylene m-Xylenem-Xylene m-Xylenem-Xylene m-Xylenem-Xylene wi-Xylenem-Xylene m-Xylenem-Xylene m-Xylenem-Xylene m-Xylene (1) (0.5) (1) (0.5) (3) (1.3) (3) (-) (1) (1) (1.3) (1-6) (1-75) (3) (1) (1) (1) (4) (0.5)m-Xylene ^0.5) m-Xylene (¡ª) m-Xylene (¡ª) m-Xylene (5)m-Xylene (¡ª) p-Xylene (¡ª)p-Xylene (0.5) p-Xylene (¡ª) p-Xylene (2) Cyclopropane (0.5)n-Propyl chloride (0.3) n-Propyl formate (0.3)Isopropyl chloride (0.3) Isopropyl alcohol (0.6)n-Butyl chloride (0.5) s-Butyl alcohol (0.6)Isobutyl bromide (¡ª) Isobutyl alcohol (1)i-Butyl chloride (1) e-Butyl chloride (0.5)^Butyl alcohol (1.2) <-Butyl alcohol (0.3)?-Butyl alcohol (0.6) 3-Hexene (0.75)3-Bromohexane (1) 3-Hexyl ether (0.18)Cyclohexene (1.5) Cyclohexyl bromide (0.3)3-Ethyl-a-pentene (0.2) Benzyl chloride (¡ª) Benzyl alcohol (¡ª) Styrene (0.3)Benzhydrol (¡ª) Methyl chloride (¡ª)Ethyl bromide (0.5) Ethyl chloroformate (-)Cyclohexene (0.7) FeCla (0.06)A1C1 3(O.1)AlCls (¡ª) A1C13(O.1)HjSOi (80%) (8) A1C13 (0.2)H2SO4 (80%) (9) A1C13 (¡ª)H2SO4 (5) A1C13 (0.4)AICI3 (0.2) HF (25)AICI3 (0.9) H2SO4 (80%) (9)HF(-) AICI3 (-)HF(¡ª) AICI3 (0.45)FeCl 3 (0.02) AICI3¡ªHC1 (0.004) Zn(-) H2SO4 (70%) (-) H2SO4 (0.5) P2O5 (-) AICI3 (¡ª) AIOI3 (CSj) (0.1) AICI3 (-) AICI3 (0.2) 25 25-60 2575 0 25 100 45 100 25 0> ° 25 20-50 25-50 40 Cold 140 80 25-80 25 4 416 5 16 1 185 16 3CO . 3 _ 4 ¡ª. 24¡ª 3 4-n-Propyl-m-xylene (19%)5-Isopropyl-m-xylene (46%) 5-Isopropyl-m-xylene (50%)'5-Isopropyl-m-xylene (48%) 4-Isopropyl-m-xylene (75%)5-s-Butyl-m-xylene (50%) 4-s-Butyl-m-xylene (50%)3,5-Dimethyl-t-butylbenzene 3,5-Dimethyl-i-butylbenzene54-Butyl-m-xylene J (23-26%) 5^-Butyl-m-xylene j (50%)t-Butyl-m-xylene (94%) 5-<-Butyl-m-xylene (89%)4-<-Butyl-m-xylene (48%) Hexylxylenes (80%)3-(m-Xylyl)-hexane (27%) 3-(m-Xylyl)-hexane (61%)5-Cyclohexyl-m-xylene (56%) 5-Cyclohexyl-m-xylene (75%) 3-EthyI-3- (3,5-dimethylphenyl)pentane (50%) 2,4-Dimethyldiphenylmethane2,4-Dimethyldiphenylmethane, 2-methyl- anthracene 1-Phenyl-l-m-xylylethane (65%) 2,4-Dimethyltriphenyhnethane Pseudocumene (pure) 2-Ethyl-l,4-dimethylbenzene (25%) 2-Ethyl-l,4-dimethylbenzene (40%) 2-Cyclohexyl-p-xylene (33%), dicyclohex-yl-p-xylene (5%) 41 4141 41 41 3939 114260 40 39 7130 39315 315315 58113 113 34529 229 188 209,284 124 231 58 * RefereDces 93-350 appear on pp. 78-82.t See the original literature (37, 262) for certain discrepancies concerning the derivatives of this hydrocarbon. X The hydrocarbon was also formed by treating the 4-isomer with aluminum chloride (40). CO TABI^E V¡ªContinued ALKTLATION OF VARIOUS ALKYLBENZENES ow o> Aromatic Com-pound (moles) Alkylating Agent(moles) Catalyst (moles) Tem- perature, °C Time,hours Products (% Yield) Refer- O ence* i_. p-Xylene (¡ª) p-Xylene (¡ª)p-Xylene (¡ª) p-Xylene (¡ª)p-Xylene (¡ª) p-Xylene (¡ª) y-Xylene (0.3) n-Propylbenzene (0.4) Cumene (1) 3-Methylcyclohexene Benzyl chloride (¡ª) Benzyl alcohol (¡ª) Styrene (¡ª)Benzhydrol (¡ª) 2,5-Dimethylbenzhy-drol (¡ª) 2-Methyl-5-isopropyl- benzhydrol (0.1)n-Propylbenzene (0.4) Propylene (1.97) A1C13 (¡ª) Zn(-) HSO ()(70%) H2SO4 (-)PO () PsO5(0.1) A1C13 (¡ª) A1C13 (0.1) 25 Cold 140 140 140 100 80 2-(Methylcyclohexyl)-p-xylene (19%) 2,5-Dimethyldiphenylmethane2,5-Dimethyldiphenylmethane, 2-methyl- anthracene 1-Phenyl-l-p-xylylethane 2,5-Dimethyltriphenyhnethane 2,5,2',5'-Tetramethyltriphenyhnethane (50-60%) 2,2'5'-Trimethyl-5-isopropyltriphenyl- methane (35%) m- and p-Di-n-propylbenzenes (50%) 1,3,5-and 1,2,4-Triisopropylbenzenes (60%,3:1), m- and p-diisopropylbenzenes, (2:1) 58 34529 229 187 146 146 24 13 O Cumene (¡ª) Pseudocumene (¡ª) Pseudocumene (¡ª) Pseudocumene t (1) Pseudocumene (¡ª)Mesitylene (¡ª) Mesitylene (¡ª)Mesitylene f (1) Mesitylene f (2)Mesitylene (1) Mesitylene (¡ª)Durene f (0.08) p-Cymene (¡ª)p-Cymene (1) Amylbenzene (1)Di-n-propylben- zene (0.01) Isobutyl chloride (¡ª) AICI3 (¡ª Methyl chloride (¡ª)Methyl chloride (¡ª) Methyl iodide (1) Styrene (0.5)Methyl chloride (¡ª) Methyl chloride (¡ª±Methyl iodide (1) Cyclohexene (0.6)Benzyl chloride (0.2) Benzyl chloride (¡ª)Benzyl chloride (0.07) p-Cymene (¡ª)Cyclohexene (0.2) oci-Amyl chloride (1)n-Propyl chloride (0.6) A1C1, (¡ª) AICI3 (-) A1C13 (0.8) H2SO4 (-) AICI3 (-)AICI3 (-) AICI3 (0.8)AICI3 (0.2) AICI3 (0.01) p-Cymene (¡ª) AICI3 (trace) AICI3 (-) A1C13(O.1) AICI3 (0.1)AICI3 (0.005) 25 80100-110 45 Cold80 100-11045 25100 (Boiling)45 25 25 120 120 3 6012 3 45 t-Butylbenzene, p-di-t-butylbenzene, iso- propyl chlorideDurene Penta- and hexa-methylbenzeneDurene and isodurene (total yield, 80- 85%)1-Phenyl-l-pseudocumylethane (75%) IsodurenePenta- and hexa-methylbenzene Isodurene and durene (total yield, 80-85%)Cyclohexybnesitylene (21%) Benzyhnesitylene (good yield), dibenzyl- mesityleneBenzyhnesitylene Benzyldurene.3,5-Triisopropyltoluene . Cyclohexyl-p-cymene (46%), dicyclohexyl- toluene (30%)Diamylbenzene Hexa-n-propylbenzene (10%) 47 209210 138 229 209 210 13858 241, 242 259117 52 58 101334 m I* References 93-350 appear on pp. 78-82.t In carbon diaulfide. Cn TABLE VI ALKYLATION OF TETBALIN to Moles of Tetralin 3 ¡ª IS 6 1 5 3 4 2.3 4 ¡ª 1.7 Alkylating Agent (moles) Methyl bromide (6*. 8) Ethylene (¡ª) Ethyl bromide (5) Ethyl bromide (3) Propylene (5.3) n-Propyl chloride (1.3) Isopropyl bromide (1) <-Butyl chloride (1) t-Butyl bromide (1) i-Amyl chloride (1) Cyclopentene (¡ª) Cyclohexene (0.5) Catalyst (moles) AlBr3 (0.05) H3PO4 (-) AICI3 (0.5) AlBr3(0.15) HF (23) AICI3 (0.15) AlBr3 (0.05) A1Q3 (0.08) AlBr3 (0.3) (Aia3 (0.08) A1C13 (-) Aia3 (0.15) Tem- perature, °C. 140-150 300 80 110-120 5-15 25-80 120-130 50 ¡ª 25 ¡ª 25 Time 48 hours ¡ª ¡ª 20 hours 20 hours 15 days 40 hours ¡ª ¡ª 48-72 hours ¡ª 3 hours Products (% Yield) 0-Methylnaphthalene (14%), ben- zene, octahydroanthracene, octa- - hydrophenanthrene f Ethyltetralin, etc. /3-Ethyltetralin (3%) ^-Ethyltetralin (28-35%), 0-(o-phen- ylbutyl)-tetralin Isopropyltetralins /3-Isopropyltetralin (10%) j8-Isopropyltetralin (37%) ^-?-Butyltetralin (20%) ^-Butyltetralin (70%) /3-t-AmyltetraJin (20%), a-i-amyltetra- lin (8%) Cyclopentyltetralin, dicyclopentylte- traUn /S-Cyclohexyltetralin (40%) Reference * 69 204 129 69 71 129 69 129 69 129 271 58 I o o OB * References 93-350 appear on pp. 78-82. f Tefralin reacts with aluminum chloride alone, yielding benzene, octahydroanthracene, and octahydrophenanthrene (69, 129); see p. 13. TABLE VII ALKTLATION OF NAPHTHALENE Moles ofNaph- thalene _ -¡ª.¡ª 0.5 ¡ª 7.1 ¡ª 4 ¡ª ¡ª 1.6 ¡ª ¡ª 1 3 3 fO.5 ¡ª ? Alkylating Agent (moles) Methylene chloride (¡ª) Methyl chloride (¡ª)Methyl bromide (¡ª) Methyl iodide (0.6) Ethylene bromide (¡ª) Ethylene (17.2) Ethylene (¡ª) Diethylbenzene (¡ª) Ethyl chloride (¡ª)Ethyl bromide (¡ª?) Ethyl iodide (1.3) Propylene (¡ª) Propylene (¡ª) Propylene (5.8) n-Propyl bromide (1.8) Isopropyl bromide (2) Isopropyl alcohol (0.75) Isopropyl alcohol (¡ª) Catalyst (moles) AlCla (¡ª)AlCls (-) A1C13 (-) AICI3 (0.6) A1CU (¡ª) ' P2O6 (0.5) H3PO4 (¡ª)AICI3 (0.4) . AICI3 (-)AICI3 (-) AICI3 (0.2) H3PO4 (-) H2SO4 (-) HF (25) A1C13 (0.2) AICI3 (0.3) H2SO4 (80%) (6) H2SO4 (96%) (-) Solvent ? _ CS2cs 2 CSj ¡ª ¡ª ¡ª ¡ª ?¡ª? ?¡ª? ¡ª ¡ª ecu'¡ª? ¡ª ¡ª ¡ª Tem- perature, °C. , 2525 25 Warm 250 300 80 ¡ª? ¡ª. Warm 200 Cold 0-72 Warm 80 80 40-45 lime, hours 1616 16 ¡ª. ¡ª 14 5 ?¡ª?¡ª ¡ª 14 ¡ª 24 4-5 6 3 ¡ª Products (% Yield) /3-Methylnaphthalene /S-Methylnaphthalene (11%)a- and /3-Methylnaphthalenes (ca. 4% each)a- and 0-MethyInaphthalenes (5%) a- and /3-Methylnaphthalenes Ethyl- and diethyl-naphthalenes Ethyl- and diethyl-naphthalenes /3-Ethylnaphthalene (30%) /3-Ethylnaphthalene/3-Ethylnaphthalene /3-Ethylnaphthalene Isopropylnaphthalene, etc. Isopropylnaphthalene, etc.Tetraisopropylnaphthalene (m.p. 125°, 98%)/3-Isopropylnaphthalene or /3-n-pro- pymaphthalene /3-Isopropylnaphthalene (60%) a- and /3-Isopropyl- 1,6-, 2,6-, and 2,7-di-, tri-, and tetra-isopropyl- naphthalenesDiisopropylnaphthalene (m.p. 38°), tetraisopropymaphthalene Reference* 127 319319 319 281 244 204 252 245136 281 204 198. 310 71 280, 281 184.lorr 18429 29 * References 93-350 appear on pp. 78-82. t Since the naphthalene is first transformed to a-naphthalenesulfonic acid, the latter may be used as the starting material. 1 02 ss TABLE VII¡ªContinued ALKYLATION OF NAPHTHALENE Moles ofNaph- thalene 0.5 0.4 0.4 0.251.2 _ 0.2 0.2 1 2.6 ¡ª 0.2 0.4 Alkylating Agent '(moles) Isopropyl alcohol (0.5) Isopropyl alcohol (0.6)Isopropyl alcohol (1.6) n-Butyl alcohol (0.25) Isobutyl chloride (0.6) Isobutyl alcohol (¡ª) Isobutyl alcohol (0.25) s-Butyl alcohol (0.25) ?-Butyl chloride (2) ?-Butyl chloride (2.7) <-Butyl chloride (¡ª) t-Butyl alcohol (0.25) <-Butyl alcohol (1.0) Catalyst (moles) AlCls (0.35) BF3 (-) BF3 (-) A1C13 (0.33)A1C1 3(O.1) H2SO4 (80%) (¡ª) AlCla (0.03) AICI3 (0.3) AICI3 (0.01) A1C13 (0.08) HF(-) A1C13(O.12) BF3 (-) Solvent Ligroin ¡ª ¡ª Ligroin¡ª ¡ª Ligroin ?¡ª ¡ª CCI4 Ligroin Tem- perature, °C. 90 25 25 ¡ªWarm 70 ¡ª 90 25^80 50-60 0 90 25 Time, hours 4 ¡ª ¡ª ¡ª ?¡ª ¡ª 5 ¡ª 2 ¡ª. 3 Products (% Yield) ¡ê-Isopropylnaphthalene (33%), di- isopropylnaphthalenes (15%), tri-isopropylnaphthalenes (11%) j3-Isopropylnaphthalene (35%) Triisopropylnaphthalenes (57%) a-Butylnaphthalene (40%)¡ê-¡ê-Butylnaphthalene (plus di-t- butylnaphthalenes)Di-*-butylnaphthalene (m.p. 142°) /3-(and a)-i-Butylnaphthalenes, di-t-butylnaphthalenes a-s-Butyhiaphthalene (20%), di-s- butylnaphthalenes (35%)Di-f-butylnaphthalenes (m.p. 82° t and 146°, good yield)/W-Butylnaphthalene (30%), di-?- butylnaphthalenes (30%)2-Butylnaphthalene (46%), di4-bu- tylnaphthalene (m.p. 81 °t, 28%),di-<-butyhiaphthalene (m.p. 148°, QO/\0/0) ^-(and a)-*-Butymaphthalene (21%),di-i-butylnaphthalene (37%, m.p. iooo\(S-t-Butylnaphthalene- (62%), di-<- butylnaphthalenes (5%, m.p. 80° and 145°) Reference * 322 53 53 268116,- 331 29 268 322 178 154 304 322 53 1> 1 1 2.6 0.2 1 3.5 1.8 0.40.4 1.31.3 1.3 0.4 2 1 t-Butyl alcohol (3) Isoamyl chloride (4)Isoamyl alcohol (¡ª) ?-Amyl alcohol (0.25) Cyclopentene (¡ª) 3-Hexene (1) Cyclohexene (1) Cyclohexene (0.5) Cyclohexene (0.6)Cyclohexanol (0.45) Benzyl chloride (0.6)Benzyl chloride (0.6) Benzyl chloride (0.6) Benzyl chloride (¡ª)Benzyl chloride (0.2) Benzyl alcohol (0.45) Benzyl ethyl ether (¡ª)Benzyl n-propyl ether (1) Benzhydrol (0.5)Benzhydrol (¡ª) HF (25) A1C13 (0.2)AICI3 (¡ª) AICI3 (0.12) AICI3 (-) HF(-) AICI3 (0.3) A1C13(O.15) BF3 (¡ª) BF3 (-) AICI3 (0.05) AICI3 (0.05) ZnCl2 (0.25) Ti (0.1) BF3 (-) P2OB (-)BF 3 (0.5) PJO6 (1) Ligroin CSj! ¡ª ¡ª ¡ª ¡ª 0-5 1 3 1 1 25 80 25 25 80150 150 Boiling 90 25 140-145 24 2 3 18 24 0.1-0.2 1 1.5 310 ?¡ª 4-5 Di-<-butylnaphthalene (m.p. 143°, 76%)0-Amylnaphthalene 04-Amylnaphthalene (62%)a- and /3-i-Amylnaphthalenes (34%), di-<-amylnaphthalenes (20%)Cyclopentyl-, di-, tri- and tetra-cy- clopentyhiaphthalene3-Naphthylhexane (30%) a- and j3-Cyclohexylnaphthalenes (19%)(3-Cyclohexylnaphthalene (30%), 2,- 6-dicyclohexylnaphthalene /3-Cyclohexyhiaphthalene (35%) 0-Cyclohexylnaphthalene (63%), 1,-4-dicyclohexylnaphthalene (9%) a-Benzylnaphthalene0-Benzylnaphthalene a-Benzylnaphthalene a-Benzylnaphthalene a-Benzylnaphthalene (25%), /3-ben-zylnaphthalene a-Benzyhiaphthalene (28%), |3-ben- zylnaphthalene (2%), dibenzyl- naphthalenes (15%), tribenzyl- naphthalenes (20%)a-Benzyhiaphthalene a-Benzyhiaphthalene (48%)a-Benzhydrylnaphthalene a-Benzhydryhiaphthalene 71 281 268 322 271 315 58 58,36a gj 5353, 366 281, 327281, 327 253, 281327 25S297 53 251255 235186 g ? References 93-350 appear on pp. 78-82. t This material has been shown to be a molecular compound of one mole of the di-t-butylnaphthalene, m.p. 146°, and two moles of an isotner, m.p. 103° (36b). TABLE VIII ALKYLATION OP MISCELLANEOUS POLTNUCLEAB AROMATIC COMPOUNDS Aromatic Com- pound (moles) 1-Chloronaphtha- lene (0.5) 1-Chloronaphtha- lene (0.8) a-Nitronaphtha- lene (1.25) a-Naphthalenesul- fonic acid (¡ª) /3-Naphthalenesul- fonic acid (0.5)j3-Naphthalenesul- fonic acid (0.5) /3-Methylnaphtha- lene (0.6)Biphenyl (¡ª) ? Biphenyl (2) Biphenyl (¡ª?) Biphenyl (10) Biphenyl (¡ª) Alkylating Agent (moles) Isopropyl alcohol (0.5) <-Amyl alcohol (0.5) Isopropyl ether (1.2) Isopropyl alcohol (¡ª) Isopropyl alcohol (3) Isopropyl alcohol (1.5) Cyclopropane (0.5) Methyl chloride (¡ª) Methyl sulfate (5) Ethylene (¡ª) Ethyl chloride (6) Ethyl bromide (¡ª) Catalyst (moles) A1C13 (0.5) AICI3 (0.2) HF (23) H2SO4 (80%) (¡ª) HaSCU (96%) (1.3)HF(24) ZnCl2¡ªHC1 (0.02)AICI3 (-) AICI3 (2.88) AICI3 (-) AICI3 (5) AICI3 (-) Solvent ¡ª ¡ª ¡ª ¡ª. ¡ª ¡ª ¡ª ¡ª o-Dichloro- benzene ¡ª Tem- perature,°C. 80-90 80-90 0-?20 80 120 0->20 30-35 100 42 100 Time, hours 2-3 2-3 20 ¡ª 12 20 4 ¡ª? 10 ¡ª Products (% Yield) 1-Chloro-r-isopropylnaphtha- lene (45%) z-<-Amyl-l-chloronaphthalene (60%)Isopropyl-1-nitronaphthalene (10%), diisopropyl-1-nitro-naphthalene (82%) 1- and 2-Isopropyl-,l,6-, 2,'6-, and 2,7-di-, tri-, and tetra-isopropyl-naphthalenes l,6-Diisopropyl-3-naphtha- lenesulfonic acidPolyisopropyl-2-naphthalene- sulfonic acidPropyl-/3-methyhiaphthalene (15%)m-Methylbiphenyl, dimethyl- biphenyl, p- and m-ter- phenyl m- and p-Methylbiphenyl(25%), dimethylbiphenyls (20%) ' m-Ethylbiphenyl, diethylbi- phenyl, p- and m-terphen- yi Refer- ence * 45 45 71 29 29 71 36 93 147 93 Biphenyl (2) Biphenyl (0.8) Biphenyl (0.7) Biphenyl (¡ª)Biphenyl (¡ª) Biphenyl (¡ª?)Diphenylmethane (1) Diphenylmethane (¡ª)Dibenzyl (0.6) Acenaphthene (1)Acenaphthene (0.3)Acenaphthene (¡ª) Fluorene (¡ª)Fluorene (0.06) Anthracene (1.5)Anthracene (1) Anthracene (0.27)Anthracene (0.6) Phenanthrene (0.75) Phenanthrene (¡ª) Ethyl sulfate (3) 2.2 4-Trimethylpentane(0.4) Cyclohexene (0.3) Benzyl chloride (¡ª)Benzyl chloride (¡ª) Benzyl chloride (0.2)Cyclohexene (0.5) 3-Methylcyclohexene Cyclohexene (0.4) 3-Hexanol (1.17)Benzyl chloride (0.3) Benzyl chloride (0.2), Propylene (¡ª)Benzyl chloride (¡ª) Isopropyl ether (3)3-Hexene (0.66) 3-Bromohexane (0.25)Benzyl chloride (1.2) t-Butyl alcohol (1.65) Benzyl chloride (¡ª) A1C13 (2.25) AlClj¡ªHC1(O.O4) AICI3 (0.1) Zn (-) Ti (0.1) AICI3 (0.15) AICI3 (-) AlCla(O.l) ZnCl2 (¡ª)ZnCl 2 (0.5) Ti (0.1) H3PO4 (-)Zn(-) HF (55)AICI3 (-) HF (2.5)Zn(0.15) HF (21) Zn(-) o-Dichloro- benzene ¡ª CSi! CSj ¡ª CS2 ¡ª ¡ª cs2 ¡ª ¡ª 5->25 80-90 25 100Boiling 9025 25 25 180125 -> 18090 200125 10 120-125 45 15-20 125 14 8 3 310 3 3 3 2 11 3 20 18 ¡ª TO- and p-Ethylbiphenyl(20%), diethylbiphenyls (40%) p-?-Butylbiphenyl (35%) p-Cyclohexylbiphenyl (40%),dicyclohexylbiphenyl (m.p. 205-206°)p-Benzylbiphenyl (50%) p-Benzylbiphenylp-Benzylbiphenyl (25%) p-Cyclohexyldiphenylmethane (27%), p-benzylbiphenyl (3%)Methylcyclohexyldiphenyl- methaneCyclohexyldibenzyl (30%) (2 isomers)3-Acenaphthylhexane (32%) 3-Benzylacenaphthene (30%) 3-Benzylacenaphthene (42%)(plus 2-benzylacenaphthene) Isopropylfluorene (25%)2-Benzylfluorene (5%) Diisopropylanthracenes (80%)Di-8-hexylanthracene (20%) Di-s-hexylanthracene (20%)9,10-Dibenzylanthracene (35%)<-Butylphenanthrenes (60%) -?- 9-Benzylphenanthrene f 147 177 58 173 259 297 58' 58 58 315 143,144 297 204 160,173 71 315 71 239 71 142,173 * References 93-350 appear on pp. 78-82.t This product, m.p. 155-156°, was I ound by Goldschmiedt (173) to yield phenanthrenequinone on chromic acid oxidation. Willgerodt and Albert (336) have prepared a benzylphenanthrene melting at 91-92° which they believe to be the 9-isomer, but Bachmann [J. Am. Chem. Soc., 86, 1363 (1934)] supports Goldschmiedt. 1 00 TABLE IX ALKYLATION OF PHENOL Moles of Phenol 1 ¡ª ¡ª 3 ¡ª 1.5 1 1 1 1 Alkylating Agent (moles) Methyl alcohol (¡ª) Ethylene (1) Ethaiiol (¡ª) Ethanol (¡ª) Ethyl ether (4) Ethyl chloroformate (¡ª) Propylene (6.75) Propylene (0.5) Propylene (2) Propylene (1) Propylene (excess) Catalyst (moles) A12O3 (-) H3PO4 (0.3) ZnCl2 (¡ª) AICI3 (-) A1CU (9) FeCl3 (-) HF(41) BF3 (0.08) BF3 (0.08) BF3 (0.05) BF3 (0.05) Solvent ¡ª ¡ª ¡ª ¡ª ¡ª ¡ª Benzene Benzene ¡ª ¡ª Tem- perature, °C. 440 225 180 120-140 145 ¡ª 5->25 0 15 20 30-40 Time, hours 16 ¡ª 6 ¡ª ¡ª 20 2 2 2 ¡ª Products (% Yield) o-Cresol, anisole 0- and p-Ethylphenol (35%), dieth- ylphenol (25%), phenetole, ethyl- phenetole p-Ethylphenol and isomers, and p- ethylphenetole Diethylphenol (36%), 0- and p-eth- ylphenols (24%) 3,5-Diethylphenol p-Ethylphenol (poor yield) 2,4,6-Triisopropylphenol (95%) o-(?)-Isopropylphenol (41%), iso- propyl phenyl ether (54%) 0 - (?) - Isopropylphenyl isopropyl ether (41%) 2,4-Diisopropylphenyl isopropyl ether (30%) 2,4,6-Triisopropylphenyl isopropyl ether (92%) Reference* 203 207 99,119,148 43 44 247 71 91 91 91 91 1> 3 3 1 0.2 1.1 n-Propyl alcohol (2) rc-Propyl alcohol (¡ª) n-Propyl alcohol (1) Isopropyl alcohol (1) Isopropyl alcohol (¡ª) Allyl iodide (3) Isobutylene (¡ª) Diisobutylene (¡ª) Diisobutylene (0.5) p-t-Octylphenol (1) n-Butyl chloride (0.2) n-Butyl alcohol (¡ª) s-Butyl alcohol (¡ª) s-Butyl alcohol (¡ª) Isobutyl alcohol (1.1) Al2O3(0.1) 1C13 (-) F3 (0.3) BF3 (0.3) Aids (-) Zn-Al (¡ª) A1C13 (-) Aia3(1.3) AICI3 (2) A1C13 (0.2) A1C13 (-) H2SO4 (¡ª) A1C13 (-) ZnCl2 (1.6) ¡ª ¡ª? ¡ª ¡ª ¡ª ¡ª ¡ª ¡ª ¡ª 400 120-140 115-160 115-160 110-120 Warm 80 80 110 140 120-140 180 12 6 1 1 6 ¡ª 6 10 4 6 6 ' 1 o-Propylphenol, n-propylphenyl ether, n-propyl o-propylphenyl ether o- and p-Propylphenols (73%) o-Isopropylphenol (28%), p-isopro- pylphenol (20%), 2,4-diisopropyl- phenyl isopropyl ether (11%) o-Isopropylphenol (32%), p-isopro- pylphenol (16%), 2,4-diisopropyl- phenyl isopropyl ether (13%^) p- and o-Isopropylphenols (52%), p-isopropylphenyl isopropyl ether (23%) n-Propylphenol p-i-Butylphenol (60-75%) t-Butylphenol p-t-Butylphenol (67%), p-t-octyl- phenol (14%) p-t-Butylphenol (75%) p-n-Butylphenol (35%), p-n-butyl- phenyl butyl ether (20%) Butylphenol (72%) p- and o-s-Butylphenol 39- and o-s-Butylphenol (52%), s- butylphenyl s-butyl ether (13%) p-t-Butylphenol (70%) 202 43 314 314 43 162 208 256 313 313 321 43 29 43 179, 237, 238, 296 0Q * References 93-350 appear on pp. 78-82. TABLE IX¡ªContinued ALKYLATION OF PHENOL Moles of Phenol 1.1 ¡ª ¡ª ¡ª 0.25 ¡ª 0.15 0.1 ¡ª 0.2 0.2 ¡ª 0.2 1 Alkylating Agent (moles) Isobutyl alcohol (¡ª) Isobutyl alcohol (¡ª) Z-Butyl chloride (¡ª) ?-Butyl chloride (¡ª) <-Butyl alcohol (0.25) Trimethylethylene (¡ª) Amylene (0.15) Amylene (0.1) 2-Pentanol (¡ª) Isoamyl chloride (0.2) Isoamyl chloride (0.2) Isoamyl alcohol (¡ª) Isoamyl chloroformate (0.2) t-Amjl alcohol (1) Catalyst (moles) H2SO4 (70%) (¡ª) A1CU (-) AICI3 (-) HF(-) AICI3 (0.125) H2SO4 (¡ª) H2SO4(0.12) p-Toluenesulfonic acid (0.005) AICI3 (-) AICI3 (0.2) AICI3 (0.2) ?ZnCl2 (¡ª) FeCl3 (-) ZnCl2 (2) Solvent ¡ª ¡ª ¡ª. Petrole- um ether ¡ª Acetic acid ¡ª ¡ª ¡ª ¡ª. ¡ª. ¡ª Tem- perature, °C. 80 ¡ª ¡ª ¡ª 25-30 ¡ª ¡ª. 100 100 90 Cold 180 25->80 180 Time, hours ? ¡ª ¡ª ¡ª 3-4 ¡ª 96 6 2 5 ¡ª 1 ¡ª. ¡ª Products (% Yield) p-<-Butylphenol, (ca. 80%) p-i-Butylphenol (60-75%) p-t-Butylphenol (60-75%) p-*-Butylphenol (85%) p-?-Butylphenol (45-60%) <-Amylphenol p-?-Amylphenol (70%) p-<-Amylphenol (65%) 2- and 3-(p-Hydroxyphenyl)pen- tane (58%) p-Isoamylphenol (10%), p-isoamyl- phenyl isoamyl ether (15%) p-i-Amylphenol (55%) p-<-Amylphenol (40%) p-i-Amylphenol p-<-Amylphenol (65%) Reference* 29 43,208 208 308 195, 208 256 98, 223 342 43 321 321 179, 237, 238 247 157 oI o s ?a 0Q 0.25 0.25 0.25 0.25 0.25 2 5 1.0 0.1 0.1 0.15 0.15 0.15 <-Amyl alcohol (0.25) 3-Hexene (¡ª) 2-Methyl-2-pentanol (0.25) 3-Methyl-3-pentanol (0.25) 2,3-Dimethyl-2-butanol (0.25) Cyclohexene (0.25) Cyclohexene (1.5) Cyclohexene (1.5) Cyclohexyl chloride (1.0) Cyclohexanol (0.15) Cyclohexanol (¡ª) 1-Methylcyclohexene (0.15) 3-Methylcyclohexene (0.15) 4-Methylcyclohexene (0.15) A1C13 (0.125) ?(-) A1C13 (0.125) AICI3 (0.125) AICI3 (0.125) H2SO4(0.1) AICI3 (0.45) AICI3 (0.45) ZnCl2(1.0) p-Toluenesulfonic acid (0.002) H2SO4 (70%) (¡ª) H2SO4 (0.1) H2SO4 (0.1) H2SOi(0.1) Petrole- um ether ¡ª Petrole- um ether Petrole- um ether Petrole- um ether Acetic acid CS2 ¡ª ¡ª ¡ª ¡ª Acetic acid Acetic acid Acetic acid 25-30 ¡ª 25-30 25-30 25-30 80 25 25 80 155 80 80 80 80 3-4 ¡ª 3-4 3-4 3-4 1 3 3 ¡ª 0.5 ¡ª 1 1 1 p-<-Amylphenol (45-60%) s-Hexylphenol, di-s-hexylphenol, tri- s-hexylphenol 2-(p-Hydroxyphenyl)-2-methylpen- tane (45-60%) 3-(p-Hydroxyphenyl)-2-methylpen- tane (45-60%) , 2 - (p - Hydroxyphenyl) - 2,3 - dimeth- ylbutane (45-60%) p-Cyclohexylphenol (17%) o-Cyclohexylphenol (15%), p-cyclo- hexylphenol (4%), cyclohexyl- phenyl ether (12%) o-Cyclohexylphenol (56%), p-cyclo- hexylphenol (20%) p-Cyclohexylphenol (20%) Cyclohexene (73%), p-cyclohexyl- phenol p-Cyclohexylphenol (50%) p-(Methylcyclohexyl)phenol f (55%) p-(Methylcyclohexyl)phenol f (55%) p-(Methylcyclohexyl)phenol f (55%) 195 315 195 195 195 289 58 58 112 342 29 289 289 289 * References 93-350 appear on pp. 78-82.f The products obtained by Schrauth and Quasebarth (289) by condensation of the three isomeric methylcyclohexenes with phenol are identical and have the same, melting point as the product prepared by Meyer and Bernhauer (29) from 4-methylcyclohexanol. The most probable structure would appear to be 1-methyl-l-(p-hydroxyphenyl)-cyclohexane. o TABLE IX¡ªContinued ALKYLATION OP PHENOL to Moles of Phenol 0.2 0.5 3 ¡ª ¡ª 2.7 ¡ª 0.5 ¡ª ¡ª 1 0.5 0.4 Alkylating Agent (moles) 4-Methylcyclohexanol (0.2) Benzyl alcohol (0.5) Benzyl alcohol (¡ª) Benzyl alcohol (¡ª) Benzyl alcohol (¡ª) Benzyl n-propyl ether (1) Benzyl chloride (¡ª) Benzyl chloride (0.4) Benzyl chloride (¡ª) A6-1,3-Dimethylcyclo- hexene (¡ª) Styrene (1) 2-Phenyl-2-propanol (0.16) A1(or2)-Octalin(0.08) Catalyst (moles) HjSO* (80%) (6) 'AlCla (0.25) H2SO4 (70%) (¡ª) ZnCl2 (¡ª) H2SO4 (-) BF3 (0.5) Zn(-) AICI3 (0.25) Ti(-) H2SO4 (¡ª) H2SO4 (1) AICI3 (0.08) HC1 (-) Solvent Petrole- um ether (CS2) ¡ª ?¡ª Acetic acid ¡ª ¡ª Petrole- um ether ¡ª Acetic acid Acetic acid ¡ª ¡ª Tem- perature, °C. 70 20-30 40 ¡ª ¡ª ¡ª ¡ª 30 ¡ª 80 25 90 80 Time, hours 5 18 ¡ª ¡ª ¡ª ¡ª ¡ª 24 ¡ª ¡ª 24-48 1 5 Products (% Yield) p-(Methylcyclohexyl)phenol f (55%) p-Benzylphenol (43-45%) p- and o-Benzylphenols (40%) p-Benzylphenol p-Benzylphenol p-Benzylphenol (48%) p-Benzylphenol p-Benzylphenol (36%) p-Benzylphenol ' 1,3-Dimethyl-x- (p-hydroxyphenyl)- cyclohexane (62%) p-Hydroxy-l,l-diphenylethane (40%) p-Hydroxy-2,2-diphenylpropane (68-72%) p-(l- (or 2-)-Decahydronaphthyl)- phenol (70%) Reference* 29 191 29 237, 238 267 255 266 191 297 289 223 332 289 I O o CD 0.3 0.75 0.75 0.04 0.5 0.75 0.75 0.75 0.75 0.75 0.75 0.75 0.75 Dihydronaphthalene (0.3) Pinene (0.15) Limonene (0.15) Benzhydrol (¡ª) Benzhydrol (0.08) 1,1-Diphenyl-l-ethanol (0.16) 1,1-Diphenyl-l-propanol (0.5) 1,1-Diphenyl-l-butanol (0.5) 1, l-Diphenyl-2-methyl- 1-propanol (0.5) 1,1-Diphenyl-l-pentanol (0.5) 1, l-Diphenyl-2-methyl- 1-butanol (0.5) l,l-Diphenyl-3-methyl- 1-butanol (0.5) l,l-Diphenyl-2-2-di- methyl-1-propanol (0.5) 1,1-Diphenyl-l-hexanol (0.5) H2SO4 (0.6) HC1 (-) HC1 (¡ª) SnCl4 (¡ª) H2SO4 (0.3) AICI3 (0.08) AICI3 (0.25) AICI3 (0.25) AICI3 (0.25) AICI3 (0.25) AICI3 (0.25) AICI3 (0.25) AICI3 (0.25) AICI3 (0.25) Acetic acid Acetic acid Ligroin Ligroin Ligroin Ligroin Ligroin Ligroin Ligroin Ligroin 25 80 80 90 90 25 25 25 25 25 25 ' 25 25 24 5 5 4 1 80-90 80-90 80-90 80-90 80-90 80-90 80-90 80-90 Tetrahydronaphthylphenol (70%) Addition product (86%) Addition product (86%) . ' p-Hydroxytriphenylmethane 2,4,6-Tribenzhydrylphenol (ca. 100%) p-Hy droxy-1,1,1 -triphenylethane (80%) p-Hydroxy-1,1,1 -triphenylpropane (87%) p-Hydroxy-1,1,1-triphenylbutane (46%) p-Hydroxy-1,1, l-triphenyl-2-meth- ylpropane (73%) p-Hydroxy-1,1,1 -triphenylpentane (30%) p-Hydroxy-1,1,1 -triphenyl-2-meth- ylbutane (13%) p-Hydroxy-1,1,1 -triphenyl-3-meth- ylbutane (40%) 3-(p-Hydroxyphenyl)-2,2-diphenyl- 3-methylbutane J (6%) p-Hydroxy-1,1,1-triphenylhexane (30%) 224 289 289 123 299 332 196 196 196 196 196 196 196 196 Is i * References 93-350 appear on pp. 78-82.t The products obtained by Schrauth and Quasebarth (289) by condensation of the three isomeric methylcycloheienes with phenol were identical and had the same melting point as the product prepared by Meyer and Bernhauer (29) from 4-methylcyelohexanol. The most probable structure would appear to be 1-methyl-l-(p-hydroxyphenyl)-cyclohexane. t The formation of this product involved a rearrangement of the carbon skeleton of the substituting group. TABLE IX¡ªContinued ALKYLAWON OP PHENOL Moles of Phenol 0.1 ¡ª. 0.05 0.1 0.1 0.3 0.1 Alkylating Agent (moles) Triphenylmethyl chloride (¡ª) Triphenylcarbinol (0.01) Triphenylcarbinol (¡ª) Triphenylcarbinol (0.02) p-Methyltriphenylcar- binol (0.01) 9-Hydroxy-9-phenyl- fluorene (0.01) Di-a-naphthylmethyl bromide (0.03) Di-a-naphthylcarbinol (0.01) Catalyst (moles) Cu (-) H2SO4 (0.2) H2SO4 (trace) ¡ª (¡ª) H2SO4 (0.2) H2SO4(0.1) ¡ª (¡ª) ¡ª (¡ª) Solvent Acetic acid ¡ª ¡ª Acetic acid Acetic acid ¡ª Acetic acid Tem- perature, 80 25 80 Boiling 25 25 Warm 115 Time, .hours 24-48 0.8 1 24-48 72 ¡ª 6 Products (% Yield) p-Hydroxytetraphenylmethane (80%) p-Hydroxytetraphenylmethane p-Hydroxytetraphenylmethane (80- 90%) p-Hydroxytetraphenylmethane (97%) p-Hydroxy-p'-methyltetraphenyl- methane 9-p-Hydroxyphenyl-9-phenylfluo- rene (95%) p-Di-a-naphthylmethylphenol (75%) p-Di-a-naphthylmethylphenol (75%) Reference* 103, 174 102 174 131 122 221, 325 243 243, 285 o o2 * References 93-350 appear on pp. 78-82. TABLE X ALKTLATION OP VABIOTJS PHENOLS AND PHENOLIC ETHERS Aromatic Com- ? pound (moles) Anisole (¡ª) Anisole (¡ª) Anisole (0.2) Anisole (¡ª) Anisole (¡ª) Anisole (0.5) Anisole (¡ª)Anisole (0.1) Anisole (0.2) Anisole (1.5) Anisole (0.4) Anisole (¡ª) Anisole (¡ª) Anisole (¡ª) Anisole (¡ª) Anisole (0.6) Alkylating Agent ?? (moles) Isopropyl alcohol (¡ª) Isopropyl alcohol (¡ª) n-Butyl chloride (0.2) s-Butyl alcohol (¡ª) Isobutyl chloride (¡ª) Isobutyl chloride (0.2) ?-Butyl chloride (¡ª)<-Butyl chloride (0.1) Isoamyl chloride (0.2) Cyclohexene (0.5) Cyclohexyl chloride \\J. ¡êdO) Benzyl chloride (¡ª)Benzyl chloride (¡ª) Benzyl chloride (¡ª) Benzyl chloride (¡ª) Benzyl alcohol (0.5) Catalyst (moles) A1CU (¡ª) A1C13 (-) Aids (0.2) AICI3 (-) AICI3 (-) AICI3 (0.2) AlClj (¡ª)ZnF 2 (¡ª)AICI3 (0.25) AlCls (0.25) AICI3 (0.05) Zn(¡ª) AICI3 (1) ¡ª. Ti (-) AICI3 (0.25) Solvent ¡ª ¡ª Ligroin ¡ª ¡ª ¡ª ¡ª¡ª Ligroin ¡ª ¡ª ¡ª ¡ª ¡ª Petroleum ether Tem-perature, °C 120 140 90 100 .¡ª. 90 Warm¡ª 90 25 70 , , ¡ª Boiling ¡ª 20 Time, hours(unless other- wisenoted) 4 6 5 2 ¡ª 5 ¡ª¡ª 5 3 4 ¡ª 3 ¡ª 48 Products (% Yield) p-Isopropylanisole (50%), p-isopropylphenol (38%) p-Isopropylanisole (30%), p-isopropylphenol (64%) ra-Butylanisolp (65%) s-Butylanisole (55%), di-s- butylanisole (16%), s-butyl- phenol (13%)p-t-Butylanisole Isobutylanisole (40%) p-<-Butylanisolep-<-Butylanisole (30%) Isoamylanisole (45%) 0- and p-Cyclohexylanisole (50%, 3 : 1)Cyclohexylanisole (15-20%) p-Benzylanisole p-Benzylanisole p-Benzylanisolep-Benzylanisole (63%), 2,4-di- benzylanisole (12%)p-Benzylanisole (46%) Refer- ence 43 43 321 43 V 115 321 11518 321 58 112 266 172 259 297 191 * Refereaces 93-350 appear on pp. 78-82. Ut TABLE X¡ªContinued ALKYLATION OF VARIOUS PHENOLS AND PHENOLIC ETHERS Aromatic Com- pound (moles) Anisole (0.1) o-Nitroanisole (1) o-Nitroanisole fn A e\(1.45) Phenetole (1.5) Phenetole (¡ª) Phenetole (¡ª) Phenetole (0.6) Phenyl ether (O.o)Phenyl acetate (2) o-Cresol (¡ª) o-Cresol (¡ª)o-Cresol (¡ª) * o-Cresol (¡ª) o-Cresol (¡ª) o-Cresol (0.9) Alkylating Agent (moles) Triphenylcarbinol t(\ t\-i \(O.U1) Isopropyl alcohol (1) Cyclohexanol (2.25) Propylene (1.5) Cyclohexyl chloride (¡ª) Benzyl chloride (¡ª) Benzyl alcohol (0.5) 3-Hexene (1.8) Benzyl chloride (1) Isobutyl alcohol (¡ª) Isobutyl chloride (¡ª)Isobutyl alcohol (¡ª) 2-Butyl chloride (¡ª) Benzyl alcohol (¡ª) Benzyl alcohol (0.9) Catalyst (moles) H2SO4 (0.2) HF (12) HF (18) H3PO4 (0.6) AICI3 (-) Ti(-) AICI3 (0.25) HF (6.5) A1C13 (-) ZnCl2 (¡ª) ZnGl2 (¡ª)H2SO4 (-) ZnCl2 (¡ª) H2SO4 (70%) (-) AICI3 (0.5) Solvent Acetic acid ¡ª ¡ª ¡ª ¡ª Petroleum etner ¡ª : ¡ª¡ª ¡ª ¡ª Petroleumether Tem- perature, ? 25 10-20 15-20 145 ¡ª ¡ª 20 5->20 Warm 180 80 .¡ª 80 ¡ª 30-35 Time, hours(unless other- wisenoted) 120 18 20 7 ¡ª. ¡ª ¡ª 3 days 0.5 ¡ª¡ª ¡ª ¡ª 18 Products (% Yield) p-Methoxytetraphenyl- Illc WlHUc ?2-Nitro-4-isopropylanisole (84%)2-Nitro-4-cyclohexylanisole (55%)Isopropylphenetole (8%), di- isopropylphenetole (15%) Cyclohexylphenetole (12%) p-Benzylphenetole (76%) p-Benzylphenetole (57%) ?-Hexylphenyl ether (61%) p-Acetoxydiphenylmethane(poor yield) 4-t-Butyl-2-methylphenol 4-<-Butyl-2-methylphenol4-i-Butyl-2-methylphenol 4-<-Butyl-2-methylphenol 4-Benzyl-2-methylphenol4-Benzyl-2-methylphenol (30%), 6-benzyl-2-methyl- phenol (2%), 4,6-dibenzyl- 2-methylphenol (20%) Refer- ence* 102 71 71 207 ' 112 297 191 71 269 115 115 29 115 29/ 77 o-Cresol (1.5) o-Cresol (¡ª) o-Cresol (0.04) o-Cresol t (0.05) o-Cresyl methyl ether (0.08)m-Cresol (3) m-Cresol % (¡ª)OT-Cresol (¡ª) m-Cresol (1.1) TO-Cresol (¡ª) m-Cresol (0.05) p-Cresol (1) p-Cresol (1.5) p-Cresol (0.05) m-n-Propylanisole (0.1) Benzyl ether (0.9) Styrene (¡ª) Benzhydrol (0.08)Triphenylcarbinol (0.03)Triphenylcarbinol (0.03)Propylene (3) Isopropyl alcohol (¡ª)Isobutyl alcohol (¡ª) Benzyl alcohol (0.9) Styrene (¡ª) Triphenylcarbinol(0.03) Benzyl alcohol (0.5) Benzyl alcohol (0.5) Benzhydrol (0.05) <-Butyl chloride (0.1) HF (15) H2SO4 (¡ª) H2SO4 (0.3)H 2"SO4(0.1) H2SO4 (0.1) HP (27) H2SO4 (¡ª) H2SO4 (¡ª) AICI3 (0.45) H2SO4 (-) H2SO4 (0.1) AICI3 (0.25) t AICI3 (0.25) H2SO4(0.15) A1C13 (0.03) ¡ª Acetic acid Acetic acid Acetic acid Acetic acid ¡ª Petroleum ether Acetic acid Acetic acid Petroleumether Petroleum ether Acetic acid ¡ª 5-* 25 25 90 25 25 0-20 35 25 48 25-30 25-30 90 0 20 ¡ª 4 24 48 18 24 ¡ª 25 18 18 . 5 2 Benzyl-o-cresol (54%), diben- zyl-o-cresol (10%)l-(4-Hydroxy-2-methyl- phenyl)-l-phenylethaneBenzhydryl-o-cresol (ca. 100%) 4-Hydroxy-3-methyltetraphen- ylmethane (ca. 100%)4-Methoxy-3-methyltetra- phenylmethane (ca. 100%)Isopropyl-m-cresols 3-Methyl-4-isopropylphenol4-t-Butyl-3-methylphenol 4-Benzyl-3-methylphenol (19%), 6-benzyl-3-methyl- phenol (21%), 4,6-dibenzyl-3-methylphenol (35%) l-(4-Hydroxy-2-methyl- phenyl)-l-phenylethane4-Hydroxy-2-methyltetra- phenylmethane (90%) §2-Benzyl-4-methylphenol (35%), 2,6-dibenzyl-4-meth- ylphenol (36%)2-Benzyl-4-methylphenol (35%), 2,6-dibenzyl-4-meth- ylphenol (36%)o,o'-I)ibenzhydryl-p-cresol (70%)2-(-Butyl-5-ra-propylanisole (60%) 71 225 299 131 131 7129 2975 225 131,286 76 76 299 140 oo * References 93-350 appear on pp. 78-82. t Similar treatment of p-cresol yields only triphenylmethane (90%) and polymerized quinomethane, O=( \=CSi (131, 286). t p-Cresol is not alkylated by this procedure (29). § The structure of this condensation product has not been definitely established; it may be 2-hydroxy-4-methyltetraphenylmethane (286). O3 TABLE X¡ªContinued ALKYLATION OP VARIOUS PHENOLS AND PHENOLIC ETHERS Aromatic Com-pound (moles) Carvacrol (1) Thymol (¡ª) a-Naphthol (¡ª)a-Naphthol (1) a-Naphthol (¡ª)/3-Naphthol (1.11) /3-Naphthol (¡ª)/3-Naphthol (1) /J-Naphthol (¡ª) /S-Naphthyl methyl ether (0.6) Alkylating Agent(moles) Cyclohexene (0.5) Amylene (¡ª) 3-Hexene (¡ª)Benzyl chloride (1) Benzhydrol (¡ª)Isopropyl alcohol (4.44) 3-Hexene (¡ª)Benzyl chloride (1) Styrene (¡ª) Isobutyl bromide (0.7) Catalyst (moles) A1C13(O.15) H2SO4 (-) ?(-)Zn(¡ª) SnCUorZnCl2(¡ª)HF (25) ?(-)Zn (-) H2SO4 (¡ª) A1C13 (0.6) Solvent Acetic acid Benzene Benzene (alcohol) Acetic acid CS2 Tem- perature, °C. 25 25 5 25 55-65 Time,hours (unlessother- wisenoted) 3 5 24 6 3 Products (% Yield) Carvacryl cyclohexyl ether(15%), cyclohexylcarvacrol (20%)4-J-Amyl-2-isopropyl-5-methyl- phenol (50%)s-Hexyl-a-naphthol Benzyl-a-naphthol (30%)4-Benzhydryl-l-naphthol Diisopropyl-/3-naphthol (94%)s-Hexyl-^-naphthol Benzyl-/3-naphthol (20%) 2-Hydroxy-l-(a-phenylethyl)- naphthalene 1 -i-Buty 1-2-methoxynaphtha- lene (70%) Refer- ence* 58 225 315105 32871 315106 225 137 >1 * References 93-330 appear on pp. 78-82. TABLE XI ALKYLATION OF POLYHYDRIC PHENOLS Aromatic Com- pound (moles) Catechol (0.1) Catechol (0.03) Catechol (¡ª) Veratrol (1) Resorcinol (0.5) Resorcinol (¡ª) Resorcinol (0.1) Resorcinol (0.1) Resorcinol (0.1) Resorcinol (0.1) Resorcinol (¡ª) Resorcinol (0.8) Alkylating Agent (moles) i-Butyl chloride (0.2) Amylene (0.08) 3-Hexene (¡ª) Allyl iodide (0.5) Acetylene (0.5) Isopropyl alcohol (¡ª) t-Butyl chloride (0.3) ?-Butyl chloride (0.3) Amylene (0.25) ?-Amyl chloride (0.3) 3-Hexene (¡ª) Cyclohexyl chloride (0.6) Catalyst (moles) FeCl3 (0.02) H2SO4 (¡ª) ?(-) Zn (0.015) HgSO4 (¡ª) H2SO4 (70%) (¡ª) FeCl3 (0.02) AICI3 (-) H2SO4 (¡ª) FeCl3 (0.02) H3BO2F2 (-) A1C13(O.15) Solvent Acetic acid * ¡ª Methyl alcohol .¡ª ¡ª ¡ª Acetic acid ¡ª ¡ª Nitro- benzene Tem- perature, °C. 80 25 ¡ª Warm 25 80 80 ¡ª 25 80 ¡ª 70 Time, hours 0.1 120 ¡ª 2.5 ¡ª ¡ª 0.3-0.4 ¡ª 120 0.1 ¡ª 4 Products (% Yield) Di-i-butylcatechol Di-i-amylcatechol (15%) s-Hexylcatechol Methyl eugenyl ether Vinylresorcinol (83%) 4-Isopropylresorcinol, 4,6-di- isopropylresorcinol Di-i-butylresorcinol mono-fr- butyl ether (40%) Di-t-butylresorcinol Di-tf-amylresorcinol Di-t-amylresorcinol (5%) s-Hexylresorcinol (62%), di-s- hexylresorcinol (20%) Cyclohexylresorcinol (5%) Refer- ence * 179 226 315 257 159 29 179 179 226 17* 315 112 I Hs * References 93-350 appear on pp. 78-82. CO TABLE XI¡ªContinued AliKYLATION OF POLTHTDBIC PHENOLS Aromatic Com- pound (moles) Resorcinol (¡ª) Resorcinol (0.2) Resorcinol mono- methyl ether (¡ª) Resorcinol di- methyl ether (¡ª) Hydroquinone (5) Hydroquinone (1.65) Alkylating Agent (moles) Benzyl chloride (¡ª) Benzyl chloride (0.1) Isopropyl alcohol (¡ª) Isopropyl alcohol (¡ª) Isopropyl alcohol (6) Isopropyl alcohol (7.6) Catalyst (moles) Zn (-) A1C13 (0.1) H2SO4 (¡ª) H2SO4 (¡ª) HF (42) HF (-) Solvent . Nitro- benzene ¡ª. ¡ª ¡ª ¡ª Tem- perature, °C. 50-70 ¡ª ¡ª 5->20 ¡ª Time, hours 2 ¡ª. ¡ª 24 ¡ª Products (% Yield) Benzylresorcinol, dibenzyl- resorcinol 4-Benzylresorcinol (50%) Monomethyl ether of diiso- propylresorcinol Dimethyl ethers of isopropyl- and diisopropylresorcinol Isopropylhydroquinone (39%) 2,4,6-Triisopropylphenol (83%) Refer- ence* 104 220 29 29 71 71 1 t-H o 8 CO Hydroquinone (0.1) Hydroquinone (0.25) Hydroquinone (¡ª) Hydroquinone di- methyl ether (0.2) 2-Methyl-l,4-naph- thohydroquinone 2-Methyl-l,4-naph- thohydroquinone Pyrogallol (0.1) Pyrogallol (¡ª) <-Butyl chloride (0.2) Amylene (0.65) 3-Hexene (¡ª) Benzyl chloride (0.15) Cinnamyl alcohol (¡ª) Phytol (¡ª) <-Butyl chloride (0.4) Amylene (¡ª) FeCl3 (0.02) H2SO4 (¡ª) ?(-) Ti (0.1) Oxalic acid (¡ª) Oxalic acid (¡ª) FeCl3 (0.02) H2SO4 (¡ª) ¡ª Acetic acid ¡ª Dioxane Dioxane Acetic acid 25 25 130-140 ioo 75 80 25 0.2 24 8 24 36 0.5 120 2,5-Di-t-butylbenzoquinone 2,5-Di-t-amylhydroquinone (50%) s-Hexylhydroquinone, di-s- hexylhydroquinone Benzylhydroquinone dimethyl ether (70%) 3-Cinnamyl-2-methyl-l ,4- naphthohydroquinone (30%) 2-Methyl-3-phytyl-l ,4-naph- thohydroquinone (30%) Di-t-butylpyrogallol Di-J-amylpyrogallol 179 226 315 297 153 152 282 226 * Keferences 93-350 appear on pp. 78-82. TABLE XII ALKYLATION OF MISCELLANEOUS ALDEHYDES, ACIDS, AND QUINONES to Aromatic Com- pound (moles) Alkylating Agent (moles) Catalyst (moles) Solvent Tem- perature, °C Time, hours Products (% Yield) Refer-ence* Benzaldehyde(0.2) Benzaldehyde (¡ª)Benzoquinone (0.1)a-Naphthoquinone (0.1)Benzoic acid (1.5) Anisaldehyde (0.1) Methyl anisate (0.08) Ethyl a-naphthoate (0.05) Ethyl a-naphthoate (0.05) Salicylic acid (1) Salicylic acid (1)Salicylic acid (¡ª) Salicylic acid (¡ª) 3-Hydroxy-2-naph -thoic acid (1) Methyl salicylate(0.04) Isopropyl chloride (0.2) <-Butyl chloride (¡ª) Benzhydrol (0.1) Benzhydrol (0.1) Isopropyl ether (3) Isopropyl chloride (0.1) Isopropyl chloride(0.08) Isopropyl chloride (0.05)n-Butyl chloride (0.05) Isopropyl alcbhol (2.5) Isobutyl alcohol (2) Isobutyl alcohol (¡ª) i-Butyl alcohol (¡ª) Isopropyl alcohol (1.2) Triphenylcarbinol(0.02) A1C13 (0.4) A1C1, (¡ª) H2SO4 (0.01) H2SO4 (0.01) HF (45) AICI3 (0.2) AICI3 (0.16) A1C13(O.1) CS2 CS2 Acetic acid Acetic acid CS2 CS2 CS2 25 2580 80 10->75 H2SO4 (80%) (60) ZnCl2 (¡ª)H 2SO4 (80%) (¡ª) H2SO4 (80%) (¡ª) HF (33) 75 180 70 70 15-20 Boiling 12 12 12 3 8 5 1 20 1 TO-Isopropylbenzaldehyde (8%conversion, 30% yield) m-t-Butylbenzaldehyde2,5-Dibenzhydrylbenzoqui- none2-Benzhydryl-a-naphthoqui- none (ca. 100%)m-Isopropylbenzoic acid 3-Isopropyl-4-methoxyben- zaldehyde (22%)Methyl 3-isopropyl-4-methoxy- benzoate (33%) .Ethyl isopropyl-a-naphthoate Ethyl butyl-a-naphthoate 2-Hydroxy-5-isopropylbenzoicacid (50%) p-<-Butylphenol + CO2 t2-Hydroxy-5-<-butylbenzoic acid (80%)2-Hydroxy-5-(-butylbenzoic acid (80%)IsopropyI-3-hydroxy-2-naph- thoic acid3-Carboxy-4-hydroxytetra- phenylmethane | (40%) 32 32 254 254 7132 168 168 168 29 23829 29 71 131 * References 93-350 appear on pp. 78-82. t On distillation of the crude product. t After hydrolysis. TABLE XIII ALKTLATION OF ANILINE Moles of Aniline i i i i i ¡ª ¡ª 0.2 ¡ª 0.1 0.1 ¡ª? 0.6 ¡ª ¡ª 0.1 Alkylating Agent (moles) Methyl chloride (¡ª) n-Propyl alcohol (1) Isopropyl alcohol (1) Isobutyl alcohol (1) Isobutyl alcohol (1) Isoamyl alcohol (¡ª) fsoamyl alcohol (¡ª) t-Amyl alcohol (0.1) Benzyl chloride (¡ª) n-Octyl alcohol (0.1) s-Octyl alcohol (0.1) Benzhydrol (¡ª) 9-Hydroxy-9-phenyl- fluorene (0.02) Di-a-naphthylmethyl bromide (¡ª) Di-or-naphthylcarbinol V ) Triphenylcarbinol (0.02) Catalyst (moles) AlClg (1) ZnCl2 (1) ZnCl2 (1) P2OB (1) ZnCl2 (1) ZnCl2 (¡ª) P2O6 (¡ª) ZnCl2 (¡ª) ZnCl2 (¡ª) ZnCl2 (0.05) ZnCl2 (0.05) ZnCl2 (¡ª) HC1 (0.6) HC1 (-) HC1 (-) HCl(0.1) Solvent ¡ª ¡ª ¡ª ¡ª ¡ª ¡ª ¡ª ¡ª ¡ª ¡ª? ¡ª Acetic acid ¡ª ¡ª Acetic acid Tem- perature, °C. 260 260 260 260 280 250 270 120 270-280 280 150 115 Warm Warm 115 Time, hours 8 ¡ª 8 8 ¡ª ¡ª. 9 ¡ª 8 8 ¡ª 1 ¡ª ¡ª 5 Products (% Yield) Dimethyltoluidine p-n-Propylaniline p-Isopropylamline p-J-Butylaniline p-<-Butylaniline (40-50%) p-Isoamylaniline (40%) p-Isoamylaniline (40%) p-i-Amylaniline p-Benzyl-N,N-dibenzylaniline p-n-Octylaniline p-s-Octylaniline (15%) p-Aminotriphenylmethane 9-p-Aminophenyl-9-phenylfluorene (80%) p-Di-a-naphthyhnethylaniUne p-DiTa-naphthylmethylaniline p-Aminotetraphenylmethane Reference* 164 240 240, 283 240, 296 240,338 249, 296, 337 249, 296 98 248 120 120 155 325 243 243, 285 320 S dI g * References 93-350 appear on pp. 78-82. 00 TABLE XIV ALKYLATION OF MISCELLANEOUS AROMATIC AMINES Aromatic Com- pound (moles) Dimethylaniline Dimethylaniline (¡ª) Dimethylaniline (¡ª) Dimethylaniline 0.012 Diphenylamine (1) Diphenylamine (1) Acetanilide (¡ª) o-Toluidine (¡ª) o-Toluidine (¡ª) o-Toluidine (¡ª) o-Toluidine (0.15) N-Methyl-o-tolui- dine (0.012) Alkylating Agent (moles) Methyl chloride (¡ª?) Benzyl alcohol (¡ª) Benzhydrol (¡ª) 9-Hydroxy-9-phenyl- fluorene (0.004) Benzyl chloride (1) Benzyl chloride (2) Benzyl chloride (¡ª) Isobutyl alcohol (¡ª) Isobutyl alcohol (¡ª) n-Octyl alcohol (¡ª) Triphenylcarbinol (0.1) 9-Hydroxy-9-phenylflu- orene (0.004) Catalyst (moles) Aid, (¡ª) ZnCl2 (¡ª) ZnCl2 (¡ª) HCl (-) ZnCl2 (1) ZnCl2 (1) ZnCl2 (¡ª) ZnCl2 (¡ª) HCl (-) ZnCl2 (¡ª) HCl (0.15) HCl (¡ª) Solvent ¡ª ¡ª Acetic acid ¡ª ¡ª? ¡ª ¡ª. ¡ª ¡ª? Acetic acid Acetic acid Tem- perature, ¡ª 150 150 115 80 80 120 280 280-300 280 115 115 Time, hours ¡ª ¡ª 4 1 ¡ª ¡ª ¡ª ¡ª ¡ª 5 2 Products (% Yield) Dimethyltoluidine p-Dimethylaminodiphenyl- methane p-Dimethylaminotriphenyl- methane 9-p-Dimethylaminophenyl-9- phenylfluorene (90%) p-Benzyldiphenylamine Dibenzyldiphenylamine p-Benzyl-N,N-dibenzylaniline 2-Amino-3-t-butyltoluene 2-Amino-5-t-butyltoluene n-Octyl-o-toluidine (40-50%) 4-Amino-3-methyltetraphenyl- methane 9-(3-Methyl-4-methylamino- phenyl)-9-phenylfluorene (90%) Refer- ence * 164 155 155 325 248 248 248 145 145 120 97,131 325 i h-H O S 2,6-Dimethyl- aniline (0.15) 0-Naphthylamine (0.3) p-Aminophenol (3) p-Anisidine (2) p-Anisidine (0.77) N-Dimethyl-p- aminophenol (2) N-Diethyl-m-phe- netidine (0.45) 2-Methoxy-l-naph- thylamine (0.6) Triphenylcarbinol (0.08) Methaiiol (1.0) Isopropyl ether (5) Isopropyl ether (3) Cyclohexanol (2) Isopropyl ether (2.1) Isopropyl ether (0.5) Isopropyl ether (1) HC1 (0.15) HC1 (0.3) HF (100) HF (60) HF (19) HF (60) HF (15) HF (22) Acetic acid ¡ª ¡ª ¡ª ¡ª ¡ª '115 240-250 10->75 10->25 10-20 10->25 10-20 5->20 0.3 12 5 20 18 20 20 20 4-Amino-3,5-dimethyltetra- phenylmethane (ca. 100%) l-Methyl-2-naphthol (15%), /S-dimethylaminonaphtha- lene, etc. Diisopropyl-p-aminophenol (12%), 4,4'-dihydroxytetra- isopropyldiphenylamine (62%) Diisopropyl-p-anisidine (38%), 4,4'-dimethoxytetraisopro- pyldiphenylamine (50%) Cyclohexyl-p-anisidine (23%) Isopropyl-N-dimethyl-p- aminophenol (42%), diiso- propyl-N-dimethyl-p-amino- phenol (9%) Isopropyl-N-diethyl-m-phe- netidine (80%) Triisopropyl-2-methoxy-l- naphthylamine (46%) 113 189 71 71 71 71 71 71 ! § * References 93-350 appear on pp. 78-82. TABLE XV ALKYLATION OF HETEBOCYCLIC AROMATIC COMPOUNDS Aromatic Com- pound (moles) Alkylating Agent (moles) Catalyst (moles) Solvent CS2 cs2cs 2CSi! C& CSi! cs2 cs2 cs2 cs2 cs2 cs2 cs2 cs2 Tem- perature, 25 25 25 25 25 25 0 0 0 0 0 0 0 Time, hours 2 2 2 2 24 24 24 24. 24 24 24 24 Products (% Yield) Refer-ence * 2-Furfural (0.5) 2-Furfural (0.5) 2-Furfural (0.5) 2-Furfural (0.5) 2-Furfural (0.5) 5-Bromo-2-furfural 2-Furyl phenyl ketone (0.05) 2-Furoic acid (0.5) Methyl 2-furoate (0.1) Methyl 2-furoate (0.1) Methyl 2-furoate (0.1) Methyl 2-furoate (0.1) Methyl 2-furoate (0.1) Methyl 2-furoate (0.1) Methyl 2-furoate (0.1) Isopropyl chloride (0.5) J-Butyl chloride (0.5) ra-Butyl chloride (0.5) Isobutyl chloride (0.5) n-Amyl chloride (0.5) Isopropyl chloride (¡ª) <-Butyl chloride (0.05) <-Butyl chloride (0.5) n-Propyl chloride (0.1) Isopropyl chloride (0.1) ra-Butyl chloride (0.1) s-Butyl chloride (0.1) t-Butyl chloride (0.1) Isobutyl chloride (0.1) n-Amyl chloride (0.1) A1C13 (0.6) AICI3 (0.6) AICI3 (0.6) AICI3 (0.6) AICI3 (0.6) AICI3 (-) AlCls(l.O) AICI3 (0.1-O.2) AICI3 (0.1-0.2) AICI3 (0.1-0.2) AICI3 (0.1-0.2) AICI3 (0.1-0.2) AICI3 (0.1-0.2) ? AICI3 (0.1-0.2) 4-Isopropyl-2-furfural (11%) 54-Butyl-2-furfural (12%) 5-f-Butyl-2-furfural (12%) 5-MButyl-2-furfural (12%) 5-Amyl-2-furfural (10%) 5-Bromo-4-isopropyl-2-furfural 5-t-Butyl-2-furyl phenyl ketone (30%) 54-Butyl-2-furoic acid (6%) Methyl 5-isopropyl-2-furoate (48%) Methyl 5-isopropyl-2-furoate (45%) Methyl 5-t-butyl-2-furoate (45%) Methyl 5-t-butyl-2-furoate (2%) Methyl 5-i-butyl-2-furoate (46%) Methyl 54-butyl-2-furoate (66%) Methyl 5-(-amyl-2-furoate (31%) 169 32 32 32 32 169 168 168 168 168 168 168 168 168 168 Methyl 2-furoate (0.1) Methyl 2-furoate (0.1) Methyl 2-furoate (0.1) Ethyl 2-furoate (-) Ethyl 5-bromo-2- furoate (0.1) Ethyl 5-bromo-2- furoate (0.74) Ethyl 5-bromo-2- furoate (0.12) Ethyl 5-bromo-2- furoate (¡ª) Ethyl 5-bromo-2- furoate (¡ª) Ethyl 5-bromo-2- furoate (0.12) Ethyl 5-bromo-2- furoate (¡ª) Thiophene (0.1) Thiophene (0.7) f-Amyl chloride (0.1) n-Hexyl chloride (0.1) 1-Methylcyclohexyl chloride (0.1) J-Butyl chloride (¡ª) Isopropyl chloride (0.1) <-Butyl chloride (0.74) n-Amyl chloride (0.12) n-Amyl bromide (¡ª) i-Amyl alcohol (¡ª) n-Hexyl chloride (0.12) n-Octodecyl bromide Benzhydryl ethyl ether (0.1) Benzhydrol (0.6) A1C13 (0.1-0.2) AICI3 (0.1-0.2) AICI3 (0.1-0.2) HF(-) AICI3 (0.1-0.2) A1C13(1.68) AICI3 (0.25) AICI3 (¡ª) AICI3 (-) AICI3 (0.25) AICI3 (-) SnCl4(0.1) P2O6 (¡ª) CS2 CS2 CS2 ecu CS2 cs2 CS2 CS2 CS2 cs2 ¡ª 0->25 25 0->25 ¡ª 0 25 25 ' 25 Cold ¡ª 24 24 24 150 24 24 24 24 ¡ª , 24 Methyl 5-(-amyl-2-furoate (82%) Methyl 5-hexyl-2-furoate (57%) Methyl 5-(l-methylcyclo- hexyl)-2-furoate (55%) Ethyl 5-?-butyl-2-furoate (54%) Ethyl 5-bromo-4-isopropyl-2- furoate (35%) Ethyl 5-bromo-4-t-butyl-2- furoate (3%) Ethyl 5-bromo-4-t-butyl-2- furoate (10% conversion, 30% yield) 5-?-Butyl-2-furoic acid t (31- 40%) 4-i-Butyl-5-bromo-2-furoic acid f (10%) Ethyl 5-bromo-4-J-butyl-2- furoate (5% conversion, 15% yield) Ethyl 5-bromo-4-?-butyl-2- furoate (46%) Dibenzhydrylthiophene (50%), benzhydrylthiophene (5%) Benzhydrylthiophene 278 168 278 308 169 32 32 33 33 32 32 317 236 * References 93-350 appear on pp. 78-82.t After hydrolysis. 78 ORGANIC REACTIONS REFESEN€ES TO TABLES 93 Adam, Ann. chim., [6] 15, 224 (1888); Bull. soc. chim., [2] 49, 98 (1888). 94 Ador and Rilliet, Bull. soc. chim., [2] 31, 244 (1879); Ber., 12, 331 (1879). 95 Albright, Morgan, and Woodworth, Compt. rend., 86, 887 (1878). 96 Allen and Underwood, Bull. soc. chim., [2] 40, 100 (1883). 97 van Alphen, Bee. trav. chim., 46, 501 (1927). 98 Ansehtttz and Beekerhoff, Ann., 327, 218 (1903). 99 Auer, Ber., 17, 670 (1884). 100 Auger, Bull. soc. chim., [2] 47, 48 (1887). 191 Austin, BuU. soc. chim., [2] 32, 12 (1879). m Baeyer and Vffliger, Ber., 35, 3018 (1902). 108Baeyer, Ber., 42, 2625 (1909). 104 Bakunin and Alfano, Gazz. chim. ital., 37, II, 250 (1907). 196 Bakunin and Barberio, Gazz. chim. ital., 33, II, 470 (1903). 106 Bakunin and Altieri, Gazz. chim. ital., 33, II, 488 (1903). 107 Balaohn, BuU. soc. chim., [2] 31,539 (1879). 108 Balsohn, BuU. soc. chim., [2], 32, 618 (1879). 109 Bandrowski, Ber., 7, 1016 (1874). 110 Barbier, Compt. rend., 79, 660 (1874). 111 Barkenbus, Hopkins, and Allen, J. Am. Chem. Soc, 61, 2452 (1939). 112 Bartlett and Garland, J. Am. Chem. Soc., 49, 2098 (1927). 118 Battegay and Kappeler, BuU. soc. chim., [4] 35, 992 (1924). 114 Baur, Ber., 24, 2832 (1891); 27, 1606 (1894). 116 Baur, Ber., 27, 1614 (1894). ?? Baur, Ber., 27, 1623 (1894). 117 Beaurepaire, BuU. soc. chim., [2] 50, 677 (1888). 118 von der Becke, Ber., 23, 3191 (1890). 119 Behal and Choay, BuU. soc. chim., [3] 11, 207 (1894). mBeran, Ber., 18, 132 (1885). 121 Bialobrzeski, Ber., 30, 1773 (1897). 122 Bistrzycki and Gyr, Ber., 37, 659 (1904). 128 Bistrzycki and Herbst, Ber.,.35, 3137 (1902). . 124 Bodroux, BuU. soc. chim., [3] 19, 888 (1898). 126 Bodroux, Compt. rend., 132, 155 (1901). 126 Bodroux, Compt. rend., 132, 1334 (1901). 127 Bodroux, BuU. soc. chim., [3] 25, 496 (1901). 128 Boedtker, BuU. soc. chim., [3] 31, 965 (1904). 129 Boedtker and Rambech, Bull. soc. chim., [4] 35, 631 (1924). 180 Boeseken, Rec. trav. chim., 22, 311 (1903). 181 Boyd and Hardy, J. Chem. Soc., 1928, 630. 182 von Braun and Deutsch, Ber?, 45, 1273 (1912). 188 von Braun and Deutsch, Ber., 45, 2182 (1912). 1MBrochet, Compt. rend., 117, 115 (1894). 186 Brown and Marvel, J. Am. Chem. Soc., 59, 1248 (1937). ""Brunei, Ber., 17, 1180 (1884). 187 Cahen, BuU. soc. chim., [3] 19, 1007 (1898). 188 Claus and Foecking, Ber., 20, 3097 (1887). 189 Clemo and Walton, /. Chem. Soc., 1928, 728. 140 Cousin and Lions, J. Proc. Roy. Soc. N.S. Wales, 70, 413 CL937). 141 Dillingham and Reid, J. Am. Chem. Soc., 60, 2606 (1938). 142Dilthey, Henkels, and Leonhard, J. prakt. Chem., 151, 114 (1938). 148 Dziewonski and Dotta, BuU. soc. chim., [3] 31, 377 (1904). 144 Dziewonski and Rychlik, Ber., 58, 2239 (1925). 145Effront, Ber., 17, 419, 2320 (1884). FRIEDEL-CRAFTS METHOD . 79 148 Elba, /. prakt. Chem., [2] 35, 476 (1886). 147Epelberg and Lowy, J. Am. Chem. Soc, 63, 101 (1941). ?sErrera, Gazz. chim. Hal., 14, 484 (1884). 149 Essner, Bull. soc. chim., [2] 36, 212 (1881). 160 Esaner and Gossin, Bull. soc. chim., [2] 42, 213 (1884). 161 Estreicher, Ber., 33, 436 (1900). 162Fieser, J. Am. Chem. Soc., 61, 3467 (1939). 153 Fieser, Campbell, Fry, and Gates, J. Am. Chem. Soc., 61, 3222 (1939). 164Fieser and Price, J. Am. Chem. Soc, 58, 1838 (1936). 166 Fischer, Ann., 206, 113, 155 (1881). 168 Fischer and Fischer, Ann., 194, 263 (1878). 167 Fischer and Griitzner, Ber., 26, 1646 (1893). 168 Fisher and Eisner, J. Org. Chem., 6, 171 (1941). 169 Flood and Nieiiwland, J. Am. Chem. Soc., 50, 2566 (1928). 160 Fortner, Monatsh., 25, 450 (1904). 161 Fournier, Bull. soc. chim., [3] 7, 651 (1892). 182 Frankland and Turner, J. Chem. Soc, 43, 357 (1883). 183 Friedel and Crafts, Bull. soc. chim., [2] 39, 195, 306 (1883). 164 Friedel and Crafts, Ann. chim., [6] 1, 449 (1884). 166 Friedel and Crafts, Ann., chim., [6] 10, 417 (1887). 188 Galle, Ber., 16, 1744 (1883). 167 Gattermann, Fritz, and Beck, Ber., 32, 1122 (1899). 168Gilman and Calloway, J. Am. Chem. Soc, 55, 4197 (1933). 169 Gilman, Calloway, and Burtner, /. Am. Chem. Soc, 57, 906 (1935). 170 Gleditsch, Bull. soc. chim., [3] 35, 1095 (1906). 171 Goldschmidt, Ber., IS, 1067 (1886). 172 Goldschmidt and Larsen, Z. physik. Chem., [A] 48,429 (1904). 173 Goldschmiedt, Monatsh., 2, 433 (1881). 174Gomberg and Kamm., J. Am. Chem. Soc, 39, 2013 (1917). 176 Gossin, Bull. soc. chim., [2] 38, 99 (1882). 178 Grosse and Ipatieff, J. Am. Chem. Soc, 57, 2415 (1935). 177 Grosse, Mavity, and Ipatieff, J. Org. Chem., 3, 448 (1938). 178 Gump, /. Am. Chem. Soc, 53, 380 (1931). 179 Gurewitsch, Ber., 32, 2424 (1899). 180 Gustavson, Compt. rend., 140, 940 (1905). 181 Gustavson, Compt. rend., 146, 640 (1908). 182 Halse, J. prakt. Chem., [2] 89, 451 (1914). 183 Hartmann and Gattermann, Ber., 25, 3532 (1892). 184 Haworth, Letsky, and Mavin, J. Chem. Soc, 1932, 1784. 186 Hemilian, Ber., 11, 202 (1878). 188 Hemilian, Ber., 13, 678 (1880). 187 Hemilian, Ber., 16, 2360 (1883). 188 Hemilian, Ber., 19, 3061 (1886). 189 Hey and Jackson, J. Chem. Soc, 1936, 1783. 190 Hirst and Cohen, /. Chem. Soc, 67, 827 (1895). 191 Huston, J. Am. Chem. Soc, 46, 2775 (1924). 192 Huston and Friedemann, J. Am. Chem. Soc, 38, 2527 (1916). 193 Huston and Friedemann, /. Am. Chem. Soc, 40, 785 (1918). 194 Huston and Goodemoot, J. Am. Chem. Soc, 56, 2432 (1934). 196 Huston and Hsieh, J. Am. Chem. Soc, 58, 439 (1936). 198 Huston and Jackson, J. Am. Chem. Soc, 63, 541 (1941). 197 Ipatieff and Corson, J. Am. Chem. Soc, 59, 1417 (1937). 198 Ipatieff, Corson, and Pines, J. Am. Chem. Soc, 58, 919 (1936). 199 Ipatieff and Grosse, /. Am. Chem. Soc, 58, 2339 (1936). 200 Ipatieff and Komarewsky, J. Am. Chem. Soc, 56, 1926 (1934). 201 Ipatieff, Komarewsky, and Pines, J. Am. Chem. Soc, 58, 918 (1936). 80 ORGANIC REACTIONS 202 Ipatieff, Orlov, and Petrov, Ber., 60, 1006 (1927). 203 Ipatieff, Orlov, and Eazoubaiev, Bull. soc. chim., [4] 37, 1576 (1925). 204 Ipatieff, Pines, and Komarewsky, Ind. Eng. Chem., 28, 222 (1936). 206 Ipatieff, Pines, and Schmerling, J. Am. Chem. Soc., 60, 353 (1938). 206 Ipatieff, Pines, and Schmerling, J. Am. Chem. Soc, 60, 577 (1938). 207 Ipatieff, Pines, and Schmerling, J. Am. Chem. Soc, 60, 1161 (1938). 208 Isagulyants and Bagryantseva, Neftyanoe Khoz., 1938, No. 2, 36 [C.A., 33, 8183 (1939)]. 209 Jacobsen, Ber., 14, 2624 (1881). 210 Jacobsen, Ber., 20, 896 (1887). 211 Jacobsen, Ber., 21, 2819 (1888). 212 Jannasch and Bartels, Ber., 31, 1716 (1898). 213 Kamienski and Lewiowna, Roczniki Chem., 14, 1348 (1934). 214 Kane and Lowy, J. Am. Chem. Soc, 58, 2605 (1936). 216 Kelbe, Ann., 210, 25 (1881). 216 Kekule and Schrotter, Ber., 12, 2279 (1879). 217 Khashtanov, J. Gen. Chem. U.S.S.R., 2, 515 (1932) [C.A., 27, 975 (1933)]. 218 Kirrmann and Graves, Bull. soc. chim., [5] 1, 1494 (1934). 219 Klages, J. prakt. Chem., [2] 65, 394 (1902). 220 Klarmann, J. Am. Chem. Soc, 48, 791 (1926). 221 Kliegl, Ber., 38, 290 (1905). 222 Koch and Steinbrink, Brennstoff Chem., 19, 277 (1938). 223 Koenigs, Ber., 23, 3145 (1890). 224 Koenigs, Ber., 24, 179 (1891). 226 Koenigs and Carl, Ber., 24, 3889 (1891). 226 Koenigs and Mai, Ber., 25, 2654 (1892). 227 Konowalow, J. Russ. Phys. Chem. Soc, 30, 1036 (1898) [Chem. Zentr., I, 777 (1899)]. 228 Konowalow and Jegerow, J. Russ. Phys. Chem. Soc, 30, 1031 (1898) [Chem. Zentr., I, 776 (1899)]. 229 Kraemer, Spilker, and Eberhardt, Ber., 23, 3269 (1890); 24, 2788 (1891). 280 Krafft, Ber., 19, 2986 (1886). 231 Kunckell and XJlex, J. prakt. Chem., [2] 87, 228 (1913). 232Kursanow, Ann., 318, 311 (1901). 233 Kursanow, J. Russ. Phys. Chem. Soc, 38, 1304 (1907). 234 Kursanow and Zel'viB, J. Gen. Chem. U.S.S.R., 9, 2173 (1939) [C. A., 34, 4062 (1940)]. 236 Lehne, Ber., 13, 358 (1880). 286 Levi, Ber., 19, 1624 (1886). 237 Liebmann, Ber., 14,1842 (1881). 288 Liebmann, Ber., 15, 150 (1882). 239 Lippmann and Fritsch, Monaish., 25, 793 (1904). 240 Louis, Ber., 16, 105 (1883). 241 Louis, Compt. rend., 95, 1163 (1882). 242 Louis, Ann. chim., [6] 6, 177 (1885). 243 Magidsohn, J. Russ. Phys. Chem. Soc, 47, 1304 (1915) [Chem. Zentr., II, 129 (1916)]. 244 Malishev, J. Am. Chem. Soc, 57, 883 (1935). 245 Marchetti, Gazz. chim. Hal., 11, 439 (1881). 246 Mayes and Turner, J. Chem. Soc, 1929, 500. 247 Meissel, Ber., 32, 2423 (1899). 248 Meldola, J. Chem. Soc, 41, 200 (1882). 249 Merz and Weith, Ber., 14, 2343 (1881). 260 Meyer and Wurster, Ber., 6, 963 (1873). 261 Meyer, J. prakt. Chem., [2] 82, 539 (1910). 262 Milligan and Reid, J. Am. Chem. Soc, 44, 206 (1922). 253Miquel, Bull. soc. chim., [2] 26, 2 (1876). 264 Mohlau, Ber., 31, 2351 (1898); Mohlau and Klopfer, Ber., 32, 2149 (1899). FRIEDEL-CRAFTS METHOD 81 266 Monacelli and Hennion, J. Am. Chem. Soc., 63, 1722 (1941). 268 Monsanto Chemical Company, Brit, pat., 452,335 [C. A., 31, 485 (1937)]. 267 Moureu, Bull. soc. chim., [3] 15, 652 (1896). 268 Nef, Ann., 298, 254 (1897). 269 Ninetzescu, Isaoescu, and Ionescu, Ann., 491, 210 (1931). 260 Noelting, Ber., 25, 791 (1892). 261 Norris and Arthur, /. Am. Chem. Soc, 62, 874 (1940). 262 Norris and Ingraham, J. Am. Chem. Soc., 62, 1298 (1940). 263 Norris and Klemka, J. Am. Chem. Soc., 62, 1432 (1940). 264 O'Connor and Sowa, J. Am. Chem. Soc, 60, 125 (1938). 266 Org. Syntheses, Coll. Vol. 2, 248, John Wiley & Sons, New York, New York, 1943. 266 Paterno, Ber., 5, 28* (1872); 5, 435 (1872). 267 Paterno and Fileti, Gazz. chim. ital., 5, 382 (1875). 268 Pavelkina, J. Applied Chem. U.S.S.R., 12, 1422 (1939) [C.A., 34, 3485 (1940)]. 269 Perkin and Hodgkinson, J. Chem. Soc, 37, 725 (1880). 270 Pines, Schmerling, and Ipatieff, J. Am. Chem. Soc, 62, 2901 (1940). 271 Pokrovskaya and Sushchik, J. Gen. Chem. U.S.S.R., 9, 2291 (1939) [C.A., 34, 5433 (1940)]. 272 Potts and Carpenter, J. Am. Chem. Soc, 61, 663 (1939). 273 Price and Lund, /. Am. Chem. Soc, 62, 3105 (1940). 274 Radziewanowski, Ber., 27, 3235 (1894). 276 Radziewanowski, Ber., 28, 1137, 1139 (1895). 276 Radziszewski, Ber., 7, 141 (1874). 277 Rayman and Preis, Ann., 223, 315 (1884). 278 Reichstein, Rosenberg, and Eberhardt, Helv. Chim. Ada, 18, 721 (1935). 279 Rennie, J. Chem. Soc, 41, 33 (1882). 280 Roux, Bull. soc. chim., [2] 41, 379 (1884). 281 Roux, Ann. chim., [6] 12, 289 (1887). 282 Rozycki, Ber.., 32, 2428 (1899). 283 Sachs and Weigert, Ber., 40, 4360 (1907); Constam and Goldschmidt, Ber., 21, 1157 (1888). 284 Savard and Hosogilt, Reo.facuUe sci. univ. Istanbul, [N.S.] 3, 27 (1937) [C.A., 32,3348 (1938)]. 286 Schmidlin and Massini, Ber., 42, 2390 (1909). 286 Schorigin, Ber., 60, 2373 (1927). 287 Schramm, Monatsh., 9, 613 (1888). 288 Schramm, Ber., 26, 1706 (1893). 289 Schrauth and Quasebarth, Ber., 57, 854 (1924). 290 Schreiner, J. prakt. Chem., [2] 81, 557 (1910). 291 Schreiner, J. prakt.'Chem., [2] 82, 294 (1910). 292 Schroeter, Ann., 48, 199 (1919). 293 Semptowski, Ber., 22, 2662 (1889). 294 Senff, Ann., 220, 225 (1883). 296 Senkowski, Ber., 23, 2413 (1890). 296 Senkowski, Ber., 24, 2974 (1891). 297 Sharma and Dutt, J. Indian Chem. Soc, 12, 774 (1935). 298 Shoesmith and McGechen, J. Chem. Soc, 1930, 2231. v 299 Shorigin, Ber., 61, 2516 (1928). 300 Silva, Bull, soc chim., [2] 38, 529 (1877). 301 Silva, Bull. soc. chim., [2] 29, 193 (1878). 302 Silva, Bull. soc. chim., [2] 43, 317 (1885). 808 Simons and Archer, J. Am. Chem. Soc, 60^2952 (1938). 804 Simons and Archer, /. Am. Chem. Soc, 60,'2953 (1938). 306 Simons and Archer, J. Am. Chem. Soc, 61, 1521 (1939). 306 Simons and Archer, J. Am. Chem. Soc, 62, 1623 (1940). 307 Simons, Archer, and Adams, J. Am. Chem. Soc, 60, 2955 (1938). 82 ORGANIC REACTIONS 808 Simons, Archer, and Passino, J. Am. Chem. Soc, 60, 2956 (1938). 809 Simons, Archer, and Randall, J. Am. Chem. Soc., 61, 1821 (1939). 810 Slanina, Sowa, and Nieuwland, J. Am. Chem. Soc, 57, 1547 (1935). 311 Smith, J. Am. Chem. Soc, 59, 899 (1937). 812 Smith and Guss, J. Am. Chem. Soc, 62, 2625 (1940). 313 Smith and Rodden, J. Am. Chem. Soc, 59, 2353 (1937).^ 814 Sowa, Hennion, and Nieuwland, /. Am. Chem. Soc, 57,^09 (1935). 816 Spiegler and Tinker, J. Am. Chem. Soc, 61, 1002 (1939). 316 Stadnikov and Kashtanov, J. Russ. Phys. Chem. Soc, 60, 1117 (1928) [C. A., 23, 2170 (1929)]. 817 Stadnikov and Goldfarb, Ber., 61, 2341 (1928). 318Stahl, Ber., 23, 992 (1890). ? 819 Tcheou and Yung, Contrib. Inst. Chem., Nat. Acad. Peiping, 2, No. 8, No. 9, 127, 149 (1936) [C. A., 31, 6646 (1937)]. 820 Tsukervanik and Sidorova, J. Gen. Chem. U.S.S.R., 7, 641 (1937) [C. A., 31, 5780 (1937)]. 821 Tsukervanik and Tambovtseva, Bull. univ. Asie centrale, 22, 221 (1938) [C. A., 34, 4729 (1940)]. 322 Tsukervanik a'nd Terent'eva, J. Gen. Chem. U.S.S.R., 7, 637 (1937) [C. A., 31, 5780 (1937)]. 328 Uhlhorn, Ber., 23, 3142 (1890). 324 Ullmann and Munzhuber, Ber., 36, 407 (1903). 826 XJllmann and von Wurstemberger, Ber., 37, 77 (1904). 826Verley, Bvtt. soc chim., [3] 19, 67 (1898). 827 Vincent and Roux, BuU. soc. chim., [2] 40, 163 (1883).' 828 Vlekke, dissertation, Freiburg, p. 46, 1905. 829 Voswinkel, Ber., 21, 2829 (1888); 22, 315 (1889). 830 Walker, Ber., 5, 686 (1872). 331 Wegscheider, Monatsh., 5, 236 (1884). 832 Welsh and Drake, J. Am. Chem. Soc, 60, 58 (1938). 888 Werner and Grob, Ber., 37, 2897 (1904). 334 Wertyporoch and Firla, Ann., 500, 287 (1933). 836 Wertyporoch and Sagel, Ber., 66, 1306 (1933). 386 Willgerodt and Albert, J. praM. chem., [2] 84, 393 (1911). 837 Willgerodt and Damann, Ber., 34, 3678 (1901). 338 WiUgerodt and Rampacher, Ber., 34, 3667 (1901). 339 Wispek and Zuber, Ann., 218, 379 (1883). 840 Wispek and Zuber, Bull, soc chim., [2] 43, 588 (1885). 341 Wunderly, Sowa, and Nieuwland, J. Am. Chem. Soc, 58, 1007 (1936). 842 Wuyts, Bull, soc chim. Belg., 26, 308 (1912). 848 Zincke, Ann., 159, 374 (1871); Ber., 6, 119 (1873). 844 Zincke, Ann., 161, 93 (1872); Ber., 6, 906 (1873). 846 Zincke, Ber., 5, 799 (1872). 846Zonew, J. Russ. Phys. Chem. Soc, 48, 550 (1916) [Chem. Zentr., I, 1497 (1923)]. 847 Diuguid, J. Am. Chem. Soc, 63, 3527 (1941). 848 Snyder, Adams, and Mclntosh, J. Am. Chem. Soc, 63, 3280 (1941). 849 Kleene and Wheland, J. Am. Chem. Soc, 63, 3321 (1941). 860 Co*rson and Ipatieff, J. Am. Chem. Soc, 59, 645 (1937). 861 Burwell and Archer, J. Am. Chem. Soc, 64, 1032 (1942). CHAPTER 2 THE WILLGERODT REACTION MARVIN CARMACK University of Pennsylvania AND M. A. SPIELMAN Abbott Laboratories CONTENTS PAGE INTRODUCTION 84 MECHANISM 6 SCOPE, LIMITATIONS, AND SIDE REACTIONS 89 By-Products 91 EXPERIMENTAL CONDITIONS AND REAGENTS 91 Ammonium Polysulfide ? 1 Added Organic Solvents 93 The Kindler Modification with Amines and Sulfur 93 Apparatus ". 3 Time and Temperature 4 Isolation of Product 94 EXPERIMENTAL PROCEDURES .95 Phenylacetamide from Acetophenone (Use of Ammonium Polysulfide) . . 95 1-Pyrenylacetamide * and 1-Pyreny lace tic Acid from 1-Acetylpyrene (Use of Ammonium Polysulfide in Dioxane-Water) 96 Methyl 0-(6-Tetralyl)propionate from 6-Propionyltetrah'n (Use of Ammo- nium Polysulfide in Dioxane-Water) 6 Phenylacetamide from Acetophenone (Use of Sulfur, Aqueous Ammonia, and Pyridine) 97 Phenylacetamide from Styrene (Use of Sulfur, Aqueous Ammonia, and Pyridine) 7 2-Naphthylacetothiomorphotide and 2-Naphthylacetic Acid from 2-Acetyl- naphthalene (Use of Morpholine and Sulfur; Kindler Procedure) .... 97 EXAMPLES OF THE WILLGERODT AND KINDLER REACTIONS 99 Table I. Examples of the Willgerodt Reaction 99 Table II. Examples of the Kindler Modification (Sulfur, and Amine) . . . 104 * Numbering of nuclei follows current practice of Chemical Abstracts. In this ex- ample, as well as in several others, the numbering differs from common usage. 83 84 ORGANIC REACTIONS , INTRODUCTION The name of Conrad Willgerodt is associated with a group of closely related reactions which have as a common feature the conversion of a carbonyl compound into an amide with the same number of carbon atoms. The original process involved the reaction of an appropriately substituted alkyl aryl ketone with an aqueous solution of yellow ammo- nium polysulfide at an elevated temperature to form an aryl-substituted aliphatic acid amide, together with a smaller amount of the correspond- ing ammonium salt of the carboxylic acid. An example is the conversion of acetophenone into phenylacetamide and ammonium phenylacetate.1 C6HBCOCH3 CN^^B*> C6H6CH2CONH2 + (C6HBCH2COONH4) The net result of the reaction is the reduction of the carbonyl group and the oxidation of the terminal methyl group. In the first work2 on the reaction 1-acetylnaphthalene was heated with ammonium polysulfide solution in a sealed tube at 210-230° for three or four days to form a substance later characterized 3 as 1-naphthyl- acetamide. Other methyl ketones such as acetophenone1 and 2,4-di- methylacetophenone 2 were found to behave in a similar manner. In each case a mixture of amide and acid salt was obtained. Extension of the reaction to ethyl, n-propy.1, and n-butyl aryl ketones led to the re- markable finding that the terminal methyl is always converted into a carbonamide group, even though it may be several carbon atoms re- moved from the original carbonyl group. Thus propiophenone gives /3- phenylpropionamide,1 butyrophenone yields 7-phenylbutyramide,1 and n-butyl p-tolyl ketone yields 5-p-tolylvaleramide.4 The publications of 3 ¡ª C6H6CH2CH2C¡ªNH2>° / CeHsC¡ªCH2CH2CH3 (j>-)CH3C6H4C¡ªCH2CH2CH2CH3 -? (p-)CH3C6H4CH2CH2CH2CH2C¡ªNH2 Willgerodt and collaborators extending over a period of nearly twenty- five years l~1 described efforts to develop the procedure ipto a useful syn- 1 Willgerodt and Merk, J. prakt. Chem., [2] 80, 192 (1909). 2 Willgerodt, Ber., 20, 2467 (1887). 3 Willgerodt, Ber., 21, 534 (1888). 4 Willgerodt and Hambrecht, /. prakt. Chem., [2] 81, 74 (1910). 5 Willgerodt, J. prakt. Chem., [2] 80, 183 (1909). 6 Willgerodt and Scholtz, J. prakt. Chem., [2] 81, 382 (1910). 7 Willgerodt and Albert, J. prakt. Chem., [2] 84, 387 (1911). THE WILLGERODT REACTION 85 thetic tool. Approximately forty ketones were investigated, but the final procedures did not differ greatly from those originally described, and the fundamental chemistry of the process was not elucidated. Although the Willgerodt reaction was known through standard refer- ences,8 it was used by only a few workers?.10. ?. 12 and remained a chem- ical curiosity until increasing interest in complex polynuclear systems led to a search for additional methods of synthesizing aryl-substituted aliphatic acids of unequivocal structure. Interest in the reaction revived after its application to the preparation of 3-acenaphthylacetic acid from 3-acetylacenaphthene.11 The requisite temperature was lowered to 160° by the use of purified dioxane to increase the mutual solubility of the ketone and aqueous ammonium polysulfide, and the yield of acid com- pared favorably with that realized by an alternative synthesis involving the Arndt-Eistert reaction. The Willgerodt reaction in the presence of dioxane has been used by several investigators 13~21 in the synthesis of a variety of aryl-substituted aliphatic acids and amides. The Kindler variation,22'23 which promises to be more useful than the original Willgerodt procedure, consists in heating the ketone with ap- proximately equimolecular amounts of sulfur and a dry amine instead of aqueous ammonium polysulfide. A thioamide is formed as the principal product and on hydrolysis with acid or alkali affords the carboxylic acid, usually in good yield. Generally a secondary aliphatic amine but some- times a primary amine or even anhydrous ammonia M is used; the devel- opment of a method for the electrolytic reduction of the thioamides to amines 26 extended the usefulness of the reaction as a new route to the synthesis of many important nitrogen bases. Early descriptions of this 8 Houben, Die Meihoden der organischen Chemie, 3d ed., Vol. Ill, pp. 867, 872, Georg Thieme, Leipzig, 1930. 9 Weitzenbock and Lieb, Monatsh., 33, 556, 563 (1912). 10 Mosettig and van de Kamp, J. Am. Chem. Soc, 55, 3444 (1933). 11 Fieser and Kilmer, /. Am. Chem. Soc, 62, 1354 (1940). 12 Smith and MacMullen, J. Am. Chem. Soc., 58, 633 (1936). 13 Bachmann and Sheehan, J. Am. Chem. Soc., 62, 2688 (1940). " Bachmann and Carmack, J. Am. Chem. Soc., 63, 2494 (1941/. 15 Hartmann and Bosshard, Helv. Chim. Ada, 24, 28E (1941). 16 Bachmann and Cortes, J. Am. Cfiem. Soc., 65, 1329 (1943). 17 Bachmann and Cronyn, J. Org. Chem., 8, 461 (1943). 18 (o) Arnold and Barnes, /. Am. Chem. Soc, 65, 2395 (1943); (6) R. T. Arnold, private communication. 19 Riegel, Gold, and Kubico, J. Am. Chem. Soc, 65, 1775 (1943). 20 (o) DeTar and Carmack, J. Am. Chem. Soc, 68, 2025 (1946); (b) Carmack and De- Tar, J. Am. Chem. Soc, 68, 2029 (1946). 21Cavalieri, Pattison and Carmack, J.'Am. Chem. Soc, 67, 1783 fl945) 22 Kindler, Ann., 431, 193, 222 (1923). 23 Kindler, Arch. Pharm., 265, 389 (1927). 24 Kindler, Ger. pat., 405,675; Chem. Zentr., 96, I, 1529 (1925). 26 Kindler and Peschke, Arch. Pharm., 270, 340 (1932). 86 ORGANIC REACTIONS procedure were placed inconspicuously in communications dealing with other subjects,22"26 and the possibilities of the process have been appreci- ated only recently.27 ArCOCH3 ¡ª¡ª^¡ª> ArCH2C ¡ª^? ArCH2COOH 8 N(CH3)2 ArCH2CH2N(CH3)2 Morpholine is well suited to the Kindler version of the Willgerodt reac- tion;28 it is cheap, and its boiling point (128°) makes possible the use of open apparatus in place of an autoclave or bomb tube. The Willgerodt reaction has been applied to a number of completely aliphatic ketones.21 For example, pinacolone is converted into i-butyl- acetamide and 2-heptanone into heptanamide. (CH3)3CCOCH3 -? (CH3)3CCH2CONH2 CH3(CH2)4COCH3 -? CH3(CH2)6CONH2 Aryl-substituted olefins and acetylenes are transformed into amides under the conditions of both the Willgerodt and Kindler procedures.20 C6H6CH2CONH2 C6H5CH=CH2 ' C6H6CH2CH2CONH2 MECHANISM The mechanism of the Willgerodt reaction is not clear. The possibility that the ketone first undergoes reduction at the carbonyl group to form a hydrocarbon which is subsequently oxidized at the terminal methyl group was rejected when it was found that an alkyl substituent such as the ethyl group is unaffected under the conditions that bring about the reaction with ketones.1'3 Willgerodt considered it unlikely that the oxi- dation of the terminal methyl group of the ketone could precede the final 26 Kindler and Peschke, Arch. Pharm., 272, 236 (1934). 27 Kindler and Li, Ber., 74, 321 (1941). 28 Schwenk and Bloch, J. Am. Chem. Soe., 64, 3051 (1942). THE WILLGERODT REACTION 87 reductive step in which the carbonyl group would be converted to a methylene unit, since there is no evidence for intermediate keto acids and since the latter cannot be converted into amides by the ammonium poly- sulfide reagent.3 He concluded that the oxygen atom of the alkyl aryl ketone can, in some unknown way, wander to the end of the chain, or, in effect, exchange place with two hydrogen atoms of the methyl group to form an aldehyde isomeric with the ketone. The aldehyde could then react with sulfur and ammonia to produce the amide and hydrogen sul- fide; indeed, aldehydes are known to yield amides under these conditions. Kindler22 suggested that the reaction may proceed by a migration of the aryl group to the carbon atom alpha to the carbonyl group; the origi- nal carbonyl group would thus become the thioamide function of the final product. To accommodate ketones higher than acetophenone, e.g., propiophenone, he postulated "" migration of the phenyl group to the end of the chain, two or more atoms removed from the original carbonyl group. First, he stated, there is the preliminary formation of the hydramine (I), which adds sulfur to give an amine sulfide (II). This is dehydrated to III, S ? R2NCCH2CH2Ar IV and then the final thioamide is formed in a rearrangement which results in the simultaneous migration of the sulfur atom, the aryl radical, and a terminal hydrogen-atom. However, evidence against this mechanism is recorded in Willgerodt's observation that isovalerophenone gives (after hydrolysis) a-methyl-7-phenylbutyric acid, VI. According to Kindler's hypothesis the ^-methyl isomer VII should result. That VI is the prod- uct seems highly probable.11 CH3 NR2 ArCCH2CH3 OH I S=NR2 -> ArCCH2CH3 ¡ª OH 11 w S=NR, ? Ar C=CHCH2H III C6HBCOCH2CH(CH3)2 - v vi CH3 'HOOCCH2CHCH2C6H6 VII On the basis of three facts¡ªthat no change in the carbon skeleton oc- curs during the reaction; that all members of a family of isomeric ali- phatic carbonyl compounds, differing from one another only in the position of the oxygen atom, form the same final product; and that un- saturated hydrocarbons can undergo reactions very similar to the 88 ORGANIC REACTIONS Willgerodt and Kindler reactions of ketones¡ªCarmack and DeTar20 have argued that there must be one fundamental mechanism involving the preliminary formation of a labile intermediate which has an unsatu- rated carbon-carbon bond in the side chain. They have postulated a series of steps involving the stepwise addition, elimination, and readdi- tion of the elements of simple molecules such as ammonia, amines, sulfur, water, or hydrogen sulfide, the net result being the migration of the func- tional group along the chain. Irreversible oxidation by the action of sul- fur when the function reaches the terminal position produces a thioamide. The type of process is illustrated schematically as follows: OH R'COCH2CH8 + R2NH ^ R'CCH2CH3 ^ NR2 R'C=CHCH3 ^± R'O=CCH3 ^ R'CH=CCH3 NR2 NR2 R'CH2CH=CH ^ R'CH2C=CH ;=± R'CH2C=CH2 NR2 \ NR2 R = alkyl or H. R'CH2CH2C=S NR2 That a carbonamide rather than a thioamide is isolated in the Willge- rodt reaction with aqueous ammonia does not constitute an argument against the above scheme, for hot aqueous ammonia29 is known to con- vert thioamides to carbonamides. The isomerization of straight-chain acetylenic compounds (with and without aromatic substituents) to products having the acetylene function in the terminal position is known to take place in the presence of sodium amide.30'31 The assumption that such unsaturated substances are intermediates in the Willgerodt reaction offers an explanation of the appearance of certain by-products. Tetra- hydronaphthoic acid, isolated in small amounts from the reaction of ethyl 6-tetralyl ketone with morpholine and sulfur,32 may arise from an oxidative attack by sulfur on an unsaturated intermediate. The pres- ence of traces of thiophenes in the reaction mixtures is explicable when it "Bernthsen, Ann., 184, 297 (1877). " Bourguel, Compt. rend., 179,686 (1925), 192,686 (1931); Ann. chim., (10) 3,207 1925). 11 Vaughn, J. Am. Chem. Soc., 55, 3455 (1933). ? Arnold, Schultz, and Klug, J. Am. Chem. Soc., 66, 1606 (1944). THE WILLGERODT REACTION 89 is considered that olefins and sulfur react at elevated temperatures to give hydrogen sulfide and thiophenes33 and that acetylenes also give thiophenes but with little evolution of hydrogen sulfide. Styrene and phenylacetylene both undergo transformation to substituted thio- phenes.20 SCOPE, LIMITATIONS, AND SIDE REACTIONS Application of the reaction under the conditions originally specified by Willgerodt usually results in yields of 20-50% of arylacetic acids or amides from acetophenone and substituted acetophenones. The modi- fied procedure in which a solvent is used gives somewhat higher yields, and when applied to the aceto derivatives of naphthalene and especially of phenanthrene, acenaphthene, and pyrene affords yields of 57-92%. When the earlier reaction conditions were applied to the higher homologs of acetophenone, such as propiophenone or butyrophenone, more by- products resulted and the yields of acids dropped to 7^0%. The three isomers, propiophenone, phenylacetone, and hydrocinnamaldehyde, all react to form /3-phenylpropionamide.20 The reaction appears to be un- successful for homologs higher than amyl, although the earlier experi- mentation was very limited and the improved procedures have not been investigated. It should be kept in mind that reactive functions such as amino, nitro, and formyl groups may undergo oxidation, reduction, or condensation under conditions of the Willgerodt reaction, hence their presence as sub- stituents on the starting compounds may lead to various side reactions. Alkyl groupi, alkoxyls, halogens (if inert) and similar unreactive groups appear to have no effect on the course of the reaction. Ketones with branched chains have been reported to undergo reaction in low yields (0.5-20%)l in a manner analogous to the straight-chain ketones without rearrangement of the carbon skeleton. Isopropyl phenyl ketone and isobutyl phenyl ketone may be cited as examples. C6H6COCH(CH3)2 -> Ce CH3 C6H6COCHi!CH(CH3)2 -> C6H6CH2CH2CHCONH2 CH3 However, subsequent investigators11'14'34 have reported experiments with branched-chain ketones in which little or no amide was obtained. 33 Baumann and Fromm, Ber., 28, 891 (1895). M Carmack, doctoral dissertation, University of Michigan, 1940. 90 ORGANIC REACTIONS Derivatives of pyridine have been studied, particularly 3-acetylpyri- dine "?36 and other heterocyclic compounds such as 5-acetyl-l-phenyl- 4-methylpyrazole and 8-acetylquinoline.35 The yield of methyl 3lpyri- dylacetate from 3-acetylpyridine was about 70%. The Willgerodt reaction is apparently not limited to aromatic aliphatic ketones. A few completely aliphatic ketones have been found to undergo the reaction, though in general the yields are lower. Pinacolone reacts with ammonium polysulfide solution containing dioxane and a large excess of sulfur to form ^butylacetamide in 58% yield. Methyl cyclo- hexyl ketone yields 40% of cyclohexylacetamide, and ethyl cyclohexyl ketone 27% of /3-cyclohexylpropionamide. The four isomeric carbonyl compounds, heptanal, 2-heptanone, 3-heptanone, and 4-heptanone, all give heptanamide in varying yields, the highest yields being obtained from the aldehyde (50%) and the methyl ketone (38%). CH3(CH2)6CHO CH3(CH2)4COCH3 -+ CH 3(CH2)6CONH2CH 3(CH2)3COCH2CH3 - CH3(CH2) 2COCH2CH2CH3 The conversion of unsaturated compounds into acids has been studied in a very limited way. The transformation of phenylacetylene into phenylacetamide proceeds under comparable conditions and in about the same yield as the conversion of acetophenone into phenylacetamide. From styrene the yield is somewhat less. 1-Phenylpropyne and 1- phenylpropene give /3-phenylpropionamide in good yields. Phenylacety- lene and styrene both produce phenylacetothiomorpholide when treated with morpholine and Sulfur. bCeHsC^CH ] HN(CH2CH2)2O + s II> C 6H6CH2CN(CH2CH2)2OC 6HBCH=CH2J The Kindler procedure has not been applied extensively. It report- edly gives somewhat higher yields with certain compounds than the Willgerodt procedure. However, compounds containing active meth- ylene groups, such as 3-acetylacenaphthene or 2-acetylfluorene, do not react satisfactorily,36 though good yields of amides result from the same ketones by reaction with ammonium polysulfide in dioxane-water solu- tion.11' 13 Only one example of an ethyl aryl ketone in the morpholine- sulfur procedure is reported;32 yields of 30-58% have been obtained with ethyl aryl ketones, dimethylamine, and sulfur.23' Ml w "Brit, pat., 558,774; Brit. C. A., BII, 102 (1944). 36 Zaugg and Rapala, private communication. THE WILLGERODT REACTION 91 It is of interest to note the behavior of molecules containing other functional groups. Carbinols form amides at somewhat higher tempera- tures than the corresponding ketones, probably by way of unsaturated intermediates. Aldehydes are converted into the corresponding carbox- ylic acid amides when heated with aqueous ammonium polysulfide,3'20 and they form substituted thioamides under conditions of the Kindler procedure. Aldimines 22- M likewise are converted to acid derivatives. Two imines derived from methyl ketones and methylamine are reported to react with sulfur to form N-methylarylthioacetamides in a manner analogous to the reaction of methyl ketones in the presence of the amine. By-ProductS. The commonest by-products accompanying the amides prepared from ketones are the corresponding hydrocarbons.8- n RCOCH3 -? RCH2CH3 A high concentration of hydrogen sulfide probably favors this side reac- tion. Methyl aryl ketones in the Willgerodt reaction produce minor amounts of thiophenes, probably mixtures of 2,4- and 2,5-diarylthiophenes.20 n ^ Ar\ ^ S S Substituted thiophenes of this type constitute the principal products isolated when colorless ammonium sulfide is used in place of ammonium polysulfide.1' u Side chains may be degraded, as in the example already cited in which 5,6,7,8-tetrahydro-2-naphthoic acid appears as a by-product in the reac- tion of ethyl 6-tetralyl ketone with morpholine and sulfur.32 Ammonium polysulfide and long-chain alkyl phenyl ketones give some benzoic acid.1 Ethyl 9-anthryl ketone,20 on the other hand, produces anthracene in 85% yield, possibly owing to the great lability of a substituent in the 9- position of anthracene. EXPERIMENTAL CONDITIONS AND REAGENTS Ammonium Polysulfide. Most of the published procedures for the Willgerodt reaction specify the use of aqueous ammonium polysulfide re- agent prepared by "saturating" concentrated aqueous ammonia with hydrogen sulfide and dissolving in the solution 10% by weight of sulfur to form a clear, deep red reagent containing the complex polysulfide. In nearly all experiments 5 cc. of such a solution has been used for*each gram of ketone. With aliphatic ketones *>?21 higher yields are obtained 92 ORGANIC REACTIONS when the proportion of sulfur is increased to as much as 10 to 20 gram atoms for each mole of ketone. It has been demonstrated M that "saturation" of aqueous ammonia by bubbling gaseous hydrogen sulfide through the liquid is a slow process and may produce almost any concentration of hydrogen sulfide up to 7 moles per liter; the concentration of ammonia also changes during the process, so that the composition of the reagent may vary widely, depend- ing upon the conditions. To ensure reproducibility of results the actual composition of the reagent should be determined by analysis. Ammonia can be titrated directly with acid; hydrogen sulfide (or its equivalent) can be determined iodometrically; and the sulfur present in free elemen- tary state or combined as polysulfide is known from the weight of sulfur used in the preparation of the reagent. In spite of the implications of most published procedures, high concen- trations of hydrogen sulfide are not desirable, except perhaps with com- pletely aliphatic compounds. It is known that ammonium sulfide can -cause reduction of carbonyl compounds.37 A convenient and reproducible method of preparing a satisfactory polysulfide reagent consists in suspending finely powdered sulfur in about ten times its weight of concentrated aqueous ammonia (15 M) and pass- ing a stream of hydrogen sulfide through the agitated suspension until all the sulfur dissolves. This process requires only a short time and produces a reagent containing approximately 0.7 mole of hydrogen sul- fide (or the equivalent) per liter. Highest yields are obtained from some ketones, e.g., acetophenone,20 with a reagent to which no hydrogen sulfide is added; the reagent con- sists of a solution or suspension of flowers of sulfur in a mixture of concen- trated aqueous ammonia and a solvent such as pyridine or dioxane. Better results are obtained with aliphatic ketones and some ketones de- rived from complex polycyclic hydrocarbons when a moderate concentra- tion of hydrogen sulfide is present initially in the reagent. When hydro- gen sulfide is not added it probably is formed as a reaction product and is present during most of the reaction period. Attempts to use colorless ammonium sulfide (no added free sulfur) have been unsuccessful,6 as the yields of amide are always lower than with the polysulfide reagent, and mixtures of by-products such as diaryl- thiophenes and hydrocarbons predominate among the products isolated. The use of sodium polysulfide in place of ammonium polysulfide 1 in the reaction of acetophenone at 220° results in the formation of only a very small amount of sodium phenylacetate contaminated with sodium beriloate. * Baumann and Fromm, Ber., 28, 907 (1895). THE WILLGERODT REACTION 93 Added Organic Solvents. The addition of 4 volumes of dioxane to every 5 volumes of ammonium polysulfide reagent " has the advantage of allowing the reaction to proceed at a much lower temperature than would be possible without the organic solvent. Side reactions, in partic- ular the formation of tarry material, are minimized, so that higher yields of amide are obtained; the amide is purer, and less hydrolysis of the amide to ammonium salt takes place. Pyridine has been found20 to be similarly effective in making possible a lower temperature of reaction. Since neither dioxane nor pyridine has been shown to take part in the Willgerodt reaction, it is presumed that their beneficial influence is due to their solvent properties, which increase tiie mutual solubility of the immiscible ketones and the" polysulfide reagent. The choice of dioxane or pyridine in a given case is governed to some extent by the type of procedure to be followed in isolating the product. The amides often precipitate directly from dioxane-water solutions upon cooling, and can be isolated by direct filtration in a state of fair purity, but many amides are soluble in pyridine-water mixtures. The Kindler Modification with Amines and Sulfur. The theoretical molecular proportions of reactants in Kindler's procedure are 1 mole of amine and 1 gram atom of sulfur for each mole of ketone. The propor- tions which have been used vary from almost the theoretical to ratios of 1.5/1.5/1 for amine, sulfur, and ketone.23' *? ?*? ?? ?? ? The amines which have been used most frequently are dimethylamine and morpholine, although methylamine,24 piperidine,23'28 and anhydrous ammonia u have been mentioned. Apparatus. All reactions with aqueous reagents must be carried out in closed systems capable of withstanding pressure. For this reason most reported experiments have been limited to runs with small amounts, usually 1 to 4 g. of ketone, in sealed glass tubes. Most procedures at present call for temperatures below 180°; at temperatures of 160-180° the pressures developed in sealed tubes seldom appear to be dangerously high; it has been estimated 6 that aS 230° the pressure may reach as high a value as 41 atmospheres. When the tubes are opened there is little residual pressure, and sometimes air is drawn into the tube. However, it is advisable to observe the precautions usual in such work. The limitations placed upon the scale of preparative reactions in sealed glass tubes have led to attempts to carry out the Willgerodt reaction in a lead-lined autoclave,6 with disappointing results. Unfortunately, in these experiments a reagent containing only colorless ammonium sulfide in- stead of ammonium polysulfide was used. The colorless reagent is known 38 M. S. Newman, private communication; Newman. J. Org. Chem., 9, 521 (1944). 94 ORGANIC REACTIONS to give poor results even in small-scale runs. Less satisfactory results have been reported for a reaction carried out in an autoclave than for the same reaction carried out on a smaller scale in a sealed glass tube.11 Excellent results have been obtained when the Willgerodt reaction (dioxane present) was carried out in a simple autoclave consisting of a short length of 2-in. iron pipe threaded on both ends and fitted with iron screw caps.18 The caps are sealed on the tube with pipe cement, and the tube with its contents is heated in a liquid metal bath. There is no reason to believe that the Willgerodt reaction could not be carried out on a still larger scale in suitable equipment. Kindler23> ** has described a special apparatus for carrying out the re- action of ketones, sulfur, and volatile aliphatic amines. When an amine is used which boils at approximately the desired temperature of reaction, no special closed apparatus is required, the reaction mixture being heated in conventional glass equipment under reflux condenser. A large-scale preparation starting with 373 g. of 2-acetylnaphthalene in a single run has been carried out (for experimental procedure see p. 97) .** Time and Temperature. Earlier experiments were usually carried out at temperatures above 200°. More recently, in runs with added dioxane, temperatures in the range 150-160° have been generally em- ployed. The time required for complete reaction is dependent upon the temperature. It appears likely, however, that the reaction periods of twelve to twenty-four hours which frequently have been used are longer than necessary, and that most reactions are complete in three to four hours at 160°. For a relatively unreactive ketone like pinacolone,21 a temperature above 200° may be required to obtain a satisfactory yield in a convenient time. The conditions in the Kindler modification with amines have been approximately the same as those in the Willgerodt reaction in aqueous solution, usually four to six hours of heating at 140- 160°; occasionally reaction times have been longer¡ªup to fifteen hours. When morpholine is employed the reaction mixture is simply heated to boiling under reflux. Information in the literature does not indicate how closely the experi- mental times and temperatures have approached the minimal values. There is reason to believe that, once the reaction to form the amide is complete, continued heating of the mixture produces little further change except for the slow hydrolysis of the amide to ammonium carboxylate salt. In the absence of specific information about optimum conditions with individual compounds, it is probably safest to err on the side of an overly long reaction period. Isolation of Product. The methods of isolating and purifying the products of the Willgerodt reaction depend upon the solubility behavior THE WILLGEEODT REACTION 95 of the products, the presence of added organic solvents, the extent of side reactions, and upon whether the amide or the free carboxylic acid is the desired final product. In general the procedures fall into two main cate- gories: (1) the amide or thioamide is isolated and purified as such; (2) the amide is hydrolyzed to the acid, which either is isolated as such or is converted into an ester that can be further purified by distillation. When the amide is insoluble in the cooled reaction mixture, as amides of high molecular weight are likely to be, it can be isolated by direct fil- tration from the reaction mixture. Often the yield can be improved by working up the nitrates for dissolved amide or for the ammonium salt resulting from hydrolysis of a portion of the amide. In working up a complete reaction mixture, or filtrates from the amide, it is advantageous to remove water, organic solvent, and as much of the volatile ammonium sulfide as possible by evaporation to dryness on a water bath or by distillation under reduced pressure; the residue contains the amide mixed with excess sulfur, small amounts of the ammonium salt of the acid, and other by-products. Separation of the amide from the sulfur is accomplished usually by extraction with a solvent such as hot water, ethanol, or carbon tetrachloride which will dissolve the amide but not the sulfur. When such a separation is not feasible, it may be neces- sary to hydrolyze the amide to the acid by heating with aqueous or ethanolic alkali or with a mineral acid. A mixture of acetic acid and con- centrated hydrochloric acid is particularly effective 14 for the hydrolysis of insoluble amides. The reaction mixture from the Kindler modification is usually taken up in ether' and washed with dilute alkali, acid, and water, after which the ether solution is dried. The residual thioamide often can be crystal- lized from ethanol or benzene-petroleum ether. When the thioamide does not crystallize, it is purified by distillation at low pressure or is hydrolyzed to a carboxylic acid with either mineral acid or alkali. The carboxylic acid can then be separated from neutral by-products and purified by standard methods. EXPERIMENTAL PROCEDURES Phenylacetamide from Acetophenone (Use of Ammonium Polysul- fide).1 An ammonium sulfide solution is prepared by passing hydrogen sulfide into concentrated aqueous ammonia until the solution is sat- urated. A mixture of 2 g. of acetophenone with 10 g. of the colorless ammonium sulfide solution and 1 g. of sulfur is heated in a closed tube for four hours at 200-220°. After the reaction mixture has cooled, it is ^reated with sufficient hydrochloric acid to decompose the ammonium 96 ORGANIC REACTIONS . polysulfide completely, refluxed with carbon black in a large volume of water to decolorize the solution and coagulate the sulfur, and then fil- tered. The clear, hot filtrate is made alkaline with sodium carbonate and when cool is repeatedly extracted with ether to remove phenylacet- amide. When the amide has been thoroughly extracted, the solution is made strongly acid with hydrochloric acid and is again thoroughly ex- tracted with ether to remove phenylacetic acid. On distillation of the ether the two groups of combined extracts give, respectively, 50% of phenylacetamide, m.p. 155°, and 13.5% of phenylacetic acid, m.p. 76°. 1-Pyrenylacetamide and 1-Pyrenylacetic Acid from 1-Acetylpyrene (Use of Ammonium Polysulfide in Dioxane-Water).14' M The reagent is prepared by suspending 1 g. of sulfur in 10 cc. of concentrated aqueous ammonia and passing hydrogen sulfide gas through the mixture until the sulfur has dissolved to form a clear, deep red solution. To this solution are added 8 cc. of dioxane and 2 g. of 1-acetylpyrene. The mixture is sealed in a glass bomb tube and heated at 160-165° for twelve hours. When the tube has cooled to room temperature, a process which requires eight hours in the heavy furnace, it is foimd to be filled with large, golden- brown prisms, which are filtered and washed with a solution of colorless ammonium sulfide in dioxane-water. The product is practically pure 1- pyrenylacetamide; yield 1.95 g. (92%); m.p. 250-252° (cor.). The mate- rial purified by sublimation at low pressure and by several recrystalliza- tions from acetic acid-chlorobenzene forms colorless needles melting at 252-253° (cor.) in an evacuated capillary tube. A total of 13.7 g. of crude amide obtained directly from several runs as described above can be hydrolyzed to the free acid by the following pro- cedure: The solid amide is dissolved in 200 cc. of glacial acetic acid in a 1-1. round-bottomed flask. Concentrated hydrochloric acid (100 cc.) is cautiously added to the boiling solution through the reflux condenser. The solution, containing a little suspended material, is refluxed for seventy-five minutes, after which the addition (through the condenser) of 100 cc. of concentrated hydrochloric acid causes the precipitation of crystals of the acid. After the mixture has been chilled for several hours, 13.4 g. of crude acid (98%) is obtained, by filtration; m.p. 223.5-225° (cor.). The acid is purified by treatment of the aqueous solution in dilute potassium hydroxide with Norit and Filter-Cel, followed by precipitation of the free acid and recrystallization from chlorobenzene. The first crop of crystalline acid amounts to 12.3 g. (90%); m.p. 227.5-228° (cor.) in an evacuated tube. Methyl p-(6-Tetralyl)propionate from 6-Propionyltetralin18 (Use of Ammonium Polysulfide in Dioxane-Water). A mixture of 20 g. of 6-pro- pionyltetralin, 80 cc. of dioxane, and 100 cc. of concentrated aqueous ammonia saturated with hydrogen sulfide and containing 10 g. of sulfur THE WILLGERODT REACTION 97 is heated in an iron tube 2 in. in diameter fitted with an iron screw cap and having a capacity of 350 cc. The screw cap is sealed with pipe ce- ment, and the tube is heated at 165° for twenty-four hours in a Wood's metal bath. When the tube has cooled it is opened, and the product is washed out with methanol. The solvents are removed by evaporation on the steam bath, and the residue is hydrolyzed by heating with 150 cc. of 25% aqueous potassium hydroxide until the odor of ammonia is no longer evident. The alkaline solution is treated with Norit, filtered, and acidified. The crude solid acid is esterified by refluxing for four hours with 200 cc. of methanol and 3 cc. of concentrated sulfuric acid. The reaction mixture is poured into 800 cc. of water and extracted with ether. The ether extract is washed with sodium bicarbonate solution and water, and the ether is removed by distillation. Distillation of the residue gives 15.5 g. (67%) of the methyl ester of /3-(6-tetralyl)propionic acid, boiling at 165-168°/12 mm. A portion of the above-mentioned crude acid after recrystallization melts at 81.5-82.5°. Phenylacetamide from Acetophenone (Use of Sulfur, Aqueous Ammonia, and Pyridine).20 A mixture of 25 g. of acetophenone, 50 cc. of concentrated (15 M) aqueous ammonia, 37.5 g. of sulfur, and 30 cc. of pyridine is heated in a sealed glass tube at 150° for one hour and at 163° for tlyee and one-half hours (heating at 165° for four hours is equally effective). The tube is cooled and opened, the contents removed, and the mixture evaporated to dryness on a water bath. The residue is extracted with approximately 500 cc. of boiling water in several portions. From the filtrate, upon cooling, 20.0 g. of phenylacetamide, m.p. 156- 158° (cor.), separates. Concentration of the filtrate affords 2.7 g. of additional amide. The oily residue from evaporation of the filtrate is washed with ether, whereupon 0.32 g. of amide separates, and from the ether layer 1.2 g. of phenylacetic acid is isolated. The acid melts at 76.3-77.3° (cor.) after recrystallization. The total yield of amide is 23.0 g. (82%), and the combined yield of amide and acid is 86%. Phenylacetamide from Styrene (Use of Sulfur, Aqueous Ammonia, and Pyridine).20 In a sealed glass tube 21.7 g. of styrene (99.5% mate- rial) is heated for four hours at 165° with the same amounts of reagents as described in the previous experiment for acetophenone; two crops of phenylacetamide are obtained, amounting to 16.1 g. (57%) of colorless plates; m.p. 158.6-160.1° (cor.). From the filtrate a second crop of 2.0 g. of crystalline phenylacetamide is obtained. This fraction contains some phenylacetic acid. The total yield of acid and amide is 64%. 2-Naphthylacetothiomorpholide and 2-Naphthylacetic Acid from 2-Acetylnaphthalene (Use of Morpholine and Sulfur; Kindler Pro- cedure).38 A mixture of 373 g. (2.2 moles) of 2-acetylnaphthalene, 105 g. (3.3 moles) of sulfur, and 290 g. (3.3 moles) of morpholine is cautiously 98 ORGANIC REACTIONS heated (in the hood) in an Erlenmeyer flask fitted with a ground-in reflux condenser. The first heating has to be moderated to prevent froth- ing due to evolution of hydrogen sulfide. After one hour the mixture is heated to vigorous refluxing, which is continued for ten to fifteen hours. The hot reaction mixture, which has separated into two layers, is poured into 1200 cc. of warm ethanol and left to crystallize. The crystals are collected and liberally washed with cold ethanol. The 2-naphthylaceto- thiomorpholide at this stage is pure enough for hydrolysis; yield 534 g. (90%); m.p. 102-108°. When only theoretical amounts of sulfur and morpholine are used the yield varies from 53% to 65%. A mixture of 388 g. (1.43 moles) of the thiomorpholide, 800 cc. of acetic acid, 120 cc. of concentrated sulfuric acid, and 180 cc. of water is brought carefully to the boiling point, then refluxed for five hours. The solution is decanted from a little tarry material into 6 1. of water and left overnight. The solid acid is removed by filtration and washed well with water. It is dissolved in aqueous alkali, filtered, and reprecipitated with hydrochloric acid. The yield at this step is 225 g. (85% based on the crude amide). The product has a slight purple cast but has a satis- factory melting point, 137-140°. Recrystallization from benzene raises the melting point to 142-143°. The overall yield of pure acid from the ketone is 76%. Note added in proof. After this chapter had gone to press two papers by King and McMillan relating to the Willgerodt reaction, J. Am. Chem. Soc., 68, 525, 632 (1946), described their independent observation - that olefins are converted into carbonamides under the conditions of the Willgerodt reaction and postulated the following sequence of steps to account for the reaction of ketones: ketone ¡ª> thioketone ¡ª> mer- captan ¡ª> olefin ¡ª> isomercaptan ¡ª? thioaldehyde ¡ª* dithioacid ¡ª> car- boxylic acid ¡ª? carbonamide. According to this picture the reagent functions first as a reducing agent, then subsequently as an oxidizing agent. The labile functional units are assumed to be thiol groups. THE WILLGERODT REACTION 99 EXAMPLES OF THE WILLGERODT AND KINDLER REACTIONS TABLE I EXAMPLES OF THE WILLGERODT REACTION (Aqueous Ammonia) Types of procedure are abbreviated as follows: A. Ammonium polysulfide in water (original WiUgerodt). B. Colorless ammonium sulfide in water. C. Ammonium polysulfide in dioxane-water. D. Ammonium hydroxide, sulfur, and pyridine-water. Methyl Aryl Ketones Ketone Formula C7H7NO C8H8O C9H9BHI) C9H9C1O C9H10O C10H12O C11H14O C12H10O Ci2Hi2N2O Ci2HuO CMHUO Aryl Group 3-Pyridyl Phenyl 2-Bromo-5-methylphenyl 4-Bromo-5-methylphenyl 2-Chloro-5-methylphenyl 4-Chloro-6-methylphenyl 4-Methylphenyl 2,4-Dimethylphenyl 2,5-Dimethylphenyl 2,4,5-Trimethylphenyl 2,4,6-Trimethylphenyl 1-Naphthyl 2-Naphthyl 5- (l-Phenyl-4-methylpyrazolyl) 5-Isopropyl-2-methylphenyl 3-Isopropyl-4-methylphenyl 3-Acenaphthyl 4-Biphenyl40 Pro- cedure C A B D A A A A A B A B A B A B A B A C A A C B C Total Yield * 70% 63% 31% 86% ¡ª ¡ª ¡ª ¡ª 53-55% 31% ¡ª ¡ª ¡ª 22% ¡ª ¡ª 34% ¡ª 23-25% ¡ª ¡ª ¡ª 57% 20% 66% Refer- ences 15,35 1,2,3 1,6 20 5 5 5 5 3, 4, 5, 39 4,6 2,3,5 6 5, 12 6 5 6- 2, 3, 5, 9 6 5,9 35 5 5 11 6 20 * The total yield refers to the sum of the yields of amide and of free acid. 39 Claus and Wehr, J. prakt. Chem., [2] 44, 85 (1891). 41 The 4-biphenyl ketone series was incorrectly referred to as "3-biphenyl" by Willgerodt; cf. Vorliinder, Ber., 40, 4535 (1907). 100 ORGANIC REACTIONS TABLE I¡ªContinued EXAMPLES OF THE WILLGERODT REACTION Methyl Aryl Ketones¡ªContinued Ketone Formula CisHisO C16H12O C16H16O Ci8Hi20 Ci8H16O Aryi tjroup 2-Fluorenyl 2-Phenanthryl 3-Phenanthryl 9-Phenanthryl t 7-(l,2,3,4-Tetrahydro)phenanthryl 9-(l,2,3,4-Tetrahydro) phenanthryl 1-Pyrenyl 3-(6-Ethyl)phenanthryl Pro- cedure C A C A C C A C C C C Total Yield * 70% ¡ª 82% ¡ª 40-82% 76% ¡ª 66% 56% 92% 82% Refer- ences 13 10 20 10 16 20 10 17 17 14 16 Methyl Alkyl Ketones C5H10O C6H12O C7H14O C8H14O C9HioO n-Propyl ?-Butyl n-Amyl Cyclohexyl Benzyl C C C cD 31% 58% 38% 40% 72% 21 21 21 21 20 Ethyl Aryl Ketones C9H10O C10H12O CnH14O C12H14O C12H16O C13H12O Ci3H16O Phenyl 4-Methylphenyl 2,4-Dimethylpheny 1 5-Indanyl 2,4,5-Trimethylphenyl 1-Naphthyl 2-Naphthyl 6-Tetralyl A B D A A C B ' A A C 50% ¡ª 82% 36-38% ¡ª ?? 68% 6% ?¡ª ¡ª ?67% 1 . 6 20 3,4 5, 41, 42 186 6 3, 5 5 18 * The total yield refers to the sum of the yields of amide and of free acid. t Willgerodt and Albert (Ref. 7) reported a reaction with a ketone to which they assigned the-struc- ture of 9-acetylphenanthrene. The correctness of the structure has been questioned by, Moaettig and van de Kamp (Ref. 10) 41 Bornhauser, dissertation, Freiburg, 1891. ? Claus, J. prakt. Chem., [2] 46, 475 (1892). THE WILLGERODT REACTION ? TABLE I¡ªContinued EXAMPLES OP THE WILLGEBODT REACTION Ethyl Aryl Ketones¡ªContinued 101 Ketone Formula C15HMO C17H14O C19H14O Aryl Group 4-Biphenyl? 2-Phenanthryl 9-Anthryl t 1-Pyrenyl Pro- cedure B C C C C Total Yield * 6% 57% 66% 0 67% Refer- ences 6 19 20 20 14 Ethyl Alkyl Ketones C7Hi40 CH14O CgHieO n-Butyl f-Butyl Cyclohexyl C C C 23% 30% 27% 21 21 21 n-Propyl Aryl Ketones 010H120 CnH14O C12H16O Ci3Hi80 C14H14O CieHjeO C2oHieO Phenyl ? 4-Methylphenyl 2,4-Dimethylphenyl 2,5-Dimethylphenyl 2,4,5-Trimethylphenyl 1-Naphthyl 4-Biphenyl 4° 1-Pyrenyl A D A A A B A B C 37% 42% 23-25% 7% 7% 6% ¡ª ¡ª 46% 1 20 4 5, 41, 42 5, 41, 42 6 3,5 6 14 n-Propyl Alkyl Ketones * The total yield refers to the sum of the yieMs of amide and of free acid. t Ethyl 9-anthryl ketone was oleaved in a unique manner, yielding 85% of anthracene. 102 ORGANIC REACTIONS TABLE I¡ªContinued EXAMPLES OF THE WILLQEEODT REACTION Other n-Alkyl Aryl Ketones Formula Ci3H18O C22H36O C23H38O C26H44O Ketone n-Hexyl phenyl ketone n-Pentadecyl phenyl ketone ra-Pentadecyl 4-methyl- phenyl ketone n-Heptadecyl 2,4-dimethyl- phenyl ketone Pro- cedure A A A A Products Heptanamide CeHsCONHa; C6HB- COOH; impure C15H31COOH S-containing oils or decomposition products S-containing oils or decomposition products Refer- ences 1 1 5 5 Ketone Formula CioHi20 CuH14O C12H16O Ci3Hi80 CieHieO C20H16O Isopropyl Aryl Aryl Group Phenyl 4-Methylphenyl 2,4-Dimethylphenyl 2,4,5-Trimethylphenyl 4-Biphenyl? 1-Pyrenyl Pro- cedure A A A B B C Ketones Products Amide, m.p. 108° Amide, m.p. 130° Amide, m.p. 120° Amide, m.p. 158° No identified product Trace of high-melt- ing S-containing solid Yield 19% ¡ª 2% 0.5% ¡ª 0 amide Refer- ences 1 4 5, 41,42 6 6 14,34 C11H14O Ci2Hi60 C14H2oO Ci7H18O C2iH18O Isobuty, Phenyl 4-Methylphenyl 2,4,5-Trimethylphenyl 4-Biphenyl4° 1-Pyrenyl Aryl Ketones A- A A B B C Amide, m.p. 118°, and benzoic acid Amide, m.p. 121° Amide, m.p. 150° Solid, m.p. 158° None isolated No amide 16- 17%? 1.8% 3-1% 0.1% 0 0 1 11 4 6 6 34 THE WILLGERODT REACTION TABLE I¡ªContinued REACTIONS RELATED TO THE WILLGERODT REACTION Unsaturated Hydrocarbons 103 Formula C8H6 C8H8 C9H8 C9H10 Hydrocarbon Phenylacetylene Styrene 1-Phenylpropyne 1-Phenylpropene Pro- cedure P P P P Products Phenylacetamide Phenylacetamide /3-Phenylpropion- amide /3-Phenylpropion- amide Yield 80% 64% Refer- ences 20 20 20 20 Aldehydes Formula C7H6O C7H14O C8H8O C9H10O Aldehyde Benzaldehyde Heptaldehyde Phenylacetaldehyde ,8-Phenylpropionaldehyde Pro- cedure A A D D Products Benzamide Heptanamide Phenylacetamide ,8-Pheny lpropi on- amide Yield 48% 48% Refer- ences 3 3,21 20 20 104 ORGANIC REACTIONS TABLE II EXAMPLES OP THE KINDLER MODIFICATION (Sulfur and Amine) Methyl Aryl Ketones Ketone Formula C7H7NO C8H7BrO C8H7C1O C8H8O QHoO C9H10O2 C10H12O Aryl Group 3-Pyridyl 4-Bromo- phenyl 4-Chloro- phenyl Phenyl 4-Methyl- phenyl 2-Methoxy- phenyl 3-Methoxy- phenyl 4-Methoxy- phenyl 4-Ethyl- phenyl Amine _ Diethyl Morpholine Morpholine Methyl Dimethyl Diethyl Morpholine Dimethyl Morpholine Morpholine Morpholine Dimethyl Diethyl Piperidine Morpholine Dimethyl Thioamide Formed N-Alkyl-3-pyridylaceto- thioamide N,N-Diethyl-3-pyridyl- acetothioamide 4-Bromophenylacetothio- morpholide 4-Chlorophenylacetothio- morpholide N-Methylphenylacetothio- amide N,N-Dimethylphenyl- acetothioamide N,N-Diethylphenylaceto- thioamide Phenylacetothiomor- pholide N,N-Dimethyl-4-methyl- phenylacetothioamide 4-Methylphenylacetothio- morpholide 2-Methoxyphenylaceto- thiomorpholide 3-Methoxyphenylaceto- thiomorpholide N,N-Dimethyl-4-methoxy- phenylacetothioamide N,N-Diethyl-4-methoxy- phenylacetothioamide 4-Methoxyphenylaceto- thiopiperidide 4-Methoxyphenylaceto- thiomorpholide N,N-Dimethyl-4-ethyl- phenylacetothioamide Yield ¡ª (10%) * 31% ¡ª 70% ¡ª 92% 80% 57% (55%) * 85% 75% ¡ª 48% ¡ª 40% " Refer-, ences 23 35 28 36,43 24 22, 23 22 28 23 36,43 28 28 22, 23, 24 22 23 43 23 * yields given in parentheses are for the free acids isolated after hydrolysis of the crude thioamide. ?Haller and Barthel, U. S. pat., 2,358,925; C. A., 39, 1948 (1945). THE WILLGERODT REACTION 105 TABLE II¡ªContinued EXAMPLES OP THE KINDLER MODIFICATION Methyl Aryl Ketones¡ªContinued Ketone Formula C10H12O3 CUHDNO C12H10O CISHHNOU C14H12O C15H12O C15H14O2 CjeHisO Aryl Group 3,4-Dimeth- oxyphenyl 2,5-Dimeth- oxyphenyl 4-Quinolyl 8-Quinolyl 1-Naphthyl 2-Naphthyl 6-Methoxy- 4-quinolyl 3-Acenaph- thyl 4-Biphenyl 2-Fluorenyl 2-Benzyloxy- phenyl 2-Phenan- thryl 9-Phenan- thryl Amine Methyl Dimethyl Morpholine ¡ª Diethyl ¡ª Morpholine ¡ª ¡ª Morpholine Morpholine Morpholine Morpholine Morpholine ¡ª Thioamide Formed N-Methyl-3,4-dimethoxy- phenylacetothioamide N,N-Dimethyl-3,4-di- methoxyphenylaceto- thioamide 2,5-DimethoxyphenyL- acetothiomorpholide N-Alkylquinolylacetothio- amide N, N-Diethylquinoly 1- acetothioamide N-Alkyl-1-naphthyl- acetothioamide 2-Naphthylacetothio- morpholide N-Alkylnaphthylaceto- thiomorpholide N-Alkyl-6-methoxy-4- quinolylacetothioamide No amide isolated 4-Biphenylacetothiomor- pholide Much tar formation 2-Benzyloxyphenylaceto- thiomorpholide* 2-Phenanthrylacetothio- morpholide N-Alkyl-9-phenanthryl- acetothioamide Yield 68% (28%) * ¡ª ¡ª ¡ª 85% 90% ¡ª? ¡ª 0 82% 0 72% (41%) * ¡ª Refer- ences 25 23,26 ,28 23 35 23 28 33 23 23 36 36 36 28 28 23 Ethyl Aryl Ketones C9H9B1O C9H9C1O C9H9FO 4-Bromo- phenyl 4-Chloro- phenyl 4-Fluoro- phenyl Dimethyl Dimethyl Dimethyl N,N-Dimethyl-4-bromo- phenylpropiothioamide N,N-Dimethyl-4-chloro- phenylpropiothioamide N,N-Dimethyl-4-fluoro- phenylpropiothioamide 40% 27 27 27 * Yields given in parentheses are for the free acids isolated after hydrolysis of the crude thioamide: 106 ORGANIC REACTIONS TABLE II¡ªContinued EXAMPLES OF THE KINDLEB MODIFICATION Ethyl Aryl Ketones¡ªContinued Ketone Formula C9H9IO C9H10O C10H12O CioHijOS C10H12O2 C11H14O C11H14O2 CuHi4O3 CwHieO C14H14O2 Aryl Group 4-Iodo- phenyl Phenyl 4-Methyl-. phenyl 4-Methylthi- ophenyl 4-Methoxy- phenyl 4-Ethyl- phenyl 3-Methyl-4- methoxy- phenyl 3,4-Dimeth- oxyphenyl 6-Tetralyl 4-Methoxy- 1-naphthyl Amine Dimethyl Dimethyl Dimethyl Dimethyl Dimethyl Dimethyl Dimethyl Dimethyl Morpholine Dimethyl Thioamide Formed N,N-Dimethyl-4-iodo- phenylpropiothioamide N,N-Dimethylphenyl- propiothioamide N,N-Dimethyl-4-methyl- phenylpropiothioamide N,N-Dimethyl-4-methyl- thiophenylpropiothio- amide N, N-Dimethyl-4-methoxy- phenylpropiothioamide N,N-Dimethyl-4-ethyl- phenylpropiothioamide N,N-Dimethyl-3-methyl- 4-methoxyphenylpropio- thioamide N,N-Dimethyl-3,4-di- methoxyphenylpropio- thioamide /3-(6-Tetralyl)propiothio- morpholide N,N-Dimethyl-4-meth- bxy-1-naphthylpropio- thioamide Yield 58% 58% ¡ª ¡ª ¡ª ¡ª 42% 35% ¡ª Refer- ences 27 23 27 27 25,27 27 27 25,27 32 27 EXAMPLES OF THE KINDLER MODIFICATION AND RELATED REACTIONS Aldehydes Formula CTHOO Compound Benzalde- hyde Amine Ammonia Dimethyl Diethyl 2-Naphthyl Product Formed Thiobenzamide N,N-Dimethylthiobenz- amide N,N-Diethylthiobenz- amide N-(2-Naphthyl)thiobenz- amide Yield 80% ¡ª ¡ª Refer- ences 22,24 22,23 22 22 THE WILLGERODT REACTION TABLE II¡ªContinued EXAMPLES OF THE KINDLER MODIFICATION AND RELATED REACTIONS A Idehydes¡ªContinued 107 Formula C8H8O C8H8O2 Compound 4-Methyl- benzalde- hyde Phenyl- acetalde- hyde 4-Methoxy- benzalde- hyde Amine Methyl Dimethyl Methyl Dimethyl Product Formed N-Methyl-4-methylthio- benzamide N,N-Dimethylphenyl- acetothioamide N-Methyl-4-methoxythio- benzamide N,N-Dimethyl-4-methoxy- thiobenzamide Yield ¡ª ¡ª ¡ª Refer- ences 22 22,24 24 22 Hydrocarbons, Imines, and Other Compounds C8H? CgHg C8H9N C9HnN C9HnNO CioHuN02 CioHuO CnH14O Ci3HnN Phenylacet- ylene Styrene N-Methyl- benzaldi- mine N-Methyl- acetophe- nonimine N-Methyl- 4-meth- oxybenz- aldimine N-Methyl-3, 4-methyl- enedioxy- acetophe- nonimine n-Propyl phenyl ketone n-Butyl phenyl ketone Benzalan- iline Morpholine Morpholine None None None None ¡ª Dimethyl t None Phenylacetothiomor- pholide Phenylacetothiomor- pholide N-Methylthiobenzamide N-Methylphenylaceto- thioamide N-Methyl-4-methoxythio- benzamide N-Methyl-3,4-methyl- enedioxyphenylaceto- thioamide N-Alkyl-7-phenylbutyro- thioamide N, N-Dimethy 1- ?-phenyl- valerothioamide Thiobenzanilide 60% 52% 80% 30% 40% 45% ¡ª ¡ª ¡ª 20 20 22,23 22,23 22,23 23 23 24 22 CHAPTER 3 PREPARATION OF KETENES AND KETENE DIMERS W. E. HANFORD * AND JOHN C. SAUER E. I. du Pont de Nemours and Company CONTENTS PAGE INTRODUCTION 109 PREPARATION OF KETENES 109 Pyrolysis of Acids, Anhydrides, Ketones, Esters, etc 109 Table I. The Formation of Ketenes by the Pyrolysis of Ketones, Acids, Acid Anhydrides, Esters, and Other Substances Ill Table II. Substances Whose Conversion to Ketenes is Described in the Patent Literature - 114 Decomposition of Malonic Acid Derivatives 6 Table III. Ketoketenes Prepared from Malonic Acid Derivatives ... 118 Regeneration of Ketenes from the Dimers 119 Table IV. Preparation of Ketenes by Pyrolysis of Ketene Dimers ... 120 Dehalogenation of a-Haloacyl Halides 120 Table V. Preparation of Ketenes by Zinc Dehalogenation of a-Haloacyl Halides 122 Miscellaneous Methods 123 Decomposition of Diazo Ketones 123 The /3-Lactone Method 4 Dehydrohalogenation of Acyl Halides by Means of Tertiary Amines. ... 124 Table VI. Preparation of Ketoketenes by Dehydrohalogenation of Acyl Halides 126 PREPARATION OF KETENE DIMERS 127 Table VII. Ketene Dimers 130 EXPERIMENTAL PROCEDURES 2 Pyrolysis 132 Ketene by Pyrolysis of Acetone 132 Malonic Anhydride Method 135 Dimethylketene 135 Dipropylketene 5 Dibenzylketene 5 ' Depolymerization 136 Dimethylketene 6 Ethylcarbethoxyketene 137 Dehalogenation of a-Haloacyl Halides 138 Ethylcarbethoxyketene 8 * Present address, M. W. Kellogg Co., 225 Broadway, New York, N. Y. 108 PREPARATION OF KETENES AND KETENE DIMERS 109 PAGE Dehydrohalogenation 138 Diheptylketene 8 Mesitylphenylketene 9 n-Butylketene Dimer 140 INTRODUCTION Ketenes are substances containing the functional group ¡ªC=C=O. I They have been classified as aldoketenes (RCH=C=O) and ketoketenes .(R2C=C=O). Although these terms carry the implication of a non- existent similarity to aldehydes and ketones, respectively, they have become generally accepted. Carbon suboxide, O=C=C=C=O, proba- bly is best considered in a class of its own. The ketenes are prepared by modifications of the general methods for the synthesis of olefins. The ketenes are much more reactive than simple olefins, however, and are more likely to enter into combination with the reagents from which they are prepared or with the solvents used or into self-condensation to yield dimers or polymers. Many of the aldoketenes, which generally are more reactive than ketoketenes, have not been iso- lated as the pure monomers. The dimers of aldoketenes (p. 127) have some of the properties of ketenes, and certain of them are useful reagents. PREPARATION OF KETENES Pyrolysis of Acids, Anhydrides, Ketones, Esters, etc. Ketene, CH2=C=O, the first member of this class, apparently can be obtained by the pyrolysis of any compound which contains the group CHr.CO¡ª. The method is of no value for the synthesis of higher homo- logs, although some have been obtained by pyrolysis, but it is the basis of the best.preparations, both laboratory and commercial, of the first member. Ketene was first prepared by the decomposition of acetone, ethyl acetate, or acetic anhydride by means of a hot platinum wire im- mersed in the liquid.1 In the pyrolysis of acetone better results are ob- tained by passing the vapor over a heated surface.2 The commercial preparation of ketene consists in the pyrolysis of acetone or acetic acid at temperatures of 550° or higher. The most useful laboratory method3 consists in passing acetone over Chromel A wire heated at 700-750°, the 1 Wilsm?e, J. Chem. Soc, 91, 1938 (1907); Wilamore and Stew-art, Proc. Chem. Soc., 23, 229 (1907); Nature, 75, 510 (1907). 2Sohmidlin and Bergman, Ber., 43, 2821 (1910). 3 Williams and Hurd, J. Org. Chem., 5, 122 (1940), 110 ORGANIC REACTIONS yield of ketene being 90-95% (see p. 132). The other product of the re- action is methane. CH3COCH3 -^> CH2=C=O + CH4 The thermal decomposition of acetone is-a free-radical chain reaction. The initiating process may consist in the generation of carbon monoxide and methyl radicals. CH3COCH3 -> 2CH3- + CO The chain process then can be represented as follows.4 CH3COCH3 + CH3- -? CH3COCH2- + CH4 CH3COCH2- -? CH3- + CH2=C=O As ordinarily prepared, ketene contains 5-10% of ethylene along with carbon monoxide and methane, all of which can be removed'by careful fractionation. Only partial purification can be effected by freezing the ketene (m.p. ¡ª134°) and holding the solid under diminished pressure; the ketene purified in this way contains about 5% of an unsaturated hy- drocarbon, which can be separated by fractionation. Principally because of the ease with which it dimerizes, ketene (b.p.* ¡ª 41°) is seldom isolated. The mixture of gases from the generator is passed into a reaction vessel in which the ketene is converted to the desired derivative. The most important industrial uses are in the manu- facture of acetic anhydride and of the dimer, known as diketene. CHs=C=O + CH3CO2H -> (CH3CO)2O 2CH2=C=O -? (CH2=C=O)2 The preparation of acetic anhydride from acetic acid at a high tempera- ture 6i 6 probably depends upon the primary formation of ketene and its reaction with acetic acid. The use of ketene as an acetylating agent is restricted by the tendency of the compound to dimerize (p. 127). Diketene is an important indus- trial intermediate in the manufacture of derivatives of acetoacetic acid (see p. 127). There have been extensive investigations of the preparation of ketene by the pyrolysis of acetone, acetic acid, acetic anhydride, and other sub- stances. The various compounds which have been subjected to pyrolysis in studies of the production of ketene and its homologs are listed in Table I. A list of the various substances whose pyrolysis to ketene and higher ketenes is described in the patent literature is given separately in Table II. * The boiling point of ketene has been recorded as ¡ª56° also, but this figur% apparently is incorrect (see ref. 17). * Rice and Walters, J. Am. Chem. Soc, 63, 1701 (1941). 5 For an example see U. S. pat., 2,278,537 [C. A., 36, 4831 (1942)]. * Hurd and Martin, J. Am. Chem. Soc, 51, 3614 (1929). PREPARATION OF KETENES AND KETENE DIMERS 111 TABLE I FOBMATION OF KETENES BY THE PYBOLYSIS OF KETONES, ACIDS, ACID ANHYDBIDES, ESTEBS, AND OTHEB SUBSTANCES A. Ketene (CH2=C=O) Raw Material Acetone Acetic acid Acetic anhy- dride Conditions Phase Liq. Vap. Vap. Vap. Vap. Vap. "Vap. Vap. Vap. Vap. Vap. Vap. Vap. Vap. Vap. Vap. Vap. Vap. Vap. Vap. Vap. § Vap. Vap. Vap. II Vap. Vap. Vap. Liq. Filament or Hot Wire Pt None Chromel A None Pt None None None Pt Fe Ni W Tube Glass Glass Glass Glass Glass Glass Glass Glass Glass Glass Glass Glass Packing None Pumice None Porcelain None Porcelain Porcelain Silica gel None None None None (Brush discharge) ¡ª ¡ª None Pt or Ni ¡ª None W None None ¡ª None None Chromel A None None Pt Glass Quartz Quartz or Pyrex Glass SiO2 Glass Glass Cu Glass ¡ª Pt Quartz Glass Glass Quartz Glass Various ^catalysts Various catalysts Quartz or Pyrex None Cu V2O6 on pumice None None Glass CeO2 None None None Porcelain Porcelain None Temp. 500-600 750 600 ¡ª 700 ca. 650 650 ¡ª ¡ª ¡ª ¡ª ¡ª 600-700 675-690 650-750 ¡ª ¡ª 700 ¡ª 520-670 506-540 ¡ª 1150 588, 635 ¡ª 800 ¡ª Yield 10% 10% 90% 17.5% 9.8% 35-15% 25-30% ¡ª ¡ª 5-7% 12% 50% 11% * t 70% ¡ª ¡ª 3% ¡ª High* ¡ª 85% ¡ª 25-60% ¡ª ¡ª "Low" ¡ª Refer- ence 1,2 2 3 7 8 9 10 11 12 13 13 13 14 15 16 17 17a 18 19 20 21 4 22 23 24 25,26 27 6 1 * The best catalyst (77% yield) was pumice containing V2O5. t The best catalyst (96.5% yield) was pumice containing V2O5. X The yield approaches 100%. i In the presence of biacetyl. II Nitrogen saturated with acetone. 112 ORGANIC REACTIONS TABLE I¡ªContinued FORMATION OP KETENES BY THE PYROLYSIS OP KETONES, ACIDS, ACID ANHYDRIDES, ESTERS, AND OTHER SUBSTANCES A. Ketene (CH2=C=O)¡ªContinued Raw Material Ethyl acetate Methyl ethyl ketone Diethyl ketone Acetylacetone Biacetyl Pinacolone Diglycolic an- hydride Acetylphthal- imide f Acetylcarba- zole Phase Liq. Vap. Vap. Vap. Vap. Vap. Vap. Vap. Conditions Filament or Hot Wire Pt None Pt Pt None None None None Tube Glass Glass Glass Glass Glass Glass Glass Glass Packing None Porcelain None None Porcelain Porcelain Porcelain None (Heated under reflux) (Heated under reflux) Temp. ¡ª 600 ¡ª 035 605-625 705 450-500 ¡ª ¡ª ? Yield ¡ª 1-3.5% 3.4- 3.7% * 7%* 16% 10-14% 'Small" 4% Low 0% t Refer- ence ? 1 28 8 8 29 29,30 29 31 32,33 32 B. Higher Ketenes Ketene (CH3)2C=C=O (C6H6)2C=C=O C2HB, C^HBOaCr c=o o=c=c=c=o V;=c=o CH2=CH/ Raw Material Isobutyrylphthalimide Diphenylacetylphthal- imide Benzilic acid Diphenylace+yl chlo- ride C2H5CH^CO2H)CO2- C2H6 CH2(CO2C2H6)2 CH2(CO2H)2 Diacetyltartaric anhy- dride Diacetoxymaleic anhy- dride Carvone Conditions Reflux, 225° Reflux, 300° Reflux, ca. 250° Distil Heat, 180-200°, P2O6 Heat, P2OB Heat, P2O6 200° Heat Heat Yield 30% Low Low Low 23% ¡ª 12% 41% 2% Refer- ence -32, 33 32,33 34 35 36 37 38 39 39a 40 * Product contained methylketene. t Aldoketenes were not obtained from the propionyl, butyryl or caproyl derivative) % The principal product was ketene dimer. PREPARATION OF KETENES AND KETENE DIMERS 113 REFERENCES FOR TABLE I 7 Hurd and Coohran, J. Am. Chem. Soc, 45, 515 (1923). " 8 Hurd, J. Am. Chem. Soc, 45, 3095 (1923). 9 Hurd and Tallyn, /. Am. Chem. Soc, 47, 1427 (1925). 10 Hurd, Org. Syntheses, Cott. Vol. I, 330, 2nd ed. (1941). u Goldschmidt and Orthner, Z. angew. Chem., 42, 40 (1929). 12 Herriot, J. Gen. Physiol., 18, 69 (1934). 13 Ott, Sehroter, and Packendorff, J. prakt. Chem., 130, 177 (1931). ? 14 Davis, J. Phys. Chem., 35, 3330 (1931). 15 Berl and KuIIman, Ber., 65, 1114 (1932). 16 Al, Angew. Chem., 45, 545 (1932). 17 Rice, Greenberg, Waters, and Vollrath, J. Am. Chem. Soc, 56, 1760 (1934). "' Rosenblum, J. Am. Chem. Soc, 63, 3323 (1941). 18 Hale, Nature, 140, 1017 (1937). 19 Pearson, Pureell, and 8aigh,.J. Chem. Soc., 1938, 409. 20 Li, Science, 90, 143 (1939). 21 Morey, Ind. Eng. Chem., 31, 1129 (1939). ^Nametkin and Fedoseeva, Khim. Referat. Zhur., 1940, No. 4, 116 [C. A., 36, 3783 (1942)]. 23 Peytral, Butt, soc chim., 31, 122 (1922). 24 Rice and Vollrath, Proc. Nail. Acad. Sci., 15, 702 (1929). 26 Doinbar and Bolstad, J. Org. Chem., 9, 219 (1944). 26 Bolstad and Dunbar, Ind. Eng. Chem., Anal. Ed., 15, 498 (1943). 27 Freri and Maximoff, Gazz. chim. ital., 70, 836 (1940) [C. A., 36, 1024 (1942)]. 28 Hurd and Kocour, J. Am. Chem. Soc, 45, 2167 (1923). 29 Hurd and Tallyn, J. Am. Chem. Soc, 47, 1779 (1925). 30 Rice and Walters, J. Chem. Phys., 7, 1015 (1939). 31 Hurd and Glass, /. Am. Chem. Soc, 61, 3490 (1939). 32 Hurd and DuU, J. Am. Chem. Soc, 54, 2432 (1932). 33 Hurd, DuU, and Williams, J. Am. Chem. Soc, 57, 774 (1935). 34 Staudinger, Ber., 44, 543 (1911). 36 Staudinger, Ber., 44, 1619 (1911). 86 Hurd, Jones, and Blunck, J. Am. Chem. Soc, 57, 2033 (1935). 37 Diels and Wolf, Ber., 39, 689 (1906). 38 Diels and Meyerheim, Ber., 40, 355 (1907). 89 Ott and Schmidt, Ber., 55, 2126 (1922). 39? Ott, Ber., 47, 2388 (1914). 40 Staudinger, "Die Ketene," p. 29, Ferdinand Enke, Stuttgart, 1912. 114 ORGANIC REACTIONS TABLE II SUBSTANCES WHOSE CONVERSION TO KETENES IS DESCRIBED IN THE PATENT LITERATURE Ketene CH2=C=O CH3CH=C=O RRC=C=O Raw Material Acetone and/or similar compounds Isopropyl alcohol Acetic acid and/or similar compounds Acetic anhydride Acetaldehyde Mesityl oxide Vinyl esters Carbon monoxide and hydrogen Alcohols and carbon monoxide Diketene Methyl acetate Methyl propionate Methyl ethyl ketone Diazoketones References 41-73a 70, 71, 74 75-91 67, 72, 92 93,94 95,96 97 98-101 102 103 104, 105 104,105 106 107 41 U. S. pat., 1,723,724 [C. 42 Brit, pat., 309,577 [C. A 43 GOT. pat., 556,367 [C. A 44 Fr. pat., 673,051 [C. A., 46 Ger. pat., 536,423 [C. A 48 Fr. pat., 730,724 [C. A., 47 Brit, pat., 377,574 [C. A 48 U. S. pat., 1,926,642 [C. 49 U. S. pat., 1,879,497 [C. 50 Fr. pat., 749,245 [C. A., 61 Brit, pat., 413,709 [C. A 62 Brit, pat., 397,025 [C. A 63 Fr. pat., 750,804 [C. A., " Ger. pat., 646,408 [C. A. ? Can. pat., 338,162 [C. A u U. S. pat., 1,975,663 [C. 67 Ger. pat., 598,953 [C. A B Ger. pat., 604,910 [C. A. 69 Can. pat., 355,618 [C. A 60 U. S. pat., 2,053,286 [C. 61 Brit, pat., 472,988 [C. A 82 U. S. pat., 2,069,243 [C, 83 U. S. pat., 2,080,562 [C, 64 TJ. S. pat., 2,184,963 [C. 66 U. S. pat., 2,232,705 [C. 88 U. S. pat., 2,258,985 [C. 87 Brit, pat., 237,573 [C. A * Ger. pat., 468,402 [C. A A., 23, 4485 (1929)]. ., 24, 630 (1930)]. ., 26, 5579 (1932)]. 24, 2474 (1930)]. ., 26, 999 (1932)]. 27, 306 (1933)]. ., 27, 3946 (1933)]. A., 27, 5753 (1933)]. A., 27, 313 (1933)]. 27, 5757 (1933)]. ., 29, 482 (1935)]. ., 28, 780 (1934)]. 28, 1052 (1934)]. ., 31, 6260 (1937)]. ., 28, 1718 (1934)]. A., 28, 7268 (1934)]. ., 28, 7268 (1934)]. ., 29, 813 (1935)]. ., 30, 2578 (1936)]. A., 30, 7127 (1936)]. ., 32, 1278 (1938)]. A., 81, 1826 (1937)]. A., 31, 4994 (1937)]. A., 34, 2866 (1940)]. A., 35, 3651 (1941)]. A., 36, 497 (1942)]. ., 20, 1415 (1926)]. , 23, 1142 (1929)] PREPARATION OF KETENES AND KETENE DIMERS 115 69 U. S. pat., 1,602,699 [C. A., 20, 3697 (1926)] 70 Brit, pat., 396,568 [C. A., 28, 483 (1934)]. 71 Fr. pat., 742,985 [C. A., 27, 3722 (1933)]. 72 Fr. pat., 722,477 [C. A., 26, 4063 (1932)]. 73 U. S. pat., 2,305,652 [C. A., 37, 3108 (1943)]. 730 U. S. pat., 2,376,748 [C. A., 39, 4621 (1945)]. 74 U. S. pat., 2,086,582 [C. A., 31, 6260 (1937)]. 75 Fr. pat., 777,483 [C. A., 29, 4029 (1935)]. 78 Ger. pat., 687,065 [C. A., 37, 5988 (1943)]. 77 Ger. pat., 734,349 [C. A., 38, 1250 (1944)]. 78 Brit, pat., 435,219 [C. A., 30, 1072 (1936)]. 79 Fr. pat., 46,965 [C. A., 31, 7893 (1937)]. 80 Brit, pat., 478,213 [C. A., 32, 4610 (1938)]. 81 Brit, pat., 478,303 [C. A., 32, 4610 (1938)]. 82 U. S. pat., 2,108,829 [C. A., 32, 2961 (1938)]. 83 U. S. pat., 2,176,419 [C. A., 34, 1037 (1940)]. *U. S. pat., 2,249,543 [C. A., 35, 6604 (1941)]. 86 Brit, pat., 478,325 [C. A., 32, 4610 (1938)]. 86 Brit, pat., 509,778 [C. A., 34, 4080 (1940)], 87 Brit, pat., 509,777 [C. A., 34, 4080 (1940)]. 88 U. S. pat., 2,202,046 [C. A., 34, 6656" (1940)]. 89 Brit, pat., 478,326 [C. A., 32, 4610 (1938)]. 90 U. S. pat., 2,295,644 [C. A., 37, 1133 (1943)]. 91 Fr. pat., 878,651. 92 U. S. pat., 2,045,739 [C. A., 30, 5597 (1936)]. 93 Brit, pat., 273,622 [C. A., 22, 1981 (1928)]. 94 U. S. pat., 1,870,104 [C. A., 26, 5315 (1932)]. 96 U. S. pat., 2,143,489 [C. A., 33, 2914 (1939)]. 96 Fr. pat., 851,816 [C. A., 36, 1944 (1942)]. "Ger. pat., 515,307 [C. X., 25, 1537 (1931)]. 98 Brit, pat., 262,364 [C. A., 21, 3626 (1927)]. 99 U. S. pat., 1,773,970 [C. A., 24, 5046 (1930)]. 100 Fr. pat., 617,428 [Chem. Zentr., I, 2686 (1927)]. 101 Fr. pat., 617,433 [Cftem. Zentr., I, 2686 (1927)]. 102 Brit, pat., 537,480 [C. 4., 36, 1336 (1942)]. 103 U. S. pat., 2,218,066 [C. A., 35, 1072 (1941)]. 104 Brit, pat., 504,626 [C. A., 33, 7818 (1939)]. 105 U. S. pat., 2,175,811 [C. A., 34, 776 (1940)]. 1M U. S. pat., 2,235,561 [C. A., 35, 4042 (1941)]. 107 Ger. pat., 220,852 [C. A., 4, 2188 (1910)]. 116 ORGANIC REACTIONS Decomposition of Malonic Acid Derivatives A method of synthesis of ketoketenes which is closely related to the pyrolysis described in the preceding section consists in the thermal de- composition of disubstituted malonic anhydrides, of either the simple or mixed types. 0 R R \ C=C=O + C0 2 R R COOCOR' R \ / c -? / R COOCOR' R C=C=O + R'COOCOR' + CO2 Monosubstituted malonic anhydrides have not yielded aldoketenes,108 but malonic acid itself yields carbon suboxide when heated with phos- phorus pentoxide.38 The disubstituted malonic anhydrides can be prepared from the corre- sponding malonic acids and acetic anhydride in the presence of a little sulfuric acid, with neutralization of the mineral acid by treatment with barium carbonate and removal of acetic acid and acetic anhydride by dis- tillation.109 The residual malonic anhydride is decomposed by heating under low pressure. This method appears to have been used only for dimethylketene (80% yield), diethylketene (55% yield), methylethyl- ketene (65% yield), and dipropyl- and diisopropyl-ketenes (50% yields). A more common method involves the decomposition of mixed anhy- drides, nearly all of which have been obtained by treating the dialkyl- malonic acid, dissolved in dry ether, with diphenylketene. The resulting mixed anhydrides, derived from the malonic acids and diphenylacetic acid, are nearly insoluble in ether and separate in almost quantitative yields. They are decomposed by heating under diminished pressure until 108 Staudinger, Anthes, and Schneider, Ber., 46, 3539 (1913). 109 Staudinger, Helv. Chim. Ada, 8, 306 (1925). PREPARATION OF KETENES AND KETENE DIMERS 117 the evolution of carbon dioxide is complete. If the ketene being prepared is easily volatile it may distil with the carbon dioxide. If a ketene of low volatility is prepared in this way it is separated from the diphenylacetic anhydride by extraction rather than by distillation, in order to prevent the occurrence of ketene interchange. For example, distillation (under diminished pressure) of a mixture of dibenzylketene and diphenylacetic anhydride results in the formation of diphenylketene and dibenzylacetic anhydride. 2(C6H6CH!!)i!C=C=O + [(C6HB)2CHCO]2O ^ 2(C6H6)2C=C=O + [(C6H6CH2)2CHCO]2O Decomposition of the mixed anhydrides prepared by means of diphenyl- ketene has been used for the production of simple dialkylketenes m- no (30-60% yields), diallylketene u0 (80% yield), dibenzylketene "° (73.5% yield), and ethylchloroketene108 [C2H5C(C1)==C=O] (50% yield). Methylphenyl ketene has been made in 75% yield, and other unsym- metrical ketoketenes no (RR'C=C=O) have been prepared in unspeci- fied yields. Attempts to prepare ketenes containing additional cumula- tive double bonds [e.g., isopropylideneketene,108'1U (CH3)2C=C=C=O] from alkylidenemalonic acids have failed. Methylethoxymalonic and diethoxymalonic acids have yielded none of the ketenes, but ethyl- phenoxymalonic and diphenoxymalonic acids appeared to give some of the corresponding ketenes.112 Cyclopropane-l,l-dicarboxylic acid gave none of the ketene.110 Dimethylketene has been obtained in unspecified yield by heating the monochloride of dimethylmalonic acid;113 it is probable that the malonic anhydride was formed as an intermediate. This method failed in at- tempted applications to diethylketene and carbon suboxide. Low yields of carbon suboxide have been obtained by treating malonyl chloride with lead, silver, or zinc oxide or with silver oxalate or malonate, and by treating silver malonate with cinnamoyl chloride;1W malonic anhydrides or mixed anhydrides may be intermediates. The ketenes which have been prepared by fliese methods are listed in Table III; unsuccessful attempts mentioned above are not repeated in the table. 110 Staudinger, Schneider, Schotz, and Strong, Helv. Chim. Ada, 6, 291 (1923). 111 Staudinger and Schneider, Heh. Chim. Ada, 6, 316 (1923). m Staudinger and Schneider, Helv. Chim. Ada, 6, 304 (1923). 113 Staudinger and Ott, Bar., 41, 2208 (1908). 114 Staudinger and St. Bereza, Bar., 41, 4461 (1908). 80 X 80 1 SI T OI T OT T o no n 0X 1 o n80 1 o n80 1 aouaiajay ; 0 %o e% 6 %9l %9Sl U )%0 8 %S 8 U ) %n U ) %& PI 9 ! A O=O=O I; I O O=O=(IO)O 9 H !! O o=o=( j a)o s H 5 oO=O=( C HO)O 9 H 9 O O=0=0 5 ( s H0 9 H 9 0 ) O=O=( S HO ) O Z HO 9 H 9 O O=O=O 2 ( 5 HOHO= !! HO ) o=o=o t(i H 8 O - M ) O=O=( s H0)0 !! H0H0= !; H O O=O=O i! ( 8 HO 8 HO ) O=O=( 8 HO)O 5 HO 8 H O O=O=O i! ( 8 HO ) O'tOOHO'WO) ] + O=O=O(/H) H <__ _ 8[S(9H 9 O)HOOOOOO1O(,H) H < - O=O=O S ( 9 H 9 O) S + ! (H*OO)O(,H) H puv sppy oiuop>j\[ vwxf p3j,vdaj,,j sapt-ipfiyuy psxiffl -uu>j,g - g 60 1 60 1 60 1 60 T 60 T oouajaj a 8 OO 4 83AI1VA M a %0 9 %0 S %9 9 %9 9 %0 8 - o=o=o(,a) a < O=O==O !! ( z H 8 O- os ? ) O=O=O 5 ( i H 8 O- M ) O=O=O i! ( i! HO 8 HO ) O=O=( 8 HO)O s HO e H O O=O=O S ( 8 HO ) ^ ¡ª x [¡ª oo(/a)aoooo¡ª1 S9pupHi(uy oiuop)pi ajdiuig vmox^ - y a Q aio y oiNonvj II I aaav x SNOixova a OINVOH O 8T I PREPARATION OF KETENES AND KETENE DIMERS 119 TABLE III¡ªContinued KETOKETENES PREPARED FBOM MALONIC ACID DERIVATIVES C. Related Preparations Ketene (CH3)2C=C=O o=c=c=c=o Prepared from (CH3)2C(CO2H)COC1 CH2(COC1)2 CH2(CO2Ag)2 CH2(CO2H)2 Reagent Heat Ag2O PbO ZnO (CO2Ag)2 CH2(CO2Ag)2 C6H6CH=CHCOC1 P2O6 Yield (?) 63% "Low" 5.5% 10.5% 5.7% 1-2% (?) Refer- ence 113 114 114 114 114 114 114 2,37 Regeneration of Ketenes from the Dimers Because of the ease with which many ketenes dimerize, the reconver- sion of the dimers to the monomers is an important adjunct to the meth- ods of synthesis of ketenes. In general, the regeneration of the mono- mers is effected by pyrolysis, but the process is smoother than the ther- mal decomposition of ketones, acids, etc. The dilution of the dimer with an inert gas has proved advantageous in some preparations.116-116 The pyrolysis of diketene produces ketene in quantitative yield,117 and the product is not contaminated with hydrocarbons, carbon monox- ide, etc., which are present in ketene produced by the cracking of acetone. In other instances also it may be possible to prepare ketenes in the state of highest purity by utilization of the dimers (for the preparation of the dimers, see-p. 127). Relatively few such preparations have been reported. -The dimers of ketene, methylketene, and dimethylketene have been converted to the monomers in yields of 86-100% by decomposition over hot filaments or in hot (550-600°) tubes. Ethylcarbethoxyketene has been prepared in 80-90% yield by heating the dimer under a pressure of 15 mm. in an oil 116 private communication from Professor J. R. Johnson, Cornell University, and taken from the doctoral thesis of C. M. Hill, entitled "Studies of Ketenes and Their Derivatives," 1941. lie Private communication from Professor J. R. Johnson, Cornell University, and taken from the doctoral thesis of J. M. Witzel, entitled "Dimethyl Ketene and Its Reaction with Cyclopentadiene," 1941.U7 Boese, Ind. Eng. Chem., 32, 16 (1940). 120 ORGANIC REACTIONS bath at 180-200°. A complete list of the ketenes prepared and the con- ditions employed (if reported) is given in Table IV. TABLE IV PREPARATION'OP KETENES BY PYROLYSIS OP KETENE DIMERS CH2=C=O CH3CH=C=O (CH3)2C=C=O CH3C(CO2CH3)==C=O C2H6C(CO2C2H6)=C=O (C2H6O2C)2C=C=O C6H6C (CO2CH3)=C=O C6H6C(CH3)=C=O (C6H6)2C=C=O Conditions of Depolymerization of the Dimer Hot platinum filament Hot tube (550-600°) Hot Nichrome wire Hot Nichrome wire Hot platinum spiral Treatment with NaOCHr¡ªCH3OH Heat at 200°/15 mm. Distillation at 15 mm. Treatment with CeHgMgBr Heat at 150° Distillation in "abs." vacuum Heat at 150° Distillation Pyrolysis Yield Quant. Quant. ¡ª 86% ¡ª * 80-90% 30% -t¡ª 70% ¡ª ¡ª ¡ª Refer- ence 117 117 115 116 118 119 120 36 36 121 122 121 121, 123 121, 124 * The product isolated was CHsCH(CO2CH3)2, evidently formed from the ketene. t The product isolated was ethyl a-benzoylbutyrate. Dehalogenation of a-Haloacyl Halides The oldest procedure for the synthesis of ketenes is the dehalogenation of a-haloacyl halides by treatment with zinc.125 There have been no R' R¡ªC¡ªC 0 X Zn R' R C=C=O + ZnX2 118 Staudinger and Klever, Ber., 44, 2215 (1911). 118 Schroeter, Ber., 49, 2697 (1916). 120 Staudinger and St. Bereza, Ber., 42, 4908 (1909). m Staudinger and Hirzel, Ber., 50, 1024 (1917). m Staudinger and Hirzel, Ber., 49, 2522 (1916). 123 Staudinger and Ruzicka, Ann., 380, 278 (1911). m Staudinger, Ber., 44, 521 (1911). 126 Staudinger, Ber., 38, 1735 (1905). PREPARATION OF KETENES AND KETENE DIMERS 121 extensive studies of the relative yields from theVarious possible dihalo compounds such as bromoacid bromides, chloroacid chlorides, bromoacid chlorides, and chloroacid bromides. In the preparation of ketene the yields obtained from bromoacetyl bromide and bromoacetyl chloride were 12% and 3.7%, respectively, but none of the product was obtained from chloroacetyl bromide or chloroacetyl chloride.126 However, a 13.5% yield of phenylketene was obtained from phenylchloroacetyl chloride.127 Later attempts to prepare ketene by the dehalogenation of bromoacetyl bromide with zinc either in boiling ether solution or in the vapor phase at 200° were unsuccessful;128 copper bronze, molten sodium, sodium iodide, or magnesium and magnesium iodide likewise failed to effect the dehalogenation. Only carbon suboxide 114' m (yield up to 80%) and ketoketenes (yields up to 95%, see Table V) have been prepared in yields above 20%. Many of the aldoketenes have not been isolated from the reaction mixtures, their presence being demonstrated only by conversion to derivatives.126' 127' 129' 129a The method has given only negative results when applied to a,/3-unsaturated a-haloacyl halides.130 The dehalogenation generally is carried out in pure ethyl ether or ethyl acetate at the reflux temperature. These solvents are especially useful because they dissolve the zinc halides and because their low boiling points facilitate control of the reaction temperature. The solvents used in this synthesis must, of course, be free from water and ethanol. Some ethyl ester may be formed through cleavage of ether (when it is used as the solvent) by the acyl halide in the presence of zinc halide. Mercury and silver have been used as dehalogenating agents instead of zinc, but they are less satisfactory.131' * Magnesium appears to have been used only with bromoacetyl bromide and a-bfomoisobutyryl bromide; the yields were about the same as those obtained with zinc. Various a-haloacyl halides which have been used in preparations or attempted preparations of ketenes are listed in Table V. * See p. 7 of ref. 40. 126 Staudinger and Kubinsky, Ber., 42, 4213 (1909). 127 Staudinger, Ber., 44, 533 (1911). m Hurd, Cashion, and Perletz, J. Org. Chem., 8, 367 (1943). 129 Staudinger and Klever, Ber., 41, 906 (1908). m" Fuson, Armstrong, and Shenk, J. Am. Chem. Soc, 66, 964 (1944). 130 Staudinger and Ott, Ber., 44, 1633 (1911). 131 Staudinger, Ann., 356, 51 (1908). 122 ORGANIC REACTIONS TABLE V PREPARATION OF KETENES BY ZINC DEHALOGENATION OF ?-HALOACYL HAMDES R(R')CXCOX' + Zn ¡ª R(R')C=C=O + ZnXX' Ketene CHi!=C=O CH3CH=C=O C2H6CH==C=O (CH3)2C=C=O (C2H6)C(CH3)=C=O HC(CO2C2H6)=C=O QH5C (CO2CH3)==C=O C6H6CH=rC=O 2,4,6-(CH3)3C6H2CH=C=O 2,4,6-(C2HB)3C6H2CH=C=O C6H6C(CH3)=C==O (C6HS)2C=C=O p-CH3C6H4C (C6H6)=C=O (p-C6H6C6H4)2C==C==O (f'6H4c==c=0C6H4-7 (CH3)2C=C=C=O C6H6CH=C=C=O o=c=c=c=o a-Haloacyl Halide X X' Br Br Br Br Br Br Br Br Br Cl Br Cl Cl Cl Cl Br Br Br Br Br Br Br Br Br Br Br Br Cl Br Cl Cl Cl Br Br Br Br Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Br Cl Br Cl Br Br [Br2C(COCl)2] ? [Br2C(COBr)2] Solvent (C2H6)2O CH3CO2C2H5* (C2H6)2O * CH3CO2C2H6 (C2H6)2O CH 3CO2C2H5 (C2H5)2O (C2H6)2O (C2H6)2O (C2H6)2O (C2H6)2O CH3CO2C2H6 (C2H6)2O ¡ª (C2H6)2O (C2H6)2O (C2H6)2O (C4H9)2O (C2H6)2O (C2H6)2O (C2H8)2O (C2H6)2O (C2H6)2O CH3CO2C2H6 CH3CO2C2H6 CH3CO2C2H6 (C2H6)2O CH3CO2C2H6 (C2HB)2O Yield 7-13% 12-14% * 11-12% * 8-12% 3.7% 4.4% 0 0 6-8% f 4-6% t 38% 28% ? 0 34% 13% t 4. , J- 80-90% 95% ? 60% 90% 0 0 0 80% f 40-50% Refer- ence 126, 132 126 126 126, 132 126 126 126 126 127, 129 129 133 133 134 135 120 125, 127 129a 129a 123 125, 131 134, 136 137 138 130 130 130 114 114 129 * Magnesium was used instead of zinc, t In solution¡ªnot isolated. 132 Staudinger and Klever, Ber., 41, 594 (1908). 133 Steudinger and Klever, Ber., 39, 968 (1906). 134 McKenzie and Christie, J. Chem. Soc, 1934, 1070. 136 Staudinger and Becker, Ber., 50, 1016 (1917). 136 Weiss, Monatsh., 40, 391 (1920). 137 Shilov. and Burmistrov, Ber., 68, 582 (1935). 138 Staudinger, Ber., 39, 3062 (1906). PREPARATION OF KETENES AND KETENE DIMERS 123 Miscellaneous Methods Decomposition of Diazo Ketones. Diphenylketene usually is pre- pared from benzil through the following series of reactions.107-1W> 140 C6H6COCOC6HB + NH2NH2 -? C6H6COC(NNH2)C6H5 -^>, C6H6COC(N2)C6H6 -> (C.H?)2C=C=O + N2 The last step is effected, by slowly dropping a benzene solution of the diazo ketone into a distilling flask heated in a metal bath at 100-110°. The residual diphenylketene is then distilled (64% yield) and redistilled (58% yield). A somewhat lower yield (45%) results when the decompo- sition is effected in ligroin; fos-benzilketazine is a by-product of the decomposition.141 Di-p-tolylketene has been prepared in unspecified yield by similar reactions.142 Mesitylphenylketene has been prepared from the diazo compound in 35% yield, but dehydrohalogenation of mesitylphenylacetyl chloride is a much superior method (see p. 139). This general method has been followed in the preparation of a few other ketoketenes from ethoxalylacetic ester and from acylacetic esters. The diazo ketones were prepared by nitrosation, reduction, and treat- ment with nitrous acid. The use of methyl acetoacetate is illustrative;119 the ketene was isolated as the dimer. CH3COCH2CO2CH3 -* CH3COCHCO2CH3 -> CH3COCHCO2CH3 -* NH2 CH3COCCO2CH3 > N2 + CH3C=C=O (47% yield of I the dimer) N2 CO2CH3 The diazo compound from methyl benzoylacetate gives phenylcarbo- methoxyketene in 70% yield when the final decomposition is carried out in refluxing xylene, but it is converted largely to the ester of phenyl- malonic acid by heating in the absence of a solvent.122 The ethyl ester of ethylmalonic acid is the principal product from the decomposition (in the absence of a solvent) of the diazo compound obtained from ethyl pro- pionylacetate.122 A small amount of the ketene evidently was formed also. The diazo compound obtained from ethyl ethoxalylacetate on decomposition in warm xylene gives 54% of dicarbethoxyketene.122 139 Schroeter, Ber., 42, 2336, 3356 (1909). 140 Smith and Hoehn, Org. Syntheses, 20, 47 (1940). "'* Ritter and Wiedeman, J. Am. Chem. Soc., 61, 3583 (1929). 142 Gilman and Adams, Rec. trav. chim., 48, 464 (1929). 124 ORGANIC REACTIONS Small pieces of platinum have been used as catalyst for the decomposi- tion of these diazo compounds. Only the ketoketenes mentioned above have been obtained from the di- azo ketones. Attempts to prepare the more highly unsaturated ketenes, C6H5CH==CHC(CO2R)=C=O and CH3CH=CHC(CO2R)=C=O from cinnamoylacetic ester and crotonylacetic ester, respectively, were unsuccessful.122 Aldoketenes could not be obtained from acetyldiazo- methane (CH3COCHN2) and benzoyldiazomethane (CeHgCOCHNg),119 nor could ketenes be obtained from diacetyldiazomethane, benzoyl- acetyldiazomethane,119 mesitoyldiazomethane,129" and 2,4,6-triisopro- pylbenzoyldiazomethane. It is of interest that methyl 5-phenyl- l,2,3-thiodiazole-4-carboxylate and methyl l,5-diphenyl-l,2,3-triazole- carboxylate do not yield ketene analogs on pyrolysis.122 The P-Lactone Method. Dimethylketene has been prepared in 50% yield by pyrolysis of a-carbomethoxy-a,/?-dimethyl-/3-butyrolactone.143 The lactone was prepared from acetone and methylmalonic acid.144 The (CH3)2CO + CH3CH(CO2H)2 ^?h° > (CH3)2C¡ªC(CH3)Co2H H2SO4 I I 0¡ªCO (CH3)2C¡ªC(CH3)CO2CH3 -^ (CH3)2C=C=O + (CH3)2CO + CO2 0¡ªCO intermediate a-carboxy lactone did not give any methylketene upon pyrolysis. However, the lactone of a-carboxy-j3-methyl-|8-butyrolactone did give a little carbon suboxide (5.2% yield).143 a-Carbomethoxy-a- (CH3)2C¡ªCHC02H -? (CH3)2CO + O=C=C=C=O + H20 0¡ªCO bromo-/8-methyl-j3-butyrolactone yielded an unspecified amount of a polymer of methylbromoketene.143 The corresponding a-carboxy lactone gave none of the expected bromoketene.143 Dehydrohalogenation of Acyl Halides by Means of Tertiary Amines. One of the oldest methods of preparing diphenylketene consists in the dehydrohalogenation of diphenylacetyl chloride with tertiary amines.146 The yield of the ketene was reported as quantitative when tripropyl- amine was the dehydrohalogenating agent, and considerably less with quinoline, whereas thermal dehydrohalogenation of the acid chloride 143 Ott, Ann., 401, 159 (1913). 144 The method is an adaptation of that of Meldrum, /. Chem. Soc, 93, 601 (1908). 146 Staudinger, Ber., 40, 1148 (1907). PREPARATION OF KETENES AND KETENE DIMERS 125 gave only a low yield.35 However, certain unsymmetrical diarylketenes have been prepared by thermal dehydrohalogenatios of the acid chlorides in the presence of not more than traces of pyridine hydrochloride.146'147 For example, mesitylphenylacetic acid, prepared from mesitylene and mandelic acid in the presence of stannic chloride, is converted into the ketene in excellent yield 146 by refluxing in benzene with thionyl chloride and a little pyridine, separation of the precipitated pyridine hydro- chloride by filtration, and distillation of the acid chloride at reduced soci2 CH3 ICH(C6H5)COC1 HC1 pressure. It is of interest to note that this ketene was formed during an attempt to carry out a Rosenmund reduction of the. acid chloride.146 In preparations of aliphatic ketoketenes 115'148 the dehydrohalogena- tions have been accomplished by treatment with slightly more than equivalent amounts of tertiary aliphatic amines, the reactions being carried out by adding the amines to solutions of the acid chlorides in inert solvents like ether, benzene, toluene, ligroin, trichloroethylene, tetra- chloroethylene, or carbon tetrachloride. Trimethylamine appears to be the most satisfactory base in the preparation of aliphatic ketoketenes, owing to the low solubility of the hydrochloride in organic solvents.' The reaction is effected by allowing the mixture to stand at room temperature for several hours, after which time the amine salt is removed by filtration and the ketene is recovered by distillation at the lowest possible pressure. Dimethylaniline and pyridine are reported to be unsatisfactory for the preparation of dialkyl ketoketenes.148 The tertiary amines must be free of primary and secondary amines. The presence of small amounts of diethylamine in the triethylamine used in such preparations leads to formation of diethylamides. Such amides were originally mistaken for "ketenium" derivatives of tertiary amines.149 The applicability of this method is limited by the fact that the tertiary 146Fuson, Armstrong, Kneisley, and Shenk, J. Am. Chem. Soc, 66, 1464 (1944). 147 Fuson, private communication. -14S U. S. pat., 2,268,169 [C. A., 36, 2737 (1942)]. 149 For a discussion, see Miller and Johnson, J. Org. Chem., 1, 135 (1936). 126 ORGANIC REACTIONS amine salts catalyze the dimerization of ketenes.132' m Consequently only those ketenes which have relatively low tendencies toward dimeriza- tion can be prepared in this way. Dialkylacetyl chlorides of low molecu- lar weight, such as isobutyryl chloride,149 and monoalkylacetyl chlorides give only dinners (see p. 129).160 Evidently no aldoketene has been pre- pared by this method. The ketenes which have been prepared by dehydrohalogenation of acyl halides are listed in Table VI. TABLE VI PREPARATION OF KETOKETENES BY DEHYDROHALOQENATION OF ACYL HALIDES R(R')CHCOX + R3"N -> R(R')C=C=O + R3"N HX Ketene (CH3)2C=C=O (n-C7Hi6)2C=C=O n-Ci2H25C (C2H6)=C=O CH2CH2 CH2 C=C=O CH2CH2 CH21 H CH2 \=C=0 HCHS)2 C ATT 2,4,6-(CH3)3C6H2C(C6H6)=C=O Dehydrohalogenating Agent (C2H6)3N (CH3)3N (CHS)3N ? (C2H6)sN C9H7N or (Q!H5)3N (C3H7)3N C9H7N Heat Distillation at reduced pressure Yield Dimer only (60%) 58% 29% 32% * 56-58% f Quant. ¡ª Low 64-67% Refer- ence 149 148 148 115 . 151 35 35 35 146, 147- * The dimer was obtained in 66% yield. t The yield is based on the formation of derivatives from the unisolated ketene. 160 U. S. pat., 2,238,826 [C. A., 35, 4970 (1941)]. 161 Staudinger and Schotz, Ber., 63, 1105 (1920). PREPARATION OF KETENES AND KETENE DIMERS 127 PREPARATION OF KETENE DIMERS All known ketenes dimerize when heated or when allowed to stand at room temperature or below for a sufficient length of time. The dimers of ketoketenes undoubtedly are derivatives of cyclobutanedione. For ex- ample, the dimer of dimethylketene has a pleasant odor similar to that of ketones; it yields two isomeric (cis and trans) glycols upon reduction; and it yields mono- and di-oximes which give the expected products in the Beckmann transformation.162 0II CH3 C CH3 \ / \ / 2(CH3)2C=C=O -? C C / \ / CH3 C CH3 II 0 The dimers of aldoketenes are much more reactive. Diketene has a harsh, irritating odor entirely unlike that of dimethylketene dimer, and its characteristic reactions resemble those of ketenes or acid anhydrides rather than those of ketones. It reacts with water and alcohols (in the presence of catalytic amounts of strong acid) to give acetoacetic acid and its esters,117 with ammonia and amines to give acetoacetamides,117 and with ozone to give pyruvaldehyde,163 reactions which are easily inter- preted on the basis of formula I. Hydrogenation over Raney nickel catalyst converts.it to /3-butyrolactone,1M a reaction most readily explica- ble on the basis of one of the lactone formulas (II and III). The addition of halogen leads to a i-haloacetoacetyl halide,166-1M a result which might CH3C0CH=C==0 CH2=C¡ªCH2 CH3C=CH CHz¡ªCO 0¡ªC=0 0¡ªC=0 CO CH2 1 11 in iv be accounted for on the basis of formula II more easily than on the basis of formula III; however, the absorption spectrum appears to be in better 162 Private communication from Professor J. R. Johnson, Cornell University, and taken from the doctoral thesis of L. L. Miller, entitled "The Structure of Some Derivatives of Dimethylketene," 1937. 163 Hurd and Williams, J. Am. Chem. Soc, 58, 962 (1936). 164 Johnson and Gross, paper presented at the American Chemical Society, Organic Division, in New York City on April 23, 1935. 166 Chick and Wilsmore, J. Chem. Soc, 97, 1978 (1910). "?Hurd and Abernethy, J. Am. Chem. Soc, 62, 1147 (1940). 128 ORGANIC REACTIONS agreement with III.167 The dipole moment of diketene agrees with values calculated for the most probable structures and does not serve to-dis- tinguish among them.168 The behavior of diketene on pyrolysis is said to be compatible only with the cyclobutanedione formula, IV.169'160 The dinners of aldoketenes yield higher polymers on moderate heating. Dehy- dracetic acid is formed from diketene; if the acetylketene formula (I) is 0 0 II II c c / / CH CHCOCHs CH CHCOCH3 CH3C C=O CH3C C=O \ \ / 0 0 used the reaction can be written as a Diels-Alder condensation. Dike- tene can be stored indefinitely at temperatures of 0° or below.117 Apparently there is yet no agreement among students of the problem of the diketene structure,117' 163~164 and it is possible that the substance actually is a mixture of readily interchangeable isomeric forms. The use of the acylketene formula I in the sequel is for convenience only. The dimers of aldoketenes undergo the same reactions as diketene and present the same problems of structure.116' * In the laboratory preparation 166 of diketene the mixture of ketene, unchanged acetone, and methane from a ketene generator is passed into a condensing system which is cooled initially in Dry Ice, and the conden- sate is allowed to warm to room temperature over a period of about twenty-four hours. The resulting mixture of acetone, diketene, and dehydracetic acid is separated by distillation under reduced pressure (50-55% of diketene). More exact control of the concentration and * Note added in proof. Bauer, Bregman, and Wrightson of Cornell University (private communication) have recently made electron diffraction studies of diketene vapor using the sector technique. They find that formulas II and III are compatible with the observed diffraction pattern and that formulas I and IV must be discarded. Since the evidence of Taufen and Murray from the Raman spectrum of liquid diketene eliminates formulas III and IV, only formula II satisfies both sets of experimental data, and it therefore appears to represent the most probable structure for the dimer. 167 Calvin, Magel, and Hurd, J. Am. Chem. Soc, 63, 2174 (1941). 168 Oesper and Smyth, /. Am. Chem. Soc, 64, 768 (1942). 169 Rice and Roberts, abstract of paper presented at 104th meeting of the American Chemical Society, Organic Division, Buffalo, New York, p. 12M, September, 1942. l?o Rice and Roberts, J. Am. Chem. Soc, 65, 1677 (1943). 161 Hurd, Sweet, and Thomas, J. Am. Chem. Soc, 55, 337 (1933). 162 Staudinger, Ber., 53, 1085 (1920). 1C3 Angus, Leckie, LeFevre, LeFevre, and Wassermann, J. Chem. Soc, 1935, 1751. 164 Taufen and Murray, J. Am. Chem. Soc, 67, 754 (1945). 165 Williams and Krynitsky, Org. Syntheses, 21, 64 (1941). PREPARATION OF KETENES AND KETENE DIMERS 129 temperature in the commercial preparation probably permits a higher conversion to diketene. Several variations of the above procedure are disclosed in the patent literature.166"176 Dimers of other ketenes also can be prepared from the monomers, but frequently it is more convenient to prepare the dimers directly by extend- ing the reaction time or increasing the reaction temperature. The most convenient preparation of higher aldoketene dimers is that of dehydro- halogenation of acyl halides with tertiary aliphatic amines.116'160' m 2RCH2COC1 + 2R'3N -> RCH2COC=C=O + 2R'3NH+C1- R In many preparations nearly quantitative yields are obtained by allow- ing the reactions to run at room temperature for about twenty-four hours. This is one of the simplest methods of bringing about the forma- tion of a new carbon-carbon bond, and it affords a very attractive route to derivatives of /3-keto acids; for example, esters of the type RCH2COCHRCO2C2H5 are obtained from the acids (RCH2CO2H) by converting the acid chlorides to the ketene dimers and allowing these to react with ethanol. RCH2COC=C=O + C2H5OH -^-4 RCH2COCHCO2C2H6 R R Mixed aldoketene dimers have been prepared by treating mixtures of two acid chlorides with tertiary aliphatic amines.150 Presumably the two monomeric ketenes are formed and combine to give the simple and mixed dimers. Three of the four possible products have been isolated from the treatment, of a mixture of acetyl and lauroyl chlorides with triethylamine. CH3COCH=C=O (14%) CH3COCI 2(CWiW CH3(CH2)10COC(C10H21)=C=O (14%) CH3(CH2)10COC1 * CH3(CH2)10COCH=C=O (12%) [CH3COC(CioH2i)=C==0, not identified] 166 U. S. pat., 2,019,983 [C. A., 30, 487 (1936)]. 167 Fr. pat., 761,731 [C. A., 28, 4072 (1934)]. 188 Can. pat., 352,920 [C. A., 29, 8008 (1935)]. 169 Brit, pat., 410,394 [C. A., 28, 6160 (1934)]. 170 TL S. pat., 1,998,404 [C. A., 29, 3689 (1935)]. 171V. S. pat., 2,103,505 [C. A., 32, 1718 (1938)]. 172 Brit, pat., 498,280 [C. A., 33, 3820 (1939)]. 173 U. S. pat., 2,216,450 [C. A., 35, 757 (1941)]. 174 Ger. pat., 700,218 [C. A., 35, 6976 (1941)]. 176 Fr. pat., 835,162,[C. A., 33, 4274 (1939)]. 176 Brit, pat., 550,486 [C. A., 38, 1534 (1944)]. 177 U. S. pat., 2,369,919 [C. A., 39, 4086 (1945)]. 130 ORGANIC REACTIONS The various ketene dimers which have been reported are listed in Table VII. No attempt has been made to give all the references to the preparation of a particular dimer; only those references which, in the authors' opinion, give the best preparative methods are listed. Experi- mental procedures for preparing ketene dimers are described on pages 1137 and 140. TABLE VII KETENE DIMERS A. Aldoketene Dimers Dimer (CH2=C=O)2 (CH3CH=C=O)2 (;so-C3H7CH=C=O)2 (ra-C4H9CH=C=O)2 C2H6COC(n-C4H9)=C=O and/or n-C6HuCOC (CH3)=C=O C2HBCOC (n-C6Hi3)=C=O and/or n-C7Hi6COC(CH3)=C=O n-CuH23COCH=C=O (n-C6Hi3CH=C=O)2 (n-Ci0H2iCH=C=O)2 (rc-Ci6H33CH=C=O)2 (C6HBCH=C=O)2 [2,4,6-(CH3)3C6H2CH= C=O]2 [ (CO2CH3)CH=C=O]2 Method of Preparation Monomer in acetone, low tempera- ture CH3COC1 + (C2H6)3N * CH3CH2COC1 + (C2HB)3N CH3CHBrCOBr + Zn i"so-C3H7CH2COCl + (C2H6)3N n-C4H9CH2COCl + (C2H6)3N CH3CH2COC1 + CH3(CH2)4COC1 + (C2H6)3N CH3CH2COC1 + CH3(CH2)6COC1 + (C2H6)3N CH3COC1 + CH3(CH2)i0COCl + (C2H5)3N CH3(CH2)6COC1 + (C2H6)3N ra-CioH2iCH2COCl + (C2H6)3N n-Ci6H33CH2COCl + (C2H6)3N C6H6CHC1COC1 + Zn 2,4,6-(CH3)3C6H2CHBrCOBr +Zn ' CO2CH3 H2C^ (heated) XCOC1 Yield 55% 14%* 60%, 74% 28%, t 36% t ? 60% 65%, 27% t 44% t 26% f 12%* 31% t 75% 90% 97% 10% ¡ª Low Refer- ence 165 150 115, 177 150 150 127 177 115, 150 150 150 150 150 177 177 177 127 129a 135 * From the preparation of simple and mixed dimers by the action of triethylamine on a mixture of acetyl and lauroyl chlorides. t From the preparation of simple and mixed dimers by the action of triethylamine on a mixture of propionyl and capryloyl chlorides. t From the preparation of simple and mixed dimers by the action of triethylamine on a mixture of propionyl and caproyl chlorides. PREPARATION OF KETENES AND KETENE DIMERS 131 TABLE VII¡ªContinued KETENE DIMBRS B. Ketoketene Dimers Dimer CO (CH3)2C C(CH3)2 CH3 CO CH3 C C C2H6 CO C2H5 CO CO (CH2)6C C(CH2)6 Xco/ CO (n-C3H7)2C C(ra-C3H7)2 CO CH3 CO CH3 \ / \ /c c / \ / \CH2=CHCH2 CO CH2CH=CH2 CO y* V (CH2=CHCH2)2C C(CH2CH=CH2)2 CO C2H6 CO C2H5 Xc/ Xc/ C2H5O2C CO CO2C2H5 Method of Preparation (CH3)2CHCOC1 + (C2H6)gN Heating of monomer Heating of monomer CH2CH2 CH2 CHCOC1 CH2CH2 (C2H6)3N Heating of monomer Heating of monomer Heating of monomer C2H6 Br C +Zn C2H6O2C COC1 From the monomer Yield 57% 84% 83% 32-66% 10% 78% 96% 80% ¡ª Ref. 149 110 110 115 no no no 120,121 36 132 ORGANIC REACTIONS TABLE VII¡ªContinued KETBNE DIMERS B. Ketoketene Dimers¡ªContinued Dimer CO \\J2a.b\J2\~')2^ ^ \S-'V2\J2xlb)2 > CeHs CO CSHB C2H5O2C CO OO2C2H5 CO (C6H6)2C C(C6H6)2 Xco/ CH3 CO CH3 C6H5 CO C6H6 C6H6CH2 CO CH2C6H5V V CH3 CO CH3 CO (C6H6CH2)2C C(CH2C6H6)2 CO Method of Preparation Heating of monomer Heating of monomer Heating of monomer Heating of monomer Heating of monomer Heating of monomer Yield Low "Nearly quanti- tative" _ "Quan-tita- tive" "Quan- tita- tive" "Nearlyquanti- tative" Ref. 121 121 35, 123 110 110 EXPERIMENTAL PROCEDURES Pyrolysis Kete'ne by Pyrolysis of Acetone.3 Description of Apparatus. The apparatus consists essentially of a Chromel A filament (0 in Fig. 1) sus- pended from the top portion of a ground-glass joint (H) so that it can be removed from the pyrolysis chamber (E) whenever desired. Filament 0 is prepared from 175 cm. of B. and S.* gauge 24 Chromel A wire (an * B. and S. refers tp Brown and Sharpe, Inc., 20 Vesey Street, New York, New York. PREPARATION OF KETENES AND KETENE DIMERS 133 alloy of 80% nickel and 20% chromium) by wrapping the wire in a tight spiral around a rod 3 mm. in diameter and stretching the coil so formed to a length of 70 cm. The filament is held in position on 15-mm.- long platinum hooks (N) sealed into the Pyrex glass rod which supports -w M- FIG. 1. them. The three hooks at the bottom of the rod are spaced 120° apart. Two platinum hooks support the filament at a distance of 11 cm. above the end. The ends of the filament 0 are connected to tungsten leads by means of nickel sleeves P, 10 mm. in length and 3.5 mm. in internal diameter, equipped with two set screws. The tungsten leads are of B. and S. gauge 24 wire and are sealed into the glass at the points Q, and above these junctions are soldered to B. and S. gauge 24 copper wire (S) at the points R. The copper leads' S are insulated by pieces of 6-mm. 134 ORGANIC REACTIONS glass tubing T, which are held by the cork stopper W. The copper wire leads are connected to a source of 110-volt alternating current, preferably through a variable resistance such as a Variac transformer. All the glass in the apparatus is Pyrex. The ground-glass joint H is a 55/50 standard taper. Chamber E is constructed from a 25-cm. length of glass tubing of 70-mm. internal diameter. Connecting tube D is 12- mm. tubing, side arm F is 15-mm. tubing, and reflux return tube G is 6-mm. tubing. Joint / is a 19/38 standard taper. Condensers / and K are of any efficient type. In the apparatus illustrated / is a double spiral condenser 50 cm. long, and K is a single spiral condenser 90 cm. long. The two are connected at the tops by a glass seal. The liquid trap L sealed to the lower end of condenser K is constructed of 35-mm. tubing and is 125 mm. long, with a stopcock for the removal of liquid from the trap. The ketene is conducted away through the tube M, of 8-mm. diameter. Operation. The acetone is placed in A, a 2-1. round-bottomed flask which is attached to the lamp by means of a rubber stopper C. Through this stopper extends a piece of 6-mm. glass tubing B which may be used to introduce more acetone when needed. The tube B must be closed when the apparatus is being operated. The introduction into A of suffi cient glass wool to extend a few centimeters above the surface of the liquid serves to prevent bumping. After M is connected to the proper apparatus, the stopcock on L is closed and the liquid in A is heated until it refluxes gently from condenser J. Five minutes' refluxing should be allowed to drive the air from chamber E. The current is then passed through filament 0, which should be heated to a dull red glow (tempera- ture 700-750°). After the operation is started the apparatus needs little attention. Occasionally, condensed liquid must be removed from trap L, in which the amount of condensate collected depends upon the temperature of the water in condensers J and K. At the end of a run the following operations must be carried out rapidly in this order: (1) the source of heat is removed from flask A, (2) the fila- ment current is turned off, and (3) the stopcock on L is opened. Calibration. The amount of ketene produced per hour may be deter- mined either by weighing the acetanilide produced by passing the effluent gas stream through excess aniline for a measured period of time or by passing the gas stream through standard alkali with subsequent titration of the unused alkali. By the second method the apparatus described was found to deliver 0.45 mole of ketene per hour. In a continuous run of ten hours 4.53 moles of ketene was produced with a net consumption of about 350 cc. of acetone from flask A. If the residual liquid and con- PREPARATION OF KETENES AND KETENE DIMERS 135 densate were pure acetone, this would represent a 95% yield, but the figure is too high, for, although the liquid is chiefly acetone, it contains small amounts of acetic anhydride, acetic acid, and ketene dimer. Malonic Anhydride Method Dimethylketene.109 To 25 g. of acetic anhydride containing a trace of concentrated sulfuric acid in a dry Claisen distilling flask protected from moisture is added 6.5 g. of dimethylmalonic acid. The solid dissolves when the mixture is shaken. The solution is allowed to stand at room temperature for two days. A small amount of powdered barium car- bonate is added, and most of the acetic acid and acetic anhydride is re- moved by distillation at 1-mm. pressure while the flask is heated gently in an oil bath. The last traces of acetic acid and acetic anhydride are removed by heating at 60° under a pressure of 1 mm. or lower. The flask is then connected to a dry receiver cooled in a Dry Ice bath, and the residual, thoroughly dry dimethylmalonic anhydride is decomposed by slowly raising the temperature of the oil bath until vigorous evolution of carbon dioxide and dimethylketene occurs (about 100°). The pressure is maintained at the lowest possible point during the decomposition. The dimethylketene (b.p. 34° at atmospheric pressure) collected in the cold receiver weighs 2.3 g. (65%). Dipropylketene.110 To 5.6 g. of dipropylmalonic acid in 5 cc. of an- hydrous ether is added 11.5 g. of diphenylketene (p. 123) with cooling in an ice bath. The clear solution begins to deposit crystals after one hour. Crystallization is completed by cooling in an ice bath, and a nearly quantitative yield of the mixed anhydride melting at 84° is ob- tained. The mixed anhydride can be recrystallized from a mixture of carbon disulfide and petroleum ether (b.p. 30-70°). The mixed anhydride (10 g.) is placed in a small Claisen flask connected to a receiver cooled in Dry Ice and acetone and is heated under a pressure of about 11 mm. and at a bath temperature of 90-100°. Decarboxylation proceeds fairly rapidly, and dipropylketene (b.p. 30°/ll mm.) distils into the cooled receiver. Diphenylacetic anhydride remains in the distillation flask. On the basis of the amount of dipropylacetanilide formed when aniline is added to the distillate, the yield of dipropylketene is 32%.* Dibenzylketene.110 A solution of 8.5 g. of dibenzylmalonic acid in 8 cc. of anhydrous ether is mixed with 11.6 g. of diphenylketene (p. 123). The" mixture is shaken mechanically for four hours, or until complete solution occurs. It is then transferred to ,an ice bath and cooled until ?This is the percentage yield cited by Staudinger (ref. 110); however, the weight of dipropylacetanilide reported by him corresponded to an 83% yield. 136 ORGANIC REACTIONS crystallization is complete. The yield of crude mixed anhydride is nearly quantitative. After recrystallization from a mixture of carbon disulfide and petroleum ether (b.p. 35-70°) it melts at 104°. The purified anhy- dride is placed in a Claisen flask and heated under reduced pressure at 110° until the evolution of carbon dioxide is complete. The dibenzyl- ketene is extracted from the residue with petroleum ether (b.p. 35-70°). The yield of dibenzylketene in the filtered extract, calculated from the weight of dibenzylacetanilide obtained by treatment of an aliquot por- tion with excess aniline, is 73%; the yield of dibenzylketene (b.p. 121¡ª 122°/0.08 mm.) which can be isolated by distillation is 2.7 g. (40%). Depolymerization Dimethylketene.116 A modification of the ordinary ketene lamp is necessary to permit the pyrolysis of the comparatively high-melting di- methylketene dimer (m.p. 115°), which tends to sublime out of the reac- tion zone. The apparatus illustrated in Fig. 2 has a triple filament made Dimethylketene Lamp Fio. 2. of No. 26 gauge Nichrome wire. For each filament (C), between 25 and 28 cm. of wire is wound around a microscope slide (2.5-cm. width) and then spot-welded to the tungsten supports (H), All joints are made of ground glass, and when the lamp is in operation they are held together by rubber bands. The circular bulb trap (D) is cooled by a stream of tap water. There are two traps (E) cooled in Dry Ice-acetone in the train (one shown in diagram); the final trap is connected to a calcium chloride tube. The filament is connected to a 110-volt a-c. source, with an am- meter and variable resistance in the circuit. The plunger (F) can be used if necessary to dislodge any sublimed dimethylketene dimer. The nitrogen gas, employed to sweep the ketene and unchanged dimer and monomer away from the filament and into the traps, is passed PREPARATION OF KETENES AND KETENE DIMERS 137 through two gas wash bottles containing Fieser's solution,* two cal- cium chloride tubes, a third wash bottle containing concentrated sulfuric acid, finally a third calcium chloride tube, and then into the lamp at the nitrogen inlet (A). A weighed amount of the dimer is placed in the reaction flask (B), and the entire system is evacuated by a water pump. Nitrogen is then drawn through the system for approximately five minutes. The water pump is then disconnected, and the nitrogen is allowed to flow under the pressure of a few centimeters of mercury. Dry Ice and acetone are next placed in the Dewar flasks for cooling the traps (E). As soon as the temperature of these traps reaches ¡ª 70° the filament is heated, and an oil bath (90-100°) is placed around the reaction flask. The oil level reaches the outlet tube ((?) of the reaction flask. The oil bath is heated to the desired temperature, usually 120°, for the duration of the run. Within a few minutes vapor is observed leaving the reaction flask, and the flow of nitrogen is regulated so that the vapor flows steadily and slowly into the circular bulb trap. The nitrogen current must not be strong enough to carry the vapor into the Dry Ice traps. At the end of the run the flow of nitrogen is stopped, the electric current is turned off, and a cork is placed in the calcium chloride tube at the end of the train. The monomeric dimethylketene, which collects for the most part in the first Dry Ice trap, may be stored in this condition until desired. With the oil-bath temperature at 120° and the Nichrome filament at a dull red heat, there are collected 6 g. of dimethylketene in E and 3 g. of unchanged dimer in D from a charge of 10 g. of starting material (86% yield of dimethylketene based on dimer consumed). The recovered dimer is washed out of the apparatus with ether. The filament is cleaned with a camel's-hair brush after each run; less than 0.05 g. of carbon is deposited during a 10-g. run. If the temperature of the oil bath is allowed to fall below 120° for an appreciable length of time or if the flow of nitrogen is slow, the yield is lower. Too strong heating of the filament also lowers the yield. Ethylcarbethoxyketene.120 To 32 g. (0.5 mole) of zinc shavings is added 104 g. (0.41 mole) of a-bromo-a-carbethoxybutyryl chloride (p. 138) in 600 cc. of absolute ether, and the mixture is refluxed for four hours. The ether solution is shaken with water, dilute hydrochloric acid, and dilute sodium hydroxide and is then dried over calcium chloride. The solvent is removed, and the residue is distilled in the highest vacuum. The yield of the dimer boiling at 113-116° ("absolute" vacuum) is 35 g. (61%). A 10-g. portion of the dimer is placed in a small distilling flask equipped with a short fractionating column connected to a receiver cooled * For details of the preparation of the solution see Fieser, J. Am. Chem. Soc., 46, 2639 (1924). 138 ORGANIC REACTIONS in Dry Ice. Depolymerization is effected by heating in an oil bath at 180-200° under a pressure of 15 mm. for about five hours. The yield of ethylcarbethoxyketene (b.p. 48°/15 mm.) is nearly quantitative. Dehalogenation of a-Haloacyl Halides Ethylcarbethoxyketene.120 a-Carbethoxybutyryl Chloride. To a solu- tion of 300 g. (1.9 moles) of a-carbethoxybutyric acid in 500 cc. of abso- lute ether is added slowly with cooling 420 g. (2 moles) of phosphorus pentachloride. The mixture is refluxed two hours to complete the reac- tion. After removal of the ether and phosphorus oxychloride by distilla- tion under reduced pressure, there is obtained 230 g. (69%) of the acid chloride boiling at 75-77°/13 mm. a-Bromo-a-carbethoxybutyryl Chloride. Into a refluxing solution of 200 g. (1.13 moles) of the acid chloride in 200 cc. of carbon disulfide is slowly dropped 190 g. (1.18 moles) of bromine. Refluxing is continued for two hours after completion of the addition. After removal of the carbon disulfide by distillation under reduced pressure, there is obtained 250 g. (87%) of the bromo derivative boiling at 95-102°/14 mm. Ethylcarbethoxyketene. A solution of 26 g. (0.1 mole) of the bromo acid chloride in 200 cc. of absolute ether is added to 15 g. (0.23 mole) of zinc shavings at such a rate that the ether refluxes gently. After the addition is complete the reaction mixture is refluxed briefly and 600 cc. of petroleum ether is added in order to precipitate the zinc chloride. If the ketene is not isolated from the solvent but converted into the anilide by addition of aniline, an amount of anilide corresponding to a 34% yield of the ketene is isolated. However, if the ketene is isolated from the solvent by vacuum distillation, the yield of monomer is much lower (not given). If pure monomeric ethylcarbethoxyketene is de- sired, it is preferable to prepare the dimer and depolymerize it thermally (p. 137). Dehydrohalogenation Diheptylketene.148 In a dry flask protected from the atmosphere 24 g. (0.09 mole) of diheptylacetyl chloride is added to a solution of 7.1 g. (0.12 mole) of trimethylamine in 150 g. (188 cc.) of anhydrous benzene. The mixture is allowed to stand at room temperature for twenty-nine hours, and the precipitated trimethylamine hydrochloride (6.8 g., 80%) is separated by rapid filtration.178 The solvent is removed from the filtrate by distillation at room temperature under about 200 mm. pressure. Dis- 178 For a simple technique of filtration with exclusion of moisture see Bost and Constable, Org. Syntheses, CoU. Vol. 2, 610 (1943). PREPARATION OF KETENES AND KETENE DIMERS 139 tillation of the residue yields 12.3 g. (60%) of diheptylketene boiling at 133-13575 mm. (rag 1.4432). Mesitylphenylketene.146'l47 Mesitylphenylacetic Acid. A mixture of 152 g. (1 mole) of a good grade of dry mandelic acid and 353 g. (400 cc, 2.9 moles) of dry mesitylene is placed in a 1-1. round-bottomed three- necked flask fitted with a mechanical stirrer (grease seal), a 250-cc. separatory funnel, and a condenser protected from moisture by calcium chloride tubes. A thermometer is inserted in the reaction mixture by way of the condenser tube, the stirrer is started, and the temperature is raised to 70° by heating over an electric light. After this temperature has been maintained for one hour (to bring most of the mandelic acid into solution), 390 g. (175 cc, 1.5 mole) of anhydrous stannic chloride is added dropwise over a period of eighty minutes. Stirring and heating are continued for eight hours more. During this period large colorless stannic chloride hydrate crystals form on the upper parts of the flask. After standing overnight at room temperature, the reaction mixture is treated with 500 cc. of water. The organic layer is separated, the aque- ous portion is extracted with one 100-cc. portion of ether, and the com- bined organic layers are diluted with 1200 cc. of ether. The ethereal so- lution is washed twice with 100-cc. portions of water and is then shaken with 100-cc. portions of 7% aqueous sodium carbonate (about fourteen washings are required for complete separation). The first two or three portions of carbonate solution cause precipitation of stannic hydroxide, and they are collected separately and filtered. The filtrate is combined with the subsequent carbonate extracts. Acidification with concentrated hydrochloric acid precipitates the acid as a white solid. It is collected by filtration on a 15-cm. Btichner funnel, washed twice with 300-cc. portions of water, and dried in the air. It weighs about 190 g. and melts at 170- 172°; it can be purified further by recrystallization from a mixture of 800 cc. of ethanol and 150 cc. of water. The yield of acid melting at 172- 173° is 165 g. (65%). Mesitylphenylketene. A mixture of 25 g. (0.1 mole) of dry mesityl- phenylacetic acid, 200 cc. of dry benzene, 13 g. (0.11 mole) of thionyl chloride purified by distillation from cottonseed oil (2.5 1. of commercial thionyl chloride to 1 1. of Puritan oil), and 0.5 cc. of dry pyridine is placed in a 300-cc. flask fitted with a ground-glass joint. A condenser equipped with a drying tube is attached, and the solution is heated under reflux for five hours. Pyridine hydrochloride is precipitated on the sides of the flask. The mixture is filtered by suction, the filtrate is introduced into a 250-cc. Claisen flask, and the solvent is removed under the vacuum of a water pump. The residue is transferred to a 60-cc. Claisen flask and distilled at a good water pump (much hydrogen chloride is 140 ORGANIC REACTIONS evolved). A golden yellow liquid boiling at 150-155°/13-14 mm. and weighing 18-19 g. (80%) is collected. Redistillation yields 15-16 g. of the ketene boiling at 125-126°/3 mm. The yellow liquid turns deep red upon storage but is regenerated upon distillation. It reacts rapidly with the moisture of the air to give mesitylphenylacetic acid. n-Butylketene Dimer.116 Into a 2-1. three-necked round-bottomed flask equipped with a reflux condenser carrying a calcium chloride tube, a motor-driven stirrer with a mercury seal, and a 150-cc. graduated dropping funnel is poured 850 cc. of anhydrous ether. Stirring is com- menced, and 134.5 g. (1.0 mole) of n^caproyl chloride, b.p. 45-45.5°/6 mm., is added rapidly through the condenser. To this well-agitated mix- ture is added dropwise from the funnel 99.9 g. (0.99 mole) of triethyl- amine, b.p. 88°, at a rate just sufficient to maintain gentle refluxing. During the addition of the first few cubic centimeters of the triethyl- amine, there is no noticeable evidence of reaction. However, as the proportion of triethylamine to n-caproyl chloride increases, the reaction proceeds with great vigor and triethylamine hydrochloride precipitates as a light orange-colored solid. The reaction mixture is stirred for one and one-half hours after the addition of the triethylamine and is then allowed to stand overnight at room temperature. The solution of the ketene dimer is removed by the inverted filtration method.178 The crude triethylamine hydrochloride can* be purified by pressing firmly on a Biichner funnel and washing thoroughly with dry ether. The pure air-dried hydrochloride weighs 135 g. (98%). The ether is removed from the filtrate by fractionation through a helix-packed column (1.5 cm. by 60 cm.). About 75 cc. of a light yellow residue which remains is transferred to a modified Claisen flask. The r^butylketene dimer boiling at 115-116°/4 mm. weighs 64 g. (65%). The n-butylketene dimer is a colorless, oily liquid possessing no distinct odor. Its physical constants are as follows: Df 0.91700; % 1.4513; MRD calculated 57.19, observed 57.50; molecular weight calculated 196.2, found (cryoscopically in benzene) 191.4. CHAPTER 4 DIRECT SULFONATION OF AROMATIC HYDROCARBONS AND THEIR HALOGEN DERIVATIVES C. M. StTTER Winthrop Chemical Company AND ARTHUR W. WESTON Abbott Laboratories CONTENTS PAGE INTRODUCTION 142 GENERAL ASPECTS OF THE REACTION 142 Sulfonation with Sulfuric Acid and Sulfur Trioxide 142 Sulfonation with Addition Compounds of Sulfur Trioxide 146 Sulfonation with Miscellaneous Reagents 147 Side Reactions , 148 APPLICATION OF THE REACTION . 149 Benzene 149 Toluene 150 Xylenes 1 Trimethylbenzenes 153 Halobenzenes 3 Alkylhalobenzenes 4 Biphenyl and Derivatives 155 Arylalkanes and Arylalkenes 6 Naphthalene 156 Anthracene 8 Phenanthrene 9 SELECTION OF EXPERIMENTAL CONDITIONS 160 ISOLATION AND IDENTIFICATION OF SULFONIC ACIDS 161 EXPERIMENTAL PROCEDURES 162 2,4,6-Trimethylbenzenesulfonic Acid (Mesitylenesulfonic Acid) 162 Sodium 1,3,5-Benzenetrisulfonate 163 4,4'-Dibromobiphenyl-3-sulfonic Acid 3 Sodium Pyrene-3-sulfonate 163 2,5-Dichlorobenzenesulfonyl Chloride 164 Benzenesulfonyl Fluoride 4 TABLES 165 141 142 ORGANIC REACTIONS INTRODUCTION This chapter deals with the direct replacement of the hydrogen atoms in aromatic hydrocarbons and their halogen derivatives by sulfonic acid, sulfonyl chloride, and sulfonyl fluoride groups. These sulfonations are more convenient and much more commonly used than indirect synthetic methods such as those which involve the reaction of an aryl halide with a sulfite, the oxidation of a disulfide, thiol, or sulfinic acid, or the conver- sion of a diazonium salt into a sulfonic acid. The reagents most often used for direct^sulfonation are (1) sulfuric acid, (2) sulfur trioxide in an inert solvent, in sulfuric acid as oleum, or as an addition product with pyridme or dioxane, (3) chlorosulfonic acid, its salts, and its anhydride (pyrosulfuryl chloride), and (4) fluorosulfonic acid. Sulfamic acid, alkali bisulfates, and sodium trihydrogen sulfate, NaH3(804)2, are employed less frequently. Combinations of reagents which have been used are sulfuric acid with phosphorus pent6xide, chlorosulfonic anhydride with aluminum chloride, sulfuryl chloride with aluminum chloride, and sulfuryl chloride with chlorosulfonic acid. GENERAL ASPECTS OF THE REACTION Sulfonation with Sulfuric Acid and Sulfur Trioxide. Various mecha- nisms for the reaction of aromatic hydrocarbons or aryl halides with sulfuric acid or with sulfur trioxide have been proposed.1 Since.the reac- tion is heterogeneous, it is not favorable for experimental study. Sol- vents that dissolve sulfuric acid or sulfur trioxide form addition com- pounds with the reagent; hence any conclusion drawn from a homogene- ous sulfonation might not be applicable to the ordinary sulfonation. One possibility is that an electrophilic reagent such as sulfur trioxide with its relatively positive sulfur atom or an ion such as HO3S+ in the case of sulfuric acidle attacks the negative center of the polarized form of the hydrocarbon, as illustrated for benzene. S-O" -=2-* H (1) 9 -OH DIRECT SULFONATION OF AROMATIC HYDROCARBONS 143 V0H <A>H 0^ OH21 0. <A>H 6 The reaction with sulfuric acid is reversible; for example, the sulfona- tion of benzene at temperatures between 100° and 200° attains equilib- rium when the concentration of sulfuric acid is 73-78%.lc'2 In order to obtain maximum yields it is necessary either to separate the sulf onic acid by continuous extraction or, more generally, to remove the water as the reaction proceeds. One industrial method of preparing henzenesulfonic acid is a modification of the Tyrer process,3 which utilizes the latter prin- ciple. The reaction is carried out at temperatures of 170-180°; the water is removed by passing benzene vapor through the reactor at such a rate that unchanged benzene is present in the condensate. The reac- tion is carried to about 95% completion.4 Two other.expedients used in manufacturing processes consist in carrying out the reaction under such a vacuum as to remove the water as it is formed,5 and in the inter- mittent addition of sulfur trioxide, which reacts with the water to form sulfuric acid.6 The water can be removed also by entrainment with an inert gas that is passed through the reaction mixture.7 The aromatic sulfonic acids undergo hydrolysis (reversal of the sul- fonation reaction) when they are heated with water or dilute acid. The sulfonic acids that are the most readily formed are the most readily hydrolyzed.8 This accounts for the variation in the relative amounts of 1 (a) Lantz, Bull. soc. chim., [5] 6, 302 (1939); (6) Spryskov, J. Gen. Chem. U.S.S.R., 8, 1857 (1938) [C.A., 33, 5820 (1939)]; (c) Guyot, Chimie & Industrie, 2, 879 (1919); (d) Courtot, Rev. gin. mat. color., 33,177 (1929); (e) Courtot and Bonnet, Compt. rend., 182,855 (1926); (f) Vorozhtzov, Anilinokrasochnaya Prom., 4, 84 (1934) [C. A., 28, 4652 (1934)]; (g) Price, Chem. Revs., 29, 37 (1941). 2 Zakharov, J. Chem. Ind. U.S.S.R., 6, 1648 (1929) [C. A., 25, 5154 (1931)]. 3 Tyrer, TJ. S. pat. 1,210,725 [C. A., 11, 689 (1917)]. 4 Killeffer, Ind. Eng. Chem., 16, 1066 (1924). 6 Downs, V. S. pats. 1,279,295 and 1,279,296 [C. A., 12, 2572 (1918)]; Bender, TJ. S. pat. 1,301,360 [C. A., 13, 1862 (1919)]. 6 Aylesworth, U. S. pat. 1,260,852 [C. A., 12,-1469 (1918)]. 7 Meyer, Ann., 433, 327 (1923); Gay, Aumeras, and Mion,- Chimie & industrie, 19, 387 (1928); Spruiskov, J. Chem. Ind. U.S.S.R., 8, 41 (1931) [C.A., 26, 2735 (1932)]. 8 (a) Ioffe, AnUinokrasochnaya Prom., 3, 296 (1933) [C. A., 28, 957 (1934)]; (6) J. Gen. ? Chem. U.S.S.R., 3,437, 505 (1933) [C. A., 28,1593 (1934)]; (c) Lantz, Compt. rend., 201,149 (1935); (d) Fedorov and Spruiskov, Org. Chem. Ind. U.S.S.R., 2, 100 (1936) [C. A., 31, 678 (1637)]. 144 ORGANIC REACTIONS isomeric sulfonic acids resulting from changes in the time allowed for reactions capable of producing isomers; an extended reaction time would be expected to favor the formation of the most stable isomer. The dif- ference in the stability of a- and /3-naphthalenesulfonic acid toward hy- drolysis provides the basis for a convenient purification of the /3-isomer.9 When a mixture of the two substances is heated to 145-155° with water, the a-isomer is completely hydrolyzed and there is little loss of the more stable /3-isomer. Since aromatic hydrocarbons or halogen derivatives are regenerated, usually in good yield, by hydrolysis of the sulfonates, sulfonation followed by hydrolysis is utilized in the separation of mix- tures of aliphatic and aromatic compounds and in the separation of mixtures, of aromatic compounds that differ in ease of sulf onation.10 The reaction of aromatic hydrocarbons with sulfur trioxide is practi- cally instantaneous and occurs under much milder conditions than are needed for other sulfonating agents. For example, the reaction of ben- zene with sulfuric acid (equal volumes) at reflux temperature reaches equilibrium only after twenty to thirty hours when 80% of the benzene is sulfonated; n the reaction with sulfur trioxide (chloroform solution) is practically instantaneous even at 0-10°, and benzenesulfonic acid can be isolated in a yield of 90%.ld'le-lf Sulfuric acid is the usual solvent for the trioxide (oleum), but certain chlorinated solvents, particularly ethylene chloride 12 and chloroform,13 and liquid sulfur dioxide are used to advantage. One interesting feature of the sulf onation reaction with sulfuric acid is that the temperature plays a striking role in the orientation. This effect has been examined most extensively in the sulf onation of toluene u and of naphthalene.16 In the sulfonation of toluene at 0° three isomers are produced in the following proportions: o-toluenesulfonic acid, 43%; m-toluenesulfonic acid, 4%; p-toluenesulfonic acid, 53%. At this tem- perature there is only a slight preference, for para substitution over ortho substitution. In the sulfonation at 100° the yields are 13% o-toluene- sulfonic acid, 8% m-toluenesulfonic acid, and 79% p-toluenesulfonic 'Masters, TJ. S. pat. 1,922,813 [C.A., 27, 5085 (1933)]; Vorozhtzov and Krasova, Anilinokrasochnaya Prom., 2, 15 (1932) [C. A., 27, 5321 (1933)]. 10 Kruber, Ber., 65, 1382 (1932). u Michael and Adair, Ber., 10, 585 (1877). 12 I. G. Farbenind. A.-G., Ger. pat. 647,988 [C. A., 31, 8074 (1937)]. 13 Courtot and Lin, Bull. soc. chim., [4] 49, 1047 (1931); Kipping, J. Chem. Soc, 91, 209, 717 (1907); Luff and Kipping, ibid., 93, 2090 (1908); Kipping and Davies, ibid., 95, 69 (1909); Marsden and Kipping, ibid., 93, 198 (1908); Bygd&i, /. prakt. Chem., [2] 96, 86 (1917); Wedekind and Schenk, Ber., 44, 198 (1911); Bad. Anilin- und Soda-Fabrik, Ger. pat. 260,562 [Chem. Zentr., 84, II, 104 (1913)]; Pschorr and Klein, Ber., 34, 4003 (1901); Hodgkinson and Matthews, J. Chem. Soc, 43, 163 (1883). "Holleman and Caland, Ber., 44, 2504 (1911). 16 Euwes, Bee. trail, chim., 28, 298 (1909). DIEECT SULFONATION OF AROMATIC HYDROCARBONS 145 acid. The extent of meta substitution is affected only slightly by the reaction temperature, but that of -para substitution is increased markedly with increasing temperature, at the expense of ortho substitution. Both the ortho and the para isomers can be partially transformed into one another by heating at 100° with sulfuric acid containing a little water; the meta isomer is stable under similar conditions.14-16 The effect of temperature on the orientation undoubtedly is a result of the reversi- bility of the sulfonation reaction; the transformation of the isomers probably proceeds through hydrolysis followed by sulfonation. In the sulfonation of naphthalene, a-naphthalenesulfonic acid is the predomi- nant product (96%) at temperatures below 80°, whereas /3-naphthalene- sulfonic acid is the main product (85%) at a temperature of 165°. Here again the a-isomer can be transformed into the more stable /3-isomer by heating with sulfuric acid. The discovery that the sulfonation of anthraquinone, winch normally occurs in the /3-position, is directed exclusively to the a-position by a small amount of mercury has prompted investigations of the effect of mercury on other sulfonations. No instances have been found in which the course of the reaction of hydrocarbons is altered drastically. The sulfonation of naphthalene 16 and of anthracene "?18 is unaffected. How- ever, the course of the reaction of sulfur trioxide-sulfuric acid with o- xylene, o-dichlorobenzene, and o-dibromobenzene is affected to a certain extent.19 The 4-sulfonic acid is the exclusive product of sulfonation in the absence of mercury; the 3-sulfonic acid is formed to the extent of 20-25% in the presence of 10% of mercury. The relative ineffectiveness of mercury in the sulfonation of hydrocarbons is understandable if it is true that the activity of mercury in the reactions of oxygen-containing compounds is due to mercuration followed by replacement with the sulfonic acid grouping. Phenols are known to be particularly susceptible to mercuration (in the ortho position), and mercury has been found to exert some effect in the sulfonation of phenols, such as a-naphthol.20 Many instances of the response of sulfonation to catalysts are known. The most active catalyst for the high-temperature sulfonation of benzene is a mixture of sodium sulfate and vanadium pentoxide.21' The sulfates of mercury, cadmium, aluminum, lead, arsenic, bismuth, and iron in- crease the rate of sulfonation of benzenesulfonic acid, whereas manganous 16 Bradfield and Jones, Trans. Faraday Soc, 37, 731 (1941). 17 Battegay and Brandt, Bull. soc. chim., [4] 31, 910 (1922). 18 Battegay and Brandt, Bull. soc. chim., [4] 33, 1667 (1923). 19 Lauer, J. prakt. Chem.) [2] 138, 81 (1933). TOHoldermann, Ber., 39, 1250 (1906). 21 Ambler and Cotton, Ind. Eng. Chem., 12, 968 (1920); Hauser and Korovits'ka, C. A., 33, 159 (1939); Senseman, Ind. Eng. Chem., 13, 1124 (1921). 146 ORGANIC REACTIONS sulfate has little effect.22'23 Benzene and its homologs are said to be sulfonated quantitatively at room temperature in the presence of in- fusorial earth or animal charcoal.24 The trisulfonation of benzene with sulfur trioxide-sulfuric acid is facilitated by the presence of mercury.22'2B One notable feature of the sulfonation reaction is the tendency of the entering sulfonic acid group to avoid a position adjacent to certain substituents. i-Butylbenzene is substituted exclusively at the 4-posi- tion,26 even under conditions where toluene is substituted to some extent at the 2-position. Under the most favorable conditions p-cymene is sulfonated to only a limited extent (15%) at the 3-position,27 which is ortho to the more, bulky alkyl substituent. In fact the first authentic sample of the 3-acid was prepared indirectly by sulfonating 2-bromo- cymene and subsequently removing the bromine from the product of sulfonation, 6-bromocymene-3-sulfonic acid.28 Particular interest in the ^ 3 CH3 H2SO4 % B^ CH(CH3)2 CH(CH3)2 CH(CH3)2 3-sulfonic acid stems from the fact that this substance, if it were readily available, would serve as a convenient starting material for the prepara- tion of thymol. Sulfonation with Addition Compounds of Sulfur Trioxide. In a broad sense all sulfonating agents are more or less stable addition products of sulfur trioxide. The more readily an atom donates an electron pair, or the more basic it is, the less active is the additionf compound with sulfur trioxide as a sulfonating agent. The most active sulfonating agents are sulfur trioxide and its addition product with itself, the known sulfur /3-trioxide, S2O6; the next most active are the addition compounds with the mineral acids, chloro- and fluoro-sulfonic-acid, and with sulfuric acid, pyrosulfuric acid (H2S2O7). Sulfuric acid is less active; this agent is not precisely a coordination compound of sulfur trioxide and water, but certain etHers such as di-(/3-chloroethyl) ether and dioxane do form stable addition complexes with sulfur trioxide that are active'sulfo- ^Behrend and Mertelsmann, Ann., 378, 352 (1911). 23 Mohrmann, Ann., 410, 373 (1915). 24 Wendt, Ger. pat. 71,556 [Frdl., 3, 19]. 26 Suter and Harrington, J. Am. Chem. Soc, 59, 2575 (1937). 26 Senkowski, Ber., 23, 2412 (1890). 27 (o) Schorger, Ind. Eng. Chem., 10, 259 (1918); (h) Phillips, J. Am. Chem. Soc, 46, 686 (1924); (c) Le Ffevre, J. Chem. Soc, 1934, 1501; (d) Kuan, J. Chem. Soc Japan, 52, 473 (1931). *" Remsen and Day, Am. Chem. J., 5, 154 (1883). DIRECT SULFONATION OF AROMATIC HYDROCARBONS 147 nating agents.29 The addition compounds with bases, such as pyri- dine,18'30 are the least active. No data- are available to distinguish between the behavior of the amine addition products, but the com- pound with trimethylamine would be expected to show little activity. A possible mechanism for the sulfonating action of these reagents that does not require preliminary dissociation into free sulfur trioxide in- volves the stereochemical inversion of the sulfur atom, the carbon atom attaching itself to the sulfur atom opposite the valence bond that is broken. This is analogous to the Walden inversion reactions by which C6H6 + O3SX -> CeHjSOaH + X replacement of a group attached'to carbon frequently occurs. Chlorosulfonic acid is not used widely for the preparation of sulfonic acids, partly because excess reagent reacts with the sulfonic acid to form the sulfonyl chloride; it is commonly employed for the prepara- tion of sulfonyl chlorides. C6H6 + CISO3H -* C6H6SO3H'+ HC1 C6H6SO3H + CISO3H -> C6H6SO2C1 + H2SO4 The reaction of fluorosulfonic acid is probably similar u-32 but has not been investigated so extensively. The action of chlorosulfonic anhy- dride 33 leads to such a complex mixture of products that this reagent is of little value. Sulfonation with chlorosulfonic acid is often carried out in an inert solvent,12'13'34 usually chloroform. Sulfonation with Miscellaneous Reagents. Sodium hydrogen sulfate36 and sodium trihydrogen disul'fate36 exert some sulfonating action, but their value is limited by the fact that they are solids at room temperature and insoluble in organic solvents. Sodium trihydrogen disulfate melts at approximately 100° and has been used in reactions carried out at higher temperatures. Sulfamic acid, which differs from sulfuric acid in that one hydroxyl group is replaced by an amino group, has only a slight sulfonating action; furthermore, sulfamic acid is a solid and is insoluble in anhydrous solvents. 29 Suter, Evans, and Kiefer, J. Am. Chem. Soc, 60, 538 (1938). 30 Baumgarten, Ber., 69, 1976 (1926); Die Chemie, 55, 115 (1942); Ger. pat. 614,821 [C. A., 25, 2156 (1931)]. 81 Steinkopf et al., J. prakt. Chem., [2] 117, 1 (1927). 32 Meyer and Schramm, Z. anorg. aMgem. Chem., 206, 24 (1932). 83 Steinkopf and Buchheim, Ber., 54, 2963 (1921). "Huntress and Autenrieth, /. Am. Chem. Soc, 63, 3446 (1941). 85 Soc St. Denis, Ger. pat. 72,226 [Frdl., 3, 195]; Ger. pat. 77,311 [Frdl., 4, 271]. 36 (a) Gebler, J. Chem. Ind. U.S.S.R., 2,-984 (1926) [C. A.,21,1450 (1927)]; (b) Lamberts, Ger. pat. 113,784 [Chem. Zentr., II, 883 (1900)]. 148 OEGANIC REACTIONS Side Reactions. The most common side reaction is the formation of a sulfone, Ar2SO2. This reaction is favored by an excess of the hydrocar- bon or aryl halide and by an active sulfonating agent, such as sulfur tri- oxide, oleum,37 or chlorosulfonic acid.38 The reaction between benzene and sulfur trioxide in the vapor phase has been patented as a method of preparing phenyl sulfone.39 The formation of 2,2'-cyclic sulfones is characteristic of biphenyl and its derivatives,40 where the structure is favorable for intramolecular sulfone formation. Sulfone formation, /TY^TY- 6C1SO3H -> + 4HC1 like sulfonation, is a reversible process; phenyl sulfone, for example, is converted by sulfuric acid into benzenesulfonic acid.41 Compounds containing bromine,42 iodine, 43- **?45 or an accumulation of alkyl groups 46> ?"?48 or of alkyl and halogen groups49 attached to the aromatic riucleus frequently undergo rearrangement or disproportiona- tion or both when treated with sulfuric acid. The redistribution of methyl and halo substituents in polysubstituted benzene derivatives under the influence of sulfuric acid is known as the Jacobsen reaction.48 Bromobenzene on refluxing with sulfuric acid gives a complex mixture of products that includes 3,'5-dibromobenzenesulfonic acid, two bromoben- zenedisulfonic acids (structure not established), p-dibromobenzene, 1,2,4,5-tetrabromobenzene, and hexabromobenzene.*2 37 Spiegelberg, Ann., 197, 257 (1879); Koerner and Paternd, Gazz. chim. Hal., 2, 448 (1872); Troeger and Hurdelbrink, J. prakt. Chem., [2] 65, 82 (1902). 88 (o) Pollak, Heimberg-Krauss, Katseher, and Lustig, Monatsh., 55, 358 (1930); (6) Dziewonski, Grunberg, and Schoen, Bull, intern, acad. polon. sci., 1930A, 518 [C. A., 25, 5419 (1931)]. 39 Carr, U. S. pat. 2,000,061 [C. A., 29, 4027 (1935)]; Planovskir and Kagan, Org. Chem, Ind. U.S.S.R., 7, 296 (1940) [C. A., 35, 3985 (1941)]. 40 Courtot and Lin, Bull, soc. chim., [4] 49, 1047 (1931). 41 Gericke, Ann., 100, 207 (1856); Kekulfi, Zeit. far Chem., 1867, 195. cHerzig, Monatsh., 2, 192 (1881). 43 Huntress and Carten, J. Am. Chem. Soc., 62, 511 (1940). 44 Neumann, Ann., 241, 33 (1887). 46 Boyle, J. Chem. Soc, 95, 1683 (1909). ? Smith and Kiess, J. Am. Chem. Soc., 61, 989 (1939). 47 Smith and Guss, J. Am. Chem. Soc, 62, 2631 (1940). 48 Smith, Org. Reactions, I, 370 (1942). 49 Jacobsen, Ber., 22, 1580 (1889). DIEECT SULFONATION OF AROMATIC HYDROCARBONS 149 The formation of by-products other than the sulfone usually can be decreased by the use of a more active sulfonating agent and of a lower reaction temperature. However, satisfactory yields of the sulfonic acid cannot be obtained under any conditions for certain reactions, among them the sulfonation of p-diiodobenzene;43> 44> ^ iodine groups generally have been found to migrate more readily than bromine or methyl groups. The reaction of p-diiodobenzene with chlorosulfonic acid is abnormal in another respect, for the principal product is 2,3,5,6-tetrachloro-l,4-di- iodobenzene.43 APPLICATION OF THE REACTION Practically any aromatic hydrocarbon or aryl halide can be sulfonated if the proper conditions are chosen. As the compound becomes more complex, however, the tendency toward the production of by-products and mixtures of isomers is increased. It is usually difficult to prevent polysubstitution of a reactive hydrocarbon. For example, even when phenanthrene is sulfonated incompletely at room temperature, some disulfonic acids are formed.60 The sulfonation of anthracene follows such a complex course that the 1- and 2-sulfonic acid derivatives are made from the readily available derivatives of anthraquinone. The following sections include comments.on the accessibility of the reaction products of the commonly available hydrocarbons and aryl halides. The examples cited and still others are listed in Tables I-XIII. Benzene (Table I, p. 165). Some of the factors involved in the indus- trial sulfonation of benzene have been discussed. In the small-scale, laboratory preparation, where the difference in cost between sulfuric acid and oleum is negligible, oleum is the preferred reagent. Benzene is added gradually to ice-cold sulfuric acid containing 5-8% of the anhy- dride; the reaction is complete after ten to fifteen minutes. Benzensul- fonic acid is isolated readily as the sodium salt by the addition of the reaction mixture to a saturated sodium chloride solution.61 The reac- tion of benzene with chlorosulfonic acid is not used for the preparation of benzenesulfonic acid because, under conditions that limit the forma- tion of the sulfonyl chloride, the acid is always accompanied by phenyl sulfone.62 Benzenesulfonyl chloride can be obtained in a yield of 75-77% by the addition of benzene to an excess of chlorosulfonic acid (room temperature).63 Fluorosulfonic acid reacts less vigorously; the addi- M Sandqvist, "Studien uber die Phenanthrensulfosauren," Dissertation, Upsala, 1912. ^ Gattermann and Wieland, "Laboratory Methods of Organic Chemistry," translation by W. McCartney of the 22nd ed., p. 181, Macmillan, 1932.62 Knapp, Zeit. filr Chem., 1869, 41.6 ?Ullmann, Ber., 42, 2057 (1909); Pummerer, Ber., 42, 1802, 2274 (1909); Clarke, Babcock, and Murray, Org. Syntheses, Coll. Vol. 1, 85 (1941). 150 ORGANIC REACTIONS tion of 55 g. of benzene to 225 g. of fluorosulfonic acid at 16-20° affords benzenesulfonyl fluoride in 62% yield31 (p. 164). m-Benzenedisulfonic acid is readily prepared, either by treating ben- zene with 20-^0% oleum at elevated temperatures (160-209°) "? M or by treating a monosulfonate with 12-20% oleum at about 210°.M Less vigorous sulfonating agents that require a longer reaction time or a higher temperature lead to the formation of some of the para isomer; for example, barium benzenesulfonate when heated with 98% sulfuric acid for forty-eight hours at 209° is converted into the m- and p-disulfonic acids in the approximate ratio of 3 : l.M 'The formation of the para isomer is favored also by the addition of mercury.22 The ortho disulfonic acid cannot be prepared by sulfonation of benzene or benzenesulfonic acid under any conditions. Treatment of benzene with a large excess of chlorosulfonic acid at 150-160° for two hours affords benzene-m-disul- fonyl chloride (28% yield) together with a small amount of the para isomer and some (phenyl sulfone)-disulfonyl chloride.38" The introduction of a third sulfo group into benzene proceeds with difficulty, but benzene-l,3,5-trisulfonic acid can be prepared in 73% yield by heating sodium benzene-l,3-disulfonate with 15% oleum in the presence of mercury for twelve hours at 275° (p. 163) P- a Toluene (Table II, p. 168). Toluene is more readily sulfonated than benzene. The reaction mixture always contains the three possible mono- sulfonic acid derivatives; the meta isomer is present in such low amounts that its presence has been demonstrated only by indirect means." The sulfonation reaction is employed for the production of both the ortho and para acids; as described earlier, by suitable control of the temperature it is possible to favor the production of one or of the other isomer. The preparation of the para sulfonic acid 66 is relatively simple since this isomer predominates in reactions carried out at temperatures above-75° with either sulfuric acid or oleum.20 The para acid can be freed from the accompanying ortho isomer either by crystallization from cold concen- trated hydrochloric acid, in which the para acid is practically insoluble, or by conversion into the sodium or calcium salt,67 either of which crystal- lizes readily. The relative proportion of the ortho sulfonic acid in the reaction mixture is never higher than 35-45%, even under the optimum conditions for the formation of this isomer.14 ?68 The separation of the "Holleman and Polak, Rec. trav. chim., 29, 416 (1910). ? Voluinkin, /. Applied Chem. U.S.S.R., 9, 885 (1936) [C. A., 30, 7555 (1936)]. "Gattermann and Wieland, op. tit., p. 183; Fieser, "Experiments in Organic Chem- istry," p. 136, Heath, Boston, 1941. 67 Bourgeois, Rec. trav. chim., 18, 426 (1899). M Fahlberg and List, Ger. pat. 35,211 [Frdl., 1, 509]; Lange, Ger. pat. 57,391 [Frdl., 3, 905]. , DIRECT SULFONATION OF AROMATIC HYDROCARBONS 151 two isomers, however, is relatively easy. On the addition of a little water the para isomer separates readily; when the mother liquor is cooled to ¡ª5° the crude ortho acid is obtained and is then purified as the barium salt, which is practically insoluble in cold water, in contrast to that of the ?para acid, which is readily soluble.14 Toluene reacts with gaseous sulfur trioxide at 40-55° to yield a mixture containing 20-24% of p-tolyl sulfone, 8% of the ortho, 7% of the meta, arid 55% of the para sulfonic acid.69 The reaction of toluene with the calculated amount of chlorosulfonic acid at 35° results in the forma- tion of the three isomeric acids in the following amounts: 59% of the para acid, 4% of the meta acid, and 37.5% of the ortho acid.M That is, the relative proportion of the three acids is roughly the same in the reaction at a given temperature with either sulfuric acid or chlorosulfonic acid. The reaction of toluene (60 g.) with excess chlorosulfonic acid (150 g.) at a low temperature leads to a mixture of monosulfonyl chlorides but gives mainly the 2,4-disulfonyl chloride at a high temperature.38" The reaction of toluene with chlorosulfonic anhydride leads to a complex mixture containing p-toluenesulfonic acid, p-toluenesulfonyl chloride, a chlorinated tolyl sulfpne, and a mixture of isomeric dichlorotoluenes.33 Toluene reacts with excess fluorosulf onic acid 31 at ordinary temperature to give a mixture of sulfonyl fluorides (89% yield), of which 40% is the ortho derivative; from the reaction at 130-140° the 2,4-disulfonyl fluoride can be isolated in 48% yield. Only one of the six possible toluenedisulf onic acids is prepared by the sulfonation reaction, toluene-2,4-disulfonic acid. This acid is the pre- dominant product of the sulfonation of toluene,60 o- and p-toluenesulfonic acid,61 and o- and p-toluenesulfonyl chloride.62 Toluene-2,4,6-trisulfonic acid is obtained from the reaction of potassium toluene-2,4-disulfonate (1 mole) with chlorosulfonic acid (3 moles) at 24O0.63 Xylenes (Table IV, p. 172). The 4-sulfonic acid is the exclusive product of the sulfonation of o-xyleneM under ordinary conditions. In the presence of mercury some of the 3-isomer is also formed.19 This isomer rearranges to the 4-isomer on heating either alone M or with sulfuric acid.66 The sulfonation of wi-xylene occurs more readily than 69 Lauer and Oda,/. prakt. Chem., [2] 143, 139 (1935). ?>Senhofer, Ann., 164, 126 (1872); Gnehm and Forrer, Ber., 10, 542 (1877). 61 Claesson and Berg, Ber., 13, 1170 (1880). ""Fahlberg, Am. Chem. J., 1, 175 (1879); 2, 182 (1880). ? Claesson, Ber., 14, 307 (1881). 64 Jaobbsen, Ber., 11, 17 (1878); 17, 2374 (1884). 65 Moody, Chem. News, 67, 34 (1893). ? : M Kizhner, J. Gen. Chem. U.S.S.B., 3, 578 (1933) [C. A., 28, 2693 (1934)]. 152 ORGANIC REACTIONS that of o- and p-xylene; the 4-sulfonic acid is the main product.67 A small amount of the 2-sulfonic acid can be isolated from a reaction con- ducted at room temperature,68 but this isomer rearranges rapidly to the 4-isomer when warmed with sulfuric acid,69 and hence is not isolated in the usual preparation. The 4-position of m-xylene is also the point of attack in the reaction with fluorosulfonic acid.81 The sulfonation of p- xylene proceeds less readily than that of either of the isomers; only one monosubstitution product, the 2-sulfonic acid,70 is possible. The reac- tion with fluorosulfonic acid yields the 2-sulfonyl fluoride.31 The dif- ference in the ease of sulfonation and desulfonation of the xylenes is utilized for the separation of the pure hydrocarbons from the xylene fraction of coal tar.71 The structure of the only known disulfonate of o-xylene, obtained by heating barium o-xylene-4-sulfonate with chlorosulfonic acid,72 is not established. The second sulfonic acid group would be expected to enter the position meta to the first to yield o-xylene-3,5-disulfonic acid. The dichloride of the same disulfonic acid is obtained from the reaction of o-xylene itself with excess chlorosulfonic acid.38" The disulfonic acid obtainable from m-xylene73 or m-xylene-4-sulf onic acid72 was originally considered to be the 2,4-disulfonic acid, partly because the same diacid was obtained by sulfonation of a sample of m-xylene-2-sulfonic acid72 and also by the elimination of bromine from 6-bromo-m-xylene-2,4- disulfonic acid.73 The former evidence, however, is not significant, for the 2-sulfonic acid has been shown to rearrange readily to the 4-sulfonic acid.69 More recent work indicates that the sulfonic acid groups are in the 4- and 6-positions;7* one piece of evidence is that the disulfonyl chloride can be converted into the known 4,6-dichloroisophthalic acid. Furthermore, a 2,4rstructure would be very unlikely in view of the fact that the entering sulfo group is known to avoid a hindered position such as the 2-position in m-xylene. The second sulfonic acid group enters 67 (o) Jacobsen, Ber., 10, 1009 (1877); Ann., 184, 179 (1877); (6) Crafts, Ber., 34, 1350 (1901). 68 PoUak and Meissner, Monatsh., 50, 237 (1928). 69 Moody, Chem. News, 58, 21 (1888). 70 Krafft and Wilke, Ber., 33, 3207 (1900); Karslake and Huston, J. Am. Chem. Soc, 36, 1245 (1914). 71 Spielmann, "The Constituents of Coal Tar," pp. 56-60, Longmans, Green, London, 1924; Weissberger, "Chemische Technologic der Steinkohlenteers," pp. 57-58, Otto Spamer, Leipzig, 1923. 72 Pfannenstill, J. prakt. Chem., [2] 46, 152 (1892). 73 Wischin, Ber., 23, 3113 (1890). 74 Pollak and Lustig, Ann., 433, 191 (1923); Holleman, Anales soc. espan. fis. quim., 27, 473 (1929) [C. A., 24, 85 (1930)]; Holleman and Choufoer, Proc. Acad. Sci. Amsterdam, 27, 353 (1924) [C. A., 18, 3183 (1924)]. DIRECT SULFONATION OF AROMATIC HYDROCARBONS 153 p-xylene in the 6-position to give p-xylene-2,6-disulfonic acid.76' M The disubstitution of p-xylene by excess chlorosulfonic acid leads to the formation of both the 2,6- and the 2,5-disulfonyl chloride in the ratio of 10 : I.74 Trimethylbenzenes (Table V, p. 175). Only one monosulfonic acid , has been obtained from each of the trimethylbenzenes. 1,2,3-Trimethyl- benzene (hemimellitene) is sulfonated in the 4-position,771,2,4-trimethyl- benzene (pseudocumene) in the 5-position.78-79 Sulfonation of 1,3,5- trimethylbenzene (mesitylene) can lead to only one monosulfonic acid, obtainable in good yield by the reaction with either sulfuric acid (90% yield, preparation p. 162)79 or oleum.80 Mesitylenesulfonyl chloride has been made by the action of sulfuryl chloride and aluminum chloride (chloromesitylene is formed also);81 the disulfonyl chloride is obtained from the reaction of mesitylene with chlorosulfonic acid 82 or with a mixture of chlorosulfonic acid and sulfuryl chloride.76 Fluorosulfonic acid converts mesitylene into the sulfonyl fluoride,31 which reacts with chlorosulfonic acid to form the disulfonyl chloride. Mesitylenedi- sulfonic acid has been made by treating mesitylene with oleum and phosphorus pentoxide; M the introduction of a third sulfonic acid group proceeds with difficulty but has been accomplished by the action of sulfur trioxide (low yield).81 Halobenzenes (Table I, p. 165). Halogen atoms attached to the benzene nucleus decrease the ease of sulfonation, and hence oleum is the preferred reagent for the sulfonation of halobenzenes, particularly since the use of the less potent sulfuric acid also favors the rearrangement of the halogen group (p. 148). Only one monosulfonic acid is obtained from any of the four monohalobenzenes, for the sulfonic acid group always enters the position para to the halogen group. p-Fluorobenzene- sulfonic acid M and p-chlorobenzenesulfonic acid w are available from the sulfonation of the corresponding halobenzenes with 10% oleum at temperatures of 60-75°. p-Chlorobenzenesulfonic acid is obtained also 76 Pollak and Sohadler, Monatsh., 39, 129 (1918). "Holleman, Choufoer, and Alozery, Rec. trav. chin?., 48, 1075 (1929). 77 (a) Jacobsen, Ber., 15, 1853 (1882); 19, 2517 (1886); (6) v. Auwers and Wieners, Ber., 58, 2815 (1925). 78 Jacobsen, Ann., 184, 179 (1877); Schultz, Ber., 42, 3602 (1909). 79 (a) Smith and Cass, J. Am. Chem. Soc., 54,1606, 1617 (1932); (6) Jacobsen, Ann., 146, 85 (1868). ""Moschner, Ber., 34, 1259 (1901). 81 Tohl and Eberhard, Ber., 26, 2940 (1893). 82 Backer, Bee. trav. chim., 64, 544 (1935). 83 Barth and Herzig, Monatsh., 1, 807 (1880). 84 HoUeman, Rec. trav. chim., 24, 26 (1905). 86 Baxter and Chattaway, /. Chem. Soc, 107, 1814 (1915). 154 ORGANIC REACTIONS from the reaction of chlorobenzene with one molecular equivalent of chlorosulfonic acid; m the sulfone and the sulfonyl chloride are formed in small amounts. p-Chlorobenzenesulfonyl chloride is obtainable in 84% yield by the reaction with excess chlorosulfonic acid at a temperature of 25°<?7 The sulfonyl chloride is converted by sulfuric acid at 160-180° into the 2,4-disulfonic acid M and by chlorosulfonic acid into the disul- fonyl chloride.38" Disulfonation of chlorobenzene can be accomplished directly by the reaction of 20% oleum at 300°,88'89 but the reaction is abnormal, for these sulfonic acid groups are meta to the chlorine atom; the product is chlorobenzene-3,5-disulfonic acid. This same disulfonic acid is obtained under the same conditions from chlorobenzene-4-sulfonic acid M and from chlorobenzene-2,4-disulfonic acid.89 In contrast to the reaction of bromob'enzene with sulfuric acid, which requires a high temperature and yields a mixture of products (p. 148), the reaction with oleum M or with chlorosulfonic acid in carbon disul- fide solution43 is normal and gives the 4-sulfonic acid and bis-(4-bromo- phenyl) sulfone. The 4-sulfonic acid is sulfonated in the 2-position by either pyrosulfuric acid M or sulfur trioxide; the reaction with oleum at high temperatures is abnormal, like that of chlorobenzene, and yields the 3,5-disulfonic acid. p-Iodobenzenesulfonic acid is prepared by the action of sulfuric acid ** or oleum44' **?91 on iodobenzene at 100°; side reactions giving rise to p-diiodobenzene and benzenesulfonic acid ** become appreciable above 100°. Alkylhalobenzenes (Table II, p. 168; Table III, p. 171; Table IV, p. 172; Table V, p. 175). In the sulfonation of benzene derivatives con- taining alkyl and halogen groups, the sulfonic acid group appears in a position para to a halogen atom rather than para to an alkyl group; thus, 2-chlorotoluene yields the 5-sulfonic acid.92' 93 However, if only ortho positions are available, the sulfonic acid produced in larger quan- tity is that in which substitution occurs ortho to the alkyl group; thus 4-chlorotoluene yields a mixture of the 2- and the 3-sulfonic acids in 86 (a) Beckurts and Otto, Ber., 11, 2061 (1878); (6) Ullmann and Korselt, Ber., 40, 641 (1907). 87 Pummerer, Ber., 42, 1802 (1909). 88 Olivier, Rec. trav. chim., 37, 307 (1918). 89 Olivier, Rec. trav. chim., 38, 351, 356 (1919). 90 Fischer, Ber., 24, 3805 (1891). 91 Langmuir, Ber., 28, 90 (1895); Troeger and Hurdelbrink, /. prakt. Chem,, [2] 65, 82 (1902); Willgerodt and Waldeyer, ibid., [2] 59, 194 (1899) 92 Hubner and Majert, Ber., 6, 790, 1672 (1873). 93 Wynne, J. Chem. Soc, 61, 1073 (1892). DIRECT SULFONATION OF AROMATIC HYDROCARBONS 155 which the 2-stilfonic acid predominates.94 Furthermore, 1,3-dimethyl- CH3 5-chlorobenzene96 and l,3-dimethyl-4,6-dichlorobenzene ** are sul- fonated exclusively in the 2-position. As in the reaction with halobenzenes, sulfuric acid is likely to bring about rearrangement of elimination of bromine.or iodine of alkylhalo- benzenes. For example, 5-bromo-l,2,4-trimethylbenzene on longstand- ing with sulfuric acid at room temperature is converted into the 3-bromo- CH3 CH3 CH3 CH3 CH3 (90% yield) (Small amount) 5-sulfonic acid and trimethyltribromobenzene.97 This reaction and simi- lar rearrangements have been discussed in detail by Smith.48 The structures of many of the sulfonic acids obtained from dihalotol- uenes (Table II) and also from other alkylhalobenzenes have not been established. Biphenyl and Derivatives (Table VII). Biphenyl-4-sulfonic acid can be prepared very satisfactorily by sulfonation with sulfuric acid in nitro- benzene solution ** (90% yield) or by the action of chlorosulfonic acid in tetrachloroethane at 5'0°.38a Sulfuric acid alone either gives a mixture of the 4-mono- and 4,4'-di-sulf onic acids with unchanged hydrocarbon or, with excess reagent, yields chiefly the di- derivative.99 The monosulfonic acid is readily freed from the disulf onic acid through its sparingly soluble copper salt; the disulf onic acid remains in solution and can be crystallized 84 Wynne and Bruce, J. Chem. Soc, 73, 731 (1898). 95 Klages and Knoevenagel, Ber., 27, 3019 (1894); Klages, Ber., 29, 310 (1896). 98 Koch, Ber., 23, 2319 (1890). 97 Smith and Moyle, /. Am. Chem. Soc., 68, 1 (1936); Jacobaen, Ber., 22, 1580 (1889). 98 Gebauer-Fiilnegg, Riesz, and Use, Monatsh., 49, 41 (1928). 99 MoCullough, V. S. pat. 1,865,776 [C. A., 26, 4346 (1932); Stoesser and Marschner, U. S. pat. 1,981,337 [C. A., 29, 478 (1935)]; Fittig, Ann., 132, 209 (1864). 156 ORGANIC REACTIONS as the potassium salt. Potassium biphenyl-4-sulfonate is converted by heating into biphenyl and the 4,4'-disulfonate.100 The reaction of biphenyl with excess chlorosulfonic acid at 0° gives the 4,4'-disulfonyl chloride (80% yield) and at 18° gives (dibenzothiophene dioxide)-2,7- disulfonyl chloride.380 Arylalkanes and Arylalkenes (Table VIII, p. 181). Diphenylmethane is sulfonated exclusively in the para position rather than in the more hindered ortho position. The 4-sulfonic acid is prepared by treating diphenylmethane with chlorosulfonic acid in chloroform solution at 0°;101 the 4,4'-disulfonic acid, by the action of oleum at 100°.102 1,2-Diphenyl- ethane (bibenzyl) when heated with sulfuric acid 103 yields a mixture of a disulfonic acid (probably 4,4') and a tetrasulfonic acid. Oleum reacts with stilbene without affecting the olefinic linkage to yield a disulfonic acid of unknown structure.104 Triphenylmethane,106 sj/m-tetraphenyl- ethane,106 and tetraphenylethylene 107 yield sulfonic acids containing one sulfo group for each benzene ring, probably in the para position. Naphthalene (Table IX, p. 182). The course of the sulfonation of naphthalene is strikingly dependent upon both the reaction temperature and time; at low temperatures the product is almost exclusively the a- isomer (96%),108 at 165° the product consists of approximately 85% /3- naphthalenesulfonic acid, 15% a-naphthalenesulfonic acid, and traces of the 1,6-disulfonic acid and of 0-naphthyl sulfone (1%).109 The pure a-acid is isolated from the former sulfonation as follows: the reaction mixture is diluted with water, filtered from unchanged naphthalene, and evaporated somewhat under vacuum at a low temperature; the a- acid dihydrate separates slowly, and is recrystallized from dilute hydro- chloric acid (m.p. 90°).108 The pure /3-acid is obtained from the high- temperature sulfonation as follows: the reaction mixture is diluted with water and filtered from the sulfone, then shaken with benzene to remove the last traces of the sulfone; the water layer is evaporated, and the /S-acid separates as the trihydrate on cooling to 10°. The pure trihydrate (m.p. 83°) is obtained after several recrystallizations from 10% hydro- chloric acid, in which it is practically insoluble at 10°. The trihydrate is converted into the monohydrate (m.p. 124°) on drying in a desiccator 100 Engelhardt and Latschinow, Zeit. far Chem., 1871, 259. 101 Wedekind and Schenk, Ber., 44, 198 (1911). 102 Lapworth, J. Chem. Soe., 73, 402 (1898). 103 Kade, Ber., 6, 953 (1873). 104 Limpricht and Schwanert, Ann., 146, 330 (1868). 106Kekul6 and Franchimont, Ber., 5, 908 (1872). 108 Engler, Ber., 11, 926 (1878). 107Behr, Ber., 5, 277 (1872). 108 Fierz and Weissenbaoh, Helv. Chim. Ada, 3, 312 (1920). 109 Witt, Ber., 48, 743 (1915). DIRECT SULFONATION OF AROMATIC HYDROCARBONS. 157 over sulfuric acid or calcium chloride.109 The a-isomer is transformed into the /3-isomer by heating the reaction mixture obtained at a low temperature; at 129° equilibrium is established after forty-two hours when the ratio of the a-acid and /3-acid is approximately 1 : 3.16 It is noteworthy that the acid group of the more stable isomer is situated in the less hindered /3-position. In the polysubstitution of naphthalene the sulfo groups are never found ortho, para, or peri (1,8) to one another; even so, six disulfonic acids, three trisulfonic acids, and one tetrasulfonic acid are obtainable by sulfonation reactions.110 Seventy-three polysulfonic acids are theo- retically possible. The acids obtainable from naphthalene by sulfonation are indicated in the chart; the symbol S used in the formulas represents the sulfonic acid group. CHART I SUWONATION OF NAPHTHALENE 110 The naphthalenesulfonic acids are important intermediates in the dyestuff industry; for a complete account of their industrial preparation see Fierz-David and L. Blangey, "Grundlegende Operationen der Farbenchemie," 5th ed., J. Springer, Vienna, 1943. 158 ORGANIC REACTIONS The disulfonation of naphthalene below 40° with oleum yields 70% of the 1,5- and 25% of the 1,6-disulfonic acid.111 In the reaction at 130°, the 1,6- and 2,7-acids predominate;111 minor amounts of the 1,3-, the 1,5-, and 1,7-acids are present.112 On sulfonation with 98% sulfuric acid at 60°, the 2-sulfonic acid is converted into the 1,6-disulfonic acid (80%) and into the 1,7-isomer (20%) .113 The 2,6-disulfonic acid is formed in sulfonations carried out above 140°,m but in a yield that never exceeds 42%;114 the main product is the 2,7-acid, which has been shown to rear- range at the reaction temperature into the 2,6-acid.114 The 2,7-acid can be obtained in high yield (78-85%) by sulfonation at 220-245° with 80-95% sulfuric acid.115 Direct high-temperature (180°) sulfonation of naphthalene with 24% oleum gives the 1,3,6-trisulfonic acid;116 the 1,3,5-trisulfonic acid116 is made by treating the 1,5-diacid with 67% oleum at 90°;m the 1,3,7- triacid is obtained by further sulfonation of the 2,6-diacid by oleum at 100°.118 ' Both the 1,3,5- and 1,3,7-trisulfonic acids yield the 1,3,5,7- tetrasulfonic acid on treatment with oleum.119 A fourth sulfonic acid group is not introduced into the 1,3,6-trisulfonic acid, even by treatment with sulfur trioxide. Anthracene (Table XI, p. 188). Anthracene is sulfonated so readily that even at low temperatures and with a mild sulfonating reagent some polysubstitution occurs. It is striking, therefore, that dilution of the reaction mixture with acetic acid (but not with water) decreases the extent of disubstitution, even with the more reactive sulfonating agents, chlorosulfonic acid or oleum.120 Under these conditions only 20% of the product consists of disulfonic acids; the 1-sulfonic acid is formed in 50% yield, the 2-acid in 30% yield. Substitution in the 2-position is favored by high temperatures,121 but this is not a result of conversion of the 1-acid into the 2-acid (as is probably true in the case of the naphthalenesulf onic 111 Fierz-David and Hasler, Hete. Chim. Ada, 6, 1133 (1923). 112 (o) Ufimtzew and Krivoschlykowa, J. praU. Chem., [2] 140, 172 (1934); (6) Chuksa- nova, Compt. rend. acad. sci. U.R.S.S., 26, 445 (1940) [C. A., 34, 5834 (1940)]. 113 Chuksanova and Bilik, AniLinokrasochnaya Prom., 4, 488 (1934) [C. A., 29, 1085 (1935)]. 1U Heid, /. Am. Chem. Soc, 49, 844 (1927). 116 Ambler, Lynch, and Haller, Ind. Eng. Chem., 16, 1264 (1924). 118 Busse, Bregman, and Trokhimovskaya, Khim. Farm. Pram., No. 1, 31 (1934) [C. A., 28, 5432 (1934)]; Ufimtzew and Krivoschlykowa, Org. Chem. Ind. U.S.S.R., 2, 144 (1936) [C. A., 31, 1021 (1937)]. 117 Erdmann, Ber., 32, 3186 (1899). 118 Cassella and Co., Ger. pat. 75,432 [Frdl., 3, 484]. u9Schmid, dissertation, Zurich, 1920 [C.A., 16, 2141 (1922)]; Fierz and Schmid, Helv. Chim. Ada, 4, 381 (1921); Bayer and Co., Ger. pat. 80,464 [Frdl., 4, 605]. m Bayer and Co., Ger. pat. 251,695 [Chem. Zentr., II, 1413 (1912)]. 121 Soc. St. Denis, Ger. pats. 72,226 [Frdl., 3, 195]; 77,311 [Frdl., i, 271]. DIRECT SULFONATION OP AROMATIC HYDROCARBONS 159 acids), for the 1-acid on heating with sulfuric acid at 150-180° is not con- verted into the 2-acid, but into the 1,5- and 1,8-disulfonic acids.18 SO.H SOSH SO3H SO3H SO3H (9 parts) (.part) Another striking observation is that the formation of the 2-acid can be depressed to as little as 1% by the use of pyridine-sulfur trioxide as the sulfonating agent, even when the reaction is carried out at tempera- tures (150-175°) that, with oleum, favor substitution in the 2-posi- tion.17'18 Although the two sulfonic acids can be separated from each other and from polysulfonic acids fairlyjreadily by fractional crystalliza- tion of the sodium or barium salts, the sulfonation reaction of anthracene is not employed commonly, since the monosulfonic acids are prepared more conveniently from the corresponding derivatives of anthraquinone. Phenanthrene (Table XII, p. 189). Phenanthrene is as readily sul- fonated as anthracene; when the reaction is carried out for three hours at 120-125° with concentrated sulfuric acid, more than 40% of the phenanthrene is converted into disulfonic acids.122 Two monosulfonic acids are isolated under these experimental conditions: phenanthrene-2- sulfonic acid (25% yield) and phenanthrene-3-sulfonic acid (27% yield).122- m The same acids are obtained by sulfonating at lOOf for eight hours (2-acid, 7% yield; 3-acid, 9% yield), and in addition a third acid, phenanthrene-9-sulfonic acid (6% yield)124 is formed. The 9-acid is formed in larger amounts at lower temperatures (14.5% at 20°, twenty days).126 A fourth monosulfonic acid, the 1-acid, is isolated from the sulfonation reaction conducted at 60° for several days.122 The yields of the four monosulfonic acids isolated under these conditions are 4% of the 1-acid, 18% of the 2-acid, 19% of the 3-acid, and 13% of the 9-acid. There is no indication that the only other possible monosulfonic acid, the 4-isomer, is ever formed, probably because the 4-position of phenanthrene is particularly hindered. The extent of disulfonation can be decreased by decreasing the time interval and, within certain limits, the quantity and strength of the sulfuric acid.126 Thus far no pure phenanthrenedisulfonic acids have been m Fieser, J. Atn. Chem. Soc, 51, 2460 (1929). "Tieser, Org. Syntheses, CoU. Vol. 2, 482 (1943). 124 Werner et al., Ann., 321, 248 (1902). ^Sandqvist, Ann., 392, 76 (1912). m Ioffe, /. Gen. Chem. U.S.S.R., 3, 448 (1933) [C. __., 28, 1694 (1934)]. 160 ORGANIC REACTIONS prepared, by the sulf onation either of phenanthrene or of a phenanthrene- sulfonic acid, but the formation of the 2,6-, 2,7-, 2,8-, 3,6-, and 3,8- disulfonic acids is inferred by the isolation of the corresponding dihy- droxy compounds from mixtures resulting from alkali fusion.127 SELECTION OF EXPERIMENTAL CONDITIONS In the sulfonation of the less reactive aromatic hydrocarbons or aryl halides, it is desirable to use 5-20% oleum, which brings about reaction at a convenient rate at moderate temperatures (0-50°); furthermore, if oleum is used, less sulfuric acid remains at the completion of the reaction to interfere with the isolation of the product. In the preparation of salts, however, this factor is of less significance. Although sulfur trioxide is even more active than oleum, it can be used to advantage only occa- sionally because it favors the formation of a sulfone. The formation of by-products is decreased by use of a solvent; a suitable solution can be prepared by passing the gaseous material, obtained by warming 60% oleum, into cold ethylene dichloride. Sulfuric acid is a satisfactory reagent for the sulfonation of the more reactive aromatic hydrocarbons; the reaction, however, is reversible, and, as ordinarily carried out, a large amount of reagent must be employed to obtain a fairly complete reaction. The excess is undesirable since it pro- motes polysubstitution. The use of excess reagent can be avoided by carrying out the reaction in an ingenious apparatus that permits removal of the water as it is formed.128 The use of a solvent in sulfonation with sulfuric acid is sometimes desirable. For example, in the sulfonation of biphenyl38a'98 the presence of a sulfonic acid group in one ring does not greatly reduce the rate of sulfonation in the other ring but does increase the solubility in sulfuric acid and therefore the chance of further sulfona- tion. This and similar compounds containing two or more substantially independent aromatic nuclei are preferably monosulfonated by using a solution of chlorosulfonic acid in chloroform, ethylene dichloride, or tetrachloroethane. The presence of one sulfo group in naphthalene de- creases the rate of sulfonation in the other ring to such an extent that a solvent is not essential;108'109 but in the monosulf onation of anthracene a solvent is desirable.120 When chlorosulfonic acid is used to prepare the sulfonic acid of polynuclear hydrocarbons a solvent such as chloroform seems to minimize the formation of the sulfonyl chloride.38" ?129' 13° m Fieser, J. Am. Chem. Soc., 51, 2471 (1929). m Meyer, Ann., 433, 327 (1923); see also p. 183 of ref. 51. w Armstrong, J. Chem. Soc, 24, 176 (1871). ""Pschorr, Ber., 34, 3998 (1901). DIRECT SULFONATION OF AROMATIC HYDROCARBONS 161 The progress of a sulfonation reaction can be followed by determining the acidic titer of a given weight of reaction mixture at suitable inter- vals,131 since for every mole of sulfonic acid produced the acidity is de- creased by one equivalent. If a sulfonation yields a mixture of mono- and di-sulf onic acids, neutralization of the diluted reaction mixture with barium hydroxide, filtration of the insoluble barium sulfate, and analysis for barium of a sample of the dried barium sulfonates obtained by evapo- ration of the filtrate will indicate the composition of the mixture. ISOLATION AND IDENTIFICATION OF SULFONIC ACIDS In a few instances it is possible to isolate the free sulfonic acid directly from the reaction mixture. The solubility of the acid is usually decreased by the addition of an inorganic acid. Several sulfonic acids have been isolated from the reaction mixture by the addition of hydrochloric acid: for example, p-toluenesulfonic acid,66 /3-naphthalenesulfonic acid,109 and m-xylene-4-sulfonic acid.^¡ªSometimes the acid can be isolated by treating an aqueous solution of the lead salt with hydrogen sulfide, re- moving the insoluble lead sulfide, and evaporating the filtrate, preferably under reduced pressure. The free acids are comparable in acidic strength to sulf uric acid; they are hygroscopic liquids or solids that are difficult to purify, and some are not even isolable. They usually form hydrates when crystallized from solvents containing water. For most purposes the alkali or ammonium salts serve equally well, and these are readily obtainable by adding a concentrated solution of the chlorides to the reaction mixture after partial neutralization with the carbonate.132 The remaining acid is converted into the salt by displacement of the equilib- rium ArSO3H + NaCl *± ArSO3Na + HCi An excess of the inorganic salt has a strong salting-out effect. An isola- tion procedure that is suitable for di- and tri-sulfonic acids as well as monosulf onic acids consists in neutralizing the diluted reaction mixture with a base that forms an insoluble sulfate (e.g., barium carbonate) and in treating the filtrate with an exact equivalent of dilute sulf uric acid; the insoluble sulfate is again precipitated, and the filtered solution con- taining the free sulfonic acid is then treated with the desired carbonate or sulfate and evaporated. The separation of isomers is often possible by fractional crystallization of various salts. The sulfonates prepared by either procedure are usually contaminated by the inorganic salt; salt-free 131 Simpson and Olsen, Ind. Eng. Chem., 29, 1350 (1937). m Gattermann, Ber., 24, 2121 (1891). ~ 162 ORGANIC REACTIONS material can often be obtained by crystallization from anhydrous ethanol. Another procedure applicable to polysulfonates, particularly azo dyes, consists in resalting the sodium sulfonate several times with sodium ace- tate (or ammonium bromide) and then removing the salting agent from the dried, ground sulfonate by repeated extraction with ethanol.133 The identification and purity of a sulfonate are difficult to establish since the salts do not melt without decomposition; the melting points of the free acids or hydrates are often not sharp. In the precise work of Holleman and Caland14 on the quantitative determination of the course of the sulf onation of toluene where the pure sulfonic acids were required as standards, the purity was established by conversion into the sulfo- chloride or into the sulf'onamide, both of which derivatives in general exhibit satisfactory melting characteristics. The sulfonic acid is readily regenerated by hydrolysis of the sulfonyl chloride; in fact, if the sulfonyl chloride is readily available, it may serve as a convenient source of the free sulfonic acid.14'1S4 Identification through conversion into the sul- fonyl chloride or into the ester has the disadvantage that an anhydrous sample of the sulfonate is required. A solid derivative that can be made from an aqueous solution of the free acid or from the sodium, potassium, or ferrous salt is the p-toluidine salt, prepared by adding p-toluidine and hydrochloric acid and allowing crystallization to occur.126'126'135 The amine salts are sparingly soluble in water and can be recrystallized from ethanol or ethanol-water mixtures. The amine salt of an impure acid remains as an oil almost indefinitely, and this property is very charac- teristic of a mixture of isomers. EXPERIMENTAL PROCEDURES 2,4,6-Trimethylbenzenesulfonic Acid (Mesitylenesulfonic Acid).78" A mixture of 100 cc. (87.6 g.) of mesitylene and 200 cc. of concentrated sulf uric acid, contained in a 500-cc. flask fitted with a short air-cooled condenser, is shaken vigorously. The temperature rises rapidly to 60°, and solution of the hydrocarbon is complete in five to ten minutes. The clear yellowish liquid that results is poured, while still warm, into 400 cc. of concentrated hydrochloric acid, kept at 10° or lower, or onto 300 g. of ice, and stirred vigorously. The sulfonic acid that precipitates is filtered with suction through a cloth filter and pressed as dry as possible. The yield of air-dried crude acid, which usually has a slight color, is 150 g. (90%); m.p. 76-78°. It may be purified by crystallization from chloro- 133Hartwell and Fieser, Org. Syntheses, Coll. Vol. 2, 145 (1943). 134 Sandqvist, Ann., 379, 79 (1911). 186 Dermer and Dermer, J. Org. Chem., 7, 581 (1942). DIRECT SULFONATION OF AROMATIC HYDROCARBONS 163 form (50 g. acid, 200 g. chloroform); the acid (46 g.) then melts sharply at 78° and is snow white. Sodium 1,3,5-Benzenetrisulfonate.26 A mixture of 50 g. of crude sodium m-benzenedisulfonate, 50 cc. of 15% oleum, and 2 g. of mercury- is placed in a 300-cc. Kjeldahl flask and is heated in a salt bath at 275° for twelve hours with occasional shaking. The cooled mixture is poured into 11. of water. The resulting solution is heated and treated with solid calcium carbonate until neutral to litmus. The calcium sulfate is filtered and washed with three 200-cc. portions of boiling water. The combined nitrates and washings are treated with a saturated solution of sodium carbonate until they are just alkaline to phenolphthalein. The mixture is digested on a steam bath and filtered through a Norit pad, and the fil- trate is evaporated to dryness. The residue, which is practically pure sodium sym-benzenetrisulfonate, is dried in an oven at 140° for four hours. The yield is 50 g. (73%). 4,4'-Dibromobiphenyl-3-sulfonic Acid.40 To a mechanically stirred solution of 20 g. of 4,4'-dibromobiphenyl in 50 cc. of anhydrous chloro- form, 20 g. of chlorosulfonic acid is added slowly so that the temperature is maintained at 40°. The solution becomes dark green, and hydrogen chloride gas is steadily evolved. At the end of three hours the reaction product is hydrolyzed, and the insoluble material is removed by cen- trifugation. Crystallization of this solid from acetic acid gives 6 g. (25% yield) of 4,4'-dibromobiphenylene-2,2'-sulfone. The solution is neutral- ized with sodium carbonate. From the chloroform layer there is obtained by evaporation 5 g. (25% yield) of the unchanged dibromobiphenyl. The addition of acid precipitates the 4,4'-dibromobiphenyl-3-sulfonic acid in small orange crystals. The yield is 8 g. (32%). The acid can be crystallized from boiling water. Doubling the quantity of chlorosulfonic acid increases the yield of acid to 11 g. There is obtained also 8 g. of sulfone together with 2.5 g. of unchanged starting material. When 20 g. of the dibromide and 40 g. of chlorosulfonic acid are heated at 60° for fifteen minutes in the absence of a solvent, the reaction product consists of 13 g. (41.5% yield) of the 3,3'-disulfonic acid, 4 g. (12.5% yield) of the coiyesponding disulfonyl chloride, and 10 g. (42% yield) of the sulfone mentioned above. Sodium Pyrene-3-sulfonate.136' m To a cooled solution of 1 equivalent of pyrene in 6 volumes of s-tetrachloroethane there is added dropwise with stirring the calculated amount of chlorosulfonic acid (2 equivalents) dissolved in an equal volume of s-tetrachloroethane. The temperature is maintained at 0-5° during the addition. The mixture is stirred for fifteen 136 Volmann, Becker, Corell, and Streeck, Ann., 531, 1 (1937). 187 Tietae and Bayer, Ann., 540, 189 (1939). 164 ORGANIC REACTIONS to twenty hours at 10-20°, and the gray-green mass is poured on ice. The original solvent is removed under reduced pressure, and the aqueous solution is heated and then filtered to remove a small amount of un- changed pyrene. Finally the hot nitrate is mixed with a boiling solution of the calculated amount of sodium sulfate in water, which precipitates the almost insoluble sodium sulfonate. This is filtered and dried. The yield is 90-92%. 2,5-Dichlorobenzenesulfonyl Chloride.138 A mixture of 1 mole of p-dichlorobenzene and 5 moles of chlorosulfonic acid is heated at 150° for one hour in a flask equipped with an air-cooled condenser. The flask is then cooled and the contents are poured on crushed ice; the chloro- sulfonyl derivative separates as a solid. This is filtered and dried. The yield of crude material is 85%. After crystallization from ethanol the substance is obtained as colorless needles that melt at 39°. Benzenesulfonyl Fluoride.31 For experiments with fluorosulfonic acid, Steinkopf recommends the use of an iron vessel with a screw top fitted with a mercury-seal stirrer, dropping funnel, thermometer well, and gas- exit tube. A small open-top iron or platinum container without a stirrer can be used only in very small-scale fluorosulfonations. To 225 g. (2.25 moles) of-fluorosulfonic acid in an iron container is added 55 g. (0.7 mole) of benzene with stirring during six hours at 16-20°. After an additional nine hours at the same temperature, with continued stirring, the reaction mixture is poured on ice and extracted with ether; the ether layer is washed with water to which sufficient calcium car- bonate is added to neutralize the acid, the ether solution is separated and concentrated, and the residue is distilled with steam. There is obtained 77.5 g. (62% yield) of an oil that distils at 90-91°/14 mm. and 203-204°/ 760 mm.; df° 1.3286 and n? 1.4932. The residue from the steam dis- tillation contains 9.5 g. of phenyl sulfone. Benzenesulfonyl fluoride may be obtained also by allowing benzenesulfonyl chloride to stand with four times its weight of fluorosulfonic acid at room temperature for twenty-four hours. 138 Stewart, J. Chem. Soc., 121, 2555 (1922). DIRECT SULFONATION OF AROMATIC HYDROCARBONS 165 TABLE I BENZENE AND ITS HALOGEN DERIVATIVES Compound Sulfonated Benzene Benzenesulfonic acid Benzenesulfonyl chloride Sodium benzene- 1,3-disulfonate Potassium ben- zene-l,3-di- sulfonate Benzene-l,3-di- sulfonic acid Benzene-l,3-di- sulf onyl chloride Bromobenzene Reagent * and Reference t A (lc, Id, le, 2, 4, 11, 51, 139, 140) B, 5-9.5% (132, 141, 142) SO3 (Id, le. If) SO3 dioxane (29) C (53) C(52) D (31) NaH3(SO4)2 (36) Nitryl sulf ate (143) A, then SO3 (144) NaH3(SO4)2 (36) B, 20% (54, 55) B, 66% (110) C (38a) A, 97 or 100% (19, 22) A (145) A (146) NaH3(SO4)2 (36b) D(31) B, 15% (25) A (147) NaH3(SO4)2 (366) D (31) A (42) B, 10% (27d, 85) C (86) C (43, 148, 149) Experimental Conditions Various conditions 3.7 parts B, warm CHCI3 solution, 0-10° CCU solution, room tem- perature; 1 day 3 moles C, 20-25°, 1 hr. * Excess benzene 4 parts of D, 9 hr. at 16-20° 2.5 parts reagent, reflux, various times ¡ª Excess A Excess reagent, heat 2 vol. B, 200-220°, 3 hr. 75°, 2hr.;90°, 1 hr. 10 parts C, 150-160°, 2 hr. 2-4 parts A, 235-250°, Hg catalyst 7 parts A, 4 parts P2O6, 280-290°, 5-6 hr. 210-275°, 60 mm., 3 hr. 1.5 parts A, 240°, 2-3 hr. 4 parts D, 20°, 24 hr. 1 part B, 2% Hg, 275°, 12 hr. High temperature 280-300° 5 parts D; 95°, 19 hr. 10 parts A, reflux 1 mole SO3, 60°, 1 hr. 1 mole C ** 5 parts C, CHCU solution, 25°. 20 min. Position of Sulf 0 Group(s) ¡ª ¡ª ¡ª ¡ª ¡ª .¡ª ¡ª ¡ª 1,3- 1,3- 1,3- 1,3- 1,3- 1,3- and 1.4- 1,3,5- 1,3- and 1,4- 1,3- ¡ª 1,3,5- 1,3,5- 1,3,5- 1,3- ¡ª 4- 4- 4- Remarks Mono-SO3H Mono-SO3H, mainly Mono-SOjH, 90% Mono-S03H, high yield Mono-SOijCl, 76%; some sulfone Mono-S03H and sulfone Mono-SO2F, 62%; also sulfone Mono-SO3H, 33- 40% Mono-SOsH Di-SO3H Di-SChiB Di-SO3H Di-SO3H, 90% D1-SO2CI 1,3-Di-SO3H, 67-69% 1,4-Di-SOsH, 31-33% Tri-SO3H 82.5% of di-SO3H mixture Di-SO3H, 100% CeHsSOiiF Tri-SO3H, 73% Tri-SO3H, 44% Tri-SO3H Di-SO2F Complex mixture Trace of 4,4'-sulf one -SO3H, smaller amounts of the 4- SO2C1 and sulfone -SO2CI * A refers to concentrated sulfuric acid; B, to oleum; C, to chlorosulfonic acid; and D, to fluoro 8ulf onio acid. t References 139-406 appear on pp. 192-197. 166 ORGANIC REACTIONS TABLE I¡ªContinued BENZENE AND ITS HALOGEN DEBIVATIVES Compound Sulfonated Bromobenzene-4- sulfonic acid Chlorobenzene Chlorobenzene-4- sulf onyl chloride Chlorobenzene-4- sulfonio acid Chlorobenzene-2,- 4-disulfonic acid Fluorobenzene Iodobeazene 1,2-Dibromoben- zene 1,3-Dibromoben- zene 1,4-Dibromoben- zene 1,2-Dichlaroben- zene Reagent * and Reference t SO3(150) H2S2O7 (90) A (151) A (152) B, 10% (85) C (860) C (43, 866, 87) B, 20% (88, 89) A, 100% (89, 153) C(38) B, 20% (88, 89) B, 20% (88, 89) B, 10% (84) C(43) A (44) A (44) B (85) C (43) B (19) B (19) C (43) C(43) B (154) C (43) * B (155, 156, 157) B (19) Experimental Conditions 200-220°, 10 hr. 8-10 parts reagent, 220- 240°, 6 hr. 10 parts A, reflux 10 hr. Excess A, 100°, 3-4 hr. 1 m?le SO3, < 60°, 1 hr. 1 mole C 4 vol. C, 25°, 1-3 hr. 5 vol. B, 300°, 6 hr. 160-180° 150-180° Excess B, 300° Excess B, 300° 70° 5 parts C, CHCI3 solution, 25°, 20 min. 5 parts C, 40°, 1 hr. 10 parts A, 25°, several days 1 part A, 170-180°, 2 hr. 1 mole SO3, < 60°, 1 hr. 5 parts C, CHCI3 solution, 25°, 20 min. ¡ª 10% Hg 5 parts C, 50° 5 parts C, CHCI3 solution, 25°, 20 min. 5 parts C, CHCI3 solution, 25°, 20 min. Various conditions 5 parts C, reflux, 1 hr. 25°, 100°, or 210° 2% or 10% Hg Position of Sulfo Group (s) 2,4- 2,4- 3,5- 4- 4- 4- 4- 3,5- 2,4- 2,4- 3,5- 3,5- 4- 4- ¡ª 4- ¡ª 4- ¡ª 4- 3- and 4- ¡ª 4- 4- 2- 2- 4- 3- and 4- Remarks Di-SO3H, 73% Di-SO3H Di-SO3H, 40% (crude) -SO3H -SO3H -SO3H, small amounts of the 4- SCteCUndsulfone -SO2CI, 84%; sul- fone, 6.2% Di-SO3H, 30% Di-SO3H Di-SO2Cl Di-SOsH, mainly Di-SO3H, mainly ¡ª -SO2CI 100% of 4,4'-sulfone Mixture 50% C6H4I2, some 4-SO3H and C8H5SO3H -SO3H and some 4,4'-sulfone 4,4'-Sulfone -SO3H 3-SO3H, 24% 3,4,3',4'-Sulfone -SO2CI, also 3% of sulfone -SO2CI -SO3H -SO2C1, 80% -SO3H 3-SO3H, 16%; 4- SO3H, 26% * A refers to concentrated sulfuric acid; B, to oleum; C, to chlorosulfonic acid; and D, to fluoro- sulfonic acid. t References 139-406 appear on pp. 192-197. DIRECT SULFONATION OF AROMATIC HYDROCARBONS 167 TABLE I¡ªContinued BENZENE AND ITS HALOGEN DERIVATIVES Compound Sulfonated 1,2-Dichloroben- zene 1,3-Dichloroben- zene 1,4-Dichloroben- zene 1,4-Diiodoben- zene 1,4-Bromochloro- benzene 1,2,4-Tribromo- benzene I,3i5-Tribromo- benzene 1,2,3-Trichloro- benzenc 1,2,4-Trichloro- benzene 1,3,5-Trichloro- benzene 1,2,3,5-Tefra- bromobenzene 1,2,4,5-Tetra- chlorobenzene Reagent * and Reference t C(43) C (43) B, 7% (156, 157) B, 45% (158) C (43) B, 10% (157, 159, 160) SO3 (161) C (138, 162) C (162) SO3 (45) C (43) B (163) C(43) H2S2O7 (164) B (165, 166, 167) C(43) C (43) C(43) C(43) B (158) B (166) C(43) Experimental Conditions 5 parts C, 50° 5 parts C, CHCI3 solution, 25°, 20 min. 230° or 100° 2.3 vol. B, 145°, 5 hr. 5 parta C, CHCI3 solution, 25°, 20 min. 25°, shake 24 hr. ¡ª 5 parts C, reflux, 1 hr. 140", 48 hr. Warm 5 parts C, 50°, 5 min. ¡ª 5 parts C, reflux, 1 hr. 6.6 parts reagent 3 or 4 parte B, 100°, 3-4 hr. 5 parts C, CHCI3 solution, 25°, 20 min. 5 parts C, CHCI3 solution, 25°, 20 min., then 80°, lhr. 5 parts C, CHCI3 solution, 25°, 20 min., then 150°, 1 hr. 5 parts C, CHCI3 solution, 25°, 20 min., then 150°, "^ 30 min. 3 vol. B, 100°, 15 hr. 3-4 vol. B, 100°, 14 days 4 parts C, reflux, 1 hr. Position of Sulfo Group(s) 4- 4- 4,6- ? 4- 2- 2- 2- 2,5- and 2,6- 2- ¡ª 2- and 3- 2- and 3- 5-(?) 2- 2- 4- 5- 2- 2, 4- ¡ª Remarks 3,4,3',4'-Sulfone -SO2CI, also 8% of sulfone -SO3H Di-SOsH -SO2CI -SO3H; almost quantitative -SO3H -SO2CI, 80% Di-SO2Cl, mainly 2,6- -SO3H, <10%, mainly polyiodo compounds 2,3,5,6-TetrachIoro- 1,4-diiodobenzene Equal amounts of two -SOaH -SO2CI, 86%, mainly the 2- Anhydride of a mono-S03H -SO3H, good yield -SO2CI -SO2CI -SO2CI -SO2CI Di-SO3H Mono-SOsH Hexachlorobenzene, 78% * A refers to concentrated sulfuric acid; B, to oleum; C, to chlorosulfonic acid; and D, to fluoro- sulf onic acid. t References 139-406 appear on pp. 192-197. 168 ORGANIC REACTIONS TABLE II ToiiUENE AND ITS HALOGEN DERIVATIVES Compound Sulfonated Toluene Toluene-2-suIfonyl chloride Toluene-4-eulfonyl chloride Toluene-4-sulfonyl fluoride ToIuene-3-sulfonic acid Toluene-2,4-di- sulfonyl fluoride Potassium toluene- 2,4-disuIfonate 2-Bromotoluene 3-Bromotoluene 4-Bromotoluene Reagent * and Reference t A, 84-100% (14, 16, 62, 168) B, 8% (20, 169) C (86a) C (14, 16, 34, 170, 171) D(31) SO3 (59) NaH3(SO4)2 (36a) S2O5CI2 (33) B, 66% (110) B (60, 62, 63, 172) C (38a) C (38o) B, 40-50% (173) B (62) D(31) D(31) B (94, 172) C(31) C (63) B (174) C. (43) B (175) C(43) B (176) Experimental Conditions Various conditions -i 2.3 parts B with or without 3% HgSOi 1 mole of C Various conditions 4 parts D; 10 hr. at 25° 40-55° 2.5 parts reagent, reflux, 15-16 hr. 1 mole reagent, 60°, 1 hr. 125°, 4 hr. 3-4 parts B, 150-180°, 2 hr., then 200° 8 parts C, 140-150°, 5 hr. 1 mole C, heat, then 10 moleij 150-160°, 5-6 hr. 4 parts B, heat slowly to 200° 140-150° 4 parts D 4 parts D, 130-140°, 3 hr. 2.5 parts B, 180°, 3-4 hr. 4 parts C, 100°, 10 hr. 3 moles C, 240° Warm, shake 5 parts C, CHCI3 solution, 25°, 20 min. 100° 5 parts C, CHCU solution, 25°, 20 min., then 50°, 10 min. 1-4 voL B, 60°, 4 days Position of Sulfo Group (s) 2-, 3-, 4- 2- and 4- 2- and 4- 2-, 3-, and 4- 2-and 4- 2-, 3-, and 4- 4- 4- 2,4- 2,4- and 2,5- 2,4- ¡ª 2,4-(?) 2,4- 4- 2,4- 2,5- and 3,5- 2,4- 2,4,6- 5- and 6- 5- 6- 6- 2- and 3- Remarks Yield of each isomer determined for each condition 82% yield (69% 4- and 31% 2-) Two -SO3H, some 4,4'-sulfone -SO2CI 89% of -SO2F (40% of 2-isomer) -SO3H; 8%, 7%, and 55% respec- tively, also 22% of 4,4'-sulfone -SO3H, 87% -SO3H and -SO2CI, also sulfone and dichlorotoluenes Di-SO3H Di-SOsH, mostly 2,4- Di-SO2Cl, 60% 4,4'-sulfone-3,3'-di- SO2CI, 42% -SO3H derivatives of -SO2CI Di-SO3H -SO2F Di-SO2F, 48% Di-SO3H D1-SO2CI Tri-SOjH 5-SOsH, mainly -SOaCl -SO3H -SO2CI 2-SO3H, mainly * A refers to con ?ntrated sulfurio acid; B, to oleum; C, to chlorosulfonic acid; and D, to fluoro' sulfonic acid. t References 139-406 appear on pp. 192-197. DIRECT SULFONATION OF AROMATIC HYDROCARBONS 169 TABLE II¡ªContinued' TOI/OTBNE AND ITS HALOGEN DEWVATIVES Compound Sulfonated 4-Bromotoluene 2-Chlorotoluene * Potassium 2- ehlorotoluene- 4-sulfonate Potassium 2- ohlorotoluene- 5-eulfonate 3-Chloro toluene 4-Chlorotoluene Potassium 4- chlorotoluene- 2-sulfonate Potassium 4- chlorotoluene- 3-sulfonate 2-Fluorotoluene 2-Iodotoluene 4-Iodotoluene 2,3-Dibromo- toluene 2,4-Dibromo- toluene 2,5-Dibromo- toluene 2,6-Dibromo- toluene 3,4-Dibromo- toluene 3,5-Dibromo- toluene 2,3-Dichloro- toluene Reagent * and Reference t C(43) B (177) A, 100% (93) B (92) C (43) B, 35% (94) B, 20% (94) A, 100% (93) C(43) A, 100% (92, 93, 94, 178) C(43) B, 20% (94) B, 20% (94) C (43) A (44) SO3 (179) SO3 (180) B (181) B (181) B (181) B (181) B (181) B (181) B (182) Experimental Conditions 5 parts C, CHCI3 solution, 25°, 20 min., then 50°, 10 min. Heat, 24 hr. 3 parts A, 60°, 10 min. Dissolve in B 5 parts C, CHCI3 solution, 25°, 20 min. 1.4 parts B, 150°, 2 hr. 1.7 parts B, 150°, 2 hr. 3 parts A, 70°, 10 min. 5 parts C, CHCI3 solution, 25°, 20 min., then 50°, 10 min. 3 parts A, 100°, 40 min. 5 parts C, CHCI3 solution, 25°, 20 min., then 50°, 10 min. 1.7 parts B, 150°, 2 hr. 1.7 parts B, 150°, 2 hr. 5 parts C, CHCls solution, 25°, 20 min. 1 part A, 100°, 4 hr. Cold, then heat 1 mole SO3, CHCI3 solution 2 parts B, 100° i 3 parts B, heat Position of Sulfo Jroup(s) 2- 2,6-(7) 5- 5- 5- 5- and 6- 3- 6-(7) 6- 2- and 3- 2- 2,5- and 2,6- 3,5- and 3,6- 5- 5-(7) 5-(7) 2- and 3- 5-(7) 5-(?) 4-(7) 3-(?) 6-(?) 2-(7) 5- and 4- or 6- Remarks -SOjCl Di-SQsH, 37% -SO3H -SO3H -SO2CI 6-SO8H, mainly -SO3H -SO3H -SO2CI 2-SO3H, 86% -SO2CI Di-SOsH Di-SO3H -SO2CI -SOaH Also diiodo com- pounds -SO3H -SO3H -SO3H -SO3H -SO3H -SO3H -SO3H -SO3H * A refers to concentrated sulfuric acid; B, to oleum; C, to chlorosulfonic acid; and D, to fluoro- sulfonio acid. t References 139-406 appear on pp. 192-197. 170 ORGANIC REACTIONS TABLE II¡ªContinued TOLUENE AND ITS HALOGEN DERIVATIVES Compound Sulfonated 2,4-Dichloro- toluene 2,5-Dichloro- toluene 2,6-Dichloro- toluene 3,4-Dichloro- toluene 3,5-Dichloro- toluene 2-Bromo-3- chlorotoluene 2-Bromo-4- chlorotoluene 2-Bromo-5- chlorotoluene 2-Bromo-6- chlorotoluene 3-Bromo-2- chlorotoluene 3-Bromo-4- chlorotoluene 3-Bromo-5- chlorotoluene 3-Bromo-6- chlorotoluene 4-Bromo-2- chlorotoluene 4-Bromo-3- chlorotoluene 2,3,4-Trichloro- toluene 3,4,5-Trichloro- toluene X Reagent * and Reference t B (182, 183) C (43) B, 10% (93) B (182) C(43) B, 5% (93) B (182) B (184)] B (184) B (184) B (184) B (184) B (184) B (184) B (184) B (184) B (184) J B (183) B, 10% (93) Experimental Conditions 2 parts B, heat 5 parts C, CHCI3 solution. 25", 20 min., then 50°, 10 min. 2 parts B, 60-70°, then 2 parts more, 100° 2 parts B, heat 5 parts C, CHCI3 solution, 25°, 20 min., then 50°, 10 min. 3 parts B, dissolve 2 parts B, heat 3 parts B, 100° 80-100° 3 parts B, 70-80° Position of Sulfo Group (s) 5- 5- 4- 3-(7) 3- 6- 2-(7) 6-(7) 5-(?) 4-(7) 3-(?) or 5-(?) 6-(?) 6-(?) 6-(?) 4-(?) 5-(?) 6-(7) 5- and 6- 2- Remarks -SO3H -SO2C1 -SO3H -SO8H -SO2CI -SO3H -SOaH -SO3H -SO3H -SO3H -SO3H -SO3H -SO3H -SO3H -SO3H -SO3H -SO3H Structures undeter- mined -SO3H *A refers to concentrated sulfuric acid; B, to oleum; C, to chlorosulfonic acid; and D, to fluoro- sulfonic acid. t References 139-406 appear on pp. 192-197. t The sulfonic acid was isolated from the sulfonation of a chlorinated toluene fraction boiling above 166°. DIRECT SULFONATION OF AROMATIC HYDROCARBONS - 171 TABLE III HIGHER ALKYLBENZENES J AND THEIR HALOGEN DERIVATIVES Compound Sulfonated Ethylbenzene Ethylbenzene-2- - sulfonic acid 2- and 4-Bromo- ethylbenzene n-Propylbenzene Isopropylbenzene n-Butylbenzene sec-Butylbenzene (-Butylbenzene Isoamylbeniene 2-Phenylpentane 3-Phenylpentane 2-Phenyl-3- methylbutane Neopentyl- benzene 2-Phenylhexane l-Phenyl-3- methylpentane 2-Phenyl-4- methylpentane n-Octylbenzene n-Dodecylbenzene n-Hexadecylben- zene n-Octadecylben- zene Reagent * and Reference t A (185) B (186, 187) C (186, 187) D (188) B, 50% (189) Heat (187) B (185, 187) A (190) B (191, 192) A (193) B (796, 191, 194) B (195) B, "very strong" (196a) B, 6% (1966) A (197) B(26) C (34) B (199) B, 6% (200) B, 6% (200, 201) B, 6% (200) B, 6% (202) B (203) B, 6% (204) B, "weak" (205) B (206) C or SO3 (207) B (208) B (208) Experimental Conditions Equal volume A added slowly to boiling com- pound By.dissolving in B 1 mole C 4 parts D, standing ¡ª 100° 1.5 vol. B added slowly to boiling mixture ¡ª Dissolve in B 100° 1-2 parts B, stir Warming 24 hr. 5 parts B, 50° Warm Dissolve, cooling Excess C, CHCI3 solution Warm slightly Warm slightly Warm Warm 2 parts B, room tempera- ture ¡ª 40° approximately Warm Room temperature C2H4CI2 solution 35-40" Approximately 40°; excess B Position of Sulfo Group(s) 4- 4- 4- 4- 2,4- ¡ª (2) 5- and (4) 2- 4- and 2- 4- and 2- 4- 4- 4- and 2- 4- Un- known 4-(?) 4- 4- 4-(?) 4-(?) 4-(?) 4-(?) 4: ? 4-(?) 4-(?) 4-(?) 4-(?) 4- 4- Remarks -SO3H -SO3H ¡ª -SO2F, 86%; trace of sulfone Di-SO3H Rearranges to tb? 4-SO3H 2-SO3H, mainly -SO3H -SO3H -SO3H; trace of 2- SO3H -SO3H -SO3H -SO3H -SO3H -SO3H ¡ª . -SO2C1, 100% Cryst. acid -SO3H -SO3H Rapid reaction Ba salt, 95% -SO3H Oily product -SO3H -SO3H Washing agent -SO3H -SO3H * A refers to concentrated sulfuric acid; B, to oleum; C, to chlorosulfonic acid; and D,*to fluoro- sulfonio acid. t References 139-406 appear on pp. 192-197. t Mixtures of alkylbenzenesulfonic acids, obtained by the sulfonation of mixed sec-alkylbenzenes which in turn have been prepared by the condensation of a mixture of olefins or alkyl chlorides with benzene, have been patented as washing or emulsifying agents.12*209 The condensation of acid chlorides with benzene, followed by reduction and sulfonation, has also been employed for this purpose.207 In a number of instances, alkylbenzenesulfonic acids have been obtained by the alkylation of ben- zene-, toluene-, or xylene-sulfonic acids.210 172 ORGANIC REACTIONS TABLE IV DiALKTLBENZENES AND THEIR HALOGEN DERIVATIVES Compound Sulfonated 1,2-Dimethyl- benzene Barium 1,2-di- methylbenzene- 4-sulfonate l,2-Dimethyl-3- ohlorobenzene l,2-Dimethyl-4- chlorobenzene l,2-Dimethyl-3- bromobenzene l,2-Dimethyl-4- bromobenzene l,2-Dimethyl-4,5- dibromobenzene 1,3-Dimethylben- nnc 1,3-Dimethylben- zene-4-sulfonyl fluoride 1,3-Dimethylben- zene-2-sulfonic acid 1,3-Dimethylben- zene-4-sulfonio add l,3-Dimethyl-4- cblorobenzene l,3-Dimethyl-5- chlorobenzene l,3-Dimethyl-4- bromobenzene l,3-Dimethyl-4- iodobenzene l,3-Dimethyl-2,4- dichlorobenzene l,3-Dimethyl-2,4- dibromobenzene Reagent * and Reference t A (64) A (19) A (66) C (34) C (38a) C(72) B (211, 212) B (211, 212) B (213) B (64) . B, 15% (65) A (676, 68, 69, 214) D (31) HSSJOT (73) D (31) C (68, 74) C (68) C (68) B (215) HaSaOr (73) B, 15% (956) B (216) A (217) C (96) C (218) Experimental Conditions 1 vol. A, warm 2% and 10% HgSO4 as catflyst 1.2 vol. A, room tempera- ture CHClj solution Excess C 2 parts C, 150° By shaking By shaking Dissolve in B By warming 10 parts B; 75°, shaking 2 parts A; 100° or less; 2 hr. 4 parts D; 5 hr. 5°; 15 hr. 20-30° 4 parts reagent; 150° 4 parts D; 100° 10 parts C; 80-90°; 4 hr. 10 parts C; 150-160°; 5 hf. 7 parts C; 150-160°; 5 hr. Dissolve in B Heat 30-40°, shaking Cold 4-6 weeks; room tempera- ture ¡ª Excess C Position of Sulfo Group(s) 4- 4- and 3- 4- 4- 3,5- 3,5-(?) 6--I J6- and 4- 5- 3- 4- 4- 4,6- 4,6- 4,6- and 2,4- 4,6- 4,6- 6- 2,6- 2- 6- 6- 6- 6- Remarks -SO3H 3-SOaH, 8 and 22% 82% dissolves in 2 hr. -SO2CI, 74-86% Di-SO2Cl Di-SOsH Mixed chloro- xylenes used 6-SO3H, mostly ? A reacts very slowly -SOaH 2-SOsH, trace -SO2F, 86% Di-SOsH Di-SO2F, 70% Di-SOzCl; mop*1" 4,6- D1-SO2CI Di-SO2Cl -SOsH Di-SOjH -SO3H; anhydride is by-product -SOjH Diiodoxylene also -SO3H -SO2CI * A refers to concentrated sulfurio acid; B, to oleum; C, to chlorosulfonic acid; and D, to fluoro- sulfonic acid. t References 139-406 appear on pp. 192-197. DIRECT SULFONATION OF AROMATIC HYDROCARBONS 173 TABLE IV¡ªContinued DiALKYLBENZENES AND THEIR HALOGEN DERIVATIVES Compound Sulfonated I,3-Dimethyl-4,6- dichlorobenzene l,3-Dimethyl-4,6- dibromobenzene l,3-Dimethyl-4,6- diiodobenzene 1,4-Dimethylben- zene 1,4-Dimethylben- chloride 1,4-Dimethylben- zene-2-sulfonyl fluoride l,4-Dimethyl-2- chioro benzene l,4-Dimethyl-2,3- dichlorobenzene l,4-Dimethyl-2,6- dichlorobenzene l,4-Dimethyl-2,5- dichlorobenzene l,4-Dimethyl-2,5- dibromobenzene 1,2-Diethylben- zene 1,3-Diethylben- zene 1,4-Diethylben-zene 1,4-Di-n-propyl- benzene 1,2-Diisopropyl- benzene 1,3-Diisopropyl- benzene 1,4-Diisopropyl- benzene 1,4-Di-f-butyl- benzene Reagent * and Reference t C (96) B (219) B (220) A (66) B (70, 221) D (31) B, 80% (75, 76) C (74) B (221) C(31) B (222) ? A (223) A (223) B (223) B, 20% (224) B (225) B (226) B (226, 227) B (228) A (229) A (229) C (230) C (230) A (231) Experimental Conditions 70-80° 25°, 6 days Room temperature 2 vol. B 4 parts D, 16 hr., 25° 140-150° Excess C Warm 4 parts C, 36 hr., 25° By shaking Reacts readily Reacts readily 100° 80-85° 50-60° Dissolve in B Dissolve in B Dissolve in B Long shaking Long shaking CCU solution CCU solution By warming Position of Sulfo Group(s) 2- 2- 6- 2- 2- 2- 2,6- 2,6- and 2,5- 2,6-(?) 2- and 2,6-di- 5- 5- 3- 3- 3- 4-(?) 4-1 i 2- 4-(?) 4- 4- 2- 2- Remarks A causes rearrange- ment -SO3H Iodine to 2,4- -SO3H, 68% -SOsH -SOjF, 85% D1-SO3H Di-SO2a; ratio 10 : 1,-alsosul- fone (38) Di-SOaH SO2CI compounds -SO3H -SO3H -SO3H -SO8H -SO3H -SO3H Mixture of isomers sulfonated -SO3H -SO3H -SO3H -SO2CI -SO2CI -SO3H * A refers to concentrated sulfurie acid; B, to oleum; C, to cUorosulfonio acid; and D, to fluoro sulfonic acid. t References 139-406 appear on pp. 192-197, 174 ORGANIC REACTIONS TABLE IV¡ªContinued DiALKYLBENZENES AND THEIB HALOGEN DEBIVATTVES Compound Sulfonated 2-Ethyltoluene 3-Ethyltoluene 4-Ethyltoluene 4-Ethyl-2(?)- chlorotoluene 4-Ethyl-2-bromo- toluene 3-n-Propyltoluene 4-n-Propyltoluene 2-Isopropyl- toluene 3-Isopropyl- toluene 3-Isopropyl-6- bromotoluene 4-Isopropyl- toluene 4-Isopropyl-2- chlorotoluene 4-Isopropyl-3- chlorotoluene 4-Isopropyl-2- bromotoluene 3-(-Butyltoluene "p-Butyltoluene" 4-Isoamyltoluene 4-n-Octyltoluene 4-n-Hexadecyl- toluene l-Ethyl-4-n- propylbenzene l-Ethyl-3-iso- propylbenzene l-Ethyl-4-iso- propylbenzene 1-Ethyl-(?H- butylbenzene l-n-Propyl-4-iso- propylbenzene Reagent * and Reference t B (232) A (233) A (234) B (235) B (235) B (235) A (236) A (237) B (238) A (239, 240) B (240) A (27a, 241, 242) A (276, 27c) . B, 15% (276, 27c) A (27d) <C (27c) B, 20% (243) C (243a, 244) B (28, 242a, 245) C (246) A (247) B, 15% (248) A (247a, 249) A (250) B (251) B (252) A (253) B (254) B, 6% (255) B (231, 256) B (256, 257) Experimental Conditions Cold or at 100° Dissolve in A 2.5 parts A at 100° 130° 130" 130° By warming 100° 50° By warming By warming 100° 3 parts A, 100° 0° * 2.8 equivalents of A ¡ª 10 parts B, shaking AddC ¡ª 1 part C 50° Dissolve in B 50° ¡ª By dissolving By dissolving 100° By dissolving By warming By dissolving By warming Position of Sulfo Group(8) ¡ª 2- and 3- ¡ª 5-(?) 5-(?) 4- and 2- and 3- 4- and 5-(?) 4- and 6- 4- 2- and 3- 2- and 3- 2- and 3- 2- and 3- 2- 5-(?) 6- 5- 5- 6-(?) 6-(?) ¡ª 2-(?) 2-(?) 2-(?) 2- and 3- 6-(?) 2-(?) ¡ª 2- and 3- Remarks Mixture, two -SO3H Mixture, two -SOSH 2-SO3H, mostly -SO3H -SO3H -SO3H -SO3H 2-SO3H, mostly - -SO3H 6-SO3H, mostly -SO3H 2-SO3H, mostly 3-SO3H, 15.6% 2-SO3H, 90%; 3- SOSH, 2.5% 3-SOaH, 20% -SO3H -SO2C1 Trace of a second compound -SO3H and -SO2CI -SO3II -SO3H -SO3H -SO3H -SO3H -SO3H -SO3H -SOjH -SO3H -SO,H -SO3H * A refers to concentrated sulfuric acid; B, to oleum; C, to chlorosulfonic acid; and D, to fluoro- sulfonio acid. t References 139-406 appear on pp. 192-197. DIRECT SULFONATION OF AROMATIC HYDROCARBONS 175 TABLE V TRIALKTLBENZENES AND HALOGEN DERIVATIVES Compound Sulfonated 1,2,3-Trimethyl- benzene (hemi- mellitene) 4-Chloro-l,2,3-tri- methylbenzene 1,2,4-Trimethyl- benzene (pseu- dooumene) 3-Bromo-l,2,4-tri- methylbenzene 5-Bromo-l ,2,4-tri- methylbenzene 6-Bromo-l,2,4-tri- methylbenzene 3-Chloro-l,2,4-tri- methylbenzene 5-Chloro-l,2,4-tri- methylbenzene 6-Chloro-l,2,4-tri- methylbenzene 5-Fluoro-l,2,4-tri- methylbenzene 5-Iodo-l,2,4-tri- methylbenzene 6-Bromo-5-fluoro- 1,2,4-trimethyl- benzene 6-Chloro-5-fluoro- 1,2,4-trimethyl- benzene 5,6-Dibromo- 1,2,4-trimethyl- benzene Reagent * and Reference t A (77) B, 20% (97) A (79o) SO2CI2 + AICI3 (81) D (31) A or B (218, 258) C (218, 258) B (49, 258, 259) B, 20% (97a) B (49, 259) B (97) B (260) B, 20% (97a) B (97a) A (261) B (261) A (262) B (262) A (261) C (261) A (261) B (261) C (261) B (49, 259) C (49, 259) Experimental Conditions 2.5 parts A, 100° 5 parts B, 15 hr., 75° 2 vol. A, 60°, 5 to 10 min. 36 hr., cold 5 parts D, 25°, 3 hr. 100° ¡ª Warm 6 parts B, 6 weeks; 70°, then 25° Heat 3 parts B, shaking Long standing 6 parts B, 4 hr., 65-70° 16 parts B, 3 days, 25° Warm Warm Long standing Long standing Room temperature, long standing Long standing Long standing ?¡ª Heat at high temperature Stand 1 to 2 hr. Position of Sulfo Group(s) 4- 5- 5- 5- 5- 5- 5- 6- 5- 3- 5- r 5- 5- 6-(?) 6-(?) ? 6-(?) ¡ª ¡ª 3- ¡ª 3- 3- ¡ª 3- Remarks High yield -SOsNa, 46% -SOjH, 85% -SOjCl, etc. -SO2F, 37% Anomalous substi- tution -SO2CI Rearranges on standing -SOjH, 90%; Br to 3-position * From dibromo com- pound -SOsNa, 80% ¡ª -SOsH, 71%; Cl to 3-position -SOjH, 44%; Cl to 3-position No rearrangement in 3 months ¡ª Also rearranges ¡ª Rearrangement Chlorine slowly re- arranges ¡ª ¡ª Decomposition and formation of SOj - Also other produota ? A refers to concentrated sulfuric acid; B, to oleum; C, to chlorosulfonic acid; and D, to fluortf- aulfonic acid. t References 139-406 appear on pp. 192-197. 176 ORGANIC REACTIONS TABLE V¡ªContinued TRIALKTLBENZENES AND HALOGEN DEMVATIVES Compound Sulfonated 1,3,5-Trimethyl- benzene (mesit- ylene) 1,3,5-Trimethyl- benzene-2-sul- fonyl fluoride 1,3,5-Trimethyl- benzene-2,4-di- sulfonic acid 2-Bromo-l,3,5-tri- methylbenzene 2-Chloro-l,3,5-tri- methylbenzene 2-Iodo-l,3,5-tri- methylbenzene 1,2,4-Triethyl- benzene 1,3,5-Triethyl- benzene 1,2,4-Triisopropyl- benzene 1,3,5-Triisopropyl- benzene l,2-Dimethyl-4- ethylbenzene l,3-Dimethyl-4- ethylbenzene 1,3-Dimethyl-S- ethylbenzene 2-Bromo-l,3-di- methyl-5-ethyl- benzene Reagent * and Reference t A (79o, 263, 264) B (796, 80) SO2CI2 + AICI3 (81) B¡ªP2Oj (83) C (82) C + SO2C12 (76) C(34) D (31) C (31) SO3 (82) * A (264, 265) B (264, 265) B, 20% (97a) B, 20% (97a) A (265) B (265) SO3 (265) C (265) A (47) B, 8% (^6) A (47, 266) C (230) B (267) C (230) A (77a, 268, 269) A (77a, 270) A (271, 272) C (272) Experimental Conditions 2 vol. A, < 60°, 5 to 10 min. 20-30° ¡ª . 30-40°, 2-3 days -5° 100°, 10 hr. CHCI3 solution 5.5 parts D, 25°, 3 hr. 4 parts C, 20° 120° 20°, 1 week 20° 9 parts B, 70°, 6 hr. 8 parts B, 60°, then 25°, 6 weeks 5 parts A, 20°, 12 hr. 5 parts B, 20°, 48 hr. Cold Excess C, many days 3 parts A, 100°, 3 hr. 1.6 parts B, 50° 2 vol. A, warm CCU solution, 30-50° 2 vol. B, shaking CCU solution, 30-50° Dissolve Warm, dissolve Dissolve 1 mole of C Position of Sulfo Group(s) 2- 2- 2- 2,4- 2,4- 2,4- 2- 2- 2,4- 2,4,6- ¡ª 4- 4- 4- ¡ª ¡ª 4- ¡ª ¡ª 5- 2- 5- 2- 2- 3- and 5- (?) 6-(?) 2- 4- Remarks -SOsH, 90% ¡ª -SO2CI Di-SO8H Di-SO3H Di-SOsH -SO2CI, 65-72% -SO2F Di-SO2Cl Tri-SOaH, low yield C?HioBr2 and CjHnSOsH Also CjHioBr2 ¡ª ? ¡ª C9H10I2 and C9H11SO3H Ci,H9I3 Also other products C?H9Cl8 No rearrangement ¡ª -SO3H as an oil -SO2CI, 99% Free acid isolated ¡ª Cryst. acid ¡ª ¡ª -SO3H and -SO2CI * A refers to concentrated sulfuric acid; B, to oleum; C, to chlorosulfonic acid; and D, to fluoro- sulfonic acid. t References 139-406 appear on pp. 192-197. DIRECT SULFONATION OF AROMATIC HYDROCARBONS 177 TABLE V¡ªContinued TBIALKYLBENZENES AND HALOGEN DEBIVATIVEB Compound Sulfonated l,4-Dimethyl-2- ethylbenzene l,2-Dimethyl-4-n- propylbenzene l,4-Dimethyl-2-n- "propylbenzene l,3-Dimethyl-4-n- propylbenzene 1,2-Dimethyl~4- iaopropylben- zene l,3-Dimethyl-4- isopropylben- zene l,3-Dimethy]-5- ferl-butyl- benzene l-Methyl-2-n- propyl-4-iso- propylbenzene l-Methyl-3,5-di- isopropylben- zene Reagent * and Reference t A (77a, 268) ¡ª (273) ¡ª (273) ¡ª (273) B, 6% (198) ¡ª (273) B (31, 231, 248, 274) C (34) D (81) B, 6% (275) C (276) Experimental Conditions Dissolve ¡ª ¡ª -¡ª ¡ª ¡ª 1 part B, 24 hr., 20-25° CHCIs 2.5 parts D; 18-22°, 16 hr. Warm ¡ª Position of Sulfo Group(s) 3- 5-(?) 5-(?) 6-(?) 3- and 5- (?) 6-(?) 2-(?) 6-(?) 2-(?) 5-(?) 2-(?) Remarks ¡ª ¡ª ¡ª 2 isomers ¡ª Also other condi- tions -SO2CI, 97% -SO2F -SO3H -SO2C1 * A refers to concentrated sulfuric acid; B, to oleum; C, to chlorosulfonic acid; and D, to fluoro- Bulfonic acid, t References 139-406 appear on pp. 192-197. 178 ORGANIC REACTIONS TABLE VI POLTALKTLBENZENES AND HALOGEN DERIVATIVES Compound Sulfonated 1,2,3,4-Tetra- methylbenzene (prehnitine) o-Chloro-1,2,3,4- tetramethyl- benzene 1,2,3,5-Tetra- methylbenzene (isodurene) 4-Chloro-l,2,3,5- te tram ethyl- benzene 1,2,4,5-Tetra- methylben- zene (durene) 3-Bromo-l,2,4,5- tetramethyl- benzene 3-Chloro-J,2,4,5- tetramethyl- benzene l-Ethyl-2,4,6-tri- methylbenzene l-Ethyl-2,4,5-tri- methylbenzene 3-Ethyl-l,2,4-tri- methylbenzene l-n-Propyl-2,4,6- tfimethylben- zene l-Isobutyl-2,4,6- trimethylben- zene l-Isopentyl-2,4,6- trimethylben- zene Reagent * and Reference t A (258, 277) C (34) B (97a, 278) A (277a) B (279) A (97, 278) B (277o, 280) C (281) C (34) A (282, 283) A (97a, 278) A (46) B (284, 285, 286) A (46, 287) B, 10% (40, 284) C (46) A (46) A (46) ' ¡ª (286) ¡ª (286) ¡ª (286) Experimental Conditions 2 vol. A, 10 min., shake CHCU solution fi hr., 25-30° 4 parts A, 10 min., 25° 2 vol. B, warm 6 parts A, 65°, 4 hr. 40°, 5 min. 2.5 parts C, cold CHCI3 solution ¡ª 6 parts A, 65°, 4 hr. 6 hr., 60-70° ¡ª ¡ª 1 vol. B, to 45° ¡ª 2 vol. A, 2 min., 55° 6 hr., 70° ¡ª ¡ª ¡ª Position of Sulfo Group 5- 5- ¡ª 4- 4- ¡ª 3- 3- - 3- ¡ª ¡ª .¡ª 3- 3-(?) t 3-(?) 3-(?) 6-(?) 6-(?) ¡ª ¡ª ¡ª Remarks 6-S0sH, 91%; no rearrangement -SO2CI, 95% QsJKCHiOsClSOaH and Ce(CH3)6Cl 4-SO3H, 60-70%; slowly rear- ranges ¡ª C8H(CH8)8C18O3H and C6(CH3)eCl 3-SOjH, 94%; slowly rearranges Some -SO2CI and Bulfone -SO2CI, 100% Rearrangement CsHCKCHiOaSOaH and C6(CH3)6C1 Rearrangement ¡ª Rearranges slowly -SO3H, 95% ¡ª -SOSH, high yield No rearrangement ¡ª ¡ª * A refers to concentrated sulfuric acid; B, to oleum; C, to chloroaulfonic acid; and D, to fluoro- sulfonic acid. t References 13&-406 appear on pp. 192-197. DIRECT SULFONATION OF AROMATIC HYDROCARBONS 179 TABLE VI¡ªContinued POLYALKYLBENZENES AND HALOGEN DERIVATIVES Compound Sulfonated l-n-Heptyl-2,4,6- trimethylben- zene 1,2,3,5-Tetra- ethylbenzene 1,2,4,5-Xtetra- ethylbenzene 1,2,4,6-Tetraiso- propylbenzene Pentamethyl- benzene Pentaethylben- zene Reagent * and Reference t B (286) C(47) A (47, 288o) C (47) C (34, 230) A (282, 2885) C(34) C(47) Experimental Conditions Dissolves 1.4 parts C, 20-30° Cold or warm 1.4 parts C, 80-30° Excess C, in CHCI3 or alone ¡ª CHCI3 solution 5 parts C, or 1 part C in CHCI3 Position of Sulfo Group 4- 4- 3- 3- 6- 6- 6- 6- Remarks Rearranges with A Rearranges -SOjH, 90% Lossofo-CaHT; -SO2CI, 97% Rearranges on standing -SO2CI, 98% -SO3H, 89% * A refers to concentrated sulfuric acid; B, to oleum; C, to chloroeulfonio aoid; and D, to fluoro- sulfonic acid. t References 13&-406 appear on pp. 192-197. 180 ORGANIC REACTIONS TABLE VII BlPHENYIi AND ITS DERIVATIVES Compound Sulfonated Biphenyl Potassium bi- phenyl-4-sul- fonate Biphenyl-4-sul- f onyl chloride 3-Methylbi- phenyl t 4-Methylbi- phenyl t 3,4'-Dimethylbi- phenyl $ 4,4'-Dimethylbi- phenyl t 2-Methyl-5-iso- propylbiphenyl 2,2'3,3'4,4'6,6'- Octamethylbi- phenyl 4,4'-Dibromobi- phenyl Reagent * and Reference t A (98, 99) C (38a) . . A (289) C (38a) C (38a) (100) B, 4% (173) A, 98% (10) A, 98% (10) A, 98% (10) A, 98% (10) B, 6% (275) C (290) C(40) A (40) B, 30% (40) C(40) Experimental Conditions CeHsNOs solution, heat 1 mole of C in CI2CHCHCI2, Excess A, heat ' Excess C, 0° 5 parts C, 24 hr., 18° ? Heat, no reagent 15-20° 0.1 part A, 40-45°, 2 hr, 0.1 part A, 40-45°, 21?r. 0.1 part A, 40-46° 0.1 part A, 40-45° 5 parts B, cold 5 parts C, 0°, 1 hr. 1 part C, CHCI3 solution, 40° Excess A, 80°, 4 hr. 6.6 parts B, 80°, 4 hr. 5.3 moles C, 60° 15 min. Position of Sulfo Group(s) 4- 4- 4,4'- 4,4'- ¡ª 4,4'- 4'- 4- 2'-(?) 2'-(?) 2'-(?) ? 5,5'- 3- 3,3'- 3,3'- 3,3'- Remarks 4-SOsH, 90% Good yield Nearly quantitative Di-SOjjCl, 80% Dibenzothiephene dioxide 2,7-di- SOjCl Also biphenyl No loss of halogen ¡ª ? ¡ª ¡ª ¡ª Mono-SO3H Di-SO2Cl, 77% -SOsH, 32%; 2,2'- sulfone, 25% Only product iso- lated Di-SO8H, 73%; sulfone-di-SOaH, 13.5% 3,3'-Di-SO3H, 41.5%; 3,3'-di- SO2CI, 12.5%; 2,2'-sulfone, 42% * A refers to concentrated sulfuric acid; B, to oleum; C, to chlorosulfonic acid; and D, to fluoro- sulfonic acid. t References 139-406 appear'on pp. 192-197. t The sulfonic acids of these hydrocarbons were obtained from the sulfonation of high-boiling frac- tions of coal tar. The pure hydrocarbons were regenerated from these acids by high-temperature hydrolysis. DIRECT SULFONATION OF AROMATIC HYDROCARBONS 181 TABLE VIII ARYLALKANES, ARTLALKENES, AND DERIVATIVES Compound Sulfonated Diphenylmethane 4-Methyldi- phenylmethane 2-Methyl-5-iso- propyldiphenyl- methane Bibenzyl Stilbene 1,1-Diphenyl-l- nropene a,a-Ws-(2,4,5-Tri- methylphenyl)- 0,/S-diohloro- ethylene 1,1-Diphenyl- 2,2,3-trichloro- butane Triphenylmethane 1,1,2,2-Tetra- phGnylethane Tetraphenyl- ethylene Reagent * and Reference t C (101) B (102) B (291) B (292) B (293) A (103) B (104) A (294) B, 20% (295) B (296) B (105) A (106) A (107) Experimental Conditions 1.3 moles C, CHClj solution, 0°, several hours Excess B, 90°, 2 days Warm 5 vol. B 100°, several hours 2 vol. A, warm Warm, 12 hr. ¡ª Room temperature, many hours Warm Hot or cold S parts A, warm Heat Position of Sulfo Group (s) 4- 4,4'- ? ¡ª ¡ª 4,4'-(?) 4p4'.(7) ¡ª ? 3,3'- or 6,6'-(?) P,p'-m 4,4',4"- (7) ¡ª Remarks -SO3H, 82% and some sulfone ¡ª Mixture; a di-SO3H isolated Mono-SO3H Di-SO3H Trace of a tetra- SO3H ¡ª 4-Phenyl-5,6- benzothio-a- pyran-1-dioxide Good yield Di-SO3H Tri-SOjH Tetra-SO3H Tetra-SO3H * A refers to concentrated sulfuric acid; B, to oleum; C, to chlorosulfonk) acid; and D, to fluoro- sulfonic acid. t References 139-406 appear on pp. 192-197. 182 ORGANIC REACTIONS TABLE IX NAPHTHALENE AND NAPHTHALBNEStrLFONic ACIDS Compound Sulfonated Naphthalene Reagent * and Reference t A (15, 297) A, 90%, 96%, 100% (15) A, 100% (108, 298, 299) A, 94% (8a, Sd, 109, 300, 301) B, 15% (299) B, 12% (15) NaH3(SO4h (36) C (148) SO3C6H6N (30) D (31) A, 100% or 86% (111, 302) B, 30% (303) C (148, 304, 305) C(38o) D (31) A (111) A, 100%, then B, 64% (111, 306) A, 80-95% (115) A, 100% (111, 305, 307) A (112&) Experimental Conditions 1 mole A, various condi- tions 129°, 2 or 7-8 hr. 2 parts A, 0°, 1 hr. 1.6 parts A, 160°, 5 min. Below 70° 129", 2 or 7-8 hr. 1.5 parts reagent, various conditions <1 part C, 10% CSj solu- tion 0.86 mole, SO3, 170°, 11 hr. 1.6 parts D, 2.4 parts of C82, 14 hr., 20° 40", 70°, 100°, 8 hr. 4 parts B, short time 2 moles C, 15-45° 10 parts C, 0°, short time 4 parts D, 75°, 6 hr. 165° 2.3 parts A, then 2.3 parts of B, <40° Vapor phase, 220-245° 4.7 parts A, 180°, 8 hr. 4 parts A, 130°, 4 hr. Position of Sulfo Group(s) 1- and 2- 1- and 2- 1- and 2- 1- and 2- 1- and 2- 1- and 2- 1- and 2- 1- and 2- 1- and 2- 1- 1,6- 1,5- 1,5- 1,5- ? 1,6- 1,5-and 1,6- 2,7- and 2,6- 1,6-, 2,6-, and 2,7- 1,3-, 1,5-, 1,6-,-1,7-, 2,6-, and 2,7- Remarks By-products and % yield determined for each condition % determined for each reagent and time 1-SOsH, mainly 2-SO,H, 80%; 1- SO3H, 15%; 2,2'- sulfone, trace 1-SO8H, chiefly 1-SOsH, respec- tively, 70% and 62% 1-SOjH, mainly, all temperatures -SO3H, a little 1,5- di-SOjH 1-SOsH, 38%; 2- SO8H, 10% I-SO2F, 16% 99%, 97%, 85% re- spectively Almost quantitative Di-SOsH; some di- SO2CI D1-SO2CI, 59% Di-SO2F, not the 1,5-; also other products 1,6-Di-SO3H, 40- 45% 1,5-Di-SO3H, 70%; 1,6-Di-SO3H, 25% 2,7-Di-SO3H, 78- 85%; a mono- SO3H, traces 1,6-Di-SO3H, 10%; 2,6-Di-SO3H, 27%;2,7-Di- SO3H, 65% ¡ª * A refers to concentrated sulfuric acid; B, to oleum; C, to chlorosulfonic acid; and D, to fluoro- Buifonic acid. t References 139-406 appear on pp. 192-197. DIRECT SULFONATION OF AROMATIC HYDROCARBONS 183 TABLE IX¡ªContinued NAPHTHALENE AND NAPHTHALENESULFONIC ACIDS Compound Sulfonated Naphthalene Naphthalene-1- sulfonic acid Sodium naph- thalene-1-sul- fonate Naphthalene-1- sulfonyl fluoride Naphthalene-1- sulfonyl chloride Naphthalene-2- sulfonic acid Naphthalene-2- sulf onyl chloride Naphthalene-2- sulfonyl fluoride Naphthalene-1,5- disulfonic acid Naphthalene-1,5- disulfonyl fluo- ride Naphthalene-1,6- disulfonic acid Naphthalene-2,6- disulfonic acid Naphthalene-2,7- disulfonio acid Naphthalene- 1,3,5-trisulfonic acid Naphthalene- 1,3,7-trisulfonic acid Reagent * and Eeference t B, 24% or 40% (116) A (15) ? D (31) C (31) D (31) C (305) A, 98% (111, 113, 308) A, 100% and K^SsO? (309) D (31) B, 4% (173) C (31) A, 100%, then B, 67% (117) C(31) A (111) B (118) A, 95% (114) B, 25% (119) B (119) B (119) Experimental Conditions 8 parts B, 180°, 1 hr. or 6 parts, 100° respectively 1 mole A, 129°, 7 hr. 4 parts D, 1 hr., 50-60° 4 parts C, 1 day 4 parts D, 24 hr., 100° 3 moles C, 100° 55-60°, 2 and 10 hr. 10 moles A and 1 mole K2S2O7, 160-170° 4 parts D, 1 hr., 50° 8 parts B, 15-20° 2.4 parts C, 2 days 1.5 parts A, 56°, then 1.4 parts B, 90°, 3.5 hr. 4 parts C, 24 hr., 100° 160°, 8 hr. 120° 1 mole A, 160°, 1-24 hr. 3 parts B, 90°, 4 hr., then 250°, 6 hr. High temperature High temperature Position of Sulfo Group (s) 1,3,6- 1- and 2- 1- 1,5- 1,5- 1,6- 1,6- and 1.7- 2,6- and 2,7- 2- ¡ª 2,6- 1,3,5- 1,3,5^ 1,3,7- 2,6- and 2,7- 1,3,5,7- 1,3,5,7- 1,3,5,7- Remarks No further reaction 47% of 1-isomer converted to 2- isomer ¡ª I-SO2F-5-SO2CI 1,5-Di-SOsF 1,6-Di-SOsH 1,6-Di-SOjH, 80%; 1,7-Di-SOjH, 20% 2,6-Di-SOs?, 12%; 2,7-Di-SO.H, 87% -SO2F, 33% -SO3H derivatives of -SO2C1 2-SO2F-6-SO2C1 ¡ª Tri-SO2Cl 2,6-Di-SOaH, 20% ¡ª Conversion to 2,6- isomer deter- mined for various times End product of sul- fonation ¡ª ¡ª * A refers to concentrated sulfuric acid; B, to oleum; C, to chlorosulfonic acid; and D, to fluoro- sulfonic acid. t References 139-406 appear on pp. 192-197. 184 ORGANIC REACTIONS TABLE X AXiKTL AND HALONAPHTHALENES Compound Sulfonated 1-Methylnaph- thalene 2-Methylnaph- thalene 1-Ethylnaph- thalene 2-Ethylnaph- thalene 1-Isopropylnaph- thalene 2-Isopropylnaph- thalene 1-Benzylnaph- thalene Coal-tar fraction (b.p. 260-365°) 2,6-Dimethyl- naphthalene 2,7-Dimethyl- naphthalene Reagent * and Reference t A (316) A (317) A (316) A (318, 319) B (320) C (316, 321, 322) A (323) A (324o) B, 21% (3246) C (326) B (320) A (326) A, 66% (327) A, 96% (312) A (312) A (328) C (328) A (329) A (330) A, 98% (330) A, 98% (330) A (330) Experimental Conditions 0.75 part A, warm, 5-6 hr. 1.8 parts A, room tempera- ture, 5-6 hr. 110° 165-170°, 5-6 hr. 1 vol. B, room temperature CCU solution, cold 0.75 part A, 95", 6 hr. 1 mole A, shake, room tem- perature 3 parts B, shake 1 mole C, CeHsNOa solu- tion, 35° 1 vol. B, room temperature 2 moles A, 70-80" 1.3 moles A, heat 40-45° ¡ª 2.5 moles A, 66° C6H5NO2 solution, room temperature 140° 0.6 part A, 40-45°, 10 hr. 1 part A, 135-140°, 3 hr. 1 part A, 35-40°, long stir- ring 1 part A, 100°, 1 hr. Position of Sulfo Group (s) 3- 4- 3- and 7- 6- ¡ª 4- and 5- 6- ¡ª ? 8- ¡ª ¡ª 6- 4- 1- 4- 4- ¡ª ¡ª ¡ª - 8- ¡ª Remarks 3-SO.H, 32% Good yield Former predomi- nates Mono-S08H 73% of mixture, mainly 4-; some sulfone 6-SOsH, 80%, no other isomers iso- lated Mixture of two mono-SOaH Mono-SOaH -SO3H Mono-SOsH Mono-SOaH 6-SOjH, 86% ¡ª ¡ª SO3H, sole product Sole product Not 4-SOjH Some 1,6-dimethyl- naphthalene-4- SO3H Some 2,6-dimethyl- naphthalene-7- SO3H and 2,3-di- methyl-?-SO3H 8-SO3H, 60%, per- haps some 1-SO?H Mixture of 3-SO3H and other -SO3H * A refers to concentrated sulfurio acid; B, to oleum; C, to chlorosulfonic acid; and D, to fluoro- sulfonic acid. t References 139-406 appear on pp. 192-197. t A number of nuclear alkylated naphthalenesulfonic acids has been prepared by treating the hydro- carbon with alcohols in the presence of chlorosulfonic acid 310'In or oleum.311' 312 Successive alkylation and sulfonation 8la or the reverse 814 has also been employed. Other procedures involve the chloromethyl- ation of naphthalene before, during, or after the sulfonation, and the condensation of an unsaturated aloohol or hydrocarbon with the sulfonated naphthalene.31' DIRECT SULFONATION OF AROMATIC HYDROCARBONS 185 TABLE X¡ªContinued ALKTL AND HALONAPHTHALENES Compound Sulfonated 1,4-Dimethyl- naphthalene 2,6-Dimethyl- naphthalene-8- sulf onic acid l,8;Dibenzyl- naphthalene Diisopropylnaph- thalene 1-Chloronaph- thalene 1 -Chloronaphtha- lene-3-eulfonio acid 1-Chloronaphtha- lene-4-sulfonio acid 1-Chloronaphtha- lene-6-sulfonic acid 2-Chloronaph- tbalene Reagent * and Reference t A (331) A, 78% (330) C (332) ¡ª (312) C (333, 334) A, 100% (335) A (336) C (336) C(43) A, 66° Be. (336, 337) B (333, 335a) B, 45% (338) B, 20% (339) A (333) B, 20% (340) B, 20% (338) B, 10% (341) A and B (342) B (335a) C (343) C(43) Experimental Conditions 2 parts A, 120° 135°, short time 100-110° ¡ª CS2 solution 2.5 moles A, 10° 56°, 78°, 98° Excess C, 30° CHCI3 solution, 5 parts, 25°, 20 min. 1-1.5 parts A, 160-170°, several hours 160° 5 parts B, 80°, 8 hr. 100° 150° 100° 5 parts B, 170°, 8 hr. 3-4 parta B, 110°, 6 hr. 130-140°, long heating Excess B, 160-180° CS2 solution, cold CHCI3 solution, 5 parts C, 25°, 20 min. Position of Sulfo Group (a] _ ¡ª 4-(?) ¡ª 4- 4- 4- ¡ª 4- 6- and 7- 4- and 5- 2,4,7- 3,5- ¡ª 4,7- 2,4,7- 4,6- 6- and 8- 6,8- 6- and 8- 8- Remarks Unknown structure Rearranges to 7-iso- mer -SO3H Mono-SOaH 4-SO3H, mainly 4-SO3H, 84%, some of 5-isomer 4-SO3H, 70%, 57%, 31% respectively Mixture of -SO2CI; 4-SO2CI is present -SO2CI ¡ª Equal amounts Some di-SOsH, probably 4,7- ¡ª Rearranges to 5- SO3H D1-SO3H Tri-SOsH Di-SOsH 8-SO3H predomi- nates Di-SO3H 8-SO3H, mainly; 6-isomer, 4% -SO2CI * A refers to concentrated sulfuric acid; B, to oleum; C, to chlorosulfonic acid; and D, to fluoro- sulfonic acid. t References 139-406 appear on pp. 192-197. t A number of nuclear alkylated naphthalenesulfonic acids has been prepared by treating the hydro- carbon with alcohols in the presence of chlorosulfonic acid310'3U or oleum.811'312 Successive alkylation and sulfonation 313 or the reverse 3U has also been employed. Other procedures involve the chloromethyl- ation of naphthalene before, during, or after the sulfonation, and the condensation of an unsaturated alcohol or hydrocarbon with the sulfonated naphthalene.315 186 ORGANIC REACTIONS TABLE X¡ªContinued ALKTL AND HALONAPHTHALENES Compound Sulfonated 2-Chloronaphtha- lene-6-sulfonic acid 2-Chloronaphtha- lene-7-eulfonic acid 2-Chloronaphtha- lene-8-sulfonic acid 1-Bromonaphtha- lene - 2-Bromonaphtha- lene 2-Bromonaphtha- lene-8-sulfonic acid 1-Iodonaphtha- lene 2-Iodonaphtha- lene 2-Iodonaphtha- lene-5- and 8- sulf onic acids 1,2-Dichloro- naphthalene 1,3-Dichloro- naphthalene 1,4-Dichloro- naphthalene Reagent * and Reference t H2S2OT (344) B, 20% (344) H2S2O7 (344) A (345, 346) H2S2O7 (344) B (347, 348, 349) C (350) C(43) C (343, 346, 351) C (43) (346) C (352) C (343, 346, 353) C (343, 346) A (346) C (346, 354) C (354) C (354) C (355) A, 100% (356) B (357) Experimental Conditions _ ¡ª 100° 150°, 5 hr. ¡ª 2 parts B, warm, few min- utes CS2 solution CHCI3 solution, 5 parts C, 25°, 20 min. CS2 solution CHCI3 solution, 5 parts C, 25°, 20 min. Heat CS2 solution CS2 solution Cold, then heat to 150° 150° 10% CS2 solution In CSto In CS2 12 parts A, room tempera- ture 160° Position of Sulfo Group (s) 6,8- ¡ª 4,7- ¡ª 6,8- 4- and 5-(?) 4- and 4- 6- and 8-(?) 8- ¡ª 4-(7) 8- and 5- 6- ¡ª 5- and 6- 5- and 7- 6- and (?) ¡ª 6-(?) 6- Remarks D1-SO3H 4,6-Di-SOsH as by- product Di-SO3H 53% of 6-isomer by rearrangement Di-SO3H -SO3H -SO3H (and SO2CI?) -SO2C1 -SO3H (and -SO2C1?) -SO2C1 Rearranges to 6-iso- mer -SO3H (and -SCfcCl?) -SO3H -SO3H Rearranges *o 6-iso- mer -SO3H -SO3H -SO3H Sulfone, mainly -SO3H -SO8H *A refers to concentrated sulfuric acid; B, to oleum; C, to chlorosuUonic acid; and D, to fluoro- Bulfonic acid. t References 139-406 appear on pp. 192-197. X A number of nuclear alkylated naphthalenesulf onic acids has been prepared by treating the hydro- carbon with alcohols in the presence of chlorosulfonic acid ""?m or oleum.311'B2 Successive alkylation and sulfonation 3W or the reverse 314 has also been employed. Other procedures involve the chloromethyl- ation of naphthalene before, during, or after the sulfonation, and the condensation of an unsaturated alcohol or hydrocarbon with the sulfonated naphthalene.*16 DIRECT SULFONATION OF AROMATIC HYDROCARBONS 187 TABLE X¡ªContinued ALKYL AND HALONAPHTHALENES X Compound Sulfonated 1,5-Diohloro- naphthalene 1,6-Dichloro- naphthalene 1,7-Dichloro- naphthalene 1,8-Dichloro- naphthalene 2,3-Dichloro- naphthalene 2,6-Dichloro- naphthalene 2,7-Dichloro- naphthalene 1,3-Dibromo- naphthalene 1,4-Dibromo- naphthalene 1,5-Dibromo- naphthalene 1,6-Dibromo- naphthalene 1,7-Dibromo- naphthalene l-Chloro-4-bromo- naphthalene 1,2,3-Trichloro- naphthalene 1,2,4-Trichloro- naphthalene 1,2,7-Triohloro- naphthalene , 1,3,6-Triohloro- naphthalene ?-Tetrachloro- naphthalene Reagent * and Reference t C (354) A, 100% (356) C (354) A and B (358) C (354, 359) C (354) C (354) C (354) C (354) A (360) A, 100% (360, 367a) B, 2% (361) A (360) A (360) A (360) C (355) B, 10% (354) A or C (354) ? (362) ? (362) B (348) Experimental Conditions CSg solution 12 parts A, room tempera- ture CS2 solution Equal volumes of A and B, warm CSj solution, low tempera- ture CS2 solution, low tempera- ture CS2 solution, low tempera- ture C82 solution, low tempera- ture CS2 solution, low tempera- ture 2 parts A, 100° 100° 2 parts B, 60°, 8 hr. 2 parts, 100" 100° 100° CS2 solution 100° 100° ¡ª ¡ª ¡ª - Position of Sulfo Group (s) 3-and (?) 3- 4- 4- 4- 4- 5- and 6- 4- 3-and (?) 5- and 7- 6- 6- 7-(?) 4-(?) 4-(?) ¡ª ¡ª ¡ª ? ¡ª. ¡ª Remarks -SO3H -SO3H -SO3H -SOSH -SO3H -SO8H -SOaH -SO3H -SO3H -SO3H -SO3H 6-SO3H, 46% -SO3H -SO3H -SO3H Sulfone (?), chiefly -SO3H -SO3H No details given No details given -SO3H *A refers to concentrated sulfuric acid; B, to oleum; C, to chlorosulfonic acid; and D, to fluoro- sulfonic acid. t References 139-406 appear on pp. 192-197. - t A number of nuclear alkylated naphthalenesulfonic acids has been prepared by treating the hydro- carbon with alcohols in the presence of chlorosulfonic acid 310'm or oleum."1' "* Successive alkylation and sulfonation a3 or the reverse 3W has also been employed. Other procedures involve the chloromethyl- ation of naphthalene before, during, or after the sulfonation, and the condensation of an unsaturated aloohol or hydrocarbon with the sulfonated naphthalene.316 188 ORGANIC REACTIONS TABLE XI ANTHRACENE AND DERIVATIVES Compound guUonated Anthracene Anthracene-2-sul- fonyl chloride Anthracene-1- sulfonic acid 9-Ben?ylanthra- cene 9,10-Dichloro- anthracene 9,10-Dibromo- anthracene Reagent * and Reference t B, 20% (18, 120) C (18, 120) SOs-CrflsN (17, 18) A (363) A, 53° B6. (121) MHSO4 (121) A (18, 363) A, 53-58° (364) B, 4% (365) A, 96% (18) A (366) A, 100%, and C (367) B, 20% (368, 369, 370) C (367) B (370) C (367) B (369, 370) B (370) Experimental Conditions 1.3 parts B, AcOH solution, 95°, 3 hr. 0.7 part C, (CH|CO)iO so- lution, 95°, 5 hr. Various solvents and condi- tions 3 parts A, 100° 2 parts A, 120-135° 1.4 parts reagent, 140°, 5.5 hr. 3 parts A, 100°, 1 hr. 4.5 parts A, 140° ¡ª 150-180°, lhr. 100° 3 parts A, 0.5 part C, 30°, 3hr. 2 parts B, C6H6NO2, 10- 15° 0.5 part C, CHCU solution, 40°, 4 hr. 5 parts B, 100° 0.6 part C, CHCI3 solution 2 parts B, CeHjNCh solu- tion, 10-15° 6-7 parts B, 100°, 1.5 hr. Position of Sulfo Group(s) 1- and 2- 1- and 2- 1- 1- and 2- 2- 2- 1,5- and 1,8- 2-, 2,6-, and 2,7- ¡ª 1,5- and 1,8- ¡ª 2- 2- 2- 2,6- and 2- 2- 2,6- and Remarks I-SO3H, 50%; 2- SO3H, 30% Equal amounts 1-SO8H; 2-SOsH, traces (1%) -SO3H -SO3H Some di-SOsH Di-SO3H Mainly the 2,7-di- SO3H Mixture Mixture: 1,5-di- SO3H, 90%;, 1,8- di-SO3H, 10% Mono-SO3H -SO3H -SO3H -SO8H Di-SOsH -SO3H -SO3H "" Di-SO3H * A refers to concentrated sulfuric acid; B, to oleum; C, to chloroeulfonic acid; and D, to fiuoro- sulfonio acid. t References 139-406 appear on pp. 192-197. DIRECT SULFONATlON OF AROMATIC HYDROCARBONS TABLE XII PHENANTHRENE AND DERIVATIVES Compound Sulfonated Phenanthrene Phenanthrene-2- sulfonic acid Phenanthrene-3- sulfonio acid Ammonium phenanthrene- 9-sulfonate l-Methyl-7-iso- propylphenan- threne 9-Bromo- and 9- ehloro-phenan- threne Reagent * and Reference t A (122, 123, 126) A (124, 126) A (122, 371) C (130) A (127) A (127) (125) A (373a, 3736) A (3736, 374) A and B (375) B (375) A, 96% (372, 376) Experimental Conditions 2 moles A, 120-125°, 3.5 hr. 100°, 8 hr. 0.6 cc. A per g., 60°, 3 days 1 mole C in boiling CHC13 1 cc. A per g., 130°, 30 min. 1 cc. A per g., 130°, 1.5 hr. 250-260° 1 part A, 100°, 5 min. 1 part A, 190°, 2 min. Room temperature, 2-3 weeks 100°, 24 hr. 0.9 part A, 100°, 2.5 hr. then 0,6 part, 150°, 0.5 hr. Position of Sulfo Group (s) 2- and 3- 2-, 3-, and 9- 1-, 2-, 3-, and 9- 2- and 3- 2,6-, 2,7-, and 2,8- 2,6-, 3,6-, and 3,8- ¡ª 2- and 6- 6- ¡ª ¡ª 3- or 6- Remarks 2-SOjH, 20%; 3- SO3H, 25%; di- SO3H, >40% 2-SO3H, 7%; 3- SO3H, 9%;9- SO3H, 6% I-SO3H, 4%;2- SO3H, 18%; 3- SO3H, 19%; 9- SOSH, 13% -SO3H, 85% of mix- ture 2,6-Di-SO3H, 54%; 2,7-, 2.1%; 2,8-, 1%. Isolated as diacetates 2,6-Di-SO3H, 10%; 3,6-, 59%; 3,8-, 0.9%. Isolated as diacetates 2-SO3H, phenan- threne, and a di- SO3H' -SO3H 6-SO3H, 69% Di-SO3H Tri-SO3H -SO3H, 65-75% * A refers to concentrated sulfuric acid; B, to oleum; C, to ohlorosulfonic add; and D, to fluoro- sulfonic acid. t References 139-406 appear on pp. 192-197. 190 ORGANIC REACTIONS TABLE XIII MISCELLANEOUS COMPOUNDS Compound Sulfonated Benzal chloride Benzotrichloride Benzotrifluoride 4-Chlorobenzo- trifluoride Phenylcyclo- hexane 3-Phenylmethyl- cyclopentane Bomylbenzene m-Tolylcyclo- hexane Hydrindene 4,7-Dimethyl- hydrindene Tetralin 6-Methyltetralin 1,1-Dimethyl- tetralin 1,1,6-Trimethyl- tetralin (ionene) Fluorene 2,7-Dibromo- fluorene Aoenaphthene Reagent * and Reference t A (377) SO3 (377) SO3 (378) SO3 (378) B (379) B (380) A (379) A (381) A (382) C (383) A (384) A (385, 386) C (386) D (31) A (387) A (388) A (389) A (390) C (391, 392) C (391) A (390, 393) SO3 (Id, 390) C (392) A (394) C (386) C (394, 395) A (394c) A (394c) Experimental Conditions ¡ª ¡ª ¡ª. 7 vol. B, cool, shake ¡ª Room temperature ¡ª. 2 parts A, shake 4.3 moles C, -10°, 15 min. 11.5 parts A, 100°, 15 min. 1.2 parts A, 100° 4.3 moles C, -5-10° 4 parts D, 15-20°, 12 hr. 1.25 parts A, 100° 1 vol. A, 90°, 2 hr. 1 vol. A, 90°, 2 hr., then stand at room tempera- ture 1 mole C with or without CHCI3 CHClj solution 4 parts A, 100° CHCI3 solution 1 mole C in CHCI3 0.8 part A, 100°, 2 hr. 0.5 part C, 125-130°, 10 hr. 1 mole C, inert solvent, near 0° 2 parts A, 100°, 8 hr. 5 parts A, 20°, 20 hr. Position of Sulfo Group (s) 2-, 3-, and 4- 3- 3-(?) ? 4- ¡ª 4-(?) 6-(?) 4- and 5- 4- and 5- 5- 5- and 6- 5- and 6- 5- and 6- 7- ¡ª 7-(?) 2- 2- 2,7- 2,7- 2- 3-(?) 3- 3,3'- 5- ¡ª ¡ª Remarks 2-SOsH, 10%; 3-, 30%; 4-, 60% -SO3H -SO3H -SO3H Substitution in ben' zene ring Mono-SOsH Quantitative, sub- stitution proba- bly in benzene ring Substitution in tolyX ring -SO3H 76% yield of mixed -SO3H 1,5-Di-SOsH, 79% 6-SO3H, mainly 80% of mixed -SO2CI -SO2F, 13% of 5- -SO3H Two mono-S03H -SO8H, 50% -SO3H; mostly 2,7- di-SOsH -SO3H Di-SO3H Also two other di- SO3H, probably 2,6- and 3,6- -SO3H -SO3H -SO3H Sulfone -SO3H, ca. 40% Di-SO3H Di-SO3H, different from above acid * A refers to concentrated sulfuric acid; B, to oleum; C, to chlorosulfonic acid; and D, to fluoro- sulfonic acid. t References 139-406 appear on pp. 192-197. DIRECT SULFONATION OF AROMATIC HYDROCARBONS 191 TABLE XIII¡ªContinued MISCELLANEOUS COMPOTTNDS Compound Sulfonated 5-Chloroace- naphthene 5-Bromoace- naphthene Octahydro- anthracene 9-Bromo8ctahy- droanthracene 9,10-Dihydro- phenanthrene Octahydro- phenanthrene (octanthrene) JTluoranthene (idryl) 1,3,5-Triphenyl- benzene Pyrene Sodium py.ene-3- sulfonate i5-Chloropyrene 2,2'-Binaphthyl Deoacyclene "Abietene" "Abietanes" Reagent * and Reference t A (396) C (38b, 397) A (386, 397) A (398) C (3986) C (3986) A (399) A (399) A (400) B (401) C (136, 137) H2S2O7 (402) A, 66% Be1. (137) A, 100%, thenB, 65% (137) A, 66° Be". (137) A, ;00% (137) A, 100%, then B, 65% (137) A, 100%, then B, 65% (137) A (4036) A (403) B (4036) A (404) A (405) A (406) Experimental Conditions 0.5 part A, 70°, 2 hr. Room temperature 80-90° 1.07 moles A, 75°, 50 min. 2.5 parts C, cool 3 parts C, cool and stir 80°, 50 min. 1.8 parts A, 70°, 15 min. 2 parts A, 100° 100° 1 mole C, CCU, or CbCH- CHCI2 solution, 15 hr. ¡ª 4.8 moles A, 15°, 2 days 13 moles A with 2.1 moles Na2SOj, then 4 parts B, 63°, stir 5 hr. 19 moles A, 5-10°, 1 hr. 22.4 moles A, 15°, 1 day 8.8 moles A, then 2.6 parts B, 20°, 15 hr. 13 moles A with 2.1 moles Na2SO4, then 3.3 parts B at 50°, 3 hr. 0.2 part A, 200°, 5-6 hr. 0.7 part A, 200°, 5-6 hr. Excess B, 200°, 5-6 hr. ¡ª 2 parts A, 0-15°, 20 hr. ¡ª Position of Sulfo Group(s) 8-(?) 3- and 8- ¡ª ¡ª 9- 10- ¡ª 9- ¡ª ¡ª 3- ¡ª 3,8- 3,5,8,10- 3,8- 3,5,8- 3,5,8,10- 5,8,10- ¡ª ¡ª ¡ª ¡ª ¡ª ¡ª Remarks -SO3H -SQ3H D1-SO3H Rearranges to oct- anthr?ne-9- SO3H, 66% -SO2CI, 98% -SO2CI, 82% Mixture of two di- SO3H -SQ3H, 76% D1-SO3H D1-SO3H -SO3H, 90-92% D1-SO3H -SO3H, 32% Tetra-SO3H, 70% 3,8-Di-SOsH, 42% 3,5-isomer, 5.7% Tri-SOsH, 10% Tetra-SOaH, 80% Tri-SO3H, 76% Two mono-SOjH Two CC-SO3H Tetra-SOsH Tri-SO3H Mono-SO3H ¡ª *A refers to concentrated sulfuric acid; B, to oleum; C, to chlorosulfonio acid; and D, to fluoro- sulfonic acid. t References 139-406 appear on pp. 192-197. 192 ORGANIC REACTIONS REFERENCES TO TABLES 139 Mohrmann, Ann., 410, 373 (1915). 140 Martinsen, Z. physik. Chem., 59, 619 (1907). 141 Hochstetter, /. Am. Chem. Soc, 20, 549 (1898). 142 Dennis, Can. pat. 177,138 [C. A., 11, 3278 (1917)]. 143 Pictet and Karl, Compt. rend., 145, 239 (1907); Bull. soc. chim., [i] 3, 1114 (1908). 144 Grillet, U. S. pat. 1,956,571 [C. A., 28, 4071 (1934)]. 146 Senhofer, Ann., 174, 243 (1874). 148 Kamens'kil-Shmidt, Mem. Inst. Chem. Ukrain. Acad. Sci., 3, 21 (1937) [C. A., 31, 5777 (1937)]. 147 Jackson and Wing, Am. Chem. J., 9, 325 (1887). 148 Armstrong, J. Chem. Soc, 24, 173 (1871). 149 Armstrong, Chem. News, 23, 188 (1871). 160 Meyer and Noelting, Ber., 7, 1308 (1874). 161 Olivier and Kleermaeker, Rec trav. chim., 39, 640 (1920). M2Glutz, Ann., 143, 181 (1867). 153 Farbw. v. Meister, Lucius, and Brilnning, Ger. pat. 260,563 [C. A., 7, 3198 (1913)]. 164Hiibner and Williams, Ann., 167, 118 (1873); Woelz, Ann., 168, 81 (1873); Boms, Ann., 187, 350 (1877). 166 Friedel and Crafts, Ann. chim., [6] 10, 413 (1887). 166 Beilstein and Kurbatow, Ann., 176, 27 (1875); 182, 94 (1876). 167 Holleman and van der Linden, Bee. trav. chim., 30, 334 (1911). m Davies and Poole, J. Chem. Soc, 1927, 1122. 169 Crauw, Rec. trav. chim., 50, 753 (1931). 160 Seel, TJ. S. pat. 2,171,166 [C. A., 34, 272 (1940)]. 161 Lesimple, Zeit. fur Chemie, 1868, 226. 162 Gebauer-Fulnegg and Figdor, Monatsh., 48, 627 (1927). 163 Armstrong, J. Chem. Soc, 97, 1578 (1910). 164 Rosenberg, Ber., 19, 652 (1886). 166 Reinke, Ann., 186, 271 (1877). ia> Basseman, Ann., 191, 206 (1878). 167 Kohlhase, J. Am. Chem. Soc, 54, 2441 (1932). 168 Engelhardt and Latschinoff, Zeit. fUr Chemie, 1869, 617; Wolkow, ibid., 1870, 321; Vallin, Ber., 19, 2952 (1886). 169 Remsen and Fahlberg, Am. Chem. J., 1, 426 (1879). I70Klaesson and Vallin, Ber., 12, 1848 (1879); Heumann and Kochlin, Ber., 15, 1114 (1882). 171 (a) Noyes, Am. Chem. J., 8, 176 (1886); (b) Harding, /. Chem. Soc, 119, 1261 (1921). 172 Klason, Ber., 19, 2887 (1886). 173 I. G. Farbenind. A.-G., Fr. pat. 837,855 [C. A., 33, 6349 (1939)]. 174 Hiibner, Retschy, Miiller, and Post, Ann., 169, 31 (1873); Miller, J. Chem. Soc, 61, 1029 (1892). 176 Hiibner and Grete, Ber., 6, 801 (1873); 7, 795 (1874); Grete, Ann., 177, 231 (1875); Wroblevski, Ber., 7, 1063 (1874). 176 Hiibner and Post, Ann., 169, 1 (1873); Jenssen, Ann., 172, 230 (1874); v. Pechmann, Ann., 173, 195 (1874); Schafer, Ann., 174, 357 (1874). 177 Kornatzki, Ann., 221, 191 (1883). 178 Vogt and Henninger, Ann., 165, 362 (1873). 179 Mabery and Palmer, Am. Chem. J., 6, 170 (1884). 180 Hiibner and Glassner, Ber., 8, 560 (1875). 181 Cohen and Dutt, /. Chem. Soc, 105, 501 (1914). 182 Cohen and Dakin, /. Chem. Soc, 79, 1129 (1901); Wynne and Greeves, Chem. News, 72, 58 (1895). 183 Seelig, Ann., 237, 129 (1887). 184 Cohen and Smithells, J. Chem. Soc, 105, 1907 (1914). DIRECT SULFONATION OF AROMATIC HYDROCARBONS 193 185 Sempotowski, Ber., 22, 2663 (1889). 186 Chrustschoff, Ber., 7, 1166 (1874). 187 Moody, Chem. News, 71, 197 (1895). 188 Steinkopf and Hiibner, J. prakt. Chem., [2] 141, 193 (1934). I89Pollak, Fiedler, and Roth, Monaish., 39, 182 (1918). 190 Moody, Chem. News, 79, 81 (1899). 191 Fittig, Schaeffer, and Konig, Ann., 149, 324 (1869). 192 Spioa, Gazz. chim. ital., 8, 406 (1878). 193 Meyer and Baur, Ann., 219, 299 (1883). 194Spiea, Ber., 12, 2367 (1879). 196 Balbiano, Gazz. chim. ital., 7, 343 (1877). 198 (a) Estreichner, Ber., 33, 436 (1900); (6) Klages, Ber., 39, 2131 (1906). 197Kelbe and Pfeiffer, Ber., 19, 1723 (1886); Baur, Ber., 24, 2832 (1891). 198 Klages and Sommer, Ber., 39, 2306 (1906). 199 Tollens and Fittig, Ann., 131, 315 (1884). 200 Klages, Ber., 36, 3688 (1903). 201 Dafert, Monatsh., 4, 616 (1883). ^Bygden, /. prakt. Chem., [2] 100, 1 (1919): ^Brochet, Compt. rend., 117, 117 (1893); Bull. soc. chim., [3] 9, 687 (1893). 204 Klages and Sautter, Ber., 37, 654 (1904), 206 Klages, Ber., 37, 2308 (1904). 206 Sohweinitz, Ber., 19, 642 (1886). w I. G. Farbenind. A.-G., Brit. pat. 453,778 [C. A., 31, 1122 (1937)]. "Krafft, Ber., 19, 2982 (1886). ^Kyrides, U. S. pat. 2,161,173 [C. A., 33, 7438 (1939)]; Stirton and Peterson, Ind. Eng. Chem., 31, 856 (1939). 210 Gilnther and Hetzer, U. S. pat. 1,737,792 [C. A., 24, 864 (1930)]. alKriiger, Ber., 18, 1755 (1885). m Claus and Bayer, Ann., 274, 304 (1893). 213 Stallard, J. Chem. Soc, 89, 808 (1906). 214Kizhner and Vendelshtein, J. Russ. Phys.-Chem. Soc, Chem. Part, 57, 1 (1926) [C. A., 20, 2316 (1926)]. 216 Jaoobsen, Ber., 18, 1760 (1885). 218Weinburg, Ber., 11, 1062 (1878). 217 Bauch, Ber., 23, 3117 (1890). 218 Jacobsen, Ber., 21, 2821 (1888). 219 Jacobsen and Weinberg, Ber., 11, 1534 (1878). 220 Tohl and Bauoh, Ber., 26, 1105 (1893). 221 Holmes, Am. Chem. J., 13, 371 (1891). ^Kluge, Ber., 18, 2098 (1885). ^Wahl, Compt. rend., 200, 936 (1936). 224 Moody and Nicholson, J. Chem. Soc, 57, 974 (1890). 226 Voswinkel, Ber., 21, 3499 (1878). 226 Voswinkel, Ber., 21, 2829 (1878); Fournier, Bull. soc. chim., [3] 7, 651 (1892); Allen and Underwood, ibid., [2] 40* 100 (1883). 227 Fittig and Konig, Ann., 144, 286 (1867); Aschenbrandt, Ann., 216, 214 (1883) t Remsen and Noyes, Am. Chem. J., 4, 197 (1883). 228 Korner, Ann., 216, 224 (1883); Remsen and Keiser, Am. Chem. J., 5, 161 (1883); see also Heise, Ber., 24, 768 (1891). 229 Uhlhorn, Ber., 23, 3142 (1890). 230 Newton, /. Am. Chem. Soc, 65, 2439 (1943). 231 Baur, Ber., 27, 1606 (1894). 232 Claus and Pieszcek, Ber., 19, 3090 (1886). 233 Wroblewski, Ann., 192, 199 (1878). ^Bayrac, Bull. soc. chim., [3] 13, 890 (1895); Ann. chim., [7] 10, 28 (1897). T* Defren, Ber., 28, 2648 (1895). 194 ORGANIC REACTIONS 236 Claus and Stiisser, Ber., 13, 899 (1880). 237 Widman, Ber., 24, 444 (1891); Claus, Ber., 14, 2139 (1881). 238 Sprinkmeyer, Ber., 34, 1950 (1901). 239 Kelbe, Ann., 210, 30 (1881); Kelbe and Czarnomski, Ber., 17, 1747 (1884); Ann., 235, 285 (1896). 240 Spica, Ber., 14, 652 (1881); Gazz. chim. Hal., 12, 487, 546 (1882); Armstrong and Miller, Ber., 16, 2748 (1883). 241 Claus and Cratz, Ber., 13, 901 (1880); Claus, Ber., 14, 2139 (1881). 248 (o) Kelbe and Koschnitsky, Ber., 19, 1730 (1886); (6) Dinesmann, Ger. pat. 125,097 [Chem. Zentr., 72, II, 1030 (1901)]. 243 (a) Junger and Klages, Ber., 29, 314 (1896); (6) Klages and Kraith, Ber., 32, 2555 (1899). 244 Carrara, Gazz. chim. ital., 19, 173, 502 (1889). 246 Claus and Christ, Ber., 19, 2162 (1886). i 246 Patern6 and Canzoneri, Gazz. chim. ital., 11, 124 (1881). 247 (o) Kelbe and Baur, Ber., 16, 2559 (1883); (6) Baur, Ber., 24, 2832 (1891); 27, 1614 (1894). 248 Noelting, Ber., 25, 785 (1892). 249 Noelting, Chimie & Industrie, 6, 722 (1921). 280 Bigot and Fittig, Ann., 141, 166 (1867). 261 Lipinski, Ber., 31, 938 (1898). 262 Krafft and Gottig, Ber., 21, 3183 (1888). 263 Widman, Ber., 23, 3080 (1890); 24, 456 (1891). 264 von der Becke, Ber., 23, 3191 (1890). 266 Klages and Keil, Ber., 36, 1641 (1903). 268 Heise, Ber., 24, 768 (1891). 267 Fileti, Gazz. cftim. ital., 21, I, 4 (1891). 258 Kelbe and Pathe, Ber., 19, 1546 (1886). 269 Jacobsen, Ber., 19, 1218 (1886). 260Franke, dissertation, Rostockfsee Tohl and Miiller, ref. 261. 261 Tohl and Miiller, Ber., 26, 1108 (1893). 262 Kurzel, Ber., 22, 1586 (1889). 263 Ravikovich, J. Buss. Phys.-Chem. Soc, 62, 177 (1930) [C. A., 24, 5588 (1930)]. 264 Rose, Amre., 164, 53 (1872). 265 Tohl and Eckel, Ber., 26, 1099 (1893). 266 Klages, J. prakt. Chem., [2] 66, 394 (1902). 267 Gustavsen, J. prakt. Chem., [2] 72, 57 (1905). 268 Stahl, Ber., 23, 988 (1890). 269 Armstrong and Miller, Ber., 16, 2259 (1883). 270 Ernst and Fittig, Ann., 139, 184 (1866). 271 Jacobsen, Ber., 7, 1433.(1874); Ann., 195, 284 (1879). 272 Tohl and Geyger, Ber., 25, 1533 (1892). 273 Uhlhorn, Ber., 23, 2349 (1890). 274 Darzens and Rost, Compi. rend., 152, 607 (1911); Valentiner, Ger. pat. 69,072 [Frdl., 3, 881]. 276 Klages, B?r., 40, 2370 (1907). 276 Schorger, /. Am. Chem. Soc, 39, 2678 (1917). ? *" (a) Smith and Cass, J.-Am. Chem. Soc, 54, 1603, 1609, 1614 (1932); (6) Jacobsen; Ber., 19, 1209 (1886). 278 Tohl, Ber., 25, 1527, 2759 (1892). 279 Bielefeldt, Ann., 198, 381 (1879); Jacobsen, Ber., 15, 1853 (1882). 280 Markownikoff, ^1??., 234, 101 (1886). 281 Jacobsen and SchnapaufF, Ber., 18, 2841 (1885). 282 Smith and Lux, J. Am. Chem. Soc, 51, 2994 (1929). 283 Jacobsen, Ber., 20, 2837 (1887); Smith and Moyle, J. Am. Chem. Soc, 55,1676 (1933). 284 Klages and Keil, Ber., 36, 1632 (1903). DIRECT SULFONATION OF AROMATIC HYDROCARBONS 195 285 Tohl, Ber., 28, 2459 (1895). 286 Klages and Stamm, Ber., 37, 1715 (1904). 287 Tohl and Karchowski, Ber., 25, 1530 (1892). 288 Jacobsen, Ber., (a) 21, 2821 (1888); (6) 20, 896 (1887). 289 Feldmann, Helv. Chim. Acta, 14, 751 (1931); Latschinow, J. Russ. Phys.-Chem. Soc., 5, 50 (1873); Ber., 6, 193 (1873); Fittig, Ann., 132, 209 (1864). 290 Knauf and Adams, J. Am. Chem. Soc, 55, 4704 (1933). 291 Zincke, Ber., 5, 683 (1872). 292 Klages, Ber., 40, 2371 (1907). 293 Mazzara, Gazz. chim. Hal., 8, 509 (1878). 291 Bergmann, Chem. Revs., 29, 538 (1941). 295 Elbs, J. prakt. Chem., [2] 47, 49 (1893). 296 Hepp, Ber., 7, 1420 (1874). 297 Merz, Zeit./Ur Chemie., 1868, 395; Merz and Weith, Ber., 3, 195 (1870); Merz and Miihlhauser, Ber., 3, 710 (1870); Brande, Quart. J. Sci., 8, 289 (1819); Chamberlain, Annals of Phil., 6, 136 (1823). 298 Fierz-David, J. Soc. Chem. Ind., 42, 421T (1923); J. R. Geigy Soc, Fr. pat. 765,771 [C. A., 28, 6726 (1934)]. 299 Landshoff and Meyer, Ger. pat. 50,411 [FrdL, 2, 241]. ' 30° Armstrong and Wynne, Ber., 24R, 718 (1891). 301 Dennis, U. S. pat. 1,332,203 [C. A., 14, 1123 (1920)]; Grishin and Spruiskov, Anilino- krasochnaya Prom., 2, 19 (1932) [C. A., 27, 4791 (1933)]. 302 Sohultz, Ber., 23, 77 (1890). 303 Ewer and Pick, Brit. pat. 2,619 [Frdl., 2, 245]. 304 Corbellini, (Horn. chim. ind. applicata, 9, 118 (1927) [C. A., 22, 2938 (1928)]; Arm- strong, Chem. News, 54, 255 (1886); Bernthsen and Semper, Ber., 20, 938 (1887). 306 Armstrong, Ber., 15, 204 (1882). 306 A.-G. fur Anilinofabrik, Ger. pat. 45,776 [Frdl., 2, 253]; Bernthsen, Ber., 22, 3327 (1889); Armstrong and Wynne, Chem. News, 55, 136 (1887). 307 Willard, Color Trade J., 15, 40 (1924). 308 Ewer and Pick, Ger. pat. 45,229 [Frdl., 2, 244]. 309 Baum, Ger. pat. 61,730 [Frdl., 3, 419]. 310 Dachlauer and Thiel, U. S. pat. 1,804,527 [C. A., 25, 3669 (1931)]. 3111. G. Farbenind. A.-G., Brit. pats. 253, 118 [C. A., 21, 2477 (1927)]; 269,155 [C. A., 22, 1365 (1928)]. 312 Meyer and Bernhauer, Monatsh., 53-54, 721 (1929); Chem. Zentr., 101, I, 354 (1930). 313 Cook and Valjavec, U. S. pat. 2,133,282 [C. A., 33, 646 (1939)]. 314 Giinther and Krauch, Ger. pat. 407,240 [Chem. Zentr., 96,1, 1791 (1925)]. 316 Kimbara, Brit. pat. 502,964 [C. A., 33, 6997 (1939)]. 316 Vesely and Stursa, Coll. Czechoslov. Chem. Commun., 3, 328 (1931) [C. A., 25, 4877 (1931)]. 317 Elbs and Christ, J. prakt. Chem., [2] 106, 17 (1923). 318 Dziewonski and Waszkowski, Bull, intern, acad. polon. sci., 1929A w 604 [C. A., 25, 1241 (1931)]. 319 Dziewonski and Otto, Bull, intern, acad. polon. sci.. 1935A, 201 [C. A., 30, 2561 (1936)]; Dziewonski and Kowalczyk, ibid., 1935A, 559 [C. A., 30, 5212 (1936)]. 320 Fittig and Remsen, Ann., 155, 115 (1870). 321 Steiger, Helv. Chim. Acta, 13, 173 (1930). 322 Vesely, Stursa, Olejriicek, and Rein, Coll. Czechoslav. Chem. Commun., 1, 493 (1929) [C. A., 24, 611 (1930)]. 323 Dziewonski, Schoen6wne, and Waldman, Ber., 58, 1211 (1925). 324 (a) Wendt, J. prakt. Chem., [2] 46, 322 (1892) ;.(6) Reingruber, Ann., 206, 377 (1881). 325 Dziewonski and Wulffsohn, Bull, intern, acad. polon. sci., 1929A, 143 [C. A., 25, 1514 (1931)]. 326 Marchetti, Gazz. chim. Hal., 11, 265, 439 (1881). 327 Levy, Ann. chim., .9, 5 (1938). 196 ORGANIC REACTIONS 828 Dziewonski and Dziecielewski, Bull, intern, acad. polon. set., 1927A, 273 [C. A,, 22, 2164 (1928)]. 329 Miquel, Bull. soc. chim., [2] 26, 5 (1876). 830 Weissgerber and Kruber, Ber., 52, 346 (1919); Gesell. fur Teerverwertung, Ger. pat. 301,079 [Chem. Zentr., 88, II, 713 (1917)]. 331 Giovannozzi, Gazz. chim. ital., 12, 147 (1882). 332 Dziewonski and Moszew, BuU. intern, acad. polon. sci., 1928, 283 [C. A., 23, 3220 (1929)]; Dziewonski and Moszew, Roczniki Chem., 9, 361 (1929)4C A., 23, 3923 (1929)]. 333 Armstrong and Wynne, Chem. News, 61, 285 (1890). 334 Armstrong and Williamson, Proc. Chem. Soc, 1886, 233; 1887, 145. 335 (a) Arnell, BuU. soc. chim., [2] 39, 62 (1883); (b) Vorozhtzow and Karlash, Anilino- krasochnaya Proni., 4, 545 (1934) [C. A., 29, 2530 (1935)]. 336 Ferrero and Bolliger, Helv. Chim. Ada, 11, 1144 (1928). 337 Oehler, Ger. pat. 76,396 [frdl., 4, 523]. 338 Oehler, Ger. pat. 76,230 [Frdl., 4, 522]. 339 Armstrong and Wynne, Chem. News, 73, 55 (1896). 340 Armstrong and Wynne, Chem. News, 61, 94 (1890). 341 Rudolph, Ger. pat. 104,902 [Chem. Zentr., 70, II, 1038 (1899)]. 842 Arnell, BuU. soc. chim., [2] 46, 184 (1886). 343 Armstrong and Wynne, Chem. News, 55, 91 (1887); 57, 8 (1887). 344 Armstrong and Wynne, Chem. News, 62, 164 (1890). 346 Armstrong, Chem. News, 58, 295 (1888). 346 Armstrong and Wynne, Chem. News, 60, 58 (1889)., 347 Jolin, Bull. soc. chim., [2] 28, 514 (1877). - *? Laurent, Ann., 72, 298 (1849). 349 Otto and Mories, Ann., 147, 183 (1868); Darmstaedter and Wiohelhaus, Ann., 152, 303 (1869). 350 Armstrong and Williamson, Chem. News, 54, 256 (1886). 361 Sindall, Chem. News, 60, 58 (1889). 362 Armstrong, Chem. News, 56, 241 (1887). 363 Houlding, Chem. News, 59, 226 (1889). 364 Armstrong and Wynne, Chem. News, 61, 273 (1890). 366 Heller, Chem. News, 60, 58 (1889). 366 Bad. Anilin- und Soda-Fabrik, Ger. pat. 229,912 [Chem. Zentr., 82, I, 358 (1911)]. 367 Arnell, dissertation, tjpsala, 1889. 368 Cleve, Ber., 24, 3477 (1891). 369 Armstrong and Wynne, Chem. News, 59, 189 (1889). 360 Armstrong and Rossiter, Chem. Netbs, 66, 58 (1892). 361 Salkind and Belikoff, Ber., 64, 959 (1931). 362 Armstrong and Wynne, Chem. News, 71, 254 (1895). 863 Liebermann and Boeck, Ber., 11, 1613 (1878); Liebermann, Ber., 12, 182 (1879). 364 Soc. St. Denis, Ger. pats. 73,961 [Frdl., 3, 196]; 76,280 [Frdl, 4, 270]. 866 I. G. Farbenind., Fr. pat. 837,855 [C. A., 33, 6349 (1939)]. m Bach, Ber., 23, 1570 (1890). 867 Bad. Anilin- und Soda-Fabrik, Ger. pat. 260,562 [Chem. Zentr., 84, II, 104 (1913)]. 368 Minaev and Federov, Bull. inst. polytech. Ivanovo-Vosniesensk, 15, 113 (1930) [C. A* 28, 4258 (1931)]. 369 Hochster Farbwerke, Ger. pat. 292,590 [Chem. Zentr., 81, II, 208 (1916)]. 370 Perkin, Ann., 158, 319 (1871). 871 Ioffe and Matveeva, Russian pat. 34,550 [C. A., 29, 2977 (1935)]. 372 Bolam and Hope, J. Chem. Soc, 1941, 843, 373 (a) Komppa and Wahlforss, J. Am. Chem. Soc, 52, 5009 (1930); (b) Fieser and Young Oid., 63, 4120 (1931). 374 Hasselstrom and Bogert, J. Am. Chem. Soc, 57, 1579 (1935). 376 Ekstrand, Ann., 185, 86 (1877); Fritzsehe, J. prakt. Chem., 82, 333 (1861). DIRECT SULFONATION OP AROMATIC HYDROCARBONS 197 ^Anschiitz and Siemienski, Ber., 13, 1179 (1880); Sandqvist, Ann., 398, 125 (1913); 417, 1, 17 (1918). 377 Lauer, J. prakt. Chem., [2] 142, 252 (1935). 3781. G. Farbenind. A.-G., Brit. pat. 463,559 [C.A., 31, 5817 (1937)]; Zitsoher and Kehlen, U. S. pat. 2,141,893 [C. A., 33, 2730 (1939)]. 379 Kursanoff, Ann., 318, 309 (1901). 380 Gustavson, Compt. rend., 146, 640 (1908). 381 Kurssanoff, J. Russ. Phys.-Chem. Soc, 38, 1304 (1907) [Chem. Zentr., I, 1744 (1907)]. 382 Spilker, Ber., 26, 1538 (189S); Moschner, Ber. 34, 1257 (1901). 383 Arnold and Zaugg, J. Am. Chem. Soc., 63, 1317 (1941). 384 Fieser and Lothrop, J. Am. Chem. Soc, 58, 2050 (1936). 385 Bamberger and Kitschelt, Ber., 23, 1563 (1890); Schroeter and Schranth, Ger. pat. 299,603 [Chem. Zentr., 90, IV, 618 (1919)]. . 386 Schroeter, Svanoe, Einbeck, Geller, and Riebensohm, Ann., 426, 83 (1922). 387 Vesely and Stursa, Coll. Czechoslov. Chem. Commun., 6, 137 (1934) [C. A., 28, 5815 (1934)]. 388 Bogert, Davidson, and Apfelbaum, J. Am. Chem. Soc, 56, 959 (1934). 389 Bogert and Fourman, J. Am. Chem. Soc, 55, 4676 (1933). 390 Courtot, Ann. chim., [10] 14, 17 (1930). 891 Courtot and Geoffrey, Compt. rend., 178, 2259 (1924). 392 Hodgkinson and Matthews, /. Chem. Soc, 43, 166 (1883). 393 Schmidt, Retzloff, and Haid, Ann., 390, 217 (1912); Courtot and Geoffrey, Compt. rend., 180, 1665 (1925). 384 (a) Dziewo"nski, Galitzerowna, and Kocwa, Bull, intern, acad. polon. sd., 1926A, 209 [C. A., 22,1154 (1928)]; (b) Dziewonski and Kocwa, ibid., 1928,405 [C. A., 23,2435 (1929)]; (c) Dziewonski and Stollyhwo, Iszy. Zjazd. Chemikdw Polskich, 1923, 57 [C.A., 18, 981 (1924)]; Ber., 57, 1531 (1924). 395 Bogert and Conklin, Coll. Czech. Chem. Commun., 5, 187 (1933) [C. A., 27, 4230 (1933)]. 396 Dziewonski and Zakrzewska-Barnaowska, Bull, intern, acad. polon. sci., 1-2A, 65 (1927) [C. A., 21, 2682 (1927)]. 397 Dziewonski, Sehoen, and Glazner, Bull, intern, acad. polon. sci., 1929A, 636 [C. A., 25, 1518 (1931)]; Dziewonski, Glasner6wna, and Orzelski, Iszy. Zjazd. Chemikdw Polskich, 1923, 57 [C. A., 18, 981 (1924)]. 398 (a) Schroeter, Ber., 57, 2003 (1924); (b) Schroeter and Gotzky, Ber., 60, 2035 (1927). 399 Schroeter, Miiller, and Hwang, Ber., 62, 645 (1929). 400 Goldschmiedt, Monatsh., 1, 227 (1880). 401 Mellin, Ber., 23, 2533 (1890). 402 Goldschmiedt and Wegscheider, Monatsh., 4, 242 (1883). 403 (a) Smith, J. Chem. Soc, 32, 558 (1877); (6) Smith and Takamatsu, ibid., 39, 551 (1881). 404 Dziewonski and Pochwalski, Iszy. Zjazd. Chemikdw Polskich, 1923, 56 [C. A., 18, 982 (1924)]. 406 Henke and Weiland, U. S. pat. 1,853,352 [C. A., 26, 3264 (1932)]. ^Gubelmann and Henke, U. S. pat. 1,853,348 [C. A., 26, 3264 (1932)]. CHAPTER 5 AZLACTONES H. E. CARTER University of Illinois CONTENTS PAGE INTRODUCTION 199 PREPARATION OP AZLACTONES 202 Azlactonization of an a-Acylamino Acid 202 Procedures 204 2-Phenyl-4-benzal-5-oxazolone 204 2-Phenyl-4-benzyl-5-oxazolone 5 2-Methyl-4%enzyl-5-oxazolone 205 a-AcetamWcinnamic Acid 5 Reaction of an Aldehyde with an Acylglycine in the Presence of Acetic Anhy- dride 205 Mechanism 5 Scope and Limitations 206 Carbonyl Component 6 Acylglycines 208 Experimental Conditions and Procedures 209 Reaction of an a-Acylamino-j3-hydroxy Acid with an Acid" Anhydride or Acid Chloride 211 Procedures 1 a-Benzoylaminocinnamic Azlactones I and II 211 Reaction of an ex-(a'-Haloacyl)-amino Acid with Acetic Anhydride .... 212 PROPERTIES AND REACTIONS OP AZLACTONES 213 General Discussion ?. 213 Hydrolysis 214 Alcoholysis 5 Aminolysis, Synthesis of Peptides 216 TYPES OP COMPOUNDS WHICH CAN BE PREPARED PROM AZLACTONES .... 217 General Discussion 217 a-Amino Acids 8 Procedures 220 Reduction of a-Benzoylaminoacrylic Acids with Sodium Amalgam , . 220 a-Keto Acids 0 Abnormal Hydrolytic Products 222 o-Nitrobenzaloxazolones 2 o-Carboalkoxybenzaloxazolones . 223 Miscellaneous Reactions 223 198 AZLACTONES 199 PAGE Procedures 224 Hydrolysis with Barium Hydroxide 224 Arylacetic Acids 4 Procedures 225 4-Chlorophenylacetic Acid 225 Arylacetonitriles 5 Procedures 225 Conversion of Arylpyruvic Acids to the Oximes 225 Conversion of Oximes to Arylacetonitriles 225 Miscellaneous 226 Isoquinoline Derivatives 226 Quinoline Derivatives 6 Imidazolone (Glyoxalone) Derivatives 227 Indole Derivatives 227 Styrylamides 8 TABLES OP AZLACTONES AND DERIVED SUBSTANCES 228 I. TJnsaturated Azlactones 229 II. Saturated Azlactones 237 III. Compounds Not Definitely Established as Azlactones 238 INTRODUCTION Azlactones may be considered anhydrides of a-acylamino acids. It is convenient to classify them into two groups, saturated and unsaturated, as shown in formulas I and II, since the two types show characteristic differences in properties. R2C4¡ª-8C=O R2C=C¡ªBC=0 V V ? R R i II Plochl,1 in 1883, prepared the first unsaturated azlactone by the con- densation of benzaldehyde with hippuric acid in the presence of acetic anhydride. However, it remained for Erlenmeyer to determine the structure of the product,2'3 to extend the reaction to other aldehydes 4~10 1 Plochl, Ber., 16, 2815 (1883). 2 Erlenmeyer, Ann., 275, 1 (1893). 3 Erlenmeyer, Ber., 33, 2036 (1900). 4 Erlenmeyer and Halsey, Ann., 307, 138 (1899). 6 Erlenmeyer and Kunlin, Ann., 316, 145 (1901). 6 Erlenmeyer and Matter, Ann., 337, 271 (1904). 7 Erlenmeyer and Stadlin, Ann., 337, 283 (1904). 8 Erlenmeyer and Wittenberg, Ann., 337, 294 (1904). 9 Erlenmeyer and Halsey, Ber., 30, 2981 (1897). 10 Erlenmeyer and Kunlin, Ber., 35, 384 (1902). 200 ORGANIC REACTIONS (aromatic and aliphatic), and to establish the usefulness of unsaturated azlactones as intermediates in the synthesis of a-keto u> 12'13 and a-amino C6H6CHO + CH2CO2H ~^? C6H6CH=C C=O NH NO I V/ COC6H6 C acids:4-14> 16> 16 Consequently, the reaction of an aldehyde with hippuric acid usually is referred to as the Erlenmeyer azlactone synthesis. Erlenmeyer was unable to prepare saturated azlactones,17 probably because he failed to appreciate the ease with which they are hydrolyzed. However, Mohr and coworkers 18~M in 1908-1910 prepared several com- pounds of this type by the action of acetic anhydride on a-acylamino R acids. This reaction has been employed in the preparation of a variety of saturated azlactones which have been used as intermediates in the synthesis of peptides.26"28 11 Erlenmeyer, Ann., 271, 137 (1892). 12 Erlenmeyer, Ann., 275, 8 (1893). 13 Erlenmeyer and Frilstiick, Ann., 284, 36 (1895). 14 Erlenmeyer, Ann., 275, 13 (1893). 16 Erlenmeyer and Kunlin, Ann., 307, 163 (1899). 16 Erlenmeyer, Ann., 337, 205 (1904). ?? Erlenmeyer, Ann., 307, 70 (1899). 18 Mohr-and Geis, Ber., 41, 798 (1908). 19 Mohr and Stroschein, Ber., 42, 2521 (1909). 20 Mohr, J. prakt. Chem., 80, 521 (1908). 21 Mohr, J. prakt. Chem. 22 Mohr, J. prakt. Chem. 23 Mohr, J. prakt. Chem. 24 Mohr, J. prakt. Chem. 81, 49 (1910). 81,473 (1910). 82, 60 (1910). 82, 322 (1910). 26 Bergmann and Grafe, Z. physiol. Chem., 187, 196 (1930). 26 Bergmann, Stern, and Witte, Ann., 449, 277 (1926). 27 Bergmann and Koster, Z. physiol. Chem., 167, 91 (1927). 28 Bergmann and Zervas, Z. physiol. Chem,., 175, 154 (1928). AZLACTONES 201 Several different structures have been suggested for the azlactones. Of these only two (formulas III and IV) have received serious considera- RCH=C C=O RCH= c=o R IV tion. The three-membered ring structure IV (called lactimide) was proposed by Rebuffat29 in 1889 and accepted by Erlenmeyer2 in 1893. However, in 1900 Erlenmeyer3 abandoned this formula in favor of the five-membered ring (III) for which he later 30 proposed the term "azlactone." The term "lactimone" also has been applied to these compounds.18'31 Although formula III has been accepted generally, Heller and Hessel32 as late as 1929 presented arguments in favor of the three-membered ring structure. Geometric isomerism is possible in the unsaturated azlactones, and there has been speculation in the literature concerning the existence of the two forms.6' '?10'33 The cis and trans isomers of benzoylaminocro- tonic azlactone u and of benzoylaminocinnamic azlactone have been isolated.36 H \ _ = \ = H N 0 CH3 N O \ / \ / c c Benzoylaminocrotonic ailactonee Azlactones are named as derivatives of amino acids, of oxazolone (Chemical Abstracts and Beilstein's Handbuxh), and of dihydrooxazole (British usage). Thus the condensation product of benzaldehyde with hippuric acid maybe called benzoyl-a-aminocinnamic azlactone, 2-phenyl- 29 Rebuffat, Ber., 22, 551c (1889). 80 Erlenmeyer, Ann., 337, 265 (1904). 31 Mohr and Kohler, Ber., 40, 997 (1907). 32 Heller and Hessel, J. prakt. Chem., 120, 64 (1928-1929). a'Bergmann and Stern, Ann., 448, 20 (1926). 34 Carter and Stevens, J. BM. Chem., 133, 117 (1940). 36 Carter and Risser, J. Biol. Chem., 139, 255 (1941). 202 ORGANIC REACTIONS 4-benzal-5-oxazolone, or 5-keto-2-phenyl-4-benzylidene-4,5-dihydro- oxazole. In this chapter the Chemical Abstracts terminology is given preference, although compounds are named as derivatives of amino acids whenever it seems desirable in the interest of clarity or brevity. PREPARATION OF AZLACTONES Azlactones have been of interest mainly as intermediates in the synthe- sis of other compounds. Saturated azlactones are obtained most often from the corresponding amino acids and are used in preparing derivatives of those amino acids. Unsaturated azlactones, on the other hand, usually are prepared by condensing an aldehyde with an acylglycine and are used in the synthesis of the corresponding amino and keto acids. Four methods by which azlactones can be prepared are discussed in the follow- ing paragraphs. Azlactonization of an a-Acylamino Acid RCHCO2H (^°> RCH C=O I (NaOAc) | | NH NO I \ / COR C R a-Acylamino acids can be converted into azlactones under the follow- ing conditions: (a) Action of an acid anhydride, either alone or in acetic acid as a solvent, on an a-acylamino acid (or, occasionally, a free a-amino acid).18"28'34'36 (b) Action of an acid anhydride34 or acid chloride36 on the sodium salt of an a-acylamino acid (or free a-amino acid) in aqueous solution, (c) Action of an acid anhydride or chloride on an a-acylamino acid in pyridine solution.37-38 Of these methods the first is the most convenient and the only one generally used; however, none of these methods is practical for the preparation of unsaturated azlactones be- cause the unsaturated acylamino acids are not readily available. The preparation of unsaturated azlactones is effected smoothly and quantitatively by heating the acylamino acid with an excess of acetic anhydride on a steam bath for five to fifteen minutes.33- u-36-39- m The 88 Bettzieche and Menger, Z. physiol. Chem., 172, 56 (1927). 87 Carter, Handler, and Melville, J. Biol. Chem., 129, 359 (1939). 88 Carter, Handler, and Stevens, J. Biol. Chem., 138, 619 (1941). 89 Bain, Perkin, and Robinson, J. Chem. Soc., 105, 2392 (1914). <° Gulland and Virden, J. Chem. Soc., 1928, 1478. AZLACTONES 203 azlactone is isolated by pouring the reaction mixture" into water, which hydrolyzes the excess acetic anhydride and causes the product to precipi- tate. The lower saturated azlactones are prepared less readily by this pro- cedure; they are liquids, unstable toward water and heat, and can be isolated only by fractional distillation. Those of low molecular weight, such as the 2,4-dimethyl-,23 2,4,4-trimethyl-,21-41 and 2,4-dimethyl-4- ethyl-oxazolone,41 boil at about the same temperature as acetic anhy- dride and have not been obtained in the pure state. Higher-boiling azlactones have been prepared in good yields by this method when the distillation was effected at the lowest possible temperature. 2-Aryloxazo- lones are synthesized more readily since they are solids and hence can be isolated by removal of the acetic anhydride under reduced pressure and recrystallization from ether or petroleum ether.19'34 Acyl derivatives of glutamic acid 42 are converted to acid anhydrides rather than azlactones on treatment with acetic anhydride. Acetylaspartic acid yields either an azlactone or an anhydride, depending upon the conditions used; ** the azlactone is formed in acetic anhydride at the reflux temperature; the anhydride, at 95°. HO2CCH2CH C=O N ' 0 C HO2CCH2CHCO2H NH ? |' CH2¡ªC=O C0 I >O I CH3CONHCH¡ªC=O CH3 The action of acetic anhydride on an a-acylamino acid in aqueous solu- tion yields an azlactone, provided that a basic catalyst, such as sodium acetate,*1 u is present. Unsaturated azlactones are prepared readily by this method. Saturated azlactones are obtained in poor yields since they undergo hydrolysis rapidly in aqueous solution. Optically active a-acyl- amino acids are racemized under these conditions as a result of the tem- porary formation of the azlactone.44 * Sodium acetate also increases the rate of azlactone formation in glacial acetic acid solutions, but no preparative application has been made of this observation.11 Levene and Steiger, J. Bid. Chem., 93, 581 (1931).42 Nicolet, J. Am. Chem. Soc, 52, 1192 (1930). "Harington and Overhoff, Biochem. J., 27, 338 (1933). "duVigneaud and Meyer. J. Biol. Chem., 99, 143 (1932-1933). 204 OEGANIC REACTIONS Saturated a-acylamino acids, are prepared by acylation of a-amino acids or, less frequently, by reduction of the corresponding unsaturated compounds. It sometimes is possible to effect both the preparation of the a-acylamino acid and the formation of the azlactone by heating the amino acid with a large excess of acetic anhydride. Leucine and phenyl- alanine26 give excellent yields of azlactones under these conditions. However, this method is not satisfactory with alanine,23 diiodotyrosine,46 isovaline,41 or a-amirioisobutyric acid,41 which yield products of high molecular weight. Unsaturated a-acylamino acids usually are obtained from the corre- sponding azlactones. Reconversion of the unsaturated acid ±o the azlactone is not, therefore, a reaction of any great preparative impor- tance. A few a-acylaminoacrylic acids have been prepared by the reac- "tion of an a-keto acid with an amide:< (R'CONH)2CC.O2H CH2R R'CONHCCO2H CHR However, the utilization of this reaction has been severely restricted by the unavailability of a-keto acids. Pyruvic acid yields mainly a,a-diacetaminopropionic acid, which can be converted into a-acetaminoacrylic acid by hot acetic acid.26' M Under the optimum conditions47 a 23% yield of a-acetaminoacrylic acid is obtained. Phenylpyruvic acid gives mainly a-acetaminocinnamic acid,48 as would be expected in view of the activating effect of the benzene ring. Benzoylformic acid tf and a-ketoglutaric acid49 have been employed as the acid components in this reaction, and benzamide,60 benzylcarba- mate,61 and chloroacetamide46 as the amide components. The prepara- tion of a-acetaminocinnamic acid by this method is described in the next section. Procedures 2-Phenyl-4-benzal-5-oxazolone.36 One gram of benzoylaminocin- namic acid is heated on the steam cone for five minutes with 10 cc. of ? Myers, J. Am. Chem. Soc., 54, 3718 (1932). *> Bergmann and Grafe, Z. physiol. Chem., 187, 187 (1930). ? Herbst, /. Am. Chem. Soc., 61, 483 (1939). 48 Shemin and Herbst, J. Am. Chem. Soc., 60, 1954 (1938). 49 Shemin and Herbst, J. Am. Chem. Soc, 60, 1951 (1938). 60 Nieolet, J. Am. Chem. Soc, 57, 1073 (1935). 61 Herbst, J. Org. Chem., 6, 878 (1941). AZLACTONES 205 acetic anhydride. The solution is poured into a mixture of ice and water and allowed to stand with occasional stirring for twenty minutes. The precipitate is removed by filtration, air-dried, and recrystallized from benzene-ethanol, yielding 0.8 g. (86%) of 2-phenyl-4-benzal-5-oxazolone; m.p. 165-166°. 2-Phenyl-4-benzyl-5-oxazolone.19 Ten grams of benzoyl-df-^-phenyl- alanine is heated on the steam bath for thirty minutes with 100 cc. of acetic anhydride. The solution is concentrated in vacuum, and the syrupy residue is dissolved in 100 cc. of petroleum ether, b.p. 60-110°. The solution is decanted from a small amount of insoluble material and is cooled. Practically pure 2-phenyl-4-benzyl-5-oxazolone crystallizes in long needles, m.p. 69-71°; yield 7.5 g. (80%). 2-Methyl-4-benzyl-5-oxazolone.26 Five grams of powdered dirfi- phenylalanine is heated at 100° for five minutes with 50 cc. of acetic anhydride. The mixture is shaken vigorously during the heating. Acetic acid and^cetic anhydride are removed under reduced pressure, and the residue is fractionated, yielding 3.1 g. (54%) of 2-methyl-4-benzyl-5- oxazolone, b.p. 118°/0-8 mm. a-Acetaminocinnamic Acid.48 A mixture of 12 g. of phenylpyruvic acid and 12 g. of acetamide is heated for three hours at 110-115° under 10-15 mm. pressure. The residue is dissolved in boiling water, and the solution is treated with Norit and allowed to cool, yielding 7.1 g. (47%) of a-acetaminocinnamic acid, m.p. 193°. Reaction of an Aldehyde with an Acylglycine in the Presence of Acetic Anhydride ArCHO + CH2CO2H Ac2° > ArCH=C¡ª?¡ª0=0 I CNaOAo) | I NH NO I \ / COR C R The, Erlenmeyer azlactone synthesis consists in the condensation of an aldehyde with an acylglycine in the presence of acetic anhydride (and usually sodium acetate). It is a special case of the Perkin condensation and as such has been discussed briefly by Johnson.62 Mechanism. Erlenmeyer believed that the reaction proceeds in two steps as shown in the equations.13'17 However, convincing evidence has accumulated that the actual condensation takes place between the alde- 62 Johnson, Org. Reactions, I, 231 (1942). 206 ORGANIC REACTIONS hyde and the azlactone formed by the action of acetic anhydride on the acylglycine. The strongest support for this mechanism is the fact that ArCHO + CH2CO2H -? ArCH¡ª CHCO2H -> ArCH=C C==O NH OH NH NO I I ? \ / COR COR C R the condensation occurs under much milder conditions than those re- quired in the Perkin condensation. In the azlactone synthesis uniformly high yields are obtained from aldehydes which give poor results or fail to react (4-imidazolealdehyde)63 in the Perkin condensation. Furthermore, CH2CO2H -? CH2 C=O ArCH°> ArCH I II NH N 0 I \ / COR C R the yields from substituted aldehydes do not vary as they do in Perkin reactions,62 which suggests that the condensation reaction is not the limiting step in the azlactone synthesis. All these data indicate that the intermediate contains an extremely active methylene group and there- fore is the azlactone rather than the acylglycine. Furthermore, benzoyl- sarcosine (benzoyl-N-methylglycine), which cannot form an azlactone, condenses with aldehydes much less readily than does hippuric acid.64' K Similarly, benzenesulfonylglycine M fails to condense with piperonal. Scope and Limitations. Carbonyl Component. For practical purposes this reaction is limited to aromatic aldehydes, of which a wide variety has been studied, and to a,/3-unsaturated aliphatic aldehydes. The sub- stitutents on the ring of the aromatic aldehydes include alkyl, fluoro, chloro, bromo, iodo, hydroxyl, alkoxy, acyloxy, carbethoxy, nitro, and various combinations of two or more of these groups. Aldehydes of the naphthalene, pyrene, biphenyl, thiophene, furan, pyrrole, indole, chro- mane, coumarane, and thiazole series also have been employed. No generalizations can bevmade concerning the effect of the structure of the aldehyde on the yield of azlactone. In several preparations the 63 Pyman, J. Ch&n. Soc, 109, 186 (1916). " Heard, Biochem. J., 27, 54 (1933). ? Deulofeu, Ber.. 67, 1642 (1934). AZLACTONES 207 yields are not reported, and in others the reaction conditions have not been comparable. The yields in this azlactone synthesis are uniformly good, ranging from 60 to 80%, with a few as high as 95%. The few lower yields reported were obtained from aldehydes belonging to no particular type and may have resulted from poor reaction conditions. The presence of an o-nitro group appears to hinder some reactions but not others. Thus, 2-nitro-3,4-methylenedioxybenzaldehyde gives a 35% yield of azlactone,66 and 2-nitro-3-methoxy-4-hydroxybenzaldehyde gives a 42% yield.67 However, 2-nitro-3,4-dimethoxybenzaldehyde gives a 75% yield of azlactone,68 and 2-nitro-5-methoxybenzaldehyde gives an 84% yield.69 In general, no substituent group has a specific or consistent effect on the yield. In this respect the azlactone synthesis differs mark- edly from the Perkin condensation. When salicylaldehyde is heated with hippuric acid, acetic anhydride, and sodium acetate, benzoylaminocoumarin is obtained along with the acetoxyazlactone.7'29> 60~62 Similar results are obtained with 2,4-dihy- CH2¡ªCO2H AcgO ^ NaOAo CO¡ªC6HB C6H6 droxybenzaldehyde63 and 2,5-dihydroxybenzaldehyde.64 It is interesting to note that only the azlactone is obtained by heating salicylaldehyde with acetylglycine, acetic anhydride, and sodium acetate.86 M Narang and Ray, /. Chem. Soc, 1931, 976. 67 Gulland, Ross, and Smellie, J. Chem. Soc, 1931, 2885. 68 Gulland, Robinson, Scott, and Thornley, J. Chem. Soc., 1929, 2924. ?? Burton, /. Chem. Soc, 1935, 1265. 60 Asahina, Buli. Chem. Soc. Japan, 6, 354 (1930). 61 Rebuffat, Gazz. chim. Hal., IS, 527 (1885). 62 Ploohl and Wolf rum, Ber., 18, 1183 (1885). ""Deulofeu, Ber., 69, 2456 (1936). 64 Neubauer and Flatow, Z. physiol. Chem., 52, 375 (1907). ? Dakin, J. Biol. Chem., 82, 439 (1929). 208 ORGANIC REACTIONS Phthalic anhydride2 and pyruvic acid M condense with hippuric acid to give products which have been assigned the following structures. 00 \ /c CO2H N c Saturated aliphatic aldehydes generally give low yields in the azlactone synthesis.6'37 a,/3-Unsaturated aldehydes such as cinnamaldehyde,6 a-n-amylcinnamaldehyde,67 and perilla aldehyde,67 which cannot undergo an aldol condensation, react satisfactorily (65-80% yields). 2-Thio- phenealdehyde diethylacetal gives yields as satisfactory as those from the CBHR free aldehyde, an observation which has led to' the suggestion that acetals might be used generally in the condensation with hippuric acid.68 This possibility should be investigated further since certain aldehydes may be destroyed slowly under the usual reaction conditions. Thioaldehydes can be condensed with hippuric acid if either cupric acetate or lead oxide is added to the reaction mixture.69 Acetone gives a 45% yield of azlac- tone.70 No other simple ketone has been tested. Acylglycines. Several acylglycines (acetyl, benzoyi, phenylacetyl, galloyl, etc.) have been used in the azlactone synthesis. Of these, ben- zoylglycine and acetylglycine have been studied most. Each has certain M Erlenmeyer and Arbenz, Ann., 337, 302 (1904). "Bodionow and Korolew, Z. angew. Chem., 42, 1091 (1929). 88 Yuan and Li, J. Chinese Chem. Soc, 5, 214 (1937). " Fischer and Hofmann, Z. physiol. Chem., 846, 139 (1936-1937). 70 Ramage and Simonsen, J. Chem. Soc., 1935, 532. AZLACTONES 209 advantages. Generally the yields with hippuric acid are somewhat higher, and the resulting azlactones are more stable. If the azlactone is to be used in preparing the a-keto acid the acetyl derivative is to be preferred since it is hydrolyzed to the keto acid under milder conditions and the acetic acid produced is separated from the a-keto acid more readily than is benzoic acid. Experimental Conditions and Procedures. 2-Phenyloxazolones usu- ally are prepared by heating a mixture of 1 mole each of aldehyde, hippuric acid, and freshly fused sodium acetate with 3 moles of acetic anhydride on the water bath for varying lengths of time. In many instances a larger proportion of sodium acetate and/or acetic anhydride has been used, ialthough there is no direct evidence that such alterations improve the yield. Indeed, some doubt exists whether sodium acetate is necessary. Originally, this component was omittedx and an 80% yield of 2-phenyl-4-benzal-5-oxazolone was obtained. Dimethylethylpyrrolealde- hyde69 and m-benzyloxybenzaldehyde n give 83 and 74% yields, respec- tively, of azlactone without the use of sodium acetate. No other such experiments have been reported. This point should be investigated further since it seems possible that in certain cases the addition of sodium acetate may actually decrease the yield. The length of heating has varied from six minutes to ten hours, but usually it is from fifteen minutes to one hour. This matter also deserves a more careful scrutiny. In several preparations excellent yields have been obtained with very short reaction times (six to fifteen minutes). It seems probable that in other preparations a shorter reaction period might give as good or better results, since even unsaturated azlactones decompose slowly on heating. Thus, 3-ethoxy-4-methoxybenzaldehyde is reported to yield 82% of the azlactone when the reaction mixture is heated for twenty minutes,72 and 78% when the heating period is one hour.73 3,4,5-Trimethoxybenzaldehyde gives a 65% yield in six min- utes n and an 85%yield in ninety minutes;7B this reaction must have been practically complete in ten minutes. With 2-nitro-3-methoxy-4- hydroxybenzaldehyde, extensive decomposition occurs if the heating is prolonged beyond ten minutes.67 The fact that hippuric acid azlactone is unstable and will not exist in the reaction mixture for an appreciable length of time also argues against a prolonged reaction time. 71 Rapson and Robinson, J. Chem. Soe., 193S, 1533. ? "Spath and Tharrer, Ber., 66, 583 (1933). 73 Barger, Eisenbrand, and Eisenbrand, Ber., 66, 450 (1933). 74 Baker and Robinson, J. Chem. Soc., 1929, 152. 78 Mauthner, Ber., 41, 3662 (1908). 210 ORGANIC REACTIONS Better results have been claimed76 in preparations effected by mixing the aldehyde, acetic anhydride, and sodium acetate in one flask, hippuric acid and acetic anhydride in another, and combining the warm solutions. However, the yields reported are little, if any, better than those obtained in the usual manner. Another variation of doubtful value is the addition of sodium acetate to a hot mixture of the other reactants.77 2-Methyloxazolones are best prepared by the method of Dakin.86 In this procedure acetylglycine is produced by heating glycine in acetic acid with 1 mole of acetic anhydride. The aldehyde, sodium acetate, and more acetic anhydride are then added, and the heating is continued two to ten hours. This procedure has the advantage over the hippuric acid synthesis that it is not necessary to prepare the acetylglycine separately. The 2-methyloxazolones can be obtained also by heating a mixture of glycine, acetic anhydride, sodium acetate, and aldehyde,33 but the yields are somewhat lower, probably owing to condensation of the aldehyde with the amino group of the glycine.65 The reaction times reported with acetylglycine are longer than those with hippuric acid, and temperatures have been higher (120-135°). Although no direct comparison has been made, it would appear that 2- methyloxazolone either condenses less readily with aldehydes than does 2-phenyloxazolone or is formed more slowly. Even so, it seems doubtful that heating longer than two hours or at a temperature above 100° is de- sirable, since under those conditions Dakin obtained yields as high as any reported. Furthermore, he indicated that more severe conditions led to lower yields. The azlactones usually are isolated either by cooling the reaction mix- ture and removing the azlactone by filtration or by pouring the cold reaction mixture into water, allowing the excess acetic anhydride to hydrolyze, and collecting the crude azlactone. The product can be. purified by recrystallization from ethanol (with the exception of a few which undergo al'coholysis), benzene, petroleum ether, or ethyl acetate. Detailed descriptions of the preparations of three azlactones by con- densations of aldehydes with acylglycines are given in Organic Syntheses. These include the syntheses of 2-methyl-4-benzal-5-oxazolone from benzaldehyde and acetylglycine,78 2-phenyl-4-benzal-5-oxazolone from benzaldehyde and hippuric acid,79 and 2-phenyl-4-(3',4'-dimethoxyben- , zal)-5-oxazolone from veratraldehyde and hippuric acid.80 ? Oliverio, Gazz. chim. Hal., 65, 143 (1935). 77 Douglas and Gulland, J. Chem. Soc, 1931, 2893. "Herbst and Shemin, Org. Syntheses, Coll. Vol. 2, 1 (1943). 78 Gillespie and Snyder, Org. Syntheses, Coll. Vol. 2, 489 (1943). 80 Buck and Ide, Org. Syntheses, Coll. Vol. 2, 55 (1943). AZLACT0NE8 211 Reaction of an a-Acylamino-P-hydroxy Acid with an Acid Anhydride or Acid Chloride OR' NH (NaOAc) III I J +R'OH COR" R' = H, CH3, CH3CO The action of acetic anhydride on an a-acylamino-/3-hydroxy (alkoxy or acyloxy) acid produces an unsaturated azlactone.13' 34~37' 81~86 The first step in this transformation is the conversion of the acyl derivative into the corresponding saturated azlactone. This saturated azlactone pos- sesses an extremely active a-hydrogen atom which splits out with the |3-substituent under very mild conditions. The cis and trans isomers of an unsaturated azlactone were obtained for the first time by this method. a-Benzoylamino-j3-methoxybutyric acid on heating for ten minutes with acetic anhydride yields a mixture of the isomeric benzoylaminocrotonic azlactones.34 The labile isomer is less soluble and hence readily isolated in the pure state. It is rapidly converted into the stable isomer by heat or by the action of cold pyridine. The two isomeric benzoylaminocinnamic azlactones have been prepared in a similar manner.36 Procedures. a-Benzoylaminocinnamic Azlactones I and 7/.3B Fifteen grams (0.05 mole) of a-benzoylamino-/3-methoxy-/3-phenylpropionic acid is suspended in 75 cc. of acetic anhydride, and the mixture is heated on a steam bath until the benzoyl derivative has dissolved completely (ten to fifteen minutes). The solution is cooled in an ice bath and filtered; 6.0-7.0 g. (48-56%) of almost pure a-benzoylaminocinnamic azlactone I, m.p. 164-166°, is collected. . The filtrate is poured into water with vigorous stirring. A light yellow solid separates as the acetic anhydride is hydrolyzed. This material is collected, washed with water, air-dried, and recrystallized from benzene, yielding 4.0-4.5 g. (32-36%) of crude azlactone II, m.p. 124-140°. The total yield is 10.0-11.5 g. (80-92%). 81 Botvinnik, Prokof'ev, and Zelinskii, Compt. rend. acad. sci. U.R.S.S., 30, 129 (1941). 82 Erlenmeyer and Bade, Ann., 337, 222 (1904). 83 Bergmann and Delis, Ann., 458, 76 (1927). 84 Dakin and West, /. Biol. Chem., 78, 745 (1928). 86 Forster and Rao, J. Chem. Soc, 1926, 1943. 86 Bergmann, Schmitt,' and Miekeley, Z. physiol. Chem., 187, 264 (1930). 212 ORGANIC REACTIONS Pure benzoylaminocinnamic azlactone I, m.p. 167-168°, is obtained by recrystailizing the crude material from 2 volumes of benzene. Recrystal- lization of crude azlactone II from benzene or ethanol does not raise the melting point appreciably. A preparation melting at 146-148° can be obtained by hydrolyzing the crude material to the corresponding acid, recrystailizing the acid from -a benzene-ethanol-petroleum ether mixture, and reconverting the purified acid to the azlactone with acetic anhydride. An 80-90% yield of a-benzoylaminocinnamic azlactone I is obtained in the above preparation if 1 cc. of pyridine is added to the reaction mixture. Reaction of an a-(a'-Haloacyl)-amino Acid with Acetic Anhydride RCH2CH CO2H (<^°N)> RCH2C C=O -? RCH=C ^C=O HN NO NO \ \ / \ / CO C C X¡ªCHR CHR CH2R The conversion of an a-(a'-haloacyl)-amino acid into an unsaturated azlactone M has not been studied extensively. A proposed mechanism M is shown in the above equations. On treatment with acetic anhydride and pyridine at room temperature, N-chloroacetyl-cS-/3-phenylalanine is converted into a-acetaminocinnamic azlactone (yield, 80%) w and N-chloroacetyl-i-tyrosineinto2-methyl-4-p-acetoxybenzal-5-oxaz.olone.87 This reaction has been applied in the synthesis of an a-keto acid from the corresponding a-amino acid. a-Bromopropionyl-<2J-methionine was con- verted into the unsaturated azlactone by the action of acetic anhydride and sodium acetate. Dilute hydrochloric acid was added, and the reac- tion mixture was heated in a water bath for five minutes, yielding a-keto-7-methiolbutyric acid, which was isolated as the phenylhydra- zone.88 CH8SCH2CH=C CO HCI| I > CHjSCH 2CH2COCO2H+CH8CH2CO2H+NH4ClN 0 V C2H6 "Bergmann, Zervas, and Lebrecht, Ber., 64, 2315 (1931).88 Cahill and Rudolph, /. Bid. Chem., 145, 201 (1942). AZLACTONES 213 PROPERTIES AND REACTIONS OF AZLACTONES General Discussion Saturated azlactones are colorless liquids or low-melting solids. Unsaturated azlactones are solids, often high-melting, and the majority have colors ranging from light yellow Cb dark red. The color, is most intense in 2-aryl-4-aralkylidene-5-oxazolones; the 2-alkyl-4-alkylidene-5- oxazolones are colorless. The azlactones behave in many respects like acid anhydrides and react with a wide variety of compounds, such as water, alcohols, amines, and hydrogen halides, which contain active hydrogen atoms. As with acid anhydrides, reaction occurs most readily with amines, less readily with alcohols, and least readily with water. RCH C=O + HX -? RCHCOX (X = ¡ªNHj, ¡ªNHR, ¡ªNR2, | | | ¡ªOR, ¡ªOH, and halogen) NO NH \/ I C , CO R R The saturated azlactones are much more reactive than the unsaturated compounds. The unsaturated azlactones can be recrystallized from boil- ing ethanol (with one known exception, see p. 215) and are not altered by long contact with water, whereas the saturated compounds are slowly hydrolyzed by water at room temperature and react even more rapidly with ethanol. Saturated azlactones are converted into thiohydantoins by ammonium thiocyanate,42-89~91 whereas unsaturated azlactones do not react with this reagent.89 RCH C=O NH4SCN RCH C=O N 0 RCON NF / c c R S Unsaturated azlactones are relatively stable to heat, whereas saturated azlactones undergo condensation reactions, often at room temperature. During this process liquid azlactones are converted into clear semi-solid waxes. The nature of the substituents has a marked effect on this reac- tion. 2-Phenyl-4,4-dialkyl-5-oxazolones are relatively stable, 2-phenyl- 89 Johnson and Scott, J. Am. Chem. Soc., 35, 1136 (1913). 90 Johnson and Scott, J. Am. Chem. Soc., 35, 1130 (1913). 91 Csonka and Nioolet, J. Biol. Chem., 99, 213 (1932). 214 ORGANIC REACTIONS 4-alkyl-5-oxazolones are less stable, and hippuric azlactone is quite un- stable, and only recently was prepared by heating hippuric acid with acetic anhydride.* R2C C=O RCH C=O CH2 C=O 0N C R V 0 \ /C R VI 0/ N \ /C R VII The difference in stability between V and VII suggests that the con- densation reactions brought about by heating may be of the aldol type, and it will be noted that in VI and VII the two unsaturated linkages flanking the 4-position produce highly active methine and methylene groups, respectively. In view of the presence in azlactones of type VI of a labile a-hydrogen atom it is not surprising that optically active substances of this type racemize very readily. So rapid is the process that an optically active azlactone never has been isolated. This property is the 'basis of two effective methods for the racemization of amino acids.44' 92>93 In one, the amino acid is heated in glacial acetic acid with 2 moles of acetic an- hydride. In the other, the sodium salt of the amino acid in aqueous solution is treated with a large excess of acetic anhydride at room tem- perature. The racemic acetyl derivative of the amino acid is produced by either procedure. Hydrolysis RCH C=O RCHCO2H | | + H2O -? | NO NH \ / I C COR R RCH=C C=O RCH=C¡ªCO2H 1 I I + H 2O -* | NO NH \ / I C COR R * Private communication from Drs. M. A. Spielman and A. W. Weston. 82 Bergmann and Koster, Z. physiol. Chem., 159, 179 (1926). M Bergmann and Zervas, Biochem. Z., 203, 280 (1928). AZLACTONES 215 Azlactones can be hydrolyzed to the corresponding acids with either alkaline or acidic37 reagents, the alkalies being considerably more effec- tive. The ease of the reaction depends to a marked extent upon the nature of the substituents on the oxazolone ring. Unsaturation in the 4-position or an aryl group in the 2-position stabilizes the molecule. Thus 2-methyl-4-benzyl-5-oxazolone is hydrolyzed by water at room temperature,26 2-methyl-4-benzal-5-oxazolone by boiling aqueous ace- tone,78 and 2-phenyl-4-benzal-5-oxazolone by boiling 1% aqueous sodium hydroxide.12 A solution of sodium hydroxide in aqueous methanol is an effective reagent for hydrolyzing azlactones.85' 94~96 It converts an azlactone into the a-acylamino ester, which is saponified. The reaction proceeds rapidly and under less drastic conditions than those required when aqueous alkali is used. In this connection it should be noted that pro- longed action of alkali may hydrolyze the a-acylaminoacrylic acid to the a-keto acid. Alcoholysis Unsaturated azlactones ordinarily do not react readily with hot alco- hols.* However, if either an acid 12> 97 or a base is added to the ethanol, the oxazolone ring is opened rapidly with the formation of an a-acyl- aminoacrylic ester. With sodium hydroxide or alkoxide the reaction is complete in three to five minutes at room temperature.6' '?36> 69> 98 With sodium carbonate as catalyst a short period of refluxing is required.99-10° Azlactones also react rapidly with higher alcohols in the presence of the sodium alkoxide.69 G4H9OH C4H9ONa> RCHCO2C4H9 | COR * 2-Phenyl-4-(2'-nitro-3'-methoxy-4'-acetoxybenzal)-5-oxazolone is an exception to this rule (see ref. 57). 94 Schmalfusz and Peschke, Ber., 62, 2591 (1929). 96 Lamb and Robson, Biochem. J., 25, 1231 (1931). 96 Slotta and Soremba, Bvr., 69, 566 (1936). "Harington and Barger, Biochem. J., 21, 169 (1927). 98 Posner and Sichert, Ber., 63, 3078 (1930). 99 Kropp and Decker, Ber., 42, 1184 (1909). 100 King and Stiller, J. Chem. Soc, 193T, 466. 216 ORGANIC REACTIONS Aminolysis, Synthesis of Peptides No systematic study has been made of the reaction of azlactones with amines. Conditions of a widely varying nature have been reported, and many of them obviously are far from optimum. However, the yields of amide or substituted amide are usually excellent, and many are prac- tically quantitative. RCH¡ª| N %- /C IR -C=01 H 0 V R'NHa -?* RCHCONHR' | NH |COR Saturated azlactones react quite vigorously with ammonia and amines.18'21> 26> **? 101 The reaction usually is effected by treating the azlactone with the pure amine or with an aqueous or ethanolic solution of the amine at room temperature. The rate of reaction of a saturated azlactone with aniline is markedly accelerated by the presence of a trace of an amine hydrochloride.88 Unsaturated azlactones react somewhat less readily with amines, and warming at 50-100° has been employed in many instances.7-8> 102 Occasionally the reaction has been effected at room temperature but with a longer reaction time.103 Much more drastic conditions have been employed, but there is no evidence that the severe conditions were essential.68 ?1M Acyldipeptides are produced by the reaction of an azlactone with an amino acid, and many have been synthesized in this way.26'103'106'106 The method consists in the addition of the azlactone to a solution of the amino acid in aqueous acetone containing an equivalent amount of sodium hydroxide. Excellent results are obtained with unsaturated RCH C=O | | + R"CHCO2Na -? RCHCONHCHCO2Na NO || \ / NH2 NH R" C | | COR' R' 101 Lettre and Fernholz, Z. physiol. Chem., 266, 37 (1940). J02Granacher and Gulbas, Helv. Chim. Ada, 10, 819 (1927). 108 Bergmann and Fruton, J. Bid. Chem., 124, 321 (1938). 101 Banerjee, J. Indian Chem. Soc, 9, 479 (1932). 106 Bergmann and Miekeley, Ann., 458, 40 (1927). m Behrens and Bergmann, J. Bid. Chem., 129, 687 (1939). AZLACTONES 217 azlactones and with many saturated azlactones. With certain saturated azlactones better yields are obtained 107 by heating the azlactone and the amino acid in acetic acid. Occasionally the ester of the amino acid has been employed 103'108 and the reaction carried out in ether, ethanol, or ethyl acetate. TYPES OF COMPOUNDS WHICH CAN BE PREPARED FROM AZLACTONES General Discussion Unsaturated azlactones furnish a convenient starting point in the syn- thesis of a variety of compounds, some of which are indicated below. ArCH=' C=O ArCH=CCO2H NH COR z-Acylaminoacrylio aoid NH COR a-Acylamino-propionic acid 1 I I ArCH2COCO2H ArCH2CHCO2H ArCH=CHNHCOR NH2 .-Keto acid i-Amino acid 1 ArCH2CO2H Arylacetio acid and ArCH2CN Arylacetonitrile Dihydroisoquinolinederivative Isoquinolinederivative Most of the reactions involve the intermediate formation of an a-acyl- aminoacrylic acid and hence are not strictly azlactone reactions. 107 Steiger, Helv. Chim. Ada, 17, 563 (1934). 108 Granacher and Mahler, Helv. Chim. Ada, 10, 246 (1927). 218 ORGANIC REACTIONS a-Amino Acids Unsaturated azlactones and acylaminoacrylic acids are converted to a-amino acids by reduction and hydrolysis. Three general methods of RCH=CCO2H RCH=< NH COR RCH2CHCO2H NH2 RCH2CHCO2H NH COR reduction which have been used for this conversion are: 1. Sodium or sodium amalgam and water or ethanol. 2. Hydriodic acid, red phosphorus, acetic acid (or acetic anhydride). 3. Catalytic hydrogenation (Pt or Pd). The reduction of a-benzoylaminoacrylic acids with an equivalent amount of 3% sodium amalgam as originally described by Erlenmeyer14 has been improved in several ways.109' n0 In a modification of the pro- cedure,110 a-benzoylaminopropionic acids are obtained in 62-80% yields by treating aqueous solutions of the sodium salts of a-benzoylamino- acrylic acids with a large excess of sodium amalgam. This method is not always satisfactory; 2-phenyl-4-(3',4',5'-trimethoxybenzal)-5-oxazolone is not reduced,111-112 and a-benzoylamino-|8-(4-methoxy-l-naphthyl)- acrylic acid gives only a 10% yield.113 a-Benzoylamino-/3-indoleacrylic acids 114~~116 and a-benzoylamino-/3-pyrroleacrylic acids 117 also are not reduced satisfactorily by sodium amalgam. However, reduction of the former is effected readily by the action of sodium and ethanol,116'116f 118'119 109 Fischer, Ber., 32, 3638 (1899). 110 Deulofeu, Armies soc. espaH. fis. quim., 32, 152 (1934). 111 Sonn, Miiller, Bulow, and Meyer, Ber., 58, 1103 (1925). m Schaaf and Labouohere, Helv. Chim. Ada, 7, 357 (1924). 113 Dey and Rajagopalan, Arch. Pharm., 277, 359, 377 (1939). 114 Restelli, Anales asoc. quim. argentina, 23, 58 (1935). 1MEUinger and Flamand, Ber., 40, 3029 (1907). u?EUinger and Flamand, Z. physiol. Chem., 55, 8 (1908). U7 Fischer and Zerweck, Ber., 56, 519 (1923). U8 Barger and Ewina, Biochem. J., 11, 58 (1917). m Ellinger and Matsuoka, Z. physiol. Chem., 91, 45 (1914). AZLACTONES 219 which also hydrolyzes a considerable proportion of the reduction product to the free amino acid. Tryptophanehas been synthesized by this pro- cedure.115 a-Phenylacetaminocinnamic acid is reduced to phenylacetyl- phenylalanine in 90-95% yield by sodium amalgam.16'120 Sufficient data are not available to show whether this result is unusual or whether phenylacetyl and perhaps other aliphatic derivatives also may give better results than the benzoyl derivatives in this reaction. The use of a mixture of hydriodic acid and red phosphorus as a reduc- ing agent for benzoylaminoacrylic acids was first reported97 in the syn- ' thesis of thyroxine, in which an alkaline agent could not be employed. The yields were improved markedly by adding acetic acid95 or acetic anhydride 121 to the reaction mixture. With the acetic anhydride-con- taining reagent the free amino acid is produced directly and alkylphenyl ether linkages are cleaved at the same time. The best results aje ob- tained from the acrylic acid or ester, although the azlactone can be used satisfactorily. Hydroxybenzaloxazolones, which are destroyed by alka- lies, are smoothly reduced by phosphorus, hydriodic acid, and acetic anhydride. This reagent has been applied successfully to a variety of compounds, the following amino acids being obtained in the yields indi- cated: phenylalanine, 65%;79 several methyl and dimethyl tyrosines, 61-78%;M o-, Wr, and p-fluorophenylalanines, 37, 78, and 41%, respec- tively; m dibromo- and dichloro-thyronines, 70-80%.m In the reduction of a-benzoylamino-/3-[4-(4'-nitrophenoxy)phenyl]-acrylic acid, the nitro group and the double bond are reduced and the benzoyl group is removed to give a-amino-/H4-(4'-aminophenoxy)phenyl]-propionic acid (yield 62%).96 Catalytic reduction has been used to a limited extent only.26'37>124'125 It seems likely that this method would be most satisfactory, except where other reducible or catalyst-poisoning groups may be present. Catalytic hydrogenation could not be used in the preparation of thyroxine m or for the reduction of pyrrole azlactones,69 Benzoylaminocrotonic azlactone is reduced smoothly over platinum catalyst in glacial acetic acid contain- ing 1 mole of water; the saturated azlactone first formed hydrolyzes immediately since it is much more reactive than the original compound.37 The conversion of an aldehyde to an amino acid containing two more carbon atoms can be effected in at least three other ways. These involve condensation of the aldehyde with hydantoin and its derivatives, with diketopiperazine, or with rhodanine. Since these methods have been 120 Erlenmeyer, Ber., 31, 2238 (1898). m Harington and McCartney, Biochem. J., 21, 852 (1927). 122 Schiemann and Roseliua, Ber., 65, 1439 (1932). 123 Schuegraf, Helv. Chim. Ada, 12, 405 (1929). m Harwood and Johnson, J. Am, Chem. Spc, 66, 468 (1934). m Herbst and Shemin, Org. Syntheses, Coll. Vol. 2,'491 (1943). 220 ORGANIC REACTIONS reviewed elsewhere,62'126' m they will notro discussed here. In general the azlactone synthesis is most satisfactory although in certain instances one or both of the other methods is preferable to it.128"131 Procedures. The preparation of d¡ê-j8-phenylalanine by the reduction and cleavage of a-benzoylaminocinnamic azlactone with phosphorus, hydriodic acid, and acetic anhydride, and the preparation of the same amino acid from a-acetaminocinnamic acid by catalytic reduction and hydrolysis, are described in Organic Syntheses.?-126 Reduction of a-Benzoylaminoacrylic Acids with Sodium Amalgam,}1" Ten grams of the acrylic acid is suspended in 100 cc. of water and reduced with 30-100 times the calculated amount of 3% sodium amalgam. The amalgam is added in 4 portions at fifteen-minute intervals. The reac- tion mixture is stirred vigorously for a period of two hours beginning with the first addition of the sodium amalgam. The mercury then is separated and the solution is filtered (if necessary), cooled in an ice bath, and acidi- fied with 10% hydrochloric acid. The saturated benzoyl derivative precipitates. It is filtered, washed with water, and recrystallized from acetic acid or water. The following a-benzoylaminoacrylic acids have been reduced to the saturated derivative in the yield indicated: a-ben- zoylaminocinnamic acid (82%); a-benzoylamino-p-methoxycinnamic acid (78%); a-benzoylamino-j3-furylacrylic acid (80%); a-benzoylamino- /3-(2,4>-dimethoxyphenyl)-acrylic acid (62%); a-benzoyIamino-/3-(3,4- methylenedioxyphenyl)-acrylic acid (74%). The saturated benzoyl derivatives are converted into amino acids in excellent yields by heating under reflux with 10-20% hydrochloric acid. a-Keto Acids Unsaturated azlactones and a-acylaminoacrylic acids are converted into a-keto acids by strong mineral acids or alkalies. RCH=C C=O RCH=CC02H| | -?? | -? RCH 2COCO2H +NO NH C COC6H5 1M Dunn in Schmidt, "Chemistry of the Amino Acids and Proteins," p. 51, Charles C. Thomas, Springfield, 1944. m Clarke in Gilman, "Organic Chemistry," 2nd ed., p. 1108, John Wiley & Sons, New York, 1943. 188 Deulofeu and Repetto, Anales soc. espaa. fis. quim., 32, 159 (1934). 129 Deulofeu, Z. physiol. Chem., 204, 214 (1932). 130 Deulofeu and Mendive, Z. physiol. Chem., 211, 1 (1932). 111 Deulofeu and Mendivebsua, Z. physiol. Chem., 219, 233 (1933). AZLACT0NE8 221 The initial cleavage may occur between the acrylic acid residue and the nitrogen atom yielding an a-keto acid and benzamide, or between the benzoyl group and nitrogen yielding an a-aminoacrylic acid and benzoic acid. In either case further hydrolysis of the nitrogen-containing frag- ment yields the final products. There is direct evidence favoring the first path. If the alkaline hydrolysis of 2-phenyl-4-benzal-5-oxazolone is stopped when the odor of ammonia is first evident, benzamide is ob- tained from the reaction mixture in 30% yield.11'132 However, there is one case in which the nitrogen remains in the hydrolysis product M- m' m as shown in the following equation. It is possible, of course, that both C6H6 reactions occur simultaneously and that various substituents may affect the relative rates. The conversion of unsaturated azlactones into a-keto acids can be effected by either strong alkalies (sodium, potassium, or barium hydrox- ide) or strong acids (usually hydrochloric) in aqueous or alcoholic solu- tions. Alkalies are much more effective and generally are used. The azlactone (or acylaminoacrylic acid) is refluxed with 10 volumes of 10% sodium or potassium hydroxide for four to six hours.8-40'71> m~m Occasionally 30-40% alkali is used with a shorter reaction time.138"140 Barium hydroxide in aqueous ethanol gives excellent results in a few cases but is unsatisfactory in others.77 This reagent has one advantage, namely, that the barium salts of a-keto acids often are insoluble in the reaction mixture. p-Hydroxybenzaloxazolones are hydrolyzed in an atmosphere of hydrogen in order to prevent oxidation of the pyruvic acids. Acids generally are less effective than bases as hydrolytic agents. They are used for aliphatic azlactones, which are more easily hydrolyzed, 132 PlSchl, Ber., 17, 1616 (1884). 133 Staler, J. Chem. Soc, 1937, 473. 184 Gulland and Virden, /. Chem. Soc., 1928, 921. 136 Hill and Short, J. Chem. Soc., 1937, 260. 186 Birch and Kobertson, /. Chem. Soc, 1998, 306. 137 Foster, Robertson, and Healy, J. Chem. Soc., 1939, 1594. 138Henze, Whitney, and Eppright, J. Am. Chem. Soc, 62, 565 (1940). 189 Canzanelli, Guild, and Harington, Biochem. J., 29, 1617 (1935). 140 Spath and Land, Monatsh., 42, 273 (1921). 222 ORGANIC REACTIONS or for aromatic azlactones which, because of the nature of substituent groups, are unstable toward alkalies. Aqueous hydrochloric acid has been used for 2-phenyl-4-ethylidene-37 and 2-phenyl-4-isopropylidene-5- oxazolone.70 Sulfuric acid (50%) or boiling ethanolic hydrochloric acid merely opens the azlactone ring of 2-phenyl-4-(2'-nitro-3'-methoxy-4'- acetoxybenzal)-5-oxazolone. However, the last reagent under pressure at 100° gives a 55% yield of a-keto ester.67 The conversion of nitroben- zaloxazolones into a-keto esters has been effected by the action of aqueous-ethanolic hydrochloric acid.141 In the preparation of a-keto acids from 2-phenyloxazolones, benzoic acid must be separated from the product. This separation has been effected by saturating the reaction mixture with sulfur dioxide, which forms a bisulfite addition product with the keto acid. Benzoic acid is then removed by nitration or extraction, and the keto acid is subse- quently regenerated. These operations are avoided by the use of 2- methyloxazolones,66'142 with the added advantage that the 2-methyl derivatives are converted more readily into keto acids than are the 2- phenyl derivatives. Thus, 90% yields have been reported 143 in the con- version of a series of 2-methyloxazolones to a-keto acids by alkaline hydrolysis to the acetaminoacryhc acids and conversion of these acids to a-keto acids with dilute hydrochloric acid. Abnormal Hydrolytic Products. 1. o-Nitrobenzaloxazolones. o-Nitro- benzaloxazolones undergo extensive decomposition when treated with alkali. The reactions are of two types, depending on the nature and posi- tion of other substituents. Unsubstituted o-nitrobenzaloxazolone yields o-nitrotoluene. The following mechanism has been suggested for this reaction.144 o-Nitrophenylpyruvic acids are known to undergo a reaction of this type,144 presumably due to vinylogous activation of the methylene CQ2H N°2 CO 2H group by the o-nitro substituent. The fact that w-nitrobenzaloxazolones give no nitrotoluene under the same conditions59 supports this interpre- tation. o-Nitrobenzaloxazolones with no substituents adjacent to the 141 Avenarius and Pschorr, Ber., 62, 321 (1929). 142 Sugasawa and Tsuda, J. Pharm. Soc. Japan, 55, 1050 (1935). 143 Niederl and Ziering, J. Am. Chem. Soc, 64, 885 (1942). 144 Burton and Stoves, J. Chem. Soc, 1937, 402. AZLACTONES 223 nitro group also decompose into toluene derivatives. However, the presence of an alkoxy group next to the nitro group leads to a different reaction as shown in the following equation.68 2-Phenyl-4-(2'-nitro-3'- CH2COCO2H NO2 c=o ?c=o CH3O CH3O methoxy^l'-acetoxybenzal)-5-oxazolone gives the isatin derivative but no aminovanillic acid.144 Several o-nitrobenzaloxazolones which decom- pose with alkali have been converted into the corresponding a-keto acids or esters by the use of ethanolic hydrochloric acid.141 2. o-Carboalkoxybenzaloxazolones. o-Carboalkoxybenzaloxazolones are converted into derivatives of isocarbostyril-3-carboxylic acid by refluxing CCO2H ?NH 10% aqueous potassium hydroxide.39' m- m If the reaction is carried out in methanol or ethanol the main product is an orthoester133 of the following structure. CC(OR)3 ?NH , 3. Miscellaneous Reactions, (a) The decomposition of azlactones to toluene derivatives, noted for o-nitrobenzaloxazolones, also has been reported for p-methoxybenzal-,138 2-methoxy-l-naphthal-,146 and 6-meth- oxy-3,7-dimethylcoumarilal-2-phenyl-5-oxazolones.137 (6) Cinnamaloxazolone on treatment with hydrochloric acid yields naphthalene and a-naphthoic acid.6'10 " 145 Mauthner, J. prakt. Chem., 95, 55 (1917). 224 ORGANIC REACTIONS Procedures. The preparations of phenylpyruvic acid by the hydroly- sis of a-acetaminocinnamic acid with 1 N hydrochloric acid and of 3,4- dimethoxyphenylpyruvic acid by the hydrolysis of a-benzoylamino-/3- (3,4-dimethoxyphenyl)-acrylic azlactone by 10%aqueous sodiumhydrox- ide are described in Organic Syntheses.14*-14T Hydrolysis with Barium Hydroxide.71 The azlactone (5 g.), barium hydroxide (20 g.), water (70 cc), and ethanol (10 cc, to prevent frothing) are heated in an oil bath under reflux until no more ammonia is evolved. The mixture is cooled, and the barium salt is filtered, washed with water, and decomposed to the arylpyruvic acid with dilute hydrochloric acid. Under these conditions 2-phenyl-4-(3'-methoxy-4'-benzyloxybenzal)- 5-oxazolone gives 3-methoxy-4-benzyloxypyruvic acid in 90% yield (ninety-six-hour reaction time); 2-phenyl-4-(3',4'-methylenedioxyben- zal)-5-oxazolone gives the pyruvic acid in 85% yield (reaction time not given); the aziactones derived from vanillin, m-hydroxybenzaldehyde, and p-hydroxybenzaldehyde give no arylpyruvic acid. Arylacetic Acids The conversion of substituted 4-benzaloxazolones to arylacetic acids is accomplished readily by hydrolyzing the aziactones to a-keto acids and oxidizing the ?,-keto acids with hydrogen peroxide. The intermediate a-keto acid usually is not isolated but rather is oxidized directly in the hydrolysis mixture. Na°H ArCH 2COCO2Na -^> ArCH2C02Na If a substituted 2-phenyloxazolone is used benzoic acid is produced, and it must be separated from the desired product. This separation has been effected by fractional distillation of the esters 146'148 or by steam distilla- tion of the benzoic acid. At least two other methods are available for preparing arylacetic acids from aromatic aldehydes. One involves the condensation of the aldehyde with rhodanine,62'im and the other160 involves the formation of the 146 Snyder, Buck, and Ide, Org. Syntheses, Coll. Vol. 2, 333 (1943). "'Herbst and Shemin, Org. Syntheses, CoU. Vol. 2, 519 (1943). 148 Cain, Simonsen, and Smith, J. Chem. Soc., 103, 1035 (1913). 149 Julian and Sturgis, J. Am. Chem. Soc., 57, 1126 (1935). ^Kindler, Metzendorf, and Dschi-yin-Kwok, Ber., 76, 308 (1943). AZLACTONES 225 cyanohydrin, which may be converted into the arylacetic acid in seyeral ways.160'161 Procedures. The preparation of 3,4-dimethoxyphenylacetic acid (homoveratric acid) is described in Organic Syntheses.146 4-Chlorophenylacetic Acid.m Five grams of 2-phenyl-4-(4'-chloroben- zal)-5-oxazolone is heated under reflux for five hours with 50 cc. of 10% aqueous sodium hydroxide. The solution is cooled in an ice bath and shaken vigorously while 25 cc. of 10% hydrogen peroxide is added slowly. The reaction mixture is allowed to stand overnight at room temperature and is acidified with dilute hydrochloric acid. The benzoic acid is re- moved by steam distillation, and the crude 4-chlorophenylacetic acid separates-when the residual solution is cooled. The crude product is recrystallized from petroleum ether, giving 1.8 g. (60%) of the pure material, m.p. 104-105°. Arylacetonitriles Arylacetonitriles also can be prepared from the a-keto acids obtained from azlactones. The a-keto acids are isolated from the hydrolysis mixture and converted into the oximes, from which the nitriles are ob- ArCH2COCO2H -? ArCH2CCO2H -^> ArCH2CN. II NOH tained by reaction with acetic anhydride. Good yields have been ob- tained with a variety of compounds.74- M1-143> IM-U? Procedures. 1. Conversion of Arylpyruvic Acids to the Oximes.1& Ap- proximately 1 mole of the arylpyruvic acid is dissolved in 800 cc. of a solution containing 2 mole equivalents of sodium hydroxide, and 1.5 moles of hydroxylamine is added. The solution is allowed to stand for thirty-six hours, and the oxime is precipitated by acidification with dilute hydrochloric acid. The yield of oxime is 95%. 2. Conversion of Oximes to Arylacetonitriles.14* The oxime is dehydrated by warming with 4 parts of acetic anhydride. Since the reaction is vio- lent the oxime is added in 3 portions to the warm reagent, the reaction being allowed to subside between additions. The nitriles are separated from the reaction mixture by fractional distillation in vacuum. The yields vary from 50 to 70%. 161 Krannichfeldt, Ber., 46, 4023 (1913). f m Mitter and Maitra, J. Indian Chem. Soc., 13, 236 (1936). ^Pfeiffer, Quehl, and Tappermann, Ber., 63, 1301 (1930).164 Buck, Baltzly, and Ide, /. Am. Chem. Soc., 60, 1789 (1938). ?* Robertson, J. Chem. Soc., 1933, 489. ""Haworth, Mavin, and Sheldrick, J. Chem. Soc., 1934, 1423. 226 ORGANIC REACTIONS 4-Methoxy-, 3,4-dimethoxy-, and 3,4-methylenedioxy-phenylaceto- nitriles have been prepared by the above methods. Miscellaneous Isoquinoline Derivatives. The preparation of derivatives of iso- carbostyryl from 2?carboalkoxybenzaloxazolones already has been dis- cussed. Derivatives of dihydroisoquinoline have been obtained indi- rectly from azlactones as shown in the following equations. CH3 I 157 CH CH3O CH=CCO2H cuCr2o4 NH COC6H6 C6H6 |CH==€HNHCOC?HB CH3O CH3O C6H6 Quinoline Derivatives. Imidazolones obtained from o-nitrobenzal- oxazolones give substituted diaminoquinolines on reduction.66 CH NHCOC6H6 CNHR N "'Sugasawa, J. Pharm. Soc. Japan, 55, 224 (1935). AZLACTONES 227 Imidazolone (Glyoxalone) Derivatives. Amides of a-acylamino- acrylic acids can be converted into imidazolone derivatives as shown in the equations: 0 ? RCH=C C=O R'NH2 RCH=C¡ªC¡ªNHR' RCH=C O=O NO NH ~* N NR'v ^ v A A R The ring closure can be effected under a variety of conditions. When R' = H the action of sodium hydroxide alone converts the amide into the imidazolone;6'8 when R' = ¡ªCH2R, heating above the melting point is required.108 Substituted anilides (R' = ¡ªCeH4R) have been converted into imidazolone derivatives by the action of phosphorus oxychloride.66' The conversion of amides of saturated a-acylamino acids into imidaz- olones has not been studied extensively.21"24 Benzoylphenylalanine amide M gives a poor yield; benzoylaminoisobutyric acid amide, a good yield.21 Certain imidazolone derivatives can be converted into dipeptides as follows.108 C6H6CH=C C=O Na.Hg C6H6CH2CH C=O H+ N NCH2CO2C2H5 > NH NCH2CO2C2H6 C6H6CH2CHCONHCH2CO2H + C6H6CHO NH2 Indole Derivatives. An indole derivative has been obtained from a substituted azlactone as shown in the following equation.168 This reac- tion has not been applied to other compounds. CH=C C=O CH8OH O2N(^ NH8 >N 0 NO2 V / ??Hffl and RobinBon, J. Chem. Soc, 1933, 486. 228 ORGANIC REACTIONS Styrylamides. Benzoylaminocinnamic acids can be decarboxylated to styrylamides by heating with copper chromite in quinoline at 120- 18O°.167'1M C6H6CH=CCO2H NH -> C6HBCH=CHNHCOC6H8 COC6H6 TABLES OF AZLACTONES AND DERIVED SUBSTANCES Those azlactones reported in the literature up to and including the 1944 Chemical Abstracts are listed in the following tables. Many of them were prepared as intermediates, and the substances to which they were converted are listed along with them. w Sugaisa-wa and Kakemi, J. Pharm. Soc. Japan, 55, 1283 (1935). AZLACTONES 229 TABLE I UNSATT7BATED AZLACTONES A. 8-Phenylr4-benzalr5-oxazolones Substituted Benzaldehyde EJnsubstituted 3-Methyl 4-Methyl 4-Isopropyl 2-Styryl 2-Fluoro 3-Fluoro 4-Fluoro 2-Chloro 3-Chloro 4-Chloro 3-Bromo 3-Fluoro-4-methoxy 3-Fluoro-4-ethoxy 3,5-Difluoro-4-methoxy 3-Chloro-4,5-dimeth- oxy 2-Brojno-4,5-dimeth- oxy 4-(4'-Iodophenoxy)2-Fluoro-4-(4'-meth- oxyphenoxy) 3,5-Dichloro-4-(4'- methoxyphenoxy) 3,5-Dibromo-4-(4'- methoxyphenoxy) 3,5-Diiodo-4-(2'- methoxyphenoxy) 3,5-Diiodo-4-(3'- methoxyphenoxy) 3,5-Diiodo-4-(4'- methoxyphenoxy) 3,5-Diiodo-4-(3'- fluoro-4'-methoxy- phenoxy) 3,5-Diiodo-4-(3',5'- difluoro-4'-meth- oxyphenoxy) 5-Chloro-3-methoxy- 4-hydroxy Azlactone References and Yields 79 (64%), 1 (80%), 2,3, 12- 14, 35, 36, 69, 77, 85, 95, 102, 103, 108, 110, 121, 132, 133, 160-166 167 168 (80%), 166 6 (80%), 169 170 UB%) 122 (35%) 122 (70%) 122 (75%), 171 145 172 (75%), 173 174 (79%), 145 145 175 (95%), 176-178 178 (65%), 176 177 (50%), 175 179 156 96 (70%) 178 (89%), 176 123 (80-85%) 123 (80%) 180 (95%) 181 (95%) 97 (90%), 121, 182 183 (90%) 177 (60-66%) 184 t (80%) Pyruvic 12, 77, 147 (90%) 173 (77%) 174 156 184 (49%) Derived Acids Acetic 160 (65%) 145 173 (57%) 145 (60%) 145 156 Amino 14, 79 (65%), 95 (8?%), 110, 121 (88%), 161, 164 / 167 (60%) 168 122 (37%) 122 (78%) 122 (41%) 172 174 175-178,* 177* (77%) 176,* 178 * (88%) 175,* 177 * (77%) 96 176,* 178 * (85%) 123 * (80%) 123 * (70-80%) 180 * (12%) 181 * (S9%) 97,* 121 * (82%) 183 * (42%) 177 * (66%) References 160-248 appear on pp. 238-239. * Alkoxyl group replaced by hydroxyl. t Hydroxyl group acetylated during azlactonizatio 230 ORGANIC REACTIONS TABLE I¡ªContinued UNSATTJBATED AZLACTONES Substituted Benzaldehyde 6-Chloro-3-methoxy- 4-hydroxy S,6-Dichloro-3-meth- oxy-4-bydroxy 5-Bromo-3-methoxy- 4-hydroxy 6-Bromo-3-methoxy- 4-hydroxy 5,6-Dibromo-3-meth- oxy-4-hydroxy 2,5,6-Tribromo-3- metho(xy-4-hydroxy 5-Bromo-3,4-dimeth- oxy 5-Iodo-3-methoxy-4- hydroxy 2-Methoxy 3-Methoxy 4-Methoxy 2,3-Dimethoxy 2,4-Dimethoxy 2,5-Dimethoxy 3,4-Dimethoxy 3,4-Methylenedioxy 3,4-Carbonyldioxy 2,3,5-Trimethoxy 2,4,5-Trimethoxy 2,4,6-Trimethoxy 3,4,5-Trimethoxy 4,5-Dimethoxy-2- methoxymethoxy . 2-Methoxy-3-methyl 4-Methoxy-3-methyl 2-Methoxy-5-ethyl 4,5-Dimethoxy-2-ethyl 2,3-Dimethoxy-5-n- propyl Azlactone References and Yields 184 t (68%) 184 t (62%) 184 t (70%) 184 t (71%) 184 t (61%) % 184 t (7?%) 184 (68%) 184 t 60, 160, 185 1*86 (53%), 60 187 (80%), 8, 60, 77, 95,102, 110, 121, 138, 148, 160, 188 189 (60%), 185, 190 110 (71%), 152, 191 40 (75%), 112 80 (69-73%), 76, 99, 124, 131,153,156,157,192,193 76 (70%), 56, 77, 99, 110, 160, 193-198 199 (74%) 200 (95%) 201 202 75 (85%), 74, 111 203 (79%) 135 (/0O%) 204 (70%) 134 205 (66%) 206 (61%) Pyruvic 184 (47%) 184 (37%) 184 (43%) 8, 77 (23%) 138, 148 190 152 40 (76%) 90, 146 (80%) 153, 156, 192 77 (85%), 99, 194, 195 201 74, 75 135 134 (70%) 205 (7/%) 206 Derived Acids Acetic 160, 185 186 (60%) 148, 160 (80%) 189 (66%), 185, 190 152, 191 (60%) 40 (80%) 146 (61%), 153, 156, 192 160 (90%), 195 200 201 202 (6/%) 74, 75 203 (57%) 135 134 (S5%) 205 (78%) 206 (83%) Amino 95,* 110, 121 * (60%), 187 110 (62%) 112* 124, 131, 193 110 (74%), 193, 196 199 t (76%) 204 * (66%) References 160-248 appear on pp. 238-239. * Alkoxyl group replaced by hydroxyl. t Hydroxyl group acetylated during azlactonization. t Carbonylaioxy group hydrolyzed. AZLACTONES 231 TABLE I¡ªContinued UNSATTJRATEB AZLACTONES Substituted Benzaldehyde 2-Ethoxy 3-Ethoxy 4-Ethoxy 2-Ethoxy-3-methoxy 3-Ethoxy-4-methoxy 4-Ethoxy-3-methoxy 3,4-Diethoxy 4-Phenoxy 3-Phenoxy-4-hydroxy 3-Benzyloxy 2-Benzyloxy 3-Benzyloxy-4-meth- oxy 4-Benzyloxy-3-meth- oxy 3,4-Dibenzyloxy 4-(4'-Methoxy- phenoxy) 2-Carbethoxymethoxy 2-Carbethoxymethoxy- 4-methoxy 2-Carbomethoxy-3,4- dimethoxy 2-Carbomethoxy 2-Hydroxy-4-methoxy 3-Hydroxy-4-methoxy 4-Hydroxy-3-methoxy 5-Hydroxy-3,4-d!- methoxy 2-Hydroxy 3-Hydroxy 4-Hydroxy 2,4-Dihydroxy 2,5-Dihydroxy 3,4-Dihydroxy 4-Hydroxy-2-methyl 4-Hydroxy-3-methyl 4-Hydroxy-2,3-di- methyl 4-Hydroxy-3,5-di-methyl 4-Hydroxy-2,5-di- methyl Azlactone References and Yields 154 (65%) 154 (86%) 154 (66%) 154 (65%) 72 (82%), 73 73 (87%) 154 (85%) - 96 (85%) 207 t (75%) 71 (74%) 185 (63%) 208 (7.8%), 194,209 77 (80%) 194 (60%) 121 (70%) 155 (54%) 155 (83%) 39 39, 133 155 t 140 t (78%), 128 X 121 X (75%), 160,1: 2044 210,1211 X 212 t (38%) 74 294 60-62,1 213 t 8,X 60,t 172.J 213 t 4 t(85%),9,t 60,J69,t 103.J 1094 1604 214 t 634 155 t 64 t (.43%) 131 t (65%), 210 t 94 X (73%) 94 X 94 X (77%) 94 f (95%) 94 X (71%) Pyruvic 154 (66%) 154 (55%) 154 (65%) 154 (55%) 73(71%) 73 (71%) 154 (55%) 71 (65%) 185 194 (6i%), 208, 209 77 (90%) 194 (0%) 155 t 155 t (83%) 140 (24%) 7 214 (36%) 64 Derived Acids Acetic 154 154 154 154 72, 73 (98%) 73 (S8%) 154 71 (90%) 185 208, 209 (88%), 77 155 t 155 t 140 160 212 (36%) 160 (80%) Amino 96 (70%) 207 (60%) 121 * (8/%) 128 (86%) 121 * (60%), 204,* 210,* 211 213 (?5%) 213 (86%) 4, 103, 109 (67%) 131 94 (81%) 94 94 (78%) 94 (65%) 94 (72%) References 160-248 appear on pp. 238-239. * Alkoxyl group replaced by hydroxyl. t Carbethoxy group hydrolyzed. % Hydroxyl group acetylated during azlactonization. 232 ORGANIC REACTIONS TABLE I¡ªContinued UNSATURATED AZLACTONES Substituted Benzaldehyde 2-Nitro 3-Nitro 4-Nitro 2-Nitro-5-methoxy 3-Nitro-4-methoxy 2-Nitro-3,4-dimethoxy 2-Nitro-4,5-dimethoxy 2-Nitro-3,4-methyl- enedioxy 2-Nitro-5-benzyloxy 2-Nitro-5-hydroxy 5-Nitro-3-methoxy-4- hydroxy 2-Nitro-3-methoxy-4- hydroxy 3,5-Dinitro-2-methoxy 3,5-Dinitro-2-hydroxy 4-(4'-Nitrophenoxy) Azlactone References and Yields 59 (61%), 56, 166, 169 77 (76%), 59, 166 59, 77, 166 59 (84%) -215 58 (75%), 39, 141 76 (89%), 169 56 (35%), 39 59 (59%) 59 * (65%) 111 * (80%) 57 * (J&%), 39, 144 158 (66%) 158 (85%) 96 (82%) Derived Acids Pyruvic 59 (0%), 169 77 (0%) 59 (0%) 58 (0%), 141 76 (0%), 169 59 (0%) 59 (0%) 57 (53%) 144 (0%) Acetic 141 ? Amino 96 t (6S%) B. %-Phenyl-4-indolal-5-oxazoloneg Carbonyl Component 2-Indolealdehyde 3-Indolealdehyde 3-Oxindolealdehyde l-Methyl-3-oxindole- aldehyde Ethyl 3-oxindolegly- oxylate Substituted 3-indole- aldehyde 2-Carbethoxy (methoxy) 2-Methyl 5-Methyl 1-Methyl Azlactone References and Yields 114 (1-acetyl) 116 (80%), 114, 115, 133; 1-acetyl 216 (83%), 69, 114 217, 218 t 217 t (S0%) 218 100 (80%), 219 119 (89%), 118 220 (0%) 221 Derived Acids Pyruvic 216 (90%?) Acetic Amino 114 (0%), 115, 116 118 (40%), 119 221 References 160-248 appear on pp. 238-239. * Hydroxyl group acetylated during azlactonization. t Nitro group reduced to amino. t The structures of these azlactones have not been established completely. AZLACTONES TABLE I¡ªContinued UNSATURATED AZLACTONES C. 2-Phenyl-4-pyrrolalr5-oxazolones 233 Carbonyl Component 2-Pyrrolealdehyde Substituted 2-pyrrole- aldehyde 3,5-DimethyI-4-ethyI 3,5-Dimethyl-4 (2'-car- bethoxy-2'-cyano)- vinyl Substituted 3-pyrrole- aldehyde 2,4,6-Trimethyl 2,o-Bimethyl-4-car- bethoxy-1-phenyl 2,5-Dimethyl-4-car- bethoxy-1-p-tolyl 2,4-Dimethyl-5-car- boalkoxy Azlactone References and Yields ? 222 69 (83%) 223 117 217 217 224 (62%), 69 Pyruvio Derived Acids Acetic Amino D. S-Phenyl-4-substitiUed-S-oxazolones Derived from Other Aromatic Ring Systems 1-Naphthaldehyde 2-Methoxy-l-naph- . thaldehyde 4-Methoxy-l-naph- thaldehyde 3-Pyrenealdehyde Furfural Phthalic anhydride 3-MethyI-6-methoxy- 2-benzofuranalde- hyde 3,7-Dimethyl-6-meth- oxy-2-benzofuran- aldehyde 3-Methyl-4,6-dimeth- oxy-2-benzofuran- aldehyde 3,5-Dimethyl-4,6-di- methoxy-2-benzo- furanaldehyde 6-Formylcoumarin 2-Thiophenealdehyde 4-Methyl-5-thiazole- aldehyde 4-Imidazolealdehyde 145 (38%) 145 (*S%) 113 (43%), 145 225 (77%) 172 (70%), 7, 98, 110,226 2, 227 137 (86%) 137 (89%) 136 136 (73%) 104 (60%) 228 (70%), 68 229 (70%), 230 53 (72%) (1-acetyl) 137 (50%) 137 00%) 136 (83%) 136 104 145 145 145 137 (69%) 136 (95%) 136 113 225 (Good) 110 (Good), 172, 226 68 (66%), 228 229 (70%), 230 53 References 160-248 appear on pp. 238-239. 234 ORGANIC REACTIONS TABLE I¡ªContinued UNSATTJRATED AZLACTONES E. bis-S-Phenyl-6-oxazolones Carbonyl Component Terephthalaldehyde Isophthalaldehyde Dinitroisophthalalde- hyde 2,2'-Dimethoxy-5,5'- diformyldiphenyl- , ether Azlactone . References and Yields 231 (97%) 231 231 (es%) 232 Derived Acids Pyruvic 231 (0%) Acetic Amino F. S~Phenyl-4-alkylidene-5-oxazolones Acetaldehyde Acetone Isobutyraldehyde Perilla aldehyde Cinnamaldehyde ot-n-Amylcinnamalde- hyde 37 (.20%), 34, 81 70 (40%), 81 5 67 (97%) 6, 10 67 (80%), 233 70, 81 10 (0%) 37 (80%) 5 G. %-Methyl-4-benzal~5-oxazolones Substituted Benzaldehyde Unsubstituted 5-Chloro-3-methoxy- 4-hydroxy 5-Chloro-3,4-dimeth- oxy 5-Bromo-3-methoxy- 4-hydroxy 5-Bromo-3,4-dimeth- oxy 3-Bromo-3-methoxy-4- hydroxy 5-Iodo-3-methoxy-4- hydroxy Azlactone References and Yields 78 (75%), 13, 26, 27, 33, 65, 83-85, 87, 105-108, 125, 162, 165, 184, 234 184 * (55%) 184 184 * (72%) 184 (70%) 184* 184 * (27%) Derived Acids Pyruvic 13, 65, 147 (00%) Acetic Amino 125 (94%) References 160-248 appear on pp. 238-239. * Hydroxyl group acetylated during azlactonization. AZLACTONES 235 TABLE I¡ªContinued UNSATURATED AZLACTONES ? Substituted Benzaldehyde 3,5-Diiodo-4-(4'-meth- oxyphenoxy) 3,5-Diiodt>4-[3',5'- diiodo-4'-(4"-meth- oxyphenoxy)-phen- oxy] 4-Nitro 2-Methoxy 4-Methoxy 3,4-Dimethoxy 3,4-Methylenedioxy 2-Hydroxy 4-Hydroxy Azlactone References and Yields 139 (92%) 235 (80%) 68 (96%) 82 143 (SS%), 142 143 (S6%), 142 65 (57%), 54, 142, 143 65 t (50%) 65 t (72%), 33, 87 ; Derived Acids Pyruvic 139 ? 142, 143 (90%) 142, 143 (00%) 142, 143 (90%) Acetic 142, 143 142, 143 142, 143 Amino 235 * (Poor) H. Miscellaneous Unsaturated Azlactones 5-Oxazolone t 4-(4'-Methyl-5'-thia- zolylmethylene)-2- methyl 4-Formal-2-methyl 4-Formal-2-ethyl 4-Isobutylidene-2- methyl 4-Benzal-2-chlorc- methyl 4-Benzal-2-benzyl 4-(3'-Methoxy-4'-hy- droxybenzal-2-o- bromophenyl References and Yields 236 (27%) 83 33 16S (70%) 86 (56%) 15 (37%), 120 184 t (61%) Pyruvic 83 Derived Acids Acetic Amino 86 15 (90%), 120 References 160-248 appear on pp. 238-239. * Alkoxy group replaced by hydroxyl. t Hydroxyl group acetylated during azlactonization. t A group of azlactones derived from acylated peptides of a-aminocinnamic acid has been described. (See refs. 165 and 237.) These compounds are of the general type: ~CHC6H6)¡ªCO CH3, CeHs and x = 0, 1, 2, 3 236 ORGANIC REACTIONS TABLE I¡ªContinued UNSATTTRATED AzkACTONES v 5-Oxazolone 4-(3'-Methoxy-4'-hy- droxy-o'-bromoben- zal) -2-o-bromo- phenyl 4-(3'-Methoxy-4'-hy- droxy-6'-bromoben- zal)-2-o-bromo- phenyl 4-(3'-Methoxy-4'-hy- droxy-5',6'-dibromo- benzal) -2-&-bromo- phenyl 4-(3'-Methoxy-4'-hy- droxy-2',S',6'-tri- bromobenzal)-2-o- bromophenyl 4-(3',4'-Diethoxyben- zal)-2-(3',4',5'-tri-methoxyphenyl) 4-(3'-Isopropoxy-4'- methoxybenzal) -2- (3',4',5'-trimethoxy- ? phenyl) 4-(3'-n-Propoxy-4'- methoxy benzal) -2- (3',4',S'-trimethoxy- phenyl) Keferences and Yields 184 * (65%) # 184 * (82%) 184 * (6*%) 184 * (¡ê8%) 1S7 (00%) 159 159 Derived Acids Pyruvio Acetic Amino 1 References 160-248 appear on pp. 238-239. * Hydroxyl group aoetylated during azlactonization. AZLACTONES TABLE II SATURATED AZLACTONES A. S-Phenyl-4-substituted S-oxazolones 237 4-Substituents None Methyl Dimethyl Benzyl . 4'-Methoxybenzyl Methyl, benzamido 3-Pyrenylmethyl Azlactone References and Yields 238, 239 22 {95%), 19, 89, 101, 240 21 (95%), 18, 108, 162 19, 24, 38 34 (66%) 50 225 Dipeptides 19, 22, 101, 240 21, 108 19,24 50 B. 2-MethyL4-8ubstituted S-oxazolones Methyl Isobutyl Dimethyl Methyl, ethyl Methyl, acetamido Methyl, phenyl Benzyl 3',5'-Diiodo-4'-acetoxybenzyl 23, 91 26,84 21, 41 41 25 (85%), 241 41 (72%), 107 26 (54%), 38, 84, 107 45 26 25 41, 107 26, 107 C. Miscellaneous Saturated Azlactones 5-Oxazolone 2-CH3CO-NH-CH2-4,4-CH3,CH3 ' 2-CH3CONHCH(CH3)-4,4-CH3,CH3 2-CH3CONHCH (C6H6CH2)-4,4- 2-C6H6CONHCH(CH3)-4,4-CH3,CH3" 2-CH3CONHC(C6H5) (CH,)- 2-CH3CONHC(C6HB) (CH3)-4-CH3 2-CH3CONHC (C6H6) (CH3)-4,4- 2-Pyrenyl-4-methyl 2-(p-Nitrophenyl)-4-isobutyl 2- (p-Phenylazophenyl)-4-isopropyl 2-(p-Phenylazophenyl)-4-isobutyl References 107 107 107 19, 22 107 107 107 225 242 243 243 References 160-248 appear on pp. 238-239, 238 ORGANIC REACTIONS TABLE III COMPOUNDS NOT DEFINITELY ESTABLISHED AS AZLACTONES 5-Oxazolone 2-Methyl-4-carboxymethyl 2-Phenyl-4-carboxymethyl i 2-CH3-4-HO2CCH2CH2- 2-Methyl-4-N-acetylimidazolemethyl . 2-Phenyl-4-imidazolemethyl 2-Phenyl-4-m-benzoylphenyl 2-CH3CH2-4-HO2CCH= 2-C6H6-4-CH3C(CO2H)== References ... 26, 43, 84 244 42, 93 28 245 246 247 66, 248 REFERENCES TO TABLES 180 Mauthner, Ann., 370, 368 (1909). 161 Erlenmeyer, Ber., 30, 2976 (1897). 162 Heller and Lauth, Ber., 52, 2295 (1919).; 163 Nicolet, /. Biol. Chem., 95, 389 (1932). 164 Erlenmeyer and Kunlin, Ann., 307, 146 (1899). 165 Doherty, Tietzman, and Bergmann, J. Biol. Chem., 147, 617 (1943). 168 Vanghelovioi and Stefanescu, C. A., 38, 5501 (1944). 167Bohm, Z. physiol. Chem., 89, 101 (1914): 168 Dakin, J. Biol. Chem., 9, 151 (1911). 169 Red'kin and Shemyakin, J. Gen. Chem. U.S.S.R., 11, 1175 (1941). 170 Natelson and Gottfried, J. Am. Chem. Soc, 63, 487 (1941). 171 Schiemann, Winkelrauller, and Roselius, Ger. pat. 621,862, Nov. 14, 1935. i72Flatow, Z. physiol.'Chem., 64,"367 (1910). 173 Buck and Ide, /. Am. Chem. Soc, 54, 3302 (1932). 174 Friedmann and Maase, Biochem. Z., 27, 97 (1910). 176 English, Mead, and Niemann,/. Am. Chem. Soc., 62, 350 (1940). 176 Schiemann, Winkelmuller, and Roselius, Ber., 66, 1435 (1932). 177 Niemann, Benson, and Mead, J. Am. Chem. Soc, 63, 2204 (1941). 178 Schiemann and Winkelmuller, J. praU. Chem., 135, 101 (1932-1933). 179 Hann, /. Wfish. Acad. Sci., 24, 464 (1934). 180 Niemann and Mead, /. Am. Chem. Soc, 63, 2685 (1941). 181 Niemann and Redemann, J. Am. Chem. Soc, 63, 1549 (1941). 182 Savitzkii, Mid. exptl. Ukraine, No. 1, 39 (1934). 183 Niemann, Mead, and Benson, J. Am. Chem. Soc., 63, 609 (1941). : 184 Raiford andi Buurman, /. Org. Chem., 8, 466 (1943). 185 Bergel, Haworth, Morrison, and Rinderknecht, J. Chem. Soc, 1944, 261. 18?Psehorr, Ann., 391, 40 (1912). 187 Dakin, J. Biol. Chem., 8, 11 (1910). 188 Vanghelovici and Moise, C. A., 38, 5500 (1944). 189 Spath and Mosettig, Ann., 433, 138 (1923). 190 Chakravarti and Swaninathan, J. Indian Chem. Soc, 11, 107 (1934). 191 Pschorr and Knoffler,.4nn., 382, 50 (1911). m Haworth, Perkin, and Rankin, J. Chem. Soc, 125, 1686 (1924). AZLACTONES 239 193 Narang, Ray, and Saohdeva, J. Indian Chem. Soc, 13, 260 (1936). 194 Schopf, Brass, Jacobi, Jordl, Macnik, Neuroth, and Slazer, Ann., 544, 30 (1940). m Buck and Perkin, J. Chem. Soc, 125, 1675 (1924). 198 Deulofeu and Mendive, Anales asoc. quim. argentina, 21, 100 (1933). 197 Labruto and Irrera, Gazz. chim. ital., 64, 136 (1934). 198 Labruto and Irrera, Gazz. chim. Hal., 65, 1201 (1935). 199 Funk, J. Chem. Soc., 99, 554 (1911). 200 Smith and LaForge, J. Am. Chem. Soc, 53, 3072 (1931). 201 Sugasawa and Sigehara, Ber., 74, 459 (1941). 202 Freudenburg and-Harder, Ann., 451, 213 (1926-1927). m Smith and LaForge, J. Am. Chem. Soc, 56, 2431 (1934). 204 Fromherz and Hermanns, Z. physiol. Chem.,*91, 194 (1914). 206 Barger and Silberschmidt, /. Chem. Soc, 1928, 2919. 206 Freudenberg and Richtzenhain, Ann., 552, 126 (1942). ^Ungnade and Orwoll, /. Am. Chem. Soc, 65, 1736 (1943). 208 Robinson and Sugasawa, J. Chem. Soc, 1931, 3163. 209 Schopf, Perrey, and Jackl, Ann., 497, 47 (1932). 210 Sugii, J. Pharm. Soc Japan, 468, 130 (1921). m Waser, Helv. Chim. Ada, 8, 117 (1925). ^Mauthner, Ann., 449, 102 (1926). 213 Blum, Arch, exptl. Pathol. Pharmakol., 59, 269 (*808). 214 Neubauer and Fromherz, Z. physiol. Chem., 70, 326 (1910-1911). 216 McRae and Hopkins, Can. J. Research, 7, 248 (1932). 2" Ellinger and Matsuoka, Z. physiol. Chem., 109, 259 (1920). 217 Fischer and Smeykal, Ber., 56, 2368 (1923). *? Homer, Ann., 548, 117 (1941). 219 Fischer and Pistor, Ber., 56, 2313 (1923). 220 Robson, /. Biol. Chem., 62, 495 (1924). 221 Wieland, Konz, and Mittasch, Ann., 513, 1 (1934). 222 Asahina and Mitsunaga, J. Pharm. Soc. Japan, 1917, No. 429, 986. 223 Fischer and Wasenegger, Ann., 461, 277 (1928). 224 Fischer, Weisz, and Schubert, Ber., 56, 1194 (1923). ^Lettre, Buchholz, and Fernholz, Z. physiol. Chem., 267, 108 (1941). 226 Deulofeu, Anales asoc quim. argentina, 20, 190 (1932). 227 Erlenmeyer, Ber., 22, 792 (1889). 228 Barger and Easson, J. Chem. Soc, 1938, 2100. 229 Buchman and Richardson, J. Am. Chem. Soc, 61, 891 (1939). 280 Harington and Moggridge, J. Chem. Soc, 1939, 443. 231 Ruggli and Schetly, Helv. Chim. Ada, 23, 718 (1940). 232 Robinson and Sugasawa, /. Chem. Soc, 1931, 3173. 233 Rutowski and Korolew, J. prakt. Chem., 119, 272 (1928). 234 Behrens, J. Biol. Chem., 136, 61 (1940). 236 Bovarnick, Bloch, and Foster, J. Am. Chem. Soc, 61, 2472 (1939). 236 Harington and Moggridge, Biochem. J., 34, 685 (1940). 237 Tietzman, Doherty, and Bergmann, J. Biol. Chem., 151, 387 (1943). 238 Karrer and Widmer, Helv. Chim. Ada, 8, 203 (1925). 239 Karrer and Bussmann, Helv. Chim. Ada, 24, 645 (1941). 240 Lettre and Haas, Z. physiol. Chem., 266, 31 (1940). 241 Bergmann and Grafe, Z. physiol. Chem., 187, 183 (1930). 242 Karrer and Keller, Helv. Chim. Ada, 26, 50 (1943). 243 Karrer, Keller, and Szonyi, Helv. Chim. Ada, 26, 38 (1943). 244 Pauly and Weir, Ber., 43, 661 (1910). 245 Kuster and Irion, Z. physiol. Chem., 184, 225 (1929). 248 Minovice and Thuringer, Bui. Soc Chim. Romdnia, 2, 13 (1920). 247 Bergmann, Kann, and Miekeley, Jinn., 449, 135 (1926). 248 Hoffmann, Ber., 19, 2554 (1886). CHAPTER 6 SUBSTITUTION AND ADDITION REACTIONS OF THIOCYANOGEN JOHN L. WOOD* Cornell University Medical College CONTENTS PAGE INTRODUCTION 241 SCOPE AND LIMITATIONS 242 , Thiocyanation of Aromatic Amines 243 Thiocyanation of Phenols . . ?? ', 245 Thiocyanation of Polynuclear Hydrocarbons 246 Addition of Thiocyanogen to Olefins and Acetylenes 246 Miscellaneous Syntheses with Thiocyanogen 247 OTHER METHODS OF SYNTHESIS OP THIOCTANO COMPOUNDS 249 USE OF THIOCYANATES IN SYNTHESIS 250 EXPERIMENTAL CONDITIONS 251 Free Thiocyanogen 1 Thiocyanogen Generated from Salts by Electrolysis 252 Thiocyanogen Generated from Salts by Chemical Reagents 253 Detection of Thiocyano Compounds 254 EXPERIMENTAL PROCEDURES 255 Thiocyanogen Solutions ? 255 Styrene Dithiocyanate 6 p-Thiocyanoaniline 256 9,10-Dithiocyanostearic Acid 256 2-Amino-4,6-dimethylbenzothiazole 256 N,N-Dimethyl-4-thiocyanoaniline 7 4-Thiocyano-l-naphthol 257 2-Amino-6-ethoxybenzothiazole 257 SURVEY OF SYNTHESES WITH THIOCYANOGEN 257 TABLE I. Aromatic Amines Substituted by Thiocyanogen 258 II. Phenols Substituted by Thiocyanogen 262 III. Polynuclear Hydrocarbons Substituted by Thiocyanogen 263 IV. Unsaturated Compounds that Add Thiocyanogen 263 V. Miscellaneous Compounds Substituted by Thiocyanogen 265 * Present address, School of Biological Sciences, The Medical School, University of Tennessee, Memphis, Tenn. 240 REACTIONS OF THIOCYANOGEN 241 INTRODUCTION The direct replacement of a hydrogen atom by a thiocyano group through the use of thiocyanogen, (SCN)2, is commonly termed thiocya- nation. This replacement reaction is limited practically to aromatic RH + (SCN)2 -? RSCN'+ HSCN amines and phenols, although a few particularly reactive aromatic hydrocarbons can be* thiocyanated. Thiocyanogen reacts with olefinic and acetylenic linkages, the reagent adding to the unsaturated linkage. R2C¡ªCR2 R2C=CR2 + (SCN)2 -> | | NCS SON Thiocyanogen reacts also with compounds of other types; it can replace a hydrogen atom attached to sulfur or nitrogen, it can replace the heavy- metal atom of certain organometallic compounds, and it can add to the triaryl derivatives of arsenic, antimony, and bismuth. ArSH + (SCN)2 -> ArSSCN + HSCN 2R2NH + (SCN)2 -* R2NSCN + R2NH2SCN 2R0NHR + (SCN)2 -> RONRSCN + RONH2RSCN R2Zn + 2(SCN)2 -?? 2RSCN + Zn(SCN)2 Ar2Hg + (SCN)2 -> ArSCN + ArHgSCN Ar3Sb + (SCN)2 -> Ar3Sb(SCN)2 The reagent is used in synthesis in essentially the same way as the halogens, with the exception that certain precautions must be observed owing to the instability of thiocyanogen. Thiocyanogen is a liquid which on cooling forms a colorless, crystalline solid melting between ¡ª3 and ¡ª 2°.1 At room temperature it polymerizes rapidly to a reddish orange, amorphous mass of indefinite composition known as pseudo- or para-thiocyanogen. Although relatively stable in inert, dry solvents, jihiocyanogen may polymerize in solution, especially under the catalytic influence of heat, light, moisture, or oxygen. Thiocyanogen is readily hydrolyzed to produce thiocyanic acid and hypothiocyanous acid. (SCN)2 + H2O -? HSCN + HOSCN The latter acid is unstable and is converted into hydrocyanic acid and sulfuric acid, both of which occur as end products of the overall hydroly- 3(SCN)2 + 4H2O -> 5HSCN + HCN + H2SO4 ' 1 S6derback, Ann., 419, 217 (1919). 242 ORGANIC REACTIONS sis. The quantitative relationships of the process are complicated by- side reactions. The extreme sensitivity of thiocyanogen toward hydrolysis and poly- merization probably accounts for the long interval between its formula- tion by Berzelius and its preparation by Bjerrum and Kirshner2 and by Soderback.1' * For this same reason, when thiocyanogen is employed in chemical reactions, it is prepared in solution and more commonly is produced in situ. Thiocyanogen is often classified as a pseudohalogen because of its re- semblance to halogens in its chemical behavior.1'3 It attacks even noble metals like gold and mercury;2 it reacts with nitric oxide,1 aqueous hydrogen sulfide,4 hydrazoic acid,6 ammonia,6 and hydrochloric acid.1'7 It is released from metal thiocyanates by the action of chlorine, bromine, and other oxidizing agents. Halogen-thiocyanogen combinations are formed with chlorine 8i 9> 10 and with iodine.11'12 Thiocyanogen is similar to iodine in its chemical reactivity but is slightly less electronegative: E°, SCN°, SCN- = 0.769; E°, 1°, I~ = 0.54.1'2 The properties and uses of thiocyano compounds have been reviewed.13 Many show toxic effects, mainly dermatitis, which vary considerably in different individuals;14 in addition, the alkyl thiocyanates produce de- generative changes in various organs of experimental animals. SCOPE AND LIMITATIONS Thiocyanogen reacts with aromatic compounds that are highly sus- ceptible to substitution with the introduction of a thiocyano group. Reactions reported thus far are mainly with phenols of the benzene and naphthalene series and with primary, secondary, or tertiary amines of the * An historical review of the attempts to prepare thiocyanogen may be found in Gold- berg, J. praki. Chem., [2] 63, 465 (1901); Kaufmann, Arch. Pharm., 263, 675 (1925). 2 Bjerrum and Kirshner, "Die Rhodanide des Goldes und das frei Rhodan," Verlag Horst und Sohn, Copenhagen, 1918; Kgl. Danske Videnskab. Selskab, [8] 5, 76 (1918) [C. A., 13, 1057 (1919)]. 3 Birckenbach and Kellerman, Ber., 58, 786 (1925); Walden and Audrieth, Chem. Revs., 5, 339 (1928). . 4 Kaufmann and Gaertner, Ber., 57, 928 (1924). 6 Wilcoxon, McKinney, and Browne, J. Am. Chem. Soc., 47, 1917 (1925). 6 Lecher, Wittwer,"and Speer, Ber., 56, 1104 (1923). 7 Soderback, Ann., 465, 184 (1928). 8 Kaufmann and Liepe, Ber., 57, 923 (1924). 'Kaufmann, Ber., 60, 58 (1927). 10 Lecher and Joseph, Ber., 59, 2603 (1926). 11 Kaufmann and Grosse-Oetringhaus, Ber., 69, 2670 (1936). 12 Birckenbach and Goubeau, Ber., 70, 171 (1937). 13 Kaufmann, Angew. Chem., 54, 168 (1941). 14 Oettingen, Hueper, and Deiehmann-Gruebler, J. Ind. Hyg. Toxuxl., 18, 310 (1936). REACTIONS OF THIOCYANOGEN 243 benzene, naphthalene, and anthracene series. Apparently the presence of other substituents, such as nitro, chloro, bromo, alkoxy, carboxyl, or carbethoxy groups, does not interfere with the reaction provided, that an active position is still available; however, the presence of a sulfonic acid group may prevent the reaction, since it is reported that p-amino- and p-hydroxy-benzenesulfonic acids do not undergo thiocyanation. Anthracene, benzanthracene and certain of its derivatives, and 3,4- benzpyrene also react with thiocyanogen. Anthracene yields a 9,10- dithiocyano derivative; but the other hydrocarbons,'which are charac- terized by the presence of one very easily substituted hydrogen atom, give only products of monosubstitution. The powerfully carcinogenic benzpyrene and methylcholanthrene both react in this manner with par- ticular ease, although the point of attack with benapyrene is the aromatic nucleus and with methylcholanthrene the reactive methylene group. Ethylene and a variety of substituted ethylenes react with thio- cyanogen to give addition products containing two thiocyano groups. The reaction appears to be fairly general in its application as indicated by addition to such compounds as amylene, cyclohexene, allyl alcohol, pinene, styrene, stilbene, anethole, isosafrole, and oleic and other un- saturated acids. The yields, when given, nearly always are high. Thio- cyanogen adds to a,|8-unsaturated ketones, but not to a,/3-unsaturated acids. The addition to other a,/3-unsaturated carbonyl or related sys- tems has not been explored. Conjugated diene systems react, as they do with halogen, to add two thiocyano groups, probably in the 1,4-posi- tions. The reactions with butadiene, isoprene, and dimethylbutadiene have been described. The acetylenic compounds that have been investi- gated in this reaction, acetylene, phenylacetyleiie, and tolan, add one molecule of thiocyanogen to give a dithiocyanoethylene. The yields are lower than with the oleflnic substances. Miscellaneous reactions of thiocyanogen have been reported, but their study has been too limited for a proper evaluation of their usefulness. Thiocyanogen has been shown to react with a variety of organometallic compounds and to replace the hydrogen on sulfur in mercaptans and thiophenols and the hydrogen on nitrogen of aliphatic amines and di- substituted hydroxylamines. These reactions doubtless are capable of further development. Thiocyanation of Aromatic Amines. The thiocyano group is intro- duced into aromatic amines with rapidity; it enters a free para position if available, otherwise an ortho position. For example, aniline is con- verted into 4-thiocyanoaniline (97% yield),16'16 o-toluidine into 4-thio- 16 Kaufmann and Weber, Arch. Pharm., 267, 192 (1929). " Kaufmann, Ber., 62, 390 (1929). 244 ORGANIC REACTIONS ? cyano-o-toluidine (80% yield),17 and anthranilic acid into 5-thiocyano- anthranilic acid (80% yield).18 The reaction when carried out in neutral solvents almost always gives a monosubstitution product, but in an acid medium and in the presence of excess reagent the reaction often leads to a disubstitution product, though in lower yield.19 For example, the dithiocyano derivatives of aniline,18'20-21 p-toluidine,17-18'22 and 2,5- xylidine22 have been prepared. Acetylation of the amino group prevents thiocyanation.23 When thiocyanation takes place in the position ortho to a primary amino group, as in p-toluidine, p-chloroaniline, p-nitroaniline, or p-amino- benzoic acid, the final product is often an aminobenzothiazole, formed by a secondary reaction between the amino and the thiocyano groups. 2-Amino-4,6-dimethylbenzothiazole is formed from 2,4-xylidine in 79% CH3 yield,23 2-amino-6-chlorobenzothiazole from p-chloroaniline in 75% yield,22 and 2-amino-6-ethoxybenzothiazole from phenetidine in 95% yield.24 The ease of formation of the thiazole derivative varies with the substituents in the primary product; thiocyanophenetidine rearranges spontaneously, whereas l-thiocyano-2-naphthylamine rearranges when warmed with ethanolic hydrogen chloride.22 The ortho thiocyano deriva- tive often can be isolated if a low temperature is maintained and if acid is excluded. The ortho thiocyano derivatives of monoalkylamines re- arrange readily into 2-iminobenzothiazolines.23 NHR ,NR C=NH iCN 17 Likhosherstov and Petrov, J. Gen. Chem. U.S.S.R., 3, 759 (1933) [C. A., 28, 2690 (1934)]. 18 Likhosherstov and Petrov, J. Gen. Chem. U.S.S.R., 3, 183 (1933) [C. A., 28, 1677 (1934)]. 19 Kaufmann and Oehring, Ber., 69, 187 (1926). 20 U. S. pat., 1,790,097 [C. A., 25, 1258 (1931)]; Brit, pat., 257,619 [C.A.,21, 3507 (1927)]; Ger. pat., 484,360 [C. A., 24, 1119 (1930)]. 21 U. S. pat., 1,787,315; V. S. pat., 1,787,316. 22 Kaufmann, Oehring, and Clauberg, Arch. Pharm., 266, 197 (1928). 23 Brewster and Dains, J. Am. Chem. Soc, 58, 1364 (1936). 24 Neu, Ber., 72, 1505 (1939). REACTIONS OF THIOCYANOGEN 245 Aromatic secondary and tertiary amines undergo thiocyanation, often more readily than primary amines. N,N-Dimethylaniline gives N,N- dimethyl-4-thiocyanoaniline (92% yield),26 and N,N-dimethyl-p-tolui- dine gives N,N-dimethyl-2-thiocyano-p-toluidine (21% yield).26 Di- phenylamine and triphenylamine are converted into dithiocyano deriva- tives, each with two of the phenyl rings substituted in the para positions.1 Two positions are potentially reactive in aminophenols, but the amino group directs the orientation of the entering group in thiocyanation.24 An example is the conversion of o-aminophenol into 4-thiocyano-2-hy- droxyaniline in 50% yield. Thiocyanation of Phenols. The reaction of phenols with thiocyanogen has not been studied so extensively as that of amines. Phenol is con- verted into 4-thiocyanophenol in 69% yield,26-27 o-cresol into 4-thio- ? cyano-o-cresol in 90% yield,16 thymol into 4-thiocyanothymol in 95% yield,16 and a-naphthol into 4-thiocyano-l-haphthol in 83% yield.28 The point of attack is again the para position if free; ortho substitution occurs when this position is blocked, as in the reaction of p-cresol and /3-naph- thol (100% yield).28 In general the yields do not appear to be quite so high as in the reaction of amines. The effect of a substituent other than an alkyl group in the position ortho to the hydroxyl group has been ex- amined to only a limited extent; the yield of the thiocyano product is lowered in the case of an alkoxyl (guaiacol, 21% yield2B), hydroxyl (pyrocatechol, 48% yield29), or carboxyl group (salicylic acid, 30% yield 30). Dithiocyanation has been reported only in the reaction of a-naphthol; the reaction can be controlled to give the monosubstitution product or disubstitution product (2,4-dithiocyano-l-naphthol, 60% yield19). Ortho thiocyanophenols rearrange similarly to the corresponding amines to yield 2-iminobenzothioxoles.16'31 The imino group is readily hydrolyzed to a keto group on hydrolysis with acid. 26Fichter and Schonmann, Helv. Chim. Ada, 19, 1411 (1936). 26 Zaboev and Kudryavtzev, J. Gen. Chem. U.8.8.R., 5, 1607 (1935) [C. A., SO, 2182 (1936)]. 27 Melinikov, Sklyarenko, and Cherkasova, J. Gen. Chem. U.S.S.B., 9, 1819 (1939) [C. A., 34, 3699 (1940); Chem. Zentr., 1940, I, 641]. 28 Kaufmann and Liepe, Ber. deut. pharm. Ges., 33, 139 (1923). 29 Machek, Monatsh., 63, 216 (1933). 30Kaufmann andXiepe, Ber., 56, 2514 (1923). 31 French pat., 852,020 [C. A., 36, 1951 (1942)]. 246 ORGANIC REACTIONS Thiocyanation of Polynuclear Hydrocarbons. Aromatic hydrocarbons of the benzene and naphthalene series do not undergo thiocyanation, but certain hydrocarbons with several condensed benzene rings do.32 An- thracene reacts with the reagent, te yield the 9,10-dithiocyano deriva- tive. Benzpyrene is substituted in the 5-position (82% yield); 1,2- benzanthracene in the two meso positions (9-derivative, 5%; 10-deriva- tive, 57%); 9-methyl- and 10-methyI-i,2-benzanthracene in the free (SCN)2 , HSCN 3, 4-Benzpyrene meso position (43% and 66%, respectively); and methylcholanthrene in the 15-position. Benzpyrene and benzanthracene and its alkyl deriv- tives also react with aromatic diazo compounds and with lead tetra- acetate, and thus are substituted far more readily than benzene or naphthalene. 1, 2-Benzanthracene 151CH-2¡ªCH 2 Methylcholanthrene Addition of Thiocyanogen to Olefins and Acetylenes. Thiocyanogen resembles iodine in its addition to double and triple bonds. The yields are usually excellent; ethylene dithiocyanate,33 styrene dithiocyanate,28 and l-(p-methoxyphenyl)-l,2-dithiocyanopropane 28 are reported to be formed in quantitative yield from the corresponding olefin, ethylene, styrene, or anethole. Pinene, allyl alcohol, isosafrole, terpineol, and stilbene are examples of other unsaturated compounds to which thio- cyanogen has been added, but in unspecified yield. Conjugated dienes, illustrated by isoprene20' u and butadiene,36 add two thiocyano groups "in the 1,4-positions, after which no further addition takes place. The yields of the dithiocyano derivative are 19% and 80%, respectively. 32 Wood and Fieser, J, Am. Chem. Soc, 63, 2323 (1941). 33 Soderback, Ann., 443, 142 (1925). 84Bruson and Calvert, J. Am. Chem. Soc, 50, 1735 (1928). 36 Miiller and Freytag, /. prakt Chem., [2] 146, 58 (1936). REACTIONS OF THIOCYANOGEN . 247 The addition of thiocyanogen to an olefin is a slow reaction but can be catalyzed by light and metals. Ethylene adds only traces of the reagent in the dark in nine days, but in sunlight the reaction is complete in two hours.33'34 Sunlight also promotes polymerization of the reagent, but the rate of this reaction in benzene is not so rapid as to interfere with the addition reaction. The reaction of thiocyanogen with unsaturated fatty acids 36 has been introduced as a method of analysis. Excess of a standardized thiocyano- gen solution is used, and the amount of unreacted reagent is titrated. Thiocyanogen reacts quantitatively with oleic acid but with only one of the two double bonds of linoleic acid and with two of the three double bonds of linolenic acid. Methyl styryl ketone and distyryl ketone, typical a,/3-unsaturated ketones, add thiocyanogen in unstated yields.37 Few other substances of the a,/3-unsaturated carbonyl type have been examined. It is reported, however, that maleic, fumaric, acrylic, crotonic, and cinnamic acids do not react with thiocyanogen.38 Substances containing a triple bond add only one mole of thiocyano- gen. Acetylene reacts under the catalytic influence of light to give dithiocyanoethylene (2Q.% yield).33 Phenylacetylene 83 and tolan33 react in the dark; the yields of the products are 50% and 20%, respectively. Acetylene diiodide yields the same product as acetylene, dithiocyano- ethylene,33 formed as a result of replacement of the iodine groups by the reagent. Dibromoethylene and thiocyanogen form an equilibrium sys- tem containing dithiocyanoethylene and bromothiocyanoethylene. C2H2Br2 + (SCN)2 <=* C2H2(SCN)2 + Br2It C2H2(SCN)Br + BrSCN Miscellaneous Syntheses with Thiocyanogen. Aliphatic primary and secondary amines react with thiocyanogen with replacement of the hydfogen atom attached to nitrogen to form thiocyanoamines.1'6 The 2RNH2 + (SCN)2 -> RNHSCN +"RNH8SCN 2R2NH -(- (SCN)2 -> R2NSCN + R2NH2SCN reaction is represented for primary amines by benzylamine 39 and tri- phenylmethylamme (55% yield),39 and for secondary amines by diethyl- amine.6 36Kaufraann, "Studien auf dem Fettgebiet," Verlag Chemie, Berlin, 1935; Kaufmann and Grosse-Oetringhaus, Ber., 70, 911 (1937). 37 Challenger and Bott, /. Chem. Soc, 127, 1039 (1925). 38 Kaufmann, Angew. Chem., 54, 195 (1941). 39 Jones and Fleek, /. Am. Chem. Soc, 50, 2018 (1928). 248 ORGANIC REACTIONS O,N-Disubstituted hydroxylamines react similarly to aliphatic amines to yield N-thiocyanohydroxylamines. O,N-Dibenzyl- and O,N-diethyl- hydroxylamine yield the corresponding N-thiocyano derivatives in 47% and 40% yields, respectively.39 C2H6ONH + (SCN)2 -> C2H6ONSCN + C2H6ONH2SCN C2H6 C2H6 C2H6 N-Acyl- and N-aroyl-diphenylhydrazines behave like diarylamines, forming N-acyl- and N-aroyl-bis-(p-thiocyanophenyl)-hydrazines in 65- 75% yields.16 (C6H6)2NNHCOR + 2(SCN)2 -> (p-NCSC6H4)2NNHCOR + 2HSCN Only a few heterocyclic substances have been investigated. Anti- pyrine is .converted into the 4-thiocyano derivative. H3CCa=CH H3CC=CSCN" I. J * I I 4Vc=0 H'c\^° i.H, La. Both 2-hydroxyquinoline (carbostyryl) and 8-hydroxyquinoline react in the 4-position, para to the nitrogen atom. (SON), Ethyl acetoacetate has been thiocyanated,28 but the primary Jhio- cyano derivative has not been isolated owing to hydrolysis to ethyl 2-hydroxy-4-methylthiazole-5-carboxylate (19% yield).28 CH3COCH2CO!iC2H6 SCN CHJCOCHCOJCJHB ^ j H6C2O2CC* 1 ^ ^ HaCCj SCONHj H S REACTIONS OF THIOCYANOGEN 249 Treatment of ethyl mercaptan with thiocyanogen affords ethyl thio- thiocyanate (50% yield),40 a compound similar to a sulfenyl chloride (RSC1) but somewhat more stable toward hydrolysis. Thiophenols C2H6SH + (SCN)2 -?? C2H6SSCN + HSCN yield analogous substances; the reaction has been applied to thiophenol (70% yield),40 to p-nitrothiophenol (75% yield),41 and to /3-thionaph- thol.40 On thiocyanation, mercury diphenyl is converted into phenyl thio- cyanate in 66% yield, and similarly zinc diethyl yields ethyl thiocyanate in small yield.1 (C6H6)2Hg + (SCN)2 -? C6H6SCN + C6H6HgSCN (C2HB)2Zn + 2(SCN)2 -> 2C2H6SCN + Zn(SCN)2 The triaryl derivatives of phosphorus, arsenic, antimony, and bismuth add thiocyanogen,42' ** with decreasing reactivity in the order indicated. The primary products are sufficiently stable to hydrolysis to be isolable (C6H6)3Sb + (SCN)2 -? (C6H6)3Sb(SCN)2 only in the reactions of triphenylstibine and triphenylbismuthine; but there is no substitution in the phenyl ring of any of these compounds, as in the reaction of triphenylamine.1 Small amounts of phenyl and a-naphthyl thiocyanate are formed as secondary products in the reac- tion of triphenyl- and tri-a-naphthyl-bismuthine.43 (C6H6)3Bi(SCN)2 -? C6HBSCN + (C6H6)2BiSCN OTHER METHODS OF SYNTHESIS OF THIOCYANO COMPOUNDS The use of thiocyanogen for the introduction of a thiocyano group is limited to substances containing either a hydrogen atom particularly sensitive to substitution or an unsaturated carbon-carbon linkage, and consequently does not have such a wide application for the preparation of aryl thiocyanates as the Gattermann and Sandmeyer reaction,44-45 in which a diazonium salt group is replaced on treatment with cuprous thiocyanate. Furthermore, the yields are usually higher in the Gatter- mann and Sandmeyer reaction; for example, 4-thiocyanosalicylic acid is 40 Lecher and Wittwer, Ber., 55, 1474 (1922). 41 Lecher and Simon, Ber., 54, 632 (1921). 42 Challenger, Smith, and Paton, J. Cfiem. Soc, 123, 1046 (1923). 43 Challenger and Wilkinson, J. Chem. Soc., 121, 91 (1922). 44 Gattermann and Hausskneckt, Ber., 23, 738 (1890); Hantzch and Hirsch, Ber., 29, 947 (1896); Korczynski, Kniatowna, and Kaminski, Bull. soc. chim., 31, 1179 (1922). 45 Dienske, Bee. trav. chim., 50, 407 (1931). 250 ORGANIC REACTIONS available in 73% yield by the diazotization method45 and in only 30% yield by thiocyanation.30 Aryl thiocyanates can also be made by the action of alkali cyanides on thiosulfates 46 or arylsulfenyl chlorides,47 and by treating lead mercaptides with cyanogen chloride or iodide.48 There are numerous instances of the reaction of alkali metal thio- cyanates with alkyl halides or sulfates49 ?50 for the preparation of alkyl mono- and poly-thiocyanates. Another method for the preparation of an alkyl thiocyanate involves cleavage of a dialkyl sulfide by treatment with cyanogen bromide;61 the second product is an alkyl bromide. When the two alkyl groups are different, the larger radical generally re- mains attached to sulfur; an example is the conversion of n-propyl n-butyl sulfide into n-propyl bromide and n-butyl thiocyanate. Thio- cyano compounds are also available from the reaction of metal mer- captides with cyanogen halides.62 USE OF THIOCYANATES IN SYNTHESIS Thiocyanates can often be utilized as intermediates in the preparation of other sulfur-containing compounds, alkylthiocarbonic acid amides, disulfides, mercaptans, sulfides, and sulfonic acids. Typical reactions are as follows: /OR' ,,O RSCN + R'OH -* RSC^ -? RSCf + R'Cl ?? ^ XNH2 2RSCN + NaOH > RSSR + NaCN + NaOCN + H2O ?? ?? " RSCN + H2 > RSH -f HCN ?? "? "? ?? RSCN + R'MgBr > RSR' + MgBrCN " RSCN + R'MgBr -5% RSH + R'CN + MgBr2 ? RSCN + [0] > RSO3H ". *8 46 Footner and Smiles, J. Chem. Soc., 127, 2887 (1925). ? Zinke and Eismayer, Ber., 51, 751 (1918). 48 Billeter, Ber., 7, 1753 (1874); Gabriel, Ber., 10, 184 (1877); Gabriel and Deutsoh, Ber., 13, 386 (1880). 49Kaufler and Pomeranz, Monatsh., 22, 492 (1901). 60 Walden, Ber., 40, 3214 (1907). 61 von Braun and Englebertz, Ber., 56, 1573 (1923); von Braun, May, and Michaelis, Ann., 490, 189 (1931). "Brit, pat., 431,064 [C. A., 29, 8220 (1935)]. 63 Knorr, Ber., 49, 1735 (1936). " Fichter and Schonlau, Ber., 48, 1150 (1915). 66 Kaufmann and Rossbach, Ber., 58, 1556 (1925). 66 Fichter and Beck, Ber., 44, 3636 (1911). "Adams, Bramlet, and Tendiok, J. Am. Chem. Soc., 42, 2369 (1920). 68 Fichter and Wenk, Ber., 45, 1373 (1912). REACTIONS OF THIOCYANOGEN 251 EXPERIMENTAL CONDITIONS Three general methods have been described for the use of thiocyanogen in substitution and addition reactions: free thiocyanogen in organic sol- vents; thiocyanogen evolved by electrolysis of concentrated aqueous solutions of alkali metal thiocyanates; and thiocyanogen liberated gradu- ally in an organic solvent from a metal thiocyanate by various reagents. Free Thiocyanogen. This method was the first to be employed and is still a useful procedure when the reaction involved is slow, as in addi- tion reactions, or when the product is difficult to purify. Usually the only contaminant of the product other than starting material is polythio- cyanogen, which is entirely insoluble in water and in organic solvents. The reagent is prepared by the action of an oxidizing agent upon thiocyanic acid or a metal thiocyanate. The oxidation of thiocyanic acid in an organic solvent is accomplished by means of such reagents as lead tetraacetate, lead peroxide, or manganese dioxide,69 but the yield is so low that the preparation from metal thiocyanates is much to be preferred. Lead thiocyanate reacts rapidly and quantitatively with bromine to form thiocyanogen and lead bromide, which is removed readily by filtration. Halogen carriers, such as phenyl iodochloride,26 sulfuryl chloride,60 or certain N-chloroamides,17-18> 61 can also be used, but do not appear to possess any advantages over bromine or chlorine. Chloroamides usually cannot be used in the thiocyanation of a phenol owing to their oxidizing action. Solvents that have been used with thiocyanogen include benzene, bromobenzene, carbon tetrachloride, chloroform, ether, ethylene bro- mide, carbon disulfide, petroleum ether, methyl acetate, nitromethane, and anhydrous formic and acetic acids. At low temperatures such sol- vents as saturated solutions of alkali thiocyanates in methanol16> 62 or acetone 63 can be used. The yield ,in the thiocyanation of amines is 20-30% higher when the reaction is carried out in a neutral medium like methanol rather than in acetic acid. The formation of a thiazole is also inhibited in a neutral solvent. Ether is usually not satisfactory because the solvent is attacked and because some of the amine is precipitated as the thiocyanate.1'19 On the other hand, thiocyanation of phenols appears to give better yields in acetic acid solution than in neutral solvents. 69 Kaufmann and Kogler, Ber., 68, 1553 (1925). 80 Spangler and Muller, U. S. pat., 1,687,596 [C. A., 23, 154 (1929)]. 61 Likhosherstov and Aldoshin, J. Gen. Chem. U.S.S.B., 5, 981 (1935) [C. A., 30, 1033 (1936)]. 62 Kaufmann and Hansen-Schmidt, Arch. Pharm., 263, 692 (1923). "Fialkov and Kleiner, J. Gen. Chem. U.S.S.B., 11, 671 (1941) [C.A., 35, 7307(1941)]. 252 ORGANIC REACTIONS Moisture must be excluded from thiocyanation solutions in order to prevent hydrolysis. Another troublesome side reaction, particularly in concentrated solutions, is polymerization, which is induced by light, heat, and the presence of hydrolysis products. Polymerization is re- ported to be dependent upon the dielectric constant of the solvent.1-62' M The limiting concentration of stable solutions of thiocyanogen depends upon the temperature and the exposure to light. Tenth normal solu- tions in the dark at 21° show 10% decomposition as follows: carbon tetrachloride, thirty-eight days; carbon disulfide, fourteen days; ethylene chloride, fourteen days. Four per cent decomposition occurs in acetic acid in ten days.62 A normal solution in carbon tetrachloride at the boil- ing point is polymerized to the extent of 90% after three hours in the sunlight as compared with 24% in the dark. At room temperature 50% polymerization occurs in twenty-four hours in the sunlight compared with 5% when the solution is kept in the dark throughout the period.30 Tenth normal solutions in carbon tetrachloride or acetic acid-acetic anhydride have been reported to be stable from one week to several months when kept in the refrigerator. Stirring is said to retard poly- merization.1 In this modification of the synthesis, the organic compound is mixed with a solution containing from 1 to 4 equivalents of thiocyanogen at room temperature. The end of the reaction, which may be slow, is often determined by the disappearance or polymerization of all the reagent. Frequently a significant yield depends upon successful initiation of the process, but the usual methods of forcing a reaction cannot be employed owing to the instability of the reagent. Free thiocyanogen is used in determining the thiocyanogen number of fats and oils,36'6B of resins,66 and of hydrocarbons;38'67'68 but for the usual synthetic reaction the preferred procedure is to generate thiocyanogen in a solution of the substance to be thiocyanated at a rate equal to the rate of the removal by reaction. The low concentration of reagent main- tained in this way minimizes polymerization. The reagent is generated from thiocyanate salts either by electrolysis or by a chemical reaction. Thiocyanogen Generated from Salts by Electrolysis. Thiocyanogen is produced when concentrated solutions of alkali thiocyanates are elec- trolyzed.19'24-27'69 Ammonium thiocyanate is most commonly used, and the electrolyzed solution is stabilized by maintaining it at tempera- 64 Bhatnagar, Kapur, and Khosla, J. Indian Chem. Soc, 17, 529 (1940). ?? McKinney, /. Assoc. Official Agr. Chem., 21, 87, 443 (1938). 66 Gardner, Pribyl, and Weinberger, Ind. Eng. Chem., Anal. Ed., 6, 259 (1934). 67 Stavely and Bergmann, J. Org. Chem., 1, 580 (1937). 68 Pummerer and Stark, Ber., 64, 825 (1931). 69 Kersteih and Hoffman, Ber., 67, 491 (1924). REACTIONS OF THIOCYANOGEN 253 tures below ¡ª8°. The stability is satisfactory provided that the con- centration of thiocyanogen does not become greater than that corre- sponding to the complex NH4(SCN)3. An amine or a phenol is dissolved in the concentrated alkali thiocyanate solution; it is usually desirable to add enough ethanol to lower the freezing point of the mixture below ¡ª8°. A cathode of copper, aluminum, nickel, or iron and a rotating graphite anode are introduced, and a current of 0.02 to 0.03 ampere per square centimeter is used for the electrolysis. If either the compound to be treated or the thiocyanation product is reduced readily, a divided com- partment cell is employed. The yields usually vary from 50 to 90%. Thiocyanogen Generated from Salts by Chemical Reagents. The compound is placed in a solution of a metal thiocyanate in acetic or formic acid,19-26 or, better, in a neutral solvent like methyl acetate, acetone, or methanol.15'16 Bromine or chlorine is added to the cooled solution at such a rate that the thiocyanogen reacts as fast as it is liberated. A neutral solvent that is susceptible to attack by halogen is protected by saturating the solution with an appropriate alkali metal halide or by using a large excess of an alkali metal thiocyanate in the reaction mixture. Other reagents for producing thiocyanogen from ammonium thiocyanate have been described; N,N-dichlorourea,18 N-chloroacetamide,17 and N-dichloropentamethylenetetramine61 in acetic acid, acetone, or methanol solution. The addition of a drop of concen- trated sulfuric acid is reported to improve the yield. The results that have been obtained do not clearly justify substitution of these reagents for the halogens. By the action of the oxidizing agent phenyl iodochloride 24 on lead thiocyanate, phenyl iodothiocyanate is formed. It has been suggested that this substance is the thiocyanating agent. C6H6IC12 + Pb(SCN)2 -> C6H6I(SCN)2 + PbCl2 Cupric thiocyanate,70 the use of which may be considered still another modification of this general procedure, shows promise of being very effective. It releases thiocyanogen merely by the dissociation of the cupric to cuprous salt. 2Cu(SCN)2 -> 2CuSCN + (SCN)2 Cupric thiocyanate, prepared in advance, or a paste of copper sulfate and sodium thiocyanate in equivalent proportions is added to a solution of the compound in methanol or acetic acid, and the mixture is warmed to 35-80° until the black cupric thiocyanate has changed completely to the white cuprous thiocyanate. The product is isolated by dilution with 70 Kaufmann and Kuchler, Ber., 67, 944 (1934). 254 ORGANIC REACTIONS water, followed by extraction with ether. This procedure has the ad- vantage over the others previously described of permitting higher temperatures for thiocyanation. The preferential thiocyanation of aromatic amines with susceptible olefmic linkages in side chains has been accomplished with this reagent.71 Still further improvement70-72 of the above method is reported to consist in the addition of a cupric salt to a solution of the amine or phenol and an inorganic thiocyanate in water, dilute acid, or 30% ethanol. Organic compounds that are insoluble in the solvents to be used can be thiocyanated successfully by this method after dispersal with commercial detergents. The presence of oxalic acid is reported to decrease color formation. Resorcinol31 and olefms 73 as well as amines have been found to react with thiocyanogen generated by this method. Detection of Thiocyano Compounds. The characterization of the products of thiocyanation does not present many difficulties. Aryl thio- cyanates do not rearrange readily upon heating into isothiocyanates (ArN=C=S), and alkyl thiocyanates rearrange only when heated to high temperatures. Allyl thiocyanates and analogous compounds, how- ever, rearrange very readily at elevated temperatures into isothio- cyanates.74 The reaction with thiol acids serves to differentiate thiocyano from isothiocyano compounds. 76 RSCN + HSCOAr -? RSCSHNCOAr RNCS + HSCOAr -> RNHCOAr + CS2 A simple test for aliphatic dithiocyanates consists in the development of a red color on the addition of ferric chloride to a solution formed by heat- ing the thiocyanate with aqueous sodium hydroxide followed by acidifi- cation.76 A few instances have been reported in which a monothiocyano compound produces a red color with ferric chloride alone.32 A more general test involves heating a thiocyanate with alkaline lead tartrate, which results in the formation of a yellow precipitate.1 The reaction with sodium malonic ester to produce a disulfide has been suggested as a qualitative test.77 A method for the quantitative determination involves heating the compound under reflux with an ethanolic solution of sodium "Arnold, Arch. Pharm., 279, 181 (1941). 72 U. S. pat., 2,212,175 [C. A., 35, 466 (1941)]; Brit, pat., 513,473 [C.A., 35, 1804 (1941)]; Brit, pat., 514,203 [C.A., 35, 4041 (1941)]; Ger. pat., 579,818 [C.A., 28, 1053 (1934)]. 73 Dermer and Dysinger, J. Am. Chem. Soc, 61, 750 (1939). "Bergmann, J. Chem. Soc, 1361 (1935); Mumm and Richter, Ber., 73, 843 (1940). 76 Wheeler and Merriam, J. Am. Chem. Soc, 23, 283 (1901). 76 Hagelberg, Ber., 23, 1083 (1890). 77 Whitmore, "Organic Chemistry," p. 542, Van Nostrand, New York, 1937. REACTIONS OF THIOCYANOGEN 255 sulfide.78 After removal of the excess sulfide, silver thiocyanate is pre- cipitated by the addition of standard silver nitrate and the excess silver ion is determined by the Volhard method. 2RSCN + Na2S -> R2S + 2NaSCN It has been noted that 20 to 30% of the nitrogen of the thiocyano ion escapes conversion to ammonia in the regular Kjeldahl digestion.79 EXPERIMENTAL PROCEDURES Thiocyanogen Solutions. Lead thiocyanate, used advantageously in the formation of thiocyanogen, is prepared from lead nitrate and sodium thiocyanate. To an ice-cold solution of 45 g. of lead nitrate in 100 cc. of water is added a^cold solution of 25 g. of sodium thiocyanate in 100 cc. of water. Lead thiocyanate precipitates as a fine, white powder. It is ' collected on a filter, washed free of nitrates with ice water, and then dried in vacuum over phosphorus pentoxide in the dark. The product should remain perfectly white. One part by weight (in grams) of lead thiocyanate is suspended in 5 to 10 parts by volume (in cubic centimeters) of the desired solvent in a glass-stoppered flask. The solution is cooled to 5-10°, and a small por- tion of 10% bromine in the same solvent is added. The mixture is shaken vigorously until the color due to the bromine disappears. The process of addition .and shaking is repeated until the calculated amount of bromine has been used. The suspended solids are allowed to settle, the thiocyanogen solution is decanted, and the residual solids are washed by decantation with small portions of the solvent. Decoloration of the bromine solution by lead thiocyanate is usually immediate; if a protracted'induction period appears to be indicated, it can be terminated readily by exposure of the solution to direct sunlight. As heat is evolved by the reaction, the flask must be cooled regularly during the preparation to maintain the low temperature neces- sary to stabilize the thiocyanogen. At the end of the reaction lead thio- cyanate should remain in about 10% excess. Solutions of pure'thio- cyanogen are water-clear and colorless. Filtration of the solution is of little advantage and is not easily accomplished without the appearance of a pink coloration indicative of the presence of moisture. Since the reaction between bromine and lead thiocyanate is quantita- tive, the amount of thiocyanogen present can be taken as equivalent to the amount of bromine added to the solution provided that the reagent is used immediately. A quantitative estimate is furnished by titration 78 Panchenko and Smirnov, J. Gen. Chem. U.S.S.R., 2,193 (1932) [C. A., 27, 245 (1933)]. 79 ValdiguiS, Bull. soc. chim. biol., 21, 609 (1939). 256 ? ~ ORGANIC REACTIONS of the iodine released when an aliquot of the solution is shaken with aqueous ^potassium iodide.4 In most syntheses it is desirable that free thiocyanogen remain in excess until the end of the reaction. The presence of the free halogenoid may be determined by the formation of a red color when a few drops of the solution are shaken with iron powder and ether. Styrene Dithiocyanate 33 (Use of Free Thiocyanogen). To a solution of 11.6 g. (0.1 mole) of thiocyanogen in 150 cc. of benzene is added 10.4 g. (0.1 mole) of styrene. The flask is set in direct sunlight. In about one- half hour a mass of fine yellow crystals forms. When the test for thio- cyanogen is negative (about two hours), the solids are filtered, washed with cold benzene, and dried in air. The yield is 17.5 g. (80%). For purification the product is crystallized from hot benzene and then from ethanol. The melting point is 101-102°. />-Thiocyanoaniline 16 (Use of Sodium Thiocyanate and Bromine). A solution of 14 g. (0.14 mole) of freshly distilled aniline and 37 g. (0.45 mole) of sodium thiocyanate in 90 cc. of methanol is cooled to 5°, and 8.5 cc. (0.155 mole) of bromine in 30 cc. of methanol saturated with sodium bromide is added with stirring. The reaction mixture is poured into 1 1. of water. The solution is neutralized with sodium carbonate. p-Thiocyanoaniline separates in colorless crystals, which after recrystal- lization from water melt at 97°; yield, 20.4 g. (97%). 9,10-Dithiocyanostearic Acidw (Use of Sodium Thiocyanate and Bromine). A solution of 2.8 g. (0.01 mole) of elaidic acid, in 60 cc. of glacial acetic acid containing 5 g. (0.06 mole) of sodium thiocyanate is warmed to 40°, and 1.5 cc. (0.29 mole) of bromine in 10 cc. of acetic acid is dropped in. The mixture is poured into water, and the product, which precipitates, is collected on a filter and washed with water to free it of thiocyanic acid. It is recrystallized from a small amount of warm ethanol. and then washed with a little petroleum ether; m.p. 79°. The mother liquor is concentrated for a second crop. The total yield of product is 2.78 g. (70%). 2-Amino-4,6-dimethylbenzothiazole 23 (Use of Sodium Thiocyanate and Bromine). A solution of 12.1 g. (0.1 mole) of 2,4-xylidine and 1.6 g. (0.2 mole) of sodium thiocyanate in 150 cc. of glacial acetic acid is cooled in ice and stirred mechanically while a solution of 16 g. (0.2 mole) of bromine in 25 cc. of acetic acid is added dropwise. The temperature is kept below 10° by external cooling throughout the addition and for thirty minutes thereafter. The product, 2-amino-4,6-dunethylbenzothi- azole hydrobromide, is collected by filtration. It is dissolved in warm water, and the base is precipitated by alkali and recrystallized from ethanol or ligroin; m.p. 140°. The yield is 13 g. (79%) of free base. 80 Kaufmann, Chem. Umschau Fette Ole Wachse Harze, 37, 113 (1930). REACTIONS OF THIOCYANOGEN -257 N,N-Dimethyl-4-thiocyanoaniline 26 (Use of Ammonium Thiocyanate and Electrolysis). A solution of 21.5 g. of dimethylaniline (0.18 inole) and 55.5 g. (0.73 mole) of ammonium thiocyanate in 48 cc. of water, 25 cc. of 95% ethanol, and 19 cc. of 35% hydrochloric acid is cooled to 0° and electrolyzed. A cathode of copper or platinum gauze and a rotating graphite anode are used to produce a current of 0.02-0.03 ampere per square centimeter. When 0.5 faraday (140% of the theo- retical amount) has been consumed the precipitated product is col- lected by filtration. It is dissolved in hydrochloric acid, reprecipitated with ammonia, and recrystallized from 90% ethanol. The yield of N,N-dimethyl-4-thiocyanoaniline is 29 g. (92%); m.p. 73°. 4-Thiocyano-l-naphthol70 (Use of Preformed Cupric Thiocyanate). The cupric thiocyanate is prepared by treating an aqueous solution of copper sulfate with an equivalent amount of aqueous sodium thio- cyanate. The precipitate is filtered and washed with ethanol and ether. A solution of 3.6 g. (0.025 mole) of a-naphthol in 30 cc. of acetic acid is warmed gently with 19 g. (0.105 mole) of cupric thiocyanate until decoloration of the copper salt is complete. The solution is filtered and diluted with water. An oil separates but soon crystallizes. Recrystalli- zation from carbon disulfide yields 3.6 g. (72%) of 4-thiocyano-l- naphthol, m.p. 112°. 2-Amino-6-ethoxybenzothiazole70 (Use of Copper Chloride and Sodium Thiocyanate). To a solution of 3.5 g. (0.025 mole) of p-pheneti- dine and 7.6 g. (0.094 mole) of sodium thiocyanate in 40 cc. of glacial acetic acid is added a solution of 12 g. (0.090 mole) of cupric chloride in 25 cc. of ethanol. The mixture is stirred for half an hour at 70°, and then the temperature is raised to 100°. Approximately 80 cc. of hot, dilute hydrochloric acid is added, and the solution is filtered. The residue is washed on the funnel with hot water. The combined filtrates are de- colorized with carbon and then are neutralized with sodium carbonate. The product, 2-amino-6-ethoxybenzothiazole, separates as crystals which have a melting point of 161°. The yield is 3.5 g. (71%). SURVEY OF SYNTHESES WITH THIOCYANOGEN The following tables record organic compounds and the products of their reaction with thiocyanogen that were reported prior to January, 1945. Many organic compounds have been shown to react with thio- cyanogen by titration data in terms of a "thiocyanogen number." Such compounds are included in the tables only if a product was isolated from the reaction mixture. An omission of the yield in the table indicates that the information was not given in the original paper. Many of the yields reported probably can be increased by application of the im- proved techniques illustrated in the more recent papers. 258 ORGANIC REACTIONS TABLE I AROMATIC AMINES SUBSTITUTED BT THIOCTANOGEN Amine Aniline o-Toluidine p-Toluidine m-Toluidine 2,4-Xylidine 2,6-Xylidine o-Chloroaniline p-Chloroaniline 4-Chloro-o-toluidine 4-Chloro-2,5- xylidine 2-Bromo-p-tolui- dine p-Nitroaniline Product p-Thiocyanoaniline 2,4-Dithiocyanoaniline 2-Amino-6-thiocyanobenzothi- azole 4-Thiocyano-o-toluidine 2-Amino-6-methylbenzothiazole 2,6-Dithiocyano-p-toluidine 4-Thiocyano-m-toluidine 4,6-Dithiocyano-TO-toluidine 2-Amino-4,6-dimethylbenzothi- azole 4-Thiooyano-2,5-xylidine 2-Amino-4,7-dimethyl-6-thio- cyanobenzothiazole 2-Chloro-4-thiocyanoaniline 2-Amino-6-chlorobenzothiazole 5-Chloro-2-thiocyano-o-toluidine 2-Amino-6-chloro-4-methyl- benzothiazole 2-Amino-6-chloro-4,7-dimethyl- benzothiazole 2-Amino-4-bromo-6-methyl- benzothiazole 2-Amino-6-nitrobenzothiazole Method* C C cc cA C C C C C B B C C C C C B C C C C C C B C C C C C C C C Yield 97% 87% 80% 78% 50% 27% 80% 15% 80% 75% 44% 39% ?81% 45% 62% 79% 47% 75% 69% Refer- ence 15, 16 19 18 70 . 17,24 1 20,72 18 19 20, 21, 22 17 82 27 26 81 70,72 17,18,22 22 27 17 17 23 22 72,83 22 37,72, 84 22 70,72 21 84 21 21 23 23 * A refers to free thiooyanogen, B to thiocyanogen generated from salts by electrolysis, and C to, thiocyanogen generated from salts by chemical reagents. EEACTIONS OF THIOCYANOGEN TABLE I¡ªContinued AROMATIC AMINES SUBSTITUTED BY THIOCYANOGEN 259 Amine 3-Nitro-p-toluidine 4-Nitro-o-toluidine 2-Hydroxyaniline 3-Hydroxy aniline o-Anisidine Phenetidine 4nthranilic acid p-Aminobenzoic acid Ethyl p-aminoben- zoate m-Aminobenzoie acid a-Naphthylamine 4-Chloro-l-naph- thylamine 18-Naphthylamino 7-Methoxy-2-naph- "thylamine Product 2-Amino-6-methyl-5-nitrobenzo- thiazole 2-Amino-4-methyI-6-nitrobenzo- thiazole 2-Hydroxy-4-thiocyanoaniline 3-Hydroxy-4-thiocyanoaniline 2-Methoxy-4-thiocyanoaniline 4-Ethoxy-2-thiocyanoaniline 2-Amino-6-ethoxybenzothiazole 4(5)-Thiocyanoanthranilic acid 2-Amino-6-carboxybenzothia- zole Ethyl 4-amino-3-thiocyanoben- zoate 3-Amino-4-thiocyanobenzoic acid 4-Thiocyano-l-naphthylamine 2,4-Dithiocyano-l-naphthyl- amine 2-Amino-5-thiocyanonaphtho- [l',2' : 4,5]-thiazole 2-Amino-5-chloronaphtho- [l',2' : 4,5]-thiazole l-Thiocyano-2-naphthylamine 2-Aminonaphtho-[2',l' : 4,5]-thi- azole 7-Methoxy-l-thiocyano-2-naph- thylamine Method* C C C C C C C C G C C C B B C C C C C C C B C C C C C C C C C Yield 50% 55% 95% 65% 60% 54% 80% 60% 54% 50% 67% 85% 80% 71% 55% 50% 94% 55% Refer- ence 23 23 24 24 72,84 15,84 24 70 22 72 15,21 18 82 85 24 72 72 22 18 18 8 82 10,19 18,20 22 21 70,72 19 20, 24, 84,86 21, 22, 72 84 * A refers to free thiocyanogen, B to thiocyanogen generated from salts by electrolysis, and C tothiocyanogen generated from salts by chemical reagents. 260 ORGANIC REACTIONS TABLE I¡ªContinued AROMATIC AMINES SUBSTITUTED BY THIOCTANOGEN Amine 7-Methoxy-2-naph- thylamine¡ªCont. /3-Anthrylamine 2,6-Diaminoanthra- cene N-Methylaniline N-Ethylaniline N-Propylaniline N-Butylahiline N-Benzylaniline N-Cetylaniline N-Oleylaniline N-Chaulmoogryl- aniline N-Ethyl-w-toluidine N-Methyl-p-tolui- dine N-Ethyl-p-toluidine N-Benzyl-p-tolui- dine N-Methylanthra- nilic acid Diphenylamine ? N,N-Dimethyl- aniline N, N-Diethylaniline N,N-Dimethyl-p- toluidine Product 2-Amino-8-methoxynaphtho- [2',1' : 4,5]-thiazole 1 -Thiocyano-2-anthrylamine 2-Aminoanthra-[2',l' : 4,5]- thiazole 2,6-Diamino-l-thiocyanoanthra- cene 2,6-Diamino-1,5-dithiocyanoan- thracene N-Methyl-4-thiocyanoaniline N-Ethyl-4-thiocyanoanilijie N-Propyl-4-thiocyanoaniline N-Butyl-4-thiocyanoaniline N-Benzyl-4-thiocyanoaniline N-Cetyl-4-thiocyanoaniline N-Oleyl-4-thiocyanoaniline N-Chaulmoogryl-4-thiocyano- aniline N-Ethyl-4-thiocyano-m-toluidine 2-Imino-3,6-dimethylbenzothi- azoline 2-Imino-3-ethyl-6-methylben- zothiazoline 2-Imina-3-benzyl-6-methylben- zothiazoline N-Methyl-4(5)-thiocyanoanthra- nilic acid Di-(4-thioeyanophenyl)-amine N,N-Dimethyl-4-thiocyano- aniline N, N-Diethyl-4-thiocyanoaniline N,N-Dimethyl-2-thiocyano-p- toluidine Method* C cc c c cc cc cA cc cc c c c A c B C B C C A C C B B Yield 65% 84% 64% 92% 79% 75% 65% 45% 84% 81% 21% Refer- ence 21 84 21 84 84 85 27,85 85 85 85,87 71 71 71 85 23 23 23 85 1 19, 20, 61,72 25 26 82 88 24 1,60 18,72 85 25 25 * A refers to free thiocy^nogen, B to thiocyanogen generated from salta. by electrolysis, and C tothiooyanogen generated from salts by chemical reagents. REACTIONS OF THIOCYANOGEN TABLE I¡ªContinued AROMATIC AMINES SUBSTITUTED BY THIOCYANOGEN 261 Amine N-Benzyl-N-methyl- aniline N-Benzyl-N-ethyl- aniline Triphenylamine m-Phenylenediamine Benzidine Sulfanilamide NSN^Dimethyl- sulfanilamide NSN^Diethyl- sulfanilamide N4-Acetylsulf anil- amide 4'-Sulfamylsulfanil- anilide N,N'-Disulfanilyl- p-phenylenedi- amine N-Sulfanilyl-p-nitro- aniline N-Sulfanilyl-p-tolu- idine Product N-Benzyl-N-methyl-4-thiocyano- aniline N-Benzyl-N-ethyl-4-thiocyano- aniline Di-(4-thiocyanophenyl)-phenyl- amine 4-Thiocyano-TO-phenylenedi- amine 4,6-Dithiocyano-m-phenylene- diamine Dithiocyanobenzidine 4-Amino-3-thiocyanobenzene- sulfonamide 2-Amino-6-sulfamylbenzothiazole 2-Amino-6-(N,N-dimethyl- sulfamyl)-benzothiazole 2-Amino-6-(N,N-diethyl- sulfamyl)-benzothiazole 2-Amino-6- (N-aoety lsulf amyl) - benzothiazole N4-(2-Amino-6-benzothiazolyl- sulf onyl) -sulfanilamide N-(Sulfanilyl)-N'-(2-amino-6- benzothiazolylsulfonyl)-p- phenylenediamine N-(2-Amino-6-benzothiazolylsul- fonyl)-p-nitroaniline N-(2-Amino-6-benzothiazolylsul- f onyl) -p-toluidine Method* C B C A A C C C C cc c, c c c c c Yield 70%. 84% 70% 75% 58% 70% 80% 65% 40% 68% 75% Refer- ence 87 85 87 1 1 18 18, 24 89 89 71 89 89 71 89 89 89 89 * A refers to free thiocyanogen, B to thiocyanogen generated from salts by electrolysis, and C tothiocyanogen generated from salts by chemical reagents. 81 Horii, J. Pharm. Soc. Japan, 55, 6 (1935) [C. A., 29, 3317 (1935)]. 82 U.S. pat., 1,816,848 [C.A., 25, 5355 (1931)]; Brit, pat., 364,060; Fr. pat., 702,829 [C.A., 25,4284 (1931)]. 83 Brit, pat., 299,327. 84 U.S. pat., 1,765,678 [C. A., 24, 4307 (1930)]; Brit, pat., 303,813 [C. A., 23, 4482 (1929)]; Ger. pat., 491,225 [C. A., 24, 2138 (1930)]. 86 Cherkasova, Sklyarenko, and Melinikov, /. Gen. Chem. U.S.S.R., 10, 1373 (1940) [C. A., 35, 3615 (1941)]. 86 Ger. pat., 493,025 [C. A., 24, 2754 (1930)]. 87 Kaufmann and Ritter, Arch. Pharm., 267, 212 (1929). 88Brewster and Schroeder, Org. Syntheses, 19, 79 (1939). 89 Kaufmann and Bilckmann, Arch. Pharm., 279, 194 (1941). 262 ORGANIC REACTIONS TABLE II PHENOLS SUBSTITUTED BY THIOCYANOGEN Phenol Phenol ?i-Cresol o-Cresol p-Cresol Guaiacol Diethylphenol Thymol Carvacrol Salicylic acid o-Naphthol 0-Naphthol Nerolin Elesorcinol Pyrocatechol Product 4-Thiocyanophenol 4-Thiocyano-TO-cresol 4-Thioeyano-0-cresol 2-Thiocyano-p-cresol 4-Thiocyanoguaiacol Thiocyanodiethylphenol 4-Thiocyanothymol Thiocyanocarvacrol 5-Thiocyanosalicylic acid 4-Thiocyano-l-naphthol 2,4-Dithiocyano-l -naphthol l-Thiocyano-2-naphthol 2-Methoxy-l-thiocyanonaphtha- lene 4-Thiocyanoresorcinol 4-Thiocyanopyrocatechol Method* A C B B C C . B C C B B B C B B C C B A C B A C C A C A C C C A C C C A B C C Yield 69% 68% 67% 25% 20% 90% 72% 40% 21% 95% 77% 76% 50% 30% 10% 83% 72% 50% 60% 100% 90% 72% 65% 60% 48% Refer- ence 1 26 27 82 24 72,84 27 15 15 27 82 27 15 25 27 15 25 27 7 4,19 27 30 19 20 28 18,19,70 59 20,84 19 18,20 28 24 72 18 28 82 29 24 * A refers to free thiocyanogen, 6 to thiooyanogen generated from salts by electrolysis, and C tothiooyanogen generated from salts by chemical reagents. REACTIONS OF THIOCYANOGEN TABLE III POLYNTJCLEAR HYDROCARBONS SUBSTITUTED BY THIOCYANOGEN 263 Hydrocarbon Anthracene 3,4-Benzpyrene 20-Methylcholan- threne 1,2-Benz anthracene 9-Methyl-l,2-benz- anthracene 10-Methyl-l,2-benz- anthracene Product 9,10-Dithiocyanoanthracene 5-Thiocyano-3,4-benzpyrene 20-Methyl-15-thiocyanocholan- threne 9-Thiocyano-1,2-benzanthracene 10-Thiocyano-l,2-benzanthracene 9-Methyl-10-thiocyano-l,2- benzanthracene 10-Methyl-9-thiocyano-l,2- benz anthracene Method* A A A A A A A Yield 45% 82% 89% 5% 57% 43% 66% Refer- ? ence 32 32 32 32 32 32 32 * A refers to free thiocyanogen, B to thiocyanogen generated from salts by electrolysis, and C tothiocyanogen generated from salts by chemical reagents. TABLE IV UNSATURATED COMPOUNDS THAT ADD THIOCYANOGEN Compound Ethylene Amylene Acetylene Acetylene diiodide Phenylacetylene Tolan Styrene Stilbene Butadiene Product 1,2-Dithiocyanoethane Dithiocyanopentane 1,2-Dithiocyanoethylene 1,2-Dithiocyanoethylene 1,2-Dithiocyano-l-phenylethyl- ene l,2-Diphenyl-l,2-dithiocyano- ethylene a, /3-Dithiocyanoethylbenzene 1,2-Diphenyl-l, 2-dithiocyano- ethane . 1,4-Dithiocyanobutene-2 Method* A A C A C A A A A A A C C A A Yield 100% 75% 15% 20% 50% 26% 100% 80% 65% 83% 80% Refer- ence 33 28- 20 i 42 20,90 33 33 33 33 28 33 19 20 33 ? 35 * A refers to free thiocyanogen, B to thiocyanogen generated from salts by eleotrolysis, and C tothiocyanogen generated from salts by chemical reagents. 264 ORGANIC REACTIONS TABLE IV¡ªContinued UNSATURATED COMPOUNDS THAT ADD THIOCYANOGEN Compound Isoprene Dimethylbutadiene AUyl alcohol Anethole Isosafrole Carvone Pinene Terpineol Terpineol methyl ether Alloocimene Cyclohexene 3-Methylcyclo- hexene Methyl styryl ketone Distyryl ketone Oleic acid Elaidic acid Erucic acid Brassidic acid Petroselenic acid Linolic acid Ethyl linolate Product l,4-Dithiocyano-2-methyl- butene-2 2,3-Dimethyl-l,4-dithiocyano- butene-2 2,3-Dithiocyanopropanol 1,2-Dithiocyano-1- (p-methoxy- phenyl) -propane 4- (Dithiocy anopropyl)-l, 2- methylenedioxy benzene Dihydrodithiocyanocarvone Dithiocyanopinane Dithiocyanomenthanol Dithiocy anomenthanol methyl ether Dihydrodithiocyanoalloocimene 1,2-Dithiocyanocyclohexane l,2-Dithiocyano-3-methyl- cyclohexane ?? Methyl a-thiocyanostyryl ketone Dithiocyanodistyryl ketone 9,10-Dithiocyanostearic acid 9,10-Dithiocyanostearic acid 13,14-Dithiocyanobehenic acid 13,14-Dithiocyanobehenic acid 6,7-Dithiocyanosteario- acid Dihydrodithiocyanolinolic acid Ethyl dihydrodithiocyanolino- late Method* C cc A A C A A A A A A A C C A A A C C A C C C C A A C A A C A A A Yield 19% 11% 100% 75% 70% 62% 60% 57% 49% 45% 75% 96% 93% Refer- ence 34 20 34 28 28 19 20 28 37 91 91 91 91 73 73 37 37 80,93 92 80 93 92 94 70,72 80 94 80 92 93 94 92 80 94 95 * A refers to free thiocyanogen, B to thiocyanogen generated from salts by electrolysis, and C tothiocyanogen generated from salts by chemical reagents. REACTIONS OF THIOCYANOGEN TABLE IV¡ªContinued UNSATURATED COMPOUNDS THAT ADD THIOCYANOGEN 265 Compound ,8-Oleostearin Hydnocarpic acid Chaulmoogric acid Product /3-Oleostearin hexathiocyanate Dihydrodithiocyanohydno- carpic acid Dihydrodithiocyanochaulmoogric acid Method* A A A Yield Refer-ence 80 96 96 * A refers to free thiocyanogen, B to thiocyanogen generated from salts by electrolysis, and C tothiocyanogen generated from salts by chemical reagents. TABLE V MISCELLANEOUS COMPOUNDS SUBSTITUTED BY THIOCYANOGEN Compound Antipyrine Carbostyryl 8-Hydroxyquinoline N-Acetyldiphenyl- hydrazine N-Benzoyldiphenyl- hydrazine N-Formyldiphenyl- hydrazine N-Phthalyldi- phenylhydrazine O,N-Dibenzyl- hydroxylamine O,N-Diethyl- hydroxylamine Product 2,3-Dimethyl-l-phenyl-4-thio- cyanopyrazolone Bis-(2,3-dimethyl-l-phenyl-5- pyrazolone-4)-l-disulfide 2-Hydroxy-4-thiocyanoquinoline 8-Hydroxy-4-thiocyanoquinoline N-Acetyl-di-(4-thiocyanophenyl)- hydrazine N-Benzoyl-di-(4-thiocyano- phenyl)-hydrazine N-Formyl-di- (4-thiocy ano- phenyl)-hydrazine N-Phthaly 1-di- (4-thiocyano- phenyl)-hydrazine 0, N-Dibenzyl-N-thiocyanohy- droxylamine 0, N-Diethyl-N-thiocyanohy- droxylamine Method* A C C cc c c c c c c Yield 56% 61% 75% 64% 68% 73% 47% 40% Refer- ence 30 70 20,72 15 15,27 15 15 15 15 39 39 * A refers to free thiocyanogen, B to thiocyanogen generated from salts by electrolysis, and C tothiocyanogen generated from salts by chemical reagents. 90 U. S. pat., 1,859,399 [C. A.. 26, 3804 (1932)]. 91 U. S. pat., 2,188,495 [C. A.', 34, 3763 (1940)]. 92 Kaufmann, Gindsberg, Rottig, and Salchow, Ber., 70B, 2519 (1937). 93Kimura, Chem. Umschau Fette die Wachse Harze, 37, 72 (1930). 94 Holde, Chem. Umschau Fette die JVachse Harze, 37, 173 (1930). 96Kimura, Ber., 69, 786 (1936). 96 Arnold, Arch. Pharm., 277, 206 (1939). ? 266 ORGANIC REACTIONS TABLE V¡ªContinued MISCELLANEOUS COMPOUNDS SUBSTITUTED BY THIOCYANOGEN Compound Benzylamine Diethylamine Triphenylmethyl- amine Diphenylmercury DiethylzinQ Ethyl mercaptan Thiophenol /3-Thionaphthol p-Nitrothiophenol Triphenylphosphine Triphenylarsine Triphenylstibine Triphenylbismuth- ine Tri-a-naphthyl- bismuthine Ethyl acetoacetate Diethyl hydrocolli- dine dicarboxylate Ammonium ligno- sulfonate Product Benzylthiocyanoamine Diethylthiocyanoamine Triphenylmethylthiocyanoamine Phenyl thiocyanate Ethyl thiocyanate Ethyl thiothiocyanate Phenyl thiothiocyanate 18-Naphthylthiothiocyanate p-Nitrophenylthiothiocyanate Triphenylphosphine sulfide Triphenylarsinehydroxy thio- cyanate Triphenylstibine dithiocyanate Diphenylbismuthine dithio- cyanate Phenyl thiocyanate a-Naphthyl thiocyanate Ethyl 2-hydroxy-4-methylthia- zole-5-carboxylate Diethyl hydrocollidine dicar- boxylate dithiocyanate Ammonium thiocyanolignosul- fonate Method* C A C A A A A A A A A A A A A A A B C Yield 55% 66% 50% 70% 75% 19% 30% Refer- ence 39 6 39 1 1 40 40 40 41 42 42 42 42,43 42 43 28 30 97 97 * A refers to free thiocyanogen, B to thiocyanogen generated from salts by eleotrolysis, and C tothiocyanogen generated from salts by chemical reagents. "Sohwabe and Preu, CeUulosechem., 21, 1 (1943), CHAPTER 7 THE HOFMANN REACTION EVERETT S. WALLIS and JOHN F. LANE * Princeton University CONTENTS PAGE THE NATURE OP THE REACTION 268 THE MECHANISM OF THE REACTION 8 THE SCOPE OF THE REACTION 273 Aliphatic, Alicyclic, and Arylaliphatic Amides 273 Monoamides 273 Diamides 4 Aliphatic Monoacid-Monoamides 275 a-Hydroxy Amides 275 Ethylenic Amides 6 a,/3-Acetylenic Amides 6 a-Keto Amides ...!.... 276 Aromatic and Heterocyclic Amides 7 Aromatic Amides and Phthalimides 277 Aryl Semicarbazides and Ureas 8 Heterocyclic Amides 279 SIDE REACTIONS 279 THE CHOICE OF EXPERIMENTAL CONDITIONS AND PROCEDURES 280 EXPERIMENTAL CONDITIONS 280 The Use of Alkaline Sodium Hypobromite 280 The Use of Alkaline Sodium Hypochlorite 1 Special Conditions for the Hofmann Reaction of Higher Aliphatic Amides and of a,|8-Unsaturated Amides 282 EXPERIMENTAL PROCEDURES 3 Neopentylamine 283 Pentadecylamine 3 2-Methyl-l,4-diaminobutane 283 Wsoserine 284 7-Truxillamic acid '. 284 w-Bromoaniline 5 Phenylacetaldehyde 285 TABULAR SURVEY OF PRODUCTS AND YIELDS OBTAINED IN THE HOFMANN RE- ACTION OF AMIDES 285 * Present address, Rutgers University, New Brunswick, N. J. 267 268 ORGANIC REACTIONS THE NATURE OF THE REACTION In the Hofmann reaction an amide is converted to an amine of one less carbon atom by treatment with bromine (or chlorine) and alkali.1 In effect the carbonyl group of the amide is eliminated. The reaction is RCONH2 + Br2 + 40H- -? RNH2 + G03= + 2Br~ + 2H2O . applicable to the preparation of amines from amides of aliphatic, aro- matic, arylaliphatic, and heterocyclic acids. The Hofmann reaction generally is carried out by dissolving the amide in a very slight excess of cold aqueous hypohalite solution, followed by rapid warming (with steam distillation if the amine produced is volatile).2 A valuable modification (p. 282) consists in carrying out the reaction in an alcoholic (usually methanolic) solution, with subsequent hydrolysis of the urethan so obtained. RCONH2 + Br2 + 2OH- + R'OH -? RNHCO2R' + 2Br~ + 2H2O RNHCO2R' + H20 -> RNH2 + CO2 + ROH THE MECHANISM OF THE REACTION Hofmann found that the reaction of acetamide with equimolecular quantities of bromine and alkali yielded N-bromoacetamide. CH3CONH2 +^Br2 + 0H~ -> CH3CONHBr + Br~ + H20 Investigation of the behavior of this and other N-haloamides showed that they react with alkali to give unstable salts.3 RCONHX + OH- -? [RCONX]- + H2O In the dry state these salts undergo a decomposition wherein the organic residue migrates from the carbon atom to the nitrogen atom, the prod- ucts being isocyanates and alkali metal halides. [RCONX]- -? RN=C=O + X- In the presence of water and an excess of alkali, the isocyanates are hydrolyzed to amines. OH" OH- + RN=C=O -? [RNHCO2]- -> RNH2 + CO3- In alcoholic solution they are converted to urethans. RN=C=O + R'OH -> RNHCO2R' 1 Hofmann, Ber.. (a) 14, 2725 (1881); (6) 15, 407 (1882); (c) 15, 762 (1882); (d) 17, 1406 (1884); (e) 18, 2734 (1885); (/) 15, 752 (1882). 2 Hoogewerff and van Dorp, Rec. trav. chim., (a) 8, 252 (1886); (6) 6, 373 (1887); (c) 10, 5 (1891); (d) 10, 145 (1891); (e) 15, 107 (1896). ? Mauguin, Ann. chim., [8] 22, 297 (1911). THE HOFMANN REACTION ?269 When one-half of the usual quantities of bromine and alkali are em- ployed, alkyl acyl ureas are obtained. The isocyanates, in the absence of excess alkali, react with the sodium salts of the haloamides to give salts of the alkyl acyl ureas from which the ureas themselves result on hydrolysis.4 [RCONX]- + RN=C=O -? [RNC¡ªNXC¡ªR]~ + H2O 0 0 -? RNHC¡ªNHC¡ªR + OX~ Isocyanates derived from the higher aliphatic amides react more rapidly with the haloamide salts than with water and alkali, so that, when these amides are subjected to the Hofmann reaction in aqueous medium, only small amounts of the expected amines are formed. Although amines arise from the hydrolysis of the alkyl acyl ureas, they are largely oxidized to nitriles by the excess of hypobromite present. RNHCONHCOR + H2O -? RNH2 + RCONH2 + CO2 RCH2NH2 + 2 OX" -? RCN + 2X~ + 2H2O However, amides of this type usually may be converted in good yield to the urethans by reaction in methanol (p. 282). In addition it may be noted that amides of a,/3-unsaturated acids and of a-hydroxyacids yield aldehydes when allowed to undergo this rear- rangement. Aryl-substituted semicarbazides yield azides, and aryl-- substituted ureas yield aryl-substituted hydrazines. These reactions are discussed more fully in a subsequent section of this chapter (p. 273). The Hofmann reaction involves a rearrangement quite similar to the Curtius rearrangement and to the Lossen rearrangement, as indicated by the following equations.6'6 0 [RC¡ªNX]- -> RN=C=O +X- (Hofmann) O RC¡ªN3 -? RN=C=O + N2 (Curtius) 0 [RC¡ªNOCOR']- -? RN=C=O + RCO2~ (Lossen). 4 (a) Stieglitz and Earle, Am. Chem. J., 30 412 (1903); (jb) Jeffreys, ibid., 22 14 (1899) 6 Stieglitz rind Slosson, Ber., 34, 1613 (1901); Stieglitz, J. Am. Chem. Soc., 30, 1797 (1908); Stieglitz and Peterson, Ber., 43, 782 (1910); Peterson, Am. Chem. J., 46,325 (1911)j Stieglitz and Vosburgh, Ber., 46, 2151 (1913); Stieglitz, Proc. Natl. Acad. Sci., 1,196 (1915). 6 Tiemann, Ber., 24, 4163 (1891). 270- ORGANIC REACTIONS Any of these reactions may be formulated by the general equation 7> 8 R:C:N:A B A:B + R:C:N R:N::C::O: and the driving force of rearrangement may be presumed to arise from the tendency of the electronically deficient nitrogen atom of the fragment (I) to acquire electrons from the neighboring carbon atom. The rate-determining step in the Hofmann rearrangement apparently is the release of the halide ion from the haloamide anion. This follows from a quantitative study of the effect of m- and p-substituents on the rates of rearrangement of benzamide derivatives.9 Thus, substituents Y that promote electron release through the carbonyl group (like methyl and methoxyl, which decrease the acidic strength of the corresponding benzoic acids) facilitate the rearrangement. K+ Conversely, substituents that withdraw electrons (like nitro and cyano groups, which increase the acidity of the corresponding benzoic acids) retard the rearrangement. The same effects are observed with substitu- ents Y in the salts of O-aroylbenzohydroxamic acids, while for substitu- ents Z the inverse effects obtain. K+C:N:0C0 Studies have been made on the mechanism of isomerization of the transient intermediate (I). It is now definitely established that in this isomerization the group R never becomes free during its migration from carbon to nitrogen. Thus the action of bromine and alkali on (+) 2-methyl-3-phenylpropionamide gives optically pure (+)2-amino-3- phenylpropane.10 The same optically pure amine may be obtained from (+)2-methyl-3-phenylpropionazide by the Curtius rearrangementu as 0 7 Jones, Am. Chem. J., 50, 414 (1913). ' Whitmore, J. Am. Chem. Soc, 54, 3274 (1932). "Hauser and coworkers, J. Am. Chem. Soc., (o) 59, 121 (1937); (6) 60, 2308 (1937); 61, 618 (1939). 10 Wallis and Nagel, J. Am. Chem. Soc, 53, 2787 (1931). i u Jones and Wallis, J. Am. Chem. Soc, 48, 169 (1926). THE HOFMANN REACTION 271 well as from derivatives of (+)2-methyl-3-phenylpropionylhydroxamic acid by the Lossen rearrangement. Moreover, the Hofmann rearrange- ment of (+)3,5-dinitro-2-a-naphthylbenzamide leads to optically pure (+)3,5-dinitro-2-a-naphthylaniline.12 Here optical activity is due to NO O2N restriction of rotation about the pivot bond between the benzene and naphthalene nuclei. If at any time during migration the migrating group had been free, the restriction would have been removed, and at least par- tial racemization would have occurred. Similar results have been ob- served in the Curtius rearrangement.13 Thus, in the rearrangement of CH; CHs, o-(2-methyl-6-nitrophenyl)-benzazide, the amine obtained is optically pure. Further support for this conclusion is found in the results of studies on the Hofmann reaction of amides such as ^,/3,/3-triphenylpropionamide 14 and /3,^-dimethylbutyramide.16 Here the migrating groups R3CCH2, if free, are extremely susceptible of rearrangement. From these amides, however, only the expected amines, i.e., /3,/3,|8-triphenylethylamine and neopentylamine, are obtained. The absence of interference of triphenylmethyl radicals in the Curtius rearrangement of acid azides 16 also is in agreement with this conclusion. In fact, experimental evidence indicates that this latter rearrangement is also unimolecular.17 Unfortunately, no quantitative studies have 15 Wallis and Moyer, J. Am. Chem. Soc, 55, 2598 (1933). 13 Bell, J. Chem. Soc, 1934, 835. " Hellermann, J. Am. Chem. Soc, 49, 1735 (1927).15 Whitmore and Homeyer, J. Am. Chem. Soc, 54, 3435 (1932). ' " Powell, J. Am. Chem. Soc, 61, 2436 (1929); Wallis, ibid., 51, 2982 (1929). "Barrett and Porter, J. Am. Chem. Soc, 63, 3434 (1941); Jones and Wallis, ibid., 48, 169 (1926); Porter and Young, ibid., 60, 1497 (1938). 272 ORGANIC REACTIONS been made, as of the Hofmann rearrangement, to show the rate-determin- ing step in this process, and hence its true mechanism is still not clearly denned. It has been established also that in rearrangements of this type the group R does not undergo a Walden inversion. Amines so obtained may be regarded as configurationally identical with the parent acids. Thus, the d, I, and dl forms of /3-camphoramidic acid on treatment with bromine and alkali yield aminodihydrocampholytic acids (II) in which the amino group is cis to the carboxyl group.18 A similar retention of configuration CH3 CH CONH2 11 NH2 accompanies the conversion of d and Z-a-camphoramidic acids to the corresponding amino acids (III).19 A further, though somewhat indi- CO2H rect, proof of the retention of configuration in the Hofmann reaction has been reported in connection with studies of replacement reactions occur- ring at a bridgehead in derivatives of apocamphane,20 while retention of configuration in the Curtius rearrangements of the azides of 1-methyl- quinic and of dihydroshikimic acids has been observed.21 Although 18 Noyes, Am. Chem. J., 24, 290 (1900); 27,432 (1902); Noyes and Knight, J. Am. Chem. Soc, 32, 1672 (1910); Noyes and Nickell, ibid., 36, 124 (1914). 19 (a) Noyes, Am. Chem. J., 16, 506 (1894); Noyes and Littleton, J. Am. Chem. Soc., 39, 2699 (1917); (5) Weir, J. Chem. Soc, 99, 1273 (1911). 20 Bartlett and Knox, /. Am. Chem. Soc., 61, 3184 (1939). 11H. O. L. Fischer and (workers, Ber., 65, 1009 (1932); Helv. Chim. Ada, 17, 1200 (1934). THE HOFMANN REACTION 273 the difficulty of relating rotation to configuration has as yet prevented extensive confirmation of the absence of Walden inversion in the Hof- mann rearrangement of aliphatic amides, the point in question has been studied in the Curtius rearrangement of optically active azides of the type, R1R2R3CC¡ªN322 and has been conclusively proved for the closely analogous Wolff rearrangement. Thus (+)l-diazo-3-phenyl-3-methyl- heptanone-2 rearranges to the configurationally identical (optically pure) (¡ª)j3-phenyl-/3-methylenanthic acid.23 This fact, in conjunction with the results obtained in cyclic systems, leaves no doubt that the Hof- 0 ? O ? 11 H 11 xlII ?? II ?? H.0 (+)RC:C:N2 -*? RC:C-r ¡ª^ (-)RCH2CO2H R mann reaction also always involves retention of configuration. Any doubts incurred from conflicting or inconclusive results of studies of this type of rearrangement on geometrical isomers need not be taken too seriously. No one has submitted any evidence to show that cis,trans isomeric changes do not precede rearrangement of this type.24 THE SCOPE OF THE REACTION Aliphatic, Alicyclic, and Arylaliphatic Amides Monoamides. Good yields of the corresponding monoamines are obtained from aliphatic monoamides unless the latter contain more than eight carbon atoms, and with such amides a modification of the usual procedure4t-26 (p. 282) using methanol gives satisfactory results. Lau- ramide on treatment with aqueous alkaline hypobromite solution gives largely N-undecyl-N'-lauryl urea,26 but treatment of the amide in meth- anol with sodium methoxide and bromine gives a 90% yield of methyl 22 Kenyon and Young, /. Cfiem. Soc, 1941, 263. 23 Lane and Wallis, J. Am. Chem. Soc, 63, 1674 (1942). 24 Jones and Mason, J. Am. Chem. Soc, 49, 2528 (1927); Alder and coworkers, Ann., 514, 211 (1934); Skita and Rossler, Ber., 72, 416 (1939). 26 Jeffreys, Ber., SO, 898 (1897). 26 Ehestadt, dissertation, Freiburg i.B., 1886. 274 ORGANIC REACTIONS undecylcarbamate which may be converted with negligible loss to the desired undecylamine. 2C11H23CONH2 Na0BV CiiH23CONHCONHCiiH23 H2O ^> CuHj8NHa H2O This method also has been applied with advantage to the production of alicyclic monoamines from monoamides. The isomeric 0-, m~, and p-hexahydrotoluamides have been converted through the urethans to the corresponding aminomethylcyclohexanes in approximately 70% yield.27 Similarly camphane-4-carboxamide has been converted to 4-aminocam- phane (56% yield). Although many conversions of alicyclic monoamides to alicyclic amines have been carried out by the usual procedure (aque- ou# alkaline hypobromite) the yields have not been reported. No special difficulties are encountered with arylaliphatic amides unless the aromatic ring contains hydroxyl or a derived function, in which event low yields may result from side reactions involving halogenation of the ring. /3-(p-Methoxyphenyl)-propionamide gives on treatment with aqueous alkaline hypobromite only 35% of the desired (3-p-methoxy- phenethylamine,28 while p-hydroxybenzamide yields exclusively 2,6- dibromo-4-aminophenol.29 /J-(3-Benzyloxy-4-methoxyphenyl)propion- amide 30 and /3-(m-benzyloxyphenyl)propionamide 31 give none of the amines. Sodium hypochlorite, which leads to a more rapid rearrange- ment, may be used to advantage in the treatment of many amides con- taining phenolic or aromatic ether functions (p. 281). Thus, piperonyl- acetamide on treatment with aqueous alkaline hypochlorite gives a 50% yield of homopiperonylamine.32 Diamides. Diamides of adipic acid and its higher homologs are converted to diamines by aqueous alkaline hypobromite or hypochlorite solutions.33 H2NCO(CH2)nCONH2 -? H2N(CH2)?tfH2 (n > 6) Application of the reaction to glutaramide has not been reported. Suc- cinamide is converted not to ethylene diamine but to dihydrouracil (IV), 17 Gut, Ber., 40, 2065 (1907). KBarger and Walpole, J. Chem. Soc., 95, 1724 (1909). 29 Van Dam, Bee. trav. chim., 18, 418 (1899). 80 Robinson and Sugasawa, J. Chem. Soc., 1931, 3166. llSchopf, Perrey, and Jackh, Ann., 497, 49 (1932). 32 Decker, Ann., 395, 291 (1913); Haworth, Perkin, and Rankin, J. Chem. Soc., 125, 1694 (1924). 33 (a) von Braun and Jostes, Ber., 59,1091 (1926); (6) von Brenkeleveen, Rev. trav. chim., 13, 34 (1894); (c) Sjolonina, Bull. soc. chim., [3] 16, 1878 (1896); (d) Bayer and Co., Ger. pats. 216,808, 232,072 [Chem. Zentr., I, 311 (1910); I, 938 (1911)]; (e) von Braun and Lemke, Ber., 55, 3529 (1922). THE HOFMANN REACTION 275 which evidently is formed by the reaction (p. 269) leading to alkyl acyl ureas.34 If an excess of alkali is employed at higher temperature /S- alanine is produced. The action of aqueous alkaline sodium hypochlorite on diethyl malonamide leads, in analogous fashion, to C,C-diethyl- hydantoin (V). Similarly maleinamide is converted to uracil (VI).36 CH2 CH2 (C2H6)2C NH CH= NH CO CO CO CO NH N CO NH H IV V VI Aliphatic Monoacid-Monoamides. The action of a dilute solution of barium hydroxide and barium hypobromite converts i-^-malamidic acid to Z-isoserine 36 (45% yield), and the same reagent converts Z-acetylaspar- agine to Z-2-imidazolidone-5-carboxylic acid (15% yield) from which l(+) /3-aminoalanine (60% yield) is obtained on acid hydrolysis.37 Higher amidic acids, like the higher monoamides, are best treated with sodium methoxide and bromine in methanol solution instead of with aqueous hypochlorite or hypobromite. Sebacamidic acid, for example, can be converted to co-carbomethoxyaminopelargonic acid in 74% yield.38 The alicyclic amidic acids are converted easily to amino acids. With aqueous alkaline hypochlorite the isomeric truxillamidic and trux- inamidic acids give the corresponding truxillamic and truxinamic acids in yields of 70-85%,39 cc-Camphoramidic acid is converted by aqueous alkaline hypobromite to 3c-ammo-l(,2,2-trimethylcyclopentane-l-carboxylic acid (formula III, p. 272) in 70% yield,19 while the conversion of /3-camphoramidic acid by this reagent to 3c-amino-2,2,3'-trimethylcyclopentane-lc-carboxylic acid (formula II, p. 272) is quantitative.18 a-Hydroxy Amides. Aldehydes are obtained when aqueous sodium hypochlorite acts on amides of a-hydroxyacids. fRCHNHa] L OH J RCHCONH2 -* [RCHNHal -? RCHO + NHS OH M Weidel and Hoithner, Monatsh., 17, 183 (1896). 36 Rinkes, Rec. trav. chim., 46, 268 (1927). 36 Freudenberg, Ber., 47, 2027 (1914). 87 Karrer, Helv. Chim. Ada, 6, 415 (1923). 38 Flaschentrager and Gebhart, Z. physiol. Chem., 192, 250 (1930). 39 (a) Stoermer and Schmidt, Ber., 58, 2716 (1925); (6) Stoermer and Sohenk, Ber., 60, 2575 (1927); (c) Stoermer and Schenk, Ber., 61, 2312 (1928); (d) Stoermer and Keller Ber., 64, 2783 (1931); (e) Stoermer and Asbrand, Ber., 64, 2793 (1931). 276 ORGANIC REACTIONS From d-gluconamide, d-arabinose results in 50% yield. Z-Arabinonamide gives a 30% yield of Z-erythrose. Similarly, benzaldehyde has been obtained from mandelamide.40 Ethylenic Amides. a,/3-Unsaturated amides give satisfactory yields of urethans when treated with methanolic sodium hypochlorite.41 Thus, cinnamic amide gives a 70% yield of methylstyrylcarbamate C6H6CH=CHCONH2 Na°C1> C6HBCH=CHNHCO2CH3 CHgOH Hydrolysis of these urethans leads directly to aldehydes, as would be. expected, and therefore is best carried out in an acid medium. Poor yields attend the conversion of /3,T- and 7,5-unsaturated amides to the corresponding unsaturated amines. Only 20% of the theoretical amount of l-amino-2-cycloheptene was obtained from 2-cycloheptene- 1-carboxamide.42 A yield of less than 15% is reported in the preparation of 2,3,3-trimethyl-l-cyclopentenylcarbinylamine from 2,3,3-trimethyl- 1-cyclopentenylacetamide.43 In the conversion of 2,2-dimethyl-3- methylenecyclopentanecarboxamide to the corresponding amine, the amine was isolated in a yield of only 40%." a,p-Acetylenic Amides. With a,/3-acetylenic amides the Hofmann reaction leads to the formation of nitriles.45 RC=sCCONH2 -> [RC=CNH2] -> RCH2C=N N-Chloro-2-octynamide, for example, on treatment with barium hydrox- ide gives a 70% yield of enanthonitrile. a-Keto Amides. The expected products of the Hofmann reaction of a-keto amides (RC0C0NH2) would be amides (RCONH2). For the only amide of this type investigated (benzoylformamide), however, it appears O that in the intermediate aroyl isocyanate (C6H5C¡ªN=C=0) the / C¡ªN linkage is more susceptible of solvolysis than the ¡ªN=C¡ª linkage, so that benzoic acid or methyl benzoate is the only product isolated.46 40Weerman, Rec. trav. chim., 37, 16 (1918). 41 Weerman, (a) Ann., 401, 1 (1913); (6) Rec. trav. chim., 37, 2 (1918). 42 Willstatter, Ann., 317, 243 (1901). "Blaise and Blanc, Bull. soc. chim., [3] 21, 973 (1899). "Forster, J. Chem. Soc, 79, 119 (1901). 46 Rinkes, Rec. trav. chim., 39, 704 (1920). , 46Rinkes, Rec. trav. chim., (a) .39, 200 (1920); (6) 45, 819 (1926); (c) 48, 960 (1929). THE HOFMANN EEACTION 277 Aromatic and Heterocyclic Amides Aromatic Amides and Phthalimides. Benzamide, naphthamide, and their homologs are converted smoothly by aqueous alkaline hypo- bromite solutions to the corresponding aromatic amines. If free or methylated phenolic hydroxyl groups are present in aromatic amides, however, halogenation of the ring is likely to occur with serious lowering of the yield. This effect is minimized by the use of hypocBlorite and a large excess of alkali, the rearrangement then being rapid enough to com- pete favorably with the side reaction of halogenation. Thus veratric amide is converted by alkaline hypochlorite to 4-aminoveratrole in 80% yield.17 With the same reagent salicylamide gives an 80% yield of 4,5- benzoxazolone, from which o-aminophenol results in 90% yield on acid hydrolysis.48 Extensive application of the reaction has been made in the production of anthranilic acid from phthalimide and of substituted anthranilic acids from substituted phthalimides. While isomeric anthranilic acids theo- retically are derivable from certain phthalimides, one usually predomi- nates or forms exclusively. Generally it is possible to correlate the pre- dominance of one product over the other with the known electronic and vicinal effects of the substituents. Formation of an N-haloimide is fol- 0II lowed by hydrolytic fission of one of the C¡ªN bonds in the alkaline medium to generate a carboxylate ion and an N-haloamide ion. Ejec- tion of a halide ion X~ and rearrangement lead to the ultimate produc- tion of the anion of the amino acid. >>CCO2- >CCO2- | >NH -> | >NX -> | -> | >C¡ªCO >C¡ªCO >CC0NX~ >CNH2 Since it is known that the hydrolysis of benzamides is facilitated by sub- O stituents which withdraw electrons from the C¡ªN linkage into the ring,49 it is evident that in the Hofm'ann reaction of 4-nitrophthalimide, 47 Buck and Ide, Org. Syntheses, Coll. Vol. 2, 44 (1943). ^Graebe and Rostowzev, Ber., 38, 2747 (1902). 49 Hammett, "Physical Organic Chemistry," McGraw-Hill Book Co., New York, 1940, p. 188. 278 ORGANIC REACTIONS for example, the nitro group by withdrawing electrons at position 1 will 0 cause preferential hydrolysis of the ¡ªC¡ªN linkage at this point, with subsequent rearrangement at position 2. Actually, 70% of the theo- retical amount of the expected 4-nitroanthranilic acid is formed.60'61 Similarly, the expected product from 3-nitrophthalic acid, 6-nitroan- C02H thranilic acid (i.e., hydrolysis at position 2), is obtained in 80% yield. Furthermore, it is known that a methoxyl group in the ortho position to OII the C¡ªN linkage in a substituted benzamide is much less effective in promoting hydrolysis than the same substituent in the para-position. In the Hofmann reaction of 3,4-dimethoxyphthalimide, hydrolysis of the O II C¡ªN linkage should occur preferentially at the 1 -position. Only the ex- CH3O pected 3,4-dimethoxyanthranilic acid is formed (35% yield).62 Successful application of the reaction has also been made to the half- amides of aromatic dicarboxylic acids. For example, 2-carboxy-4,5- dichlorobenzamide is converted readily by the action of alkaline sodium hypochlorite to 4,5-dichloroanthranilic acid.63 Aryl 'Semicarbazides and Ureas. An interesting application of the Hofmann reaction has been made to aryl semicarbazides MSeidel and Bittner, Monatsh., 23, 418 (1902). 51 Kahn, Ber., 35, 471 (1902). 62 Kuhn, Ber., 28, 809 (1905). ?? Villiger, Ber., 42, 3547 (1909). THE HOFMANN REACTION 279 (ArNHNHCONH2).64 These compounds are first oxidized by hypo- chlorite to aryl diazocarboxamides ArNHNHCONH2 + OC1" -> ArN=NCONH2 + H2O + Cl~ which apparently undergo the usual rearrangement, the expected prod- uct (ArN¡ªN¡ªNH2), however, being immediately oxidized by hypo- chlorite to an aryl azide (ArN3). The overall reaction thus consumes three molecules of hypochlorite. ArNHNHCONH2 + 3 OC1" + 2 OH~ -? ArN3 + 3H2O + CO2" + 3C1~ Phenyl semicarbazide may be converted to phenyl azide in 30% yield. Further examples are included in the tables at the end of the chapter. A limited application of the reaction has been made to aryl ureas. N-Chloro-N'-2,4,6-trichlorophenylurea gives 2,4,6-trichlorophenylhydra- zine on treatment with alkali. N-Chloro-N'-phenylurea, however, gives p-chlorophenylhydrazine as the only isolable product. The yields in these reactions are reported as very poor.66 Heterocyclic Amides. Little use has been made of the reaction in the degradation of amides containing a five-membered heterocyclic ring attached to the carbonyl group. l,2,2,5,5-Pentamethylpyrrolidine-3- carboxamide has been converted to l,2,2,5,5-pentamethyl-3-aminopyr- rolidine by the action of alkaline potassium hypobromite, but the yield is not stated.68 An unsuccessful attempt to convert isoxazole-5-carboxam- ide to the corresponding amine also has been reported.67 The action of alkaline hypobromite, however, converts the isomeric picolinamides to aminopyridines,58 and 3- and 4-quinolinecarboxamides to the corresponding aminoquinolines.69 Pyridine-3,4-dicarboxamide has also been converted to 3-amino-4-picolinic acid.60 The yields in these reactions, however, rarely have been given (see table). SIDE REACTIONS With higher aliphatic amides as well as with many alicyclic amides the most serious side reaction is that leading to the formation of alkyl acyl ureas (p. 269). As noted elsewhere (pp. 282, 269), this reaction is sup- " Darapsky, J. prakt. Chem., 76, 433 (1907). 66 Elliott, J. Chem. Soc, 123, 804 (1923). 66 Pauli and Schaum, Ber., 34, 2289 (1901). 67 Freri, Gazz. chitn. tied., 62, 459 (1932). 68 (a) Pollak, Monatsh., 16, 54 (1895); Phillips, Ann., 288, 263 (1895); (6) Camps, Arch. Pharm., 240, 354. 68Claus and Howitz, J. prakt. Chem., [2] 50, 237 (1894); Claus and Frobenius, ibid., [2] 66, 187 (1897); Wenzel, Monatsh., 15, 457 (1894). 60 Gabriel and Coleman, Ber., 35, 2844, 3847 (1902). 280 ORGANIC REACTIONS pressed practically completely when the aqueous alkaline hypobromite solution customarily employed is replaced by methanolic sodium methox- ide and bromine. The low yields attending the rearrangement of unsaturated amides have been attributed41a to interference by the reaction just discussed coupled with oxidation of the double bond by the hypobromite present. The products of oxidation have not been isolated and characterized, how- ever. Such reactions may be avoided with a,/3-unsaturated amides by employing methanolic sodium hypochlorite (p. 282), but the action of this reagent on other types of unsaturated amides has yet to be investi- gated. With aromatic amides, hydrolysis prior to rearrangement may occur to such an extent that the yield is lowered seriously. Amides like p-nitrobenzamide, having a substituent which withdraws electrons from / the C¡ªN linkage, are particularly susceptible, since the withdrawal of electrons facilitates hydrolysis and inhibits rearrangement. The rear- rangement, however, has a higher temperature coefficient than the hydrolysis, so that a high reaction temperature (90-100°) reduces the interference to negligible proportions.9 Substituents like hydroxyl or methoxyl facilitate rearrangement but also promote the halogenation of the ring, particularly by hypobromite. The use of sodium hypochlorite to circumvent such interfering ring halo- genation has been discussed (pp. 274, 277). THE CHOICE OF EXPERIMENTAL CONDITIONS AND PROCEDURES The Use of Alkaline Sodium Hypobromite. The procedure most commonly adopted in carrying out the Hofmann reaction is essentially that developed by Hoogewerff and van Dorp,2 in which the amide is first dissolved in a cold alkaline solution of sodium or potassium hypobromite. Rearrangement to the amine then occurs when the resulting solution is warmed to about 70°. A generally satisfactory procedure is the follow- ing: A solution of sodium hypobromite is prepared at 0° by adding bro- mine (0.6 cc; 0.012 mole) to a solution of sodium hydroxide (2.4 g., 0.06 mole) in 20 cc. of water. To the cold solution is added the finely divided amide (0.01 mole), and the mixture is stirred until solution is complete. The solution is warmed to 70-80° to effect rearrangement, and after a short time (usually fifteen to twenty minutes) it is subjected to distilla- tion with steam, the product being collected in a slight excess of dilute hydrochloric acid. Evaporation of the distillate gives the hydrochloride THE HOFMANN REACTION 281 of the desired amine, which is freed from impurities by washing with ether. If the amine is not volatile with steam, it may be removed from the reaction mixture by extraction with ether and precipitated as the hydrochloride from a dry ethereal solution with gaseous hydrogen chlo- ride. If the amine solidifies readily, it frequently can be removed from the reaction mixture by filtration and purified by recrystallization from a suitable solvent. Alternatively, if the benzoyl derivative of the amine is desired, as for example when the amine is to be used in the von Braun reaction, it can be prepared directly by stirring benzoyl chloride and sodium hydroxide into the reaction mixture after the rearrangement has been completed.33" An excess of bromine amounting to 10-20% is advisable, since even with the most carefully prepared hypobromite solutions only 80 to 90% of the expected activity is realized.61 A larger excess is usually to be avoided, however; otherwise the yield of amine may be seriously reduced by the side reactions discussed earlier. Occasionally, if the resulting amine is relatively unreactive toward the reagent, a considerable excess of both alkali and bromine may be employed without adverse conse- quences, sometimes, indeed, to considerable advantage when the amide is also unreactive. Thus 3,5-dinitro-2-a-naphthylbenzamide is con- verted most smoothly to 3,5-dinitro-2-a-naphthylaniline when the amide (0.01 mole) is treated with a hypobromite solution prepared from 0.16 mole (8 cc.) of bromine and 1.5 mole (60 g.) of sodium hydroxide in 100 cc. of water.12 In addition, it must be emphasized that only hypobromite solutions which have been freshly prepared are satisfactory. Serious loss of activity always occurs on standing, even in the dark.61 The Use of Alkaline Sodium Hypochlorite. Although alkaline hypo- bromite solutions have been used more generally in the Hofmann reac- tion (primarily because bromine is easily weighed or measured volumet- rically), sodium hypochlorite has certain advantages. The use of this reagent permits a lower reaction temperature and in many instances re- sults in a distinctly higher yield of the desired amine, particularly when the amide possesses either protected or unprotected aromatic hydroxyl groups.48- 62 The maximum yields obtainable with hypobromite and with hypochlorite in the conversion of some phthalimides to the corre- sponding anthranilic acids, summarized in the accompanying table, clearly show the advantage of using sodium hypochlorite. Distinctly better results with-hypochlorite are reported also in the conversion of o- benzylbenzamide to o-benzylaniline. A 0.5 N solution of sodium hypo- chlorite, suitable for use in the Hofmann reaction, may be prepared by 61 Graebe, Ber., 35, 2753 (1902). 62 Cf. also Bayer and Co., Ger. pat. 233,551 [Chem. Zentr., I, 1263, 1334 (1911)]. 282 ORGANIC REACTIONS allowing 210 g. of concentrated hydrochloric acid (sp. gr. 1.17) to flow through a dropping funnel onto 16.15 g. of potassium permanganate in an ordinary distilling flask and collecting the chlorine so produced in 11. of cold 10% sodium hydroxide. When y-truxillamidic acid is treated MAXIMUM YIELDS OF ANTHRANILIC ACIDS OBTAINABLE FROM PHTHALIMIDES BY THE HOFMANN REACTION WITH ALKALINE HYPOCHLOBITE AND HYPOBROMITE 4S Phthalimide 3,6-Dichlorophthalimide Trichlorophthalimide Tetrachl<5rophthalimide Hypochlorite 95% 90 90 98 Hypobromite 75% 73 76 95 with the theoretical quantity of this solution at 40° for two hours, y- truxillamic acid is produced in 68% yield.396' 63 The concentration of . sodium hypochlorite in the solution, which is reasonably stable in the dark, may be determined directly from the weight of permanganate used (10 g. KMnO4 o 11 g. Cl2). Special Conditions for the Hofmann Reaction of Higher Aliphatic Amides and of a,p-Unsaturated Amides. As mentioned earlier, amides of the higher aliphatic acids are converted to the corresponding amines in poor yield by the usual technique. Such amides, however, are smoothly converted to methyl carbamates if bromine (1 mole) is added rapidly with thorough mixing to a methanolic solution of the amide (1 mole) con- taining sodium methoxide (2 moles). RC0NH2 + Br2 + 2NaOCH3 -> RNHCO2CH3 + 2NaBr + CH30H Warming the solution completes the reaction in a few minutes. The urethan is isolated easily from the reaction mixture, and the amine may be obtained in good yield by saponification with sodium, potassium, or calcium hydroxide (p. 283).ib'25 A somewhat similar procedure is recommended for the degradation of amides of a,/3-unsaturated acids. The amide, dissolved in methanol, is treated with the theoretical amount of a solution 0.8 M in both sodium hypochlorite and sodium hydroxide. The conversion of the a,/3-unsatu- ? rated amide to the urethan (which in many instances crystallizes directly from the reaction mixture) occurs rapidly when the solution is warmed on the water bath. Hydrolysis of the urethan in acid medium then gives the corresponding aldehyde in good yield. This method has been applied successfully to the amides of several types of a,/3-unsaturated acids.41' a 63 Bernstein and Wallis, J. Org. Chem., 7, 261 (1942). THE HOFMANN REACTION 283 EXPERIMENTAL PROCEDURES Neopentylamine.16 Two and four-tenths cubic centimeters of bromine is added dropwise to a solution of 7.2 g. of sodium hydroxide in 60 cc. of water cooled to 0°. To the clear yellow solution is added immediately 3.50 g. (0.0304 mole) of /3,/J-dimethylbutyramide (m.p. 131°), and stirring is continued for one hour after the amide dissolves. The reaction mixture is then warmed slowly. At room temperature a yellow turbidity appears; at about 50° the solution becomes colorless and an oily layer separates. One hundred cubic centimeters of water is added, and the mixture is dis- tilled until no more oil comes over. The distillate is collected in dilute hydrochloric acid. The yellow solution becomes colorless on heating and on evaporation yields neopentylamine hydrochloride as a white crystalline residue. The residue is dissolved in absolute ethanol, and the solution is evaporated to dryness and washed with ether. The product is dried to constant weight (3.60 g., 94%) in vacuum; m.p. (dec.) 273°. Pentadecylamine.46 A solution of 25.5 g. (0.10 mole) of palmitamide in 90 cc. of methanol is mixed with a solution of 4.6 g. (0.20 atom) of sodium in 145 cc. of methanol. To this solution is added with thorough mixing 16 g. (0.10 mole) of bromine. The resulting solution is heated for ten minutes on the water bath, after which it is rendered just acid with acetic acid. The methanol is then removed. The product is washed with water to remove sodium bromide. It is then dissolved in ligroin. The ligroin solution is filtered to remove traces of palmitamide, the ligroin is removed by evaporation, and the product is recrystallized twice from ethanol. The yield of pure methyl pentadecylcarbamate (m.p. 61-62°) is 24-27 g. (84-94%). ? The urethan (20 g.) is thoroughly mixed with 70 g. of calcium oxide to which 30 cc. of water has been added. The mixture is distilled, and the distillate is taken up in ligroin. The ligroin solution is first dried over potassium hydroxide, then over sodium. Finally the solvent is removed by evaporation, and the product is distilled twice over sodium. The yield of pure pentadecylamine (m.p. 36.5°; b.p. 298-301°) is almost quantitative. 2-Methyl-l,4-diaminobutane.33<" Fifty-one grams of bromine is stirred into a mixture of 71 g. of sodium hydroxide, 142 cc. of water, and 200 g. of ice. To the resulting solution 25 g. (0.16 mole) of /S-methyl- adipamide is added in small portions with stirring. The mixture is warmed on the water bath until clear, and heating is continued until four hours in all have elapsed. The solution is then cooled, filtered, and shaken with 60 g. of benzoyl chloride. The crude dibenzoyl derivative is 284 ORGANIC REACTIONS removed by nitration and recrystallized twice from 95% ethanol. The yield of pure product is 35 g. (72%). The hydrochloride of 2-methyl-l,4-diaminobutane is obtained readily by heating the dibenzoyl derivative in a sealed tube for three hours at 130° with an excess of concentrated hydrochloric acid. Z-Isoserine.36 To a solution of 20 g. (0.15 mole) of ^/3-malamidic acid in 530 cc. of 0.0286 N barium hydroxide is added a solution of 25 g. of bromine in 650 cc. of water. After five minutes the clear, reddish brown solution is poured into 2400 cc. of 0.0286 N barium hydroxide. The color disappears. Over a period of one hour the temperature of the reaction mixture is gradually raised to 90°, at which temperature it is kept for an additional hour. It is then boiled for a short time, saturated with carbon dioxide, and the solution finally decanted from the precipitate. The hot solution is treated with a slight excess of sulfuric acid and then boiled for one hour with a large amount of lead dioxide until the evolution of am- monia ceases and the hydrobromic acid is destroyed. The filtered solu- tion is freed from lead with hydrogen sulfide and evaporated to a volume of 50 cc. Hot ethanol is then added until a slight turbidity appears, and the mixture is finally poured cautiously into 500 cc. of boiling ethanol. Z-Isoserine precipitates immediately. Eight grams of a crude product is obtained which on recrystallization from water gives 7 g. (45%) of pure Z-isoserine; m.p. (dec.) 200°. y-Truxillamic Acid.396' M A 0.5 N solution of sodium hypochlorite is prepared by allowing 21.0 g. of hydrochloric acid (sp. gr. 1.17) to flow through a dropping funnel onto 1.62 g. of potassium permanganate in an ordinary distilling flask. The chlorine so produced is collected in 100 cc. of cold aqueous 10% sodium hydroxide. To 2.95 g. (0.010 mole) of 7-truxillamidic acid is added 40 cc. of this solution. The mixture is then kept at 85^40° for two hours. At the end of this time it is cooled to room temperature, neutralized with dilute hydrochloric acid, and finally made just basic to litmus with dilute sodium hydroxide solution. The solution is filtered to remove a small amount of insoluble material, and carbon dioxide is passed through the filtrate until a precipitate begins to form (at this point, if too much sodium hydroxide solution has been added, it is sometimes necessary to add a few drops of hydro- chloric acid to induce precipitation). Carbon dioxide is then passed through the solution for an additional hour, at the end of which time 2.18 g. (68% of pure -y-truxillamic acid trihydrate has separated. The dried product is insoluble in most solvents; it can be characterized as the methyl ester, m.p. 83.5-84°. By acidification of the aqueous mother, liquor, unchanged 7-truxillamidic acid may be recovered. THE HOFMANN REACTION 285 m-Bromoaniline.64 A solution of 10.2 g. of potassium hydroxide and 10.8 g. of bromine in 100 cc. of water is poured on 12 g. (0.060 mole) of m-bromobenzamide. The mixture is then added to a solution of 14.4 g. of potassium hydroxide in 25 cc. of water. The temperature is main- tained at 70-75° for about forty-five minutes. Finally the amine is dis- tilled with steam. The yield of crude m-bromoaniline so obtained is 8.9 g. (87%); it distils without decomposition at 250°. Phenylacetaldehyde.41 An alkaline solution of sodium hypochlorite is prepared by passing 55 g. of chlorine into a mixture of 600 g. of cracked ice and a cold solution of 100 g. of sodium hydroxide (95%) in 150 cc. of water. Water is then added until the total volume of the^solution is 11. (The solution is best kept in the dark until used.) To a solution of 14.7 g. (0.1 mole) of cinnamic amide (m.p. 147°) in 125 cc. of methanol is added 130 cc. of the stock solution of sodium hypochlorite. The mixture is warmed on the water bath. A thick sludge of crystals soon forms. The mixture is cooled rapidly and filtered, and the crystals are washed with dilute ethanol and with water. The yield of methyl styrylcarbamate so obtained is 13 g. (70%), m.p. 117-118°. Twenty-five grams of the urethan is dissolved in 100 cc. of warm ethanol, and to the solution is added gradually 48 cc. of 6 N sulfuric acid. Carbon dioxide is evolved, and some urethan precipitates, but redis- solves quickly when the solution is warmed. When all the sulfuric acid has been added, the aldehyde is distilled at once with steam. The product so obtained is a colorless oil, b.p. 9O-92°/20 mm. The yield is good. TABULAR SURVEY OF PRODUCTS AND YIELDS OBTAINED IN THE HOFMANN REACTION OF AMIDES The following table summarizes examples of the Hofmann reaction reported prior to September 1942. The amides are listed by their molecular formulas in the order of increasing number of carbon atoms. Within a group having the same number of carbon atoms, the listing is arranged so that amides having one oxygen and one nitrogen atom ap- pear first in the order of increasing hydrogen content, next those having two or more oxygen atoms and one nitrogen atom in the same order, then those having one oxygen atom and two nitrogen atoms and so on, until finally the list is concluded with amides containing other elements be- sides carbon, hydrogen, oxygen, and nitrogen. An exception to this order is to be found in the listing of N-bromoamides which have first been prepared in a pure state and then treated with aqueous or alcoholic 64 Beokmann and Correns, Ber., 55, 850 (1922). 286 ORGANIC REACTIONS alkali to effect the rearrangement. These are listed in parentheses under the parent amides. The second column lists the name of the amide, and the third column describes the hypohalite used. Unless otherwise noted, water is the solvent, and the requisite amount of the appropriate alkali metal hydroxide is present in the reaction mixture. For the N-bromoamides, the hydroxide or alkoxide used to effect rearrange- ment is listed in this column, the solvent being water for hydroxides or the appropriate alcohol for alkoxides. The name of the product is given in the fourth column. The product is usually an amine or its hydrochloride, between which no differentia- tion is made in this table. Occasionally the reaction affords first a ure- than or urea,'which is then hydrolyzed to an amine or an aldehyde. When hydrolysis has occurred the initial and final products are listed in the column under subdivisions (a) and (6). The yields reported in the fifth column, based upon the weight of amide initially taken, are given to the nearest 5% or are reported only as good (G) or poor (P). A dash indicates that no yield was reported. If the reaction was conducted in two stages, subdivisions (a) and (b) are again employed: under (a) is given the yield of urethan (or urea) based on the amount of amide taken; under (6), the yield of amine (or aldehyde) based on product (a). PRODUCTS AND YIELDS OBTAINED IN HOFMANN REACTIONS OP AMIDES oo C1-C3 Formula CH4ON2 C2H6ON (C2H4ONBr) (C2H3ONBrNa) C2H4ONC1 C3H7ON (C3H6ONBr) (C3H6ONBrNa) Amide Name or Structural Formula Urea Acetamide N-Bromoacetamide N-Bromoacetamide, sodium salt Chloroacetamide Propionamide N-Bromopropionamide N-Bromopropionamide, sodium salt Reagent NaOGl, NaOH KOBr; Ca(OBr)2; NaOBr NaOBr(CH3OH) NaOC2H5 NH3 KOBr KOBr NaOC2H6 NH3 Product . Hydrazine Methylamine Methyl methylcarbamate Ethyl methylcarbamate Methylurea N-Chloromethyl-N'-chloro- acetylurea Ethylamine Ethyl ethylcarbamate Ethylurea Yield 60% 70-80% ¡ª ¡ª 80% ¡ª 85% 80% 30% Refer- CI1CC 65 lc,66 67 3 3 le lc 3 3 C4-CB C4H7ON C4H9ON (C4H8ONBr) (C4H7ONBrNa) C4H8ONBr Cyclopropanecarboxamide n-Butyramide Isobutyramide N-Bromoisobutyramide N-Bromoisobutyramide, sodium salt a-Bromoisobutyramide KOBr KOBr KOBr NaOC2H6 ¡ª NaOBr Cyclopropylamine n-Propylamine Isopropylamine Ethyl isopropylcarbamate Isopropyl isocyanate Acetone _ 90% 90% ¡ª ¡ª 55% 68 lc lc 3 3 170 C4H3O2N C4H6O2N (C4H4O2NBr) C4H9O2N C4H6O3N C4H7O4N C4H6O2N2 C4H8O2N2 C6H9ON CsHsONBr C5H11ON CSHHOBN C6Hio02N2 C6H9O3N2Br Maleinimide Succinimide N-Bromosuccinimide Ethoxyacetamide Maleinamidic acid Z-/S-Malamidic acid Ethyloxamate Maleinamide Succinamide 2-Pentenoamide Cyclobutanecarboxamide a-Bromocyclobutanecarboxamide Isovaleramide Trimethylacetamide Z-Arabinonamide Methylsuccinamide N-Bromo-j3-carbomethoxyamino- propionic acid NaOCl KOBr NaOCH3 KOBr NaOCl Ba(OBr)2, Ba(OH)2 KOBr NaOCl KOBr NaOCl (CH3OH) KOBr NaOCl(CH3OH) NaOBr(CH3OH) NaOBr KOBr KOBr NaOCl KOBr NaOCH3 CH=CH O=C NH /3-Alanine CH3OCONHCH2CH2CO2CH3 N-Ethoxymethyl-N'-ethoxy- acetylurea Formylacetic acid Z-Isoserine Ethyl carbamate Uracil (0) Dihydrouracil (b)/3-Alanine (a) Methyl 1-butenylcarbamate (6) Butyraldehyde Cyclobutylamine (0) Methyl cyclobutylcarbamate (6) Cyclobutylamine (a) Methyl cyclobutylcarbamate (6) Cyclobutylamine Cyclobutanone Isobutylamine iert-Butylamine Z-Erythrose a-Methyl~/3-alanine 1,2-Dicarbomethoxyaminoethane 40-45% 40-45% 40% ¡ª 85% f 50% P 55% (?)- (6)- (0) ¡ª (b)- ¡ª (a)- (b) 20% (a) 90% (&)- P 90% 45-65% 30% t ¡ª ¡ª 35 69,70,71, 791 a 70 le 35 36 73 35 34 46c 74,75 76 77 171 U 20,78 40 34 79 * References 65-173 are listed on pp. 305-306. t As semicarbazone. % As benzylphenylhydrazone. PRODUCTS AND YIELDS OBTAINED IN HOPMANN REACTIONS OF AMIDES¡ªContinued C6 Formula C6Hi30N (QsHtfONBr) C*HMO?N C6H6ON2 C6H12O2N2 C6H9O2N2 C6HBON2C1 C6H4ON2Cl2 G6H3ON2Cl3 Amide Name or Structural Formula Caproamide Isocaproamide /3,/3-Dimethylbutyramide N-Bromo-2-ethylbutyramide d-Gluconamide d-Galactonamide f-Mannonamide a-Picolinamide Nicotinamide 7-Picolinamide Adipamide l{¡ª)Acetylasparagine 6-Chloronicotinamide 3,5-Dichloro-a-picolinamide 3,4,5-Trichloro-a-picolinamide Reagent KOBr KOBr NaOBr NaOH NaOCl NaOCl NaOCl KOBr KOBr KOBr NaOCl NaOBr Ba(OBr)2 KOBr NaOBr NaOBr Product ji-Amylamine Isoamylamine Neopentylamine 3-Aminopentane d-Arabinose d-Lyxose Z-Arabinose 2-Aminopyridine 3-Aminopyridine 4-Aminopyridine 1,4-Diaminobutane 1,4-Diaminobutane (a) l{¡ª)2-Imidazolidone-5-car- boxylic acid (6) i(+)/3-Aminoalanine 3-Amino-6-chloropyridine 2-Amino-3,5-dichloropyridine 2-Amino-3,4,5-trichloropyridine Yield 90% 90% 90% 6% 50% f 30% t 60% f ¡ª ¡ª ¡ª ¡ª 60% (a) 15% (6) 60% 50% ¡ª ¡ª Refer- ence * \c lc 15 80 40 40 40 586. 81 58 586 33d 33e 37 82 83 84 c7 CTHTON (C7H6ONC1) (C7H6ONBr) OrHnON CVHuON C7H13ON C7H16ON C7H7O2N C7H8ON2 CjH14ON2 C7H4O2N2 C7Hi402N2 C7H6O3N2 Benzamide N-Chlorobenzamide N-Bromobenzamide 1-Cyclohexenecarboxamide 2-Methylcyclopentanecarboxamide Cyclopentylacetamide Enanthamide 2-Methylcapramide o-Salicylamide p-Hydroxybenzamide 2-Furanacrylamide 6-Methylnicotinamide Hexahydroanthranilamide Pyridine-3,4-dicarboximide /3-Methyladipamide Diethylmalonamide 2-Carboxypyridine-3-carboxamide 3-Carboxypyridine-2-carboxamide 3-Carboxypyridine-4-carboxamide 4-Carboxypyridine-3-carboxamide NaOH KOH NaOCl(CHsOH) NaOBr NaOBr KOBr KOBr NaOCl NaOBr Ba(OBr)2 KOBr NaOCl(CH3OH) NaOCl KOBr NaOBr NaOBr NaOCl NaOBr NaOBr NaOBr NaOBr (a) Diphenylurea (6) Aniline Aniline Cyclohexanone 2-Methyl-l-aminocyclopentane Cyclopentylcarbinylamine n-Hexylamine 2-Methyl-n-amylamine (0) 4,5-Benzoxazolone-2 (6) o-Aminophenol 7,9-Dibromo-4,5-beiizoxazolone-2 2,6-Dibromo-4-aminophenol 2,4,6-Tribromo-3-aminophenol (a) Methyl furfurylcarbamate (6) 2-Furanacetaldehyde 2-Methyl-5-aminopyridine 1,2-Cyclohexanediamine 0-Amino-7-picolinic acid 2-Methyl-l,4-diaminobutane C, C-Diethylhydantoin /3-Amino-a-picolinic acid 2-Aminonicotinic acid 4-Aminonicotinic acid /3-Amino-7-picolinic acid (a) 90% (6) 90% 95 ¡ª ¡ª ¡ª 70% ¡ª (0) 80% (6) 70% 35% 70% (a) 50% (6) 40% 55% ¡ª ¡ª 70% ¡ª ¡ª ¡ª ¡ª ¡ª 48 9a 466 85 86 lc, 26 87 48 29 29 29 46a 89 88 90 33a, d 36 91 92 93 60 * Heferences 65-173 are listed on pp. 305-308. t As diphenylhydrazone. J As p-bromophenylhydraaone. PRODUCTS AND YIELDS OBTAINED IN HOPMANN REACTIONS OP AMIDES¡ªContinued 8 to Formula (C7H6O3N2Br) C7H9ON3 C7H7O2N3 CTHSOSN* C7H6ONBr (C7H6ONBr2) C7H6ONC1 <C7H6ONBrCl) C7H6ONF (C7H6ONC1F) C7H6ONBr2 C7H4ONBr3 . Amide Name or Structural Formula Nitrobenzamide N-Bromo-o-nitrobenzamide N-Bromo-m-nitrobenzamide N-Bromo-p-nitrobenzamide Phenylsemicarbazide Pyridine-3,4-dicarboxamide p-Nitrophenylsemicarbazide m-Bromobenzamide p-Bromobenzamide N-Bromo-ro-bromobenzamide Chlorobenzamide N-Bromo-o-chlorobenzamide N-Bromo-m-chlorobenzamide N-Bromo-p-chlorobenzamide Fluorobenzamide N-Chloro-o-fluorobenzamide 2,6-Dibromobenzamide 2,4,6-Tribromobenzamide Reagent KOH KOH NaOCH3 NaOC2H6 KOH NaOC2H6 NaOCl KOBr NaOCl KOBr KOBr KOH NaOCH3 KOH KOH KOH Ba(OH)2 KOBr KOBr Product o-Nitraniline m-Nitraniline Methyl m-nitrophenylcarbamate (a) Ethyl m-nitrophenylcarbamate (6) m-Nitraniline ' p-Nitraniline Methyl p-nitrophenylcarbamate Phenyl azide |3-Amino-y-picolinic acid p-Nitrophenyl azide m-Bromoaniline p-Bromoaniline m-BromoanUine Methyl m-bromophenylcarbamate o-Chloroaniline m-Chloroaniline p-Chloroaniline o-Fluoroaniline 2,6-DibromoaniIine 2,4,6-Tribromoaniline Yield 70% 90% (a) ¡ª (6) 55% 50-90% ¡ª 55% ¡ª 35% 90% G 90% 90% 90% 95% 89% ¡ª Refer- ence * 9a 9a 79,94 94 9a 94 60 64 64 9a 79 9a 9a 9a 95 96 96 C7H7O4N6 C7H7ON2CI C7H4ON2Cl4 C7H8ON3Br o-Sulfobenzamide N-Chloro-N'-phenylurea N-Chloro-N'-2,4,6-trichlorophenyl- urea p-Bromophenylsemicarbazide NaOBr NaOH NaOH NaOCl o-Sulfanilic acid p-Chlorophenylhydrazine 2,4,6-Trichlorophenylhydrazine p-Bromophenyl aride ¡ª P P 75% 97 55 55 54 c8 C8H9ON (C8H8ONBr) CsH3ON (CsHuONCl) CsHisON * Phenylacetamide N-Bromo-p-toluamide 2-Cycloheptenecarboxamide 2,5-.Eradomethylenecyclohexane-l- carboxamide N-Chloro-2-ootynamide 1-Methylcyclohexanecarboxamide Hexahydro-o-toluamide * Hexahydro-m-toluamide Hexahydro-p-toluamide KOBr KOH KOBr Ba(OH)2 NaOBr(CH3OH) NaOBr(CH3OH) NaOBr(CH3OH) NaOBr(CH3OH) Benzylamine p-Toluidine l-Amino-2-cycloheptene l-Amino-2,5-e7?iomethylenecyclo- hexane Enanthonitrile" (0) Methyl 1-methylcyclohexyl- carbamate (6) 1-Methyl-l-aminocyclohexane (a) Methyl 2-methylcyclohexyl- carbamate (6) 2-Methyl-l-aminocyclohexane (0) Methyl 3-methylcyclohexyl- carbamate (6) 3-Methyl-l-aminocyclohexane (0) Methyl 4-methylcyclohexyl- carbamate (6) 4-Methyl-l-aminocyclohexane 60-85% 98% 20% ¡ª 70% (a) ¡ª (6) ¡ª (a) 95% (6) 75% (a) 95% (6) 70% (a) ¡ª (6) 90% le, 2a 9a 42 98 35 27 27 27 27 * References 65-173 tie listed on pp. 305-306. CO PRODUCTS AND YIELDS OBTAINED IN HOFMANN REACTIONS OP AMIDES¡ªContinued Amide Formula ? C8HITON (CgHieONBr) C8HBO2N CsHjOzN C8H9O2N (C8H8O2NBr) CgHyOsN C8H16O2N2 C8H8O2N2 Name or Structural Formula Cyclohexylacetamide Cycloheptanecarboxamide Caprylamide /3-Methylenanthamide ce-Ethylcaproamide N-Bromo-a-propylvaleramide Phthalimide Benzoylformamide Mandelamide o-Methoxybenzamide f N-Bromoanisamide Piperonylamide Suberamide Benzoylurea Reagent NaOBr(CH3OH) NaOBr NaOBr KOBr KOBr NaOBr NaOH KOBr NaOCl NaOCl(C2H6OH) NaOCl NaOCl(CH3OH) NaOCl NaOCl KOH NaOBr NaOBr NaOCl Product (0) Methyl hexahydrobenzylcar- bamate (6) Hexahydrobenzylamine Hexahydrobenzylamine Cycloheptylamine 7i-Heptylamine 2-Methyl-l-aminohexane 3-Aminoheptane 4-Aminoheptane Anthranilic acid Anthranilic acid Methyl anthranilate Benzoic acid Methyl benzoate Benzaldehyde o-Methoxyaniline f p-Anisidine reor-Piperonylamine 1,6-Diaminohexane Benzoylhydrazine Yield (a)- (6) 70% -r- 95% 30-65% ¡ª ¡ª 85% 75-85% 95% 70% ¡ª ¡ª ¡ª G ¡ª 30^0% ¡ª ¡ª Refer- ence * 27 99 172 lc, 26 100 101 80 2c, 48 48 102 46c 46c 40 48 9a 103 33c 173 2 o C8H6O6N2 C8Hn0N3 C8H7ONBr2 C8H4O2NC1 C8H3O2NBr2 C8H3O2NC12 C8H6O3NC1 CgHsiOiiNCla C8HO2NBr4 C8HO2NBr2Cl2 C8HO2NCl4 3-Nitrophthalimide 4-Nitrophthalimide 2-Carboxy-3-nitrobenzamide p-Tolylsemicarbazide 2,6-Dibromo-4-methylbenz amide 4-Chlorophthalimide 4,5-Dibromophthalimide 3,6-Dichlorophthalimide 4,5-Dichloro-2-carboxybenzamide 3,4,6-Trichlorophthaliniide Tetrabromophthalimide 4,5-Dibromo-3,6-dichlorophthal- imide Tetracbiorophthalimide NaOCl; Ca(OCl)2 KOBr NaOCl KOBr NaOCl NaOBr NaOCl NaOCl NaOBr NaOCl NaOCl NaOBr NaOCl KOC1 NaOCl NaOBr; NaOCl 6-Nitroanthranilic acid 6-Nitroanthranilic acid 3-Nitroanthranilic acid 4-Nitroanthranilic acid 5-Nitroanthranilic acid 6-Nitroanthranilic acid p-Tolyl azide 2,6-Dibromo-4-methylaniline 4-Chloroanthranilic acid 3-Chloroanthranilic acid 4,5-Dibromoanthranilic acid 3,6-Dichloroanthranilic acid 3,6-Dichloroanthranilic acid 4,5-Dichloroanthranilic acid 3,4,6-Trichloroanthranilic acid 3,4,6-Trichloroanthranilic acid Tetrabromoanthranilic acid 4,5-Dibromo-3,6-dichloroanthra- nilic acid Tetrachloroanthranilic acid 80% ¡ª p 70% 20% 85% 75% ¡ª 70% 25% ¡ª 75% 90% ¡ª 75% 90% ¡ª ¡ª 95-100% 50 51 50 50 51, 104 54 96 105 105 106 48, 107 53,48 53 48 48, 108 106 106 48, 109 c9 C9H7ON (C9H6ONC1) C9H9ON Phenylpropiolamide N-Chlorophenylpropiolamide Cinnamic amide NaOCl(CH3OH) Ba(OH)2 NaOCl(CH3OH) NaOCl(C2H6OH) Phenylacetonitrile Phenylacetonitrile (a) Methyl styrylcarbamate (6) Phenylacetaldehyde N-Styryl-N-cinnamoylurea ¡ª ? (a) 70% (6) G 45 45 41a 41a 41a * References 65-173 are listed on pp. 305-306.t Conversions of this amide and the o- and p- ian isomers to the amines (in unspecified yields) with NaOBr are reported in ref. 29. PRODUCTS AND YIELDS OBTAINED IN HOFMANN REACTIONS OP AMIDES¡ªContinued Formula C9HUON C9H16ON C9H17ON CgHwON C9HUO2N C9H9O3N CgHuOaN tC9H?O4N Amide Name or Structural Formula 0-Phenylpropionamide Hydratropamide 2,2-Dimethyl-3-methylenecyclo- pentaneoarboxamide 2,3,3-Trimethylcyclopentanecar- , boxamide 3-Isopropylcyclopentanecarboxam- ide Cycloheptylacetamide 2-Nonenamide Pelargonamide /3-(o-Hydroxyphenyl)-propionamide jS-(p-Hydroxyphenyl)-propionamide 2-Carboxy-a-toluamide Veratric amide 5-Methoxypiperonylamide Reagent KOBr NaOCl NaOBr(CH3OH) NaOBr(C2H6OH) NaOBr NaOBr NaOBr NaOBr(CH3OH) KOBr NaOCl(CH3OH) NaOBr NaOCl NaOCl KOBr NaOCl . NaOCl Product /3-Phenethylamine /3-Phenethylamine Methyl a-phenethylcarbamate Ethyl /3-phenethylcarbamate a-Phenethylamine l-Amino-2,2-dimethyl-3-methyl- enecyclopentane l-Amino-2,3,3-trimethylcyclo- pentane (0) Methyl 3-isopropylcyclopen- tylcarbamate (6) l-Amino-3-isopropylcyclopen- tane Cycloheptylcarbinylamine (0) Methyl 1-oetenylearbamate (6) Caprylaldehyde Octylamine o-Hydroxy-/3-phenethylamine p-Hydroxy-/S-phenethylamine o-Carboxybenzylamine 4-Aminoveratrol 5-Methoxy-nor-piperonylamine Yield 30-60% ¡ª ¡ª ¡ª 60% 40% ¡ª (a) ¡ª (6)- 40% (a) 50% (6)G 45% ¡ª ¡ª ¡ª 80% ¡ª Refer- ence * le, 2a 110 110 110 111 44 112 113 99 466 lc, 26 114 114 115 47 116 I a § C9Hi60N2 C9Hi80N2 C9H8O3N2 ?C9H10O5N2 3,6-Dicarboxybenzamide 2,4-Dicarboxybenzamide l-Methyl-2,6-en<Zoinethylene-3- piperidinecarboxamide 2,2,5,5-Tetramethylpyrollidiiie-3- carboxamide Azelaic amide o-Nitrocinnamic amide ro-Nitrocinnamic amide p-Nitrocinnamic amide 2-Nitro-3,4-dimethoxybenzamide KOBr KOBr KOBr KOBr NaOBr NaOCl(CH3OH) NaOCl(CH3OH) NaOCl(CH3OH) NaOBr 3,6-Dicarboxy aniline 2,4-Dicarboxy aniline l-Methyl-2,6-e?<2omethylene-3- aminopiperidine 2,2,5,5-Tetramethyl-3-amino- pyrrolidine 1,7-Diaminoheptane (a) Methyl o-nitrostyrylcarbamate (6) o-Nitrophenylacetaldehyde (a) Methyl m-nitrostyrylcarbam- ate , (6) rrc-Nitrophenylacetaldehyde (o) Methyl p-nitrostyrylcarbam- ate ? (b) ra-Nitrophenylacetaldehyde 2-Nitro-3,4-dimethoxy aniline 60% (o)- (6)- (a)- (6)P 85% 117 117 118 119 33c 41a 41a 41a 120 C10OH13ON C10H17ON o-n-Propylbenzamide a-Methyl-/3-phenylpropionamide /3-Phenylbutyramide a,a-Dimethyl-a-toluamide 2,2,3-Trimethyl-2-cyclopentenyl- acetamide 2,3,3-Trimethyl-l-cyclopentenyl- acetamide 1-Apocamphanecarboxamide NaOBr KOBr KOBr NaOBr KOBr KOBr NaOBr(CH3OH) o-n-Propylaniline l-Phenyl-2-aminopropane 2-Phenyl-l-aminopropane 2-Phenyl-2-aminopropane 2,2,3-Trimethyl-2-cyclopentenyl- carbinylamine 2,3,3-Trimethyl-l-cyclopentenyl- carbinylamine (a) Methyl l-apocamphylcarbam- ¡êLuG (6) 1-Aminoapocamphane 65-95% 60% 35%- 15% P (a) 60% (6) 85% 121 10, 122 123 124 43, 125 43 20 * References 65-173 are listed on pp. 305-306. PRODUCTS AND YIELDS OBTAINED IN HOFMANN REACTIONS OF AMIDES¡ªContinued GO Amide Formula C10H19ON C10H21ON C10H11O2N C10H13O2N Name or Structural Formula 1,2,2,3-Tetramethylcyclopentane- carboxamide l-Methyl-3-isopropylcyclopentane- carboxamide 2-Methyl-2-isopropylcyclopentane- carboxamide 2,2,3-Trimethylcyclopentyl- acetamide 3,5-Dimethylcyclohexyl- acetamide Capramide o-Methoxycinnamic amide p-Methoxycinnamic amide i8-(p-Methoxyphenyl)propionamide Reagent KOBr NaOBr KOBr NaOBr(CH3OH) KOBr NaOBr KOBr NaOCl(CH3OH) NaOCl(CH3OH) NaOBr Product 1,2,2,3-Tetramethyl-l-amino- cyclopentane l-Methyl-3-isopropyl-l-amino- cyclopentane 2-Methyl-2-isopropyl-l-amino- cyclopentane (a) Methyl 2-methyl-2-isopropyl- cyclopentylcarbamate (6) 2-Methyl-2-isopropyl-l-amino- cyclopentane 2,2,3-Trimethylcyclopentyl- carbinylamine' 3,5-Dimethylhexahydrobenzyla- mine re-Nonylamine (a) Methyl o-methoxystyrylcar- bamate (6) o-Methoxyphenylacetaldehyde (a) Methyl p-methoxystyrylcar- bamate (6) p-Methoxyphenylacetaldehyde p-Methoxy-|8-phenethylamine Yield ¡ª ¡ª (0) 90% (6) 80% ¡ª ¡ª P (?) ¡ª (&)- (a) 65% ?) ¡ª 35% Refer- ence * 126 127 1286 129 130 128a lc 416 416 114,28 1 > o CioHii03N CioHwOsN CioH1903N C10H9O4N CioHi304N CioH8ON2 C10Hi6ON2 C10H20ON2 C10H18O2N2 C10H20O2N2 Ci0H8O3N2 C10H10O6N2 CIOHTON2C1 CnHioON CnHnON Piperonylacetamide 3,5-Dimethyl-4-carboxybenzamide a-Camphoramidic acid jS-Camphoramidic acid Sebacamidic acid 3,4-Dimethoxyphthalimide ? 2,3,4-Trimethoxybenzamide 3,4,5-Trimethoxybenzamide 3-Quinolineearboxamide 4-Quinolinecarboxamide 2,2,3'-Trimethyl-3c-cyanocyclo- pentanecarboxamide 1,2,2,5,5-Pentamethylpyrrolidine- 4-carboxamide Cyclopentanecarboxamide-1- [o-isobutyramide]-3 Sebacamide 3-Acetaminophthalimide 4,6-Dimethyl-3,5-diearboxypyri- dine-2-carboxamide 2-Chloro-3-quinolinecarboxamide 3-Arninonaphthalene-2-carboxamide Cinnamalacetamide NaOCl NaOBr NaOBr; NaOCl NaOBr NaOCH3; Br2 NaOCl NaOCl NaOCl KOBr KOBr NaOBr KOBr NaOBr(CH3OH) NaOBr NaOCl NaOBr NaOBr NaOCl NaOCl(CH3OH) Homopiperonylamine 2,6-DimethyJ-4-aminobenzoic acid 1*, 2,2-Trimethyl-3<;-aminocyclopen- tanecarboxylic acid 2,2,3'-Trimethyl-3c-aminocyclo- pentanecarboxylic acid (a) ai-Carbomethoxyaminopelar- gonic acid (b) u-Aminopelargonic acid 3,4-Dimethoxyanthranilic acid 2,3,4-TrimethoxyaniJine 3,4,5-Trimethoxy aniline ! 3-Aminoquinoline 4-Aminoquinoline 1 c-Amino-2,2,3'-trimethyl-3<:- cyanocyclopentane 1,2,2,5,5-Pentamethyl-4-amino- pyrrolidine 3, l'-6is[Carbomethoxyamino]-l- methylcyclopentane 1,8-Diaminooctane 6-Aminoanthranilic acid 4,6-Dimethyl-2-amino-pyridine- dicarboxylic acid-(3,5) 2-Chloro-3-aminoquinoline 4,5-0,/3'-Naphthimidazol-2-one (a) Methyl styrylvinylcarbamate (6) Styrylacetaldehyde 50% ¡ª 70% . 100% (0) 75% (6)100% 35% ¡ª 75% 75% ¡ª ¡ª ¡ª ¡ª ¡ª 35% 20% ¡ª 85 (0) 70% (6) 70% 32 131 19 18 38 52 132 132 133 2d, 59 134 56 135 336, 136 105 137 133 138 46a * References 65-173 are listed on pp. 305-306. PRODUCTS AND YIELDS OBTAINED IN HOPMANN REACTIONS OF AMIDES¡ªContinued Formula CnH13ON CHHIBON C11H23ON CnHisOjN CUH17O2N CuHisOaN CnHuOsN CHH13O4N CnHuAN Amide Name or Structural Formula l-Methyl-2-indancarboxamide 1-Indanacetamide Camphane-4-earboxamide Undecanoamide /3-(o-Ethoxyphenyl)propionamide 18- (m-Ethoxyphenyl)propionamide 2-Ketocamphane-4-carboxamide /3-(3,4-Dimethoxyphenyl)pro- pionamide i8-(3,5-Dimethoxyphenyl)pro- pionamide a-Camphoramidic acid methyl ester 5-Methoxypiperonylacetamide 3,5-Dime'thoxy-4-ethoxybenzamide Reagent NaOBr NaOBr NaOBr(CH3OH) NaOBr NaOCl NaOCl NaOBr(CH3OH) NaOCl NaOCl NaOBr NaOCl NaOCl Product l-Methyl-2-aminoindan 1-Indylcarbinylamine (a) Methyl 4-camphanylcarbam- ate (6) 4-Aminocamphane (0) N-Decyl-N'-undecanoylurea (6) n-Decylamine o-Ethoxy-(3-phenethylamine m-Ethoxy-/3-phenethylamine (a) Methyl 4-camphorylcarbam- ate (6) 4-Aminocamphor3,4-Dimethoxy-/3-phenethylamine 3,5-Dimethoxy-/3-phenethylamine 21!,2',3'-Trimethyl-3<!-aminocyclo- pentanecarboxylic acid methyl ester 5-Methoxyhomopiperonylamine 3,6-Dimethoxy-4-ethoxyaniline Yield 15% 15% (a) 80% (6) 70% (?)- (? ¡ª ¡ª 75% (a) 75% (6) 65% ¡ª ¡ª ¡ª ¡ª 85% Refer- ence * ?4 139 139 140 26 114 132 140 141 142 19 143 144 CiiHioOjNi" CuHio02N2 CuHiiON3 CnHisONCI 2-Methyl-4-quinolinecarboxamide 6-Methoxy-4-quinolinecarboxamide /3-Naphthylsemicarbazide 2-Chloro-4-camphanecarboxamide NaOBr KOBr NaOCl NaOBr(CH3OH) 2-Methyl-4-aminoquinoline 6-Methoxy-4-aminoquinolinl /3-Naphthyl azide (a) Methyl 2-chloro-4-camphanyl- carbamate (b) 4-Aminocamphene ¡ª ¡ª ¡ª (a) 75% (&)- 145 146 54 140 C12-C13 Ci2H2iON C^HasON C12H7O2N C12HUO2N C12Hi0O2N2 C13H11ON C13H27ON r^ CHCONH, Lauramide pm-Naphthalenedicarboximide 3-Methoxynaphthalene-2-carbox- amide /3-Benzoyl-a-picolinamide 2-Phenylbenzamide Tridecanamide NaOBr NaOBr NaOBr(CH3OH) NaOBr KOBr NaOBr NaOBr NaOBr (0) N-Undecyl-N'-laurylurea (b) Undecylamine (0) ^lethyl undecylcarbamate (b) Undecylamine 8-Amino-l-naphthoic acid 2-Amino-3-methoxynaphthalene 2-Amino-3-benzoylpyridine 2-Phenylaniline (a) N-dodecyl-N'-tridecanoyl- urea (b) Dodecylamine ¡ª (a) ¡ª (b) - (a) 90% (b) G ¡ª ¡ª ¡ª ¡ª (0)- (b) - 147 26 4b 148 149 150 151 152 * References 65-173 are listed on pp. 305-306. CO O PBODTJCTS AND YIELDS OBTAINED IN HOFMANN REACTIONS OF AMIDES¡ªContinued woto Formula Ci4H13ON CMH^ON Ci4H9O2N C14Hn02N Ci4Hi2O3N2 Amide Name or Structural Formula o-Benzylbenzamide Tetradecanamide 9-Keto-l-fiuorenecarboxamide 9-Keto-4-fluorenecarboxamide o-Benzoylbenzamide o-(2-Methyl-6-nitrophenyl)benz- amide Reagent NaOCl KOBr NaOBr(CH3OH) KOBr KOBr NaOBr NaOBr T> J i.Product o-Benzylaniline (a) N-Tridecyl-N'-tetradecanoyl- urea (6) Tridecylamine (a) Methyl tridecylcarbamate (6) Tridecylamine l-Amino-9-fluorenone 4-Amino-9-fluorenone o-Benzoylaniline o-(2-Methyl-6-nitrophenyl)- aniline "V* UYield 45% (o)G (6) - (a) 95% (&) 70% ¡ª 80% 40% ¡ª Refer- ence * 48 152,153 154 155 156 157 158 Cl6 C15H9O5N o-(p-Toluyl)benzamide 1-Anthraquinonecarboxamide 1,8-Dihydroxy-3-anthraquinone- carboxamide l-Nitro-2-anthraquinonecarboxam- ide NaOBr KOBr NaOCl KOBr o-(p-Toluyl) aniline 1-Aminoanthraquinone 1,8-Dihydroxy-3-aminoanthra^ quinone l-Nitro-2-aminoanthraquinoEe 70% 60% 159 160 161 162 C16-C17 C16H12ON C16H33ON (Ci6H32ONCl) Ci6Hi602N C17H13ON C17Hi40N Ci7Hn06N 2-Phenylquinoline-4'-carboxamide Palmitamide N-Chloropahnitamide o-(2,4-Dimethylbenzoyl)benz- amide o-a-Naphthylbenzamide 2-Phenyl-3-methylquinoline-4- carboxamide 3,5-Dinitrc-2-a-naphthylbenzamide KOBr NaOBr(CH3OH) NaOBr(C2H6OH) NaOCH3 NaOBr NaOBr KOBr NaOBr 2-Phenyl-4'-aminoquinoline (0) Methyl pentadecylcarbamate (6) Pentadecylamine (0) Ethyl pentadecylcarbamate (6) Pentadecylamine (0) Methyl pentadecylcarbamate (6) Pentadecylamine o-(2,4-Dimethylbenzoyl)aniline o-a-Naphthylaniline 2-Phenyl-3-methyl-4-aminoquino- line 3,5-Dinitro-2-a-naphthylaniline 80% (a) 80% (6) G (a) 50% (6) G (a)- (6) G ¡ª 15% 25% 163 46 46 46,25 164 165 166 12 c18 Ci8H37ON Ci8Hi3OaN CisHiyOsN Stearamide o-a-Naphthoylbenzamide a-Truxillamidic acid 7-Truxillamidic acid NaOBr NaOBr(CHsOH) NaOBr NaOCl NaOCl (a) N-Heptadecyl-N'-stearyl- urea (6) Heptadecylamine (a) Methyl heptadecylcarbamate (6) Heptadecylamine o-a-Naphthoylaniline a-Truxillamic acid 7-Truxillamic acid (0)- (6) - (a) 90% (6) G ¡ª 85% 70% lc 46 167 39d 39b * References 65-173 are listed on pp. 305-306. PRODUCTS AND YIELDS OBTAINED IN HOFMANN REACTIONS OF AMIDES¡ªContinued Amide Formula Name or Structural Formula t-Truxillamidic acid /3-Truxinamidic acid 5-Truxinamidic acid 3-Methyl-4'-isopropyl-2,2'- biphenyldicarboxamide Reagent NaOCl NaOCl NaOCl KOBr Product e-Truxillamic acid /S-Truxinamic acid 5-Truxinamic acid 3-Methyl-4'-isopropyl-2,2'- diaminobiphenyl Yield 80% 70% 25% Refer- ence * 39a, c 396 39e 168 C21-C28 I o CsiH19ON (C2iHi80NBr) C28H67ON ^,/3,/3-Triphenylpropionamide N-Bromo-ft/3,j3-triphenylpropion- amide C27H66CONH2 (montanamide) NaOC2H6 NaOBr(CH3OH) (a) Ethyl /3,/3,/S-triphenylethyl- carbamate (6) j3,/3,/3-Triphenylethylamine C27H66NHCO2CH3 (a)- Q>) ¡ª 14 169 * References 65-173 are listed on pp. 305-306. THE HOFMANN REACTION 305 REFERENCES TO TABLE 66 Schestakov, Chem. Zentr., I, 1227 (1905). 66 Francois, Compt. rend., 147, 430, 680 (1908). 67 Lengfeld and Stieglitz, Am. Chem. J., 16, 370 (1894). 68 Kiahner, J. Russ. Phys. Chem. Soc, 37, 308 (1906) [Chem. 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Chem., 133, 19 (1932). 90 Kirpal, Monatsh., 23, 243 (1902). 91 Kirpal, Monatsh., 29, 228 (1908). 92 Phillips, Ber., 27, 840 (1894); Ann., 288, 259 (1895). 93 Kirpal, Monatsh., 23, 243 (1902). 94 Swartz, Am. Chem. J., 19, 304 (1897). 96 Rinkes, Chem. Zentr., I, 822 (1919). 98 Holleman, den Hollander, and van Hoeften, Rec. trav. chim., 40, 327 (1921). 97 Bradshaw, Am. Chem. J., 35, 339 (1906). 98 Komppa and Beckmann, Ann., 612, 172 (1934). 99 Wallach, Ann., 353, 298 (1907). 100 Levene and Marker, J. Biol. Chem., 95, 153 (1932). 101 Kenyon and Young, J. Chem. Soc, 1941, 263. 102 Basler Chemische Fabrik, Ger. pat., 139,218 [Frdl., 7,118; Chem. Zentr., I, 745 (1903)]. 103 Rupe and von Majewski, Ber., 33, 3403 (1900); van Linge, Rec. trav. chim., 16, 50 (1897). 104 Bogert and Chambers, J. Am. Chem. Soc, 27, 652 (1905). 108 Moore, Marrach, and Proud, J. Chem. 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Soc, 95, 1162 (1909). 117 Wegscheider, Perndonner, and Auspitzer, Monatsh., 31, 1297 (1910). 118 Willstatter and Mailer, Ber., 31, 2661 (1878). 306 ORGANIC REACTIONS n?Pauly and Rossbach, Ber., 32, 2005 (1899); Pauly, Ann., 322, 97 (1902). 120 Pisovschi, Ber., 43, 2142 (1910). 121 Gottlieb, Ber., 32, 962 (1898). 122 Edeleanu, Ber., 20, 618 (1887). 123 von Braun, Grabowski, and Kirschbaum, Ber., 46, 1280 (1913). 124 Brander, Rec. trav. chim., 37, 68 (1918). 126 Blanc and Desfontaines, Compt. rend., 138, 697 (1904); BuU. soc chim., [3] 31, 385 (1904). 126 Errera, Gazz. chim. Hal., 22, (I) 221 (1892). 127 Wallach, Ann., 369, 79 (1909). 128 Wallach, (a) Ann., 414, 232 (1918); (5) 414, 239 (1918). 129 Bouveault and Lavallois, BuU. soc. chim., [4] 7, 685 (1916). 130 Blaise and Blanc, BuU. soc. chim., [3] 27, 74 (1902); Blanc and Desfontaines, Compt. rend., 136, 1143 (1903). 131 Noyes, Am. Chem. J., 20, 812 (1898). 132 Graebe and Suter, Ann., 340, 227 (1905). 133 Mills and Watson, /. Chem. 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Soc, 1931, 373. 150 Kirpal, Monatsh., 27, 375 (1907). 161 Graebe and Rateanu, Ann., 279, 266 (1894). 162 Lutz, Ber., 19, 1440 (1886). 153 Reiner and Will, Ber., 18, 2016 (1885). 164 Blau, Monatsh., 26, 99 (1906). 156 Goldschmidt, Monatsh., 23, 893 (1902). 166 Graebe and Schestakow, Ann., 284, 311 (1895). 167 Graebe and Ullmann, Ann., 291, 13 (1896). 168 Bell, J. Chem. Soc, 1934, 835. 169 Kippenberg, Ber., 30, 1133 (1897). 160 Graebe and Blumenfeld, Ber., 30, 1116 (1897). 161 Oesterle, Chem. Zentr., I, 142 (1912). 162Tierres, Ber., 46, 1641 (1913). 163 John and Ottawa, J. prakt. Chem., 133, 13 (1932). 184 Drawert, Ber., 32, 1260 (1899). 166 Graebe and Honigsberger, Ann., 311, 271 (1900). "'John and Ottawa, J. prakt. Chem., 131, 310 (1931). 167 Graebe, Ber., 29, 827 (1896). 168 Lux, Monatsh., 31, 945 (1910). 169 Ryan and Algar, Proc. Roy. Irish Acad., 30, B, 97 (1913) [Chem. Zentr., II, 2051 (1913)]. l7?Kishner, Chem. Zentr., I, 1219 (1905). 171 Kishner, Chem. Zentr., I, 1220 (1905). 172 Willstatter, Ann., 317, 219 (1901). "3 Schestakov, Chem. Zentr., II, 1703 (1905). CHAPTER 8 THE SCHMIDT REACTION HANS WOLFF A. E. Staley Manufacturing Company Decatur, Illinois CONTENTS PAGE INTRODUCTION 308 MECHANISM OP THE REACTION 309 SCOPE AND LIMITATIONS 310 The Reaction of Hydrazoic Acid with Organic Acids 310 Aliphatic and Alicyclic Acids ? ? ., 310 Aromatic Acids 312 Application of the Schmidt Reaction to Acids 313 The Reactions of Hydrazoic Acid with Lactones, Anhydrides, Esters, and Acid Halides 314 The Reactions of Hydrazoic Acid with Aldehydes and Ketones 314 Aldehydes 5 Ketones 316 The Conversion of Ketones to Imido Esters 318 The Reactions of Excess Hydrazoic Acid with Aldehydes and Ketones. The Formation of Tetrazoles 318 The Reaction of Hydrazoic Acid with Quinones 320 The Reactions of Hydrazoic Acid with Functional Groups, Other than Car- bonyl 321 Nitriles 1 Hydrocyanic Acid, Cyanamide, Cyanogen, and Isocyanides 322 Oximes, Amides, Amidoximes, Lactams, Hydroxamic Chlorides, Imide Chlorides, and Dichloroketones 322 Imido Esters 324 The Reaction of Hydrazoic Acid with Unsaturated Hydrocarbons .... 324 EXPERIMENTAL CONDITIONS 327 The Preparation of Hydrazoic Acid Solutions.' 327 The Reaction of Hydrazoic Acid with Carbonyl Compounds 328 The Generation of Hydrazoic Acid in Situ 328 Temperature 328 Solvents 9 Catalysts 9 The Isolation of the Reaction Products 329 307 308 ORGANIC REACTIONS PAGE EXPERIMENTAL PROCEDURES , 330 The Preparation of Amines and Derivatives of Amines 330 Heptadecylamine from Stearic Acid 330 5-Ethoxy-l-(¡ê-ethoxybutyl)-amylamine from 6-Ethoxy-2-(4-ethoxybutyl)- caproic Acid 330 Lactam of 16-Aminohexadecanoic Acid from Cyclohexadecanone .... 330 Ethyl N-Methylacetimidate 330 The Preparation of Tetrazoles 1 1,6-Dimethyltetrazole 331 1,5-Cyclohexamethylenetetrazole 331 l-n-Hexyl-5-aminotetrazole 1 TABLES OF COMPOUNDS PREPARED BY THE SCHMIDT REACTION 332 INTRODUCTION The reaction between equimolar quantities of hydrazoic acid and car- bonyl compounds in the presence of strong mineral acid has become known as the Schmidt reaction. It affords a convenient method for the preparation of amines from acids according to the following scheme. RC02H + HN3 ^% RNH2 + C02 + N2 Aldehydes yield nitriles and fonnyl derivatives of amines, and ketones yield amides. RCHO + HN3 ^% RCN and RNHCHO RCOR + HN3 -^? RCONHR + N2 With hydrazoic acid in large excess (two or more moles), aldehydes and ketones yield substituted tetrazoles. H so RC^====NRCOR + 2HN 3 ¡ª^-4 | |RN N \ /? N The reaction of carbonyl compounds with hydrazoic acid was first reported by Karl Friedrich Schmidt in 1923 in a study of the decompo- sition of hydrazoic acid by sulfuric acid. He observed that benzene had an accelerating effect on the decomposition 1<2 and that the products ob- tained differed according to the temperature at which the reaction was carried out; at room temperature hydrazine sulfate was the main prod- uct, but at a temperature of 60-70° aniline sulfate was formed in high 1 Schmidt, Z. angew. Chem., 36, 511 (1923). 2 Schmidt, Ada Acad. Aboensis, Math, et Phys., [2] 38 (1924) [C. A., 19, 3248 (1925); Ber., 57, 704 (1924)]. THE SCHMIDT REACTION 309 yields. Acting on the hypothesis that during the decomposition of hy- drazoic acid a free imide radical (NH) is formed which is capable of adding to a reactive group, Schmidt added benzophenone to the reaction mixture. A very fast reaction occurred, an"d a quantitative yield of benzanilide was obtained.1'2'3 MECHANISM OF THE REACTION The mechanism of the Schmidt reaction has not been established with certainty. Schmidt proposed a mechanism in which the hydrazoic acid is cleaved by the strong mineral acid to nitrogen and the imide radical (NH). This radical is supposed to add to the carbonyl group, followed by a rearrangement either directly or by a Beckmann transformation of an intermediate oxime to the amide.2'4 OH R2C¡ªN¡ª R2C=O + [NH] RCONHK Oliveri-Mandala advanced a mechanism involving addition of the hydrazoic acid molecule to the carbonyl group.6 This mechanism was elaborated by Hurd 6 and shown by Briggs and Lyttleton 7 to be more acceptable in the light of later evidence. Hurd proposed the activation of hydrazoic acid (I) by concentrated sulfuric acid to an active form (II); this adds to the carbonyl forming III. The transient adduct (HI) loses nitrogen to yield an unstable immo derivative (IV) which immediately undergoes a Beckmann type rearrangement and yields the amide (V) R2C=O R2C¡ªNNssN:H in HN¡ªN=N: II -Nj RCONHR 8 Ger. pat., 427,858 [Frdl., 15, 221 (1928)]; U. S. pat., 1,564,631 [C. A., 20, 423 (1926)]. ? Schmidt, Ber., 58, 2413 (1925). 6 Oliveri-Mandala, Qazz. chim. Hal., 56, I, 271 (1925). 6 Hurd, in Gilman, "Organic Chemistry," /, 699, 1st ed., John Wiley & Sons, 1938. 7 Briggs and Lyttleton, /. Chem. Soc., 1943, 421. 310 ORGANIC REACTIONS o-1 + RC¡ªN 11OH iH -N2 " o- . " RC¡ªNH 11 OH This mechanism also accounts for the formation of amines from acids. If one of the R. groups in IV is hydroxyl, the intermediate carbamic acid VI decomposes to an amine and carbon dioxide. RC02H [RNHC02H] -? RNH2 + C02 VI The formation of tetrazoles can be accounted for by further action of hydrazoic acid on the intermediate IV, before completion of the rear- rangement. Although aromatic animation by hydrazoic acid could be explained by a similar mechanism,6 evidence has been presented that it proceeds in a different fashion.8 It appears that this reaction proceeds through an (NH) or (NH2)+ radical. The aromatic amination requires higher tem- peratures than the carbonyl reaction, a fact that lends -support to the view that the two reactions proceed by different mechanisms. SCOPE AND LIMITATIONS The Reaction of Hydrazoic Acid with Organic Acids Aliphatic and Alicyclic Acids. The Schmidt reaction has found its most extensive application in the preparation of amines from acids. With straight-chain aliphatic acids the yield of amine generally increases with the length of the chain.9-10 Thus, n-caproic acid yields 70% of amylamine 9 and stearic acid, 96% of heptadecylamine.11 This generali- zation does not hold for acids of more complicated structure. In the naphthenic acid series, where the lower members contain one and the higher members two cyclopentane rings, the yields drop with the in- crease of molecular complexity.10 Dibasic acids, in general, react bi- functionally to give diamines, and the yields improve as the distance between carboxyl groups increases. Thus, succinic acid gives ethyl- enediamine (8%),12 adipic acid yields tetramethylenediamine (83%) ,13 and dodecamethylenedicarboxylic acid gives dodecamethylenediamine 8 Keller and Smith, J. Am. Chem. Soc, 66, 1122 (1944). - 8 Adamson and Kenner, J. Chem. Soc, 1934, 838. 10 v. Braun, Ann., 490, 100 (1931). 11 Briggs, De Ath, and Ellis, J. Chem. Soc, 1942, 61. 12 Oesterlin, Z. angew. Chem., 45, 536 (1932). 13 Ger. pat., 500,435 [Frdl., 17, 2612 (1932); U. S. pat., 1,926,756 [C. 4.,27,5752 (1933)]. THE SCHMIDT REACTION 311 (90%) .14 Malonic acids, however, yield a-amino acids which do not re- act further with hydrazoic acid.11-15 No acid containing three or more carboxyl groups has been studied. The reaction proceeds quite smoothly even with acids in which the carboxyl group is inert to many reagents. Thus, carboxyl groups at- tached to tertiary carbon atoms as in campholic acid (VII),10'16 podo- carpic acid (VIII),11 and the isobutyric acid derivative (IX) 17 are re- placed by amino groups in good yields. (CH3)2CCO2H p H2C CHCH3 vn vm OH A good yield (70%) of /3-phenylethylamine is obtained from j3-phenyl- propionic acid, but the introduction of methoxyl groups in the benzene ring causes a sharp drop in the yields of the amines.12 Cinnamic acid yields phenylacetaldehyde, probably through forma- tion of styrylamine (X), rearrangement to the aldimine (XI), and hydrol- ysis.12 Aniline is obtained as a by-product, and no explanation has been given for its formation. C6HBCH=CHCO2H + HN3 -? [C8H6CH=CHNH2] -* x [C6HBCH2CH=NH] -?? C6HBCH2GHO XI The Schmidt reaction cannot be applied to acids which are unstable toward concentrated sulfuric acid. Thus, a-halo acids are dehydrohalo- genated under the reaction conditions.18'18a The replacement of a carboxyl group attached to an asymmetric car- bon atom in an optically active molecule has been studied. No racemi- zation occurs in the transformation of active methylbenzylacetic acid to a-benzylethylamine, or of fencholic acid to fenchelylamine.19 A di- methylcampholic acid, however, yields a dimethylcamphelylamine of M v. Braun and Anton, Ber., 64, 2865 (1931). 16 Adamson, J. Chem. Soc, 1939, 1564. 16 Ger. pat., 544,890 [Frdl., 18, 3054 (1933)]. 17 Prelog, Heimbach, and Rezek, Ann., 545, 231 (1940). 18 v. Braun, Ber., 67, 218 (1934). 180 Gilman and Jones, J. Am. Chem. Soc, 65, 1458 (1943). 19 v. Braun and Friehmelt, Ber., 66, 684 (1933). 312 ORGANIC REACTIONS lower rotation than that of the amine obtained by a Hofmann degrada- tion.20 An amino group alpha to a carboxyl group in aliphatic amino acids has an inhibiting effect upon the reactivity of the carboxyl group. Thus, the following aliphatic amino acids and their derivatives are reported to be unreactive toward hydrazoic acid:12 glycine, hippuric and nitrohip- puric acids, a- and /3-alanine, phenylalanine, acetylalanine, phenyl- aminoacetic acid, N-(p-toluenesulfonyl)phenylalanine, /3-phenyl-j8-arni- nohydrocinnamic acid, and N-(p-toluenesulfonyl)/3-phenyl-/3-amino- hydrocinnamic acid. Similarly, di- and poly-peptides do not react with hydrazoic acid.21 The protection given to a carboxyl group by an amino group decreases or disappears as the two groups are further separated. This makes it possible to synthesize diamino acids from a-amino-di- carboxylic acids. Ornithine and lysine have been prepared in very satisfactory yields from a-aminoadipic acid and a-aminopimelic acid, respectively.15 H2OC(CH2)3CHCO2H + HN3 NH2 NH2 Similarly, l-phenylpiperidine-4-carboxylic acid has been converted to 4- amino-1-phenylpiperidine.22 Aromatic Acids. The position and type of ring substitution in aro- matic acids have a marked effect on the reaction rates and yields of amines.7 ?" ?12 p-Toluic acid yields 70% of p-toluidine, but from m-toluic acid only 24% of m-toluidine is obtained.11 If the time at which half of the total volume of nitrogen is evolved can be considered a measure of the reaction rate, the general conclusion can be drawn that in meta- substituted benzoic acids the reaction rates are in reverse order of the acidities as measured by dissociation constants.7 This generalization applies to the reaction rates but not to the yields of amines obtained from different meta-substituted benzoic acids. Of the aromatic dibasic acids, the three phthalic acids on treatment with hydrazoic acid yield the corresponding aminobenzoic acids with mere traces of the diaminobenzenes.7'12 Anthranilic acid and its deriva- tives in which one hydrogen on the amino group is replaced by acetyl, benzoyl, or p-toluyl are inert to hydrazoic acid.12 These compounds thus resemble in activity a-amino acids and their derivatives in the aliphatic series. The following pyridine and quinoline acids resemble a-amino acids and also do not react: pyridine-2-carboxylic acid, pyridine-2,3- 20 v. Braun and Kurtz, Ber., 67, 225 (1934). 21 NeUes, Ber., 65, 1345 (1932). JS Cerkovnikov and Prelog, Ber., 74, 1648 (1941) [C. A., 37, 125 (1943)]. THE SCHMIDT REACTION 313 dicarboxylic acid, 216-dimethylpyridine-3,5-dicarboxylic acid, quinoline- 6-carboxylic acid, and quinoline-8-carboxylic acid.12 Similarly, very little 2,2'-diaminobiphenyl is obtained from diphenic acid, the main product being phenanthridone.23 CO2H CO2H CO2H NH2 CO¡ªNH Highly substituted or hindered aromatic dibasic acids like tetrachloroj phthalic acid and naphthalic acid fail to undergo the Schmidt reaction.23 Application of the Schmidt Reaction to Acids. The Schmidt reaction affords an additional method to the Hofmann and Curtius degradation of acids to amines having one less carbon atom. Schmidt's method pre- sents two advantages over the older methods: it is a one-step reaction and thus avoids the isolation of intermediates; the yields often are higher than those from either the Hofmann or Curtius degradation. Thus, the naphthenic acids are degraded in 70-90% yields to the corresponding amines by the Schmidt reaction and in yields of only 25-35% by the Hofmann degradation.10 From cyclobutane-l,2-dicarboxylic acid the as- and trans-1,2-diaminocyclobutanes are obtained in 35% and 55% yields by the hydrazoic acid method and in only 17% and 12% yields by the Curtius degradation.24 In general, it may be advantageous to use the Schmidt reaction for the preparation of amines if the free acids are the available raw materials; if, however, the esters or amides are more acces- sible, the Curtius or Hofmann degradations may be preferred. The use of hydrazoic acid requires precaution on account of the toxicity of the reagent; its explosiveness presents no special hazards under controlled laboratory conditions. Large-scale reactions with hydrazoic acid pro- ceed with generation of much heat and great violence, thus involving the dangers of explosion.26 The hydrazoic acid degradation of naphthenic acids was an invaluable aid in von Braun's investigation of mixtures of naphthenic acids.10'26 In his studies on alkaloids Prelog used the Schmidt reaction extensively.17- 27~88 23 Caronna, Gazz. chim. Hal., 71, 475 (1941) [C. A., 87, 118 (1943)]. 24 Buchman, Reims, Skei, and Schlatter, /. Am. Chem. Soc., 64, 2696 (1942). ? Ger. pat., 455,585 [Frdl., 16, 2862 (1931)]; U. S. pat., 1,637,661 [C. A., 21, 3057 (1927)]. 26' v. Braun and Wittmeyer, Ber., 67, 1739 (1934). 27 Prelog and Boii6evi6, Ber., 72, 1103 (1939). 88 Prelog, Cerkovnikov, and TJstricev, Ann., 535, 37 (1938). 29 Prelog and Heimbach, Ber., 72, 1101 (1939). 80 Prelog, Heimbach, and Seiwerth, Ber., 72, 1319 (1939). 81 Prelog and Schonbaum, Ann., 545, 256 (1940). ?2 Prelog and Seiwerth, Ber., 72, 1638 (1939). u Prelog, &>Stari6, and GuStac, Ann., 545, 247 (1940). 314 / ORGANIC REACTIONS The Schmidt reaction cannot be used on acids unstable towards sul- furic acid or on acids containing aromatic rings that are readily sul- fonated. The Curtius reaction can be used on such compounds; in one of its modifications (see p. 339), in which an acid chloride is treated with sodium azide in boiling benzene and thus transformed directly to the amine,34-36'36 it is almost as direct as the Schmidt process. For a more detailed comparison of the Schmidt, Hofmann, and Curtius reactions see p. 363. The Reactions of Hydrazoic Acid with Lactones, Anhydrides, Esters, and Acid Halides Phthalide and phenolphthalein appear to be the only lactones which have been subjected to the Schmidt reaction,37 and both proved to be unreactive. Acetic anhydride gives a yield of 85% of methyl amine.13 Phthalic anhydride yields isatoic anhydride, benzimidazolone, and an- thranilic acid.37 From methyl or ethyl benzoate a small amount of aniline is obtained, the bulk of the ester being recovered.11'13 Benzoyl chloride also yields aniline.13 It would appear from the limited number of experiments per- formed that the reaction products from acid derivatives and hydrazoic acid are identical with those obtained directly by use of the correspond- ing acid but that the yields are lower. The Reactions of Hydrazoic Acid with Aldehydes and Eetones Aldehydes and ketones are more reactive towards hydrazoic acid than acids. Therefore it is possible to control the reaction of a keto acid or M Forster, J. Chem. Soc, 95, 433 (1909). 38 Naegeli and Stefanovitsoh, Helv. Chim. Ada, 11, 609 (1928); Naegeli, Gruntuch, and Lendorff, ibid., 12,227 (1929); Naegeli and Lendorff, ibid., 15,49 (1932); Naegeli and Vogt- Markus, ibid., 15, 60 (1932); Naegeli and Tyabji, ibid., 16, 349 (1933). M.Schroeter, Ber., 42, 3356 (1909). 37 Csronna, Gazz. chim. Hal., 71, 189 (1941) \C. A., 36, 3173 (1942)]. THE SCHMIDT REACTION 315 keto rater, by using a molar quantity of hydrazoic acid, in such a manner that only the ketone group enters the reaction. It is to be expected that molecules containing both carboxyl and aldehyde groups will react ex- clusively on the aldehyde although no experiments with compounds of this type have been reported. Aldehydes. Acetaldehyde is the only aliphatic aldehyde whose be- havior towards hydrazoic acid has been reported; it yields acetonitrile.3 From benzaldehyde two reaction products, benzonitrile and formani- lide, are obtained.2-3> 25 CHO + HN3 - The relative yields of the two products depend upon the amount of sul- furic acid added to the reaction mixture. In an experiment in which 4 cc. of the acid was added to a solution of 10.6 g. of benzaldehyde and 4.8 g. of hydrazoic acid in 150 cc. of benzene, the yields of the nitrile and anilide were 70% and 13%, respectively; when 30 cc. of sulfuric acid was added the yields were 5% and 50%, respectively.3 Ketones. With symmetrical ketones the Schmidt reaction yields the corresponding substituted acid amides. RCOR + HN3 -> RCONHR Thus methylacetamide and benzanilide are obtained from acetone and benzophenone, respectively, in quantitative yields.1'2'3 Symmetrical ketones of a more complex structure have not yet been investigated. Un- symmetrical ketones can react in two different ways. RCOR' + HN3 -? RCONHR' and RNHCOR' Both reactions have been shown to occur when levulinic acid is treated with an equimolar amount of hydrazoic acid,38 hydrolysis of the reaction mixture yielding /3-alanine, acetic acid, methylamine, and succinic acid.12'38 CH3CONHCH2CH2CO2H -> CH3COCH2CH2CO2H + HN3 CH3CO2H + NH2CH2CH2CO2H CH3NHCOCH2CH2CO2H -> CH3NH2>+ CO2HCH2CH8CO2H 81 Moyer and Wolff, unpublished observation. 316 ORGANIC REACTIONS Since the main reaction product is 0-alanine, the propionic acid group evidently migrates more readily than the methyl group. It appears that in aliphatic and alicyclic /3-keto esters the acetic or substituted acetic ester residue migrates in preference to the hydrocarbon residue; thus the reaction of substituted acetoacetic esters with hydrazoic acid affords a convenient way to synthesize a-amino acids in excellent yields.2'2B R CH3COC¡ªCO2C2HB + HN3 -* R' R CH3CONHC¡ªCO2C2H6 + H2O -? R' R H2NC¡ªCO2H + C2H6OH + CH3CO2H R' This reaction is particularly useful for the preparation of a-disubsti- tuted a-amino acids, R2C¡ªCO2H, which cannot be prepared by the NH2 more conventional condensation syntheses. By the same scheme, /3-amino acids should result from substituted levulinic acids. An exception to the preferential formation of acyl- amino acids is found in the ?-,j3-unsaturated ketone, benzalacetone, from which only N-methylcinnamamide has been isolated.11 C6H5CH=CHCOCH3 + HN3 -? C6H6CH=CHCONHCH3 Apparently there is no tendency to form an N-vinyl acetamide in this instance. The only diketone that has been brought into reaction with hydrazoic acid is benzil.39 A careful investigation of the products of reaction with 2 moles of hydrazoic acid revealed that 1 mole reacted to form phenyl- glyoxanilide, which in turn reacted in two different ways with the second " Spielman and Austin, J. Am. Chem, Soc., 59, 2658 (1937). THE SCHMIDT REACTION 317 mole of hydrazoic acid, yielding mainly N-benzoyl-N'-phenylurea and some oxanilide. C8H6C¡ªCC6HBII II 0 0 HN3 -* C6HBC¡ªCNHC6H6II II 0 0 C6H6NHCONHCOC6H6 HN3 C6H6NHCOCONHC6H6 Benzoic acid, aniline, and several tetrazole derivatives also have been isolated as by-products of this reaction. Essentially the same reaction products have been obtained from phenylglyoxylic anhydride.40 Hydrazoic acid reacts with cyclic ketones in the same way as with open-chain ketones, yielding cyclic amides (lactams) by ring enlarge- ment.5 ? ?? *? 41^? CH2 CH2 CH2/ \ I.I CH2 CH2 CI12 CH.2 r 1 + HN, -? 1 1 CH2 CH2 NH CH2 \ / ? \ / c c ?II o II o + HN3 NH In the alkyl aryl ketones which have Ijeen investigated (acetophe- none, a-hydrindone, etc.) the aryl groups migrate preferentially, yield- ing N-aryl amides. From the reaction product of ethyl cyclohexanone-2-carboxylate and hydrazoic acid, a-aminopimelic acid is obtained by hydrolysis.16-26 This is the sole product when concentrated sulfuric acid is used as catalyst. 40 Caronna, Oaiz. chim. ital., 71, 585 (1941) [C. A., 37, 118 (1943)]. 41 Adamson and Kenner, J. Chem. Soc, 1939, 181. 42 Briggs and De Ath, /. Chem. Soc., 1937, 456. 48 Ruzicka, Goldberg, Hurbin, and Boeckenoogen, Helv. Chim. Ada, 16, 1323 (1933). 318 ORGANIC REACTIONS If, however, traces of water are present in the reaction mixture and gase- ous hydrogen chloride is the catalyst, the intermediate lactam hydrolyzes partially to a-aminopimelic acid which reacts further to yield rfWysine.16 CH2 / CH2 CO CH2 CHCO2C2H6 \ / CH2 I-HN3 CHjr¡ªCO1 1 CH2 NH OH2 CHCO2C2H6 ^-+ \ /CH 2 CO 2H (CH2)4 Hi CHNH2 NH2 *, (CH2)4 V 1 CHNH2 CO2H CO2H To obtain a maximum yield of dHysine, the keto ester is allowed to react with hydrazoic acid in the presence of a stream of hydrogen chloride; the reaction mixture is then hydrolyzed and evaporated to remove the hy- drochloric acid, and the residue is treated with hydrazoic acid and con- centrated sulfuric acid. In a similar manner, ethyl cyclopentanone-2- carboxylate yields a-aminoadipic acid and dZ-ornithine. The Conversion of Ketones to Imido Esters. Imino esters may be pre- pared by the reaction' of hydrazoic acid with ketones in the presence of alcohol.4*.? N¡ªCH3-HC1 HCI ?y CH3COCH3 + HNS + C2H6OH > CHSC OC2H6 CH2¡ªCH2 CH2¡ª CH2¡ªCH2 HCI N-HC1CH 2 C=O + HN3 + C4H9OH CH2¡ªCH2 CH2¡ªCH2¡ªC¡ªOC4H9 The Reactions of Excess Hydrazoic Acid with Aldehydes and Ketones. The Formation of Tetrazoles In the reactions discussed above, hydrazoic acid is used in equimolar quantity or in only slight excess. Even so, tetrazoles sometimes are ob- 44 Schattner, thesis, Heidelberg, 1929. 46 Ger. pat., 488,447 [Frdl., 18, 3048 (1933)]; U. S. pat., 1,889,323 [C. A., 27,1361 (1933)] THE SCHMIDT REACTION 319 tained as by-products.3'2B' **?46 Thus, phenyltetrazole is a by-product of the reaction of benzaldehyde.26 C6H6CHO + 2HN3 -? | | NH N \ / N Similarly tetrazoles are' formed in small amounts when large cyclic ke- tones are treated with hydrazoic acid in equivalent amounts,47 and sev- eral tetrazoles are formed when benzil is treated with 2 equivalents of hydrazoic acid.39 If the substituted tetrazoles are desired as the main reaction products, an excess (2 molar equivalents or more) of hydrazoic acid is introduced. Acetone yields 1,5-dimethyltetrazole readily.2'48 CH8COCH3 + 2HN3 - The behavior of benzophenone is exceptional; it does not yield 1,5- diphenyltetrazole but reacts with 3 moles of hydrazoic acid to form 5- phenylimino-l-phenyl-l,2-dihydrotetrazole.2'48 N ^ N NH CsHsCOCeHs + 3HN3 -? | | C6H6N=C NC6H6 Cyclic ketones react normally. The 1,5-cyclopentamethylenetetrazole obtained from cyclohexanone and hydrazoic acid is known commercially by the name of Metrazole or Cardiazole;2'48 it is a heart stimulant. CH2 / \ CH2¡ªCH2v CH2 CO | XC N | | + 2HN3 -> CH2 | | CH2 CH2 | /N N \ / 2¡ªCH/ \ /" CH2 N Tetrazoles have been prepared from many other cyclic ketones such as polymethylene cycloketones,26- "?49 camphor, and thujone.60 48 v. Braun and Heymons, Ber., 63, 502 (1930). 47 Ruzicka, Goldberg, and Hurbin, Helv. Chim. Ada, 16, 1335 (1933). 48 Ger. pat., 439,041 [Frdl., 15, 333 (1930)]; U. S. pat., 1,599,493 [C. A., 20, 3460 (1926)] 49 Brit, pat., 555,140 [C. A., 39, 944 (1945)]. 60 Ger. pat., 606,615 [Frdl., 21, 675 (1936)]; U. S. pat., 2,029,799 [C. A., 30,1950 (1936)], 320 ORGANIC REACTIONS The amides which are formed by the reaction of hydrazoic acid with ketones apparently are not intermediates in the formation of tetrazoles. It has been shown that e-caprolactam, which is obtained from cyclohex- anone and hydrazoic acid, does not react further with hydrazoic acid.2 No tetrazoles are formed from N-benzoyl-N'-phenylurea, a fact which indicates that the tetrazoles formed from benzil and hydrazoic acid do not arise from further reaction of the major product.39 Unlike most ke- tones, benzil does not give a higher yield of tetrazoles if an excess of hydrazoic acid is employed.39 The Reaction of Hydrazoic Acid with Quinones The reaction of quinones with hydrazoic acid has been effected in the absence of strong mineral acid, and therefore such syntheses are not con- sidered true Schmidt reactions. Treatment of benzoquinone with a large excess of hydrazoic acid in benzene solution results in the formation of azidohydroquinone.61 I + HN3 From 1,4- or 1,2-naphthoquinones, however, good yields of 2-amino-l,4- naphthoquinone and 4-amino-l,2-naphthoquinone, respectively, are ob- tained when glacial acetic acid serves as solvent and 1.7 equivalents of sodium azide is added.62 3-Bromo-l,2-naphthoquinone yields 3-bromo- O 0 HN, NH2 HN3 NH2 81 Oliveri-Mandala and Calderaro, Gazz. chim. ital., 45,1, 307 (1915); Oliveri-Mandala, ibid., 45, II, 120 (1915).62 Fieser and Hartwell, J. Am. Chem. Soc, 57, 1482 (1935). THE SCHMIDT REACTION 321 4-amino-l,2-naphthoquinone. However, certain substituents hinder the reaction. _ Neither 2-methyl-l,4-naphthoquinone nor 4-methyl-l,2- naphthoquinone reacts with hydrazoic acid.62 Phenanthrenequinone gives phenanthridone, retenequinone forms 1- methyl-7-isopropylphenanthridone, and chrysenequinone gives a- naphthophenanthridone.63 No reaction occurs with acenaphthenequi- none. 0 0 )-NH The Reactions of Hydrazoic Acid with Functional Groups Other than Carbonyl Many functional groups besides the carbonyl group react with hydra- zoic acid to give tetrazoles. In most of these reactions no catalyst is re- quired. The tetrazoles thus obtained frequently are formed by rear- rangement of intermediate azides. Since it may be desired to apply the Schmidt reaction to a molecule containing other functional groups or to a mixture of compounds, a few of the reactions leading to the formation of tetrazoles will be discussed briefly. Nitriles. Nitriles usually do not react with hydrazoic acid unless concentrated sulfuric acid is present, in which case they yield tetrazoles.64 The first step of the reaction may consist in the formation of carbodii- mides, which are known to react with hydrazoic acid to form tetrazoles.66'66 BCN + HN3 -> HN=C=NR R = aliphatic or aromatic HN=C=NR + HN3 Several of these 5-amino-l-alkyltetrazoles have been prepared in satis- factory yields. If the reaction is carried out with a dinitrile, it is possible to obtain either the corresponding bistetrazole or the tetrazolenitrile, from which the tetrazolecarboxylic acid is readily accessible. Thus, 63 Carolina, Gazz. chim. Hal., 71, 481 (1941) [C. A., 37, 118 (1943)]. 64 v. Braun and Keller, Ber., 65, 1677 (1932). 66 Oliveri-Mandala, Gazz. chim. Hal., 52, II, 139 (1922). "Stollfe, Ber., 65, 1289 (1922); Stolle and Henke-Stark, J. prakt. Chem., (2), 134, 261 (1930). 322 ORGANIC REACTIONS from octamethylene dicyanide, the mono- and bis-tetrazoles have been prepared.64 NC(CH2)8CN + HN3 -? H2NC N N CNH2 H2NC===N I I + I I I I NC(CH2)8N N N N¡ª(CH2)8¡ªN N \ / \ / \ / N N N Ethyl tetrazolecarboxylate has been obtained from ethyl cyanof ormate in the absence of a catalyst.67 N==CCO2C2H6 NCCO2C2HB + HN3 -? | | N NH \ / Hydrocyanic Acid, Cyanamide, Cyanogen, and Isocyanides. From the reaction of hydrazoic acid with hydrocyanic acid an 80% yield of tetrazole is obtained; no catalyst is required.68 NH N CH HCN + HNS -> || || N N Similarly tetrazole is obtained from cyanamide, 5-aminotetrazole from dicyanamide,69 and 5-cyanotetrazole from cyanogen.60 Isocyanides yield substituted tetrazoles.61 RN CH RNC + HN3 -? | || N N \ / N Oximes, Amides, Amidoximes, Lactams, Hydroxamic Chlorides, Imide Chlorides, and Dichloroketones. The preparation of 1,5-penta- methylenetetrazole from cyclohexanoneoxime and sodium azide in the " Oliveri-Mandala, Gazz. chim. Ual., 41, I, 59 (1911). ' u Dimroth and Fester, Ber., 43, 2219 (1910). MStolle, Ber., 62, 1118 (1929). 60 Oliveri-Mandala and Passalaoqua, Gazz. chim. Ual., 41, II, 430 (1911). a Oliveri-Mandala and Alagna, Gazz. chim. Ual., 40, II, 441 (1910); Oliveri-Mandala, AM accad. IAncei, 19, I, 228 (1910) [C. A., 4, 2455 (1910)]. THE SCHMIDT REACTION 323 presence of fuming sulfuric acid or chlorosulfonic acid has been de- scribed.62 CH2 / CH2 CH2 CISO3H CH2 C=NOH CH2 C=NOSO3H \ / \ / CIl2 CH2 NaN? CH2¡ªCHI CH2 I / CH2¡ªCH/ 2N|| N N In the preparation of tetrazoles from oximes, monosubstituted amides, and amidoximes the use of acid chlorides such as thionyl chloride, ben- zenesulfonyl chloride, or phosphorus chlorides transforms the compounds into imide chlorides, which then yield tetrazoles upon treatment with sodium azide.44' 62'63 N R2C=NOH RCONHR NaNs [R2C=NC1] NaNa [RC(C1)=NR] % R N =N N CH2- CH2 CH2 RC(NH2)=NOH CH2¡ª CH2 [RC(NH2)=NC1] NaN8 /CO CH // ?N CC1 CH2¡ªCH CH2 /C -N N N MGer. pats., 538,981 [Frdl, 17, 2604 (1932)]; 574,943 [Frdl., 19, 1437 (1934)]. 63Ger. pata., 540,409 [Frdl., 17, 2608 (1932)]; 545,850 [Frdl., 17, 2605 (1932)]; 543,025 [Frdl., 17, 2607 (1932)]; 576,327 [Frdl., 20, 762 (1935)]. 324 ORGANIC REACTIONS. Similarly tetrazoles are formed from hydroxamic chlorides.64 N NOH C6HBC \ Cl + NaN3 - C6H5C=N HON¡ªN / \ N Many imide chlorides react with free hydrazoic acid but do not react with sodium azide.65 N-Phenylbenzimido chloride reacts readily with sodium azide and yields 1,5-diphenyltetrazole.66 N ? Cl / / N N C6H6C + NaN3 -> || | \ C6H6C NC6H6 NC6H5 2-Chloropyridine and 2-chloroquinoline, which may be regarded formally as imide chlorides, also yield benzotetrazole and naphthotetrazole re- spectively. No catalysts are needed for the imide chloride reactions.66 Cl N¡ªN + HN3 Diphenyldichloromethane on treatment with sodium azide yields the diazide, which on heating forms diphenyltetrazole 67 but on addition to 70% sulfuric acid yields 98% of benzanilide.68 Imido Esters. Imido esters react readily with sodium azide to form 5-substituted tetrazoles.69 NH OR / / RC N RC + NaN3 -> || || \ N N NH The Reaction of Hydrazoic Acid with Unsaturated Hydrocarbons The formation of aniline from benzene has been mentioned in the in- troduction.1- 2,3,26 Similarlyf xylidine is obtained when hydrazoic acid "Forster, /. Chem. Soc, 96, 184 (1909). 85 v. Braun and Rudolph, Ber., 74, 264 (1941). ?? Schroeter, Ber., 42, 3356 (1909). 67 Schroeter, Ber., 42, 2336 (1909). 68 Gotzky, Ber., 64, 1555 (1931). 69 Ger. pat., 521,870 [Frdl., 17, 2603 (1932)]. THE SCHMIDT REACTION 325 is decomposed by concentrated sulfuric acid in xylene solution.3 These nuclear aminations do not proceed at temperatures essentially below 60-70°.7 Small amounts of o- and p-toluidine have been obtained from toluene and hydrazoic acid with ultraviolet light or with aluminum chlo- ride as catalyst.8 A very interesting reaction of hydrazoic acid with unsaturated aliphatic or cyclic compounds is referred to in a patent70 according to which aliphatic compounds form Schiff's bases in high yields. From amylene RC=CHR" + HN3 RC=NCH2R" R' R' the products isolated after hydrolysis are acetone, methyl ethyl ketone, methylamine, and ethylamine. The formation of these products can be explained by hydrolysis of the two intermediate ketimines. CH3C=CHCH3 + HN3 -> CH3C=NCH2CH3 and CH3CH2C=NCH3 CH3 CH3 CH3 Cyclic unsaturated compounds undergo ring enlargement. CH2¡ªCH CH2¡ªCH CH2 HN3 CH2¡ªCH CH2 \ N For example', from camphene, a mixture of 50% of a- and 25% of ;8-N- dehydrocamphidine is claimed. CH3 CH3 CH3 C CH2 CH2 CH2 CH3CCH3 CHII CH HN3 H2SO4 CH2 CH CH CH, CH3CCH3 N + CH3CCH8 CH2 CH2 CH CH2 CH CH Compounds which contain tertiary hydroxyl groups or halogen atoms and therefore can form unsaturated hydrocarbons by dehydration or de- hydrohalogenation also can react to yield Schiff's bases in high yields. R3CX + HN3 ^% R2C=NR 70 Ger. pat., 583,565 [Frdl., 20, 947 (1935)]. HX X = OH or halogen 326 OEGANIC REACTIONS From the reaction of tf-butyl chloride with hydrazoic acid in the pres- ence of concentrated sulfuric acid a yield of 70% of acetone and 80% of methylamine has been reported. HN3 ^¡ª\ (CH3)2C=NCH3 CH3COCH3 + CH3NH2 Anethole dibromide yields a-bromopropionaldehyde and 75% of p-anisi- dine. There may be an analogy between this reaction and the formation CH; H2SO4 CH3< NH2 + CH3CHBrCHO HBrCHBrCHs + HN3 N=CHCHBrCH3 of aniline from cinnamic acid (p. 311), which could yield an intermediate of the structure C6H5N=CHCH2CO2H. Benzohydrol is reported to yield 90% of benzalaniline. H2SO4HN 3 C6H6CH=NC6H6 Menthol reacts as follows. CH3 CH CH2 CH2 CH2 CHOH CH CH(CH3)2 HN3 H2SO4 CH3 CH / CH2 CH2 CH2 NII CH CH CH(CH3)2 (18%) Borneol reacts in an analogous manner. CH3 CH CH2 CH2 CH2 N C CH(CH3)2 CH, CH CH2 CH2 CH2 NH C(CH3)2 (50%) THE SCHMIDT REACTION 327 EXPERIMENTAL CONDITIONS The Schmidt reaction can be carried out with a solution of hydrazoic acid in an appropriate organic solvent * or with sodium azide directly. The direct method has the advantage of eliminating one step and avoid- ing the isolation of the very poisonous hydrazoic acid. Most of the reac- tions reported, however, have been carried out with free hydrazoic acid, and when both methods have been reported on the same compound the yield was higher when free hydrazoic acid was used.16 Other authors claim, however, that sodium azide may be used without detrimental ef- fect to the yield,12 and the claim seems to be corroborated by the in- creased use of sodium azide in recent investigations.17'22> 27~33> 71 The Preparation of Hydrazoic Acid Solutions10 Since hydrazoic acid is very poisonous, all reactions involving it should be carried out under a good hood. If some hydrazoic acid has been inhaled accidentally, resulting in a feeling of pressure in the head, the drinking of a few cubic centimeters of 96% alcohol has been suggested to relieve these symptoms. Hydrazoic acid has a pungent odor. In a large three-necked flask containing a dropping funnel, thermome- ter, efficient stirrer, and gas outlet tube, a paste is prepared from equal weights of technical sodium azide and warm water. To this paste, chloroform or benzene is added (about 40 cc. for each 6.5 g. of sodium azide used) and the mixture is cooled to 0°. While the mixture is stirred and cooled, concentrated sulfuric acid is added dropwise (1 mole of sul- furic acid for 2 moles of sodium azide). The temperature should not ex- ceed 10°. After the addition of the calculated amount of acid, the mix- ture is cooled to 0° and the organic layer is decanted and dried over anhydrous sodium sulfate. The strength of the chloroform or benzene solution of hydrazoic acid can be determined by pipetting (not using mouth suction) a few cubic centimeters into a glass-stoppered bottle, shaking it with 30-50 cc. of distilled water, and titrating with a standard alkali solution. Usually the concentration of hydrazoic acid ranges from 4% to 10%. * Note added in proof. Sanford, Blair, Arroya and Sherk [J. Am. Chem. Soc, 67, 1941 (1945)] have added dry gaseous hydrogen azide to ketones in benzene solution in the presence of sulfuric acid. The ketones used and the amides isolated were: CHaCOCHaCHs, CH3CONHC2H6 (70%); CH3COCH2CH(CH3)2, CH3CONHCH2CH(CH3)2 (71%); CH3COCeH5, CH3CONHC6H6 (90%); CHaCOCeJLiCHa (p), CHsCONHC?HiCH3 (p) (90%); CHsCOCeHiOCHs (p), CH3CONHC6H4OCH3 (p) (50%); CH3COC,0H7 (0), CH3CONHCioH7 (0) (73%); CH3CH2COC6H6, CH3CH2CONHC?H6 (90%); (C?Hj)2CO CeH6CONHC6H6 (80%); CeHjCONHCEUCHa (p), CeH6CONHCeH4CHa (p) (82%). 71 Arnold, Ber., 76, 777 (1943). 328 ORGANIC REACTIONS The Reaction of Hydrazoic Acid with Carbonyl Compounds The Schmidt reaction with a carbonyl compound can be carried out in essentially three different ways: 1. Addition of hydrazoic acid. The organic acid or ketone is dissolved in at least twice its volume of concentrated sulfuric acid (plus chloroform or benzene in the case of a ketone). To the solution the hydrazoic acid solution is added with stirring. This method is preferable for the prepa- ration of amines from acids.10- ?? 13~16>19- u- ?-38- ?*? 72~74 The speed of the reaction can be observed by passing the escaping gases through a wash bottle. The gas stream should be lively but not violent. The amount of hydrazoic acid used is generally from 1 to 1.2 moles of hydra- zoic acid for one carbonyl group. After all the acid has been added, stirring is continued until gas evolution has ceased. 2. Addition of concentrated sulfuric acid. To a stirred solution of the organic acid, ketone, or aldehyde in chloroform (or benzene) and hydra- zoic acid (1 to 1.2 moles), concentrated sulfuric acid is added dropwise. This method avoids prolonged contact of the carbonyl compound with concentrated sulfuric acid. It is the only method that has been used for the reaction of aldehydes with hydrazoic acid.2-?.". ??.?>.? 3. Addition of the carbonyl compound and hydrazoic acid. A mixture of the carbonyl compound (1 mole) and the hydrazoic acid solution (1 to 1.2 moles) is added with stirring to concentrated sulfuric acid or to a con- centrated sulfuric acid-chloroform mixture.2'3-43 The Generation of Hydrazoic Acid in Situ To a stirred solution of the carbonyl compound in chloroform and con- centrated sulfuric acid, sodium azide is added in small portions, until after addition*of 1.0 to 1.2 moles of sodium azide no more gas is devel- oped.12- 15- ". 22, as, 27-33,37,71 jt is possible that better yields might be achieved by an activation of technical sodium azide with hydrazine hydrate,21 a process which is reported to give better results in the forma- tion of isocyanates from acid halides and sodium azide. Temperature The Schmidt reaction with aldehydes and ketones always is carried out with cooling of the reaction mixture in an ice bath. The temperature 72 v. Braun and Pinkernelle, Ber., 67, 1056 (1934). "Cosciug, Wien. Chem. Z%, 46, 145 (1943) [C. A., 38, 4575 (1944)]. 74 Jansen and Pope, Proc. Roy. Soc. London, A154, 53 (1936); Chemistry & Industry, 51, 316 (1932). THE SCHMIDT REACTION 329 range for the preparation of amines from acids is from 35° to 50° and in most cases is maintained between 40° and 45°. The reaction is exother- mic, and the temperature can be controlled by the rate of addition of the hydrazoic acid solution. Only if the reaction is sluggish is a higher tem- perature of advantage. Glycine is obtained in only 29% yield from malonic acid at 40°, whereas the yield is 46% at 50°.15 The yield of aniline from benzoic acid is 85% if the reaction is carried out at 40° and drops to 44% when boiling chloroform is used as a solvent.11 However, the drop in yield with higher temperature may be due to loss of hydra- zoic acid (b.p. 37°). Solvents In almost all preparations the hydrazoic acid is dissolved in chloro- form or benzene. Since chloroform is completely inert towards hydra- zoic acid it may be preferable, but under most conditions benzene is just as satisfactory. Trichloroethylene also has been used successfully as a solvent.7 The addition of dioxane has been found to be of value in the preparation of dZ-phenylalanine from benzylmalonic acid.11 Ethyl ether is not a satisfactory solvent,11 although its use has been mentioned in patents.8 Catalysts Concentrated sulfuric acid in amounts of 2-4 cc. for 1 g. of carbonyl compound has been used most extensively as the catalyst for the Schmidt reaction. In dilute sulfuric acid the yield decreases sharply.2' u The yield of aniline from benzoic acid drops from 85% to 15% if 75% sulfuric acid is used.11 Other catalysts mentioned are hydrogen chloride;16'43 phosphorus trichloride, oxychloride, pentoxide, and pentachloride; thionyl chloride; ferric chloride, stannic chloride; sulfoacetic acid and other sulfonic acids;2B phosphoric acid;3 aluminum chloride;ffi and ultra- violet light.8 There is no evidence that any of these catalysts is as good as concentrated sulfuric acid. The Isolation of the Reaction Products The amines are isolated either by liberation from the crystalline amine sulfate, or by steam distillation of the alkalized water extract of the re- action mixture, or by ether extraction of the alkaline solution.* In the preparation of amino acids the isolation may be effected by forming an appropriate derivative such as a picrate or phosphotungstate.16 330 ORGANIC REACTIONS EXPERIMENTAL PROCEDURES The Preparation of Amines and Derivatives of Amines Heptadecylamine from Stearic Acid.11 To a solution of 15 g. (0.53 mole) of purified stearic acid (m.p. 69.5°) in 500 cc. of benzene, 30 cc. of concentrated sulfuric acid is added and the mixture stirred vigorously at 40°. One and two-tenths moles of hydrazoic acid (52 cc. of a 5.3% solu- tion in benzene) is then added slowly. After the reaction has ceased (about two hours), the acid layer is poured into water to precipitate the sulfate of heptadecylamine, which may be crystallized from ethanol as white plates that turn brown at 195° and decompose at 200°. The yield is 96%. 5-Ethoxy-l-(4-ethoxybutyl)-amylamine from 6-Ethoxy-2-(4-ethoxy- butyl)-caproic Acid.27 To a mixture of 6.3 g. (0.024 mole) of the acid, 41 cc. of concentrated sulfuric acid, and 80 cc. of chloroform is added with stirring at 50-55°, 1.82 g. (0.042 mole) of sodium azide in small portions. After all the azide has been added the mixture is heated for another thirty minutes at 50°, diluted with ice, and made alkaline. The reac- tion mixture is steam-distilled, hydrochloric acid is added to the distil- late, and the solution is filtered. The free amine is liberated from its hydrochloride by the addition of alkali. The amine is taken up in ether, dried over potassium hydroxide, and distilled in vacuum (b.p. 162°/15 mm.). The yield is 4.7 g. or 84%. Lactam of 16-Aminohexadecanoic Acid from Cyclohexadecanone.43 To a stirred mixture of 50 cc. of concentrated sulfuric acid and 150 cc. of benzene, cooled in an ice bath, is added a solution of 15.3 g. (0.0643 mole) of cyclohexadecanone and 2.9 g. (0.0674 mole) of hydrazoic acid in 150 cc. of benzene. After fifteen minutes, ice is added to the reaction mixture, and the benzene layer is separated and washed with a dilute sodium hydroxide solution. The product obtained by concentration of the benzene layer can be purified by distillation (b.p. 171-178°/1 mm.), and crystallization of the distillate from acetone. The yield of pure lactam, melting at 125-126°, is 14 g. (86%), Ethyl N-Methylacetimidate.46 A mixture of 58 g. (1 mole) of acetone and 600 cc. of a benzene solution of hydrazoic acid containing 65 g. (1.5 moles) of hydrazoic acid is added dropwise with stirring to 250 cc. of ethanol previously saturated with hydrogen chloride; the temperature is kept below 25° by cooling, if necessary. When no more gas is evolved, the benzene and excess ethanol are evaporated; the residue consists of the very hygroscopic imido ester hydrochloride. The free base, liberated by treatment with strong alkali, is dissolved in ether. The ether solution THE SCHMIDT KEACTION 331 is carefully dried and distilled. Ethyl N-methylacetimidate boiling at 99-100° is obtained in 50% yield. The Preparation of Tetrazoles 1,5-Dimethyltetrazole.48 To a mixture of 35 g. (0.814 mole) of hydra- zoic acid dissolved in about 500 cc. of benzene and 50 cc. of concentrated sulfuric acid, 15.7 g. (0.27 mole) of acetone is added dropwise with stirring and cooling. Approximately 5 1. of nitrogen is evolved. The acid layer is then diluted with ice and neutralized with sodium carbonate, and ethanol is added to precipitate the sodium sulfate. After filtration, the solution is concentrated and the mercuric chloride complex of the reac- tion product is obtained by adding a cold saturated aqueous solution of mercuric chloride. The addition compound melts at 111°. The free 1,5-dimethyltetrazole is obtained by decomposing an aqueous solution of the addition product with hydrogen sulfide and evaporating the filtrate to dryness. The product is recrystallized from petroleum ether; it melts at 71°. The yield is about 80%. 1,5-Cyclohexamethylenetetrazole.47 A solution of 12 g. (0.101 mole) of cycloheptanone and 11.5 g. (0.267 mole) of hydrazoic acid solution in 280 cc. of benzene is added during forty-five minutes with stirring and ice cooling to a mixture of 60 cc. of concentrated sulfuric acid and 100 cc. of benzene. The brownish green reaction mixture is diluted with iee and ice water. The benzene layer contains practically none of the reaction product. The sulfuric acid layer is made alkaline with sodium hydroxide and extracted exhaustively with ether. The crystalline product boils at 135-140°/0.1 mm. and melts after recrystallization from benzene at 66-68°. l-n-Hexyl-5-aminotetrazole.64 To a mixture of 11.1 g. (0.1 mole) enanthonitrile and a benzene solution containing 10.7 g. (0.25 mole) of hydrazoic acid, 44 g. of concentrated sulfuric'acid is added dropwise with stirring at 35^10°. The temperature rises to about 45°. After cessation of the reaction, the benzene layer is separated and the sulfuric acid layer is diluted with ice. The addition of alkali precipitates a solid which con- tains some alkali sulfate. On recrystallization from ethanol, 1-w-hexyl- 5-aminotetrazole melting at 162° is obtained in 60% yield. 332 ORGANIC REACTIONS OF COMPOUNDS PREPARED BY THE SCHMIDT REACTION Parent Compound Acid, monobasic Caproic (CBHUCO2H) Enanthic (C6Hi3CO2H) Caprylic (C7H16CO2H) Pelargonic (C8Hi7CO2H) Capric (C9H19CO2H) Undecylic (Ci0H2iCO2H) Stearic (C17H35CO2H) Naphthenic (C6HUCO2H to CUH21CO2H) (Ci7H33CO2H) Phenylacetic Dibenzylacetic Dicyclopentylacetic a-Benzylpropionic Podocarpic (CtfHgjQs) * CO2H CH2 CH2 HV V V \s \s v^ H CH2 CH2 CO2H Spiroheptanedicarboxylic /3-Phenylpropionic /3-(p-Methoxyphenyl)propi- onic Cyclohexanecarboxylic /3-(2,4-Dimethoxyphenyl)pro- pionic ¡ê-(2,3,5-Trimethoxyphenyl)- propionic Cinnamic Campholic Pencholic Dimethylcampholic l-Phenylpiperidine-4-car- boxylic 5-Ethoxy-2- (3-ethoxypropyl) - valeric Product n-Pentylamine" n-Hexylamine n-Heptylamine n-Octylamine n-Nonylamine n-Decylamine n-Heptadecylamine Amines (CeHuNH2 to CnH21NH2) CuHssNHa Benzylamine A/S'-Diphenylisopropylamine Dicyclopentylmethylamine ^-Phenylisopropylamine C16H21ONH2 H2N CH2 CH2 HV xc/ V H CH2 CH2 NH2 Spiroheptanediamine /3-Phenethylamine P- (p-Methoxyphenyl) ethy 1- amine Cyclohexylamine /3-(2,4-Dimethoxyphenyl)ethyl- amine Aniline Phenylacetaldehyde Camphelylamine Fenchelylamine Dimethylcamphelylamine 4-Amino-l-phenylpiperidine 4-Ethoxy-l-(3-ethoxypropyl)- butylamine Yield 70-75% 90% 96% 70-85% 80% 75, 92% Over 70% 70% 73% 95% 70% 55% 82% Traces 0% 32% 43% 88%, 75% 91% 75% 85% By ti- tration Refer- ence 9 9, 14 9 9 9 9 11 10,16 26 14 12, 13 12 18 19. 11 74 12 12 12 12 12 . 12 10, 16 10, 16, 1Q 20 22 29 * For^ie structure of podocarpic acid, see formula VIII, p. 311. THE SCHMIDT REACTION 333 TABLE OF COMPOUNDS PREPARED BY THE SCHMIDT REACTION¡ªContinued Parent Compound 6-Ethoxy-2-(4-ethoxybutyl)- caproic 7-Ethoxy-2-(5-ethoxyamyl)- enanthic 7-Ethoxy-2- (3-ethpxypropy 1) - enanthic 6-Ethoxy-3- (3-ethoxypropyl) - caproic Hexahydroindanyl-5-acetic 5-Methyl-hexahydroindanyl- 6-acetic 4-Tetrahydropyrancarboxylic 4-Tetrahydropyranacetic /3-(4-Tetrahydropyranyl)- propionic a-(4-Tetrahydropyranyl)- propionic a- (4-Tetrahydropyranyl) - butyric /3-(4-Tetrahydropyranyl)- butyric a-Methyl-a-(4-tetrahydro- pyranyl)-propionic #-(4-Tetrahydropyranyl)- valeric Benzoic Toluic Salicylic 3,4,5-Trimethoxybenzoic m-Chlorobenzoic m-Bromobenzoic m-Iodobenzoic m-Hydroxybenzoic ?i-Methoxy benzoic ro-Ethoxybenzoic Product 5-Ethoxy-l-(4-ethoxybutyl)- amylamine 6-Ethoxy-l-(5-ethoxyamyl)- hexylamine 6-Ethoxy-l- (3-ethoxypropyl) - hexylamine 5-Ethoxy-2- (3-ethoxypropyl) - amylamine 5-Aminomethylhexahydroin- dane 5-Methyl-6-hexahydroindanyl- methylamine 4-Tetrahydropyranylamine 4-Tetrahydropyranmethyl- amine 2-(4-Tetrahydropyranyl)- ethylamine 1 - (4-Tetrahydropyranyl)- ethylamine l-(4-Tetrahydropyranyl)- propylamine 2-(4-Tetrahydropyranyl)- propylamine l-Methyl-l-(4-tetrahydro- pyranyl)-ethylamine 2-(4-Tetrahydropyranyl)- butylamine Aniline Toluidine o- m- P- o-Aminophenol 3,4,5-Trimethoxyaniline m-Chloroaniline m-Bromoaniline m-Iodoaniline m-Aminophenol m-Aminoanisole m-Aminophenetole Yield 84% 78% 78% 85% By ti- tration 87% 44% 52.5% 51.4% 66.5% 68% 74.5% 50% 63% 85% 46% 24% 70% 21% 35% 75%* 72%* 62%* 80%* 77%* 73%* Refer- ence 27 31 32 30 71 71 28 28 28 17 17 33 17 33 7,12, i Qlo 11 12 12 7 7 7 7 7 7 * Not corrected for the reoovered acid. 334 ORGANIC REACTIONS TABLE OP COMPOUNDS PREPARED BY THE SCHMIDT REACTION¡ªContinual Parent Compound m-Cyanobenzoic m-Toluic o-Methoxybenzoic p-Methoxybenzoic o-Nitrobenzoic p-Nitrobenzoic m-Nitrobenzoic Acid, dibasic Malonic Benzylmalonic Succinic Adipic Dodecamethylenedicar- boxylic l,2,2-Trimethyl-l,3-cyclo- pentanedicarboxylic (cam- phoric) Cyclobutanedicarboxylic Homocamphoric o-Phthalic m-Phthalic p-Phthalic 3-Nitrophthalio Glutamic Diphenic Acid, amino a-Aminoadipic tt-Aminopimelic e-Aminocaproic "y-(o-Aminophenyl)-butyric Product m-Aminobenzonitrile rre-Toluidine o-Aminoanisole p-Aminoanisole o-Nitroaniline p-Nitroaniline m-Nitroaniline Glycine aWhenylalanine Ethylenediamine Tetramethylenediamine Dodecamethylenediamine l,3-Diamino-2,2,3-trimethyl- cyclopentane 1,2-Diaminocyclobutane Homocamphoramine Anthranilic acid o-Diaminobenzene m-Aminobenzoic acid p-Aminobenzoic acid p-Diaminobenzene 3-Nitroisatoic acid d-a,7-Diaminobutyric acid Phenanthridone + 2,2'- diaminobiphenyl <M-Ornithine dl-Lysine Pentamethylenediamine T-(o-Aminophenyl)-propyl- amine Yield 59%* 42%* 80%* 78%* 68%,* 83% 41%,* 83% 63%,* 83% - 29% 16% 8% 80%, 83%, * 70% 90% 75% cis 35%, trans 55% 84.6% 79% 3% 57% . 79% 3% 42% 75% 74%. 70% 44% Refer- ence 7 7 7 7 7,'12 7, 12 7,12 15 11 12 12, 13, 72 14 16 24 73 12 7 12 23 15 23 15 15 13 42 * Not corrected for the recovered acid. THE SCHMIDT REACTION 335 TABLE OF COMPOUNDS PBBPABED BT THE SCHMIDT REACTION¡ªContinued Parent Compound Anhydride Acetic Phthalic 3-Nitrophthalic Diphenic Phenylglyoxylic Esters Ethyl benzoate Methyl benzoate Acid chloride Benzoyl chloride Aldehydes Acetaldehyde Benzaldehyde m-Nitrobenzaldehyde Ketones Acetone Levulinic acid Methyl levulinate Ethyl acetoacetate Ethyl a-ethylacetoacetate Ethyl a-isopropylacetoacetate Ethyl a-isoamylacetoacetate Ethyl a-benzylacetoacetate Ethyl a-dimethylacetoacetate Ethyl a-dibenzylacetoacetate Diethyl acetylsuccinate Cyclopentanone Cyclohexanone Cyclooctanone 2-Methylcyclohexanone Product Methylamine Isatoic anhydride Benzimidazolone Anthranilic acid 3-Nitroisatoic acid 5-Nitrophenylurea 2-Amino-3-nitrobenzoic acid Phenanthridone Oxanilide, benzoylphenylurea, and tetrazoles Aniline Aniline Aniline Acetonitrile Benzonitrile Formanilide ro-Nitroaniline m-Nitrobenzonitrile Methylacetamide /3-Alanine Succinic acid Methyl-/3-aminopropionate Glycine a-Amlnobutyric acid Leucine a-Aminoisoamylacetic acid /3-Phenylalanine Ethyl-a-(N-acetyl)-aminoiso- butyrate Dibenzylaminoacetic acid Aspartic acid Piperidone e-Caprolactam 8-Aminocaprylic acid lactam Tetrazole 6-Aminoenanthic acid lactam Yield 85% 24-30% 26% 80% 64% 70% 13% 17% 83% Quanti- tative 56% 10% 30% 80-98% 80-98% 80-98% 80-98% 80-98% ¡ª 80-98% 80-98% ¡ª 70% 70% 22% 45% Refer- ence 13 37 23 23 40 11, 13 11 13 3 2, 3, 25 2 2 38 38 2 2 2 2 2 25 " 2 2 46 2, 3, 46 43 46 336 ORGANIC REACTIONS TABLE OF COMPOUNDS PREPARED BY THE SCHMIDT REACTION¡ªContinued Parent Compound Cyclohexadecanone o-Hydrindone a-Tetralone Ethyl cyclopentanone-2-car- boxylate Ethyl cyclohexanone-2-car- boxylate Acetophenone Benzophenone Methyl /3-phenylethyl ketone a-Benzyl-a-methylacetone Benzalacetone Benzil Isatin or Acetylisatin N-Ethylisatin Product 16-Aminohexadecanoic acid lactam Dihydrocarbostyril Homodihydrocarbostyril a-Aminoadipic acid and dl- ornithine a-Aminopimelic acid and dl- lysine Acetanilide Benzanilide N-(/3-Phenylethyl) acetamide N-(/3-Phenylisopropyl) acetam- ide N-Methyl cinnamamide N-Benzoyl-N'-phenylurea (and some oxanilide) Anthranilamide o-Ethylaminobenzamide Yield 86% 68% 70% 40% (orni- thine) 60% (lysine) 77% Quanti- tative 62.5% 48% > ¡ª 30-60% ¡ª Refer- ence 43 42 42 15 15 42 2,3 11 11 11 39 40 40 CHAPTER 9 THE CURTIUS REACTION PETEE A. S. SMITH University of Michigan CONTENTS PAGE INTRODUCTION 338 SCOPE AND LIMITATIONS OF THE REACTION 340 Effect of Structure and Substituente 0 Saturated Monocarboxylic Acids . , 340 Unsaturated Acids 341 Di- and Poly-carboxylic Acids 343 Preparation of Diamines 3 Preparation of Aldehydes and Ketones 345 Stepwise Degradation to Amino Acids 6 Hydroxy Acids 349 Keto Acids 352 Amino Acids 3 Acylated Amino Acids 354 Carbamic Acids 5 Halogenated Acids 6 Nitro Groups 358 Cyano Acids 9 Sulfonamide, Sulfide, and Other Sulfur-Containing Groups 359 Azo, Diazo, and Azido Groups 360 Heterocyclic Systems 361 Thiocarbamyl Azides, Imido Azides, and Hydroximido Azides 362 Comparison of the Curtius, Hofmann, and Schmidt Reactions 363 RELATED REACTIONS 366 The Lossen Rearrangement 366 The Tiemann Reaction 6 Treatment of Silver Salts with Halogens 366 SELECTION OF EXPERIMENTAL CONDITIONS 6 Preparation of Hydrazides . 366 Preparation of Azides 369 From Hydrazides 9 Isolation of Azides 373 From Acid Chlorides and Sodium Azide 373 Other Methods of Preparing Azides 5 Rearrangement of Azides 375 Preparation of Isocyanates 6 * Preparation of Ureas 6 337 338 ORGANIC REACTIONS PAGE Preparation of Urethans 377 Preparation of Acylamines 7 Preparation of Amines 8 EXPERIMENTAL, PROCEDURES 381 Reagents 381 Note on the Handling of Hydrazine 381 Anhydrous Hydrazine 381 Activation of Sodium Azide 382 Hydrazide Method 2 Ester to Amine via Urethan 2 Benzylamine from Ethyl Phenylaoetate 382 Preparation of an Acylamine 383 N-Q3-3,4-Dibenzyloxyphenylethyl)-homopiperonylamide 383 Preparation of an Aldehyde 4 Phenylacetaldehyde from Benzylmalonic Ester 384 Preparation of an a-Amino Acid from a Malonic Ester 384 3-Phenylalanine from Benzylmalonic Ester 384 Preparation of an a-Amino Acid from a Cyanoacetic Ester 385 Gly cine from Cyanoacetic Ester 385 Reverse- Addition Procedure 386 1,4-Diaminocyclohexane from Hexahydroterephthalic Acid 386 Use of Amyl Nitrite 386 4-Hydroxy-2-methylpyrimidine-5-methylamine 386 Sodium Azide Method 7 Dry Procedure 387 Acid Chloride to Amine via Isocyanate 387 Benzylamine Hydrochloride from Phenylacetyl Chloride 387 Wet Procedure 387 Acid Chloride to Isocyanate and Amine 387 m-Isocyanatoazobenzene and wi-Aminoazobenzene from Azobenzene- m-carbonyl Chloride 387 Undecyl Isocyanate from Lauroyl Chloride 388 SURVEY OP THE CURTIUS REACTION 388 Nomenclature 388 Yields, References, and Symbols 8 INDEX TO TABLE 390 TABLE OF COMPOUNDS SUBJECTED TO THE CURTIUS REACTION 392 INTRODUCTION The decomposition of acid azides to isocyanates and nitrogen is known as the Curtius rearrangement. The reaction is a preparative method RCON3 -? RN=C=0 + N2 for isocyanates and for compounds derivable from isocyanates, such as urethans, ureas, amides, and amines. When coupled with a hydrolytic . THE CURTIUS REACTION 339 step, the Curtius rearrangement becomes a practical procedure for replacing a carboxyl group by an amino group. The overall process of converting an acid through its azide to an amine is commonly referred to as the Curtius reaction. RCO2H -? RCON3 -> RN=C=O -> RNH2 Curtius, through his studies on diazo esters, discovered successively hydrazine, hydrazides, azides, and hydrazoic acid; in 1890 he encoun- tered the rearrangement of acid azides, although he did not recognize its true nature at the time.1' 2 Since then abundant investigations by Curtius and others have elucidated the reaction and demonstrated its generality. Acid azides are commonly prepared by treating acid hydrazides in cold, aqueous solution with nitrous acid. The required hydrazides are prepared from esters l>y reaction with hydrazine. Acid azides can also be made by treatment of acid chlorides with sodium azide. In Curtius' RCO2CH3 + NH2NH2 -> RC0NHNH2 + CH30H RCONHNH2 + HN02 -? RCONS + 2H2O ' RCOC1 + NaN3 -?? RCON3 + NaCl numerous papers, the route to the azide through the hydrazide is the one described almost exclusively, although the acid chloride-sodium azide method was early known to him 3 and was used by others.4' *?e Naegeli and his students 7- ?? '? 10 have demonstrated that the sodium azide method is satisfactory and often preferable; they have also re- viewed critically the hydrazide method. Azides can be rearranged in inert solvents like benzene and chloro- form, from which the isocyanates can be isolated, or in the presence of reagents like alcohol or water which will react with the intermediate isocyanates to form urethans or ureas. Amines or their salts are ob- tained by hydrolysis of the isocyanates, urethans, or ureas. [ RNCO226] Hso BOON, - EN-=C=oj^¡ª_^^^ BNH, 1 Curtius, Ber., 23, 3023 (1890). 2 Curtius, J. prakt. Chem., 50, 275 (1894). 8 Lindemann, Helv. Chim. Ada, 11, 1027 (1928). *Forster, J. Chem. Soc., 95, 184 (1909). ? Lindemann and Weasel, Ber., 58, 1221 (1925). ? Schroeter, Ber., 42, 2336 (1909). 'Naegeli, Gruntuoh, and Lendorff, Helv. Chim. Ada, 12, 227 (1929). 8 Naegeli and Lendorff, Helv. Chim. Ada, 12, 894 (1929). ?Naegeli and Lendorff, Helv. Chim. Ada, 15, 49 (1932). 10 Naegeli and Stefanovioh, Helv. Chim. Ada. IV, 609 (1928). 340 ORGANIC REACTIONS Other types of azides undergo analogous rearrangement.11- 12-1S Sulfonyl azides, however, do not rearrange. The mechanism of the Curtius rearrangement is discussed in the chapter on the Hofmann reaction (p. 268). SCOPE ANb LIMITATIONS OF THE REACTION The Curtius degradation has been carried out successfully on ali- phatic, alicyclic, aromatic, and heterocyclic acids, on saturated and unsaturated acids, and on acids containing various functional groups. It may be expected to succeed for almost any carboxylic acid, and is, therefore, a general method for preparing isocyanates and the com- pounds obtainable from isocyanates, such as urethans, ureas, and amines. The reaction possesses the advantage of yielding primary amines which are scrupulously free of secondary and tertiary amines and in which the position of the amino group is usually unequivocal,. Effect of Structure and Substituents The structure of the acid or the presence of substituents may affect certain steps in the Curtius reaction. Although it is usually a matter of choice whether the hydrazide method or the sodium azide method is employed for the preparation of a given azide, for certain azides one of the methods may fail completely or may be preferable because of the structure of the acid or the presence of certain groups in the molecule. As a rule the rearrangement of azides to isocyanates proceeds without difficulty. The product obtained by hydrolysis of the isocyanate is not always an amine; certain isocyanates yield aldehydes or ketones. Saturated Monocarboxylic Acids. Azides of saturated acids can be prepared almost equally well by reaction of the hydrazides with nitrous acid or by reaction of the acid chlorides with sodium azide. The latter method is superior for very low-molecular-weight acids, whose hydra- zides and azides are difficult to extract from water; by this method acetyl chloride is converted to methyl isocyanate through the azide in 60-72% yields.14- 15 From lauroyl chloride, 86% of undecyl isocyanate is obtained by the sodium azide method.16 The reaction of acid an- 11 Curtius, Darmstaedter, Pringsheim, and Stangassinger, J. prakt. Chem., 91, 1 (1915). "Franklin, Chem. Revs. 14, 219 (1934). 13 Porter, "Molecular Rearrangements," Chemical Catalog Co., 1928. "Schroeter, Ber., 42, 3356 (1909). 15 Slotta and Lorena, Ber., 68, 1320 (1925). u Allen and Bell, Org. Syntheses, 24, 94 (1944). THE CURTIUS REACTION 341 hydrides with sodium azide has been reported; methyl isocyanate was obtained in 78% yield from acetic anhydride.160 Low-molecular-weight esters react quite readily with hydrazine, but heavier ones must be coerced. Aromatic esters are less reactive than aliphatic esters toward hydrazine, and they and the more resistant ali- phatic esters occasionally require prolonged heating with hydrazine at elevated temperatures in a sealed tube. Branching of the carbon chain alpha to the ester group retards hydrazide formation; in contrast with ethyl acetate, which reacts spontaneously with hydrazine at room temperature, ethyl pivalate (ethyl trimethylacetate) requires a tempera- ture of 140°, And adamantane-l,3-dicarboxylic ester (I) failed to form a hydrazide under all conditions (unspecified) that were tried.17 Simple saturated azides rearrange quantitatively to isocyanates as judged from the volume of nitrogen evolved. The actual yields of the isocyanates are slightly lower, particularly when the molecular weight is low, owing to volatilization with the nitrogen. This loss is eliminated when the rearrangement is carried out in alcohol, and excellent yields of urethans are obtained. Both the isocyanates and the urethans can be hydrolyzed smoothly to the amines. Unsaturated Acids. The formation of olefinic acid azides by the sodium azide procedure appears to be limited only by the availability of the acid chloride. Examples of a,/3-olennic acid azides prepared by this method are crotonyl,18 cinnamoyl,18-19 and methacrylyl x azides. The hydrazide route to the azide is sometimes complicated by side reac- tions. The esters of oleic acid and elaidic acid give the respective hydra- zides in good yield under the usual conditions, but severe treatment causes reduction of the unsaturated hydrazides to stearoyl hydrazide.21 1W Colucci, Can. J. Research, 23B, 111 (1945). 17 Prelog and Seiwerth, Ber., 74, 1769 (1941). "> Jones and Mason, J. Am. Chem. Soc., 49, 2528 (1927). *? u Forster, /. Chem. Soc., 95, 433 (1909). 20 Coffman, V. S. pat. 2,335,012 [C. A., 38, 2772 (1944)]. ai Van Alphen, flee. trav. chim., 44, 1064 (1925). 342 ORGANIC REACTIONS Conversion of the hydrazides of a,j3-olefinic acids to azides is frequently impossible owing to cyclization upon treatment with nitrous acid. Cin- namoyl hydrazide and nitrous acid, for example, yield l-nitroso-5- phenyl-3-pyrazolidone.22 Crotonyl hydrazide 23 and m-nitrocinnamoyl H2N hydrazide 24 behave analogously. Fumaryl hydrazide,25 on the other hand, reacts normally with formation of fumaryl azide. In the reac- tion of the unsaturated hydrazides with nitrous acid, there is little likeli- hood of nitrosating the double bond, because of the rapidity with which the hydrazide function reacts with nitrous acid. Among the azides which have been prepared successfully by both the acid chloride-sodium azide procedure and the hydrazide method are the azides of chaulmoo- gric (II),10 bornylenecarboxylic (III),26'27-2S oleic, erucic, and unde- cenoic acids,29 CH8 a CH=CH H2C CH(CH2)12CON8 CH2-CH2 H3CCCH8 CH m "CHII* JO¡ªCONj a,j8-Olefinic azides rearrange to vinyl isocyanates; for example, metha- crylyl azide yields a-methylvinyl isocyanate.30 Certain vinyl isocyan- ates polymerize readily; the products of the rearrangement of the azide 22 Muckermann, Ber., 42, 3449 (1909). 23 von Braun, Ber., 67, 218 (1934). u Curtius and Bleicher, /. prafci. Chem., 107, 86 (1924). . 26 Curtius and Radenhausen, J. prakt. Chem., 52, 433 (1895). MBredt and HUbing, Chem. Ztg., 35, 765 (1911). "Bredt, Perkin, Hilbing, Lankshear, and Regout, J. prakt. Chem., 89, 225 (1914). 28 Bredt-Savelsberg and Bund, J. prakt. Chem., 131, 46 (1931). 29 Oskerko, Mem. Inst. Chem. Ukraine Acad. Sd., 2, 69, 79, 293 (1935) [C. A., 31, 4644 (1937)]. ""Coffman, U. S. pat. 2,335,012 [C. A., 38, 2772 (1944)]. THE CURTIUS REACTION 343 formed from acrylyl chloride and sodium azide are polyvinyl isocyanate (30%) and only a little of the monomer.31 Hydrolysis of the vinyl iso- cyanates or the related urethans and ureas yields aldehydes or ketones RCH=CHCON3 -? RCH=CHNCO HOH RCH2CHO rather than amines. Epicamphor (IV) is obtained in 93% yield bornylenecarbonyl chloride through the azide III. from H2C CO The esters of acetylenic acids, with the exception of a,j3-unsaturated acids, can be converted to hydrazides. Ethyl stearolate 32 and ethyl undecynoate 83 readily give hydrazides, the latter in 80% yield. Esters of a,/3-acetylenic acids react with hydrazine to form pyrazolones; for example, ethyl tetrolate gives 3-methyl-5-pyrazolone.34 CH3 C || N CH2I CO N H In the single attempt to form an acetylenic azide, the sodium azide method failed with phenylpropiolyl chloride.36 Di- and Poly-carboxylic Acids. Preparation of Diamines. The pres- ence of more than one carboxyl group does not interfere with the con- version of the acids to the amines. Adipyl hydrazide is formed from the 31 Jones, Zomlefer, and Hawkins, J. Org. Chem., 9, 500 (1944). 82 Oskerko, J. Gen. Chem. U.S.S.R., 8, 334 (1938); Mem. Inst. Ukrain. Acad. Set., 4, 329 (1937) [C. A., 32, 5377 (1938)]. 33 Oskerko, J. Gen. Chem. U.S.S.B., 7, 595 (1937) [C. A., 31, 5761 (1937)]. 34 Oskerko, J. Gen. Chem. U.S.S.R., 8, 330 (1938); Mem. Inst. Ukrain. Acad. Set., 4, 195 (1937) [C. A., 32, 3334 (1938)]. 36 Forster and Stotter, J. Chem. Soc, 99, 1337 (1911). 344 ORGANIC REACTIONS ester in 94% yield SSp 37 and smoothly gives putrescine hydrochloride ' HNOs H2NNHOC(CH2)4CONHNH2 ^ > 05°Reflux 94% N8OC(CH2)4CON3 Reflux 80% 100% C1H8N(CH2)4NHSC1 in 72% yield.37 Hexahydroterephthalic acid can be degraded to 1,4- diaminocyclohexane in high yield;-11 phthalic acid can be converted to o-phenylenediamine; M and trimesic acid yields l,3,5-tris(carbethoxy- amino) benzene without difficulty.39 Succinyl azide is obtained readily from the acid chloride and sodium azide.40 The preparation of the hydrazide from the ester is complicated by the formation of small amounts of the cyclic secondary hydrazide (V); this side reaction can be avoided, however, by the choice of the proper reaction conditions. CO2C2H6 CONHNHj CO H2C NH,NH2 Ha9 , H29 1!fHI > I +11 H2C H2C H2C NH \ \ \ / CO2C2H5 CONHNH2 CO Ethylene diisocyanate, which is formed by rearrangement of succinyl diazide, can be hydrolyzed to ethylenediamine;41 with ethanol it gives an imidazolidone (VI) instead of a normal urethan, but the imidazoli- done can be hydrolyaed readily to ethylenediamine.9 NCO NCO2C2H6 H2C ~~ H2CI + C 2HBOH -> 1 coH 2C H2C \ NCO NH I vi * Curtius, Hallaway, and HeU, J. prakt. Chem., 89, 481 (1914).87 Unpublished observations of the author. "Lindemann and Schultheis, Ann., 464, 237 (1928). * Curtius, Bourcart, Heynemann, and Sohmitz, /. prakt. Chem., 91, 39 (1915). *°Schroeter and Seidler, /. prakt. Chem., 105, 165 (1923). "Curtius, J. prakt. Chen., S3, 210 (1895). THE CURTIUS REACTION 345 Phthalyl azide must be prepared from the acid chloride because the esters of phthalic acid on treatment with hydrazine form exclusively the secondary hydrazide.41" CO2R + NH2NH2 - CO2R Preparation of Aldehydes and Ketones. Monosubstituted malonyl azides can be synthesized readily from the dihydrazides. Urethans of grem-diamines result when the azides are rearranged in alcohol; these urethans are hydrolyzed rapidly by mineral acids to aldehydes. Di- ethyl benzylmalonate can be converted to phenylacetaldehyde in about 70% yield by this procedure.42 CO2C2H6 CONHNH2 C?HBCH2CH > C,H6CH2CH -> v 95% v CO2C2H6 C0NHNH2 CON3 NHCO2C2H6 CsHeCHjCH ¡ª> C6H6CH2CH ¡ª-> C6H6CH2CHO CON3 NHCO2C2H6 This attractive method for preparing aldehydes has seen almost no application to synthesis. The degradation of the azides of disubstituted malonic acids gives ketones, as illustrated by the conversion of butane-l,2,2-tricarbonyl hydrazide to'l-aminobutanone-2 in 70% yield.43 C0NHNH2 0 H2NNHC0¡ªCH2CCH2CH3 -* C1H3N¡ªCH2CCH2CHS C0NHNH2 The formation of hydrazides from the esters of disubstituted malonic esters becomes increasingly difficult with increase in the size of the sub- stituents. Diethyl benzylmethylmalonate with excess hydrazine in 410 Curtius and Davidis, /. prakt. Chem., 64, 66 (1896). 42 Curtius and Mott, /. prakt. Chem., 94, 323 (1916). "Curtius and Gund, J. prakt. Chem., 107, 177 (1924). 346 ORGANIC REACTIONS boiling butanol yields 75% of the dihydrazide; diethyl dibenzylmalo- nate gives a poor yield, and diethyl bis(mesitylmethyl)malonate does not react with hydrazine.44 The formation of substituted azides from malonyl chlorides and sodium azide has not been reported. Stepwise Degradation to Amino Acids. There are several approaches to the transformation of a di- or poly-carboxylic acid to an amino acid. The most satisfactory procedure makes use of the ester acids and their salts. They react with hydrazine to form hydrazide acids, which may be degraded through the azide acids to amino acids. From substituted malonic esters a-amino acids are obtained. (For the preparation of a-amino acids from substituted cyanoacetic esters, see p. 359.) Thus, the potassium salt of the monoethyl ester of methylmalonic acid, which is prepared by half hydrolysis of the diethyl ester, gives alanine ethyl ester hydrochloride in 67% yield.46 Many other amino acids have CO2K CO2K CH3CH > CH3CH -* \ 98% CO2C2H6 CONHNH2 CO2H CO CO2C2H6 CH3CH -? CHsCH | > CH3CH \ \ /CO 67% CONs NH NH3C1 been prepared in this way; among them are /3-phenylalanine (44% yield),46 a-amino-n-butyric acid (41% yield),46 a-amino-n-valeric acid (43% yield),47 and 6-nitroanthranilic acid.48 2-Carboxy-3-nitrobenza- zide when heated in ethanol is esterified (through intermediate forma- tion of o-nitrophthalic anhydride), but when heated in dry chloroform rearranges to the isatoic anhydride.48 H [ NCO CO2H NO2 44 P. A. S. Smith and L. E. Miller, unpublished results. ? Curtius and Sieber, Ber., 54, 1430 (1921). * Curtius and Sieber, Ber., 55, 1543 (1922). 47 Curtius, Hoohsohwender, Meier, Lehmann, Benckiser, Schenck, Wirbatz, Gaier, and Muhlhausser, J. prakt. Chem., 135, 2U (1930). 48 Curtius and Semper, Ber., 46, 1162 (1913). THE CURTTUS REACTION 347 The ester acids may also be converted to ester acid chlorides and then by reaction with sodium azide to ester azides. By these steps 3,4-dichloro-5-carbethoxypyrrole-2-carbonyl chloride49 and sebacic ethyl ester chloride 60 have been converted to the corresponding ester azides, which were then rearranged; l-carbethoxyheneicosane-21-car- bonyl chloride has been converted to w-aminobehenic acid in 66% yield." Cyclic anhydrides of certain dibasic acids can be converted directly to hydrazide acids for degradation to amino acids. Diphenic anhy- dride 62 and its 4-nitro derivative 63 react with hydrazine to form the corresponding hydrazide acids. Phthalic anhydride, on the other hand, gives only the secondary hydrazide.64' w Succinic anhydride has not been tried, but succinimide gives succinamyl hydrazide.56 Succinhydra- zidic acid can be formed from succinic anhydride indirectly through ethyl hydrogen succinate or succinamic acid.66 Succinimide-N-acetic ester and hydrazine give succinamyl hydrazide-N-acethydrazide (VII), which by reaction with nitrous acid followed by rearrangement and hydrolysis of the product yields #-alanine.67 CH2¡ªCOV CH2CONHCH2CONHNH2 CH2COO- f >NCH2CO2C2H6 ->? | -> | CH2¡ªCCK CH2CONHNH2 CH2NH3+ VII The esters of di- or poly-basic acids in which the groups are not struc- turally equivalent can usually be converted directly into ester hydra- zides by reaction with hydrazine. Since the ester of an aromatic acid is much less reactive than the usual aliphatic ester, it is often possible to form the hydrazide from an aliphatic ester without affecting the aromatic ester group, when both types are present. This is illustrated by the conversion of o-carbethoxyphenoxyacetic ester with cold hydra- zine to o-carbethoxyphenoxyacethydrazide; by refluxing with excess hydrazine the dihydrazide is formed in 95% yield.68 N-(o-Carbometh- oxyphenyl)-glycine ester behaves similarly, and many examples in the 49 Fischer and Elhardt, Z. physiol. Chem., 257, 61 (1939). 60 Flaschentrager and Halle, Z. physiol. Chem., 192, 253 (1930). 61 Flaschentrager, Blechman, and Halle, Z. physiol. Chem., 192, 257 (1930). 52 Labriola, Anales asoc. qtilm. argentina. 25, 121 (1937) [C. A., 32, 4970 (1938)]. 63 Labriola and Felitte, J. Org. Chem., 8, 536 (1943). 54 Curtius and Davidis, /. prakt. Chem., 64, 66 (1896). "Gheorghiu, Bull. soc. chim., [4] 47, 630 (1930); Gheorghiu, ibid., [4] 53, 151 (1933); Diels, Alder, Friedrichsen, Klare, Winkler, and Schrum, Ann., 505, 103 (1933). 66 Curtius, J. prakt. Chem., 92, 74 (1915). "Curtius and Hechtenberg, J. prakt. Chem., 105, 289 (1923). "Curtius, Moll, and Fingado, J. prakt. Chem., 125, 106 (1930). 348 ORGANIC REACTIONS pyrrole series have been described.69' M> 61> 62 The conversion of diesters of symmetrical dibasic acids to ester hydrazides has been successful only with certain compounds, such as the esters of terephthalic acid,64 bisdiazoacetic acid,63 and oxalic acid.64 Esters of certain polybasic acids upon treatment with a limited amount of hydrazine yield mixed primary-secondary hydrazides, often called hydrazi hydrazides, and thus some of the carboxyl groups are protected against degradation. Hemimellitic esterforms ahydrazihydrazide(VIII), and a hydrazi azide, which on rearrangement and hydrolysis yields o-aminophthalhydrazide (IX).39 l-Phenylpropane-2,2,3-tricarboxylic ester has also been partially degraded through its hydrazi azide (X).65 CONHNH2O NNH NH ?CO¡ªNH C6XI5CH.2 Q\ I * I XCO¡ªNH CON8x Attempts have been made to obtain hydrazide azides by causing di- hydrazides to react with one molecule of nitrous acid. The resulting compounds are unstable, however, and generally undergo intramolecu- lar acylation with elimination of hydrazoic acid and formation of cyclic or polymeric secondary hydrazides. Diphenic dihydrazide is an excep- CON8/ R \ CONHNH, CO/ NNH -> R | \ /NH CO tion, for the hydrazide azide (XI) can be isolated and by heating in ethanol is converted to phenanthridone (XII).66 The formation of a C=N H2NNH XI HO XII "Fischer and Heidelmann, Ann., 527, 115 (1937). ? Fischer, Sus, and Weilguny, Ann., 481, 159 (1930).61 Fischer and Thurnher, Z. phyaiol. Chem., 204, 68 (1932).82 Fischer and Waibel, Ann., 512, 195 (1934).68 Curtius and Rimele, Ber., 41, 3108 (1908).M Curtius and Hochschwender, J. prakt. Chem., 91, 415 (1915).65 Curtius and Sandhaas, J. prakt. Chem., 125, 90 (1930). ? Labriola, J. Org. Chem., 5, 329 (1940). THE CURTIUS REACTION 349 small amount of 7-amino-j3-phenylbutyric acid from j8-phenylglutaryl .dihydrazide 67 and nitrous acid suggests that here, too, the hydrazide azide might be isolated. Some diazides and presumably some polyazides can be caused to rearrange stepwise. Phthalyl diazide yield's o-isocyanatobenzazide when heated in benzene* and N-carbomethoxyanthranilic azide w when heated in methanol; the second azide group also rearranges on longer beating. Spontaneous half-rearrangement is exhibited by 1-p-xylyl- CON \ CON NCO CONs HCO2CH3 NH2 CO2H CON3 NH2 NH2 l,2,3-triazole-4,5-dicarbonyl diazide; when the dihydrazide (XIII) is treated with aqueous nitrous acid, the isocyanate azide (XIV) is formed CH N N \ C¡ªCONHNH2 Z¡ªCONHNH2 XIII -CONs XIV in situ in 92% yield.68 Pyridine-2,5-dicarbonyl diazide also under- goes stepwise rearrangement.69 Partial solvolysis of polyazides has received virtually no attention in spite of its attractive possibilities. Salicylyl azide-O-acetazide when treated with aniline at 0° yields salicylyl azide-O-acetanilide; the re- maining azide group can be rearranged by heating in ethanol to give the urethan in 90% yield.70 Succinazidylglycyl azide shows a similar behavior.67 Hydroxy Acids. Hydroxyl groups in an acid often complicate the conversion to an amino alcohol either by preventing the formation of 67 Jackson and Kenner, J. Chem. Soc, 1928, 165. " ?? Bertho and Holder, J. prakt. Chem., 119, 189 (1928). "? Meyer and Staffen, Mmatsh., 34, 517 (1913). 70 Curtius, Moll, and Fingado, J. prakt. Chem., 125, 106 (1930). 350 ORGANIC REACTIONS the azide or by causing the azide or the isocyanate to behave abnor- mally. Acylation or alkylation of the hydroxyl groups usually over- comes these difficulties. Azides containing hydroxyl groups have been prepared by both the hydrazide and the sodium azide methods. The hydrazides of acids con- taining hydroxyl groups in the lactone-forming positions can usually be produced from the corresponding esters or the lactones, but on treat- ment with acid the hydrazides lose hydrazine and yield the lactones. This behavior has suggested that the compounds are not true hydra- zides (XV) but hydrazino lactones (XVI).71' n However, the successful R2C¡ª(CH2)BCO¡ªNHNH2 R2C¡ª(CH2)n OH 0¡ªC¡ªOH NHNHaxv xyi preparation of azides which rearrange normally from certain of the hydroxy hydrazides casts doubt on the cyclic formula.38'73 Lactones from acids containing secondary or tertiary hydroxyl groups show in- creased resistance to the action of hydrazine, and some such lactones cannot be made to react.74 Hydroxy isocyanates have never been isolated because of the inter- action of the hydroxyl and isocyanate groups with the formation of cyclic or polymeric urethans. The products are usually readily hydro- 0 / \HO-R-CONs -> (HO-R-NCO) -> (-0-R-NHC0-), or R CO \ / NH lyzed to amino alcohols. a-Hydroxy azides exhibit a unique behavior; the intermediate isocyanates lose cyanic acid, and aldehydes or ke- tones are formed.76'76 When the rearrangement is carried out in water, OH OH / / R2C -> R2C -? R2C0 + HNCO \ CON3 NCO 71 Blaise and Kohler, Bull. soc. chim., [4] 7, 410 (1910). 72 Blane, Bull. soc. chim., [4] 3, 295 (1908); [3] 33, 890, 903 (1905). 73 Curtius and Sauerberg, J. prakt- Chem., 125, 139 (1930). "Teppeoia, Rec. trav. chim., 42, 30 (1923). 75 Curtius, J. prakt. Chem., 94, 273 (1916). "Schroeter, Chem.-Ztg., 32, 933 (1908). THE CURTIUS REACTION 351 the cyanic acid can be detected by reaction with semicarbazide to form insoluble hydrazodicarboxamide, H2NCONHNHCONH2.77 This reac- tion can be used as a test for an a-hydroxy acid.76'78 Diphenylglycolyl azide yields benzophenone and phenylurea when it is heated in ani- line.79 The rearrangement of hydroxy azides in which the hydroxyl Q group is in a lactone-forming position succeeds only in certain instances, as in the conversion of o-hydroxymethylbenzazide to o-aminobenzyl alcohol or of the lactone of o-hydroxyphenylacetic acid to a derivative of o-hydroxybenzylamine.38 Frequently the y- and 5-hydroxy azides revert to the lactone through loss of hydrazoic acid; this reaction occurs less readily when a non-polar solvent is used in the rearrangement. (Cf. behavior of 2-carboxy-3-nitrobenzazide, p. 346.) Non-acylated RCH¡ªCH2 RCHCH2CH2CON3 -> | | + HN3 I O CH2 OH \ / CO sugar acid azides always lose hydrazoic acid so readily that they cannot be isolated or degraded.78 The effect of alkylation or acylation of hydroxyl groups on the degra- dation of certain azides is illustrated in the following examples. The diazide of mucic acid,79 prepared from the hydrazide, behaves likfe the azide of a typical a-hydroxy acid; m it loses cyanic acid after rearrange- ment and yields a mixture of tartaric dialdehyde and a double internal urethan. Tetraacetylmucyl diazide, however, when heated in an inert solvent forms the corresponding isocyanate (or a polymer thereof).81 Acetone-quinide through its hydrazide and azide (XVII) yields 78% of 4,5-isopropylidenedioxy-3-hydroxycyclohexanone (XVIII), but its di- methyl ether forms the internal urethan (XIX) in 57% yield.82 Tetra- 77 Lebouoq, /. pharm. chim., 5, S61 (1927). 78 Weerman, Rec. trav. chim., 37, 52 (1917). 79 Curtius, van der Laan, Aufhauser, Goldberg, von Hofe, Ohlgart, Darapsky, and Sau- vin; J. prakt. Chem., 95, 168 (1917). 80 Jones and Powers, J. Am. Chem. Soc., 46, 2518 (1924). 81 Diels and Loflund, der., 47, 2351 (1914). 82 Fiaoher and Dangschat, Ber., 65, 1009 (1932). 352 ORGANIC REACTIONS ? CON, >. XIX acetylquinyl azide (XX), prepared from the acid chloride and sodium azide, when heated in toluene gives 0,N-diacetyl-p-aminophenol (XXI) in 98% yield.88 CHsCOO \ OCOCH3 ^=,^ CHsCOO-/ \f -> CH3C00/ \NHCOCH3 / ' CONS ^¡ª' CH3C00 XX XXI Keto Acids. Keto acids have received little attention from the stand- point of the Curtius degradation. Some keto acids have been converted to amino ketones by the use of hydrazone hydrazides or oxime hydra- zides as intermediates. These are treated with nitrous acid to give the keto azides or oxime azides, which rearrange normally in good yields.62 Removal of the hydrazone group takes place simultaneously with the formation of the azide. (Even stable hydrazones can be cleaved by this means; thus the hydrazone and corresponding diphenylhydrazone of a ketone obtained from the degradation of vomicine react with nitrous acid with formation of the original ketone, nitrous oxide, and ammonia or diphenylamine.84) 2,4-Dimethyl-3-acetylpyrrole-5-carboxylic ester has thus been degraded to a derivative of the corresponding amine 62 in good yield. Methyl brucinonate has been converted through its oxime to a hydrazide and an azide, which has been rearranged.86 /9-Keto esters react with hydrazine to form pyrazolones M'87 and con- sequently are not susceptible of Curtius degradation through the hydra- 88 Fischer, Ber., 64, 775 (1921). 84 Wieland and Homer, Ann., 528, 95 (1937). "Leuchs and Gladkorn, Ber., 56, 1780 (1923). ? Curtius, J. prakt. Chem., 50, 508 (1894). a von Rothenburg, /. prakt. Chem., 51, 43 (1895). THE CURTIUS REACTION 353 zides. The difficulty of obtaining /3-keto acid chlorides has precluded the use of the sodium azide method. Blocking the /3-keto group by oxime formation does not succeed since hydroxylamine is eliminated when such compounds are treated with hydrazine. Amino Acids. Aliphatic primary amino acid azides have not been isolated, and in only a few instances have attempts been made to pre- pare them from the corresponding hydrazides. Nitrous acid attacks both the hydrazide and the primary amino group to yield mixtures of unidentified products.88 When both the amino group and the carboxyl group are attached to an aromatic nucleus, the amino azide can be formed by the use of diazonium salts (p. 372). Diazonium salts react with p-aminobenzhydrazide to form p-aminobenzazide without affect- ing the amino group; the resulting aaide can be rearranged and the product hydrolyzed to p-phenylenediamine.88 Nitrous acid causes the ArCONHNHa + Ar'N2Cl -> ArCON3 + Ar'NH3Cl replacement of the aromatic amino group by hydroxyl, yielding a hy- droxy azide, from which an aminophenol is eventually obtained. By this means 3-nitro-5-aminophenol has been prepared from 3-nitro-5- aminobenzhydrazide.89 If the amino group is ortho to a carboxyl group, cyclization to a triazine takes place when the hydrazide is treated with nitrous acid. Anthranilyl hydrazide (XXII) yields hydroxybenztria- zine (XXIII),90 and 2-amino-3-naphthoyl hydrazide yields a naphtho- triazine.90 2,6-Diaminoisonicotinyl hydrazide is attacked first at the NH2 T!ONHNH2 XXII amino groups by nitrous acid and cannot be degraded to the triamine.91" The preparation of secondary amino acyl azides has been very re- stricted in the aliphatic and benzene series. N-Phenylglycyl hydra- 88 Curtius, Jansen, Colosser, Donselt, and Kyriacou, J. prakt. Chem., 95, 327 (1918). 89 Curtius and Riedel, J. prakt. Chem., 76, 238 (1907). 90 Fries, Walter, and Schilling, Ann., 516, 248 (1935). ?i? Meyer and von Beck, Mmiatsh., 36, 731 (1915). 354 ORGANIC REACTIONS zide is converted by nitrous acid to N-phenyl-N-nitrosoglycyl azide.2t Indefinite products are obtained from iminodiacethydrazide.916 In CH2CON3 C6H5NHCH2CONHNH2 + HNO2 -> C6H6¡ªN ? NO the pyrrole series, normal degradation is entirely successful; the pyrrole nitrogen does not become nitrosated.69'60'92'93'94'96 Although tertiary amino groups are also unaffected by nitrous acid, the usual procedure for isolating azides must be modified on account of the basicity of the molecule. In the aliphatic and benzene series no conclusive results have been reported,88 but in heterocyclic compounds, where the tertiary amino group is a component of the nucleus, many successful degrada- tions have been accomplished. 6-Methylnicotinic ester, for example, yields 63% of 2-methyl-5-aminopyridine.96 Acylated Amino Acids. The complications arising in the Curtius degradation of amino acids are eliminated to a large extent when the amino group is acylated. Many azides of acylated aliphatic a-amino acids have been synthesized, not for the purpose of rearranging them to diamines which can be hydrolyzed to aldehydes, but for use as acylating agents in place of the less tractable acid chlorides. Curtius and his students have explored this field extensively.97"104 Bergmann has employed the azides of acylated amino acids for the stepwise degradation of peptides, as illustrated by the conversion of hippurylalanine to hippuramide and acetaldehyde. Hippurylalanine is converted through its ester and hydrazide to its azide, which is heated with benzyl alcohol to give 1-hippuramido-l-carbobenzoxyaminoethane. This upon hydrogenation is cleaved to hippuramide and acetaldehyde.105 915 Curtius and Hofmann, J. prakt. Chem., 96, 202 (1918). ' 82 Fischer and Endermann, Ann., 531, 245 (1937). 93 Fisoher, Guggemos, and Sohafer, Ann., 540, 30 (1939). 91 Fischer and Miiller, Z. physiol. Chem., 132, 72 (1924). 96 Piccinini and Salmoni, Gazz. chim. ital., 32,1, 246 (1902); Atti accad. Lincei, [5] 9,1, 859 96 Graf, J. prakt. Chem., 133, 19 (1932). 97 Curtius and Curtius, J. prakt. Chem., 70, 158 (1904). 98 Curtius and Gumlich, J. prakt. Chem., 70, 195 (1904). 99 Curtius and Lambotte, J. prakt. Chem., 70, 109 (1904). 100 Curtius, Laurent, Petridis, and Zimmerli, /. prakt. Chem., 94, 93 (1916). 101 Curtius and Lenhard.J. prakt. Chem., 70, 230 (1904). 102 Curtius and van der Linden, J. prakt. Chem., 70, 137 (1904). 103 Curtius and Miiller, J. prakt. Chem., 70, 223, (1904). 104 Curtius and Wlistenfeld, J. prakt. Chem., 70, 73 (1904). m Bergmann and Zervas, J. Biol. Chem., 113, 341 (1936); Science, 79, 439 (1934). THE CURTIUS REACTION ? 355 C6H6CONHCH2CONH¡ªCHCH3 CON3 C6H6CONHCH2CONH¡ªCHCH3 H2/Pd> v HjO NHCO2CH2C6H5 C6H6CONHCH2CONH2 + CH3CHO + NH3 + CO2 + C6H6CH3 Acylated aromatic amino acids can often be degraded successfully. 2-Acetamido-3-naphthoyl hydrazide gives the azide, which rearranges to N-acetylnaphthimidazolone.91 COCH3 ,NHCOCH3 CON3 Protection of amino groups from nitrous acid by acylation is not always successful, for deacylation may occur during treatment of the esters with hydrazine. Ethyl 2,6-dibenzamidoisonicotinate when treated with hydrazine gives 2,6-diaminoisonicotinyl hydrazide;106 the ethyl ester of phthalylglycine is similarly cleaved to glycyl hydra- zide and phthalhydrazide, a general reaction for phthalimides m (see p. 381). Carbamic Adds. The esters of carbamic acid or substituted carbamic acids (urethans) do not react readily with hydrazine, but the correspond- ing carbamyl chlorides do. The semicarbazide or substituted semi- carbazides that result yield carbamyl azides 108 with nitrous acid. Most carbamyl azides are prepared more conveniently from the carbamyl chlorides and sodium azide. Monosubstituted carbamyl azides can also be synthesized from isocyanates and hydrazoic acid.109' ll0> 1U RNCO + HN3 -* RNHCON3 The azide of carbamic acid, NH2CON3, rearranges only with diffi- culty; among the products only a trace of a hydrazine compound was 1011 Meyer and von Beck, Monatsh., 36, 731 (1915). 107 Ing and Manske, J- Chem. Soc., 1926, 2348. W Thiele, Ann., 283, 37 (1894). "? Hantzsoh and Vagt, Ann., 314, 339 (1901). 110 Oliveri-Mandald and Calderaro, Gazz. chim. ital, 43, I, 538 (1913). 111 Oliveri-Mandala and Noto, Gazz. chim. ital., 43, I, 514 (1913). 356 ORGANIC REACTIONS found.112 The failure of monosubstituted carbamyl azides, RNHCON3, to rearrange has been explained on the basis of an isourea structure, RN=C(OH)N3)m° for the azide. Disubstituted carbamyl azides rearrange. The rearrangement is facilitated when one of the substitu- ents is an aromatic group; usually cyclization to the aromatic ring fol- lows the rearrangement. N-Ethyl-N-phenylcarbamyl azide when heated in boiling xylene gives 1-ethylindazolone (XXIV) in 68% yield.113 CON3 C2H6 Halogenated Acids. Halogenated azides undergo rearrangement in the usual manner to isocyanates, from which halo amines are obtained by hydrolysis. If the halogen is in the a-position, the resulting halo- genated isocyanate is hydrolyzed to an aldehyde or ketone. This reac- Br Br R2CO + HBr + HNCOR2C -> CON3 R2C \ NCO tion was adapted by von Braun to the structure proof of naphthenic acids.23 Thus, dicyclopentylacetic acid is converted through the bromo acid chloride (XXV) to dicyclopentyl ketone in 60% yield.23 Halo- C6H9 C5H9¡ªC¡ªCON3 - AT C6H9 -> C5H9¡ªC¡ªNCOA,V- c¡ªcoci Br XXV XXVI genated aromatic acid azides can be degraded without complication to the halogenated aromatic amines. The preparation of aliphatic halogenated acid azides is accomplished most advantageously from the acid chlorides and sodium azide. The course from the ester through the hydrazide is not applicable ordinarily 112 Curtius and Schmidt, J. pmkt. Chem., 105, 177 (1914). 1120 Hurd and Spence, J. Am. Chem. Soc, 49, 266 (1927). 113 Stolid, Nieland, and Merkle, J. prakt. Chem., 116, 192 (1927). THE CURTIUS REACTION 357 since the halogen atom is replaced by the hydrazino group. Special methods for synthesizing certain halogenated hydrazides are available. Halogens may be added to an olefinic hydrazide; 5-phenyl-a,/3,7,5-tetra- bromovaleryl hydrazide is prepared by addition of bromine to /3-styryl- acrylyl hydrazide.114 Diazo hydrazides have been used with success for the preparation of several halogenated hydrazides; for example, diazoaceturic ester reacts with hydrazine to yield the hydrazide (XXVII, 82% yield), which reacts with dry hydrogen chloride to give chloro- aceturyl hydrazide (XXVIII).116 Iodoaceturyl and bromoaceturyl N2CHCONHCH2CONHNH2 -> C1CH2CONHCH2CONHNH3C1 + N2 XXVII XXVIII hydrazides have been prepared similarly.116 Direct bromination con- verts 2,4-dimethylpyrrole-5-carbonyl hydrazide to 2,4-dimethyl-3- bromopyrrole-5-carbonyl hydrazide.60 In the pyrrole series halogenated azides can be prepared by direct halogenation. 2,4-Dimethyl-3-ethylpyrrole-5-carbonyl azide has been brominated to 2-bromomethyl-3-ethyl-4-methylpyrrole-5-car- bonyl azide;60 and 2-methyl-3,4-diethylpyrrole-5-carbonyl azide (XXIX) has been chlorinated with sulfuryl chloride to 2-trichloro- methyl-3,4-diethylpyrrole-5-carbonyl azide, which on treatment with methanol yields 3,4-diethyl-2-carbomethoxy-5-carbomethoxyaminopyr- role (XXX).93 Dichlorination is also successful; 2,4-dimethyl-3-bromo- C2H6 .^ C2H6 CHj-1L >-CON3 ClsC-lL JL-CONg CH300C-4^ ^^-NHCO^HaN N H HXXIX pyrrole-5-carbonyl azide yields 2-(dichloromethyl)-3-bromo-4-methyl pyrrole-5-carbonyl azide (XXXI), which on mild alcohorysis gives 2-formyl-3-bromo-4-methylpyrrole-5-carbonyl azide (XXXII).62 Br¡ªij a¡ªCH3 C2H5OH Br¡ªn- n¡ªCH3 C12CH¡ªl^ JI¡ªCON3 * OCH¡ª^ J¡ªCON3 N N H H XXXI XXXII Aromatic fluorine, chlorine, and bromine compounds are ordinarily unaffected by hydrazine, and many fluoro, chloro, and bromo benz- hydrazides have been made by the hydrazide as well AS by the sodium 114 Riedel and Schulz, Ann., 367, 14 (1909). 116 Curtius and Welde, Ber., 43, 862 (1910). lieCurtius and Callan, Ber., 43, 2457 (1910). 358 ORGANIC REACTIONS azide method. If the halogen is activated by ortho or para nitro groups, as in 3,5-dinitro-4-chlorobenzoic ester, treatment with hydrazine may cause its replacement.117 Halogens in the a- and 7-positions of pyridine are reactive; ethyl 4,5-dichloronicotinate is converted by hydrazine to 4-hydrazino-5-chloronicotinyl hydrazide,118 and 2,4-dihydroxy-6-chloro- nicotinamide to 2,4-dihydroxy-6-hydrazinonicotinyl hydrazide.119 The halogens (even iodine) in the /3-position of the pyridine ring are unaf- fected 120 by hydrazine. Iodine in the benzene nucleus is sometimes removed by hydrazine through replacement or reduction; from ethyl 3-iodo-2-naphthoate and hydrazine, /3-naphthoyl hydrazide is obtained.121 Ethyl p-iodobenzoate yields p-iodobenzhydrazide,122 but ethyl o-iodobenzoate yields the internal hydrazide of o-hydrazinobenzoic acid.123 CO2C2H5 Nitro Groups. The Curtius degradation has been applied to only one nitro aliphatic azide; ethyl nitrocyanoacetate is converted through its hydrazide and azide to a urethan.124 In the aromatic series, nitro- NCCHCON3 -? NCCHNHCO2C2H6 NO2 NO2 substituted benzazides can be degraded readily to nitroarylamines.126 Many of the intermediate isocyanates have been isolated 126> 127> 128 and have proved to be useful reagents for characterizing amines and alcohols.129' 13Cl 131 117 Milller, Zimmermann, Hoffmann, and Weisbrod, J. prakt. Chem., Ill, 273 (1925). 118 Graf, Lederer-Ponzer, Kopetz, Purkert, and Laszlo, /. prakt. Chem., 138, 244 (1933) 119 Schroeter and Finck, Ber., 71, 680 (1938). 120 Graf, Lederer-Ponzer, and Freiberg, Ber., 64, 21 (1931). mGodstein and Cornamusaz, Helv. Chim. Ada, 15, 935 (1932). 122 Sah and Hsu, Rec. trav. chim., 59, 349 (1940) [C. A., 35, 4362 (1941)]. 123 Kahl, Chem. Zentr., 1904 II, 1493. 124 Darapaky and Hillers, J. prakt. Chem., 92, 297 (1925). 126 Curtius, Struve, and Radenhausen, J. prakt. Chem., 52, 227 (1895). 126 Naegeli and Tyabji, Helv. Chim. Ada, 16, 349 (1933). 127 Naegeli and Tyabji, Helv. Chim. Ada, 17, 931 (1934). 128 Schroeter, Ber., 42, 2336 (1909). 129 Blanksma and Verberg, Rec. trav. chim., 53, 988 (1934). 130 Meng and Sah, J. Chinese Chem. Soc., 4, 75 (1936). 151 Sah and Ma, J. Chinese Chem. Soc., 2, 159 (1934). THE CURTIUS REACTION 359 The conversion of nitro aromatic acid chlorides to the azides with sodium azide is very generally applicable.126-127- 132' 133- 1M The adap- tation of the hydrazide method sometimes involves complications due to the reducing action of hydrazine. o-, m-, and p-Nitrobenzhydrazide can be prepared from the esters in almost quantitative yields.136- 136 3,5-Dinitrobenzhydrazide is formed in satisfactory yield from the corre- sponding ester, but, if a large excess of hydrazine is employed and the reaction mixture is refluxed for twenty-four hours, 3-nitro-5-aminp- benzhydrazide89 results in 60% yield. Ethyl 2,4-dinitrobenzoate, on the other hand, yields only ethyl 2-nitro-4-aminobenzoate or ethyl 2- nitro-4-aminobenzhydrazide.137 The half ester of p-nitrobenzylmalonic acid through its hydrazide yields p-nitrophenylalanine in normal fash- ion, but the diethyl ester of bis(p-nitrobenzyl)malonic acid gives only the cyclic secondary hydrazide of bis(p-aminobenzyl)malonic acid.47 Cyano Acids. Cyano azides rearrange to cyano isocyanates, which can be hydrolyzed to amino acids. Only a-cyano acids have been studied. NCCHCON3 -? NCCHNCO -> -00CCHNH3+ xv x\. it The availability of substituted cyanoacetic esters and the ease of conversion to cyanoacethydrazides and azides have made this method of preparing a-amino acids an attractive one. Leucine, a-amino-n- valeric acid, a-amino-7,<5-dimethylvaleric acid,138 valine, phenylalanine, tyrosine, and a-amino-5-phenoxyvaleric acid 139 have been prepared by this general procedure though in yields not always high. (For the preparation of a-amino acids from substituted malonic esters, see p. 346.) In isolated instances hydrazine reacts with the cyano group- ing to give resinous products,139 amidrazones [RC(NH2)=NNH2], or pyrazoles.140 Cyanoacetyl chloride polymerizes readily 40 so that the reaction with sodium azide to1 form cyanoacetazide has not been applied. Sulfonamide, Sulfide, and Other Sulfur-Containing Groups. The presence of sulfonamide and sulfide groups in an acid does not interfere with the conversion of the carboxyl' group through the azide to an l32Naegeli, Tyabji, and Conrad, Helv. Chim. Ada, 21, 1127 (1938). 133 Lindemann and Pabst, Ann., 462, 29, 41 (1928). 134 Lindemann and Wessel, Ber., 58, 1221 (1925). 1 136 Curtius and Melsbach, J. prakt. Chem., 81, 523 (1910). 136 Curtius and Trachmann, J. prakt. Chem., 51, 165 (1895). 137 Curtius and Bollenbeok, J. prakt. Chem., 76, 281 (1907). ? m Darapsky, Decker, Steuernagel, and Schiedrum, J. prakt. Chem., 146, 250 (1936). 139 Gagnon, Gaudry, and King, J. Chem. Soc, 1944, 13, 140 von Rotbenburg, Ber., 27, 685 (1894). 360 ORGANIC REACTIONS amjno group. Mercapto acids have not been studied. o-Sulfonamido- benzhydrazide, from saccharin and hydrazine,141 is converted quantita- tively into the azide, which yields o-aminobenzenesulfonamide or its derivatives.142 Similarly, the following have been degraded: 2-ethyl- mercapto-6-hydroxypyrimidine-5-acetic acid,143 o-(a-thienylthio)benzoic acid,144 several tetrahydrothiophenecarboxylic acids,146' 146> 147 thio- phenecarboxylic acids,148- 149> 160 and thiazolecarboxylic acids.181' 162' 153 Azo, Diazo, and Azido Groups. Aliphatic diazo azides have never been synthesized. Diazo hydrazides, however, are quite readily pre- pared since hydrazine under mild conditions does not affect the diazo group in a diazo ester. Prolonged treatment with hydrazine may lead to a triazole or cause hydrolysis of the diazo group. Diazoacetylglycyl- glycine ester gives a hydrazide in 72% yield by gentle warming with hydrazine; by long heating with hydrazine in the presence of water, hydroxyaceturylglycyl hydrazide is formed, and by extensive heating with excess hydrazine the hydrazine salt of 5-hydroxytriazole-l-acetyl- glycyl hydrazide (XXXIII) is produced.164 The diazo group in diazo N2CHCONHCH2CONHCH2CO2R HOCH2CONHCH2CONHCH2CONHNH2 N2CHCONHCH2CONHCH2CONHNH2; N N¡ªCH2COCH2CONHNH2V XXXIII hydrazides has always been replaced by some other group such as halo- gen 116> 116 or acetoxy 164 before the degradation to azides and amines is continued. Diazoacetamide gives azidoacethydrazide on treatment with hydrazine.165 The presence of an aromatic azo group does not interfere with the 141 Schrader, J. prakt. Chem.', 95, 312 (1917). 142Schrader, J. prakt. Chem., 95, 392 (1917). 143 Litzinger and Johnson, J. Am. Chem. Soc., 58, 1936 (1936). 144 Steinkopf, Schmitt, and Fiedler, Ann., 527, 237 (1937). 146 Brown and Kilmer, J. Am. Chem. Soc, 65, 1674 (1943). 148 DuVigneaud, Hofmann, and Melville, /. Am. Chem. Soc, 64, 188 (1942). 147 Kilmer, Armstrong, Brown, and DuVigneaud, J.'Biol. Chem., 145, 495 (1942). 148 Cheney and Piening, J. Am. Chem. Soc, 66, 1040 (1944). 148 Curtius and Thyssen, /. prakt. Chem., 65, 1 (1902). 160 Robinson and Todd, J. Chem. Soc, 1939, 1743. 151 Cerecedo and Tolpin, J. Am. Chem. Soc, 59, 1660 (1937). 162 Hinegardner and Johnson, J. Am. Chem. Soc, 52, 3724 (1930). 163 Hinegardner and Johnson, J. Am. Chem. Soc, 52, 4139, 4141 (1930). 164 Curtius and Callan, Ber., 43, 2447 (1910). 166 Curtius, Darapsky, and Bookmiihl. Ber., 41, 344 (1908). THE CURTIUS REACTION 361 degradation of the azide to an amine. m- 126 and p- 37 Phenylazobenza- zide can be degraded to the corresponding isocyanates and amines in C6H6N=N¡ªi /)¡ªCON3 -> C6H6N=N¡ª{ )>¡ªNCO excellent yields. 7-Phenylazodipicolinazide gives a phenylazo dia- mine.166 The preparation of azo azides is accomplished preferably N=NC6H5 N=NC6H6 N3OC CON3 H2N NH2 through the azo acid chloride and sodium azide. The hydrazide pro- cedure may sometimes involve extra steps owing to the reducing action of hydrazine on the azo group; the azo ester is converted to a hydrazo hydrazide which must be reoxidized to the azo hydrazide before the azo azide is made. ? The azido group is frequently unaffected during the conversion of the azide to an amine unless it is in the a-position. Ethyl /3-azidopropionate reacts with hydrazine to give /3-azid6propionhydrazide, which through the azide yields j3-azidoethylamine.167- 168 Ethyl y-azidobutyrate, on the other hand, gives a mixture of products in this series of reac- tions.167- 1M All the azido azides have characteristic explosive insta- bility; the reaction of sodium azide with azidoacetyl chloride led to "some very alarming explosions." 16° If the azido group is in the ex- position, it is lost in a manner similar to an a-halogen during hydrolysis of the isocyanate with formation of an aldehyde or ketone. R2C=O + HN3 + C02 Heterocyclic Systems. The degradation of acids of several hetero- cyclic compounds has been mentioned in previous sections. In general almost every kind of heterocyclic carboxylic acid has been degraded successfully by the Curtius procedure, at least as far as the isocyanate 168 Chichibabin and Ossetrowa, J. Am. Chem. Soc, 56, 1711 (1934). 167 Curtius, Ber., 45, 1057 (1912). 168 Curtius and Franzen, Ber., 45, 1037 (1912). 169 Curtius and Giulini, Ber., 45, 1045 (1912). 160 Forster and Miiller, /. Chem. Soc, 97, 1056 (1910). CON3 R2C Ns NCO / -? R2C N3 362 ORGANIC REACTIONS or urethan stage. The free amines in many instances are inherently unstable. Some molecules containing active methylene groups are nitrosated during the formation of the azide from the hydrazide. Pyra- zolone-3-acetazide (XXXIV) yields 4-isonitrosopyrazolone-3-acetazide (XXXV).161 C¡ªCH2CONHNH2 HON=C C¡ªCH2CON3 O=C N O=C N N " H H XXXIV XXXV Thiocarbamyl Azides, Imido Azides, and Hydroximido Azides. Thio- semicarbazides react with nitrous acid 162' and isothiocyanates react with hydrazoic acidm to yield azides of marked stability. For this RNHCSNHNH2 + HONO -? RNHCSN3 <- RNCS + HN3 reason they were postulated at first as thiatriazoles. The thiocarba- myl,164 methylthiocarbamyl,165 allylthiocarbamyl,166 and phenylthio- carbamyl 162> 163 azides have been investigated. The thiocarbamyl azides lose nitrogen when heated with concentrated hydrochloric acid with formation of the hydrochlorides of bases which are probably iso- thiocyanoamines, RNHNCS; thiocarbamyl azide gives a crystalline hydrochloride, N2H2CS ? HC1. By the action of nitrous acid on amidra- zones, high-melting, stable compounds are produced which appear to ^NH f ^NHl /yN¡ªNH f R¡ªCf " ?\N=N R¡ªC -? R¡ªCf XNHNH 2 I. XN 3 be tetrazoles.166 Similarly, hydrazide oximes give hydroxytetrazoles.166a p rv OH¡ª \ \ ,,? I \MTT\TTJ \HNO2NH^H2 X ^_N R¡ªC R¡ªC( -N M1 Curtius and Kufferath, J. prakt. Chem., 64, 334 (1901). 182 Freund and Hempel, Ber., 28, 74 (1895). 183 Oliveri-Mandala, Gazz. chim. Hal., 44, I, 670 (1914). 164 Freund and Schander, Ber., 29, 2500 (1896). "? Freund and Schwartz, Ber., 29, 2491 (1896). "? Pinner, Ber., 30, 1871 (1897). ?"? Wieland, Ber., 42, 4199 (1909), THE CURTIUS REACTION 363 The same substances are formed by the reaction of hydroxamyl chlorides with sodium azide.167 Comparison of the Curtius, Hofmann, and Schmidt Reactions The Curtius, Hofmann (see p. 267), and Schmidt (see p. 307) reac- tions are in that order decreasingly mild, decreasingly flexible, and in- creasingly expeditious. The last-named quality varies somewhat with the available starting material, whether the free acid or the ester. The Curtius reaction lends itself to the preparation of isocyanates, sym- and as-ureas, amides, urethans, and amines at will, and provides a wide choice of experimental conditions. For synthetic purposes the Hofmann reaction can be used only to prepare sym-ureas, urethans, and amines directly, and halting the reaction at a desired intermediate is often not possible. The variety of experimental conditions is narrower and more limited. The Schmidt reaction on carboxylic acids or derivatives has been applied as a preparative method only to the production of amines; although urethans and isocyanates have been prepared occasionally by this reaction, it can hardly be considered a preparative method for them. Amides can be prepared by the Schmidt reaction only from ke- tones. The choice of experimental conditions employable in the Schmidt reaction is narrow. The Curtius and Schmidt reactions can be run in completely anhy- droxylic environment, in the Schmidt reaction by use of such catalysts as stannic chloride instead of the customary sulfuric acid. All three reactions can be carried out under anhydrous conditions, but only in the Curtius and Hofmann reactions can an anhydrous alcohol be used as a solvent. Since the Curtius reaction is successful under conditions ranging from neutral to strongly acid, compounds may be degraded without exposure to strong acid or alkali. In the Hofmann reaction it is difficult to avoid a certain amount of exposure to strong alkali; in the Schmidt reaction all the required catalysts are strong acids in the Lewis sense and act as catalysts for a variety of other reactions. Compounds very sensitive to oxidation may be attacked by the nitrous acid used for converting a hydrazide to an azide, but the sodium azide method is non-oxidizing. Although it is possible to avoid exposure to free halogens in the Hofmann reaction by using a previously pre- pared hypohalite solution, such solutions are themselves powerful oxi- dizing agents. The conditions of the Schmidt reaction are essentially non-oxidizing as far as organic compounds are concerned. 167 Forster, /. Chem. Soc., 95, 433 (1909). 364 ORGANIC REACTIONS The classical Curtius degradation of the ester through the hydrazide, azide, and urethan to the amine is rather tedious when all the inter- mediates are isolated, and the yields are lowered by the concomitant mechanical losses. Even though in good practice these steps can be telescoped, the hydrazide modification of the Curtius reaction still is more laborious than the Hofmann and Schmidt reactions. The acid chloride-sodium azide method through the azide to the amine can be made as short as the Hofmann reaction, but it is still necessary to pre- pare the acid chloride, and the method cannot be condensed to the one step of the Schmidt reaction. The Hofmann reaction through the amide, N-haloamide, and urethan involves almost as many steps as the classical Curtius reaction, but these steps can nearly always be con- densed into one operation, as compared with two for the usual proce- dure from the hydrazide by the Curtius method. The conservation of time by the Schmidt reaction is due chiefly to the fact that the reaction can be run directly on the free acid. This advantage disappears to a large extent when the ester or amide is the available -starting material, for, although the Schmidt reaction can be run on these derivatives, it is not generally satisfactory, and the ester or amide must usually be hydrolyzed to the free acid before the Schmidt reaction can be success- fully applied. When esters of carboxylic acids are the compounds immediately at hand, the Curtius reaction is favored. Hydrazides can be made from esters more readily than can amides, and frequently more readily than the esters can be hydrolyzed. When amides are available, the Hof- mann reaction is naturally the most convenient, although amides can be converted to hydrazides without difficulty if for other reasons the Curtius reaction is more suitable. Syntheses in large quantities introduce two other factors. The cost- determining reagents, named in the order of decreasing cost, are hydra- zine, sodium azide, and chlorine; therefore, the Hofmann reaction utilizing chlorine is the cheapest procedure. Since hydrazoic acid and many azides are poisonous as well as treacherously and violently explo- sive, it is not prudent to handle large quantities of hydrazoic acid or to isolate large amounts of azides of unproved stability. The Schmidt reaction, however, has been run with as much as 6 moles of hydrazoic acid at one time, and the Curtius reaction with as much as kilogram quantities. The acid chloride-sodium azide method may not be well adapted to large-scale work because of the difficulty of control. The Hofmann reaction has been used successfully on an industrial scale, and there appears to be no limit to the size of run that can be made. The degradation of both carboxyl groups of malonic acids can be THE CURTIUS REACTION 365 accomplished only by the Curtius reaction; the Hofmann and Schmidt reactions bring about the degradation of only one of the carboxyl groups. Succinic acids also are best degraded by the Curtius reaction for the same reason, although some diamine can be obtained by the Schmidt reaction. Uns^turated acids are converted to amines most satisfactorily by the Curtius reaction (sodium azide method). The Hofmann reaction is applicable with certainty only to a,j3-olefinic acid amides, since the olefin group in another position is likely to be halogenated by the re- agent. The Schmidt reaction is applicable to all olefinic acids, although there is a possible danger of sulfonation at the site of unsaturation. Keto acids are degraded best by the Hofmann reaction. The applic- ability of the Curtius reaction to keto-acids is limited; the Schmidt reaction occurs preferentially on the keto group iather than on the carboxyl group. Acylated amino acids are degraded most satisfactorily by the Cur- tius method, but non-acylated amino acids must be degraded by the Hofmann method, which usually leaves the amino group unattacked. However, the Hofmann reaction is not suitable for degrading peptides because of the strongly hydrolytic conditions required, and the Curtius reaction is the preferred method. a-Amino acids are inert to the Schmidt reaction. Aromatic acids containing active halogen are degraded by the Cur- tius reaction (sodium azide method); the Hofmann reaction is not applicable, and the Schmidt reaction has not been attempted. Aro- matic acids with substituents like amino or methoxyl which cause the ring to be highly susceptible to halogenation or sulfonation must ordi- narily be degraded by the Curtius reaction, although the Schmidt reac- tion might also be successful. 2-Hydroxy-3-naphthoic acid undergoes bromination in the ring when subjected to the Hofmann reaction, but the Curtius reaction through the hydrazide gives a cyclic urethan in 63% yield.168 The Curtius and Schmidt reactions are inapplicable to sugar acids. The Hofmann degradation has been applied successfully in this field. The amides of carbamic acids (ureas) can be degraded to hydrazines by the Hofmann reaction; urea gives a good yield of hydrazine. The Curtius reaction succeeds only with disubstituted carbamic acids, and the Schmidt reaction has not been applied. There are remarkably few amines for which yields are reported by the Curtius, Hofmann, and Schmidt reactions, and no significant con- clusions can be drawn from the results that are available. 168 Fries and Hass, Ber., 58, 2845 (1925). 366 ORGANIC REACTIONS BELATED REACTIONS The Lossen Rearrangement. Alkali salts of hydroxamic acids and derivatives undergo rearrangement to isocyanates according to the fol- lowing equation: RCO¡ªNK¡ªOCOCH3 -> RN=C=O + CH3CO2K This reaction, known as the Lossen rearrangement, has seen but little synthetic application 27 ? 169 ? no and possesses no distinct advantages over the Curtius, Hofmann, and Schmidt reactions. It appears to be useful when hydroxamic acids result as primary products. The reaction has been reviewed recently.171 The Tiemann Reaction. Amidoximes undergo rearrangement to as-ureas when treated first with benzenesulfonyl chloride and then with water.172- 173 This is the Tiemann reaction, which has so far been pri- RCNH2 -> RNHCONH2 NOH marily of theoretical interest. It might have application where the acid to be degraded is available only in the form of its nitrile, since nitriles can be converted readily to amidoximes by hydroxylamine. Treatment of Silver Salts with Halogens. Silver salts of carboxylic acids lose carbon dioxide when treated with chlorine or bromine, and alkyl halides are produced in good yield.174' 176 Although this reaction is not related to the Curtius reaction, it can be used to convert an acid to an amine when coupled with one of the many methods for replacing a halogen atom by an amino group. SELECTION OF EXPERIMENTAL CONDITIONS Preparation of Hydrazides Hydrazides are prepared by much the same reactions as amides, with the significant difference that precautions must be taken to avoid the formation of secondary hydrazides, RCONHNHCOR, through acyla- tion of the primary hydrazides, RCONHNH2, initially formed. 169 Thiele and coworkers, Ann., 295, 136, 167 (1897); ibid., 309, 189 (1899). 170 Mohr, J. prakt. Chem., 71, 133 (1905); Bredt, Perkin, Hilbing, Lankshear, and Reg out, /. prakt. Chem., 89, 225 (1914). 171 Yale, Chem. Revs., 33, 209 (1943). 172 Tiemann, Ber., 24, 4162 (1891). 178Pinnow, Ber., 24, 4167 (1891); 26, 604 (1893). 174Prelog and Zelan, Helv. Chim. Ada, 27, 535 (1944). 176 Hunsdiecker and Hynssdiecker, Ber., 75, 291 (1942). THE CURTIUS REACTION 367 The usual procedure is to treat the methyl or ethyl ester of the acid with hydrazine. For most purposes the commercially available 85% aqueous hydrazine hydrate is preferable to anhydrous hydrazine and is generally employed. The formation of hydrazides from esters often proceeds spontaneously at room temperature with marked evolution of heat; if the reaction is not spontaneous, heating on a steam bath for periods varying from five minutes to several days commonly suffices to give excellent yields. Esters which react with great difficulty have been converted to hydrazides at elevated temperatures in a bomb,62- 176 but there is some danger of decarboxylation under these conditions;62 temperatures above 180° should be avoided. The hydrazides usually crystallize on cooling, and often during the heating, and frequently need only be collected and dried to be obtained analytically pure. Occa- sionally, small amounts of secondary hydrazide are formed. Since secondary hydrazides are insoluble in dilute acid, and much less soluble than the primary hydrazides in organic solvents, it fe usually not diffi- cult to remove them. The formation of secondary hydrazides can be kept to a minimum by dropping the ester into an excess of boiling hydra- zine hydrate at such a rate that a second liquid phase never accumu- lates.11- 177- m Hydrazides can also be purified by conversion to their crystalline isopropylidene derivatives by warming with acetone; the derivatives are then cleaved to the hydrazide hydrochlorides by treat- ing their ethereal solutions with dry hydrogen chloride.179 Only occa- sionally have hydrazides been purified by distillation.176 The practice is to be avoided, since, at the high temperatures usually necessary for distillation, hydrazides frequently condense to form heterocyclic com- pounds.180 The use of a common solvent, such as ethanol, is indicated where the ester is markedly immiscible with hydrazine hydrate; it is frequently unnecessary to add sufficient solvent to bring about complete misci- bility at the start. However, the presence of two immiscible phases for an appreciable time should be avoided as it favors the formation of secondary hydrazide and retards the reaction as well. Unreactive esters may be refiuxed profitably with hydrazine in a higher-boiling alcohol, such as butyl or amyl alcohol.37- 181- 182 The progress of hydrazide for- mation can often be followed by observing the rate of disappearance of 176 Wieland, Hintermader, and Dennstedt, Ann., 452, 1 (1927). 177Curtius and Dellschaft, /. prakt. Chem., 64, 419 (1901). 178 Curtius and Hille, J. prakt. Chem., 64, 401 (1901). 178 Curtius and Bockmuhl, Ber., 45, 1033 (1912). 180 Wieland, "Die Hydrazine," Verlag Ferdinand Enke, Stuttgart, 1913. 181 Sohopf, Perrey, and Jack, Ann., 497, 49 (1932). 182 Windaus and Raiehle, Ann., 537, 157 (1939). 368 ORGANIC REACTIONS the ester layer. The more reactive anhydrous hydrazine is useful with inert esters and for preparing very hygroscopic hydrazides which are difficult to free from water.46- * On the other hand, anhydrous hydra- zine, being a more vigorous reagent in every respect than the hydrate, is more likely to react with other functional groups in addition to the ester group. * The preparation of hydrazides from acid chlorides is an uncertain procedure which frequently gives rise to large quantities of secondary hydrazide.118- 176 Indeed, the secondary hydrazide may be the only product if an unsuitable procedure is followed. The most successful method is to add slowly a chilled solution of the acid chloride in ether to a well-stirred, chilled alcoholic solution of hydrazine hydrate con- taining considerably more than the 2 moles theoretically required.10 The product is usually separated from the hydrazine hydrochloride formed at the same time by extracting the latter with water. Where the ester is extremely unreactive, this may be the only practicable method for preparing the hydrazide.183 On the other hand, if the acid chloride must be made, it is usually more expedient to convert it directly to the azide by reaction with sodium azide. Amides can be converted to hydrazides by heating them with the theoretical amount or a slight excess of hydrazine hydrate, usually in the absence of a solvent. Since substituted amides, such as those occur- ring in peptide linkages, are more resistant than primary amides, pep- tide hydrazides can be prepared from peptide amides in good yield.105 In general, amides appear to be more sluggish than esters in their reac- tion with hydrazine,106 though a few amides, e.g., benzamide,184 have been reported to react more smoothly. The reaction of hydrazine with amides has sometimes been used to cleave amide linkages occurring in natural products (ergotamine 186). Hydrazides have been prepared only infrequently by the more dras- tic procedure of fusing the hydrazine salts of acids.- This process may give rise to secondary hydrazides in large amount. When applied to acetic,186 propionic,186 and citronellic acids,187 among others, it gives good yields. Anhydrides have been little used for the preparation of hydrazides. Most phthalic anhydride derivatives give only cyclic, secondary hydra- * Cf. Cheney and Piening, /. Am. Chem. Soc, 67, 1040 (1945), for an alternative method in which water is removed by means of a Soxhlet apparatus charged with a drying agent. 183Buning, Rec. trail, chim., 40, 327 (1921). 184 Curtius and Struve, J. prakt. Chem., 50, 295 (1894). m Stall and Hofmann, Helv. Chim. Ada, 26, 922, 944 (1943). m Curtius and Franzen, Bar., 35, 3240 (1902). 187Sabetay, Compt. rend., 190, 1016 (1930). THE CURTIUS REACTION 369 zides (see p. 345), which are useless for the preparation of azides. Di- phenic anhydride (see p. 347) and its 4-nitro derivative (see p. 347) yield the hydrazide acids. Isatoic anhydrides (XXXVI) appear to be excellent sources of hydrazides of certain amino acids.90-91 The reac- C CO C¡ªCO - N2H4 -? /C\ ^NHNH2 + C02 NH¡ªCO NH2 XXXVI tions of hydrazine with lactones, azlactones, anthranils, and similar compounds are not yet clearly denned. In some reactions true hydra- zides have been obtained, which have been converted to the azides and rearranged;38> 73 in others, products of uncertain structure are formed, isomeric with the normal hydrazide, or frequently both isomerides are obtained together.188- 189 All such doubtful compounds are listed in the tables as hydrazides without regard to the original authors' opinions of their structure. Azides prepared from hydrazides derived from un- saturated azlactones readily lose hydrazoic acid to regenerate the azlactones.190' m Hydrazides can also be prepared by the Hofmann degradation of acylureas,192 by the reaction of isocyanates with hydrazine,193 and by the reduction of acylnitramides,109-193 but these methods are of no im- portance in connection with the Curtius reaction. Preparation pf Azides From Hydrazides. All the techniques for converting hydrazides into azides are based on the reaction of the hydrazide with nitrous acid, with the exception of the rarely used diazonium method. The principal variables are: solvent, method of isolating the azide, pH, and the order of the addition of the reactants. The reaction is nearly always carried out at ice-bath temperatures. The choice of method is governed by the following considerations: the solubility of the hydrazide and of the azide, the acidic or basic prop- 188 HeUer and Lauth, Ber., 52, 2295 (1919). 189 Heller and Siller, /. prakt. Chem., 116, 9 (1927). 190 Vanghelovici and Moise, Soc. Chim. Romania Sect. Soc. romane Stiinte, Bvl. Chim. pura apl., [2] 3A, 85 (1941-1942) [C. A., 38, 5500 (1944)]. 191 Vanghelovici and Stefaneacu, Soc. Chim. Romania Sect. Soc. romane Stiinte, Bui Chim. pura apl., [2] 3A, 159 (1941-1942) [C. A., 38, 5501 (1944)]. 192 Schestakov, Ber., 45, 3273 (1912); J. Ruas. Chem. Soc., 40, 330 (1908). 193 Backer, flee. trav. chim., 34, 187 (1915). 370 ORGANIC REACTIONS erties of the molecule, the presence or absence of acid-sensitive groups, the expldsiveness of the azide, the physical state of the azide, and the subsequent disposition of the azide. The procedure to be followed in the absence of complicating factors, and thus the one most frequently used, is in outline as follows. The hydrazide, being basic, is dissolved in a slight excess of dilute aqueous hydrochloric acid, and the solution is chilled to 0-5° by means of an ice bath. The cold solution is covered with ether to extract the azide as soon as it is formed, and a concentrated aqueous solution of 1 mole of sodium nitrite is added with good mechanical stirring at such a rate that the temperature does not rise above 10°. Immediately upon com- pletion of- the addition, the ethereal azide layer is separated, washed with a little sodium bicarbonate solution, and dried. It is then heated with absolute alcohol, usually with simultaneous fractionation of the ether; the resulting urethan can be hydrolyzed to the amine when desired. The only solvents which have seen appreciable use in the reaction of hydrazides with nitrous acid are water, alcohol, and acetic acid. Water is the solvent of choice when conditions permit. An alcohol is frequently chosen as the solvent when anhydrous conditions are desired; alkyl nitrites and dry hydrogen chloride are then generally used as the source of nitrous acid. The alcohol technique is indicated when the azide is difficult to extract from water or is easily hydrolyzed,194- 196> 198 as when basic nitrogen groups are present in the molecule. It has also been employed for hydrazides that are not very soluble in aqueous acid.197-198 The azide is usually rearranged in situ by boiling the solu- tion, although it can often be isolated by dilution with water.198 The alkyl nitrite method has failed occasionally.78' 120' 199 Aqueous sodium nitrite 20° and nitrogen trioxide81 also have been used with alcohols as solvents. Acetic acid, 50% to glacial, is a useful solvent for the conversion of high-molecular-weight hydrazides to azides.. It is employed with 148> 183 or without1U- 162' 201-202'203'204 the addition of a mole of mineral acid; 194 Jensen and Howland, /. Am. Chem. Soc, 48, 1988 (1926). ^Windaus and Opitz, Ber., 44, 1721 (1911). 196 Windaus and Vogt, Ber., 40, 3691 (1907). m Pschorr, Einbeck, and Spangenberg, Ber., 40, 1998 (1907). 198 Sharp, J. Chem. Soc., 1936, 1234. 199 Kermack and Muir, J. Chem. Soc, 1931, 3089. a* Toschi, Gazz. chim. ital., 44, I, 443 (1914). 201 Endermann and Fischer, Ann., 538, 172 (1939). 202 Goldstein and Stern, Helv. Chim. Ada, 23, 809, 818 (1940). 203 Pschorr and Schroter, Ber., 35, 2726 (1902). 804 Vollmann, Becker, Corell, and Streeck, Ann., 531, 44, 58, 137 (1937). THE CURTIUS REACTION ? 371 without the mineral acid the formation of some secondary hydrazide is more likely.206 The customary technique consists in dissolving the hydrazide in glacial acetic acid, with heat if necessary, chilling rapidly so that the hydrazide will separate in finely divided form if, it is insol- uble in the cold solvent, and adding cracked ice and the required amount of aqueous sodium nitrite. Subsequent dilution with water causes the azide to separate, if it has not already done so. When a mineral acid is used in conjunction with acetic acid, a good procedure is to dissolve the hydrazide in a relatively small volume of glacial acetic acid. Subse- quent dilution with even large quantities of dilute aqueous mineral acid frequently does not cause precipitation, but the azide separates at once when sodium nitrite is added. This technique is recommended also for hydrazides which, though soluble, dissolve only slowly in aqueous min- eral acid. A mixture of benzene and acetic acid also has been found satisfactory as a reaction medium.181'206 Acetone has been used as the solvent in the preparation of three azides from the hydrazides in the indoxazene series.207 The advantage of acetone is not clear. v "Reverse addition," that is, addition of acid to a solution of the hydra- zide and sodium nitrite, has found much application,36' 349 particularly with acid-sensitive molecules.82' 160' 208' 209 The reverse-addition tech- nique is not recommended except where excess acid must be avoided, since a higher pH favors the formation of secondary hydrazides by the reaction 41- 205-210> 2U RCON3 + RCONHNH2 -> RCONHNHCOR + HN3 Another disadvantage is the low solubility of most hydrazides in neutral or alkaline solutions. Cyclobutane-grem-dicarbonyl hydrazide unex- pectedly gives a better yield of its diazide by the reverse-addition pro- cedure.210 No simultaneous addition techniques have been reported.. The closest approximation is the substitution of gaseous nitrogen trioxide for sodium nitrite and acid.94> 177'212' 213 This reagent has seen little use, probably because of its inconvenience and the difficulty in meas- uring the exact amount. 206Pschorr and Einbeck, Ber., 38, 2067 (1905). 206 Schopf, Jack, and Perrey, Ann., 497, 59 (1932). 207 Lindemann and Cissfee, J. prakt. Chem., 122, 232 (1929). 208 Curtius and Portner, J. prakt. Chem., 58, 190 (1898). 209Dimroth, Ann., 364, 210 (1908). 210 Curtius and Grandel, /. prakt. Chem., 94, 339 (1916). 211 Curtius, Sohofer, and Schwan, J. prakt. Chem., 51, 180 (1895). 212 Curtius and Heidenreioh, /. prakt. Chem., 52, 454 (1895). 213 Curtius, Schatzlein, Wiengreen, and Krauth, /. prakt. Chem., 89, 508 (1914). 372 ORGANIC REACTIONS Hydrochloric acid is most commonly employed for the generation of nitrous acid from sodium nitrite, although sulfuric and nitric acids are equally satisfactory. The amount of acid employed varies from the stoichiometric to a large excess of concentrated acid, being governed by the solubility of the hydrazide and by the ease with which the secondary hydrazide forms. Acetic acid 214-216> 216'2n has been used frequently, especially with acid-sensitive molecules, but with greater likelihood of the formation of secondary hydrazide. Isoxazole-5-carbonyl hydra- zide 218 and citraconyl hydrazide 21Si 219 yield the secondary hydrazides in acetic acid, but the azides are formed in mineral acid. Hippuryl- aspartyl hydrazide,97 glutaryl hydrazide,220 and N-nitrosoiminodiacetyl hydrazide 221 show no apparent reaction when treated with sodium nitrite and acetic acid, but the addition of mineral acid causes the azides to precipitate. Since the reaction of nitrous acid with hydrazides is rapid and exo- thermic, the reactants should be brought together no faster than the heat can be dissipated; a rise in temperature is likely to lower the yield by decomposition of nitrous acid or of ftie azide or of both. Slow addition provides time for the interaction of the azide with unchanged hydrazide to produce the secondary hydrazide; rapid addition lessens the extent of this side reaction.181-222 For effective cooling, ice is generally added directly to the reaction mixture; the addition of Dry Ice to the super- natant ether layer has been recommended as being even more effi- cient.222 The use of diazonium salts instead of nitrous acid to convert aromatic hydrazides to azides Wi 126 has received very little study, though it is a potentially applicable method for hydrazides carrying other functional groups which might be attacked by nitrous acid. For example, p-phenyl- enediamine has been obtained in this way from p-aminobenzhydrazide (see p. 353). The cold, aqueous solution of 1 equivalent -of diazonium salt is added to a cold solution of the hydrazide containing excess acid. If precipitation of the azide does not begin at once, the addition of sodium acetate usually initiates it. Under special conditions, the inter- mediate diazo hydrazides, RCONHNHN=NAr, can be isolated and 214 Blomquist and Stevenson, /. Am. Chem. Soc., 56, 146 (1934). 216 Curtius and Leimbach, J. prakt. Chem., 65, 20 (1902). 216 Manske and Robinson, J. Chem. Soc., 1927, 240. 217 Miki and Robinson, J. Chem. Soc., 1933, 1467. 2U!Freri, Atti accad. Lincei, 22, II, 264 (1935) [C. A., 30, 6374 (1936)]. 219 Freri, Gazz. chim. iioX. 66, 23 (1936) [C. A., 30, 6387 (1936)]. 220 Curtius and Clemm, J. prakt. Chem., 62, 189 (1900). 221 Curtius, Darapsky, and Miiller, Ber., 41, 356 (1908). 222 Weissberger and Porter, J. Am. Chem. Soc., 65, 62 (1943). THE CURTIUS REACTION " 373 can subsequently be caused to decompose into the azide and amine.223-224 The diazo hydrazides obtained from aliphatic hydrazides decompose, however, into the acid amide and aryl azide, and diazonium salts there- fore cannot be employed to prepare aliphatic acid azides. Isolation of Azides. When the reaction of the hydrazide with nitrous acid is carried out in aqueous solution, the azide is usually extracted as fast as it is formed, usually with ether, but sometimes with other solvents such as chloroform 63-82 and carbon tetrachloride.225 Azides containing a high proportion of azide nitrogen (ca. 25%) should be handled only in solution, since the pure azides are likely to be danger- ously explosive. High-molecular-weight azides are usually innocuous crystalline solids and can be isolated as such. Since azides which are prepared in acetic acid as the solvent are usually of high molecular weight, they are best precipitated by dilution with water. Azides pre- pared in alcohol are not usually isolated. From Acid Chlorides and Sodium Azide. The reaction between an acid chloride and sodium azide can be carried out under anhydrous con- ditions according to procedures described by Schroeter,14 Forster,167 and Naegeli,10 or with aqueous sodium azide according to Lindemann.226 The dry method is the only practical one for highly reactive chlorides, such as acetyl chloride, or for the preparation and rearrangement of very unstable azides. It provides a means of carrying out the reaction sequence RCO2H -* RC0C1 -? RCON3 -?RNCO -? RNH2 in the same reaction vessel as one multiple step. On the other hand, it is not a rehable method, for many acid chlorides are inert to dry sodium azide. The reaction is sometimes difficult to control, since the heating required for the formation of the azide may also cause rearrangement; the two exothermic reactions occurring simultaneously sometimes get out of con- trol, particularly when large amounts are being handled (see p. 364). The use of aqueous sodium azide requires the isolation of the azide as an extra operation, but the reaction is more reliable, easier to control, and usually much faster. A small reduction in yield may sometimes be expected. In the dry method, the acid chloride dissolved in an inert solvent is stirred and/or heated with powdered sodium azide (ammonium azide has also been used91). Part or all of the azide may be converted to the isocyanate at the same time, a step that is completed by refluxing. The isocyanate may then be isolated as such by distillation or concentration, or it may be converted to the urea, urethan, or amihe by the appro- priate method. 223 Curtius, Ber., 26, 1263 (1893). 224Dimroth and Montmollin, Ber., 43, 2904 (1910). 225 Curtius and Ulmer, J. prakt. Chem., 125, 54 (1930). 226 Lindemann and Schultheis, Ann., 451, 241 (1927). 374 ORGANIC REACTIONS The dry method owes its unreliability in part to the insolubility of inorganic azides in organic solvents. Individual lots of sodium azide vary greatly in their reactivity, and the reactivity of a given lot varies with age.10'28 Sodium azide prepared according to Thiele 227 from hydrazine and ethyl nitrite appears to give better results 7 than the commercial product, which is prepared from sodamide and nitrous, oxide. It is uncertain whether the variable activity is due to a surface condition or to the presence or absence of some trace of impur- ity. The Nelles procedure 228 for activating commercial sodium azide by trituration with hydrazine followed by precipitation with ace- tone gives a product apparently as active as Thiele's. Nevertheless many chlorides, particularly those of heterocyclic acids, cannot be made to react satisfactorily with dry sodium azide even of the activated variety.120' 126' 144'229 Benzene,7-230 toluene,231 xylene,230 nitrobenzene,144 pyridine,23 amyl ether,14 ethyl ether,10' 18' 180 o-nitrotoluene,160 bromobenzene,180 and acetic acid 9- m have been used as solvents in the dry method. Ethyl ether is not to be generally recommended because its boiling point is below the decomposition temperature of many azides; Naegeli records an explosion traceable to an accumulation of azide when using this solvent.7 If the isocyanate is to be distilled, the boiling point of the solvent should not be too close to that of the isocyanate. In the wet method, a concentrated aqueous solution (ca. 25%) of sodium azide is stirred into a solution of the acid chloride in an organic solvent miscible with water. The kind of sodium azide is immaterial. The reaction mixture is usually kept at or below room temperature. The organic solvents that have been used are acetone,132- 138> 233> 234 methanol,132 ethanol,113'236 dioxane,132'234 and acetic acid,6'226 of which acetone appears to be the most generally satisfactory. Acetic acid is not the best choice for either the wet or dry method, since it may react with the acid chloride to form the free acid and acetyl chloride, with consequent loss in yield and contamination of the product.9 The azide is precipitated completely by further dilution with water. Some azides have been prepared in the absence of any solvent except the water for the sodium azide; 16 this procedure is practicable only when both the 227 Thiele, Ber., 41, 2681 (1908). 228 Nelles, Ber., 66, 1345 (1932). 229 Spoerri and Erickson, J. Am. Chem. Soc., 60, 400 (1938). 230Komppa and Beckmann, Ann., 512, 172 (1934). 231 Grewe, Ber., 76, 1076 (1943). 232Hofmann and Bridgewater, J. Am. Chem. Soc., 67, 738 (1945). 233 Powell, J. Am. Chem. Soc., 51, 2436 (1929). 234 Rusohig, Med. & Chem., 4, 327 (1942) [C. A., 38, 4954 (1944)]. 2S'StoUe, Ber. 57, 1063 (1925). THE CURTIUS REACTION 375 acid chloride and azide are liquids, and it is not to be generally recom- mended. A two-phase system consisting of the ethereal acid chloride and aqueous sodium azide has been used sometimes.232 Other Methods of Preparing Azides. Ketenes uo and isocyanates U1 react with hydrazoic acid to produce azides, but these methods are of no importance for a Curtius degradation. Rearrangement of Azides The readiness with which azides rearrange varies from rapid, spon- taneous reaction at room temperature 183 to complete inertness.236 The vast majority of azides rearrange at a convenient rate somewhere in the temperature range 20-150°, and their rearrangement is usually brought about by refluxing in a solvent boiling in the neighborhood of 80°. Experience has shown that an hour at this temperature is frequently sufficient for the reaction, but some azides require a longer time or a higher temperature. Many aromatic azides are rearranged most con- veniently at the temperature of boiling toluene, and some of the more recalcitrant carbamyl azides must be boiled in xylene or decalin. Some danger attends the use of a solvent boiling too high, however, because the rearrangement is exothermic and its rate has a high temperature coefficient. The heat of rearrangement is often sufficient to raise the temperature of the reaction mixture to a point where the rearrange- ment gets violently out of control, unless this rise is curtailed by the boiling of the solvent. A recommended procedure for dealing with a new azide is to start with a solvent boiling at about 80°; if the rearrangement appears to be too slow at this temperature, a higher- boiling solvent is added and the original low-boiling solvent is distilled. Alternatively, a relatively large volume of solvent can be taken in order to distribute and absorb the heat of the rearrangement. The choice of a solvent boiling far above the optimum rearrangement temperature is often unavoidable, for it may be desired to fractionate the resulting isocyanate from the solvent, or, in the dry sodium azide method, a higher temperature may be necessary for the formation of the azide. The reaction may then need to be moderated by application of an ice bath, a stream of water, or a wet rag to the reaction vessel at appro- priate intervals. It should be obvious from the foregoing remarks that the rearrange- ment of azides in the complete absence of a solvent is highly hazardous; however, it has sometimes been accomplished successfully.237 Catalyst? 236 Bertho, J. prakt. Chem., 120, 89 (1928). 237 Biihler and Fierz-David, Helv. Chim. Ada, 26, 2123 (1943). 376 ORGANIC REACTIONS have not been studied, but ultrasonic waves have been found to speed up the rearrangement markedly.238-239 The rearrangement of azides is unimolecular, and the rate appears to be independent of the nature of the solvent. The progress of the rearrangement is indicated by the rate of evolu- tion of nitrogen and can be followed by watching the formation of bub- bles in the hot liquid, by gauging the flow of gas through an attached mercury trap, or more elegantly by collecting the evolved nitrogen in a calibrated azotometer.7 Undecomposed azides can be detected by hydrolysis with aqueous alkali,* followed by mild acidification of the aqueous extract with nitric acid and precipitation of white, very insol- uble silver azide (explosive when dry!) with silver nitrate. Preparation of Isocyanates. Isocyanates are prepared by rearrang- ing azides in inert solvents such as ethers, chloroform, benzene and its homologs, malonic ester, and ligroin. If the isocyanate is to be iso- lated, the solvent is removed by distillation,- or, if the isocyanate is the lower boiling, it is distilled directly. In this operation, a safety shield is advisable to guard against a possible explosion of yet undecomposed azide. Isocyanates can be converted to sym-ureas by reaction with water, to urethans by reaction with alcohols, to as-ureas by reaction with amines, or to acylamines by reaction with anhydrous acids or acid anhydrides, or they can be hydrolyzed directly to amines. Acylamines can also be obtained from isocyanates by reaction with Grignard re- agents.214' 24°. 241 RN=C=O + R'MgBr -? RN=C¡ªR' -^* RNHCOR' i , HjO OMgBr One occasionally encounters isocyanates that polymerize more or less readily to isocyanurates, which are sometimes extremely difficult to hydrolyze and are recognizable by their inertness and insolubility. Examples are m-nitrophenyl126 and benzyl242 isocyanates. Such iso- cyanates should be submitted to further reaction before polymerization sets in. Preparation of Ureas. sym-Ureas are best prepared from azides by heating in a moist inert solvent, like acetone,126 benzene, chloroform, or ether; aqueous alcohols usually give rise to a mixture of the urea and * Acid azides in general hydrolyze about as readily as acid anhydrides. 238 Barrett and Porter, J. Am. Chem. Soc., 63, 3434 (1941). 289 Porter and Young, J. Am. Chem. Soc., 60, 1497 (1938). 240Burtner, J. Am. Chem. Soc, 56, 666 (1934). 841 Singleton and Edwards, J. Am. Chem. Soc., 60, 540 (1938). 242 Letts. Ber.. 5, 91 (1872>. THE CUKTIUS REACTION - 377 the urethan. The formation of sym-nveas from the isocyanates can be formulated as follows: RNCO' + H2O -> CO2 + RNH2 RNH2 + RNCO -* RNHCONHR Azides can also be converted to sym-ureas by merely heating them with water. This is a dangerous procedure, since the water-insoluble azides sometimes detonate under such treatment.126 A possible side reaction when azides are heated with water alone is hydrolysis to the acid with loss of hydrogen azide;243> 244 further loss may occur by complete hydrol- ysis of some of the isocyanate to the amine.243'244 These losses are minimized under the previously mentioned conditions.126 " as-Ureas are obtained best by heating the azide in an inert solvent and treating the resulting isocyanate with the desired amine.18' 131 They also result from heating the azide with the amine directly in an inert solvent,180 but this technique not infrequently gives rise to an amide by direct reaction of the amine with the azide without rearrangement. Preparation of Urethans. Urethans are prepared by refluxing azides in absolute alcohols. When the azide is originally prepared in ethereal solution, the solution is dried, a large excess of absolute alcohol is added, and most of the ether is removed.by distillation. The urethans are iso- lated by evaporation or distillation of the excess solvent. Urethans from higher alcohols, such as benzyl alcohol and cholesterol, are usually prepared from a small excess of the alcohol in toluene or xylene. Although the ethyl urethans have been the ones most commonly pre- pared from azides, almost any urethan can be prepared with the appro- priate alcohol. Rearrangement in methanol usually succeeds as well as in ethanol, but occasionally, because the decomposition temperature of the azide may be above the boiling point of methanol, the azide is recovered unchanged or is converted to the methyl ester.89 RCONS + CH3OH -? RCO2CH3 + HN3 Preparation of Acylamines. Heating azides with anhydrous organic acids usually gives rise to acylamines, along with more or less of the sym-urea.. This reaction proceeds through mixed anhydrides of the RCON3 + R'CO2H ?-? RNHCOR' + CO2 + N2 type RNHCOOCOR',245 which either may lose carbon dioxide on heat- 24SCurtius, /. prakt. Chem., 58, 243 (1895). 244 Curtius, J. prakt. Chem., 87, 513 (1913). 246 Naegeli and Tyabji, Helv. Chim. Ada, 18, 142 (1935). 378 OEGANIC REACTIONS ing to form the acylamine or may disproportionate into symmetrical anhydrides, one of which then decomposes to the sym-urea.127-246 ,, RNHCOR' + C02RNHCOOCOR' < ^ RNHCOOCONHR + R'COOCOR'I RNHCONHR + CO2 The predominating reaction is determined by the structure of the acid and azide concerned and by the temperature at which the reaction is carried out. Aromatic azides (through their isocyanates) give largely sym-ureas and anhydrides, whereas aliphatic azides give mostly acyl- amines (60-80% yield).127-245- 246> 247 The structure of the acid has little effect except as it influences the pK of the carboxyl group; stronger acids, such as cyanoacetic and trichloroacetic, give almost entirely acyl- amine, even with aromatic isocyanates.127 Room temperature favors the formation of the acylamine, whereas higher temperatures favor the disproportionation reaction.127 It appears preferable to rearrange the azide in an inert solvent first, and then to treat the isocyanate formed with the anhydrous acid. A number of azides have been converted to the corresponding acetyl amines by heating them in an excess of acetic anhydride, with or with- out the addition of a catalytic amount of sulfuric acid.129- 18°- 202> *>*?248-249 Diacetyl amines appear to be intermediates, but they are usually hydro- lyzed to the monoacetyl amines during the isolation procedure.202 Acetic anhydride is a useful alternative reagent when glacial acetic Wd gives largely the sym-urea.. Preparation of Amines. Of the many ways of converting azides to amines, the direct hydrolysis of the intermediate isocyanates would appear to be the most efficient, since the reaction is much more rapid than the hydrolysis of either urethans or ureas. Nevertheless, this route to the amine has seen relatively little use, partly because isocyan- ates are converted by water quite easily to sym-wceas. It is wise not to risk valuable compounds, available in small amount only, with this method. No one method for converting azides to amines can be said to be the best, and the method must be chosen with due regard for the chemistry of the other functional groups in the molecule. Isocyanates are converted expeditiously to amine hydrochlorides by warming them with concentrated hydrochloric acid; the most con- 246 SohBpf and Salzer, Ann., 544, 1 (1940). 247 Stevenson and Johnson, J. Am. Chem. Soc, 69, 2525 (1937). 848 Goldstein and Viaud, Helv. Chim. Ada, 27, 883 (1944). 248 Lindemann and Cissee, Ann. 469, 44 (1929). THE CURTIUS REACTION 379 venient technique consists in adding a severalfold excess of acid to a warm solution of the isocyanate in the solvent in which it has been ob- tained from the azide.7- 26° The evolution of carbon dioxide usually commences at once and may even become violent; a reflux condenser is therefore advisable with volatile isocyanates. Removal of solvents and excess acid by distillation leaves the amine hydrochloride. Small amounts of the sym-xirea,, which can be removed by filtration, occa- sionally accompany the amine; the use of hydrochloric acid previously saturated with hydrogen chloride at 0° aids in avoiding the formation of the urea.7 Isocyanates are also hydrolyzable by heating with aqueous or alco- holic alkali,23- 1M> 261> 2B2 a procedure of value with acid-sensitive mole- cules. The initial product of such treatment is sometimes the alkali carbamate, RNHC00~M+, which usually remains dissolved. On acid- ification the carbamic acids decarboxylate spontaneously to amines.263 The alkaline hydrolysis of an isocyanato group attached to an asym- metric carbon atom may lead to racemization, but with acid hydrolysis the activity is preserved.264 Distillation from slaked lime has been used to hydrolyze refractory isocyanates to amines,7'2B6 as well as to hydrolyze urethans and ureas. The isocyanate is mixed with an excess of slaked lime in a retort, and the amine is distilled under atmospheric pressure (a fore-run of solvent may be collected). The method is not satisfactory for low-molecular- weight compounds on account of the volatility but is of advantage where milder methods fail. The yields are commonly of the order of 50-70%. In a less reliable method of converting azid.es to amines the azide is heated directly with acidulated water. sym-Ureas frequently accompany the amines,6-126 if, indeed, they are not formed exclu- sively.6- 202'248' 249 Hydrolysis of the azide to the acid and hydrogen azide occasionally occurs.202-266 Strong acetic acid, in which azides are frequently soluble, is a useful reagent.3-53- 12°-207-267 Partially diluted acetic acid (3 : 1 to 1 : 1) appears to produce less sj/m-urea than does glacial acetic acid. On the other hand, the formation of sym-uxea, is more likely to occur with acetic acid than with a stronger acid, such as sulfuric acid.5' 127-249 Rearrangement of azides in concentrated sulfuric 260 Naegeli, Grtintuch, and Lendorff, Helv. Chim. Ada, 12, 234 (1929). 261 Bell, Chemistry & Industry, 1933, 584; /. Chem. Soc., 1934, 835. 262 John and Lukas, J. prakt. Chem., 130, 332 (1931). 263 Meyer and Topsch, Monatsh., 35, 189 (1914). 2M Kenyon and Young, /. Chem. Soc, 1941, 263. m Naegeli and Vogt-Markus, Helv. Vhim. Ada, 15, 60 (1932). m Goldstein and Studer, Helv. Chim. Acta, 17, 1485 (1934). 267 Graf, J. prakt. Chem., 133, 36 (1932). 380 ORGANIC REACTIONS acid approximates closely the conditions of the Schmidt reaction, and amines are accordingly obtained; m> X29 but there is some question re- garding the advisability of introducing azides indiscriminately into such a reagent.5-126' 1M Urethans, being usually stable, purifiable, and crystalline, are con- venient stopping points in the conversion of azides to amines. Although they are more difficultly hydrolyzed than isocyanates, they are more easily handled. The common procedure is to heat them with concen- trated hydrochloric acid, either under reflux OP in a sealed tube at ele- vated temperatures. The reflux method'is often slow, requiring several hours to several days; the sealed-tube method is inconvenient, par- ticularly with large amounts. Hydrochloric acid hydrolysis has the advantage that all reagents can be removed by distillation and the amine hydrochloride isolated without ever making the solution alkaline. The addition of alcohol or acetic acid occasionally facilitates the hydrol- ysis of urethans. Alkaline hydrolysis of urethans has been conducted in aque- ous 120,168,509,268 an(i m alcoholic 106-16°-2M- m solution, and with either alkali metal hydroxides or barium 146> 16° hydroxide. With barium hydroxide, the progress of the reaction, can be followed conveniently by watching the precipitation of barium carbonate. The alcoholic medium appears to give a cleaner reaction. The common procedure consists in refluxing the urethan for several hours with an excess of the alkaline reagent, usually in about 20-40% concentration, although the alkali can be more dilute. Metal carbamates occasionally result initially just as in the alkaline hydrolysis of isocyanates. Hydrolysis of urethans by distillation from slaked lime often succeeds where other methods fail; it cannot be used with low-molecular-weight urethans because of their volatility.10-261> 262 A few urethans have been heated with ammonia in a bomb tube to bring about cleavage to amines.197'*>*?S06 The prin- cipal advantage is the mildness of the reagent. Benzyl urethans can be converted to amines by mild hydrogenation. The benzyl group is removed as toluene1, and the carbamic acid which results decarboxylates to the amine. This method, originated by B,NHCO2CH2C6H5 -^> RNH2 + CO2 + C6H6CHs Pd , 288 Fischer and Dangschat, Helv. Chim. Ada, 17, 1200 (1934). 269 Jambuserwala, Holt, and Mason, J. Chem. Soc., 1931, 373. 260 Mayer and Sieglitz, Ber., 55, 1835 (1922). * 261 Vanghelovici, Bui. Soc. Chim. Romania, 20A, 231 (1938) [C. A., 34, 4073 (1940)]. 262 Windaus and Dalmer, Ber., S3, 2304 (1920). THE CURTIUS REACTION 381 Hans Fischer and his students,62 has been adapted to the stepwise degra- dation of peptides.105 The advantage of this method is that the condi- tions can be made almost completely non-hydrolytic. Benzyl urethans also appear to be more readily hydrolyzed by conventional methods than methyl and ethyl urethans.262"' 262!> Another essentially non-hydrolytic method for cleaving urethans and ureas has been developed by Ing and Manske.107-2M The carboalkoxy group of the urethan is first replaced by the phthalyl group, usually in excellent yields, by fusion with phthalic anhydride. The resulting RNHCO2C2H6 +|| I 0 -?? II | NR + CO2 + C2HBOH NCO phthalimides are readily split into amines and sec-phthalhydrazide by Warming with alcoholic hydrazine. The phthalhydrazide is easily re- NR + NH2NHi! -?? RNH2 moved by virtue of its sparing solubility in most solvents. Occasionally the reaction halts with the formation of an addition compound between hydrazine and the phthalimide, which, however, can be decomposed to the amine hydrochloride and phthalhydrazide by the addition of dilute hydrochloric acid. This method, being quick and moderately conven- ient, is receiving wider application.1B2p 158-211> 264 EXPERIMENTAL PROCEDURES Reagents Note on the Handling of Hydrazine. Hydrazine, alone or in solution, attacks rubber and cork rapidly. Apparatus should have ground-glass connections, if possible. Hydrazine does not cause such joints to "freeze." Anhydrous Hydrazine. The best procedure for preparing anhydrous hydrazine is distillation of hydrazine hydrate from solid potassium 26211 Jensen and Hansen, Dansk. Tids. Farm., 17, 189 (1943) [C. A., 39, 2058 (1945)]. 2626 Barkdoll and Ross, J. Am. Chem. Soc., 66, 951 (1944). ^Manske, J. Am. Chem. Soc., 61, 1202 (1929). 264 Manske, Can. J. Research, 4, 591 (1931) [C. A., 25, 4880 (1931)]. 382 ORGANIG REACTIONS hydroxide.266 Excellent directions for this method have been published in Organic Syntheses.,266° Ground-glass apparatus is preferable to the corks covered with tin foil specified in these directions. Since hydra- zine has been known to decompose with violence during distillation, distillation should be carried out behind a safety screen. Activation of Sodium Azide. (A) (Modified37 procedure of Nelles.228) Twenty grams of pure sodium azide is moistened with 0.5-1.0 cc. of 85% hydrazine hydrate and ground in a mortar until homogeneous. After standing for twelve hours the material is dissolved in the minimum amount of hot water (ca. 40 cc.) in a 2-1. beaker. About 0.5-1.0 1. of cold acetone is added, and the mixture is allowed to stand for about an hour. The precipitated sodium azide is collected, washed with acetone, and dried in air. The resulting cake is crushed in a mortar and dried for a short time in vacuum; yield, 12-17 g. Sodium azide thus acti- ? vated begins to lose its activity after a day, but the activity can be regenerated at any time by dissolving the-sodium azide in water and reprecipitating with acetone. . (B) Improved directions for the preparation of active sodium azide from hydrazine and ethyl nitrite according to Thiele 227 have been pub- lished by Naegeli and Vogt-Markus,265 and by Newman.466 Hydrazide Method ESTER TO AMINE VIA URETHAN Benzylamine from Ethyl Phenylacetate. (Method of Curtius and Boetzelen266 with\modifications.37) Ethyl phenylacetate (16.4 g., 0.1 mole), 85% hydrazine hydrate (7.5 cc, 0.1 mole), and absolute ethanol (10 cc.) are refluxed for six hours. The phenylacethydrazide which crystallizes from the cooled mixture is collected and washed with a little cold ether; yield, 12-15 g. (80-100%); m.p. 110-112°. A solu- tion of 15 g. (0.1 mole) of the hydrazide in 150 cc. of ice water contain- ing 17 cc. of 6 N hydrochloric acid is placed in an ice-salt bath, 100 cc. of ether is added, and a solution of 7.5 g. of spdium nitrite in 15-20 ce. of water is then added at a moderate rate, while the reaction mixture is stirred rapidly. If necessary, cracked ice is added directly to the reac- tion mixture in order to keep the temperature below 10°. The ether layer is separated, and the aqueous layer is extracted with 50-cc. por- tions of fresh ether. The combined ethereal extracts are washed with a little sodium bicarbonate solution, then with water, and finally dried 265 Raschig, Ber., 43, 1927 (1910). 2660 Smith and Howard, Org. Syntheses, 24, 53 (1944). "? Curtius and Boetzelen, J. prakt. Chem., 64, 314 (1901). THE CURTIUS REACTION 383 for five minutes over calcium chloride. The ethereal solution of the azide is decanted from the drying agent into a flask containing 40 cc. of absolute ethanol, and the ether is distilled through a short column until the residual volume is about 50 cc. The full heat of a steam bath is then applied to complete the decomposition of the azide and to re- move the excess ethanol. The residue of ethyl N-benzyl urethan, which sets to a cake on cooling, weighs 11-13 g. (60-70%). The entire quantity is refluxed with 20 cc. of concentrated hydrochloric acid and 10 cc. of glacial acetic acid until the oily layer has disappeared (twelve to thirty-six hours). The mixture is then distilled nearly to dryness from a steam bath under reduced pressure (water pump). The solid residue is dissolved in 50 cc. of warm water, and the solution is filtered from any insoluble matter. Distillation of the filtrate to dryness and recrystallization of the residue from hot absolute ethanol give 7-8 g. (ca. 80%) of benzylamine hydrochloride; m.p., ca. 250°. An alternative procedure is to add the dried ethereal solution of the azide to 50 cc. of dry benzene, remove the ether by distillation, and then continue as described in the dry sodium azide procedure (p. 387). PREPARATION OF AN ACYLAMINE N-(p-3,4-Dibenzyloxyphenylethyl)-homopiperonylamide.206'24S A mix- ture of 30 g. of /3-3,4-dibenzyloxyphenylpropionic ester, 32 g. of hydra- zine hydrate, and 16 cc. of amyl alcohol is refluxed for five hours. The crystalline hydrazide, which separates on cooling, is washed with water and ether; yield, 82%; m.p. 138°. A solution of 5.64 g. of the hydrazide in a mixture of 20 cc. each of glacial acetic acid and benzene is chilled to ¡ª5°. To it is then added all at once a chilled solution of 1.5 g. of sodium nitrite in 5 cc. of water with shaking. After the solution has stood for thirty minutes in the ice bath, 125 cc. of benzene is added and the entire solution is poured carefully into 650 cc. of well-cooled 1.5 N sodium carbonate solution. The benzene layer is separated, and the aqueous phase is extracted with benzene. The combined extracts are dried first over sodium sulfate, then over calcium chloride, and are finally distilled at normal pressure to a volume of about 50 cc. After the solution has been refluxed for two hours to complete rearrangement of the azide, a solution of 3.3 g. of homopiperonylic acid in a little dry benzene is added, and the reflux- ing is continued for ten hours with protection from moisture. The resulting solution is extracted with sodium carbonate solution and then evaporated to give the crystalline amide; yield, 74%; m.p. 119-121° after two recrystallizations from benzene. 384 ORGANIC REACTIONS PREPARATION OF AN ALDEHYDE Phenylacetaldehyde from Benzylmalonic Ester.42 A mixture of 100 g. of ethyl benzylmalonate, 50 g. of hydrazine hydrate, and 10 cc. of absolute ethanol is refluxed for six hours on a steam bath. The dihydrazide is filtered from the cooled mixture and washed with a little ethanol and ether; after drying on a clay plate and then in vacuum, the crude product weighs 91-91.5 g. (ca. 100%) and melts at 164°. A solu- tion of 11.1 g. of this dihydrazide in a cold solution of 9.8 g. of concen- trated sulfuric acid in 44 cc. of water is covered with 50 cc. of ether and cooled to ¡ª 5° in an" ice-salt bath. A solution of 10.35 g. of sodium nitrite in 21 cc. of water is added slowly with stirring, the ether layer is then separated, and the aqueous phase is extracted once with ether. After the combined ethereal extracts have been dried for one hour over sodium sulfate at 0°, 100 cc. of absolute ethanol is added, and the mix- ture is refluxed for three hours; during this time most of the ether is allowed to escape. The resulting solution of the grem-diurethan is con- centrated to a syrup and allowed to crystallize in vacuum over sulfuric acid; yield, 10.5 g. (75%); m.p. 166°. (If the next step is to be per- formed immediately, the crystallization is unnecessary.) A mixture of 4.2 g. of the urethan and 50 g. of 2% sulfuric acid is steam-distilled, the distillate is extracted with ether, and the extracts' are dried over sodium sulfate. Distillation gives 1 g. (56%) of phenyl- acetaldehyde; b.p. 81-82°/12 mm. If the aldehyde is isolated from the steam distillate as the crystalline benzoylhydrazone by treatment with benzhydrazide, the yield is increased to 98%. PREPARATION OF AN ?-AMINO ACID FROM A MALONIC ESTER P-Phenylalanine from Benzylmalonic Ester.46 A filtered solution of 46 g. of pure potassium hydroxide in 800 cc. of absolute ethanol is added to a solution of 200 g. of ethyl benzylmalonate in 100 cc. of absolute ethanol. After one day the mixture is freed from solvents by distilla- tion and dried in vacuum over sulfuric acid. The resulting cake is rubbed in a mortar with absolute ethanol, filtered, and dried; the weight of potassium ethyl benzylmalonate is 176 g. (84.6%). A mixture of 100 g. of the above salt and 20 g. of anhydrous hydra- zine in 75 cc. of absolute ethanol is refluxed for one and one-half hours and then cooled in a vacuum desiccator over sulfuric acid to remove part of the ethanol and excess hydrazine. The product is rubbed with fresh absolute ethanol, filtered, and washed with absolute ether. The weight of potassium benzylmalonhydrazidate is 93.2 g. (98.5%). THE CURTIUS REACTION 385 A solution of 10 g. of the hydrazidate in 200 cc. of water is combined with a solution of 2.8 g. of sodium nitrite in 25 cc. of water. While the solution is stirred with 200 cc. of ether, a solution of 8 g. of concentrated hydrochloric acid in 25 cc. of water is added slowly at room tempera- ture. The ether layer, containing most of the benzylmalonazidic acid, is removed, and the aqueous layer is extracted twice with ether. The combined extracts are washed with a little cold water and dried over- night with sodium sulfate. The ether is then distilled by gentle heating; the residue begins to foam on further heating, and then becomes semi- solid. The resulting isatoic anhydride is cooled, filtered, and washed with ether; yield, 3.4 g. (44%); m.p. 127-128°. A mixture of 5 g. of the anhydride and 25 cc. of concentrated hydrochloric acid is evaporated on a steam bath to incipient crystallization, and the solution is cooled. The crystals of /3-phenylalanine hydrochloride are filtered, washed with a little ice-cold concentrated hydrochloric acid, and dried in vacuum over potassium hydroxide; yield, 5.2 g. (nearly 100%), m.p. 234-235°, dec. The nitrate from the isatoic anhydride yields some additional /3-phenylalanine on treatment with hydrochloric acid. < PREPARATION OF AN <X-AMINO ACID FROM A CYANOACETIC ESTER Glycine from Cyanoacetic Ester.267 A solution of 10 cc. of ethyl cyanoacetate and 12 cc. of hydrazine hydrate (14.2 cc. of 85% hydra- zine hydrate) in 50 cc. of absolute ethanol is refluxed for one hour. The solvents are then removed by distillation, and 25 cc. of ether is added to the syrupy residue. The resulting crystals of cyanoacethydrazide are recrystallized from absolute ethanol; yield, 9 g. (100%); m.p. 110- 112°. A chilled solution of 4.5 cc. of concentrated hydrochloric acid in 20 cc. of water is added to a chilled solution of 5 g. of the hydrazide in 10 cc. of water, and the solution is covered with 25 cc. of ether. The mixture is cooled to 0° in an ice bath, and a solution of 3.45 g. of sodium nitrite in 10 cc. of water is added slowly with stirring. The ether layer is sepa- rated, and the aqueous phase is extracted twice with 10-cc. portions of ether. After short drying ov,er magnesium sulfate, the combined ethe- real extracts are added to 50 cc. of absolute ethanol, the ether is largely removed by distillation through a short column, and the solution is refluxed until nitrogen evolution ceases. After concentration to about 15 cc, 50 cc. of 95% ethanol is added and then a saturated solution of 32 g. of barium hydroxide octahydrate in boiling water. The solution is refluxed for four hours on a sand bath, cooled, and treated with 267 Sah, J. Chinese Chem. Soc, i, 198 (1936). 386 ORGANIC REACTIONS 5.56 cc. of concentrated sulfuric acid in 20 cc. of water. The mixture is again brought to the boiling point, cooled, and filtered. The nitrate is tested for excess of either barium or sulfate ions, and the excess is re- moved by careful addition of the indicated reagent and filtration. The filtrate is concentrated to a volume of 5 cc, and the glycine is precipi- tated by the addition of 5 cc. of absolute ethanol; yield, 2.05 g. (54%). REVERSE-ADDITION PROCEDURE 1,4-Diaminocyclohexane from Hgxahydroterephthalic Acid.u A mixture of 20 g. of dimethyl irans-hexahydroterephthalate, 20 g. of hydrazine hydrate (23.5 g. of 85%), and 20 cc. of absolute ethanol is refluxed on a steam bath for two hours; crystals appear in a few minutes. The mixture is cooled and filtered, and the dihydrazide is washed with ethanol and with ether; weight, 18.8 g. (94%). A solution of 5 g. of the dihydrazide in 800 cc. of warm water is poured into a solution of 5 g. of sodium nitrite in 3 1. of water, the solution is cooled to 5°, and 7 cc. of glacial acetic acid is added with stirring. One or two grams of sodium nitrite is then added, and the precipitated azide is removed after forty-five minutes and washed with water. After drying for four hours in vacuum in an ice chest, the azide weighs 4.8 g. (86%). A solution of 5 g. of the azide in 200 cc. of absolute ethanol is refluxed for two hours, filtered, and concentrated in vacuum. On cooling, 5,2- 5.5 g. (90-95%) of the urethan crystallizes; m.p. 236°. A mixture of 4.8 g. of the urethan and 50 cc. of concentrated hydrochloric acid is heated for seven hours at 120° in a sealed tube (or for twenty-four hours under reflux) and then evaporated to dryness. The resulting 1,4-dia- minocyclohexane dihydrochloride weighs 3.3-3.4 g. (95-98%). USE OF AMYL NITRITE 4-Hydroxy-2-methylpyrimidine-5-methylamine.267a A mixture of 100 g. of 4-hydroxy-2-methylpyrimidine-5-acetic ester and 135 cc. of 50% ' hydrazine hydrate is heated on a steam bath for two hours, during which time the ester dissolves and the hydrazide separates. The hydra- zide is filtered from the cooled solution and recrystallized from ethanol; m.p. 246°; yield, 80-85%. To a suspension of 20 g. of the hydrazide in 300 cc. of absolute ethanol containing 6 g. ol hydrogen chloride is added 19.3 g. of amyl nitrite; the mixture is then warmed to 50-60° and kept there until nitrogen evolu- tion ceases (about one hour). During this heating the hydrazide slowly M7° Todd, Bergel, Fraenkel-Conrat, and Jacob, J. Chem. Soc., 1936, 1601. THE CURTITJS REACTION 387 dissolves and the jellylike urethan hydrochloride separates. Ether is added to the cooled solution to complete the separation of the urethan hydrochloride, which is filtered and dried in a desiccator; m.p. 209°; yield, 98%. A mixture of 5 g. of the urethan hydrochloride and 50 cc. of concen- trated hydrochloric acid is heated for two hours at 100° in a sealed tube. The resulting clear solution is evaporated to a small volume in vacuum. The addition of ether causes the amine hydrochloride to crystallize; yield, 100%; m.p. 278-282° after recrystallization from absolute ethanol. Sodium Azide Method DRY PROCEDURE Acid Chloride to Amine via Isocyanate. Benzylamine Hydrochloride from Phenylacetyl Chloride.*1 A suspension of 6 g. of freshly activated sodium azide * (p. 382) in 100 cc. of dry benzene containing 13 g. of phenylacetyl chloride is refluxed for twenty hours on a steam bath while protected from moisture by a calcium chloride tube. The cooled suspension is then filtered with suction directly into a 300-cc. round- bottomed flask; a little benzene is used to rinse the flask and is poured through the filter. Fifty cubic centimeters of concentrated hydrochloric acid is added all at once to the filtrate, and the mixture is refluxed on a steam bath for two and one-half hours; during this time the crystals which at first form in the benzene layer entirely disappear. The cooled layers are separated, and the benzene layer is washed with a little water. Evaporation or distillation to dryness of the combined aqueous phases leaves 11.3 g. (94%) of benzylamine hydrochloride; m.p. 255-257°. WET PROCEDURE Acid Chloride to Isocyanate and Amine. m-Isocyanatoazobenzene and m-Aminoazobenzene from Azobenzene-m-carbonyl Chloride. (Method ' of Naegeli and Tyabji186 with modifications.87) A solution of 0.7 g. of sodium azide in 2 cc. of water is added to a chilled solution of 2.45 g. of azobenzene-m-carbonyl chloride in acetone (25 cc.) with swirling and cooling in an ice bath. The resulting suspension is diluted after about fifteen minutes with about 50 cc. of water to complete the separation of the azide, and the azide is filtered, washed with a little water, pressed as dry as possible, and dried in vacuum; m.p. 76-77°; weight, 2.2 g. ? (ca, 90%). The dried azide in 5 cc. of dry benzene is heated under * If unactivated sodium azide (Eastman Kodak Company) is used, 10.4 g. (85%) of benzylamine hydrochloride is obtained. 388 ORGANIC REACTIONS reflux in an oil bath at 90-100° until the nitrogen'evolution ceases (one to four hours). Distillation of the benzene in vacuum leaves about 2 g. (nearly theoretical yield) of crystalline m-isocyanatoazobenzene; m.p. 45-46°. (If boiling toluene or xylene is substituted for benzene, the rearrangement is completed in a few minutes, but the subsequent removal of the solvent is more tedious.) If the amine is desired, the solution of the isocyanate is warmed with about 10 cc. of 50% aqueous potassium hydroxide; m-aminoazobenzene (m.p. 67°) is rapidly formed and is obtained in about the theoretical yield by distillation of the or- ganic solvent. The corresponding p-carbonyl chloride can be degraded similarly in almost identical yield.37 Undecyl Isocyanate from Lauroyl Chloride. Excellent directions for this preparation are given in Organic Syntheses.16 SURVEY OF THE CURTIUS REACTION The following table is intended to include all examples of the Curtius reaction, partial or complete, published before May, 1945; neverthe- less, there are probably some omissions. It is unnecessary to emphasize that the recorded yields are not necessarily the maximum and that the conditions are not always the optimum. Nomenclature. The names by which the compounds are listed in the table are those which emphasize the parent acid, in order to facilitate ready'location. Thus "benzoic ester" is used instead of "ethyl ben- zoate." Ethyl esters are referred to simply as "ester"; all other esters are specifically designated. Cyclic anhydrides, lactones, and azlactones are listed under the parent acid rather than under heterocyclic com- pounds. Yields, References, and Symbols. The presence of a reference num- ber in parentheses indicates that the compound was isolated in the yield given or in an unreported yield, indicated by a dash. The pro- cedure employed is shown by a symbol (Sd, Ua, etc.) in parentheses. The yield of any compound is based on the preceding intermediate appearing on the same line, except that the yield of urethan is based on the azide or preceding intermediate and not on the isocyanate. In the amine column, the symbols indicate the compound (or its precursor if it was not isolated) on which the yield is based. It will be noted that the overall yield from starting material to product cannot always be calculated, because of the failure of the investigator to report the jields in all steps. (Sd) or (Sw) alone, without a- yield and reference number, indicates that the azide was not isolated but was made by the method expressed THE CURTIUS REACTION 389 by the symbol and was used further. For these entries the yield of a compound immediately following the azide is based on the acid chloride and not on the azide. In the isocyanate column are reported all other compounds isomeric with the isocyanate which are formed under the same conditions, such as internal urethans, isatoic anhydrides, and isocyanurates. Where these occur, the entry is starred (*); stars are also used in the urethan column to indicate that the products are sym-meas. No distinction is made among urethans derived from different alcohols; nearly all, how- ever, are ethyl urethans. A number of hydrazides and azides are listed in the column headed "Starting Material." This is done when the structure of the precursor does not supply the identity of the hydrazide or azide obtained from it; the precursor is then identified in a footnote. The following symbols indicate the various procedures which were employed; if no symbol occurs in the azide column, the azide was pre- pared by the action of nitrous acid on the hydrazide. Most of the sym- bols correspond to the initial letters of the compound and procedure involved. Sd = sodium azide (dry method). Sw = sodium azide (wet method). Ua = urethan or urea, acid hydrolysis. Ub = urethan or urea, basic hydrolysis. la = isocyanate, acid hydrolysis. Ib = isocyanate, basic hydrolysis. L = lime distillation of urethan or urea. P = phthalimide prepared from urethan or urea and cleaved by hydrazine. C = carbobenzoxyl group (of benzylurethan) removed by hydro- genation. X = azide prepared by other methods. Z = amine or acylamine prepared by other methods. INDEX TO TABLE ALIPHATIC ACID DERIVATIVES PAGE Derivatives of Saturated Acids 392 Monocarboxylic Acids 392 Halogen Groups 3 Ether Groups 3 Hydroxyl Groups , 394 Keto Groups 395 Amino and Amide Groups 395 Other Groups 7 Dicarboxylic Acids and Cyano Acids 398 Malonic Acids 398 Cyanoaeetic Acids 9 Other Dicarboxylic Acids 400 Polycarboxylic Acids ' 403 Unsaturated Acids 404 Ethylenic Acids 4 Monocarboxylic Acids. 404 Dicarboxylic Acids 5 Acetylenic Acids 405 CAHBAMIC ACID DERIVATIVES Alkyl- and Aryl-carbamic Acids 406 Thiocarbamic Acids 407 Carbazic Acids 7 AIJCYCLIC ACID DERIVATIVES Saturated Acids 408 Cyclobutane Derivatives 408 Cyclopentane Derivatives 8 Cyclohexane Derivatives 8 Derivatives of Other Alicyclic Systems 409 Unsaturated Acids 410 ABYLALIPHATIC ACID DERIVATIVES Monocarboxylic Acids 411 Saturated Acids 1 a-Monoaryl Substituted Acids 411 |3-Monoaryl Substituted Acids 1 ?y- to wAryl Substituted Acids 4 Polyaryl Substituted Acids. . 414 Unsaturated Acids 414 Polycarboxylic Acids 5 390 THE CURTIUS REACTION 391 AROMATIC ACID DERIVATIVES PAGE. Benzenecarboxylic Acids 417 Halogen Groups 8 Nitro Groups 419 Ether Groups 420 Hydroxyl Groups 1 Amino and Amide Groups 423 Other Groups 425 Biphenylcarboxylic Acids 5 Naphthalenecarboxylic Acids 426 Phenanthrenecarboxylic Acids 7 Acids of Other Aromatic Ring Systems 427 HETEROCYCMC ACID DERIVATIVES * ' Ethyleneimine Acids 428 Pyrrole Acids 8 Pyrrylaliphatic Acids 8 Pyrrolecarboxylic Acids . . . , 430 Halogen Groups 431 Hydroxyl and Keto Groups 3 Polypyrrole Acids 4 Jndole Acids 434 Acids of Other Pyrrole Ring Systems 435 Furan Acids 5 Furylaliphatic Acids 435 Furancarboxylic Acids 5 Acids of Other Furan Ring Systems 436 Thiophene Acids 437 Pyrazole Acids 7 Imidazole Acids 8 Thiazole Acids 438 Triazole (1,2,3) Acids 439 Pyridine Acids 440 Quinoline Acids ' 442 Acids of Other Pyridine Ring Systems 443 Pyrazine Acids 444 Pyrimidine Acids 4 Acids of Other Six-Membered Heterocyclic Ring Systems 445 * The ring systems listed here include their bydrogenated derivatives. COMPOUNDS SUBJECTED TO THE CURTIUS REACTION ALIPHATIC ACID DERIVATIVES to Starting Material Formic ester Acetic ester Acetic acid Acetyl chloride Acetic anhydride Ketene Propionic ester Propionic acid Propionyl chloride Butyric ester Isobutyric ester Isovaleric ester Pivalic ester Pivalyl chloride 7-Methylvaleric ester ra-Heptanoyl chloride Isoamylacetic ester a-Ethyl-7-methylvaleric ester Hydrazide ¡ª (211) ¡ª (211, 268, 269) 95% (186) 80% (178) 92% (186) 80% (270) 99% (271),-(272) Good (178), ¡ª 273) - (176) 0% (176) Quantitative (271) Quantitative (271) 76% (271) Azide (Sd) (Sd) (Sd) (X) Yields N- methylcarbamyl azide (Sd) Good (178) 65% (237) Poor (Sd) (237) (Sd) Isocyanate 72% (14), 62% (15) 78% (16a) 50% (37) 56% (271) 94% (237) 50% {271) Urethan - (179) 44% (178) Quant. (271) * Good (178) - (237) - (271) * 55% (271) 30% (271) * Amine, etc. 65% (la), 63% (Z) (7) Good (Ua) (178) Good (Ua) (178) - (237) Quant. (Ua) (271) 71% (la) (228) 95%(Ua),73%(L)(271) Quant. (Ua) (271) I GO tt-Isbbutyl-a-ainylacelic ester Laurie ester Lauroyl chloride Palmitic ester Palmitoyl chloride Stearoyl chloride Chloroacetic ester Chlorbacetyl chloride Chloroacetyl bromide Trichloroacetic ester Trichloroacetyl chloride Broinoacetyl bromide es-Bromocaprylyl chloride a-Bromodibutylacetyl chlo- ride Ethoxyacetic ester Wr-Propoxyacetic ester Isoamyloxyacetic ester Benzyloxyacetic ester 77% (271) 89% (213) 93% (177) 0% (116) 0% (274) 0% (274) 82% (79) 88% (79) 81% (79) - (275) (Sw) (Sd) 87% (177) (Sd) (Sd) (Sd) (Sd) 0% (Sd) (274, 228) (Sd) (Sd) (Sd) - (79) -(79) - (79) * 54% (271) 86% (16) 66% (14) ¡ª (HI) - (HI) Quant. (271) * ¡ª (213) - (177) ¡ª (79) ¡ª (79) -(79) 93% (Ua) (271) ¡ª (Ua, L) (213) 80% (la), 76% (Z), 71% (L) (7), 67% (Z) (9) ¡ª (Ua, L) (177) 96% (la), 80% (L), 82% (Z) (7) 94% (la), 81% (Z), 75% (L) (7) 30% (Ib) (23) Enanthal 77% (Ib) (23) Dibutyl ketone ¡ª (Ua) (79) Formalde- hyde ¡ª (Ua) (79) Formalde- hyde ¡ª (Ua) (79) Formalde- hyde References 268-464 appear on pp. 446-449. CO CO COMPOUNDS SUBJECTED TO THE CURTIUS REACTION¡ªContinued AMPHATIC ACID DEBITATTVEB¡ªContinued Co 8 Starting Material ?y-Phenoxybutyric ester Glycolic ester Lactic acid Lactic ester Hydracrylic ester -y-Valerolactone S-Valerolactone ?-Methylbutyrolactone ar-Methyl-r-valerolactone 0-Methyl-T-vaterolactone (a- or /J-) Isopropyl butyro- lactone a-Methyl--y-caprolactone e-Octanolactone /S-Isopropyl-5-valerolactone -y-Nonanolactone ot-Methyl-7-nonanolactone ot-Methyl-S-nonanolactone d-Gluconolactone i-Arabinolactone {-Mannonolactone Metasaccharinic laetone Other sugar acid lactones Hydrazide 83% (263) 97% (157) -(186) 94% (79) -(79) ¡ª (276, 277) 60% (278) -(72) . ¡ª (277, 279) ¡ª (276, 277) ¡ª (72) ¡ª (277, 279) - (71) -(72) - (71) ¡ª (276, 277) ¡ª (276, 277) -(78) -(78) Quantitative (78) -(78) ¡ª (280, 281) Azide 57% (157), - (41) Poor (79) 0% (79) 0% (278) Isocyanate - Urethan 62% (263) * - (41, 157) ¡ª (79) Acetal- dehyde Amine, etc. - (P) (263) Hippurylglycolic ester Levulinic ester Glycine ester N-Phenylglycine ester Aceturic ester Chloroaceturyl hydrazide Bromoaceturyl hydrazide Iodoaceturyl hydrazide Acetoxyaceturyl hydrazide Phenylureidoaceturic ester Diazoaceturic ester Isopropylureidoacetic ester N-(4-Methylamyl)-ureido- acetic ester Phenylureidoacetic ester Benzamidomethylureido- acetic ester Hippuric ester Hippuramide p-Bromohippuric ester m-Nhrohippuric ester p-Nitrohippuric ester Yields hippuryl hydrazide and glycolyl hydra- zide (275) -(86) - (282) ' ¡ª (25) ¡ª (25, 100) (116) t (116) f (116) f (154) f 96% (101) 82% (115) 99% (271) -(271) 70% (101) -(100) ¡ª (243, 283) ¡ª (243) 91% (285) 85% (285) 89% (100) 0% (282) Yields N-nitroso- N-phenylglycine azide (25) - (25), 0% (100) 57% (116) 66% (116) 18% (116) 86% (101) - (271) - (271) 92% (101) -(100) 90% (243) 89% (285) 49% (285) ¡ª (100) 94% (244) * ¡ª (285)* -(285)? 37% (116) 74% (116) 94% (116) - doi) - doi) -(284) 75% (285), 76% (244) * -(285) !? References 268-454 appear on pp. 446-449. t Prepared from diazoaceturyi hydraude. W CO C COMPOUNDS SUBJECTED TO THE CURTIUS REACTION¡ªContinued ALIPHATIC ACID DEBIVATTVES¡ªContinued CO .Starting Material Pbthalylglycine ester Carbobenzoxy-d-alanylglycine ester Carbobenzoxy-J-alanylglycine ester Chloroaceturylglycyl hydra- zide Hydroxyaceturylglycyl hydrazide Phenylureidoaceturylglycine ester Diazoaceturylglycine ester Hippurylglycine ester p-Nitrohippurylglycine ester Benzoylalanylglycine ester Hippurylglycylglycine ester Benzoyl-tros (glycyl)-glycine ester Benzoyl-tetrafcis (glycyl)- glycine ester N,N-Dimethylalanine ester N,N-Dimethyl-/3-alanine ester Benzoylalanine ester Hydrazide (25) sec-Phthalhy- drazide and gly- cyl hydrazide 78% (454) -(454) (116) f (154) f 86% (101) 72% (154) 85% (104),-(283) 89% (100) 95% (102) 70% (104), ¡ª(283) 90% (104) 70% (282) - (88) -(88) 96% (102) Azide Good (454) - (454) 90% (101) ¡ª (104) ¡ª (100) 24% (102) ¡ª (104) 50% (104) 0% (282) -(88) 0% (88) 60% (102) Isoeyanate 85% (100)*- Urethan ¡ª (101) ¡ª (100, 104) ¡ª' (102) Amine, etc. ¡ª (104) Formaldehyde ¡ª (Z) (88) Acetaldehyde 1> s 33 Carbobenzoxyglycyl-J- alanine ester Hippurylalanine ester Hippury W-alanine amide Benzoylalanylalanine ester Hippurylalanylalanine ester 18-Hippuramidobutyric ester /3-Hippuramidobutyryl-/3- aminobutyric ester 7-Hippuramidobutyric ester a-Benzamidoisobutyryl chloride a-Benzamidoisobutyric azlactone N-Benzoylleucine methyl ester Carbobenzoxyglycyl-Z-alanyl- Z-leucine ester HippuryM-alanyl-Heucine amide Diazoacetic ester Diazoacetamide Triazoacetic ester Triazoacetyl chloride ? a-Triazopropionic ester /3-Triazopropionic ester ?y-Triazobutyric ester 87% (105) 85% (99) 75% (105) {¡ª (102) 75% (99) 80% (98) -(98) ¡ª (103) ¡ª (188) ¡ª (188) 88% (105) 60% (105) 43% (105) 0% (155) Yields triazoacet- hydrazide, q.v. (155) 46% (179), ¡ª(155) 82% (158) 71% (158) Good (159) 46% (105) 80% (99) 87% (105) - (102) 70% (99) -(98) -(98) 57% (105) ¡ª (179, 155) (Sd) ¡ª (158) ¡ª (159) ¡ª (160) -(99) 13% (105) -(99) -(98) 32% (105) 43% (105) - (157) 52% (158) ¡ª (158) - (159) ¡ª (C) (105) Acetalde- hyde 50% (Ua) (98) 82% (C) (105) 72% (C) (105) Isovaler- aldehyde Quantitative (TJb) (157) 64% (Ub) (157) CO 5References 268-154 appear on pp. 446-449. t Prepared from diazoaceturylglycyl hydrazide. COMPOUNDS SUBJECTED TO THE CURTIUS REACTION¡ªContinued ALIPHATIC ACID DEBIVATIVBS¡ªContinued CO tooo Starting Material Malonic ester Ethyl potassium malonate Bromomalonic ester Methylmalonic ester Ethyl potassium methylmal- onate Dimethylmalonic ester Ethylmalonic ester Ethyl potassium ethylmalo- nate n-Propylmalonic ester Ethyl potassium n-propylmal- onate Isopropylmalonic ester Hydrazide Quantitative (286), Good (211), ¡ª (47, 287, 288, 289), 26% (47) Ester hydrazide 98% (46) Yields hydrazino- mSlonyl hydra- zide (288) 59% (290), ¡ª (286, 288) Quantitative (45) Monohydrazide Poor (290) 85% (291), ¡ª(288, 292) Quantitative (46) 96% (47), 61% (288) 96% (47) 77% (288) Azide -(41) -(47) ¡ª (290) ¡ª (290) 40% (291) Isocyanate 4% (47) * 41% (46) * 94% (47) Urethan -(41) ¡ª (290) -(47) -(290) 51% (46) 26% (47) Amine, etc. - (Ua) (41) ¡ª (Ua) (290) Acetalde- hyde - (Ua) (47) 67% (la) (45) alanine methyl ester ¡ª (Ua) (290) Acetone 70% (Ua) (291) Pro- pionaldehyde Quantitative (la), 67% (Ua) (46) 46% (Ua) (47) Butyr- aldehyde 43% (la) (47) o-Amino- valeric acid o o i 02 Ethyl hydrogen isopropyl- malonate Ethyl potassium isopropyl- makraate Potassium isopropylmalona- mate n-Butylmalonic ester Ethyl potassium isobutylmal- onate Potassium isobutylmalona- mate Isoamyhnalonic ester Ethyl potassium isoamylmal- onate Potassium isoamylmalona- mate jS-Hydroxyethyhnalonic ester lac tone 7-Chloro-/3-hydroxypropyl- malonic ester lactone Cyanoacetic ester Isonitrosocyanoacetic ester Nitrocyanoacetic methyl ester n-Propylcyanoacetic ester Quantitative (293) Monohydrazide 98% (47) 21% (47) Dihydrazide 73% (288) 85% (47) 0% (47) Quantitative (290) -(47) -(47) Ester hydrazide -(73) Dihydrazide 81% (73) ¡ª (294) Ester hydrazide Quantitative (124, 140, 267) 60% (124) 48% (124) -(47) Poor (290) Lactone azide - (73) ¡ª (124, 222) 79% (124) 62% (124) 37% (47) - (47) * -(290) -(73) -(124) -(124) -(124) 90% (Ua) (47) Valine 68% (la) (47) a-Amino acid ¡ª (Ua) (290) Isobutyl- acetaldehyde 63% (la) (47) a-Amino acid 81% (Ua) (47) a-Amino acid 38% (Ua) (124), 54% (Ub) (267) f Glycine ¡ª (Ua) (124) Oxalic acid 0% (Ua) (124) 31% (Ua) (138) a-Am- ino acid References 268-454 appear on pp. 446-449 t Yield based on the hydraiide. COMPOUNDS SUBJECTED TO THE CURTIUS REACTION¡ªContinued ALIPHATIC ACID DERIVATIVES¡ªContinued Starting Material Isopropylcyanoacetic ester ?y-Phenoxypropylcyanoacetic ester Isobutylcyanoacetic ester Isoamylcyanoacetic ester Carbonic ester Chlorof ormic methyl ester Oxalic ester Oxamic ester N-Phenyloxamic ester N-Benzyloxamic ester Oxalylglycolic ester Succinic ester Succinyl chloride Hydrazide 84% (138) 70% (295) 66% (64) Monohydrazide ? 61% (296), - (211, 297) Dihydrazide ¡ª (299) ¡ª (300) -(301) Yields oxalyl hy- drazide and gly- colyl hydrazide (275) ¡ª (211, 286, 287, 297) Azide -(138) - (295) ¡ª (Sd) (212) - (298), 0% (211) 28% (64) ¡ª (301) ¡ª (41), 0% (211) (Sd) (Sd) Isocyanate 65% (57) -(40) Urethan 38% (139) 54% (138) -(138) 23% (64) .0% (298) 65% (64) ¡ª (301) ¡ª (41, 57) -(40) Amine, etc. 60% (Ua) (139) Valine 40% (Ua) (139) a- Amino acid 51% (Ua) (138) Leucine 26% (Ua) (138) a-Am- ino acid ¡ª (Ua) (41) 3% (Ua) (57) 75% (la), - (Z) (9) Ii I Ethyl hydrogen succinate Succinamic acid Succinylglycolic ester Glutaric ester Adipic ester Adipyl chloride Ethylsuccinic ester Pimelic ester Suberic ester Sebacic ester Sebacic ester chloride Sebacyl chloride Heptane-l,7-dicarbonyl azide 1-Carbethoxyheneicosane- 21-carbonyl chloride Perhydronorbixin chloride 2-Methyltridecane-l,13-di- carbonyl chloride Bromosuccinic ester Malic ester Tartarie methyl ester ¡ª (56) -(56) Quantitative (275) of succinyl hy- drazide and gly- colyl hydrazide 94% (220), 19% (56) 94% (37), 90% (11) 69% (303) 60% (11) 80% (11), ¡ª (304) 78% (305) ¡ª (306) 0%(U5) Quantitative (79), -(297) ¡ª (307) 15% (56) ¡ª (220) 61% (11) (Sd) ¡ª (11, 304) 91% (305) (Sd) (Sd) (Sd) (Sd) -(79) 63% (79) ? ¡ª (302) ¡ª (303) ¡ª (302) 94% (50) ¡ª (302) 7% (56) -(220) 84% (11), 84% (37) 29% (303) 43% (11) ¡ª (11, 304) 99% (305) - (79) 10%<79)Gly- oxal 0% (Ua) (56) ¡ª (Ua) (220) 83% (Ua) (11), 90% (Ua) (37), 72% (la) (37) 68% (la) (9) ¡ª (Ua, la) (303) - (Ua) (11) 97% (Ua) (11), - (304) Quantitative (Ua) (305), ¡ª (P) (263) 76% (la) (50) 81% (la), 52% (L), 73% (Z) (9) * 66% (la) (51) 50% (la) (8) . ¡ª (Ua) (79) Amino- acetaldehyde 39 References 268-151 appear on pp. 446-149. ? COMPOUNDS SUBJECTED TO THE CUETIUS REACTION¡ªContinued ALIPHATIC ACID DERIVATIVES¡ªContinued Starting Material Tartaric ester Shellolic ester Mucic ester Tetraacetylmucyl chloride Oxalacetic ester Iminodiaeetie ester N-Nitrosoiminodiacetic ester Succinyl glycine Phenylsuccinylglycine ester Dibenzoylcystine ester Dihippurylcystine methyl ester Aspartic ester Asparagine Hydrazide 99% (79) ¡ª (308) 98% (79) 77% (81) 0% (87) t 84% (309) -(221) - (57), 0% (25) ¡ª (303) ¡ª (88) ¡ª (88) -(88) ¡ª (88) Monohy- drazide Azide 0%(308) 72% (79) 47% (X) (81) 58% (Sw) (81) Poor (309) 99% (309), ¡ª (221) 75% (303) ¡ª (88) ¡ª (88) -(88) Isocyanate 70% (79) * + 33% tartralde- hyde Good (81) * Urethan 91% (309) 36% (303) -(88) -(88) Poor (88) Am- inoacetalde- hyde Amine, etc. ¡ª (Ua) (98) Diazacy- clobutane-l,3-dicar- boxylic ester ¡ª (Ua) (88) Aldehyde ¡ª (Ua) (88) Aldehyde § ¡ê o N,N-Dimethylaspartic ester Hippurylaspartic ester Benzoylaminomethylureido- succinic ester p-Bromobenzoylaminometh- ylureidosuccinic ester Glutaramyl chloride N-acetic ester Benzoylglutamic methyl ester Hippuryl-2-alanyl-Z-leucy]4- glutamic methyl ester Hydrazodioxalic ester Triazosuccinic ester Cyanosuccinic ester a./J-Dicyanopropionic ester Tricarballylic ester aym-Ethanetetracarboxylic ester Butane-l,2,2-tricarboxylic ester ocCyanoadipic ester ot-Cyanopimelic ester Pentane-l,l>5,5-tetracarbbx- ylic ester -(88) 90% (97) 87% (100) -(100) ¡ª (310) Dihydra- zide 80% (105) , 97% (105) Quantitative (64) ¡ª (311) Good (37) 0% (139) - (312) 97% (313) ¡ª (313) Mixed pri- sec-hydrazide 92% (43) - (139) ¡ª (139) 60% (210) 50% (97) 87% (100) - ¡ª (100) 64% (105) 70% (105) -(64) 42% (311) - (312) ¡ª 25% (313) ¡ª (313) Ethanetri- carbonyl azide 0% (139) 0% (139) Quantitative (210) ¡ª (100) * ? Poor (88) Am- inoacetalde- hyde -(97) -(100) 48% (310) 25% (105) 52% (105) JEW (64) - (312) ¡ª (312) Gly- oxal 78% (43) ¡ª (Ua) (97) Amino- acetaldehyde 16% (Ua) (310) 7-Am- inobutyric ester-HC1 61% (C) (105) 50% (C) (105) ¡ª (Ua) (64) ¡ª (Ua) (312) 90% (Ua) (43) 1-Amino- . 2-butanone ¡ª (Ua) (210) Dialde- hyde References 288-454 appear on pp. 446-449. t Some pyraiolone-3-carbonyl hydratide is formed. COMPOUNDS SUBJECTED TO THE CURTIUS REACTION¡ªContinued ALIPHATIC ACID DERIVATIVES¡ªContinued o Starting Material Citric ester Amine-N,N,N-triacetic ester, Hippurylaspartylaspartic ester Benzamidomethylureido- ethylenedicarbamylaspar- tic ester Hippurylaspartylaspartyl- hydrazidiaspartic ester Acrylyl chloride Methacrylyl chloride Crotonic ester Crotonyl chloride Isocrotonyl chloride d-Citronellic acid Undecenoic methyl ester Undecenoyl chloride Hydrazide Quantitative (297), 91% (296),- (79, 287, 289) ¡ª (79) Mixed pri- sec-hydrazide ¡ª (309) 89% (97) ¡ª (100) - (97) 88% (22) (314) ¡ª (187) -(29) Azide 64% (79) -(79) ¡ª (309) ¡ª (97) Mixed sec- hydrazide azide ¡ª (100) (Sd) (Sd) 0% (22, 314) 47% (Sd) (18) ¡ª (Sd) (18) - (29) - (S) (29) Isocyanate 5% (31) + 30% polymer ¡ª (20) -(29) Urethan 0% (79) 43% (18) * Poor (18) * -(29) Amine, etc. ¡ª (Ua) (79) Diamino- acetone o i CO Oleie methyl ester Oleyl chloride Oleic acid? Elaidic acid? Erucic methyl ester Erucyl chloride |8-Chloroisocrotonic ester Fumaric methyl ester Citraconic methyl ester Itaconic methyl ester Mesaconic methyl ester Dicarbethoxyglutaconic ester Tetrolic ester ?-Undecynoic ester Stearolic ester Acetylenedicarboxylic ester -(29) ¡ª (21) Stearoyl hydrazide ¡ª (21) Stearoyl hydrazide - (29) 0% (219) Yields 6- methylpyrazo- lone -(25) Good (219) ¡ª (219) ¡ª (219) ¡ª (315) Yields malonyl hydra- zide 0% (34) Yields 3- methylpyrazo- lone-5 ¡ª (33, 316) -(32) ¡ª (87, 161) Yields pyrazolone-3- carboxylic ester or hydrazide, q.v. ¡ª (29) - (S) (29) -(29) - (S) (29) ¡ª (25) Good (219), ¡ª (218) ¡ª (219) ¡ª (219) -(29) -(29) - (29) -(29) ¡ª (25) References 268-454 appear on pp. 446-449. ? COMPOUNDS SUBJECTED TO THE CURTIUS REACTION¡ªContinued CARBAMIC ACID DERIVATIVES Starting Material Semicarbazide Cyanic acid Methyl isocyanate Dimethylcarbamyl chloride Diethylcarbamic ester Diethylcarbamyl chloride Diisobutylcarbamyl chloride Diisoamylcarbamyl chloride Chloromethyl isocyanate Benzohydryl isocyanate Phenylcarbamic ester Phenylurea N-Methyl-N-phenylcarbamyl chloride N-Ethyl-N-phenylcarbamyl chloride N-Methyl-N-o-tolylcarbamyl chloride N-Ethyl-N-o-tolylcarbamyl chloride Hydrazide - (317) 0% (319) ¡ª (298) 90% (101) Azide ¡ª (212, 109) ¡ª (X) (109) - (X) (110) 80% (Sd) (318) 0% (Sd) (319) 80% (Sd) (318) 68% (Sd) (318) - (X) (111) - (X) (110) ¡ª (268, 298) - (101) 64% (Sd) (113) 60% (Sd) (113) Quantitative (Sd) (113) - (Sd) (113) Isocyanate ¡ª (112) Hydia- zodicarbon- amide ? (318) ? (318) ¡ª (113) An in- dazolone 68% (113) An indazolone 12% (113) + .31% of inda- zolone 28% (113) Urethan - 0% (268, 298) Amine, etc. Poor (la) (318) o I N-Ethyl-N-p-tolylcarbamyl chloride N-Phenyl-N-benzylcarbamyl chloride Diphenylcarbamyl chloride Di-p-tolylcarbamyl chloride N-Ethyl-N-?-naphthylcarba- myl chloride N-Phenyl-N-ct-naphthylcar- bainyl chloride N-Phenyl-N-^-naphthylcar- bamyl chloride N,N-DiT3-naphthylcarbamyl chloride Thiocarbamyl hydrazide Methyl isothiocyanate Ethyl isothiocyanate Allyl isothiocyanate Phenyl isothiocyanate p-Tolyl isothiocyanate Hydrazinedicarboxylic ester a-Phenyl-^-benzalcarbazyl chloride ?*-Phenyl-/S-o-chlorobenzal- carbazyl chloride ¡ª (379) -(165) - (165) - (165) - (162) 57% (320) ? 97% (318) Quantitative (Sd) (318) ¡ª (Sw) (235) -(200) 98% (Sd) (318) 80% (Sd) (318) Quantitative (Sd) (318) 97% (Sd) (318) 77% (Sd) (318) 62% (164) -(165) 73% (165) 66% (165) Good (162), ¡ª (163) - (X) (163) ¡ª (320, 321) 94% (Sd) (318) 99% (Sd) (318) ¡ª (318) An in- dazolone *99% (318) An indazolone 89% (235) An indazolone 11% (318) + 37% of inda- zolone 50% (318) An indazolone 58% (318) An indazolone 96% (318) An indazolone 94% (318) An indazolone ¡ª (164) -(165) -(165) -(163) -(163) 0% (321) 0% (322) 0% (322) 0% (321) ? References 268-454 appear on pp. 446-449. COMPOUNDS SUBJECTED TO THE CURTIUS REACTION¡ªContinued ALICTCUC ACID DERIVATIVES Starting Material Cyclobutane-l,l-dicarboxylic ester cis-Cyclobutane-l,2-dicarbox- ylic ester trans-Cyclobutane-l,2-dicar- boxylic ester cis-Cy clopentane-1,3-dicar- boxylic methyl ester Dicyclopentylacetyl chlo- ride a-Bromocyclopentylacetyl chloride ?-Bromodicyclopentylacetyl chloride Dihydrohydnocarpic acid Dihydrochaulmoogric acid cis-Cy clohexane-1,3-dicarbox- ylic methyl ester <ror?s-Cyclohexane-l,3-dicar- boxylic methyl ester frana-Cyclohexane-l ,4-dicar- boxylic methyl ester * Hydrazide 58% (210) 80% (323) Quantitative (323) 84% (324) 93% (325) ¡ª (325) 94% (11) Azide (Sd) (Sd) (Sd) (Sd) (Sd) 86% (11) Isocyanate Urethan 55% (323) 60% (323) -(324) 62% (325) 79% (325) 95% (11) Amine, etc. 26% (Ua) (210) Cyclo- butanone Quantitative (Ub) (323) Quantitative (Ub) (323) - (Ua) (324) 35% (la) (23) 30% (Ib) (23) Aldehyde 60% (Ib) (23) Ketone 76% (la), 43% (Z), - (L) (255) 43% (Z), - (la, L) (255) Quantitative (Ua) (325) Quantitative (Uai (325) 97% (Ua) (11) ? >1 3 O 1-Bromocyclohexanecarbonyl chloride Tetraacetylquinyl chloride 4,5-Isopropylidenequinic lac- tone l-0-Methyl-4,5-isopropyl- idenequinic lactone Dihydroshikimic methyl ester Decalin-x-carboxylic methyl ester Decalin-z-carbonyl chloride 2,5-Endomethylenecyclohex- anecarbonyl chloride ezo-2,5-Endomethylenecyclo- hexanecarbonyl chloride endo-2,5-Endomethylene- cyclohexanecarbonyl chlo- ride trans-3,6-Endomethylenecy- clohexane-l,2-dicarbonyl chloride 2,5-Endomethylenecyclohex- ane-1-acetyl chloride Adamantane-l,3-dicarboxylic methyl ester 13-Methyl-asym-octahydro- phenanthrene-9-carbonyl chloride 80% (82) 75% (82) 85% (258) -(29) ¡ª (326) 0% (17) (Sd) - 39% (Sw) (83) -(29) - (S) (29) (Sd) (Sd) (Sd) ¡ª (326) (Sd) (Sd) (Sd) 97% (83) * v- Acetoxyacet- anilide 78% (82) * Ke- tone 57% (82) * 72% (258) * -(29) Quant. (230) 57% (Ib) (23) Cyclo- hexanone 99% (la) (230) Quantitative (la) (326) Quantitative (la) (326) ¡ª (Ua?) (326) - (la) (326) - (la) (327). 68% (Ia)?231) > o References 268-454 appear on pp. 446-449. COMPOUNDS SUBJECTED TO THE CURTIUS REACTION¡ªContinued ALICTCLIC ACID DEMVATIVBS¡ªContinued Starting Material 13,14-Trimethyleneoctahy- drophenanthrene-9-car- bonyl chloride 9-Methyl-9,10-dihydrophe- nanthrene-10-carboxylic methyl ester 3-Methoxy-9,10-dihydrophe- nanthrene-9-carboxylic methyl ester 3,4-Methylenedioxy-9,10-di- hydrophenanthrene-9-car- boxylic methyl ester Desoxycholic ester Cholanic ester Cholic ester Hydnocarpic acid Chaulmoogric ester Chaulmoogryl chloride Chaulmoogric acid Bornylene-3-carboxylic ester Hydrazide -(330) ¡ª (331) - (331) - (261) ¡ª (328) - (329) 80% (10) 0% (27) Azide (Sd) ¡ª (331) -(331) ¡ª (261) ¡ª (328) -(329) (Sd) (Sd) (Sd) Isocyanate Urethan ¡ª (331) ¡ª (331)'* - (261) -(328) 50% (10) 90% (10) Amine, etc. - da) (231) ¡ª (Ua) (330) 9-Methyl- phenanthrene ¡ª (Ua) (331) 3-Meth- oxyphenanthrene - (L) (261) - (?) (328) 70% (la), 54% (Z), - (L) (255) 26% (Ua) (10) 78% (la), 45% (Z, L) (255) a I Borfiylene-3-carbonyl chloride Acetoxy-4wsnor-cholenyl chlo- ride 94% (27), - (26) (Sd) ¡ª (Sw) (234) -(234) 86% (Ua) (27), - (26) 93% (la) (28) Epicamphor - da) (234) ABYLALIPHATIC ACID DERIVATIVES Phenylacetic ester Phenylacetyl chloride (+)-ce-Phenylpropionic acid p-Chlorophenylacetic ester j>-Nitrophenylacetic ester 2,4-Dinitrophenylacetic ester 3,4-Dimethoxyphenylacetic ester O-Hydroxyphenylacetic lac- tone Mandelic ester 0-Phenylpropionic ester /S-Phenylpropionyl chloride /S-Phenylisobutyryl chloride d-jS-Phenylisobutyryl chloride Quantitative (266) 80% (213) Quantitative (213) ¡ª (332) ¡ª (333) ¡ª (349, 350) 97% (351) 97% (334), ¡ª(335) Good (266) (Sd) (Sd) - (213) Quantitative (213) ¡ª (38), 0% (350) - (351) Quantitative (334), -(335) (Sd) - (Sd) (342) 97% (Sd) (342) j -(38)* -(35) ¡ª (342) Good (266) ¡ª (213) ¡ª (213) ¡ª (351) Benzal- dehyde ¡ª (334, 335) 97% (343) * 83% (Ua) (266) 95% (la) (37) 68% (la) (254), 35% (la) (341) Quantitative (Ua) (213) 91% (Ua) (213) - db) (38) 91%(Ua)(334),¡ª Ua) (335) 96% (la) (342) References 268-464 appear on pp. 446-449. COMPOUNDS SUBJECTED TO THE CURTIUS REACTION¡ªContinued ABYLALIPHATIC Acm DERIVATIVES¡ªContinued ito Starting Material /}-Bromo-/3-phenylpropionic acid /}-Methoxy-/3-phenylpropionic methyl ester /3-o-Methoxyphenylpropionic methyl ester /5-p-Methoxyphenylpropionic methyl ester /J-wi-Benzyloxyphenylpropi- onic ester 0-3,4-Dimethoxyphenylpro- pionic methyl ester |S-3,4-Dimethoxyphenylpro- pionic ester l8-3-Benzyloxy-4-methoxy- phenylpropionic ester jS-3,4-Dibenzyloxyphenyl- propionic ester /3-2,3)4-Trimethoxyphenyl- propionic ester /J-2,4,5-Trimethoxyphenyl- propionic methyl ester Hydrazide ¡ª (336) Yields /S- phenylhydracryl- yl hydrazide 53% (337) Quantitative (205) 93% (338) 95% (181) Quantitative (453) 95% (181) Quantitative (181) 82% (206), ¡ª (179) ¡ª (339) ¡ª (338) - Azide 95% (337) Good (338) 90% (181) - (453) f 90% (181) - (246) Isocyanate - (246) Urethan 60% (337) -(205) Good (338) -(339) 59% (338) Amine, etc. 55% (Ua) (337) ¡ª (Z) (205) 94% (Ua) (338) - (Z) (181) - (Z) (181) 74% (Z) (246), ¡ª .(Z) (206) ¡ª (Ua) (339) Trihy- droxyphenylethyl- amine 68% (Ua) (338) I o I j9-3,4,5-Trimethoxyphenyl- propionic methyl ester /3-Hydroxy-j3-phenylpropionic ester 0-0-Hydroxyphenylpropionic lactone /3-Phenylisocaprolactone /3-Piperonylhydracrylyl hydra- zide o-Benzamido-/3-phenyIpro- pionic methyl ester a-Hippurylamino-/3-phenyl- propionic ester dt-Tyrosine ester 2-Tyrosine ester N-Benzoyltyrosine ester /3-1-Naphthylpropionic acid /8-2-Naphthylpropionic ester /3-2-(9,10-Dihydrophenan- thryl)-propionic methyl ester. (3-2-Phenanthrylpropionic ester /3-3-Phenanthrylpropionic ester /S-7-(2-Methoxy-9,10-dihydro- phenanthryl)-propionic methyl ester 60% (336), ¡ª (352) - (205) -(76) 94% (105) ¡ª (103) 94% (88) -(88) ¡ª (88) 90% (260) 88% (344) 85% (345) -(346) -(346) 90% (345) ¡ª (336, 352) - (76) - (103) 0% (88) 0% (88) ¡ª (88) * 98% (340) Quant. (6),* ¡ª (76, 352) * 0% (76) 76% (352) * 48% (340) t 8% (205) * 63% (105) ¡ª (88) 51% (260) -(344) Poor (346) Poor (346) 65% (Ua) (205) - (la) (352) 65% (C) (105) Quantitative (Ub) (260) - (Ub) (344) 75% (Ub) (345) 59% (Ub) (345) References 268-454 appear on pp. 446-449. t Converted to corydaldine in "poor" yield. t Yield based on isocyanate. WWa a CO COMPOUNDS SUBJECTED TO THE CURTIUS REACTION¡ªContinued ARYLAUPHATIC ACID DERIVATIVES¡ªContinued Starting Material a-Bromo-8-phenylvaleryl chloride a,i8,'>',S-Tetrabromo-5-phenyl- valeryl hydrazide Diphenylketene Dibenzylacetyl chloride Triphenylacetyl chloride Diphenylglycolic lactone o-Hydroxydiphenylacetic lac- tone p-Hydroxydiphenylacetic ester Desylglyoxalic ester Cinnamic ester Cinnamoyl chloride Allocinnamoyl chloride Hydrazide (114) f 41% (176) 63% (79) - (278) Quantitative (353) Yields diphenyl- pyrazolonecar- boxylic ester (354) 54% (22, 314) Azide ' (Sd) ¡ª (X) (110) Di- phenylmethyl- carbamyl azide 90% (Sw) (233). -(79) ¡ª (278) - 0% (22, 314) 12% (Sd) (18), ¡ª (Sd) (167) (Sd) (Sd) Isocyanate ¡ª (233) 0% (278) 72% (18), - (167) 77% (228) Urethan ¡ª (233) ¡ª (79) Benzo- phenone Poor (278) ¡ª (353) ¡ª (167) 98% (18) * 9% (18) * Amine, etc. 59% (Ib) (23) Aldehyde - (Ub) (278) - (Ib) (353) 1 2 o OT-Nitrocinnamic ester 0-Styrylacrylic eater Phenylpropiolyl chloride Benzalaceturic azlactone Benzalhippuric azlactone Benzalhippuric methyl ester p-Methylbenzalhippuric az- lactone p-Methylbenzalhippuric methyl ester o-Nitrobenzalhippuric azlac- tone m-Nitrobenzalhippuric azlac- _ tone 7re-Nitrobenzalhippuric methyl ester p-Nitrobenzalhippuric azlac- tone p-Nitrobenzalhippuric methyl ester p-Methoxy benzalhippuric azlactone p-Methoxy benzalhippuric methyl ester Benzylmalonic ester Ethyl potassium benzylmalo- nate 82% (24) ¡ª (114) 77% (188) 75% (188), ¡ª(191) - (191) ¡ª (191) - (191) - (191) - (191) ¡ª (191) - (191) - (191) ¡ª (190) -(190) 96% (42), ¡ª (288) 99% (46) 76% (348) 0% (Sd) (35) - (191) - (191) - (191) ¡ª (191) - (191)' -(190) 69% (348) 0% (191) 0% (191) 0% (191) 0% (191) 0% (191) 0% (190) 75% (42) 72% (46) Poor (Ua) (348) Alde- hyde 98% (Ua) (42) Phenyl- acetaldehyde 57% (Ua) (46) Phenyl- alanine 3 aI References 268¡ª454 appear on pp. 446-449. t Prepared from 0-styrylacrylyl faydrazide. en COMPOUNDS SUBJECTED TO THE CURTIUS REACTION¡ªContinued ARYLALIPHATIC ACID DERIVATIVES¡ªContinued Ci Starting Material Benzylcyanoacetic ester Ethyl potassium p-nitro- benzylmalonate p-Methoxy benzylcyanoacetic ester Phenylsuccinic ester m-Xylene-a-malonic ester Ethyl potassium m-xylene- a-malonate Benzylsuccinyl hydrazide (J-Phenylglutaric ester |8-Phenylglutaryl chloride /3-p-Methoxyphenylglutaric ester 2,3-Dimethoxyphenylglutaric ester Benzylmethylmalonic ester iS-Phenylethylmethylmalonic ester 2,4,6-Trimethylbenzyhnalonic ester Hydrazide 85% (139) 77% (47) 95% (139) 96% (303) 88% (347) 99% (47) - (65) f -(67) -(67) -(67) 73% (44), Poor (290) 60% (44) Good (44) Azide Quantitative (47) ¡ª (347^ ¡ª (65) (Sd) Isocyanate (303) 61% (47) * t Urethan - (347) 98% (67) - (67) -(67) Amine, etc. 50% (Ua) (194) Phenyl- alanine ¡ª (la) (47) Amino acid 30% (Ua) (139) Amino acid 36% (Ua) (303) ¡ª (Ua) (347) Aldehyde 88% (la) (47) Amino acid 43% (Ua) (67) ? 48% (la) (228) ¡ª (Ua) (67) p-Hydroxy- diamine ¡ª (Ua) (67) dihydroxy- diamine 20% (Ua) (44) Phenyl- acetone 47% (Ua) (44) Benzyl- acetone ca. 25% (Ua) (44) Alde- hyde 1 o i 02 bis(2,4,6-Trimethylbenzyl)- malonic ester bis(jJ-Nitrobenzyl)-nialonic ester l-Phenylpropane-2,2,3-tricar- boxylic ester 0% (44) 0% (47) 67% (65) Mixed pri-sec-hydrazide 90% (65) - (65) ? -(65) AROMATIC ACID DERIVATIVES Benzoic acid Benzoyl chloride Benzoie ester Benzamide o-Toluic ester m-Toluic ester p-Toluyl azide p-Toluyl chloride p-Toluic ester ¡ª (186) Quantitative (10), -(184) 90% (184), 75% (355), - (269) Good (184) 81% (356) Quantitative (356) ¡ª (186) Quantitative (356) 57% (Sw) (238), Quantitative (233) (Sd) (Sd) 79% (355), ¡ª (284) ¡ª (78) Phenylcar- bamylbenzhy- drazide ¡ª (Sw) (132) ¡ª (14, 352) 93% (352), 87% (6), 73% (355) ¡ª (132) ¡ª (238) * - (284), - (41, 239, 244, 268) * 69% (la) (228) ¡ª (Ua) (284) 98% (Ua) (41) 9 References 268-454 appear on pp. 446-449. t Prepared from l-phenylpropane-2,2,3-tricarboxylic ester. COMPOUNDS SUBJECTED TO THE CURTIUS REACTION¡ªContinued AROMATIC ACID DERIVATIVES¡ªContinued oo Starting Material Phthalyl chloride Phthalic ester Isophthalyl chloride Isophthalic ester Terephthalic ester Hemimellitic ester Trimesic ester o-Fluorobenzamide wi-Chlorobenzoic ester p-Chlorobenzoic ester o-Bromobenzoic ester m-Bromobenzoyl chloride m-Bromobenzoie ester Hydrazide 0% (54) 0% (54, 287) -(54) 70% (54), - (287) ¡ª (54) Ester hy- drazide Quantitative (39) Mixed prisec- hydrazide -(39) 80% (359)' 97% (360), - (361). ¡ª (123) ¡ª (125, 364) 98% (208), 90% (365) Azide ¡ª (Sw) (357) Isa- toyl diazide ¡ª (Sw) (38) Good (54) ¡ª (54) Ester azide -(39) -(39) ¡ª (359) Quantitative (360), ¡ª (362) ¡ª (363) (Sd) Quantitative (208), 95% (366) Isocyanate ¡ª (38) o-Iso- cyanatobenza- zide ¡ª (38) Diiso- cyanate -(358) Urethan 70% (357) -(54) 40% (39) * -(39) ¡ª (359) * ¡ª (360) Amine, etc. 50% (Ub) (357) o-Phen- yleneurea - (Ua) (54) 54% (Ua) (39) o-Amino- phthalhydrazide ¡ª (Ua) (39) 3,5-Dicar- bethoxyaminoaniline and phloroglucinol ¡ª (U) (359) ¡ª (Ua) (360) 90% (Ib) (126) 92% (Ua) (208) I 1 0Q p-Bromobenzoic acid p-Bromobenzoic ester 2,6-Dibromobenzoyl chloride 2,6-Dibromobenzoic ester 2,6-Dibromo-4-methylbenzoyl chloride 2,6-Dibromo-4-methylbenzoic ester 2,4,6-Tribromobenzoyl chlo- ride 2,4,6-Tribromobenzoic ester o-Iodobenzoic ester p-Iodobenzoic ester o-Nitrobenzoyl chloride o-Nitrobenzoic ester m-Nitrobenzoyl chloride ro-Nitrobenzoic ester p-Nitrobenzoyl chloride p-Nitrobenzoic ester 2-Nitrc-6-carbomethoxy ben- zoic acid 2,4-Dinitrobenzoyl chloride 2,4-Dinitrobenzoic ester - (186) 93% (123), ¡ª (208), 89% (367) ¡ª (183) 0% (183) -(183) 0% (183) ¡ª (183) 0% (183) 0% (123) 90% (359) Quantitative (136), 96% (371), ¡ª (135) Quantitative (135), - (136) Quant. (136), 88% (373), - (135) ¡ª (48) Hydrazide acid Yields 2-nitro-4- aminobenzoic ester (137) 90% (368), ¡ª (208) ¡ª (370) - (Sw) (132) 94% (371), - (125, 284) Quant. (Sw) (126) 90% (130), ¡ª (125, 284, 372) - (Sw) (126) 85% (374), ¡ª (125, 284) -(48) 91% (Sw) (132) - (132) Quantitative (6) Quant. (126) Quant. (358), ¡ª (372) - (126) 90% (371) - (48) * 82% (132) - (208), ¡ª (368) * - (370) ¡ª (284, 371) ¡ª (125, 284) Quant. (374), ¡ª (125, 284) ¡ª (132) 72% (Ua) (208) ¡ª (Ua) (183) ¡ª (Ua) (183) - (Ua) (183) ¡ª (Ua) (284) ¡ª (Ua) (125, 284) 94% (Ib) (126) ¡ª (Ua) (125, 284) - (I) (48) aI a H S References 268-454 appear on pp. 446-449. Ito COMPOUNDS SUBJECTED TO THE CURTIUS REACTION¡ªContinued AROMATIC ACID DERIVATIVES¡ªContinued 8- Starting Material Hydrazide Azide Isocyanate Urethan Amine, etc. 3,5-Dinitrobenzoyl chloride 3,5-Dinitrobenzoic ester 3,5-Dinitro-4-methylbenzoic methyl ester 2,4,6-Trinitrobenzoyl chloride 2-Chloro-3,5-dinitrobenzoyl chloride 4-Chloro-3,5-dinitrobenzoyl chloride 2-Chloro-4-methyl-3,5-dinitro- benzoyl chloride 2-Bromo-3,5-dinitrobenzoyl chloride 4-Bromo-3,5-dinitrobenzoyl chloride 2-Bromo-4-methyl-3,5-dini- trobenzoyl chloride o-Methoxybenzazide m-Methoxybenzoyl chloride Anisoyl chloride Anisic ester 69%(89),64%(131) 70% (375) 0% (5) - (377) 95% (378), 75% (135) - (Sw) (129), - (Sd) (126) 99% (131), ¡ª (89) 90% (375) 82% (Sw) (132), 40% (Sw) (376) - (Sw) (129) - (Sw) (5, 129) - (Sw) (133) - (Sw) (129) - (Sw) (129) - (Sw) (133) ¡ª (Sw) (132) ¡ª (Sw) (132) 95% (378), 75% (379), ¡ª (140) ¡ª (126) ¡ª (131) ¡ª (132, 376) -(358) - (132) ¡ª (132) 80% (379) Quantitative (89) ¡ª (375) ¡ª (132) ¡ª (129) ¡ª (129) ¡ª (129) ¡ª (129) ¡ª (133) ¡ª (132) * - (132) 85% (378),* - (140) - (Z) (129) 97% (la) (126) - (Ua) (89) (Z) (129) (Z) (5) (Z) (133) (Z) (129) (Z) (129) (Z) (133) I O I jpJDthoxybenzoic ester . Yeratrie methyl ester 3,5-Bimethoxybenzoic methyl ' ester 3,4,5-Trimethoxybenzoic methyl ester 3,4,5-Trimethoxybenzoic ester Hemipinic a-monomethyl ester Hemipinic /3-monomethyl ester o-Carbethoxyphenoxyacetic ester O-(N-Phenylcarbamyl- methyl)-salicylyl azide. O-Acetylsalicylyl chloride O-Acetyl-3,5-dibromosancyryl chloride Salicylic ester Salicylic methyl ester m-HydroxybeDzoic ester 95% (378), 89% (225) 93% (279) 50% (380) ¡ª (332) ¡ª (381) 33% (382) (Dihy- drazide, 3%) (382) Hydrazide acid 26% (382) Dihy- drazide 95% (58) Dihydra- zide ¡ª (58) o-Carbeth- oxyhydrazide 86% (383), 73% (135), ¡ª (123, 125) ¡ª (125) ¡ª (125) 95% (378) 74% (379) 84% (380) - (381) -(58) -(58) (58) t ¡ª (Sw) (226) 96% (Sw) (226) 78% (383), ¡ª (125) ¡ª (125) 81% (225) Quant. (379) * ? ¡ª (58) ¡ª (226) ¡ª (226) ¡ª (358) * ¡ª (358) * 85% (378) * Quant. (225) ¡ª (379) ¡ª (380) ¡ª (58) -(58) 90% (58) ¡ª (226) ¡ª (226) - (125) * ¡ª (125) * ¡ª (Ua) (225) p-Amino- phenol 0% (Ua) (58) - 0% (Ua) (58) ¡ª (Ua) (58) Benzomor- pholone ¡ª (Ua, Z) (226) fel I 00 References 268-454 appear on pp. 446-449. t Prepared from the preceding diazide. to COMPOUNDS SUBJECTED TO THE CURTIUS REACTION¡ªContinued AROMATIC ACID DERIVATIVES¡ªContinued to Starting Material p-Hydroxybenzoic ester 2-Hydroxy-3,5-dibromoben- zoyl chloride 3-Nitro-5-hydroxybenzazide Gallic ester Phthalide a-Methylphthalide a,a-Dimethylphthalide a-Ethylphthalide a,ot-Diethylphthalide ct-Phenylphthalide a,a-DiphenylphthaIide 6-Nitrophthalide 5-Nitro-ot-methylphthalide 5-Nitro-a,oe-dimethylphthal- ide 5-Nitrc-a-ethylphthalide 5-Nitro-a,a-diethylphthalide 6-Chlorophthalide 6-Bromophthalide 5-Chloro-a-methylphthalide 5-Bromo-oe-metliylphthalide S^Chloro-a-ethylphthalide Hydrazide - (125) - (123) ¡ª (38, 287, 350) 0% (384) 0% (384) 0% (384) 0% (384) 0% (384) 0% (384) ¡ª (287, 384) ¡ª (384) 0% (384) 0%(384) 0% (384) ¡ª (384) ¡ª (384) ¡ª (384) -(384) 0% (384) Azide Quantitative (125) - (Sw) (226) (89) t ¡ª (38), 0% (350) Isocyanate ¡ª (358) * ¡ª (226) * ¡ª (38)* Urethan - (125) * -(89) Amine, etc. - (Ub) (89) ¡ª (Ib) (38) I o i CO 5-Bromo-a-ethylphthalide 5,6-Dimethoxyphthalide 3-Nitro-5,6-dimethoxy- phthalide Anthranilic ester Isatoic acid Isatoyl diazide N-Acetylanthranilic ester N-Acetylanthranilic amide N-Acetylanthranilic aziac- tone' N-Oxalylanthranilic aziactone N-Malonylanthranilic aziac- tone N-Anthranilylanthranilic aziactone N'-Acetyl-N-anthranilylan- thranilic aziactone m-Aminobenzoic ester p-Aminobenzoic ester N-Methylanthranilic methyl ester 0% (384) ¡ª (287) Yields 3-nitro-5- methoxy-6-hy- drazinophtbalide (287) 80% (135) 75% (90) Anthra- nilyl hydrazide 0% (385, 386) 0% (385) - (385) ¡ª (385) -(385) -(188) 82% (188) - (125) Good (88) 70% (386) 65% (189), 0% (90) - (357) t -(385) - (125) 80% (189), - (125) - (125) * 60% (357) 0% CUb) (357) - (la) (125) o cj § 3 o References 268-454 appear on pp. 446-449. t Prepared from 3-nitro-5-aminobenzhydrazide. t Prepared from phthalyl chloride. COMPOUNDS SUBJECTED TO THE CURTIUS REACTION¡ªContinued AROMATIC ACID DERIVATIVES¡ªContinued Starting Material N-Methyl-N-acetylanthra- nilyl hydrazide o-Carbethoxyphenylglycine ester N-(N'-Phenylcarbamyl- methyl)-anthranilyl azide N,N-Dimethylanthranilic methyl ester 6-Nitroisatoic acid 2-Nitro-4-aminobenzoic ester 3,Nitro-5-aminobenzhydra- zide 3,5-Dinitro-4-anilinobenzoyl chloride 5-Aminophthalide 3-Amino-5,6-dimethoxy- phthalide 5-Amino-a-methylphthalide 5-Amino-a,a-dimethyl- phthalide 5-Aminc-4,6-dibromc-a,o:-di- methylphthalide Hydrazide (386) f 90% (58) ¡ª (58) o-Carbeth- oxy hydrazide ¡ª (88) - (387) 70% (137) (89)§ ¡ª (287, 384) - (287) 0% (384) 0% (384) 9% (384) Azide 80% (58) -(58) (58) t -(88) - (387) - (137) ¡ª (89) 3-Nitro-5- hydroxybenza- zide - (Sw) (5) Isocyanate ? Urethan -(58) -(58) - (58) * -(88) ¡ª (137) -(5)* Amine, etc. 0% (Ua) (58) 0% (Ua) (58) - (Ub) (137) > 5-Amino-a,a-diethylphthalide 5-Amino-4,6-dibromo-a,a-di- ethylphthalide Azobenzene-m-carbonyl chlo- ride Azobenzene-p-carbonyl chlo- ride o-Sulfamylbenzoic ester Saccharin Biphenyl-p-carbonyl chloride Biphenyl-p-earboxylic ester d and Z-6-Nitro-2-methylbi- phenyl-2'-carbonyl chloride" Diphcnic anhydride Diphenic ester I and dJ-6,6'-Dimethylbiphen- yl-2,2'-dicarbonyl chloride 4-Nitrodiphenic methyl ester 4-Nitrodiphenic anhydride 6-Nitrodiphenic methyl ester 0% (384) 0% (384) 85% (141) 20% (141) o-Sul- famylbenzhydra- zide 0% (176) 90% (176) ¡ª (52) Diphenic hydrazidic acid 55% (66), - (52) 45% (53), - (388) 90% (53) Hydra- zidic acid 85% (388) 90% (Sw) (126) Good (Sw) (37) Quantitative (141) (Sd) ¡ª (66r -(66) ¡ª (66, 388) Hy- drazide azide (Sd) -(53) Good (37) 57% (142) * Good (37) - (142) ¡ª (66) Phenan- thridone -(66) ¡ª (66, 388) Phe- nanthridone ¡ª (53) 7-Nitro- phenanthri- done Quantitative (Ib) (126) - (Ib) (251) - (Ub) (66), - (la, Ub) (388) - (Ib) (251) References 268-454 appear on pp. 446-449. t Prepared from N-methylanthranilyl hydrazide. % Prepared from the preceding diaxide. S Prepared from 3,5-dinitrobenzoic ester. s CO o to C COMPOUNDS SUBJECTED TO THE CURTIUS REACTION¡ªContinued AROMATIC ACID DERIVATIVES¡ªContinued Starting Material l-2,2'-Dimethoxy-6,6'-dicar- bomethoxybiphenyl ct-Naphthoyl chloride (?) /3-Naphthoic ester /8-Naphthoic methyl ester /J-Naphthoyl chloride 4-Methyl-l-naphthoic ester 2-Methyl-l-naphthoic ester 2-Methyl-l-naphthoyl chlo- ride 5,8-Dichloro-2-naphthoic methyl ester 5-Bromo-2-naphthoic methyl ester 5,8-Dibromo-2-naphthoic ester 3-Iodo-2-naphthoyl chloride 3-Iodo-2-naphthoic ester 3-Methoxy-2-naphthoic methyl ester 3-Hydroxy-2-naphthoic ester 3-Amino-2-naphthoic ester Hydrazide ¡ª (389) - (377) 75% (365) 90% (121) - (121) ¡ª (260) 0% (260) ¡ª (260) 85% (248) Quantitative (202) Quantitative (202) 55% (121) Yields /8-naphthoyl hydrazide (121) 94% (259) - (391) ¡ª (91) Azide 94% (390), - (256) 98% (248) Quantitative (202) Quantitative (202) 85% (121) 70% (168) Isocyanate -(202) 90% (168) * Urethan Quant. (390), -(256) ¡ª (260) ¡ª (260) 80% (248) ¡ª (202) 85% (202) - (121) 72% (259) 85% (168) Amine, etc. ¡ª (Ub) (260) ¡ª (Ub) (260) - (Z) (248) ¡ª (Z) (202) 90% (Z) (202) 85% (Z) (121) 93% (Ub), 85% (L) (259), Quant. (Ua) (259) Hydroxy amine 70% (Ua), 65% (Ib) (168) 1 o 3-Carboxyamino-2-naphthoic anhydride 3-Acetylamino-2-naphthoic azlactone 3-Phenanthroic methyl ester 9-Phenanthroic ester 3-Methoxy-6-phenanthroic ester 3-Methoxy-9-phenanthroic ester 3-Methoxy-9-phenanthroic ester 3,4-Dimethoxy-8-phenan- throic acid? 3,4-Dimethoxy-9-phenan- throic ester 2,3,4,5-Tetramethoxy-9-phe- nanthroic methyl ester 2,3,4,6-Tetramethoxy-9-phe- nanthroic methyl ester 2,3,4,6-Tetramethoxy-9-phe- nanthroic ester 2,3,4,7-Tetramethoxy-9-phe- nanthroic methyl ester Fluoranthene-4-carboxylic ester Fluoranthene-12-carboxylic ester Pyrene-4-carbonyl chloride -(91) 88% (91) 77% (37) 90% (203) 83% (392) 98% (392) ¡ª (392) - (197) 81% (393) ¡ª (332) -(332) 76% (198) ¡ª (332) -(394) -(394) 93% (204) 0% (91) -(91) Quantitative (203) Good (393) 77% (198) ¡ª (394) Quantitative (394) - (91) * 80% (203) 40% (392) 88% (392) 90% (392) 80% (197) 80% (393) ? 82% (198) ¡ª (394) 95% (394) ¡ª (Ua) (203) 9-Phe- nanthrol 80% (Z) (203) - (Z) (392) - (Z) (392) 65% (Z) (392) 90% (Z) (197) ¡ª (Ub) (393) 95% (Ub) (198) ¡ª (Ua) (394) Quantitative (Ua) (394) 68% (Z) (204) I 00 to References 268-454 appear on pp. 446-149. COMPOUNDS SUBJECTED TO THE CURTIUS REACTION¡ªContinued AROMATIC ACID DERIVATIVES¡ªContinued HETEEOCTCLIC ACID DERIVATIVES tooo Starting Material Pyrene-3,8-dicarbonyl chlo- ride Pyrene-3,10-dicarbonyl chlo- ride 3,4-Benzpyrene-lO-carboxylic methyl ester Hydrazide -(204) -(204) - (182) Azide - (182) Isocyanate Urethan Amine, etc. (Z) (204) - (Z) (204) ¡ª (Z) (182) Ethyleneimine-2,3-dicarbox- ylic anhydride (?) N-Carbamylethyleneimine- 2,3-dicarboxylic ester (?) Succinimide-N-acetic ester 2,4-Dimethylpyrrole-5-acetic ester 2,4-Dimethylpyrrole-3-j8- propionic methyl ester 2-Phenylpyrrole-5-j3-propionic ester l-Methyl-2-phenylpyrrole- 5-/S-propionic methyl ester 40% (395) Mono- hydrazide ¡ª (395) Yields succinhy- drazidylglycyl hydrazide (57) Quantitative (62) -(60) 80% (150), ¡ª (396) 84% (397) 75% (395) ¡ª (395) 0% (60) 85% (397) 0% (395) ¡ª (150) Poor (Ub) (150) 57% (Ub) (398) 1> s 3s l,5-Diphenylpyrrole-2-jS- propionic ester 2,4-Dimethyl-5-carbethoxy- pyrrole-3-/3-propionic acid 2,4-Dimethyl-5-carbethoxy- pyrrole-3-/3-propionic methyl ester 2,4-Dimethyl-3-03-methyl- malonic ester)-pyrrole-5- carboxylic ester 2,4-Dimethyl-3-(/3-cyano-/3- carbethoxyethyl)-pyrrole- 5-carboxylic ester 5-Carbethoxypyrrole-3-/S- acrylic ester 2,4-Dimethyl-5-carbethoxy- pyrrole-3-iS-acrylic methyl ester 2,4JDimethyl-5-carbethoxy- j}yrrole-3-/3-acrylic acid 2-Chloromethyl-4-methyl-5- carbethoxypyrrole-3-acrylyl azide 2-p-Anisylpyrrole-5-/3-propi- onic ester 2-Methoxymethyl-4-methyl- 5-carbethoxypyrrole-3- acrylyl azide 97% (397), - (452) 67% (399) Dihy- drazide Quantitative (60) Monohydrazide 90% (61) Aliphat- ic dihydrazide 90% (61) Aliphatic monohydrazide 35% (59) Aliphatic monohydrazide ¡ª (60) Hydrazide acid Quantitative (150) 92% (397) ' -(60) 70% (61) 150% (61) 33% (60) Aliphatic monoazide t 63% (59) -(60) (59) t 0% (150) (59) t - (60) * ? ¡ª (60) 72% (61) 72% (61) Poor (60) 38% (59) 59% (Ub) (398) - (Ua) (60) SS References 268-154 appear on pp. 446-149. f Prepared from the 2-methyl azide. J Prepared from the 2-chloromethyl azide. CD COMPOUNDS SUBJECTED TO THE CURTIUS REACTION¡ªContinued HETEBOCTOUC ACID DERIVATIVES¡ªContinued CO o Starting Material 3-Methyl-4-hydroxypyrrole- 4-/?-propionic methyl ester 4-Methyl-5-hydroxypyrrole- 3-(3-propionic methyl ester Pyrrole-2-carboxylic methyl ester 2,4-Dimethylpyrrole-3-car- boxylic ester 2,4-Dimethylpyrrole-5-car- boxylic ester 2,3,4-Trimethylpyrrole-5- carboxylic ester 2,3,5-Trimethylpyrrole-4-car- boxylic ester 2,4-Dimethyl-3-ethylpyrrole- 5-carboxylic ester 2,3-Dimethyl-4-ethylpyrrole- 5-carboxylic ester 2-Methyl-3,4-diethylpyrrole- 1-carboxylic ester 2-Methyl-3,4-diethylpyrrole- 5-carboxylic ester Hydrazide 72% (400) 93% (400) Quantitative (95) -(60) 98% (60) 86% (49) Poor (399) 97% (60) 87% (201) Yields 2-methyl- 3,4-diethylpyr- role-5-carbonyl hydrazide (93) 80% (93) Azide 80% (400) 80% (400) 61% (95) 0% (60) Quantitative (60), - (62) 55% (49) 87% (399) 84% (60) ¡ª (201) 81% (93) Isocyanate Urethan ¡ª (400) -(400) -(95) -(60)* 42% (49) * 46% (60),* - (399) * Quant. (93),* -T49) * Amine, etc. - (Ua), 0% (Ub) (95) 16% (Z) (60) - (Z) (93) - (Z), 0% (C) (93) I 2,4-Dimethyl-3-vinylpyrrole- 5-carboxylic ester 2,4-DimethylpyrTole-3,5-di- carboxylic ester 2,4-Pimethylpyrrole-3-car- boxylic ester-5-carboxylic acid 2,4-Dimethylpyrrole-3-car- boxylic acid-5-carboxylic ester 2,4-Dimethyl-3-cyanopyrrole- 5-carboxylic ester 2-Carbethoxy-3-ethyl-4-meth- ylpyrrole-5-carbonyl azide 2-Methyl-4-ethylpyrrole-2,5- dicarboxylic ester 2,4-Dimethyl-3-bromopyr- roJe-5-carbonyl azide 2-Carbomethoxy-3-bromo-4- methylpyrrole-5-carbonyl azide 2-Formyl-3-bromo-4-methyl- pyrrole-5-carbonyl azide Yields 2,4-dimeth- ylpyrrole-5-car- bonyl hydrazide (60) Quantitative (62), - (60), 0% (94) ¡ª (62) 6-Monohy- drazide 0% (62) Yields 2,4-dimeth- ylpyrrole-5-car- bonyl hydrazide (62) 86% (49) Quantitative (92) 82% (62) Quantitative (62) 52% (49) (201) t Good (92) (62) t (62) § (62) |[ - (201) * Quant. (62) 59% (49) - (201) 0% (92) 66% (62) * 93% (62) - (Z), 0% (la) (201) 94% (62) References 268-454 appear on pp. 446-449. t Prepared from the 2-methyl azide. X Prepared from the 3-acetyl azide. § Prepared from the 2-trichlorometliyl azide. || Prepared from the 2-dicbloromethyl azide. 1 COMPOUNDS SUBJECTED TO THE CURTIUS REACTION¡ªContinued HBTEROCYCLIC ACID DERIVATIVES¡ªContinued CO to Starting Material 2-Cliloromethyl-3,4-dimethyl- pyrrole-5-carbonyl azide 2-Chloromethyl-3-ethyl-4- methylpyrrole-5-carbonyl azide 2-Bromomethyl-4-methyl- pyrrole-5-carbonyl hydra- zide 2-Bromomethyl-3-ethyl-4- methylpyrrole-5-carbonyl azide 2-Dichloromethyl-3,4-dimeth- ylpyrrole-5-carbonyl azide 2-Dichloromethyl-3-ethyl-4- methylpyrrole-5-carbonyl azide 2-Dichloromethyl-3,4-diethyl- pyrrole^5-carbonyl azide 3,4-Dichloropyrrole-2,5-dicar- boxylio acid 3,4-Dichloropyrrole-2-car- bonyl chloride-5-carboxylic - ester Hydrazide Quantitative (49) 94% (49) Monohy- drazide Azide (49) f (60) f - (60) % (60) § (49) § ? (60) § (93) § 52% (49) 44% (49), 72% (Sw) (49) Isocyanate Urethan 57% (49) Amine, etc. ? I 2 Q0 2-Dichloromethyl-3-bromo-4- methylpyrrole-5-carbonyl azide 2-Trichloromethyl-3-bromo- 4-methylpyrrole-5-carbonyl- azide 2-Methoxymethyl-3-ethyl-4- methylpyrrole-5-carbonyl azide 2-Methoxymethyl-3,4-di- ethyIpyrrole-5-carbonyl azide 2-Hydroxy-5-methylpyrrole- 4-carboxylic ester 2-Hydroxy-3,5-dimethylpyr- role-4-carboxylic ester 2,4-Dimethyl-3-formylpyr- role-5-carbonyl azide 2-Fonnyl-3-ethyl-4-methyl- pyrrole-5-carbonyl azide 2-Formyl-3-methyl-4-ethyl- pyrrole-5-carbonyl azide 2-Formyl-3,4-diethylpyrrole- 6-carbonyl azide * 55% (94) 67% (94) (62) § (62) || (60) H (93)1 ? 41% (94) 81% (94) (60, 62) ft (60, 399) ? (201) tt (93) tt ¡ª (94) -(94) Quant. (62) 58% (399), ¡ª (201) 79% (201) 72% (93) 0% (Ub) (94) 0% (Ub) (94) 58% (C), 0% (Ua) (62) a 5 3 References 268-454 appear on pp. 446-449. t Prepared from the 2-methyl azide. X Prepared from the 2-methyl hydrazide. § Prepared from the 2-methyl azide. || Prepared from the 2-methyl azide. IT Prepared from the 2-chloromethyl azide. tt Prepared from 2,4-dimethylpyrrole-5-carbonyl aside. XX Prepared from the 2-dichloromethyl azide. COMPOUNDS SUBJECTED TO THE CURTIUS REACTION¡ªContinued HETEKOCTCLIC ACID DERIVATTVES¡ªContinued Starting Material ? 2,4-Dimethyl-3-acetylpyrrole- 6-carboxylic ester 2,4-Dimethyl-5-carbethoxy- pyrrole-3-ethanoneoxalic ester 4,4'-Dimethyl-3,3'-diethyl- 5,5'-dicarbethoxypyrro- methene ? - 3,3',5,5'-Tetramethyl-4,4'-di- j3-propionic ester pyrro- methene 4,4'-Dimethyl-3,3'-di-/3-meth- ylmalonic ester-6,5'-dicar- bethoxypyrromethene Iso-uroporphyrin octamethyl ester 6-Bromopyrroporphyrin ester Indole-3-/3-propionic ester Indole-2-carboxylic methyl ester 5,7-Dinitroindole-2-carbox- ylic methyl ester Hydrazide 80% (62) Hydra- zide hydrazone 0% (94) -(60) - (60) 89% (61) 88% (61) Quantitative (401) Quantitative (216) ¡ª (95) 80% (402) Azide 81% (62) Ketone azide -(61) 75% (61) - (216) ¡ª (95) Quantitative (402) Isoeyanate ¡ª (62) * / t 77% (216),* ¡ª (264)* Urethan ' Quant. (62) * -(61) -(264) -(95) 63% (402) Amine, etc. - (C) (62) * ¡ª (P) (263, 264) 0% (Ua, Ub) (95) 1 o o O-Ethyldinitrostrycholcar- boxylic ester Dinitrostrychnic ester Dinitroisostrychnic ester 3,5,7-Trjnitroindole-2-carbox- ylic methyl ester Carbazole-9-acetic ester Dihydrobrucininic ester Brucinonic oxime methyl ester Tetrahydrofuran-2-/9-propi- ionic ester Tetrahydrofuran-2-w-pentanol- 3,4-dicarboxylic ester Furan-2-j3-propionic ester 2-Phenylfuran-5-/3-propionic ester 2-p-Anisylfuran-5-j8-propionic ester 3,4-Dicarbomethoxyfuran- 2-acetic methyl ester 2-Furoyl chloride 2-Furoic ester 3-Puroic ester Quantitative (403) -(404) ¡ª (404) -(402) ¡ª (405) 95% (85) 88% (406) ¡ª (262) -(407) ¡ª (262) Quantitative (150) -(150) -(408) ¡ª (215, 409, 410) 75% (240) ¡ª (403) ¡ª (404) ¡ª (402) ¡ª (405) 68% (85) ¡ª (406) ¡ª (262) 92% (Sw) (241) (Sd) 66% (410), ¡ª (215, 409) ¡ª (240) 75% (247), 73% (241) Poor (214) -(240) 48% (403) - (404) -(402) ¡ª (405) 43% (85) Iso- brucinolone -(406) ¡ª (262) ¡ª (407) ¡ª (262) 90% (150) -(150) Quant. (409), Poor (215), - (410) ¡ª (L) (262) ¡ª' (Ub) (407) - (L) (262) 60% (Ub) (150) Poor (Ub) (150) 89% (Z) (241) 0% (Ua, Ub) (215, 409), 0% (L) (410) 95 3 References 268-454 appear on pp. 446-449. COMPOUNDS SUBJECTED TO THE CURTIUS REACTION¡ªContinued HETEROCYCMC ACID DEMVATIVES¡ªContinued Starting Material 5-Methyl-2-furoyl chloride 5-Methyl-2-furoic ester 2-Methyl-3-furoic ester 2,4-Dimethyl-3-furoic ester 2,5-Dimethyl-3-furoic ester Furan-3,4-dicarbonyl chlo- ride 2-Methylfuran-3,4-dicarbox- ylic ester 2-Methylfnran-3,4-dicarbonyl chloride 2-(<tf-Acetoxyamyl)furan-3,4- dicarbonyl chloride Furan-2-u-valeryl piperidide- 3,4-dicarbonyl chloride 5-Bromo-2-furoic ester 3,4-Dihydroxyfuran-2,5-di- carboxylic methyl ester Benzodihydrofuran-2-carbox- ylic ester Benzofuran-2-carboxylic ester Hydrazide - (214) 93% (247), 91% (240), ¡ª (214) - (214) 95% (247), - (214) 0% (232) - (214) 91% (412) Good (413) - (414) Azide (Sd) - (215) 95% (247), - (214, 240) - (214) 96% (247), ¡ª (214) Quant. (Sw) (411) (Sw) (Sw) (Sw) - (214) 60% (412) 75% (413) - (414) Isocyanate 35% (214) ¡ª (214, 240, 247) - (214) - (214) 57% (232) - (214) - (412) * Quant. (358) Urethan - (214) ¡ª (214, 247) - (214) ¡ª (214) Good (411) 77% (232) 46% (232) - (214) Poor (412) 88% (413) - (414) Amine, etc. 73% (Z) (247), - (240) 80% (Z) (247) 0% (Ua, Ub) (413) 0% (Ua, Ub) (414) I a to 9 S Tetrahydrodibenzofuran- 3-y-n-butyric ester Dibenzofuran-3-7-n-butyric ester Dibenzofuran-3-7-(7-oxobu- tyric acid) cis-Tetrahydrothiophene-2,5- dicarboxylic ester Tetrahydrothiophene-3,4-di- carboxylic ester 2-Phenylthiophene-5-jS-propi- onic methyl ester 2-p-Anisylthiophene"-5-/3-pro- pionic methyl ester o-(ot-Thienylthio)-benzoyl chloride Thiophene-2-carboxylic ester 3-Benzamido-4-carbethoxy- thiophene-2-w-valeryl azide Biotin ester Pyrazolinedicarboxylic ester Pyrazoline-3,4,5-tricarboxylic ester Pyrazole-3-carboxylic es- ter (?) Pyrazole-3,5-dicarboxylic es- ter (?) References 268-154 appear on pp. ¡ª (415) ¡ª (415) 0% (415) Yields a pyrazone 23% (145) 11% (147) Quantitative (150) Quantitative (150) 65% (144) 91% <149) 91% (148) Mono- - hydrazide ¡ª (146) 86% (416) -(39) ¡ª (39) Mixed pri- seo-hydrazide ¡ª (415a) ¡ª (415a) 146-449. - (144) (Sd) 93% (149) 93% (148) - (146) -(39) -(39) ¡ª (415a) ¡ª (415a) ? 77% (144), 5% (144) - (415) 66% (415) 53% (145) 88% (147) - (150) 80% (150) 60% (149) 95% (148) ¡ª (146) -(39) ¡ª(415a) ¡ª (415a) - (Ub) (415) 77% (Ub) (415) 0% (Ua) (145) 58% (Ua) (147) 60% (Ub) (150) g 60% (Ub) (150) O c! a0% (Ua) (149) ? 58% (U) (148) g ¡ª (Ub) (146) Triamine 8 O 0% (Ua) (39) * ¡ª (Ua, Ub) (415a) ¡ª (Ub) (415a) 43 7 COMPOUNDS SUBJECTED TO THE CURTIUS REACTION¡ªContinued HETEKOCYCLIC ACID DERIVATIVES¡ªContinued oo Starting Material Pyrazole-3,4,5-tricarboxylic ester ? 4-Isonitrosopyrazolone- 3-carboxylic ester Imidazole-5-acetic ester Imidazole-4-(3-propiouic ester Imidazole-4-carboxylic ester Imidazolone-4,5-dicarbonyl hydrazide Isoxazole-5-carboxamide5-Methylisoxazole-3-carbox- ylic methyl ester 4-Methylthiazole-5-acetic ester bis (2-Phenylthiazolyl-4- methyl) acetic ester 2-Phenylthiazole-4-j3-propi- onic ester 2-p-Anisylthiazole-4-/S-propi- onic ester 2-(3,4-Dimethoxyphenyl)- thiazole-4-#-propionic ester Hydrazide -(39) ¡ª (39) Mixed pri- sec-hydrazide ¡ª (87) Hydrazone hydrazide 80% (195) ¡ª (196) Quantitative (417) (395) f 84% (418) , 80% (418) 81% (151) 75% (152) 80% (152) 95% (153) 94% (153) Azide -(39) 67% (39) Quantitative (417) 49% (418) Quantitative (418) 80% (152) 90% (152) 94% (153) 90% (153) Isocyanate 85% (152) * ? Urethan -(39) 77% (39) 50% (417) 53% (418) 83% (418) 70% (152) 66% (F) (152) 97% (153) * 90% (153) * Amine, etc. 0% (Ua) (39) 0% (Ua) (39) 35% (Ua) (195) 55% (Ua) (196) 0% (Ua) (418) 65% (Ua) (418) 2-Ben- zoyl-5-methylisoxaz- olone-3 60% (P) (152) 68% (P) (153) 38% (P) (153) 2,4-Dimethylthiazole-5-car- boxylic ester l-Benzyl-4,5-dihydrotriazole- 4,5-dicarboxylic ester 4,5-Dicarbethoxy-4,5-dihydro- triazole-1-acetic ester 4-Hydroxytriazole-3-acethy- drazide 5-Hydroxytriazole-l-aceturyl hydrazide l-Phenyltriazole-5-carboxylic ester 2-Phenyltriazole-4,5-dicar- boxylic methyl ester l-Benzyltriazole-4,5-dicarbox- ylic ester l-p-Methylbenzyltriazole-4,5- dicarboxylic methyl ester Triazole-l,4,5-tricarboxylic methyl ester 4,5-Dicarbomethoxytriazole- 1-acetic methyl ester 4,5-Dicarbamyltriazole-l- acetic methyl ester 4,5-Dicarbomethoxytriazole- 1-a-propionic methyl ester 84% (418a) 73% (301) 62% (419) - (115) % (154)§ ¡ª (209) 60% (416) - (301) 80% (68) 90% (419) 92% (419) - (419) - (419) ¡ª (301) ¡ª (209) ¡ª (301) 92% (68) Azide isocyanate 60% (418a) Quant. (209) * 21% (68) Azide sym-vaea, 32% (Ua) .(418a) ¡ª (Ub), 0% (Ua) (209) References 268¡ª454 appear on pp. 446¡ª449. t Prepared from N-carbamylethyleneimine-2,3-dicarboxylio ester. t Prepared from diazoaceturic ester. I Prepared from diazoaceturylglycine ester. 3 § o COMPOUNDS SUBJECTED TO THE CUKTIUS REACTION¡ªContinued HETEBOCTCLIC ACID DEBIVATIVES¡ªContinued Starting Material 4,5-Dicarbomethoxytriazole- l-/3-propionic methyl ester Picolinic ester Nicotinic ester Nicotinamide Isonicotinic ester 6-Methylnicotinic ester 4-Chloropicolinic methyl ester 4-Chloropicolinyl chloride 2,6-Dichloroisonicotinic methyl ester 4,6-Dichloropicohnic methyl . ester 5,6-Dichloronicotinic ester 5-Bromonicotinic methyl ester 5-Bromonicotinyl chloride 4-Iodopicolinic methyl ester Hydrazide ¡ª (419) Quantitative (420) Quantitative (421) 53% (422) ¡ª (420) 97% (96) 89% (120) ¡ª (106) - (257) ¡ª (118), 5-Chloro- 6-hydrazinonico- tinyl hydrazide ¡ª (118) 0% (1*8) ¡ª (120) Azide ¡ª (419) ¡ª (421) ¡ª (422) Poor (420) 70% (96) 0% (Sd) (120) ¡ª (106) - (257) ¡ª (118) - (120) Isocyanate Urethan 36% (420) ¡ª (421) - (106) ¡ª (257) ¡ª (118) -(120) Amine, etc. ¡ª (Ua) (420) ¡ª (Ua) (421) 93%(Ub)(96),21%(Z) (96) 99% (Z) (120), ¡ª (Ua, Ub) (120) 91% (Ub) (106) ¡ª (Z) (257), ¡ª (Ua) (257) 4-Chloro-6- iodo-2-aminopyridine - (Ub) (118) - (Ua, Z) (120) I H O 2,4-Dihydroxy-6-chloronico- tinamide 2,6-Diaminoisonicotinicmethyl ester 2,6-Dibenzamidoisonicotinic methyl ester 2-Hydrazino-6-chloroisonico- tinyl hydrazide 2,4-Dihydroxy-6-hydrazino- nicotinyl hydrazide Quinolinic methyl ester Quinolinie anhydride Pyridine-2,4-dicarboxylic methyl ester Pyridine-2,5-dicarboxylic methyl ester Pyridine-2,6-dicarboxylic methyl ester Cinchomeronic methyl ester 2,6-Dimethylpyridine-3,5-di- carboxylic ester ¡ª (119), 2,4-Dihy- droxy-6-hydra- zinonicotinyl hy- drazide ¡ª (106) ¡ª (106), 2,5-Dia- minoisonicotinyl hydrazide - (106) f ¡ª (119) t - (420) 0% (55) -(253) -(69) - (420) ¡ª (253), ¡ª (55, 420) Monohy- drazide* 85% (423) 0% (106) ¡ª (253) ¡ª (69) ¡ª (420) - (253) 84% (423) ¡ª (253) ¡ª (69) Also azide 4irethan ¡ª (420) -(253) 70% (Ub) (253) ¡ª (Ua) (69) Good (Ub) (420), Poor (Ua) (420) ¡ª (Ub) (253) 48% (Ua) (423) s a in References 268-454 appear on pp. 446-449. t Prepared from 2,6-dichloroisonicotinic methyl ester. t Prepared from 2,4-dihydroxy-6-<!hloroniootinamide. COMPOUNDS SUBJECTED TO THE CURTIUS REACTION¡ªContinued HETEBOCTCLIC ACID DEMVATTVES¡ªContinued Starting Material 4-Phenylazopyridine-2,6-di- carboxylic methyl ester 0-2-Quinolylpropionic ester 2-Phenylquinoline-4-/3-propi- onic methyl ester 6,7-Dimethoxyquinaldine-4-/3- propionic methyl ester Cinchoninic ester Quinaldine-3-carboxylic ester 2-Phenylcinchoninic ester 2-PhenylcinchoninyI chloride 2-Phenylcinchoninyl chloride hydrochloride 2-p-Tolylcinchoninic ester. 2-Phenyl-3-methylcincho- ninic ester 2-Phenyl-3-methylcincho- ninyl chloride 2-Phenyl-6-methylcinchoninic ester Hydrazide 93% (156) Quantitative (199) 97% (427) ? 88% (217) 86% (424) ¡ª (426) 99% (429) 94% (430) -(431) 97% (432) 0% (433) 97% (433) Quantitative (434) Azide ¡ª (156) 0% (199) 82% (217) - (425) - (426) 88% (429) 95% (432) 94% (433) 94% (434) Isocyanate 91% (429) 93% (432) Quant. (434) Urethan 57% (156) 82% (427) 76% (217) (428) 92% (425) -(426) 94% (429) 84% (432) 96% (433) * 66% (434) Amine, etc. 93% (Ub) (156)' O§ 90% (Ua) (427) ¡ê? 80% (Ua), - (F) (217) O ft 91% (U) (425) > Quantitative (Ua), ¡ª ¡ê: (Ib) (429) 2 Quantitative (Ua), 78% <Ib) (432) Quantitative (Ua), 56% (la) (434) 2-Phenyl-8-methylcinchoninic ester 2-Chlorocinchoninic ester 2-p-Bromophenylcinchoninic ester 2-Phenyl-6-bromocinchoninic ester 6-Methoxycinchoninie ester 6-Methoxyquinoline-8-car- boxylic ester 6-Ethoxyquinoline-8-carbonyl azide 2-Phenyl-6-methoxycincho- ninic ester 2-Phenyl-6-ethoxycinchoninic ester 6-Hydroxycinchoninic ester 2-Phenyl-6-hydroxycincho- ninic ester 2-Hydrazinocinchoninyl hy- drazide Acridine-9-propionie ester Acridine-10-butadiene-a,/S,7,?- tetracarboxylic methyl es- ter - (434) ¡ª (424) 2-Hydra- zinocinchoninyl hydrazide -(435) - (435) 98% (436) ¡ª (437) 87% (439) Quantitative (252) 97% (440) 99% (441) - (424) f ¡ª (194) ¡ª (442) 94% (434) ¡ª (435) -(435) 94% (436) - (437) Quantitative (439) 93% (252) 83% (440) ¡ª (441) ? -(434) 95% (436) 99% (439) 99% (252) Quant. (440) * -(434) - (435) - (435) Quant. (436) - (437) 74% (439) 57% (252) 86% (440) 85% (441) ¡ª (194) 77% (Ua) (434) ¡ª (Ua) (435) - (Ua) (435) 74%(Ua),0%(Ib)(436) ¡ª (L) (437) ¡ª (Z) (438) Quantitative (Ua), 96% (Ib) (439) 92% (Ib), 84% (Ua) (252) 86% (Ua), 78% (Ib) (440) 96% (Ua) (441) ¡ª (Ua) (194) 9 s 2 References 268-454 appear on pp. 446-449. t Prepared from 2-ohlorocinchoninic ester. COMPOUNDS SUBJECTED TO THE CURTIUS REACTION¡ªContinued HETEKOCTCLIC ACID DERIVATIVES¡ªContinued Starting Material- Acridine-9-carboxyIic ester 3,4-Dihydro-l,2-naphthacri- dine-14-carbonyl chloride Benzo[/]quinoline-l-carbox- ylic methyl ester 5,6-Dihydro-5,6-dichloro- benzo[/]quinoline-5-car- boxylic methyl ester Lysergic amides (e.g¡ê, ergot- amine) Dihydrolysergic amides Chitenin ester Pyrazine-2,5-dicarbonyl chlo- ride Pyrazine-2,5-dicarboxylic methyl ester 4,5-Benzpyrazine-3-carboxylic ester Uracil-5-acetic ester Hydrazide ¡ª (443) 91% (444) 23% (445) 82% (445) Preced- ing hydrazide 70% (185) ¡ª (446) 92% (447) 97% (229) 80% (448) 97% (143) Azide ¡ª (443) Quantitative (445) Good (185) 0% (Sd) (229) 90% (229) ¡ª (448) ¡ª (143) Isocyanate 85% (444) 79% (229) 91% (143) Urethan 63% (444) 95% (447) 84% (229) 60% (448) Good (143) Amine, etc. Quant. (Ua), 56% (Ib) (444) 78% (Z) (445) ¡ª (Ua, Ub, la), 0% (Ib) (229) 75% (Ua) (448) ¡ª (Ua) (143) I 3 I 2-Methy]-4-hydroxypyrimi- dine-5-acetic ester 2-Ethylmercapto-6-hydroxy- pyrimidine-5-acetic ester Quinoxaline-2-pyruvic ester Quinoxaline-3-carboxylic ester Dihydrotetrazine-3,6-dicar- boxylic ester Tetrazine-3,6-dicarbonyl ester azide Indoxazene-3-earbonyl chlo- ride Indoxazene-3-carboxylic ester 6-Chloroindoxazene-3-carbox- ylic ester 6-Nitroindoxazene-3-carbox- ylic methyl ester 6-Aeetamidoindoxazene-3- carboxylic ester 85% (449) 96% (143) 72% (450) Hydra- zone hydrazide ¡ª (451) 99% (63) Monohy- drazide ¡ª (63) Dihydra- zide ¡ª (207) - (207) - (249) - (207) 57% U43) 27% (63) Tetra- zinedicarbonyl ester azide, q.v. - (63) See preceding com- pound - (Sw) (3) ¡ª (207) ¡ª (207) - (249) ¡ª (207) Quant. (143) * - 98% (449) 84% (143)" -(63) -(207) Quantitative (Ua) (449) ¡ª (Ua) (143) Uracil-5- methylamine 0% (Ua) (63) ¡ª (Z) (3) (207) - (Z) (207) - (Z) (249) ¡ª (Z) (207) H O an References 268-454 appear on pp. 446-449. 446 ORGANIC REACTIONS REFERENCES FOR TABLE 868 Curtius and Hofmann, J. prakt. Chem., 53, 513 (1896) 269 Stolle, J. prakt. Chem., 69, 145 (1904). 270 Stolle and Zinsser, J. prakt. Chem., 69, 486 (1904). 271 Curtius, Sieber, Nadenheim, Hambsoh, and Bitter, J. prakt. Chem., 125, 152 (1930). 272 Stolle and Gutmann, /. prakt. Chem., 69, 497 (1904). Stolle and Hille, J. prakt. Chem., 69, 481 (1904). 274 Spiegel and Spiegel, Ber., 40, 1733 (1907). 276 Curtius and Schwan, J. prakt. Chem., 51, 353 (1895). 276 Blaise and Luttringer, BuU. soc. Mm., [3] 33, 1095 (1905). 277 Blaise and Luttringer, Compt. rend., 140, 790 (1905). 278 Darapsky, Berger, and Neuhaus, J. prakt. Chem., 147, 145 (1936) 279 Blaise and Luttringer, BuU. soc. chim., [3] 33, 816 (1905). 280 van Marie, Rec. trav. chim., 39, 549 (1920). 281 Kiliani, Ber., 55, 2817 (1922); 58, 2361 (1925). 282 Curtius and Levy, J. prakt. Chem., 70, 89 (1904) 283 Curtius, Ber., 35, 3226 (1902). 284 Curtius, Ber., 27, 778 (1894). 286 Curtius, Hallaway, and Heil, J. prakt. Chem., 89, 481 (1914). 286 Billow and Weidlich, Ber., 39, 3372 (1906). 287 Blanksma and Bakels, Rec. trav. chim., 58, 497 (1939). 288 Blanksma and de Graf, Rec. trav. chim., 57, 3 (1938); thesis, Leiden, 1930 [C. A., 24, 5723 (1930)]. 23 Turner and Hartman, J. Am. Chem. Soc, 47, 2044 (1925). 290 Curtius and Casar, /. prakt. Chem., 94, 299 (1916). 281 Curtius and Rechnitz, J. prakt. Chem., 94, 309 (1916). 292 Billow and Bozenhardt, Ber., 42, 4801 (1909). ' 293 Fischer and Brauns, Ber., 47, 3181 (1914). 294Traube and Lehmann, Ber., 34, 1975 (1901). 296 Resting, Ber., 57, 1321 (1924). 296 Franzen and Sohmitt, Ber., 58, 222 (1925). - 297 Franzen and Ostertag, Z. physiol. Chem., 119, 150 (1922). 298 Curtius and Burkhardt, J. prakt. Chem., 58, 205 (1898). 299 Kerp and Unger, Ber., 30, 585 (1897). 800 Sah and Han, Science Repts. Natl. Tsing Hua Univ., A3, 469 (1936) [C. A., 31, 3825 (1937)]. 301 Curtius and Raschig, J. prakt. Chem., 125, 466 (1930). 302 Dickey and Straley, U. S. pat., 2,360,210 (to Eastman Kodak Company); [C. A., 39, 946 (1945)]. 303 Curtius, von Brilning, and Derlon, J. prakt. Chem., 125, 63 (1930). 304 Curtius and Clemm, Ber., 29, 1166 (1896). 306 Curtius and Steller, J. prakt. Chem., 62, 212 (1900). 306 Ruzicka and Stoll, Helv. Chim. Ada, 10, 691 (1927). 307 Frankland and Slator, J. Chem. Soc., 83, 1363 (1903). 308 Nagel and Mertens, Ber., 72, 985 (1939). 309 Curtius and Hoffmann, J. prakt. Chem., 96, 202 (1918). " 31° Curtius and Hechtenberg, J. prakt. Chem., 105, 319 (1923). 811 Curtius and Hartmann, Ber., 45, 1050 (1912). 112 Curtius and Hesse, J. prakt. Chem., 62, 232 (1900). 313 Curtius and Thiemann, J. prakt. Chem., 94, 364 (1916). 314 Muckerman, J. prakt. Chem., 83, 513 (1911). 815 Ruhemann, Ber., 27, 1661 (1894). 316 Oskerko, Mem. Inst. Ukrain. Acad. Sci., 3, 577 (1936) [C. A., 31, 7844 (1937)]. ?? Vogelesang, Rec. trav. chim., 62, 5 (1943) [C. A., 39, 1393 (1945)]. THE CURTIUS REACTION 447 818Stollf, Nieland, and Merkle, J. prakt. Chem., 117, 185 (1927). 319 Hurd and Spenee, J. Am. Chem. Soc., 49, 266 (1927). 820 Stolle, Ber., 43, 2468 (1910). 321 Stolle and Krauch, Ber., 47, 728 (1914). 322 Stolle and Merkle, J. prakt. Chem., 119, 275 (1928). 823 Buchman, Keims, Skei, and Schlatter, /. Am. Chem. Soc., 64, 2696 (1942). 824 Diels, Blom, and Koll, Ann., 443, 246, 257 (1925). 326 Skita and Rossler, Ber., 72, 461 (1939). 326 Alder, Stein, Rolland, and Schulze, Ann., 514, 211 (1934). 327 Alder and Wuidemuth, Ber., 71, 1956 (1938). 328 Vanghelovici, Bui. Soc. Chim. Romdnia, 19A, 35 (1937) [C. A., 33, 639 (1939)]. 829 Bondi and Miiller, Z. physiol. Chem., 47, 499 (1906). "^Windaus, Schramme, and Jensen, Ber., 57, 1875 (1924). 331 Windaus and Eiokel, Ber., 57, 1871 (1924). 332 Cook, Graham, Cohen, Lapaley, and Lawrencq, /. Chem. Soc., 1944, 322. 333 Aggarwal, Khera, and Ray, J. Chem. Soc., 1930, 2354. 334 Curtius and Jordan, J. prakt. Chem., 64, 297 (1901). 336 San and Kao, Science Repts. Natl. Tsing Hua Univ., A3, 525 (1936) [C. A., 31, 3889 (1937)]. 836 Darapsky, J. prakt. Chem., 96, 321 (1917). 337 Sah and Tseu, J. Chinese Chem. Soc., 5, 134 (1937)! 338 Jansen, Rec. trav. chim., 50, 291 (1931). 339 Barger and Ewins, J. Chem. Soc., 97, 2253 (1910). 340 Manske and Holmes, J. Am. Chem. Soc., 67, 95 (1945). 341 Bernstein and Whitmore, J. Am. Chem. Soc., 61, 1324 (1939). 342 Jones and Wallis, /, Am. Chem. Soc., 48, 169 (1926). 343 Wallis, J. Am. Chem. Soc, 51, 2982 (1929). 844 Mayer and Schnecko, Ber., 56, 1408 (1923). 346Stuart and Mosettig, J. Am. Chem. Soc, 62, 1110 (1940). 346 van de Kamp, Burger, and Mosettig, J. Am. Chem. Soc, 60, 1321 (1938). 347 Curtius and Marangolo, J. prakt. Chem., 94, 331 (1916). 348 Curtius and Kenngott, J. prakt. Chem., 107, 99 (1924). -34? Stoermer, Ann., 313, 86 (1900). 350 Wedel, Ber., 33, 766 (1900). 351 Curtius and Miiller, Ber., 34, 2794 (1901). 382 Schroeter, Frdl., 10, 1309 (1910-12). 363 Darapsky and Berger, J. prakt. Chem., 147, 161 (1936). 364 Borsche and Hahn, Ann., 537, 236 (1939). '" Kindlmann, Oesterr. Chem. Ztg., 42, 15 (1939) [C. A., 33, 6275 (1939)]. 366 Stolle and Stevens, /. prakt. Chem., 69, 366 (1904). 367 Darapsky and Gaudian, J. prakt. Chem., 147, 43 (1936). . 358 Stoermer, Ber., 42, 3133 (1909). 869 Schiemann and Baumgarten, Ber., 70, 1416 (1937). 360 Curtius and Foerster, J. prakt. Chem., 64, 324 (1901). 361 Sah and Wu, Science Repts. Natl. Tsing Hua Univ., A3, 443 (1936) [C. A., 30, 8148 (1936)]. 382 Sah'and Wu, /. Chinese Chem. Soc, 4, 513 (1936) [C. A., 31, 3891 (1937)]. 363 Kao, Fang, and Sah, J. Chinese Chem. Soc, 3, 137 (1935) [C. A., 29, 6172 (1935)]. 364 Kao, Science Repts. Natl. Tsing Hua Univ., A3, 555 (1936) [C. A., 31, 3825 (1937)]. 386 Chen and Sah, /. Chinese Chem. Soc.,-i, 62 (1936); Kao, Tao, Kao, and Sah, ibid., 4, 69 (1936) [C. A., 30, 8074 (1936)]. 366 Sah and Chang, Rec. trav. chim., 58, 8 (1939). 367 Wang, Kao, Kao, and Sah, Science Repts. Nail. Tsing Hua Univ., A3, 279 (19351 [C. A., 30, 2875 (1936)]. 388 Sah, Kao, and Wang, J. Chinese Chem. Soc, 4, 193 (1936). 889 Sah and Hsu, Rec trav, chim., 59, 349 (1940). 448 ORGANIC REACTIONS *"> Sah and Young, Rec trav. chim., 59, 357, 364 (1940) [C. 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Soc., 1934, 1263. 464 Bergmann and Fruton, J. Biol. Chem., 117, 189 (1937). 466 Newman, J. Am. Chem. Soc, 57, 732 (1935). INDEX Numbers in bold-face type refer to experimental procedures Acetamide, reaction with bromine and alkali, 268 Acetamido-3-naphthoyl hydrazide, 355 Acetaminocinnamic acid, 205 Acetic anhydride, as an azlactonizing agent, 202-212 commercial preparation of, 110 Acetoacetic acid and derivatives, prepa- ration from diketene, 127 Acetoacetic ester condensation, Vol. I Acetoacetic esters, reaction with thio- cyanogen, 248 in Schmidt reaction, 316 Acetone, conversion to ketene, 109-114, 132 mechanism of, 110 in Schmidt reaction, 330, 331 ? Acetone quinide, 351 Acetophenone in Willgerodt reaction, 95,97 Z-Acetylasparagine, 275 Acetylenes, reaction with thiocyanogen, 246-248 table, 263 in Willgerodt reaction, 86, 88 Acetylenic amides in Hofmann reaction, 276 2-Acetylnaphthalene in Kindler-Will- gerodt reaction, 97 N-Acetylnaphthimidazolone, 355 1-Acetylpyrene in Willgerodt reaction, 96 Acid halides, dehydrohalogenation of, 124-126, 138, 139, 140 tables, 126 in Schmidt reaction, 314 Acids, aromatic, alkylation of, 72 conversion to amines, 267-449 Active methylene compounds in Will- gerodt reaction, 90 Acylamino acids, azlactonization of, 202-205 451 Acyl glycines in Erlenmeyer azlactone synthesis, 208 Adamantane-l,3-dicarboxylic ester, 341 |8-Alanine, preparation by Curtius reac- tion, 347 Alanine ethyl ester hydrochloride, prepa- ration of, 346 Alcohols, in Friedel-Crafts reaction, 1-82 in Willgerodt reaction, 91 Aldehydes, aromatic, alkylation of, 72 preparation of, by Curtius reaction, 343, 345, 350, 356, 384 by Hofmann reaction, 269, 275, 276, 280, 282, 285 reaction with hydrazoic acid, 308, 314, 315, 318 in Willgerodt reaction, 91 Aldoketenes, 108-140 Alkylation, by free radicals, 15 by Friedel-Crafts reaction, 1-82 alkylating agents, 4-5 relative reactivity of, 4 aromatic compounds alkylated, 5 catalyst assistants, 3 catalysts, relative activity of, 2 dealkylation, 14, 16 destructive alkylation, 8 experimental conditions, 16 experimental procedures, 16-19 isomerization of alkyl groups, 7 limitations, 13 mechanism, 4 migration of halogen atoms, 14 orientation, 8-M) rearrangement of alkyl groups, 6-8 related processes, 12, 14 tables, 21-82 Alkylbenzenes, alkylation of, 48-51 sulfonation of, 150-153, 156, 168-179 Alkyl halides, in Friedel-Crafts reaction, 1-82 452 INDEX Alkyl halides, relative reactivity of, 4 Alkylhalobenzen.es, sulfonation of, 154- 155, 171-179 Alkylthiocarbonic acids, preparation of amides of, 250 Allyl alcohol in Friedel-Crafts allevia- tions, 3 Allyl chloride in Friedel-Crafts alkyla- tions, 3 Aluminum alkoxides, reduction with, Vol. II Aluminum chloride, 1-82 procedure for use of, in Friedel-Crafts reaction, 16 reaction with benzene, 21 Amides, Hofmann reaction of, 267-306 , optically active, in Hofmann reaction, 270-271 preparation of, 83-107, 377 . reaction with hydrazoic acid, 322 Amidoximes, reaction with hydrazoic acid, 322 Amidrazones, 362 A ruination of heterocyclic bases by alkali amides, Vol. I Amines, aliphatic, reaction with thio- cyanogen, 247 aromatic, alkylation of, 73-75 reaction with thiocyanogen, 243-245 -tables, 258-261 preparation of, by Curtius reaction, 337-149 by Hofmann reaction, 267-306 by Schmidt reaction, 307-336 tertiary, as dehydrohalogenating agents, 124-126 Amino acids, preparation of, 218-220, 275, 284, 312, 316, 318, 346, 359, 384, 385 acyl derivatives, 354 deacylation of, by hydrazine, 355 racemization of, 203, 214 amides, from azlactones, 215 azlactonization of, 202, 204, 205, 211, 212 in Curtius reaction, 353 esters, from azlactones, 215 TO-Aminoazobenzene, 387 Aminobenzothiazoles, formation of, 244, 267 l-Amino-2-butanone, 345 4-Aminocamphane, 274 l-Amino-2-cycloheptene, 276 Aminodihydrocampholytic acids, 272 ? 2-Amino-4,6-dimethylbenzothiazole, 256 2-Amino-6-ethoxybenzothiazole, 267 Amino group, primary aromatic, replace- ment by hydrogen, Vol. II 16-Aminohexadecanoic acid, lactam of, 330 Aminomethylcyclohexanes, 274 o-Aminophenol, 277 o-Aminophthalhydrazide, 348 Aminopyridines, 279 Aminoquinolines, 279 Aminoveratrole, 277 Ammonium polysulfide, 84, 91, 96, 96 Ammonium sulfide, 92 Ammonium thiooyanate, reaction with azlactones, 213 ? Anhydrides, cyclic, reaction with hydra- zine, 347 in Schmidt reaction, 314 Aniline, alkylation of, 73 reaction with thiocyanogen, 266 Anisole, alkylation of, 14 Anthracene, sulfonation of, 149, 158- 159, 188 Anthranilic acid, 277 derivatives, 278 Anthranils, reaction with hydrazine, 369 Anthranilyl hydrazide, 353 Anthraquinone, sulfonation of, 145 Antimony compounds, reaction with thiocyanogen, 241 Z-Arabinosamide, 276 <2-Arabinose, 27& Arndt-Eistert synthesis, Vol. I Arsenic compounds, reaction with thio- cyanogen, 241 Arsinic and arsonic acids, preparation of by Bart, Bechamp, and Rosen- mund reactions, Vol. II Arylacetic acids, preparation of, 89, 99- 100, 224, 225 Arylacetonitriles, preparation of, 225 Arylalkanes, sulfonation of, 156, 181 Arylalkenes, sulfonation of, 156, 181 Aspartic acid, acetyl derivative, 203 Autoclave, 94 INDEX 453 Azides, as acylating agents, 354 detection of, 376 isolation of, 373 preparation of, 269, 369-375 rearrangement of, 375 Azido group, effect on Curtius reaction, 360 Azlactones, 198-239 alcoholysis of, 215 aminolysis of, 216 hydrolysis of, 214-220 preparation of, 202, 204, 206, 211, 212 properties of, 213-215 reactions of, 213-228, 369 saturated, 198-239, 206 tables, 229-238 unsaturated, 198-239, 206, 211 use in synthesis, 217-239 Azlactonization, 198-239 Azobenzene-ro-carbonyl chloride, 387 Azo group, effect on Curtius reaction, 360 Beckmann rearrangement, relation to Schmidt reaction, 309 Benzalacetone in Schmidt reaction, 316 Benzamide, 277 Benzene, alkylation of, 1-82 sulfonation of, 143, 144, 149, 150, 165 disulfonation, 150 trisulfonation, 146, 150 Benzenedisulfonic acids, 150 Benzenesulfonic acid, 143, 144 Benzenesulfonyl chloride, 149 Benzenesulfonyl fluoride, 150, 164 Benzenesulfonyl glycine, 206 Benzenetrisulfonic acid, 146, 150,163 Benzil in Schmidt reaction, 316 Benzophenone, reaction with hydrazoic acid, 319 4,5-Benzoxazolone, 277 Benzoylaminoacrylic acids, reduction of, 220 Benzoylaminocinnamic acid, azlactoniza- tion of, 204, 212 Benzoylaminocinnamic azlactone, 204 eis and trans forms, 201, 211 Benzoylaminocoumarin, 207 . Benzoylaminocrotonic azlactone, cis and trans forms, 201, 211 a-Benzoylamino-/S-methoxybutyric acid, 211 Benzoylformic acid, reaction with amides, ? 204 Benzoyl-dZ-/3-phenylalanine, azlactoniza- tion of, 206 Benzoylsarcosine, 206 Benzylamine, preparation of, 382, 387 Benzylamine hydrochloride, preparation of, 387 Benzylmalonic ester in Curtius reaction, 384 Benzylmalonyl hydrazide, 384 /3-(3-Benzyloxy-4-methoxyphenyl)-propi- onamide, 274 (3-(m-Benzyloxyphenyl)-propionamide, 274 Benzylurethans, hydrogenolysis of, 380 Biaryls, unsymmetrical, preparation of, Vol. II Biphenyl, sulfonation of, 155, 180 Biphenyl derivatives, sulfonation of, 155, 180 Bismuth compounds, reaction with thio- cyanogen, 241 Bornylenecarboxazide, 342 Boron fluoride in Friedel-Crafts reaction, 3, 5, 6, 8, 9, 14, 16, 18 m-Bromoaniline, 286 m-Bromobenzamide in Hofmann reac- tion, 286 Bromobenzene, sulfonation of, 148, 154, 165 a-Bromo-o-carbethoxybutyryl chloride, 138 Bucherer reaction, Vol. I t-Butylbenzene, 17 n-Butylketene dimer, 140 Camphane-4-carboxamide, 274 Camphoramidic acids in Hofmann reac- tion, 272, 275 Cannizzaro reaction, Vol. II Carbamic acids in Curtius reaction, 355 a-Carbethoxybutyryl chloride, 138 a-Carboalkoxybenzaloxazolones, reac- tions of, 283 oi-Carbomethoxyaminopelargonic acid, 275 454 INDEX Carbonyl gompounds, conversion to amides, 83-107 in Erlenmeyer azlactone synthesis, 206 reactions with hydrazoic acid, 307-336 2-Carboxy-3-nitrobenzazide, reactions of, 346 Cardiazole, 319 Chaulmoogric azide, 342 Chloroaceturyl hydrazide, 357 Chlorobenzene, sulfonation of, 153, 165- 167 ' Chloromethylation of aromatic com- pounds, Vol. I - 2-Chloropyridine, reaction with hydra- zoic acid, 324 2-Chloroquinoline, reaction with hydra- zoic acid, 324 > Chlorosulfonic acid as sulfonating agent, 146, 147, 149, 163, 184 Cinnamic amide, in Hofmann reaction, 286 in Schmidt reaction, 311 Cinnamoyl hydrazide, reaction with nitrous acid, 342 Claisen rearrangement, Vol. II Clemmensen reduction, Vol. I Cupric thiocyanate, 253, 267 Curtius reaction, 269, 273, 337-449 comparison with Hofmann and Schmidt reactions, 313, 363 experimental conditions, 366 experimental procedures, 381 mechanism, 269 of optically active azides, 273 related reactions, 267, 307, 366 scope, 340 tables, 388-449 Cyanamide, reaction with hydrazoic acid, 322 Cyanoacethydrazide, 386 Cyanoacetic ester in Curtius reaction, 386 Cyano acids, in Curtius reaction, 359 Cyanogen, reaction with hydrazoic acid, 322 Cyclialkylation, 12 Cyclobutanediones, 127-132 Cycloheptanone, reaction with tydrazoic acid, 331 Cycloheptene-1-carboxamide, 276 Cyclohexadecanone in Schmidt reaction, 330 1,5-Cyclohexamethylenetetrazole, 331 /3-Cyclohexylnaphthalene, 18 Cyclopropane in Friedel-Crafts reaction, 5 Dehalogenation of a-haloacyl halides, 120, 138 tables, 122 Dehydrohalogenation of acyl halides, 124, 138, 139, 140 tables, 126 O,N-Diacetyl-p-aminophenoV, 352 Diamides in Hofmann reaction, 274, 283 Diamines, preparation of, by Curtius reaction, 343 by Hofmann reaction, 274, 283 by Schmidt reaction, 312 1,4-Diaminocyclohexane, 386 Diazoaceturic hydrazide, 357 Diazoacetylglycylglycine ester, reaction with hydrazine, 360 Diazocarboxamides, 279 Diazo group, effect on Curtius reaction, 360 Diazohydrazides, 357 Diazoketones, conversion to ketones, 123 preparation of, 123 Diazonium salts in preparation of azides from hydrazides, 353, 372 Dibasic acids in Curtius reaction, 343 Dibenzylketene, 136 N - (/3 - 3,4-Dibenzyloxyphenylethyl)-h o- mopiperonylamide, 383 /3-3,4-Dibenzyloxyphenylpropionhydra- zide, 383 ¡ê-3,4-Dibenzyloxyphenylpropionic ester in Curtius reaction, 383 2,6-Dibromo-4-aminophenol, 274 ' 4,4'-Dibromobiphenyl, sulfonation of, 163 4,4'-Dibromobiphenyl-3-sulfonic acid, 163 2,5-Dichlorobenzenesulfonyl chloride, 164 Dichloroketones, reaction with hydrazoic acid, 322 2-(Dichloromethyl)-3-bromo-4-methyl-. pyrrole-5-carbonyl azide, 357 INDEX 455 Dicyclopentylacetic acid, 356 Dicyclopentyl ketone, 356 Dienes, reaction with thiocyanogen, 246 table, 263 C,C-Diethylhydantoin, 275 Diethylmalonamide, 275 ? Diheptylketene, 138 Dihydrooxazoles, 201 Dihydroshikimic acids in Hofmann reac- tion, 272 Dihydrouracil, 274 Diiodobenzene, sulfonation of, 149 Diketene, 119, 127-129 Diketones in Schmidt reaction, 316 Dimethylaniline, reaction with thio- cyanogen, 257 ft/S-Dimethylbutyramide in Hofmann reaction, 271, 283 Dimethylketene, 135, 136 dimer, 136 2,2-Dimethyl-3-methylenecyclopen- tanecarboxamide, 276 . 1,5-Dimethyltetrazole, 331 N,N-Dimethyl-4-thiocyanoaniline, 257 Dioxane as solvent in Willgerodt reac- tion, 85, 93 Diphenic dihydrazide, 348 Diphenylglycolyl azide, 351 Dipropylketene, 135 Disulfides, preparation of, 250 9,10-Dithiocyanostearic acid, 256 Elaidic acid, reaction with thiocyanogen, 256 Elba reaction, Vol. I Enanthonitrile, reaction with hydrazoic acid, 331 Epicamphor, 343 Erlenmeyer azlactone synthesis, 205- 210 experimental conditions and proce- dures, 209-210 mechanism, 205 scope, 206 Z-Erythrose, 276 Esters, in Friedel-Crafts reaction, 1-82 in Schmidt reaction, 314 Ethers in Friedel-Crafts reaction, 1¡ª82 5-Ethoxy-l-(4-ethoxybutyl)-amyl amine, 330 6-Ethoxy-2-(4-ethoxybutyl)-caproic acid in Schmidt reaction, 330 Ethyl acetoacetate, reaction with thio- cyanogen, 248 Ethyl N-benzyl urethan, 383 Ethylcarbethoxyketene, 137, 138 Ethylene diisocyanate, 344 1-Ethylindazolone, 356 Ethyl o-iodobenzoate, reaction with hydrazine, 358 Ethyl N-methylacetimidate, 330 Ethyl phenylacetate in Curtius reaction, 382 Ethyl tetrolate, 343 Ferric chloride in Friedel-Crafts reaction, 2, 3, 16, 18 Fluorine compounds, aliphatic, prepara- tion of, Vol. II Fluorobenzene, sulfonation of, 153, 166 Formamides from aldehydes and hydra- zoic acid, 308 Friedel-Crafts reaction, 1-82 Fries reaction, Vol. I d-Gluconamide, 276 Glutamic acid, acyl derivatives of, 203 Glycine, 385 Glyoxalone derivatives, formation of, 227 Halo acids, in Curtius reaction, 356 in Schmidt reaction, 311 a-(o'-Haloacyl)-amino acids, conversion to unsaturated azlactones, 212 N-HaJoamides, 268 Halobenzenes, alkylation of, 44 sulfonation of, 153-154, 165-167 Hemimellitic ester, reaction with hydra- zine, 348 Heptadecylamine, 330 Heterocyclic acids in Curtius reaction, 361 Heterocyclic amides in Hofmann reac- tion, 279 Heterocyclic compounds, alkylation of, 76-77 in Willgerodt reaction, 90 Hexahydroterephthalic acid in Curtius reaction, 386 Hexahydroterephthalyl hydrazide, 386 456 INDEX Hexahydrotoluamides in Hofmann reac- tion, 274 l-n-Hexyl-5-aminotetrazole, 331 Hippurylalanine, 354 Hofmann reaction, 267-306 comparison with Curtius and Schmidt reactions, 313, 363 experimental conditions, 280-283 experimental procedures, 283-285 mechanism of, 268-273 scope, 273-279 side reactions, 279-280 tables, 285-306 Homopiperonylamine, 274 Hydrazide oximes, 362 Hydrazides, in Curtius reaction, 337-349 hydrazi, 348 preparation of, 366-369 primary-secondary, 348 purification of, 367 reaction with thiocyanogen, 248 secondary, 348, 371 Hydrazine, anhydrous, preparation of, 381 apparatus for use with, 381 Hydrazines, aryl, formation of, 269 Hydrazino lactones, 350 Hydrazoic acid, generation in situ for Schmidt reaction, 328 preparation of solutions of, 327 reactions with organic compounds, 307-336 Hydrocarbons, aromatic, alkylation of, 1-82 identification of, 10 thiocyanation of, 243, 246 table, 263 Hydrocyanic acid, reaction with hydra- zoic acid, 322 Hydrogen fluoride in Friedel-Crafts reactions, 2, 3, 4, 5, 14, 16, 18 Hydroxamic acids, derivatives of, 270 optically active, in Lossen rearrange- ment, 271 Hydroxamic chlorides, reaction with hydrazoic acid, 322 Hydroximido azides, 362 Hydroxy acids, amides of, in Hofmann reaction, 269, 275 in Curtius reaction, 274 p-Hydroxybenzamide, 274 Hydroxy isocyanates, 350 Hydroxylamines, reaction with thio- cyanogen, 248 4-Hydroxy-2-methylpyrimidine-5-acet- hydrazide, 386 4-Hydroxy-2-methylpyrimidine-5-acetic ester in Curtius reaction, 386 4-Hydroxy-2-methylpyrimidine-5- methylamine, 386 Hydroxyquinolines, reaction with thio- cyanogen, 248 Z-2-Imidazolone-5-carboxylic acid, 275 Imidazolone derivatives, 227 Imide chlorides, reaction with hydrazoic acid, 322 Imide radical in Schmidt reaction, 309 Imido azides, 362 Imido esters, formation in Schmidt reac- tion, 318 reaction with sodium azide, 324 Iminobenzothiazoles, formation of, 244 2-Iminobenzothioxoles, formation of, 245 Indazolones, 356 Indole derivatives, formation of, 227 Iodobenzene, sulfonation of, 166 Isatoic anhydrides, 369 Isocyanates, 268 hydrolysis of, 378 polymerization of, 376 preparation of, 376 reaction with hydrazoic acid, 355, 375 m-Isocyanatoazobenzene, 387 Isocyanides, reaction with hydrazx>ic acid, 322 Isocyanurates, 376 4,5-ISopropylidenedioxy-3-hydroxy- cyclohexanone, 351 Isoquinoline derivatives, formation of, 226 Msoserine, 275, 284 Isothiocyanoamines, 362 Jacobsen reaction, 148, Vol. I Ketene, commercial preparations of, 109, 114 mechanism of formation from acetone, 110 INDEX 457 Ketene, preparation of, 109, 111, 112, 114, 132 uses of, 110 Ketene dimers, 108-140 conversion to ketenes, 119-120, 136, 317 mixed, 129 preparation of, 127-132, 137, 140 structure of, 127-128 tables, 130-132 Ketene lamp, 133, 136 Ketenes, preparation of, 108-140 from acids, 109, 114 from acyl halides, 124-126, 138, 139 from anhydrides, 109-114 from diazoketones, 123 from dimers, 119-120, 136, 137 from esters, 109-114 from a-haloacyl halides, 120-122, 138 fromketones, 109-114, 132 from /3-lactones, 124 from malonic acid derivatives, 116- 118, 136 tables, 111-114, 118-119, 120, 122, 126 reaction with hydrazoic acid, 375 Keto acids in Curtius reaction, 352 a-Keto acids, amides of, in Hofmann reaction, 276 degradation of, 225 oxidation of, 224, 225 oximes of, 225 preparation oi, 200, 220-222 reaction with amides, 204, 205 |8-Keto acids and derivatives, preparation of, from ketene dimers, 129 a-Ketoglutaric acid, reaction with amides, 204 Ketoketenes, 108-140 Ketones, conversion to amides, 83-107 cyclic, formation by intramolecular acylation, Vol. II preparation by Curtius reaction, 343- 345, 350, 356 reaction with hydrazoic acid, 308, 314-319 table, 335-336' Kindler modification of Willgerodt reac- tion, 85-107 Lactams, reaction with hydrazoic acid, 322 Lactones, reaction with hydrazine, 369 in Schmidt reaction, 314 /3-Lactones, conversion to ketenes, 124 preparation of, 124 Lauramide in Hofmann reaction, 273 Lauroyl chloride, 388 Lead thiocyanate, 251, 255 Lossen rearrangement, 269, 366 Lysine, preparation of, 312, 318 Z-/3-Malamidic acid, 275 Maleinamide, 275 Malonic anhydrides, 116-119 conversion to ketenes, 116-119, 135 mixed, 116-119, 136 preparation, 116-119, 136 simple, 116-119, 135 Mannich reaction, Vol. I Mercaptans, formation of, 250 Mercury diphenyl, reaction with thio- cyanogen, 249 Mesitylene, sulfonation of, 162 Mesitylenesulfonic acid, 162 Mesitylphenylacetic acid, 139 conversion to mesitylphenylketene, 139 Mesitylphenylketene, 125, 139 /3-p-Methoxyphenylethylamine, 274 /3-(p-Methoxyphenyl)-propionamide, 274 /3-Methyladipamide in Hofmann reac- tion, 283 Methylation, 13, 15 2-Methyl-4-benzyl-5-oxazolone, 206 N-Methylcinnamamide in Schmidt reac- tion, 316 2-Methyl-l,4-diaminobutane, 283 2-Methyl-3,4-diethylpyrrole-5-carbonyl azide, 357 Methyl pentadecylcarbamate, 283 1-Methylquinic acid in Hofmann reac- tion, 272 Methyl styrylcarbamate, 286 Methyl undecylcarbamate, 274 Metrazole, 319 Morpholine, use in Kindler-Willgerodt reaction, 86 Naphthalene, alkylation of, 53-55 derivatives, sulfonation of, 184-187 458 INDEX Naphthalene, sulfonation of, 145, 156- 158, 182-183 Naphthalenesulfonic acids, hydrolysis of, 144 Naphthamide, 277 Naphthenic acids, conversion to amines, 310 1-Naphthol, reaction with thiocyanogen, 267 2-Naphthylacetic acid, 97 2-Naphthylacetothiomorpholide, 97 Neopentylamine, 271, 283 Nitriles, formation of, 269, 276, 308 reaction with hydrazoic acid, 321 o-Nitrobenzaloxazolones, reactions of, . 222 Nitrogen trioxide, reaction with hydra- zides, 371 Nitro group, effect in Curtius reaction, 358 Olefinic hydrazides, reaction with halo- gens, 357 Olefins, in Friedel-Crafts reaction, 1-82 reaction with hydrazoic acid, 325 reaction with thiocyanogen, 246-247 table, 263-265 in Willgerodt reaction, 86 Organometallic compounds, reactions with thiocyanogen, 241 Ornithine, preparation of, 312, 318 Oxazolones, 198-239 Oxidation of a-keto acids, 224, 225 Oximes, reaction with hydrazoic acid, 322 Palmitamide in Hofmann reaction, 283 Pentadecylamine, 283 Peptides, in Curtius reaction, 354 preparation of, 216 Periodic acid oxidation, Vol. II Perkin reaction and related reactions, Vol.1 Phenanthrene, sulfonation of, 149, J59, 189 Phenanthridone, preparation of, 348 p-Phenetidine, reaction with thiocy- anogen, 257 Phenols, alkylation of, 14, 58-71 thiocyanation of, 245 table, 262 Phenylacetaldehyde, preparation of, 285, 311, 345, 384 Phenylacetamide, 96, 97 Phenylacethydrazide, 382 Phenylacetyl chloride in Curtius reac- tion, 387 Phenylacetylene in WiUgerodt reaction, ? 90 dZ-/3-Phenylalanine, acetylation and az- lactonization of, 205 preparation of, 384 m- and p-Phenylazobenzazides, 361 Phenylazodipicolinazide, 361 2-Phenyl-4-benzal-5-oxazolone, 204, 229 derivatives, 209, 229-232 2-Phenyl-4-benzyl-5-oxazolone; 206 N-Phenylglycyl hydrazide, 354 Phenyl iodothiocyanate, 253 l-Phenylpropane-2,2,3-tricarboxylic es- ter, reaction with hydrazine, 348 1-Phenylpropene in Willgerodt reaction, 90 1-Phenylpropyne in Willgerodt reaction, 90 Phenylpyruvic acid, reaction with acet- amide, 205 Phthalic acid, esters of, in reaction with hydrazine, 345 Phthalimides, 277, 278 cleavage by hydrazine, 381 Phthalyl diazide, rearrangement of, 349 Piperonylacetamide, 274 Polyazides, partial solvolysis of, 349 Polybasic acids in Curtius reaction, 343 Polynuclear aromatic compounds, alkyl- ation of, 56-57 Potassium benzylmalonhydrazidate, 384 Potassium ethyl benzylmalonate, 384 6-Propionyltetralin in Willgerodt reac- tion, 96 Putrescine dihydrochloride, preparation from ethyl adipate, 344 Pyrazolone-3-acetazide, 362 Pyrazolones, 343, 352 Pyrene, sulfonation of, 163 Pyrene-3-sulfonic acid, sodium salt, 163 1-Pyrenylacetamide, 96 1-Pyrenylacetic acid, 96' Pyrolysis, preparation of ketenes by, 109-120, 123-124, 132-137 INDEX 459 Pyruvic acid, reaction with amides, 204 Pyruvic acids, degradation of, 225 oxidation of, 224, 225 oximes of, 225 preparation of, 220-222, 224, 229-235 Quinoline derivatives, formation of, 226 Quinones, alkylation of, 72 reaction with hydrazoie acid, 320 Reduction, of acylaminoacrylic acids, 218, 220 of unsaturated azlactones, 218 Reformatsky reaction, Vol. I Resolution of alcohols, Vol. II Salicylamide, 277 Schiff's bases, formation from olefins, 325 Schmidt reaction, 307-336 comparison with Curtius and Hofmann reactions, 313, 363 experimental conditions, 327-330 experimental procedures, 330-331 mechanism, 309 of optically active acids, 311 scope, 310-327 tables, 332-336 Sebacamidic acid, 275 Semicarbazides, aryl, in Hofmann reac- tion, 269, 278 Silver salts of acids, reaction with halo- gen, 366 Sodium azide, 314, 323, 324, 327 activation of, 382 activity of, 374 reaction with acid anhydrides, 340 reaction with acid chlorides, 340 Sodium hypobromite, 280 Sodium hypochloride, 280 Sodium polysulfide, 92 Stearic acid in Schmidt reaction, 330 Styrene dithiocyanate, 256 Styrene in Willgerodt reaction, 90, 97 Styrylamides, formation of, 227 Succinamide, 274 i Succinimide-N-acetic. ester in Curtius reaction, 347 Succinyl azide, 344 Succinyl hydrazide, 344 Sulfide group, effect in Curtius reaction, 359 Sulfides, preparation of, 250 Sulfonamide group, effect in Curtius reaction, 359 Sulfonation of aromatic compounds, 141-197 by-products from, 148 catalysts for, 145 with chlorosulfonic acid, 146, 147, 149, 163, 164 experimental conditions, 160 experimental procedures, 162-164 with fluorosulfonic acid, 146, 147, 149, 164 mechanism, 142, 147 with oleum, 141-197, 163 orientation, 144 rearrangements in, 148 side reactions, 148 with sodium hydrogen sulfate, 147 with sulfamic acid, 147 with sulfuric acid, 141-197, 162 with sulfur trioxide, 143, 144, 146 tables, 165-197 Sulfonic acids, 141-197 hydrolysis of, 143 identification of, 161 indirect syntheses of, 142 isolation of, 161 preparation of, from thiocyanates, 250 Sulfonyl chlorides, preparation of, 147 Sulfuric acid, in Friedel-Crafts reactions, 3 in sulfonations, 141-197 Sulfur trioxide, addition compounds of. 146 Tetraacetylquinyl azide, 352 Tetralin, alkylation of, 52 /?-(6-Tetralyl)-propionic acid, methyl ester, 96 Tetrazolecarboxylic acid, 321 Tetrazoles, 362 hydroxy, 362 preparation of, 308-324, 331 Thiazole derivatives, formation of, 248 Thioamides, preparation of, 85-107 Thiocarbamyl azides, 362 460 INDEX Thiocyanates, preparation of, 240-266 use in synthesis, 250 Thiocyanation, 240-266 Thibcyanoamines, formation of, 247 o-Thiocyanoanilines, rearrangement of, 244 p-Thiocyanoaniline, 266 Thiocyano compounds, 240-266 detection of, 254 determination of, 255 preparation of, 240-266 reaction with thiol acids, 254 use in synthesis, 250 Thiocyanogen, 240-266. hydrolysis of, 241-242 polymerization of, 242, 252 preparation of, 251-254 by chemical means, 253, 256 from cupric thiocyanate, 253, 267 by electrolysis, 252, 267 solutions of, 255 ? solvents for, 251 N-Thiocyanohydroxylamines, 248 4-Thiocyano-l-naphthol, 257 a-Thiocyanophenols, rearrangement of, 245 Thiohydantoins, formation of, 213 Thiophenes, formation of, in Willge- rodt reaction, 88, 91 Thiophenols, reaction with thiocyanogen, 249 Thymol, preparation of, 146 Tiemann reaction, 366 Tiffeneau rearrangement, 15 Toluene, alkylation of, 45-47 sulfonation of, 144, 150, 151, 162, 168 Toluene-2,4-disulfonic acid, 151 Toluenesulfonic acids, 144, 150 Toluenetrisulfonic acid, 151 Triazines, 353 sj/ra-Triethylbenzene, 16 2,4,6-TrLsopropylphenol, 18 Trimethylbenzenes, sulfonation of, 153, 162, 175-176 2,3,3-Trimethyl-l-cyclopentylacetamide, 276 /3,/3,/3-Triphenylethylamine, 271 /3,/3,0-Triphenylpropionamide in Hof- mann reaction, 271 Truxillamic acids, 275, 284 Truxillamidic acids, 275, 284 Truxinamic acids, 275 Truxinamidic acids, 275 Undecylamine, 274 Undecyl isocyanate, 388 Unsaturated acids, amides of, in Hof- mann reaction, 269, 276, 280, 282, 285 in Curtius reaction, 341 Uracil, 275 Urea derivatives, alkyl acyl, 269, 273, 275, 279 aryl, 269, 278 preparation of, 376 Urethans, 268, 269, 288-304 hydrolysis of, 380 preparation of, from azides, 377 Veratric amide, 277 Vinyl isocyanates, 342 Vomicine, 352 Willgerodt reaction, 83-107 apparatus for, 93 experimental conditions, 91-94 experimental procedures, 95-98 limitations, 89-91 mechanism, 86-89 scope, 89-91 side reactions, 89-91 tables, 99-107 Wolff rearrangement of optically active diazoketones, 273 Xylenes, sulfonation of, 151, 172 2,4-Xylidine, reaction with thiocyanogen, 256 Zinc chloride in Friedel-Crafts reactions, 3,4 Zinc diethyl, reaction with thiocyanogen, 249