Chemistry 206 Advanced Organic Chemistry Handout–26A Matthew D. Shair Monday , November 18, 2002 An Organizational Format for the Classification of Functional Groups. Applications to the Construction of Difunctional Relationships D. A. Evans Functional Group Classification Chemistry 206, 2001 An Organizational Format for the Classification of Functional Groups. Applica- tions to the Construction of Difunctional Relationships D. A. Evans Department of Chemistry & Chemical Biology, Harvard University, Cambridge, MA, 02318 Introduction Among the subdisciplines of chemistry the area of organic synthesis is probably the least organized in terms of unifying concepts and general methodology. This conclusion has been made quite obvious by the relative scarcity of critical monographs covering this important topic.1 The wide structural diversity of organic molecules, the vast abundance of organic reactions, and the restrictions imposed upon these reactions when applied to the synthesis of a complex structure all contribute to the magnitude of the problem of making generalizations in this area. However difficult the overall task of explicitly defining a priori a total synthesis of an organic structure may be, there are certain simplifying features which can be developed to generate logical sets of potential synthetic pathways to a given molecular target . Some of the general guidelines which help to de- fine this task have been outlined.2 Recently, some of the problems associated with reducing synthetic de- sign to a mathematical basis and the application of machine computation to synthetic analysis have been re- ported.3,4 Difunctional Relationships. One aspect of the synthesis of any polyfunctional target structure deals with strategies associated with the construction of arrays of relationships between heteroatom func- tional groups which may be denoted as F1, F2, etc. The general reactions illustrated below simply represent the union of two monofunctional organic fragments where the functional groups F1, F2 provide the necessary activation for the coupling process. In these reactions, the oxidation states of the associated car- bon fragments are purposely left undefined. In relating the generalized notation below to a real situation, if F1-C-C were an enolate, Equation 1 might be used to represent a generalized aldol or Mannich reaction while equation 3 might represent a Michael reaction. C C F1 F2 C C F 2 C C F1 C C F1 C C C F 2 C F2 C C F1 C CCC CC C CC C F 1F1 F 2F 2 (3) (2) (1) + + + Henrickson has provided some useful generalizations on the construction of difunctional relation- ships which are worth summarizing. For example, he defines the construction span as the number of carbons linking F1 and F2. In the cases illustrated above, the product of the reaction illustrated in Equation 1 has a construction span of three. The construction fragments are then defined as the monofunctional reactants, such as F1-C-C and F1-C. In general, construction spans are limited to six or less. This is a consequence of the fact that the operational utility of a given functional group diminishes as it is removed 1 ) (a) Corey, E. J.; Cheng, X.-M. The Logic of Chemical Synthesis; Wiley, New York, 1979. (b) Fuhrhop, J.; Penzlin, G. Organic Synthesis: Concepts, Methods, Startimg Materials; Verlag Chemie, Weinheim, 1983. (c) Carruthers, W. Some Modern Methods of Organic Synthesis, 3nd ed.; Cambridge Univ. Press, Cambridge, 1987. (d) Organic Synthesis, The Disconnection Approach; Wiley, New York, 1982. (e) Payne, C. A.; Payne, L.B. How To Do An Organic Synthesis; Allyn and Bacon., Boston, 1969. (f) Ireland, R. E. Organic Synthesis, Prentice-Hall, Inc., Englewood Cliffs, 1969.2 ) (a) Corey, E. J. Pure Appl. Chem. 1967, 14, 19. (b) Corey, E. J. Quart. Rev. 1971, 25, 455.3 ) (a) Hendrickson, J. B. J. Am. Chem. Soc. 1971, 93, 6487. (b) Ugi, I; Gillespie, P. Angew. Chem. Int. Ed. 1971, 10, 914. (c) Corey, E. J.; Wipke, W. T.; Cramer, III, R. D.; Howe, W. J. J. Am. Chem. Soc. 1972, 94, 421. (d) Corey, E. J.; Cramer, III, R. D.; Howe, W. J. ibid. 1972, 94, 440, and earlier references cited therein. (e) Corey, E. J.; Howe, W. J.; Pensak, D. A. ibid. 1974, 96, 7724. (f) Blair, J.; Gasteiger, J.; Gillespie, C.; Gillespie, P. D.; Ugi, I. Tetrahedron 1974, 30, 1845. (g) Bersohn, M. J. Chem. Soc., Perkin I 1973, 1239. 4 ) (a) Thakkar, A. J. Fortschritte Chem. Forschung 1973, 39, 3. (b) Dungundji, J.; Ugi, I. ibid. 1973, 39, 19. (c) Gelernter, H.; Sridharan, N. S.; Hart, A. J.; Yen, S. C.; Fowler, F. W.; Shue, J.-J. ibid. 1973, 41, 113. Functional Group Classification page 2 from the C-C bond being formed. The problem of site or ambident reactivity in systems possessing ex- tended conjugation is the principal liability in the extension of the construction span. This point is illus- trated below for both conjugate addition and enolate alkylation (Scheme I). MeO2C MeO2C R RNuMeO2C RNu RMeO OM RMeO RMeO OO El ElScheme I The Problem of Ambident Reactivity64 γ-alkylationγα El(+)Nu(-) El(+)H+H+α-alkylation1,4 Addition1,6 Addition H+H+Nu(-) The objectives of the present discourse are to present an organizational format which can serve to correlate strategies for the construction simple pairwise functional group relationships. As a result of the overwhelming predisposition of nature to employ polar rather than free radical processes in the biosynthesis of organic compounds the chosen organizational format reflects this bias in reaction type. The designation of reactions as polar is recognized to be rather arbitrary since known reactions vary widely in their polar character, ranging from essentially nonpolar radical reactions and weakly polar electrocyclic reactions to strongly polar ionic processes. Of primary concern in this discussion will be those reactions that involve charged species at some point along the reaction coordinate. Charge Affinity Patterns. In order to describe an organizational model for the classification and synthesis of heteroatom-heteroatom (difunctional) relationships in organic molecules, two familiar ideas will be employed. The first is that in a given target molecule the various bonds can be ionically "disconnected" (eq 4, 5). That is, if the A-B bond could be cleaved heterolytically, the indicated set of polar fragments would result. This antithetic process suggests ionic precursors suitable for the construction of the target molecule via polar coupling processes. The second well accepted idea is that functional groups determine site reactivities on a carbon skeleton based upon known reactions. That is, the oxygen atom in both acetone and anisole dictates the site reactivities that are displayed for each molecule with nucleophilic and electrophilic reagents. Thus, if the molecule A-B contained one or more functional groups proximal to the bond to be disconnected, one pair of ionic precursors, eq 6 or 7, would be strongly favored as plausible precursors. In such a case the favored ionic precursors to A-B could be symbolized with either (+) or (-) in the target molecule, e.g.5 As an example, two possible polar disconnections for ketone 1 are illustrated below. The parity labels in the target structure suggest plausible monofunctional precursors from which the target structure can be assembled by polar processes. It is also evident that the heteroatom functional groups, =O and -OH, strongly bias the indicated polar disconnections. R C CH3 O CH2 O R C CH2 O CH2 OH R C CH O CH2 TA TB (+) (–) (+) (–) (–) (–) (–)(+)(–)(+)(–) (–)(+)(–)(+) OH21 Scheme II Polar Disconnections and Charge Affinity Pattterns 5 ) The use of the symbols, (+) and (-), in no way represents formal positive or negative charges and will always be bracketed to denote this distinction. Other forms of notation have been considered such as (0) and (1) to denote a potential site of electrophilicity or nucleophilicity; however, the chosen symbols convey more direct information to the organic chemist. A B A B (5) (4)A: – B+ B:–A: + A B A B A: + B:– B+A: –(+)(–) (–)(+) (6) (7) Functional Group Classification page 3 For any given atom or heteroatom assemblage which is defined as a functional group linked to a carbon skeleton, the parity labels, (+) and (-), may be employed to denote the positional polar site reactivity, or charge affinity pattern which the functional group confers upon the carbon framework. For the simple molecules shown below (Scheme III) containing a homogeneous set of activating functions, E, there are associated charge affinity patterns 2 - 5 of which each is a sub-pattern of the generalized structure 6. Note that the carbonyl function is defined as =O rather that C=O in this discussion. You might contemplate why this functional group is defined in this fashion. CH C O OR H2C CH CH2 OH CH2 H2C C O H H3C CH2 CH2 Br CH3C C E1C C C E2C C C E3C C C E4C C C EC 2 (–) (+) (+)(–) (+)(+) (+) (+) 3 4 5 (+)(+) (–) 6 Scheme III Charge Affinity Patterns of Common Functional Groups The notion that an organic structure can be viewed as an "ion assemblage" has an interesting history originating with the work of Lapworth and others.6,7 Although the ion assemblage viewpoint was developed historically to predict site reactivity in both aliphatic and aromatic systems, this description of an organic structure is equally instructive in defining rational sets of synthetic pathways for a given target structure employing heterolytic processes as the primary set of coupling reactions. Indeed, the thought processes associated with the construction of organic molecules operate intuitively to recognize many sub- units of a given structure in terms of polar fragments. The present use of parity labels to denote viable polar fragments simply formalizes this intuition. Classification of Functional Groups (FG). In order to organize general strategies that have been developed to construct heteroatom-heteroatom relationships from monofunctional precursors it is useful to develop a self-consistent classification scheme for single functional groups (FG) based on the concepts of polar disconnection and conferred site reactivity towards nucleophiles and electrophiles. The proposed scheme recognizes the dominate inductive and resonance components of various substituents and establishes8 broad categories for activating functions which correlate similar conferred chemical properties to carbon.9 Four possible functional group cate- gories (F1-F4) are shown below. Those FGs which are more electronegative than carbon provide in- ductive activation defining the electrophilic potential at the point of attachment denoted as (+). In a com- plementary fashion, FGs which are less electronegative than carbon provide inductive activation creating nucleophilic potential at the point of attachment denoted as (–). Since FG activation through induction and resonance are independent variables which contribute to the overall FG reactivity pattern, four possible classes of functional groups can be defined (Scheme IV). This discussion is reminiscent of the classifica- tion of FGs according to their impact on electrophilic aromatic substitution.10 C F2 C F3 C F4 C E C GC A C F1(+) Scheme IV Classification of Functional Groups (+)Induction Resonance (+) (–) (+) (–) (–) (–) Symbol (+) (–)(±) 6 ) (a) Lapworth, A. Mem. Proc. Manchester Lit. Phil. Soc. 1920, 64, 1. (b) Lapworth, A. J. Chem. Soc. 1922, 121, 416. (c) Lapworth, A. Chem. Ind. 1924, 43, 1294. (d) Lapworth, A. ibid. 1925, 44, 397. For an excellent review of Arthur Lapworth's contributions to chemistry see: Saltzman, M. J. Chem. Ed. 1972, 49, 750-753. 7 ) (a) Vorl?nder, D. Chem. Ber. 1919, 52B, 263. (b) Stieglitz, J. J. Am. Chem. Soc. 1922, 44, 1293.8 ) See reference 3c for an alternate classification scheme for functional groups.9 ) For an analysis of the relative importance of field and resonance components of substitutent effects see: Swain, C. G.; Lupton, Jr., E. C. J. Am. Chem. Soc. 1968, 90, 4328.10 ) March, J. Advanced Organic Chemistry, 4th ed.; Wiley-Interscience: New York, 1992; pp 507-512. Functional Group Classification page 4 E & G-Functions. From the preceding discussion, one might opt for the creation of four classes of functional groups; however, for the sake of simplicity, three FG class designations will be chosen. To organize activating functions into common categories it is worthwhile to define "hypothetical" functional groups E, and G,11 having the charge affinity patterns denoted in 6 and 7 respectively. Given the appropriate oxidation state of the carbon skeleton, such functional groups confer the indicated potential site reactivity patterns towards both electrophilic and nucleophilic reagents. Any functional groups whose reactivity pattern conforms to the ideal pattern or to a sub-pattern of these hypothetical functions will be thus classified as an E- or G-function respectively. For example, the halogen and oxygen-based functional groups in four molecules illustrated in Scheme III may be classified as E-functions since their respective charge affinity patterns conform to a subset of the charge affinity pattern of the hypothetical E-function. A-Functions. A third hypothetical function, A, (A for amphoteric!) can be defined which has an unbiased charge affinity pattern as in 8. Such an idealized functional group activates all sites to both nucleophilic and electrophilic reactions and, as such, include those functions classified as either E or G. The importance of introducing this third class designation is that it includes those functional groups having non-alternate charge affinity patterns as in 9, 10 and 11. The differentiation of polar reactivity patterns can be described in an alternative manner. Starting with an ideal A-function, one could imagine a process in which the reactivity pattern is gradually polarized towards E- or G-behavior (Scheme V). Since site reactivity is not an on-off property but varies continu- ously over a wide range, one could further subdivide A-class functions into those functions with a bias towards E-class or G-class properties. Such a bias could be denoted by the dominant subordinate charge affinity notation in 12 and 13; however, for the concepts to be presented in this discourse, such A-function subclasses are nonessential. It should be emphasized that the purpose of the E- and G-classification is not to rigidly pigeon-hole functional groups based on site reactivity, but only to separate those which are strongly polarized toward E or G behavior. The decision has been made to avoid the pursuit of an overly detailed FG classification scheme since such attempts will dangerously oversimplify problems since an es- sentially contiguous function cannot be segmented in to discrete parts. C C AC C C AC C C AC C C GC C C EC (+–)(+–)(+–) 12 Hypothetical A-function (±) (±)(±) (±)(±) (±) (–)(–) (+) (+)(+) (–) Hypothetical E-function Hypothetical G-function Scheme V Alternate vs Nonalternate Reactivity Patterns 13 11 ) The symbol E was selected to denote electrophilic at the point of attachment to the carbon skeleton Unfortunately, the symbol N cannot be used to represent those FGs which are nucleophilic at the point of attachment since this is also the symbol for nitrogen. To avoid this conflict, the symbol G was chosen for this FG class designation. C C EC C C GC (+)(+) (–) 6 7 (+)(–) (–) Hypothetical E-function Hypothetical G-function C C AC C C A C C A C A Hypothetical A-function 8 (+–) (+–) (+–) 9(+)(+) (–) (–) 10 11(+–) Functional Group Classification page 5 FG Classification Rules. In the proposed classification scheme the following rules are followed in the assignment of class designations to functional groups. a73 Activating functions are to be considered as heteroatoms appended to or included within the carbon skeleton. a73 Activating functions are inspected and classified according to their observed polar site reactivi- ties. a73 Since both proton removals and addition processes are frequently an integral component in functional group activation, the function, its conjugate acid or base, and its possible proton tautomers are considered together in determining its class designation. a73 The oxidation state of the FG is de-emphasized since this is a subordinate strategic considera- tion. E-Functions. For example, carbonyls and carbonyl derivatives will be represented as =X where X may be either oxygen or substituted nitrogen. Well recognized exceptions to the polar class designations illustrated in Scheme I may be found in the chemistry of CO and HCN. In these instances the carbon bearing the heteroatom exhibits well-defined nucleophilic properties. Accordingly these two functional groups will be classified as A-functions by inspection (vide infra). OR O O C E NR2 NR N X, X = halogenAlso consider all combinations of of above FGs; e.g =O + OR exception: exception: (+)Table I. Common E-Functions: Symbol: G-Functions. Typical G-class functions are the Group I-IV metals whose reactivity pattern, falls into a subset of 7. C C GCCH CH2 LiH2C CH3 CH2 MgBr (–)(–) (+)(–) (–) (–) 7 A-Functions. A-functions are usually more structurally complex FGs composed of polyatomic assemblages of nitrogen, oxygen and their heavier Group V and VI relatives (P, As, S, Se). Typical A- functions, classified by inspection, are provided in Table II. NO2 NOR C A SR PR2 P(O)R2 NNR2 N(O)R N2 N S(O)R SO2R SR2 PR3+ + (±)Table II. Common A-Functions: Symbol: Functional groups possessing the following general structure, =N-X where X is a hetroatom bearing a nonbonding electron pair, have an expanded set of resonance options which create either an electrophilic or nucleophilic potential at the point of attachment. Remarkably, the dual electronic properties of oximes were first discussed by Lapworth12 in 1924 before the modern concepts of valence bond reso- nance was developed. R H N X: R H N X: R H N X: a73 These FG's are capable of conferring both (+) and (–) at the point of attachment. (+) (+) (–) (–) X = OR, NR2 12 ) Lapworth, A. Chemistry and Industry 1924, 43, 1294-1295. Functional Group Classification page 6 A Case Study: The Nitro Group. As an example, the class designation of the nitro function is determined by an evaluation of the parent function, its nitronic acid tautomer, as well as conjugate acid and base 14 and 15. N O O CH2R NHO O CHR N O O CHR N HO HO CHR+– – + +–– H-tautomer conjugate base conjugate base + nitronic acid nitronate anion, 14 15 From the collection of transformations of the nitro group one finds that the dominate mode of reac- tivity of the nitronate anion 14 is that of a G-function while the protonated nitronic acid 15 mirrors the re- activity of an E-function. N HO HO CHR FG C FG CN O O CHR 15 14 (+)+ + – – The dominate polar site reactivity (–) The typical behavior of nitronate anions 14 is summarized in the representative transformations provided in Scheme VI. These moderately nucleophilic species, although they are not readily alkylated, readily undergo aldol and conjugate addition reactions. + NO + N–O–O –O CH2–R CH–R + N O –O El + NO–O R CH–R + N O –O CH2–R Scheme VI Selected Reactions of the Nitronate Anion base pKa ~ 10 El(+) The Reaction: a71 a71– The charge affinity pattern: (–) a73 This reactivity pattern may be extended via conjugation: It is no surprise that the charge affinity pattern of this FG may be extended by conjugation, and α,β-unsaturated nitro compounds readily participate in conjugate addition reactions (Scheme VII). R H N X: R H N X: R H N X: + NO –O CH CH R + N O –O CH2 CH NuR + N O –O CH CH R + N –O –O CH CH R + N–OO Scheme VII Selected Reactions of the Nitronate Anion X = OR, NR2 (–) (–) (+) (+) a73 The resonance feature which has been exploited: Nu(–) (–) (+)The Reaction: The charge affinity pattern: (–) (+) + (+) (+) (+)Nitro aromatics: a20a20 Functional Group Classification page 7 The non-alternate behavior of the nitro functional group is dramatically illustrated in the transfor- mations provided in Scheme VIII. In both instances the derived anions 16 and 17 are highly nucle- ophilic.13 The non-alternate charge affinity patterns of these nucleophiles is provided. N O N O O C O C CH3 Li CH2Li CH3 N O O C CH3 H FG C FG C CN O O C CH3 CH3 17 16 Scheme VIII Deprotonated Nitronate Anions (–) (–) (–) (–) n-BuLi-78 °C (9) (8)-78 °CLDA – – + + – – – – + – – + The nitro group also exhibits the potential of undergoing direct displacement under specific condi- tions, a general transformation characteristic of E-functions. A recent review by Tamura provides numer- ous literature precedents for this general class of reactions.14 while table III provides some of the cited re- actions. Although the NO2 group cannot be considered as a general leaving group, there are a number of conditions under which this moiety can be exploited, particularly when it is either allylic or tertiary. N O O CH R R Nu CH R R FG C– + (+)Nu(–) (10)+ NO2– NO2 NH N(CH2)5 CH(CO2Me)2 SO2Ph PhNO2 Ph Me Me SPh NO2 SiMe3 Me Me Me NO2 OMet-Bu Me Me SPh Me Ph SPh NO2 Me Ph SPh CN Pd(PPh3)3 NaCH(CO2Me)2 NaO2SPh Pd(PPh3)3 Pd(PPh3)3 SnCl4 74% Anisole 94%SnCl4 TiCl465% 73%TiCl4 Me3SiCN Table III. Representative Substitution Reactions of the Nitro Group (eq 10). A particularly useful transformation of the nitro group is the Nef Reaction, a process which trans- forms NO2 into =O (Scheme IX). A recent comprehensive review of this transformation provides a detailed discussion of this process.15 In addition to the Pinnick review, Seebach has also written a comprehensive review of the diverse chemistry of the nitro functional group.16 13 ) (a) Henning, R.; Lehr, F.; Seebach, D. Helv. Chim. Acta 1976, 59, 2213-2217; (b) Seebach, D.; Henning, R.; Lehr, F.; Gonnermann J. Tetrahedron Lett. 1977, 1161-1164.14 ) Tamura, R.; Kamimura, A.; Ono, N. Synthesis 1991, 423-434.15 ) Pinnick, H. W.; Org. Reactions 1990, 38, 655-792.16 ) Seebach, D.; Colvin, E. W.; Lehr, F.; Weller, T.; Chimia 1979, 33, 1-18. Functional Group Classification page 8 + N RRO– O H + N R O RR + N R HO – O R R O – O H + N R + N RR R – O – O HO HON R R HO HO OHO R R N HH HO HO 1) HO – nitronate anion HO – H+ a73 Overall Transformation: a73 Mechanism nitronic acid H + H2O - H ++ Scheme IX The Nef Reaction G-Property E-Property The Diazo Functional Group. This functional group provides one of the best illustrations of an A-function. As illustrated in Scheme X, both (–) and (+) polar site reactivity is observed in is reactions with carboxylic acids. + N RRO– O H + N R O RR + N R HO – O R R O – O H + N R + N RR R – O – O HO HON R R HO HO OHO R R N HH HO HO 1) HO – nitronate anion HO – H+ a73 Overall Transformation: a73 Mechanism nitronic acid H + H2O - H ++ Scheme IX The Nef Reaction G-Property E-Property The same overall reactivity pattern is expressed by the diazo functional group in the Tiffeneau- Demjanov ring expansion reaction17 wherein diazomethane functions as the nucleophilic agent in the first step and the functional group is lost as a leaving group in the subsequent step (Scheme XI). O OHO CH2–N2 RN2 C RN2 C CH2N2 EtOH + (–) (+) Restriction: Starting ketone must be more reactive than product ketone Scheme XI The Tiffeneau-Demyanov Ring Expansion -N2 17 ) For a monograph on ring expansion reactions see: Hesse, M. Ring Enlargement in Organic Chemistry; VCH: New York, 1991. Functional Group Classification page 9 Sulfur-Based Functional Groups Sulfonium Salts. The dual electronic behavior of sulfur functions may be illustrated in the reac- tions of sulfur ylids which are excellent examples of A-functions. As illustrated in Scheme XII, sulfonium salts are effective in carbanion stabilization, a characteristic of G-functions, and sulfonium salts are effective leaving groups, a characteristic of E-functions. S CH3RR R2S C R2S C S CH3RR Me NuS R R S CH2RR Scheme XII. Sulfonium Salts: Modes of Reactivity a71a71 – + H +a73 Carbanion Stablization: pKa (DMSO) ~ 18 a73 Leaving Group Potential: Good + SN2 +Nu:+ a71a71 + + (–) (+) The non-alternate reactivity pattern of trimethylsulfonium ylids is revealed in the cyclopropanation of unsaturated ketones as illustrated in the case below (Scheme XIII).18 O O – SMe Me O –SMe Me S CH2MeMe O R2S C R2S C –+ a71a71 Scheme XIII. Reactions of Sulfonium Ylids: Conjugate Addition (–) (+) + + (+) a73 Nonalternate reactivity pattern revealed in consecutive reactions Sulfones. Other types of sulfur-derived functional groups exhibit reactivity profiles similar to that exhibited by sulfonium salts. A number of excellent applications of the arylsulfonyl functional group illus- trate this point. Two applications utilizing the sulfone functional groups are presented below. The phenylsufonyl moiety strongly stabilizes carbanions and may be equated with the –CN FG in its potential for hydrocarbon acidification.19 In addition, this FG is a respectable leaving group in selected situations. In comparisons with sulfonium ions (Scheme XV), arylsulfonyl-stabilized carbanions are more nucleophilic than sulfonium ylids (G-property), while ArSO2- is a poorer leaving group than Me2S- (E- Property). Me S Me Ph O O Li S CH2RR Me S Me Ph O O S CH3RR Me S Me Ph O OpKa ~ 25 BuLi more nucleophilic than: –+ a71a71 poorer leaving group than: + Scheme XV. Sulfones: Modes of Reactivity 18 ) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1352-1364.19 ) For an excellent compilation of pKa data for organic functional groups in DMSO see: Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456-463. Functional Group Classification page 10 Julia's use of phenylsulfonyl carbanions in the synthesis of trans-chrysanthemic acid provides the justification for defining this functional group as an A-function (Scheme XVI).20 R2SO2 CR2SO2 C Me S Me Ph O O Li Me OEt Me Me O Me SO2Ph OLi OEt Me Me CO2Et H H (–) (+) trans chrysanthemic acid (+) Scheme XVI. The Julia Chrysanthemic Acid Synthesis The dual electronic properties of the sulfone functional group are illustrated in the Julia synthesis of vitamin A (Scheme XVII).21 In this application, the E-property of the FG is exploited in the base-induced elimination reaction to generate the fully conjugated polyene. Li SO2PhMe Me MeMe SO2PhMe Me MeMe CO2R Me CO2R Me Br R2SO2 C R SO2PhMe O – OR Me Me MeMe CO2R Me R2SO2 C (+)(+) (–) Julia & Co-workers, Bull. Soc. Chim. Fr. 1985 , 130 (–) KOH/MeOH - PhSO2 – Scheme XVII. The Julia Vitamin A Synthesis For additional reading on the utility of the utility of sulfones in organic synthesis a monograph on this subject has recently appeared.22 Several other reviews providing extensive literature coverage are worth reading.23 Organoboranes. The boron atom exhibits many of the common reactions normally attributed to metals, and when bound to carbon, serves as an excellent source of nucleophilic carbon.24 The transfor- mations provided in (Table IV) represent but a few cases which demonstrate the G-properties of this acti- vating function.25,26,27,28,29,30,31 20 ) (a) Julia, M.; Guy-Rouault, Bull. Soc. Chim. Fr. 1967, 1141. (b) Campbell, R. V. M.; Crombie, L.; Findley, D. A. R.; King, R. W.; Pattenden, G.; Whiting, J. J. Chem. Soc., Perkin Trans. I 1975, 897. 21 ) Arnould, D.; Chabardes, P. Farge, G.; Julia, M. Bull. Soc. Chim. Fr. 1985, 130.22 ) Simpkins, N. S. Sulfones in Organic Synthesis, Pergamon Press, New York 1993. 23 ) (a) Trost, B. M. Bull. Chem. Soc. Jpn. 1988, 61, 107-124. (b) Magnus, P. D. Tetrahedron, 1977, 33, 2019-2045.24 ) (a) Brown, H. C. Boranes in Organic Chemistry, Cornell University Press, New York 1973. (b) Cragg, G. M. L. Organoboranes in Organic Synthesis, Marcel Dekker, New York, 197325 ) (a) Kow, R.; Rathke, M. J. Am. Chem. Soc. 1973, 95, 2715. (b) Zweifel, G.; Fisher, R. P.; Horng, A. Synthesis 1973, 37. (c) Matteson, D. S. ibid. 1975, 147.26 ) Negishi, E.; Abramovitch, A.; Merrill, R. E. J. Chem. Soc., Chem. Commun. 1975, 138.27 For a recent citation on allylboron-based nucleophiles see: Wang, Z.; meng, X. J.; Kablaka, G. W. Tetrahedron Lett. 1991, 32, 5677-5680 and references cited therein. 28 ) Marshall, J. A. Synthesis 1971, 229.29 ) (a) Brown, H. C.; Rhodes, S. P. J. Am. Chem. Soc. 1969, 2149, 2149. (b) Hawthorne, M. F.; Dupont, J. A. J. Am. Chem. Soc. 1958, 80, 5830.30 ) (a) Pelter, A.; Subrahmanyan, C.; Laub, R. J.; Gould, K. J.; Harrison, C. R. Tetrahedron Lett. 1975, 1633. (b) Pelter, A.; Harrison, C. R.; Kirkpatrick, D. ibid. 1973, 4491. (c) Pelter, A.; Harrison, C. R. J. Chem. Soc., Chem. Comm. 1974, 828. (d) Naruse, M.; Utimoto, K.; Nozaki, H. Tetrahedron 1974, 30, 3037. Functional Group Classification page 11 B RR B CH2RR R B CH2RR R R2B H CO R C A R C OBR2 AC B Ph R Cl C O R Me B R R R C APhR C O Me Me C A B(OH)2 OTs Me B(OH)3 OTs Me R2B Cl Ph Ph C APh Cl(HO)3B B R R C B CH R CH2 R2B C AR El R R' R' R B R R R R'El CR C AR OH O OH C 31 30 29 28 27 25 stereochemical aspects of this reaction not determined 2) H2O2 1) additionG – (–) (+–) El(+) = n-C6H13I, C3H5Br, ethylene oxide, CH2I2, MeSO3H (+–)(–)– δ+ δ– El(+)F – (–)E HO– – HO–D (–) +– (–)+ C B A ReactionEntry (–) Charge Affinity Pattern El(+)–base Table IV. Reactivity Patterns for Organoboranes 26 + (–)(–) The potential for non-alternate charge affinity patterns for boron have been revealed in the reactions of acetylenic and vinylic boron ate complexes (Table IV, entries F, G).30,31 These compounds exhibit high nucleophilicity towards a variety of electrophiles to the boron atom. The origin of such β-nu- cleophilicity could be a consequence of σ?pi conjugation32 (e.g., 19) not observed with the heavier metallic elements which are attacked by electrophiles α to the metal where the alternate mode of conjugation 18 is possible.33 In principle, both types of conjugative stabilization are possible with a range of organometaloids; however, in practice this is not the case. It would be expected that the effects of 31 ) (a) Utimoto, K.; Uchida, K.; Nozaki, H. Tetrahedron 1973, 30, 4527. (b) Utimoto, K.; Uchida, K.; Nozaki, H. Chem Lett. 1974, 1493.32 ) (a) Harmon, G. D.; Traylor, T. G. Tetrahedron Lett. 1975, 939, and reference cited therein. (b) for example of σ?pi delocalization of type 25 involving R3B— see Hanstein W.; Traylor, T. G. ibid. 1967, 4451; (c) for the reaction of vinylsilanes electrophiles see Miller, R. B.; Reichenbach, T. ibid. 1974, 543, and references cited therein.33 ) Kitching, W. in "Organometallic Reactions," Vol. 3, E. I. Becker and M. Tsutsui, Ed., Wiley-Interscience, New York 1972, pp. 319-398. Functional Group Classification page 12 σ?pi conjugation, such as that illustrated in 24, would be more important in those systems having shorter C- M bonds, a situation which may be unique to boron. It is noteworthy that the other group III and IV organometallic compounds, R3M—CH=CH2 (M = Al, Si, Ge, Sn) react with electrophilic reagents α to the metal. These elements all exhibit polar reactivity patterns common to G-class functions. C CHM HH R R R C C H M H H R R R El C CH M H H El El(+) (11) 1918 α β + α-attack β-attack + Metals. In deriving a class designation for metals, M, bound to carbon, two reaction types are considered. Metals undergoing exclusive substitution at the metal-carbon bond by electrophiles, El+, are classified as G-functions (eq 12), while metals which are involved in redox processes (eq 13) are classified as A-functions since such organometallic compounds also exhibit G-type behavior. R M R El R M R Nu+ Nu(–) El(+)+ (+) (–) + M(–) (13) (12)M(+)+(–) (+) The organic chemistry of Tl(III),34and Pd(II)35 (eq 14-16) illustrate the role of metals as leaving groups (reductive elimination). Oxidative addition reactions of metal carbonyl anions and alkyl halides provide examples of the reverse process.36 In general, transition metal-mediated cross-coupling reactions provide a useful illustration of the A- classification of redox metals (eq 17).37 The assignment of charge affinity labels to R1 and R2 in this case is arbitrary. Employing polar processes as the basis set of synthetic reactions, existing functional groups may be organized according to their known chemical properties. Any number of positions may be taken relative to the classification of atom reactivity. The goal of this section has been to define a general classification scheme which may be used to organize the multitude of different strategies which have been developed to construct pairwise functional group relationships in organic molecules. 34 ) Taylor, E. C.; McKillop, A. Acc. Chem. Res. 1970, 3, 338.35 ) Trost, B. M. Acc. Chem. Res. 1980, 13, 385-393.36 ) Ellis, J. E. J. Organomet. Chem. 1975, 86, 1.37 ) (a) Neuman, S. M.; Kochi, J. K. J. Org. Chem. 1975, 40, 599. (b) Normant, J. F. Synthesis 1972, 63. (c) Tamao, K.; Kiso, Y.; Sumitani, K.; Kumada, M. J. Am. Chem. Soc. 1972, 94, 9268. (d) Tamaki, A.; Magennis, S. A.; Kochi, J. K. ibid. 1973, 95, 6487. TlX2 I OMe OMeTlX2 OMe PdX R R LnMLnM RR C A reductive elimination M = Pd, Fe, Cu, Ni (17)+ (–) (+) NaCH(CO2Me)2 (16)- Pd(0) MeOH- TlX (15) (14)- TlX2 KI CH(CO2Me)2 Functional Group Classification page 13 Classification of Difunctional Relationships. One of the basic assumptions employed in synthetic design involves the maximum utilization of existing functionality at all intermediate points in the construction of a polyfunctional molecule. Such guidelines aid in minimizing the number of side reactions and protection-deprotection steps during the assemblage operation. In the synthesis of even simple difunctional organic molecules, the relative positioning of the two activating functions on the carbon framework strongly influences the reaction types that will usually be employed to establish the difunctional relationship. Using the general notation devel- oped in the previous section for activating functions, two distinct classes of difunctional relationships which may be defined between ideal E- and G-functions which may be defined are illustrated in Table V. Paths. Difunctional relationships between heteroatoms having "matched" charge affinity patterns will be defined as consonant while unmatched relationships will be labeled dissonant. It should be pointed out that the charge affinity notation is unnecessary to define the appropriate relation; other parity labels could serve equally well. For example, the number of bonds between E- and G- functions could be used to define the appropriate relationship. Employing E-functions for the purpose of illustration, the two carbonyl groups in 20a have a matched charge affinity pattern along the potential construction path. Since they are separated by three atoms they can be defined as 1,3-consonant (1,3-C). The symbol notation 20b transmits information relative to the E—E' positioning along the construction path and since the E-symbol represents a homogeneous class of electronically equivalent functional groups, a common symbol is employed. In those cases where it is necessary to recognize oxidation states of carbon to derive a symbolic structural notation, one may easily do so. Me OMe O O Me NMe2 O Me OMe Cl OMe E1 E2 H OMe O O E1 E2 Li OTHP G E O E NH O E Li CH2 Cl GC E ORNH 2 O E1 E2 Me CO2R O Me E1 E2 OO E2E1 O E O O E O E Consonant Relationships Symbol Notation 1,3–C 1,5–C 1,4–C C-cycles Table V. Consonant & Dissonant Difunctional Pairwise Functional Group Relationships NotationSymbolDissonant Relationships 1,1–D 1,2–D 1,4–D 1,2–D, 1,4–D D-cycles Me OMe O O E1 E2 E2 E1 O O (–) (+)(+) (–) (–) (+) (+) (+) (+) (-) symbol deleted for convenience 20a 20b 21a 21b Functional Group Classification page 14 Cycles. In cyclic structures, a heteroatom attached to or contained within the cycle creates a relationship with itself. For non-arbitrary mathematical considerations it is convenient to define an even- membered ring with or without a single functional group as consonant and corresponding odd- membered rings as dissonant. For the bicyclic ketone 21a, both of the oxygen heteroatoms, denoted as E1 and E2, establish consonant relationships with each other via all bond paths and individually by virtue of their position either attached to or contained within an even-membered ring. Consonant and Dissonant Bond Paths. In contrast to the uniformity with which consonant relationships may be established through common classes of polar processes, the synthetic methods and functional groups required for the construction of the bonds define a D-relationship are quite varied and involve either more steps, more functional groups or more reactive intermediates than reactions leading to C-paths. This statement will be reinforced in a series of case studies (vide infra); however a single case is presented to reinforce this assertion. Consider the Michael transform executed on the 1,5- and 1,4-dike- tones shown below (eq 18, 19). In the first instance, the transform may be executed using only the func- tional groups illustrated; however, this is not possible with the dissonant dicarbonyl relationship since one of the resulting polar fragments will be electronically mismatched with its associated FG. In the illustrated disconnection (eq 19), the electronically mismatched fragment is the carbonyl anion. R1 R2 R1 O O O R2 O O R1 R2 NO2 R1 O O R2 OR 1 R2 NO 2 O R2 OR 1 (±)(±) Nef Michael (+)(+) (–)(–)(+) (+) a54 Acyl anionequivalent (20) (19) (18) Acyl anion (–) a54 (–) (+)(+) (–) (–)(+) (+) Michael1,4-Dissonant Relationship 1,5-Consonant Relationship Michael (+)(+) (–)(+) (–)(–) (–)(+) (+)(+) One possible solution to the construction of this dissonant relationship is through FG manipula- tion. In the present instance the application of the Nef transform (vide supra) provides the opportunity to match the charge affinity patterns so that the Michael transform may be properly executed. The use of A- functions in this fashion is just one of a number of strategies which may be employed to construct disso- nant difunctional relationships. In conclusion, dissonant pairwise relationships, either identified in simple acyclic molecules or within complex cyclic structures, generally pose a greater synthetic challenge and represent seams of lower flexibility within the carbon framework. At this point, it may be instructive to the reader to contemplate a synthesis strategy based on how and when D-relationships are incorporated into target structures. This point will be addressed later in the discussion. Synthesis of Consonant Difunctional Relationships. Every complex polyfunctional molecule may be analyzed structurally in terms of its individual consonant or dissonant construction paths or cycles. For example, in the alkaloid lupinine (22) all possible construction paths interconnecting E1 and E2 are consonant. On the other hand, mesembrine (23)38 contains the potential dissonant paths and cycles illustrated in heavy lines. Consonant paths within the polyatomic framework define seams in the structure that may be constructed using aldol and related condensation processes. 38 ) (a) Curphey, T. J.; Kim, H. L. Tetrahedron Lett. 1968, 1441. (b) Keely, S. L.; Tahk, F. C. J. Am. Chem. Soc. 1968, 90, 5584. (c) Stevens, R. V.; Wentland, M. P. ibid. 1968, 90, 5580; (d) Shamma, M.; Rodrigues, H. R. Tetrahedron 1968, 24, 6583. N CH2OH E1 E2 22 (lupinine) (+) (+) (+) (+) (+) (+) Functional Group Classification page 15 a73 Regarding the number of different possibilities available for the synthesis of a consonant di- functional relationship interconnected by n bonds, there exists a set of n different connective operations that may be employed to establish any bond along the construction path from monofunctional or consonant polyfunctional precursors.39 NO Me OMe OMe E2 Ar E1 E2 Ar E1 E2 Ar E1 E2 Ar E1 N Ar O Me Shortest consonant bond path2323 (lupinine) dissonant bond paths (cycles) In the analysis of potential routes to structures like lupinine, identify the shortest consonant bond path and then proceed to carry out all polar disconnections along that bond path (Scheme XVIII). Since there four bonds interconnecting =O and N (E1 and E2), there will be four associated transforms which one may execute using the illustrated functional groups. In each set of precursors the intrinsic polar reactivity patterns of the heteroatoms are accommodated in the coupling process. The resulting adducts containing the requisite nitrogen-oxygen relationship may then be ranked in order of desirability by considering criteria such as chemical feasibility of the coupling step, ease of subsequent transformation to the target structure, and availability of precursor fragments. In the present example, transforms A and B might be more highly ranked that transform C while transform D might be discarded since it does not lead to struc- tural simplification. E2 Ar E1 E2 Ar E1 HN Ar O Me E2 Ar E1 E2 Ar E1 N Ar HO Me N Ar Me E2 Ar E1 RO2C N Ar Me (–)(–) (–) (+)(+) Shortest consonant bond path (+) (–)(+) equivalent to: equivalent to: (+) (–)(+)(–) + (–) (+) (–)(+) equivalent to: equivalent to: (+) (–)(+)(–) (–) (–) +HO– A B C D Scheme XVIII In those cases when a given consonant or dissonant relationship is separated by a significant number of bonds, it is strategically worthwhile to consider the option of incorporating additional functions to aid in the construction of the desired target molecule. The relative placement of such a functional group is of prime importance in dictating the subsequent polar disconnections that are perceived in generating a plausible synthetic tree. This point is illustrated when considering plausible precursors to ketone 24 (Scheme XIX). In this structure, the =O FG establishes a 1,5-relationship with itself on the six-membered ring. Through the addition of an appropriate second 39 ) The presence of a quaternary or bridgehead center along the construction path limits bond construction to those adjacent to the center. O R E1 R(+) (+) (+) 24 46 2 Functional Group Classification page 16 activating function to the target molecule 24, an expanded set of potential disconnections is created. In the placement of the second FG, the charge affinity pattern of the resident FG should be used. For example, consider the installation of a second FG, E2, at the (+) sites on the ring to set up aldol or Claisen transforms. In a complementary fashion the addition of C-E2 fragments to the (–) sites will open up the execution of the two possible Dieckmann transforms.40 The preceding analysis leads to the three precursors 26a-26c. Each of which contains a 1,5-consonant difunctional relationship between the carbonyl functions. These subgoals now become the focus of the next level of analysis wherein the preceding logic is again applied. It should be emphasized that the precursors illustrated in Scheme XIX are not inclusive but represent one set which leads to the generation of a synthetic tree based upon aldol and related reactions. The point to be emphasized is that in the first stage of the analysis where functionality is being added to the target structure, consonant, rather than dissonant relationships should be created. E1 R E1 RE2 E1 R E2 E1 RE 1 R E1 R R MeO R E2 O E2 O ROH O R OH O O R Me O R RO2C CO2R H O R CO2R RO2C (+) (+)(+) Where (+) add E2 Where (-) add C-E2(–) (–)(–) equivalent to: equivalent to: equivalent to: equivalent to: Scheme XIX 25a 25b 25c 25d Aldol Aldol Dieckmann Dieckmann A B C D 26a 26b 26c 40 ) To be completely rigorous with regard to this analysis, the addition of C-E2 to the 4-position should also be considered; however, the E1-E2 construction span from such a precursor is sufficiently large as to render this precursor less attractive than the other precursors 25a-25d.