有机化学（英文原版）：Chapt12

443 CHAPTER 12 REACTIONS OF ARENES: ELECTROPHILIC AROMATIC SUBSTITUTION I n the preceding chapter the special stability of benzene was described, along with reac- tions in which an aromatic ring was present as a substituent. In the present chapter we move from considering the aromatic ring as a substituent to studying it as a functional group. What kind of reactions are available to benzene and its derivatives? What sort of reagents react with arenes, and what products are formed in those reactions? Characteristically, the reagents that react with the aromatic ring of benzene and its derivatives are electrophiles. We already have some experience with electrophilic reagents, particularly with respect to how they react with alkenes. Electrophilic reagents add to alkenes. A different reaction takes place when electrophiles react with arenes. Substitution is observed instead of addition. If we represent an arene by the general formula ArH, where Ar stands for an aryl group, the electrophilic portion of the reagent replaces one of the hydrogens on the ring: Ar H Arene H11001 E Y H9254H11001 H9254H11002 Electrophilic reagent H11001Ar EHY Product of electrophilic aromatic substitution CC Alkene H11001 E Y H9254H11001 H9254H11002 Electrophilic reagent E C C Y Product of electrophilic addition Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website We call this reaction electrophilic aromatic substitution; it is one of the fundamental processes of organic chemistry. 12.1 REPRESENTATIVE ELECTROPHILIC AROMATIC SUBSTITUTION REACTIONS OF BENZENE The scope of electrophilic aromatic substitution is quite large; both the arene and the electrophilic reagent are capable of wide variation. Indeed, it is this breadth of scope that makes electrophilic aromatic substitution so important. Electrophilic aromatic substitu- tion is the method by which substituted derivatives of benzene are prepared. We can gain a feeling for these reactions by examining a few typical examples in which benzene is the substrate. These examples are listed in Table 12.1, and each will be discussed in more detail in Sections 12.3 through 12.7. First, however, let us look at the general mecha- nism of electrophilic aromatic substitution. 12.2 MECHANISTIC PRINCIPLES OF ELECTROPHILIC AROMATIC SUBSTITUTION Recall from Chapter 6 the general mechanism for electrophilic addition to alkenes: The first step is rate-determining. It is the sharing of the pair of H9266 electrons of the alkene with the electrophile to form a carbocation. Following its formation, the carbocation undergoes rapid capture by some Lewis base present in the medium. The first step in the reaction of electrophilic reagents with benzene is similar. An electrophile accepts an electron pair from the H9266 system of benzene to form a carbocation: This particular carbocation is a resonance-stabilized one of the allylic type. It is a cyclo- hexadienyl cation (often referred to as an arenium ion). H H11001 E H H11001 E H H11001 E Resonance forms of a cyclohexadienyl cation H11001 slow Y H11002 H E Y H9254H11001 H9254H11002 Benzene and electrophile H H11001 E Carbocation slow Y H9254H11002 H9254H11001 E CC Alkene and electrophile E C C H11001 Carbocation H11001 Y H11002 H11001 fast E C C Y Product of electrophilic addition E C C H11001 Carbocation Y H11002 Nucleophile 444 CHAPTER TWELVE Reactions of Arenes: Electrophilic Aromatic Substitution Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website PROBLEM 12.1 In the simplest molecular orbital treatment of conjugated sys- tems, it is assumed that the H9266 system does not interact with the framework of H9268 bonds. When this MO method was used to calculate the charge distribution in cyclohexadienyl cation, it gave the results indicated. How does the charge at each carbon compare with that deduced by examining the most stable resonance struc- tures for cyclohexadienyl cation? Most of the resonance stabilization of benzene is lost when it is converted to the cyclohexadienyl cation intermediate. In spite of being allylic, a cyclohexadienyl cation H HH H H H 0 H110010.33 0 H 0 H110010.33 H110010.33 12.2 Mechanistic Principles of Electrophilic Aromatic Substitution 445 TABLE 12.1 Representative Electrophilic Aromatic Substitution Reactions of Benzene Reaction and comments 1. Nitration Warming benzene with a mix- ture of nitric acid and sulfuric acid gives nitrobenzene. A nitro group (±NO 2 ) replaces one of the ring hydrogens. 3. Halogenation Bromine reacts with ben- zene in the presence of iron(III) bromide as a catalyst to give bromobenzene. Chlorine reacts similarly in the presence of iron(III) chloride to give chlorobenzene. 4. Friedel-Crafts alkylation Alkyl halides react with benzene in the presence of alu- minum chloride to yield alkylbenzenes. 5. Friedel-Crafts acylation An analogous reaction occurs when acyl halides react with benzene in the presence of alumi- num chloride. The products are acylben- zenes. 2. Sulfonation Treatment of benzene with hot concentrated sulfuric acid gives ben- zenesulfonic acid. A sulfonic acid group (±SO 2 OH) replaces one of the ring hydro- gens. Equation H Benzene H11001 Sulfuric acid HOSO 2 OH Benzenesulfonic acid (100%) SO 2 OH H11001 Water H 2 O heat H Benzene H11001 Bromine Br 2 Bromobenzene (65–75%) Br H11001 Hydrogen bromide HBr FeBr 3 H Benzene H11001 tert-Butyl chloride (CH 3 ) 3 CCl tert-Butylbenzene (60%) C(CH 3 ) 3 H11001 Hydrogen chloride HCl AlCl 3 0°C H Benzene H11001 H11001 Hydrogen chloride HCl Propanoyl chloride CH 3 CH 2 CCl O 1-Phenyl-1- propanone (88%) CCH 2 CH 3 O AlCl 3 40°C H11001 Nitric acid HNO 3 Nitrobenzene (95%) NO 2 H11001 Water H 2 O H 2 SO 4 30–40°C Benzene H A model showing the electrostatic potential of this carbocation can be viewed on Learning By Modeling. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website is not aromatic and possesses only a fraction of the resonance stabilization of benzene. Once formed, it rapidly loses a proton, restoring the aromaticity of the ring and giving the product of electrophilic aromatic substitution. If the Lewis base (:Y H11002 ) had acted as a nucleophile and added to carbon, the prod- uct would have been a nonaromatic cyclohexadiene derivative. Addition and substitution products arise by alternative reaction paths of a cyclohexadienyl cation. Substitution occurs preferentially because there is a substantial driving force favoring rearomatization. Figure 12.1 is a potential energy diagram describing the general mechanism of electrophilic aromatic substitution. In order for electrophilic aromatic substitution reac- tions to overcome the high activation energy that characterizes the first step, the elec- trophile must be a fairly reactive one. Many electrophilic reagents that react rapidly with alkenes do not react at all with benzene. Peroxy acids and diborane, for example, fall into this category. Others, such as bromine, react with benzene only in the presence of catalysts that increase their electrophilicity. The low level of reactivity of benzene toward H11001 Y H11002 H H11001 H E Cyclohexadienyl cation fast Observed product of electrophilic aromatic substitution E H H11001 H Y H H E Y Not observed—not aromatic 446 CHAPTER TWELVE Reactions of Arenes: Electrophilic Aromatic Substitution H Energy Reaction coordinate E E E E H H H11001 E±Y H11001 H±Y H11001 Y δH11002 Y δH11002 Y H11002 H δH11001 δH11001 FIGURE 12.1 Energy changes associated with the two steps of electrophilic aromatic substitution. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website electrophiles stems from the substantial loss of resonance stabilization that accompanies transfer of a pair of its six H9266 electrons to an electrophile. With this as background, let us now examine each of the electrophilic aromatic substitution reactions presented in Table 12.1 in more detail, especially with respect to the electrophile that attacks benzene. 12.3 NITRATION OF BENZENE Now that we’ve outlined the general mechanism for electrophilic aromatic substitution, we need only identify the specific electrophile in the nitration of benzene (see Table 12.1) to have a fairly clear idea of how the reaction occurs. Figure 12.2 shows the application of those general principles to the reaction: The electrophile (E H11001 ) that reacts with benzene is nitronium ion ( H11001 NO 2 ). The concentra- tion of nitronium ion in nitric acid alone is too low to nitrate benzene at a convenient rate, but can be increased by adding sulfuric acid. H11001HO H11001 N O O H11002 Nitric acid H11001 2HOSO 2 OH Sulfuric acid H11001 O N O Nitronium ion H11001 H 3 O H11001 Hydronium ion 2HOSO 2 O H11002 Hydrogen sulfate ion H Benzene H11001 HONO 2 Nitric acid NO 2 Nitrobenzene (95%) H11001 H 2 O Water H 2 SO 4 30–40°C 12.3 Nitration of Benzene 447 H H Benzene and nitronium ion slow O Step 1: Attack of nitronium cation on the π system of the aromatic ring Step 2: Loss of a proton from the cyclohexadienyl cation N H11001 O Cyclohexadienyl cation intermediate H11001 O H11002 H Cyclohexadienyl cation intermediate H11001 O N H11001 O H11002 H H O Water fast Nitrobenzene O H11001 H H OH H11001 Hydronium ion O N H11001 N H11001 O H11002 FIGURE 12.2 The me- chanism of the nitration of benzene. An electrostatic po- tential map of nitronium ion can be viewed on Learning By Modeling. The role of nitronium ion in the nitration of benzene was demonstrated by Sir Christo- pher Ingold–the same person who suggested the S N 1 and S N 2 mechanisms of nucle- ophilic substitution and who collaborated with Cahn and Prelog on the R and S nota- tional system. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website Nitration of the ring is not limited to benzene alone, but is a general reaction of compounds that contain a benzene ring. It would be a good idea to write out the answer to the following problem to ensure that you understand the relationship of starting mate- rials to products in aromatic nitration before continuing to the next section. PROBLEM 12.2 Nitration of 1,4-dimethylbenzene (p-xylene) gives a single prod- uct having the molecular formula C 8 H 9 NO 2 in high yield. What is this product? 12.4 SULFONATION OF BENZENE The reaction of benzene with sulfuric acid to produce benzenesulfonic acid, is reversible but can be driven to completion by several techniques. Removing the water formed in the reaction, for example, allows benzenesulfonic acid to be obtained in vir- tually quantitative yield. When a solution of sulfur trioxide in sulfuric acid is used as the sulfonating agent, the rate of sulfonation is much faster and the equilibrium is dis- placed entirely to the side of products, according to the equation Among the variety of electrophilic species present in concentrated sulfuric acid, sulfur trioxide is probably the actual electrophile in aromatic sulfonation. We can repre- sent the mechanism of sulfonation of benzene by sulfur trioxide by the sequence of steps shown in Figure 12.3. PROBLEM 12.3 On being heated with sulfur trioxide in sulfuric acid, 1,2,4,5- tetramethylbenzene was converted to a product of molecular formula C 10 H 14 O 3 S in 94% yield. Suggest a reasonable structure for this product. 12.5 HALOGENATION OF BENZENE According to the usual procedure for preparing bromobenzene, bromine is added to ben- zene in the presence of metallic iron (customarily a few carpet tacks) and the reaction mixture is heated. H Benzene H11001 Br 2 Bromine Br Bromobenzene (65–75%) H11001 HBr Hydrogen bromide Fe heat Benzene H11001 SO 3 Sulfur trioxide SO 2 OH Benzenesulfonic acid H 2 SO 4 H Benzene H11001 HOSO 2 OH Sulfuric acid SO 2 OH Benzenesulfonic acid H11001 H 2 O Water heat 448 CHAPTER TWELVE Reactions of Arenes: Electrophilic Aromatic Substitution Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website Bromine, although it adds rapidly to alkenes, is too weak an electrophile to react at an appreciable rate with benzene. A catalyst that increases the electrophilic properties of bromine must be present. Somehow carpet tacks can do this. How? The active catalyst is not iron itself but iron(III) bromide, formed by reaction of iron and bromine. Iron(III) bromide is a weak Lewis acid. It combines with bromine to form a Lewis acid- Lewis base complex. H11001Br Br Lewis base FeBr 3 Lewis acid FeBr 3 H11001 H11002 Br Br Lewis acid-Lewis base complex H11001 3Br 2 Bromine 2Fe Iron 2FeBr 3 Iron(III) bromide 12.5 Halogenation of Benzene 449 O H Benzene and sulfur trioxide slow Step 1: Sulfur trioxide attacks benzene in the rate-determining step Step 3: A rapid proton transfer from the oxygen of sulfuric acid to the oxygen of benzenesulfonate completes the process. Step 2: A proton is lost from the sp 3 hybridized carbon of the intermediate to restore the aromaticity of the ring. The species shown that abstracts the proton is a hydrogen sulfate ion formed by ionization of sulfuric acid. S O H11002 H11001 H Cyclohexadienyl cation intermediate O O S H11001 H11001 O H11002 O H11002 H11001 Cyclohexadienyl cation intermediate fast H H11002 OSO 2 OH Hydrogen sulfate ion Benzenesulfonate ion H11001 HOSO 2 OH Sulfuric acid Benzenesulfonate ion H±OSO 2 OH Sulfuric acid fast H11001 H11002 OSO 2 OH Hydrogen sulfate ion Benzenesulfonic acid H O S H11001 O H11002 O H11002 O H11002 O H11002 O S H11001 O H11002 O±O S H11001 O H11002 O S H11001 O H11002 FIGURE 12.3 The me- chanism of sulfonation of benzene. An electrostatic po- tential map of sulfur trioxide can be viewed on Learning By Modeling. Iron(III) bromide (FeBr 3 ) is also called ferric bromide. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website Complexation of bromine with iron(III) bromide makes bromine more elec- trophilic, and it attacks benzene to give a cyclohexadienyl intermediate as shown in step 1 of the mechanism depicted in Figure 12.4. In step 2, as in nitration and sulfonation, loss of a proton from the cyclohexadienyl cation is rapid and gives the product of elec- trophilic aromatic substitution. Only small quantities of iron(III) bromide are required. It is a catalyst for the bromination and, as Figure 12.4 indicates, is regenerated in the course of the reaction. We’ll see later in this chapter that some aromatic substrates are much more reactive than benzene and react rapidly with bromine even in the absence of a catalyst. Chlorination is carried out in a manner similar to bromination and provides a ready route to chlorobenzene and related aryl chlorides. Fluorination and iodination of benzene and other arenes are rarely performed. Fluorine is so reactive that its reaction with benzene is difficult to control. Iodination is very slow and has an unfavorable equilibrium constant. Syntheses of aryl fluorides and aryl iodides are normally carried out by way of functional group transformations of arylamines; these reactions will be described in Chapter 22. 12.6 FRIEDEL–CRAFTS ALKYLATION OF BENZENE Alkyl halides react with benzene in the presence of aluminum chloride to yield alkyl- benzenes. H Benzene H11001 (CH 3 ) 3 CCl tert-Butyl chloride C(CH 3 ) 3 tert-Butylbenzene (60%) H11001 HCl Hydrogen chloride AlCl 3 0°C 450 CHAPTER TWELVE Reactions of Arenes: Electrophilic Aromatic Substitution H H Benzene and bromine–iron(III) bromide complex slow Br±Br±FeBr 3 Cyclohexadienyl cation intermediate H11001 Step 2: Loss of a proton from the cyclohexadienyl cation yields bromobenzene. Step 1: The bromine–iron(III) bromide complex is the active electrophile that attacks benzene. Two of the π electrons of benzene are used to form a bond to bromine and give a cyclohexadienyl cation intermediate. Br H11001 Tetrabromoferrate ion H Cyclohexadienyl cation intermediate H11001 Tetrabromoferrate ion fast Bromobenzene Hydrogen bromide Iron(III) bromide H11002 H11002 H11001 Br±FeBr 3 Br H11001 H±Br H11001 FeBr 3 Br Br±FeBr 3 H11002 FIGURE 12.4 The mechanism of bromination of benzene. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website Alkylation of benzene with alkyl halides in the presence of aluminum chloride was dis- covered by Charles Friedel and James M. Crafts in 1877. Crafts, who later became pres- ident of the Massachusetts Institute of Technology, collaborated with Friedel at the Sor- bonne in Paris, and together they developed what we now call the Friedel–Crafts reaction into one of the most useful synthetic methods in organic chemistry. Alkyl halides by themselves are insufficiently electrophilic to react with ben- zene. Aluminum chloride serves as a Lewis acid catalyst to enhance the elec- trophilicity of the alkylating agent. With tertiary and secondary alkyl halides, the addi- tion of aluminum chloride leads to the formation of carbocations, which then attack the aromatic ring. Figure 12.5 illustrates attack on the benzene ring by tert-butyl cation (step 1) and subsequent formation of tert-butylbenzene by loss of a proton from the cyclohexadienyl cation intermediate (step 2). Secondary alkyl halides react by a similar mechanism involving attack on benzene by a secondary carbocation. Methyl and ethyl halides do not form carbocations when treated with aluminum chloride, but do alkylate benzene under Friedel–Crafts conditions. AlCl 3 H11001 H11002 Cl(CH 3 ) 3 C tert-Butyl chloride– aluminum chloride complex tert-Butyl cation (CH 3 ) 3 C H11001 H11001 AlCl 4 H11002 Tetrachloroaluminate anion H11001(CH 3 ) 3 CCl tert-Butyl chloride AlCl 3 Aluminum chloride AlCl 3 H11001 H11002 Cl(CH 3 ) 3 C Lewis acid-Lewis base complex 12.6 Friedel–Crafts Alkylation of Benzene 451 H Benzene and tert-butyl cation slow Step 1: Once generated by the reation of tert-butyl chloride and aluminum chloride, tert-butyl cation attacks the H9266 electrons of benzene, and a carbon-carbon bond is formed. Step 2: Loss of a proton from the cyclohexadienyl cation intermediate yields tert-butylbenzene. C H11001 H Cyclohexadienyl cation intermediate H11001 C(CH 3 ) 3 C(CH 3 ) 3 C(CH 3 ) 3 H11001 Cyclohexadienyl cation intermediate fast H Cl Tetrachloroaluminate ion tert-Butylbenzene H11002 H11001 HCl Hydrogen chloride CH 3 CH 3 CH 3 AlCl 3 H11001 Aluminum chloride AlCl 3 H11001 FIGURE 12.5 The mechanism of Friedel–Crafts alkylation. An electrostatic potential map of tert-butyl cation can be viewed on Learning By Modeling. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website The aluminum chloride complexes of methyl and ethyl halides contain highly polarized carbon–halogen bonds, and these complexes are the electrophilic species that react with benzene. One drawback to Friedel–Crafts alkylation is that rearrangements can occur, espe- cially when primary alkyl halides are used. For example, Friedel–Crafts alkylation of benzene with isobutyl chloride (a primary alkyl halide) yields only tert-butylbenzene. Here, the electrophile is tert-butyl cation formed by a hydride migration that accompa- nies ionization of the carbon–chlorine bond. PROBLEM 12.4 In an attempt to prepare propylbenzene, a chemist alkylated benzene with 1-chloropropane and aluminum chloride. However, two isomeric hydrocarbons were obtained in a ratio of 2:1, the desired propylbenzene being the minor component. What do you think was the major product? How did it arise? Since electrophilic attack on benzene is simply another reaction available to a car- bocation, other carbocation precursors can be used in place of alkyl halides. For exam- ple, alkenes, which are converted to carbocations by protonation, can be used to alky- late benzene. PROBLEM 12.5 Write a reasonable mechanism for the formation of cyclohexyl- benzene from the reaction of benzene, cyclohexene, and sulfuric acid. Alkenyl halides such as vinyl chloride (CH 2 ?CHCl) do not form carbocations on treatment with aluminum chloride and so cannot be used in Friedel–Crafts reactions. H 2 SO 4 Benzene H11001 Cyclohexene Cyclohexylbenzene (65–68%) CH 3 CH 3 H C CH 2 AlCl 3 H11002 H11001 Cl Isobutyl chloride– aluminum chloride complex H11001 CH 3 CH 3 C H CH 2 tert-Butyl cation H11001 H11002 AlCl 4 Tetrachloroaluminate ion H Benzene H11001 (CH 3 ) 2 CHCH 2 Cl Isobutyl chloride C(CH 3 ) 3 tert-Butylbenzene (66%) H11001 HCl Hydrogen chloride AlCl 3 0°C CH 3 H11001 X AlX 3 H11002 Methyl halide–aluminum halide complex CH 3 CH 2 H11001 X AlX 3 H11002 Ethyl halide–aluminum halide complex 452 CHAPTER TWELVE Reactions of Arenes: Electrophilic Aromatic Substitution Other limitations to Friedel–Crafts reactions will be encountered in this chap- ter and are summarized in Table 12.4. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website Thus, the industrial preparation of styrene from benzene and ethylene does not involve vinyl chloride but proceeds by way of ethylbenzene. Dehydrogenation of alkylbenzenes, although useful in the industrial preparation of styrene, is not a general procedure and is not well suited to the laboratory preparation of alkenylbenzenes. In such cases an alkylbenzene is subjected to benzylic bromination (Section 11.12), and the resulting benzylic bromide is treated with base to effect dehy- drohalogenation. PROBLEM 12.6 Outline a synthesis of 1-phenylcyclohexene from benzene and cyclohexene. 12.7 FRIEDEL–CRAFTS ACYLATION OF BENZENE Another version of the Friedel–Crafts reaction uses acyl halides instead of alkyl halides and yields acylbenzenes. The electrophile in a Friedel–Crafts acylation reaction is an acyl cation (also referred to as an acylium ion). Acyl cations are stabilized by resonance. The acyl cation derived from propanoyl chloride is represented by the two resonance forms Acyl cations form by coordination of an acyl chloride with aluminum chloride, followed by cleavage of the carbon–chlorine bond. The electrophilic site of an acyl cation is its acyl carbon. An electrostatic poten- tial map of the acyl cation from propanoyl chloride (Figure 12.6) illustrates nicely the concentration of positive charge at the acyl carbon. The mechanism of the reaction between this cation and benzene is analogous to that of other electrophilic reagents (Fig- ure 12.7). CH 3 CH 2 C H11001 O H11001 CH 3 CH 2 CO Most stable resonance form; oxygen and carbon have octets of electrons H Benzene H11001 CH 3 CH 2 CCl O Propanoyl chloride AlCl 3 carbon disulfide 40°C CCH 2 CH 3 O 1-Phenyl-1-propanone (88%) H11001 HCl Hydrogen chloride Benzene H11001 CH 2 CH 2 Ethylene HCl, AlCl 3 630°C ZnO CH 2 CH 3 Ethylbenzene CH CH 2 Styrene 12.7 Friedel–Crafts Acylation of Benzene 453 CH 3 CH 2 C O Cl Propanoyl chloride H11001 AlCl 3 Aluminum chloride Tetrachloro- aluminate ion AlCl 4 H11002 Propanoyl cation H11001 CH 3 CH 2 COCH 3 CH 2 C O AlCl 3 H11002 H11001 Cl Lewis acid-Lewis base complex H11001 An acyl group has the gen- eral formula RC± O X Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website PROBLEM 12.7 The reaction shown gives a single product in 88% yield. What is that product? Acyl chlorides are readily available. They are prepared from carboxylic acids by reaction with thionyl chloride. RCOH O Carboxylic acid H11001 SOCl 2 Thionyl chloride Hydrogen chloride HClRCCl O Acyl chloride H11001 Sulfur dioxide SO 2 H11001 CH 3 O OCH 3 OCH 3 H11001 (CH 3 ) 2 CHCH 2 CCl O AlCl 3 454 CHAPTER TWELVE Reactions of Arenes: Electrophilic Aromatic Substitution Step 1: The acyl cation attacks benzene. A pair of π electrons of benzene is used to form a covalent bond to the carbon of the acyl cation. Step 2: Aromaticity of the ring is restored when it loses a proton to give the acylbenzene. H11001 Cyclohexadienyl cation intermediate fast H Cl Tetrachloroaluminate ion H11001 H Hydrogen chloride H11002 AlCl 3 H11001 Aluminum chloride AlCl 3 H H Benzene and propanoyl cation slow O H11001 C CH 2 CH 3 Cyclohexadienyl cation intermediate H11001 1-Phenyl-1-propanone P O X O X O X Cl W CCH 2 CH 3 CCH 2 CH 3 CCH 2 CH 3 FIGURE 12.6 Electrostatic potential map of propanoyl cation [(CH 3 CH 2 C?O) H11001 ]. The re- gion of greatest positive charge (blue) is associated with the carbon of the C?O group. FIGURE 12.7 The mechanism of Friedel–Crafts acylation. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website Carboxylic acid anhydrides, compounds of the type , can also serve as sources of acyl cations and, in the presence of aluminum chloride, acylate benzene. One acyl unit of an acid anhydride becomes attached to the benzene ring, while the other becomes part of a carboxylic acid. PROBLEM 12.8 Succinic anhydride, the structure of which is shown, is a cyclic anhydride often used in Friedel–Crafts acylations. Give the structure of the prod- uct obtained when benzene is acylated with succinic anhydride in the presence of aluminum chloride. An important difference between Friedel–Crafts alkylations and acylations is that acyl cations do not rearrange. The acyl group of the acyl chloride or acid anhydride is transferred to the benzene ring unchanged. The reason for this is that an acyl cation is so strongly stabilized by resonance that it is more stable than any ion that could con- ceivably arise from it by a hydride or alkyl group shift. 12.8 SYNTHESIS OF ALKYLBENZENES BY ACYLATION–REDUCTION Because acylation of an aromatic ring can be accomplished without rearrangement, it is frequently used as the first step in a procedure for the alkylation of aromatic compounds by acylation–reduction. As we saw in Section 12.6, Friedel–Crafts alkylation of benzene with primary alkyl halides normally yields products having rearranged alkyl groups as substituents. When a compound of the type ArCH 2 R is desired, a two-step sequence is used in which the first step is a Friedel–Crafts acylation. Benzene RCCl AlCl 3 O X reduction Acylbenzene CH 2 R Alkylbenzene CR O C H11001 R OC More stable cation; all atoms have octets of electrons H11001 R O CC Less stable cation; six electrons at carbon O O O H Benzene H11001 CH 3 COCCH 3 O O Acetic anhydride CH 3 COH O Acetic acid AlCl 3 40°C H11001CCH 3 O Acetophenone (76–83%) RCOCR O O 12.8 Synthesis of Alkylbenzenes by Acylation–Reduction 455 Acetophenone is one of the commonly encountered ben- zene derivatives listed in Table 11.1. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website The second step is a reduction of the carbonyl group (C?O) to a methylene group (CH 2 ). The most commonly used method for reducing an acylbenzene to an alkylbenzene employs a zinc–mercury amalgam in concentrated hydrochloric acid and is called the Clemmensen reduction. The synthesis of butylbenzene illustrates the acylation–reduction sequence. Direct alkylation of benzene using 1-chlorobutane and aluminum chloride would yield sec-butylbenzene by rearrangement and so could not be used. PROBLEM 12.9 Using benzene and any necessary organic or inorganic reagents, suggest efficient syntheses of (a) Isobutylbenzene, C 6 H 5 CH 2 CH(CH 3 ) 2 (b) Neopentylbenzene, C 6 H 5 CH 2 C(CH 3 ) 3 SAMPLE SOLUTION (a) Friedel–Crafts alkylation of benzene with isobutyl chlo- ride is not suitable, because it yields tert-butylbenzene by rearrangement. The two-step acylation–reduction sequence is required. Acylation of benzene puts the side chain on the ring with the correct carbon skeleton. Clemmensen reduc- tion converts the carbonyl group to a methylene group. Another way to reduce aldehyde and ketone carbonyl groups is by Wolff–Kishner reduction. Heating an aldehyde or a ketone with hydrazine (H 2 NNH 2 ) and sodium or potassium hydroxide in a high-boiling alcohol such as triethylene glycol (HOCH 2 CH 2 OCH 2 CH 2 OCH 2 CH 2 OH, bp 287°C) converts the carbonyl to a CH 2 group. Both the Clemmensen and the Wolff–Kishner reductions are designed to carry out a specific functional group transformation, the reduction of an aldehyde or ketone carbonyl to a methylene group. Neither one will reduce the carbonyl group of a carboxylic acid, nor H 2 NNH 2 , KOH triethylene glycol, 175°C CH 2 CH 2 CH 3 Propylbenzene (82%)1-Phenyl-1-propanone CCH 2 CH 3 O AlCl 3 Benzene H11001 (CH 3 ) 2 CHCH 2 Cl Isobutyl chloride C(CH 3 ) 3 tert-Butylbenzene (66%) 456 CHAPTER TWELVE Reactions of Arenes: Electrophilic Aromatic Substitution Benzene AlCl 3 Zn(Hg) HCl CH 2 CH 2 CH 2 CH 3 Butylbenzene (73%)1-Phenyl-1-butanone (86%) CCH 2 CH 2 CH 3 O H11001 Butanoyl chloride CH 3 CH 2 CH 2 CCl O AlCl 3 Zn(Hg) HCl Benzene H11001 2-Methylpropanoyl chloride (CH 3 ) 2 CHCCl O CCH(CH 3 ) 2 O 2-Methyl-1-phenyl-1-propanone (84%) CH 2 CH(CH 3 ) 2 Isobutylbenzene (80%) Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website are carbon–carbon double or triple bonds affected by these methods. We will not discuss the mechanism of either the Clemmensen reduction or the Wolff–Kishner reduction, since both involve chemistry that is beyond the scope of what we have covered to this point. 12.9 RATE AND REGIOSELECTIVITY IN ELECTROPHILIC AROMATIC SUBSTITUTION So far we’ve been concerned only with electrophilic substitution of benzene. Two impor- tant questions arise when we turn to analogous substitutions on rings that already bear at least one substituent: 1. What is the effect of a substituent on the rate of electrophilic aromatic substitu- tion? 2. What is the effect of a substituent on the regioselectivity of electrophilic aromatic substitution? To illustrate substituent effects on rate, consider the nitration of benzene, toluene, and (trifluoromethyl)benzene. Toluene undergoes nitration some 20–25 times faster than benzene. Because toluene is more reactive than benzene, we say that a methyl group activates the ring toward electrophilic aromatic substitution. (Trifluoromethyl)benzene, on the other hand, undergoes nitration about 40,000 times more slowly than benzene. We say that a triflu- oromethyl group deactivates the ring toward electrophilic aromatic substitution. Just as there is a marked difference in how methyl and trifluoromethyl substituents affect the rate of electrophilic aromatic substitution, so too there is a marked difference in how they affect its regioselectivity. Three products are possible from nitration of toluene: o-nitrotoluene, m-nitro- toluene, and p-nitrotoluene. All are formed, but not in equal amounts. Together, the ortho- and para-substituted isomers make up 97% of the product mixture; the meta only 3%. Because substitution in toluene occurs primarily at positions ortho and para to methyl, we say that a methyl substituent is an ortho, para director. Nitration of (trifluoromethyl)benzene, on the other hand, yields almost exclusively m-nitro(trifluoromethyl)benzene (91%). The ortho- and para-substituted isomers are minor components of the reaction mixture. H11001 CH 3 Toluene HNO 3 Acetic anhydride CH 3 NO 2 o-Nitrotoluene (63%) H11001 CH 3 NO 2 m-Nitrotoluene (3%) NO 2 CH 3 p-Nitrotoluene (34%) CH 3 Toluene (most reactive) Benzene CF 3 (Trifluoromethyl)benzene (least reactive) 12.9 Rate and Regioselectivity in Electrophilic Aromatic Substitution 457 Examine the molecular models of toluene and (trifluo- romethyl)benzene on Learning By Modeling. In which molecule is the electrostatic potential of the ring most negative? How should this affect the rate of nitration? How do the charges on the ring carbons of toluene and (trifluoromethyl)benzene relate to the regioselectivity of nitra- tion? Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website Because substitution in (trifluoromethyl)benzene occurs primarily at positions meta to the substituent, we say that a trifluoromethyl group is a meta director. The regioselectivity of substitution, like the rate, is strongly affected by the sub- stituent. In the following several sections we will examine the relationship between the structure of the substituent and its effect on rate and regioselectivity of electrophilic aro- matic substitution. 12.10 RATE AND REGIOSELECTIVITY IN THE NITRATION OF TOLUENE Why is there such a marked difference between methyl and trifluoromethyl substituents in their influence on electrophilic aromatic substitution? Methyl is activating and ortho, para-directing; trifluoromethyl is deactivating and meta-directing. The first point to remember is that the regioselectivity of substitution is set once the cyclohexadienyl cation intermediate is formed. If we can explain why we will understand the reasons for the regioselectivity. A principle we have used before serves us well here: a more stable carbocation is formed faster than a less stable one. The most likely reason for the directing effect of methyl must be that the cyclohexadi- enyl cation precursors to o- and p-nitrotoluene are more stable than the one leading to m-nitrotoluene. One way to assess the relative stabilities of these various intermediates is to exam- ine electron delocalization in them using a resonance description. The cyclohexadienyl cations leading to o- and p-nitrotoluene have tertiary carbocation character. Each has a resonance form in which the positive charge resides on the carbon that bears the methyl group. Ortho attack This resonance form is a tertiary carbocation CH 3 NO 2 H H11001 CH 3 NO 2 H H11001 CH 3 NO 2 H H11001 CH 3 NO 2 H H11001 and H11001 CH 3 NO 2 H are formed faster than H11001 CH 3 NO 2 H H11001 CF 3 (Trifluoromethyl)benzene HNO 3 H 2 SO 4 CF 3 NO 2 o-Nitro(trifluoro- methyl)benzene (6%) H11001 CF 3 NO 2 m-Nitro(trifluoro- methyl)benzene (91%) NO 2 CF 3 p-Nitro(trifluoro- methyl)benzene (3%) 458 CHAPTER TWELVE Reactions of Arenes: Electrophilic Aromatic Substitution Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website Para attack The three resonance forms of the intermediate leading to meta substitution are all secondary carbocations. Meta attack Because of their tertiary carbocation character the intermediates leading to ortho and to para substitution are more stable and are formed faster than the one leading to meta substitution. They are also more stable than the secondary cyclohexadienyl cation intermediate formed during nitration of benzene. A methyl group is an activating sub- stituent because it stabilizes the carbocation intermediate formed in the rate-determining step more than a hydrogen does. It is ortho, para-directing because it stabilizes the car- bocation formed by electrophilic attack at these positions more than it stabilizes the inter- mediate formed by attack at the meta position. Figure 12.8 compares the energies of acti- vation for attack at the various positions of toluene. NO 2 H CH 3 H11001 NO 2 H CH 3 H11001 NO 2 H CH 3 H11001 CH 3 H11001 NO 2 H CH 3 H11001 NO 2 H This resonance form is a tertiary carbocation H11001 CH 3 NO 2 H 12.10 Rate and Regioselectivity in the Nitration of Toluene 459 (a) E act (benzene) (b) E act (ortho) (c) E act (meta) (d) E act (para) Energy CH 3 CH 3 CH 3 NO 2 NO 2 NO 2 NO 2 CH 3 CH 3 CH 3 H H H H H11001 H11001 H11001 H11001 , NO 2 + , NO 2 + , NO 2 + , NO 2 + FIGURE 12.8 Comparative energy diagrams for nitronium ion attack on (a) benzene and at the (b) ortho, (c) meta, and (d) para positions of toluene. E act (benzene) H11022 E act (meta) H11022 E act (ortho) H11022 E act (para). Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website A methyl group is an electron-releasing substituent and activates all of the ring carbons of toluene toward electrophilic attack. The ortho and para positions are activated more than the meta positions. The relative rates of attack at the various positions in toluene compared with a single position in benzene are as follows (for nitration at 25°C): These relative rate data per position are experimentally determined and are known as partial rate factors. They offer a convenient way to express substituent effects in elec- trophilic aromatic substitution reactions. The major influence of the methyl group is electronic. The most important factor is relative carbocation stability. To a small extent, the methyl group sterically hinders the ortho positions, making attack slightly more likely at the para carbon than at a single ortho carbon. However, para substitution is at a statistical disadvantage, since there are two equivalent ortho positions but only one para position. PROBLEM 12.10 The partial rate factors for nitration of tert-butylbenzene are as shown. (a) How reactive is tert-butylbenzene toward nitration compared with benzene? (b) How reactive is tert-butylbenzene toward nitration compared with toluene? (c) Predict the distribution among the various mononitration products of tert- butylbenzene. SAMPLE SOLUTION (a) Benzene has six equivalent sites at which nitration can occur. Summing the individual relative rates of attack at each position in tert- butylbenzene and benzene, we obtain tert-Butylbenzene undergoes nitration 15 times faster than benzene. All alkyl groups, not just methyl, are activating substituents and ortho, para direc- tors. This is because any alkyl group, be it methyl, ethyl, isopropyl, tert-butyl, or any other, stabilizes a carbocation site to which it is directly attached. When R H11005 alkyl, and are more stable than H11001 R E H R E H H11001 H11001 R EH tert-Butylbenzene Benzene H11005 2(4.5) H11001 2(3) H11001 75 6(1) H11005 90 6 H11005 15 C(CH 3 ) 3 33 75 4.54.5 CH 3 4242 2.52.5 58 11 11 1 1 relative to 460 CHAPTER TWELVE Reactions of Arenes: Electrophilic Aromatic Substitution Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website where E is any electrophile. All three structures are more stable for R H11005 alkyl than for R H11005 H and are formed more quickly. 12.11 RATE AND REGIOSELECTIVITY IN THE NITRATION OF (TRIFLUOROMETHYL)BENZENE Turning now to electrophilic aromatic substitution in (trifluoromethyl)benzene, we con- sider the electronic properties of a trifluoromethyl group. Because of their high elec- tronegativity the three fluorine atoms polarize the electron distribution in their H9268 bonds to carbon, so that carbon bears a partial positive charge. Unlike a methyl group, which is slightly electron-releasing, a trifluoromethyl group is a powerful electron-withdrawing substituent. Consequently, a CF 3 group destabilizes a car- bocation site to which it is attached. When we examine the cyclohexadienyl cation intermediates involved in the nitra- tion of (trifluoromethyl)benzene, we find that those leading to ortho and para substitu- tion are strongly destabilized. Ortho attack Para attack CF 3 H11001 NO 2 H CF 3 H11001 NO 2 H Positive charge on carbon bearing trifluoromethyl group; very unstable H11001 CF 3 NO 2 H Positive charge on carbon bearing trifluoromethyl group; very unstable CF 3 NO 2 H H11001 CF 3 NO 2 H H11001 CF 3 NO 2 H H11001 CH 3 C H11001 Methyl group releases electrons, stabilizes carbocation more stable than HC H11001 more stable than F 3 CC H11001 Trifluoromethyl group withdraws electrons, destabilizes carbocation C F H9254H11002 F H9254H11002 F H9254H11002 H9254H11001 12.11 Rate and Regioselectivity in the Nitration of (Trifluoromethyl)benzene 461 Recall from Section 4.10 that effects that are transmitted by the polarization of H9268 bonds are called inductive effects. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website None of the three major resonance forms of the intermediate formed by attack at the meta position has a positive charge on the carbon bearing the trifluoromethyl substituent. Meta attack Attack at the meta position leads to a more stable intermediate than attack at either the ortho or the para position, and so meta substitution predominates. Even the inter- mediate corresponding to meta attack, however, is very unstable and is formed with dif- ficulty. The trifluoromethyl group is only one bond farther removed from the positive charge here than it is in the ortho and para intermediates and so still exerts a significant, although somewhat diminished, destabilizing effect. All the ring positions of (trifluoromethyl)benzene are deactivated compared with benzene. The meta position is simply deactivated less than the ortho and para positions. The partial rate factors for nitration of (trifluoromethyl)benzene are Figure 12.9 compares the energy profile for nitration of benzene with those for attack at the ortho, meta, and para positions of (trifluoromethyl)benzene. The presence of the electron-withdrawing trifluoromethyl group raises the activation energy for attack at all the ring positions, but the increase is least for attack at the meta position. CF 3 4.5 H11003 10 H110026 4.5 H11003 10 H110026 67 H11003 10 H110026 67 H11003 10 H110026 4.5 H11003 10 H110026 11 11 1 1 compared with NO 2 H CF 3 H11001 NO 2 H CF 3 H11001 NO 2 H CF 3 H11001 462 CHAPTER TWELVE Reactions of Arenes: Electrophilic Aromatic Substitution (a) E act (benzene) (b) E act (ortho) (c) E act (meta) (d) E act (para) Energy CF 3 CF 3 CF 3 CF 3 NO 2 NO 2 NO 2 NO 2 H H H H + + + + , NO 2 + , NO 2 + , NO 2 + , NO 2 + CF 3 CF 3 FIGURE 12.9 Comparative energy diagrams for nitro- nium ion attack on (a) ben- zene and at the (b) ortho, (c) meta, and (d ) para posi- tions of (trifluoromethyl)- benzene. E act (ortho) H11022 E act (para) H11022 E act (meta) H11022 E act (benzene). Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website PROBLEM 12.11 The compounds benzyl chloride (C 6 H 5 CH 2 Cl), (dichloro- methyl)benzene (C 6 H 5 CHCl 2 ), and (trichloromethyl)benzene (C 6 H 5 CCl 3 ) all undergo nitration more slowly than benzene. The proportion of m-nitro-substituted prod- uct is 4% in one, 34% in another, and 64% in another. Classify the substituents ±CH 2 Cl, ±CHCl 2 , and ±CCl 3 according to each one’s effect on rate and regio- selectivity in electrophilic aromatic substitution. 12.12 SUBSTITUENT EFFECTS IN ELECTROPHILIC AROMATIC SUBSTITUTION: ACTIVATING SUBSTITUENTS Our analysis of substituent effects has so far centered on two groups: methyl and triflu- oromethyl. We have seen that a methyl substituent is activating and ortho, para-directing. A trifluoromethyl group is strongly deactivating and meta-directing. What about other substituents? Table 12.2 summarizes orientation and rate effects in electrophilic aromatic sub- stitution reactions for a variety of frequently encountered substituents. It is arranged in order of decreasing activating power: the most strongly activating substituents are at the top, the most strongly deactivating substituents are at the bottom. The main features of the table can be summarized as follows: 1. All activating substituents are ortho, para directors. 2. Halogen substituents are slightly deactivating but are ortho, para-directing. 3. Strongly deactivating substituents are meta directors. Some of the most powerful activating substituents are those in which an oxygen atom is attached directly to the ring. These substituents include the hydroxyl group as well as alkoxy and acyloxy groups. All are ortho, para directors. Hydroxyl, alkoxy, and acyloxy groups activate the ring to such an extent that bromina- tion occurs rapidly even in the absence of a catalyst. Br 2 acetic acid OCH 3 Anisole Br OCH 3 p-Bromoanisole (90%) HO Hydroxyl RO Alkoxy RCO O Acyloxy H11001 acetic acid OH Phenol HNO 3 NO 2 OH o-Nitrophenol (44%) H11001 NO 2 OH p-Nitrophenol (56%) 12.12 Substituent Effects in Electrophilic Aromatic Substitution: Activating Substituents 463 Phenol and anisole are among the commonly en- countered benzene deriva- tives listed in Table 11.1. Electrophilic aromatic substi- tution in phenol is discussed in more detail in Section 24.8. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website The inductive effect of hydroxyl and alkoxy groups, because of the electronega- tivity of oxygen, is to withdraw electrons and would seem to require that such sub- stituents be deactivating. The electron-withdrawing inductive effect, however, is over- come by a much larger electron-releasing effect involving the unshared electron pairs of oxygen. Attack at positions ortho and para to a carbon that bears a substituent of the type gives a cation stabilized by delocalization of an unshared electron pair of oxygen into the H9266 system of the ring (a resonance or conjugation effect). OR 464 CHAPTER TWELVE Reactions of Arenes: Electrophilic Aromatic Substitution TABLE 12.2 Classification of Substituents in Electrophilic Aromatic Substitution Reactions Effect on rate Very strongly activating Activating Standard of comparison Deactivating Strongly deactivating Very strongly deactivating Strongly activating Effect on orientation Ortho, para-directing Ortho, para-directing Ortho, para-directing Meta-directing Meta-directing Ortho, para-directing ±R ±Ar ±CH?CR 2 ±CPN ±SO 3 H ±CF 3 ±NO 2 Substituent ±NH 2 ±NHR ±NR 2 ±OH ±NHCR O X ±OR ±OCR O X ±CH O X ±CR O X ±COH O X ±COR O X ±CCl O X ±H ±X (X H11005 F, Cl, Br, I) ±CH 2 X (alkyl) (aryl) (alkenyl) (cyano) (sulfonic acid) (trifluoromethyl) (nitro) (amino) (alkylamino) (dialkylamino) (hydroxyl) (acylamino) (acyloxy) (alkoxy) (formyl) (acyl) (carboxylic acid) (ester) (acyl chloride) (hydrogen) (halogen) (halomethyl) Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website Ortho attack Para attack Oxygen-stabilized carbocations of this type are far more stable than tertiary carbocations. They are best represented by structures in which the positive charge is on oxygen because all the atoms have octets of electrons in such a structure. Their stability permits them to be formed rapidly, resulting in rates of electrophilic aromatic substitution that are much faster than that of benzene. The lone pair on oxygen cannot be directly involved in carbocation stabilization when attack is meta to the substituent. Meta attack The greater stability of the carbocations arising from attack at the ortho and para posi- tions compared with the carbocation formed by attack at the position meta to the oxy- gen substituent explains the ortho, para-directing property of hydroxyl, alkoxy, and acy- loxy groups. Nitrogen-containing substituents related to the amino group are even more strongly activating than the corresponding oxygen-containing substituents. Oxygen lone pair cannot be used to stabilize positive charge in any of these structures; all have six electrons around positively charged carbon. OR H11001 H E H11001 OR H E H11001 OR H E H11001 HE OR HE H11001 OR Most stable resonance form; oxygen and all carbons have octets of electrons OR H11001 HE H11001 OR HE E OR H H11001 E H H11001 OR H E H11001 OR Most stable resonance form; oxygen and all carbons have octets of electrons H H11001 E OR 12.12 Substituent Effects in Electrophilic Aromatic Substitution: Activating Substituents 465 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website The nitrogen atom in each of these groups bears an electron pair that, like the unshared pairs of an oxygen substituent, stabilizes a carbocation site to which it is attached. Since nitrogen is less electronegative than oxygen, it is a better electron pair donor and stabi- lizes the cyclohexadienyl cation intermediates in electrophilic aromatic substitution to an even greater degree. PROBLEM 12.12 Write structural formulas for the cyclohexadienyl cations formed from aniline (C 6 H 5 NH 2 ) during (a) Ortho bromination (four resonance structures) (b) Meta bromination (three resonance structures) (c) Para bromination (four resonance structures) SAMPLE SOLUTION (a) There are the customary three resonance structures for the cyclohexadienyl cation plus a resonance structure (the most stable one) derived by delocalization of the nitrogen lone pair into the ring. Alkyl groups are, as we saw when we discussed the nitration of toluene in Sec- tion 12.10, activating and ortho, para-directing substituents. Aryl and alkenyl substituents resemble alkyl groups in this respect; they too are activating and ortho, para-directing. PROBLEM 12.13 Treatment of biphenyl (see Section 11.7 to remind yourself of its structure) with a mixture of nitric acid and sulfuric acid gave two principal products both having the molecular formula C 12 H 9 NO 2 . What are these two products? The next group of substituents in Table 12.2 that we’ll discuss are the ones near the bottom of the table, those that are meta-directing and strongly deactivating. 12.13 SUBSTITUENT EFFECTS IN ELECTROPHILIC AROMATIC SUBSTITUTION: STRONGLY DEACTIVATING SUBSTITUENTS As Table 12.2 indicates, a variety of substituent types are meta-directing and strongly deactivating. We have already discussed one of these, the trifluoromethyl group. Several of the others have a carbonyl group attached directly to the aromatic ring. Br H H11001 NH 2 H11001 Br H NH 2 H11001 Br H NH 2 Most stable resonance structure Br H H11001 NH 2 H 2 N Amino R H N Alkylamino R R N Dialkylamino O RC H N Acylamino 466 CHAPTER TWELVE Reactions of Arenes: Electrophilic Aromatic Substitution Aniline and its derivatives are so reactive in elec- trophilic aromatic substitu- tion that special strategies are usually necessary to carry out these reactions effec- tively. This topic is discussed in Section 22.15. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website The behavior of aromatic aldehydes is typical. Nitration of benzaldehyde takes place sev- eral thousand times more slowly than that of benzene and yields m-nitrobenzaldehyde as the major product. To understand the effect of a carbonyl group attached directly to the ring, consider its polarization. The electrons in the carbon-oxygen double bond are drawn toward oxy- gen and away from carbon, leaving the carbon attached to the ring with a partial posi- tive charge. Using benzaldehyde as an example, Because the carbon atom attached to the ring is positively polarized, a carbonyl group behaves in much the same way as a trifluoromethyl group and destabilizes all the cyclo- hexadienyl cation intermediates in electrophilic aromatic substitution reactions. Attack at any ring position in benzaldehyde is slower than attack in benzene. The intermediates for ortho and para substitution are particularly unstable because each has a resonance structure in which there is a positive charge on the carbon that bears the electron-with- drawing substituent. The intermediate for meta substitution avoids this unfavorable jux- taposition of positive charges, is not as unstable, and gives rise to most of the product. For the nitration of benzaldehyde: C NO 2 H H11001 H H9254H11002 O H9254H11001 Ortho attack Unstable because of adjacent positively polarized atoms Meta attack H11001 H NO 2 C H H9254H11002 O H9254H11001 Positively polarized atoms not adjacent; most stable intermediate H11001 NO 2 H C H H9254H11002 O H9254H11001 Para attack Unstable because of adjacent positively polarized atoms orCH O CH H11001 O H11002 CH O H9254H11002 H9254H11001 HNO 3 H 2 SO 4 C OH Benzaldehyde C OH NO 2 m-Nitrobenzaldehyde (75–84%) Aldehyde CH O Ketone CR O Carboxylic acid COH O Acyl chloride CCl O Ester COR O 12.13 Substituent Effects in Electrophilic Aromatic Substitution: Strongly Deactivating Substituents 467 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website PROBLEM 12.14 Each of the following reactions has been reported in the chem- ical literature, and the principal organic product has been isolated in good yield. Write a structural formula for the isolated product of each reaction. (a) Treatment of benzoyl chloride with chlorine and iron(III) chloride (b) Treatment of methyl benzoate with nitric acid and sulfuric acid (c) Nitration of 1-phenyl-1-propanone SAMPLE SOLUTION (a) Benzoyl chloride has a carbonyl group attached directly to the ring. substituent is meta-directing. The combination of chlorine and iron(III) chloride, introduces a chlorine onto the ring. The product is m-chlorobenzoyl chloride. A cyano group is similar to a carbonyl for analogous reasons involving resonance of the type Cyano groups are electron-withdrawing, deactivating, and meta-directing. Sulfonic acid groups are electron-withdrawing because sulfur has a formal posi- tive charge in several of the resonance forms of benzenesulfonic acid. When benzene undergoes disulfonation, m-benzenedisulfonic acid is formed. The first sulfonic acid group to go on directs the second one meta to itself. SO 3 H 2 SO 4 Benzene SO 3 H Benzenesulfonic acid SO 3 H 2 SO 4 SO 3 H SO 3 H m-Benzenedisulfonic acid (90%) Ar SOH O O Ar SOH O O H11001 H11002 Ar SOH O O H11001 H11002 Ar SOH O H11002 O 2H11001 H11002 C N H11001 H11002 CN or CN H9254H11001 H9254H11002 CCl O Benzoyl chloride Cl CCl O m-Chlorobenzoyl chloride (isolated in 62% yield) Cl 2 FeCl 3 ±CClA O X (C 6 H 5 CCH 2 CH 3 ) O X (C 6 H 5 COCH 3 ) O X (C 6 H 5 CCl) O X 468 CHAPTER TWELVE Reactions of Arenes: Electrophilic Aromatic Substitution Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website The nitrogen atom of a nitro group bears a full positive charge in its two most sta- ble Lewis structures. This makes the nitro group a powerful electron-withdrawing deactivating substituent and a meta director. PROBLEM 12.15 Would you expect the substituent ±N H11001 (CH 3 ) 3 to more closely resemble in its effect on rate and regioselectivity in elec- trophilic aromatic substitution? Why? 12.14 SUBSTITUENT EFFECTS IN ELECTROPHILIC AROMATIC SUBSTITUTION: HALOGENS Returning to Table 12.2, notice that halogen substituents direct an incoming electrophile to the ortho and para positions but deactivate the ring toward substitution. Nitration of chlorobenzene is a typical example of electrophilic aromatic substitution in a haloben- zene; its rate is some 30 times slower than the corresponding nitration of benzene. The major products are o-chloronitrobenzene and p-chloronitrobenzene. PROBLEM 12.16 Reaction of chlorobenzene with 4-chlorobenzyl chloride and aluminum chloride gave a mixture of two products in good yield (76%). What were these two products? Since we have come to associate activating substituents with ortho, para-directing effects and deactivating substituents with meta, the properties of the halogen substituents appear on initial inspection to be unusual. This seeming inconsistency between regioselectivity and rate can be understood by analyzing the two ways that a halogen substituent can affect the stability of a cyclo- hexadienyl cation. First, halogens are electronegative, and their inductive effect is to draw HNO 3 H 2 SO 4 Cl Chlorobenzene Cl NO 2 o-Chloronitrobenzene (30%) H11001 Cl NO 2 m-Chloronitrobenzene (1%) H11001 Cl NO 2 p-Chloronitrobenzene (69%) N(CH 3 ) 2 or ±NO 2 NO 2 Nitrobenzene Br 2 Fe NO 2 Br m-Bromonitrobenzene (60–75%) Ar N H11001 O O H11002 H11001 H11002 Ar N O O 12.14 Substituent Effects in Electrophilic Aromatic Substitution: Halogens 469 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website electrons away from the carbon to which they are bonded in the same way that a triflu- oromethyl group does. Thus, all the intermediates formed by electrophilic attack on a halobenzene are less stable than the corresponding cyclohexadienyl cation for benzene, and halobenzenes are less reactive than benzene. Like hydroxyl groups and amino groups, however, halogen substituents possess unshared electron pairs that can be donated to a positively charged carbon. This electron donation into the H9266 system stabilizes the intermediates derived from ortho and from para attack. Comparable stabilization of the intermediate leading to meta substitution is not possible. Thus, resonance involving halogen lone pairs causes electrophilic attack to be favored at the ortho and para positions but is weak and insufficient to overcome the electron- withdrawing inductive effect of the halogen, which deactivates all the ring positions. The experimentally observed partial rate factors for nitration of chlorobenzene result from this blend of inductive and resonance effects. The mix of inductive and resonance effects varies from one halogen to another, but the net result is that fluorine, chlorine, bromine, and iodine are weakly deactivating, ortho, para-directing substituents. 12.15 MULTIPLE SUBSTITUENT EFFECTS When a benzene ring bears two or more substituents, both its reactivity and the site of further substitution can usually be predicted from the cumulative effects of its sub- stituents. In the simplest cases all the available sites are equivalent, and substitution at any one of them gives the same product. Cl 0.0290.029 0.00090.0009 0.137 E H X H11001 E H H11001 X Ortho attack EH H11001 X EH H11001 X Para attack All these ions are less stable when X H11005 F, Cl, Br, or I than when X H11005 H X H11001 E H X H11001 E H H11001 X EH 470 CHAPTER TWELVE Reactions of Arenes: Electrophilic Aromatic Substitution Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website Often the directing effects of substituents reinforce each other. Bromination of p- nitrotoluene, for example, takes place at the position that is ortho to the ortho, para- directing methyl group and meta to the meta-directing nitro group. In almost all cases, including most of those in which the directing effects of indi- vidual substituents oppose each other, it is the more activating substituent that controls the regioselectivity of electrophilic aromatic substitution. Thus, bromination occurs ortho to the N-methylamino group in 4-chloro-N-methylaniline because this group is a very powerful activating substituent while the chlorine is weakly deactivating. When two positions are comparably activated by alkyl groups, substitution usually occurs at the less hindered site. Nitration of p-tert-butyltoluene takes place at positions ortho to the methyl group in preference to those ortho to the larger tert-butyl group. This is an example of a steric effect. HNO 3 H 2 SO 4 CH 3 C(CH 3 ) 3 p-tert-Butyltoluene C(CH 3 ) 3 CH 3 NO 2 4-tert-Butyl-2-nitrotoluene (88%) Br 2 acetic acid NHCH 3 Cl 4-Chloro-N-methylaniline NHCH 3 Cl Br 2-Bromo-4-chloro-N-methylaniline (87%) Br 2 Fe CH 3 NO 2 p-Nitrotoluene CH 3 Br NO 2 2-Bromo-4-nitrotoluene (86–90%) AlCl 3 CH 3 CH 3 1,4-Dimethylbenzene (p-xylene) H11001 CH 3 COCCH 3 OO CH 3 CH 3 CCH 3 O 2,5-Dimethylacetophenone (99%) 12.15 Multiple Substituent Effects 471 Problems 12.2, 12.3, and 12.7 offer additional examples of reactions in which only a sin- gle product of electrophilic aromatic substitution is pos- sible. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website Nitration of m-xylene is directed ortho to one methyl group and para to the other. The ortho position between the two methyl groups is less reactive because it is more sterically hindered. PROBLEM 12.17 Write the structure of the principal organic product obtained on nitration of each of the following: (a) p-Methylbenzoic acid (d) p-Methoxyacetophenone (b) m-Dichlorobenzene (e) p-Methylanisole (c) m-Dinitrobenzene (f) 2,6-Dibromoanisole SAMPLE SOLUTION (a) Of the two substituents in p-methylbenzoic acid, the methyl group is more activating and so controls the regioselectivity of electrophilic aromatic substitution. The position para to the ortho, para-directing methyl group already bears a substituent (the carboxyl group), and so substitution occurs ortho to the methyl group. This position is meta to the m-directing carboxyl group, and the orienting properties of the two substituents reinforce each other. The prod- uct is 4-methyl-3-nitrobenzoic acid. An exception to the rule that regioselectivity is controlled by the most activating substituent occurs when the directing effects of alkyl groups and halogen substituents oppose each other. Alkyl groups and halogen substituents are weakly activating and weakly deactivating, respectively, and the difference between them is too small to allow a simple generalization. 12.16 REGIOSELECTIVE SYNTHESIS OF DISUBSTITUTED AROMATIC COMPOUNDS Since the position of electrophilic attack on an aromatic ring is controlled by the direct- ing effects of substituents already present, the preparation of disubstituted aromatic com- pounds requires that careful thought be given to the order of introduction of the two groups. Compare the independent preparations of m-bromoacetophenone and p-bromoace- tophenone from benzene. Both syntheses require a Friedel–Crafts acylation step and a bromination step, but the major product is determined by the order in which the two HNO 3 H 2 SO 4 CH 3 CO 2 H p-Methylbenzoic acid CH 3 CO 2 H NO 2 4-Methyl-3-nitrobenzoic acid HNO 3 H 2 SO 4 CH 3 CH 3 m-Xylene NO 2 CH 3 CH 3 2,4-Dimethyl-1-nitrobenzene (98%) 472 CHAPTER TWELVE Reactions of Arenes: Electrophilic Aromatic Substitution Problem 12.38 illustrates how partial rate factor data may be applied to such cases. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website steps are carried out. When the meta-directing acetyl group is introduced first, the final product is m-bromoacetophenone. When the ortho, para-directing bromine is introduced first, the major product is p-bro- moacetophenone (along with some of its ortho isomer, from which it is separated by dis- tillation). PROBLEM 12.18 Write chemical equations showing how you could prepare m-bromonitrobenzene as the principal organic product, starting with benzene and using any necessary organic or inorganic reagents. How could you prepare p-bromonitrobenzene? A less obvious example of a situation in which the success of a synthesis depends on the order of introduction of substituents is illustrated by the preparation of m-nitroace- tophenone. Here, even though both substituents are meta-directing, the only practical synthesis is the one in which Friedel–Crafts acylation is carried out first. When the reverse order of steps is attempted, it is observed that the Friedel–Crafts acylation of nitrobenzene fails. Benzene HNO 3 H 2 SO 4 Nitrobenzene (95%) NO 2 CH 3 COCCH 3 AlCl 3 O X O X no reaction CH 3 COCCH 3 AlCl 3 O X O X Benzene Acetophenone (76–83%) CCH 3 O HNO 3 H 2 SO 4 m-Nitroacetophenone (55%) CCH 3 O NO 2 CH 3 COCCH 3 AlCl 3 O X O X Benzene Br Bromobenzene (65–75%) Br CCH 3 O p-Bromoacetophenone (69–79%) Br 2 Fe Br 2 AlCl 3 CH 3 COCCH 3 AlCl 3 O X O X Benzene CCH 3 O Acetophenone (76–83%) Br CCH 3 O m-Bromoacetophenone (59%) 12.16 Regioselective Synthesis of Disubstituted Aromatic Compounds 473 Aluminum chloride is a stronger Lewis acid than iron(III) bromide and has been used as a catalyst in electrophilic bromination when, as in the example shown, the aromatic ring bears a strongly deactivating substituent. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website Neither Friedel–Crafts acylation nor alkylation reactions can be carried out on nitroben- zene. The presence of a strongly deactivating substituent such as a nitro group on an aromatic ring so depresses its reactivity that Friedel–Crafts reactions do not take place. Nitrobenzene is so unreactive that it is sometimes used as a solvent in Friedel–Crafts reactions. The practical limit for Friedel–Crafts alkylation and acylation reactions is effectively a monohalobenzene. An aromatic ring more deactivated than a mono- halobenzene cannot be alkylated or acylated under Friedel–Crafts conditions. Sometimes the orientation of two substituents in an aromatic compound precludes its straightforward synthesis. m-Chloroethylbenzene, for example, has two ortho, para- directing groups in a meta relationship and so can’t be prepared either from chloroben- zene or ethylbenzene. In cases such as this we couple electrophilic aromatic substitution with functional group manipulation to produce the desired compound. The key here is to recognize that an ethyl substituent can be introduced by Friedel–Crafts acylation followed by a Clemmensen or Wolff–Kishner reduction step later in the syn- thesis. If the chlorine is introduced prior to reduction, it will be directed meta to the acetyl group, giving the correct substitution pattern. A related problem concerns the synthesis of p-nitrobenzoic acid. Here, two meta- directing substituents are para to each other. This compound has been prepared from toluene according to the procedure shown: Since it may be oxidized to a carboxyl group (Section 11.13), a methyl group can be used to introduce the nitro substituent in the proper position. PROBLEM 12.19 Suggest an efficient synthesis of m-nitrobenzoic acid from toluene. 12.17 SUBSTITUTION IN NAPHTHALENE Polycyclic aromatic hydrocarbons undergo electrophilic aromatic substitution when treated with the same reagents that react with benzene. In general, polycyclic aromatic hydrocarbons are more reactive than benzene. Since, however, most lack the symmetry of benzene, mixtures of products may be formed even on monosubstitution. Among poly- cyclic aromatic hydrocarbons, we will discuss only naphthalene, and that only briefly. HNO 3 H 2 SO 4 Na 2 Cr 2 O 7 H 2 SO 4 CH 3 NO 2 CH 3 p-Nitrotoluene (separate from ortho isomer) NO 2 CO 2 H p-Nitrobenzoic acid (82–86%) 474 CHAPTER TWELVE Reactions of Arenes: Electrophilic Aromatic Substitution CCH 3 O Acetophenone CH 3 COCCH 3 AlCl 3 O X O X Cl 2 AlCl 3 Zn(Hg) HCl Benzene m-Chloroacetophenone CCH 3 O Cl m-Chloroethylbenzene CH 2 CH 3 Cl Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website Two sites are available for substitution in naphthalene, C-1 and C-2, C-1 being normally the preferred site of electrophilic attack. C-1 is more reactive because the arenium ion formed by electrophilic attack there is a relatively stable one. Benzenoid character is retained in one ring, and the positive charge is delocalized by allylic resonance. Attack at C-1 Attack at C-2 To involve allylic resonance in stabilizing the arenium ion formed during attack at C-2, the benzenoid character of the other ring is sacrificed. PROBLEM 12.20 Sulfonation of naphthalene is reversible at elevated tempera- ture. A different isomer of naphthalenesulfonic acid is the major product at 160°C than is the case at 0°C. Which isomer is the product of kinetic control? Which one is formed under conditions of thermodynamic control? Can you think of a reason why one isomer is more stable than the other? (Hint: Build space-filling models of both isomers.) 12.18 SUBSTITUTION IN HETEROCYCLIC AROMATIC COMPOUNDS The great variety of available structural types causes heterocyclic aromatic compounds to range from exceedingly reactive to practically inert toward electrophilic aromatic sub- stitution. Pyridine lies near one extreme in being far less reactive than benzene toward sub- stitution by electrophilic reagents. In this respect it resembles strongly deactivated aro- matic compounds such as nitrobenzene. It is incapable of being acylated or alkylated under Friedel–Crafts conditions, but can be sulfonated at high temperature. Electrophilic substitution in pyridine, when it does occur, takes place at C-3. N Pyridine SO 3 H N Pyridine-3-sulfonic acid (71%) SO 3 , H 2 SO 4 HgSO 4 , 230°C H11001 E H H11001 E H H11001 E H EH H11001 EH H11001 CH 3 CCl AlCl 3 O X Naphthalene 1 2 1-Acetylnaphthalene (90%) CCH 3 O 12.18 Substitution in Heterocyclic Aromatic Compounds 475 The electrostatic poten- tial map of pyridine on Learning By Modeling clearly shows its de- creased H9266 electron density. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website One reason for the low reactivity of pyridine is that its nitrogen atom, since it is more electronegative than a CH in benzene, causes the H9266 electrons to be held more tightly and raises the activation energy for attack by an electrophile. Another is that the nitro- gen of pyridine is protonated in sulfuric acid and the resulting pyridinium ion is even more deactivated than pyridine itself. Lewis acid catalysts such as aluminum chloride and iron(III) halides also bond to nitro- gen to strongly deactivate the ring toward Friedel–Crafts reactions and halogenation. Pyrrole, furan, and thiophene, on the other hand, have electron-rich aromatic rings and are extremely reactive toward electrophilic aromatic substitution—more like phenol and aniline than benzene. Like benzene they have six H9266 electrons, but these H9266 electrons are delocalized over five atoms, not six, and are not held as strongly as those of ben- zene. Even when the ring atom is as electronegative as oxygen, substitution takes place readily. The regioselectivity of substitution in furan is explained using a resonance descrip- tion. When the electrophile attacks C-2, the positive charge is shared by three atoms: C-3, C-5, and O. Attack at C-2 Carbocation more stable; positive charge shared by C-3, C-5, and O. When the electrophile attacks at C-3, the positive charge is shared by only two atoms, C-2 and O, and the carbocation intermediate is less stable and formed more slowly. Attack at C-3 Carbocation less stable; positive charge shared by C-2 and O. H E HH H H11001 2 O H E HH H O H11001 H H H H E H11001 3 O H EH11001 O 5 H H H O H11001 H H H H E O Furan H11001 BF 3 CH 3 COCCH 3 OO Acetic anhydride O CCH 3 O 2-Acetylfuran (75–92%) H11001 CH 3 COH O Acetic acid more reactive than more reactive than Benzene N Pyridine H N H11001 Pyridinium ion 476 CHAPTER TWELVE Reactions of Arenes: Electrophilic Aromatic Substitution Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website The regioselectivity of substitution in pyrrole and thiophene is like that of furan and for similar reasons. PROBLEM 12.21 When benzene is prepared from coal tar, it is contaminated with thiophene, from which it cannot be separated by distillation because of very similar boiling points. Shaking a mixture of benzene and thiophene with sulfuric acid causes sulfonation of the thiophene ring but leaves benzene untouched. The sulfonation product of thiophene dissolves in the sulfuric acid layer, from which the benzene layer is separated; the benzene layer is then washed with water and distilled. Give the structure of the sulfonation product of thiophene. 12.19 SUMMARY Section 12.1 On reaction with electrophilic reagents, compounds that contain a ben- zene ring undergo electrophilic aromatic substitution. Table 12.1 in Section 12.1 and Table 12.3 in this summary give examples. Section 12.2 The mechanism of electrophilic aromatic substitution involves two stages: attack of the electrophile on the H9266 electrons of the ring (slow, rate- determining), followed by loss of a proton to restore the aromaticity of the ring. Sections See Table 12.3 12.3–12.5 Sections See Tables 12.3 and 12.4 12.6–12.7 Section 12.8 Friedel–Crafts acylation, followed by Clemmensen or Wolff–Kishner reduction is a standard sequence used to introduce a primary alkyl group onto an aromatic ring. Section 12.9 Substituents on an aromatic ring can influence both the rate and regio- selectivity of electrophilic aromatic substitution. Substituents are classi- fied as activating or deactivating according to whether they cause the ring to react more rapidly or less rapidly than benzene. With respect to regio- selectivity, substituents are either ortho, para-directing or meta-directing. A methyl group is activating and ortho, para-directing. A trifluoromethyl group is deactivating and meta-directing. 12.19 Summary 477 H11001H11001 slow fast Y H11002 H Benzene E Y H9254H11001 H9254H11002 Electrophilic reagent H H11001 E Cyclohexadienyl cation intermediate Product of electrophilic aromatic substitution E H11001 H Y H 2 NNH 2 , NaOH triethylene glycol, heat CH 2 CH 3 CH 2 CH 3 CH 2 CH 3 1,2,4-Triethylbenzene CH 3 CCl AlCl 3 O X 1,3,4-Triethylacetophenone (80%) CH 2 CH 3 CH 2 CH 3 CH 2 CH 3 CH 3 C O 1,2,4,5-Tetraethylbenzene (73%) CH 2 CH 3 CH 2 CH 3 CH 2 CH 3 CH 3 CH 2 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website 478 CHAPTER TWELVE Reactions of Arenes: Electrophilic Aromatic Substitution TABLE 12.3 Representative Electrophilic Aromatic Substitution Reactions Reaction (section) and comments Nitration (Section 12.3) The active electro- phile in the nitration of benzene and its derivatives is nitronium cation ( : O?N?O : ). It is generated by reaction of nitric acid and sulfuric acid. Very reactive arenes those that bear strongly activating sub- stituents undergo nitration in nitric acid alone. Halogenation (Section 12.5) Chlorination and bromination of arenes are carried out by treatment with the appropriate halogen in the presence of a Lewis acid catalyst. Very reactive arenes undergo halogenation in the absence of a catalyst. Friedel Crafts alkylation (Section 12.6) Car- bocations, usually generated from an alkyl halide and aluminum chloride, attack the aromatic ring to yield alkylbenzenes. The arene must be at least as reactive as a halo- benzene. Carbocation rearrangements can occur, especially with primary alkyl halides. Friedel Crafts acylation (Section 12.7) Acyl cations (acylium ions) generated by treat- ing an acyl chloride or acid anhydride with aluminum chloride attack aromatic rings to yield ketones. The arene must be at least as reactive as a halobenzene. Acyl cations are relatively stable, and do not rearrange. Sulfonation (Section 12.4) Sulfonic acids are formed when aromatic compounds are treated with sources of sulfur trioxide. These sources can be concentrated sulfuric acid (for very reactive arenes) or solutions of sulfur trioxide in sulfuric acid (for ben- zene and arenes less reactive than ben- zene). : :H11001 General equation and specific example F Fluorobenzene NO 2 F p-Fluoronitrobenzene (80%) HNO 3 H 2 SO 4 SO 3 H 2 SO 4 H 3 C CH 3 CH 3 H 3 C 1,2,4,5-Tetramethylbenzene 2,3,5,6-Tetramethylbenzenesulfonic acid (94%) H 3 C CH 3 CH 3 H 3 C SO 3 H Br 2 CS 2 p-Bromophenol (80 84%) BrHOHO Phenol Nitric acid HNO 3 H11001 Water H 2 O Arene ArH Nitroarene ArNO 2 H11001 H 2 SO 4 H11001 Sulfur trioxide SO 3 ArSO 3 H Arenesulfonic acid ArH Arene H11001ArH Arene Halogen X 2 Aryl halide ArX H11001 Hydrogen halide HX FeX 3 H11001ArH Arene RX Alkyl halide ArR Alkylarene H11001 Hydrogen halide HX AlCl 3 H11001 Br Cyclopentyl bromideBenzene Cyclopentylbenzene (54%) AlCl 3 H11001ArH Arene Acyl chloride RCCl O ArCR O Ketone H11001 HCl Hydrogen chloride AlCl 3 H11001ArH Arene Acid anhydride RCOCR O O H11001 Carboxylic acid RCOH O AlCl 3 Ketone ArCR O Anisole CH 3 O p-Methoxyacetophenone (90 94%) CCH 3 CH 3 O O CH 3 COCCH 3 AlCl 3 O X O X Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website Sections How substituents control rate and regioselectivity in electrophilic aro- 12.10–12.14 matic substitution results from their effect on carbocation stability. An electron-releasing substituent stabilizes the cyclohexadienyl cation inter- mediates corresponding to ortho and para attack more than meta. Conversely, an electron-withdrawing substituent destabilizes the cyclo- hexadienyl cations corresponding to ortho and para attack more than meta. Thus, meta substitution predominates. Less stabilized when G is electron-releasing H11001 G E H Stabilized when G is electron-releasing G E H H11001 Stabilized when G is electron-releasing H11001 G EH 12.19 Summary 479 TABLE 12.4 Limitations on Friedel–Crafts Reactions 1. The organic halide that reacts with the arene must be an alkyl halide (Section 12.6) or an acyl halide (Section 12.7). These will react with benzene under Friedel–Crafts conditions: These will not react with benzene under Friedel–Crafts conditions: Rearrangement is especially prevalent with primary alkyl halides of the type RCH 2 CH 2 X and R 2 CHCH 2 X. Aluminum chloride induces ionization with rearrangement to give a more stable carbocation. Benzylic halides and acyl halides do not rearrange. The first alkyl group that goes on makes the ring more reactive toward further substitution because alkyl groups are activating substituents. Monoacylation is possible because the first acyl group to go on is strongly electron-withdrawing and deactivates the ring toward further substitution. EWG: 2. Rearrangement of alkyl groups can occur (Section 12.6). 3. Strongly deactivated aromatic rings do not undergo Friedel-Crafts alkylation or acylation (Section 12.16). Friedel–Crafts alkylations and acylations fail when applied to compounds of the following type, where EWG is a strongly electron- withdrawing group: 4. It is sometimes difficult to limit Friedel- Crafts alkylation to monoalkylation. Vinylic halides and aryl halides do not form carbocations under conditions of the Friedel–Crafts reaction and so cannot be used in place of an alkyl halide or an acyl halide. EWG CH, O CR, O COH, O COR, O CCl O SO 3 H,NO 2 ,CF 3 , C N, H Cl Alkyl halide CH 2 Cl Benzylic halide CCl O Acyl halide Cl Aryl halide Cl Vinylic halide Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website Substituents can be arranged into three major categories: 1. Activating and ortho, para-directing: These substituents stabilize the cyclohexadienyl cation formed in the rate-determining step. They include , , ±R, ±Ar, and related species. The most strongly activating members of this group are bonded to the ring by a nitrogen or oxygen atom that bears an unshared pair of electrons. 2. Deactivating and ortho, para-directing: The halogens are the most prominent members of this class. They withdraw electron den- sity from all the ring positions by an inductive effect, making halobenzenes less reactive than benzene. Lone-pair electron dona- tion stabilizes the cyclohexadienyl cations corresponding to attack at the ortho and para positions more than those formed by attack at the meta positions, giving rise to the observed regioselectivity. 3. Deactivating and meta-directing: These substituents are strongly electron-withdrawing and destabilize carbocations. They include ±CF 3 ,,±CPN, ±NO 2 and related species. All the ring positions are deactivated, but since the meta positions are deactivated less than the ortho and para, meta substitution is favored. Section 12.15 When two or more substituents are present on a ring, the regioselectiv- ity of electrophilic aromatic substitution is generally controlled by the directing effect of the more powerful activating substituent. Section 12.16 The order in which substituents are introduced onto a benzene ring needs to be considered in order to prepare the desired isomer in a multistep syn- thesis. Section 12.17 Polycyclic aromatic hydrocarbons undergo the same kind of electrophilic aromatic substitution reactions as benzene. Section 12.18 Heterocyclic aromatic compounds may be more reactive or less reactive than benzene. Pyridine is much less reactive than benzene, but pyrrole, furan, and thiophene are more reactive. PROBLEMS 12.22 Give reagents suitable for carrying out each of the following reactions, and write the major organic products. If an ortho, para mixture is expected, show both. If the meta isomer is the expected major product, write only that isomer. ±CR O X ±OR±NR 2 Less destabilized when G is electron-withdrawing H11001 G E H Destabilized when G is electron-withdrawing G E H H11001 Destabilized when G is electron-withdrawing H11001 G EH 480 CHAPTER TWELVE Reactions of Arenes: Electrophilic Aromatic Substitution Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website (a) Nitration of benzene (b) Nitration of the product of part (a) (c) Bromination of toluene (d) Bromination of (trifluoromethyl)benzene (e) Sulfonation of anisole (f) Sulfonation of acetanilide (g) Chlorination of bromobenzene (h) Friedel–Crafts alkylation of anisole with benzyl chloride (i) Friedel–Crafts acylation of benzene with benzoyl chloride (j) Nitration of the product from part (i) (k) Clemmensen reduction of the product from part (i) (l) Wolff–Kishner reduction of the product from part (i) 12.23 Write a structural formula for the most stable cyclohexadienyl cation intermediate formed in each of the following reactions. Is this intermediate more or less stable than the one formed by electrophilic attack on benzene? (a) Bromination of p-xylene (b) Chlorination of m-xylene (c) Nitration of acetophenone (d) Friedel–Crafts acylation of anisole with (e) Nitration of isopropylbenzene (f) Bromination of nitrobenzene (g) Sulfonation of furan (h) Bromination of pyridine 12.24 In each of the following pairs of compounds choose which one will react faster with the indicated reagent, and write a chemical equation for the faster reaction: (a) Toluene or chlorobenzene with a mixture of nitric acid and sulfuric acid (b) Fluorobenzene or (trifluoromethyl)benzene with benzyl chloride and aluminum chloride (c) Methyl benzoate or phenyl acetate with bromine in acetic acid (d) Acetanilide or nitrobenzene with sulfur trioxide in sulfuric acid (e) p-Dimethylbenzene (p-xylene) or p-di-tert-butylbenzene with acetyl chloride and alu- minum chloride (f) Benzophenone or biphenyl (C 6 H 5 ±C 6 H 5 ) with chlorine and iron(III) chloride 12.25 Arrange the following five compounds in order of decreasing rate of bromination: benzene, toluene, o-xylene, m-xylene, 1,3,5-trimethylbenzene (the relative rates are 2 H11003 10 7 , 5 H11003 10 4 , 5 H11003 10 2 , 60, and 1). (C 6 H 5 CC 6 H 5 ) O X (C 6 H 5 NHCCH 3 ) O X (C 6 H 5 OCCH 3 ) O X (C 6 H 5 COCH 3 ) O X CH 3 CCl O X (C 6 H 5 NHCCH 3 ) O X Problems 481 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website 12.26 Each of the following reactions has been carried out under conditions such that disubstitu- tion or trisubstitution occurred. Identify the principal organic product in each case. (a) Nitration of p-chlorobenzoic acid (dinitration) (b) Bromination of aniline (tribromination) (c) Bromination of o-aminoacetophenone (dibromination) (d) Nitration of benzoic acid (dinitration) (e) Bromination of p-nitrophenol (dibromination) (f) Reaction of biphenyl with tert-butyl chloride and iron(III) chloride (dialkylation) (g) Sulfonation of phenol (disulfonation) 12.27 Write equations showing how you could prepare each of the following from benzene or toluene and any necessary organic or inorganic reagents. If an ortho, para mixture is formed in any step of your synthesis, assume that you can separate the two isomers. (a) Isopropylbenzene (j) 1-Bromo-2,4-dinitrobenzene (b) p-Isopropylbenzenesulfonic acid (k) 3-Bromo-5-nitrobenzoic acid (c) 2-Bromo-2-phenylpropane (l) 2-Bromo-4-nitrobenzoic acid (d) 4-tert-Butyl-2-nitrotoluene (m) Diphenylmethane (e) m-Chloroacetophenone (n) 1-Phenyloctane (f) p-Chloroacetophenone (o) 1-Phenyl-1-octene (g) 3-Bromo-4-methylacetophenone (p) 1-Phenyl-1-octyne (h) 2-Bromo-4-ethyltoluene (q) 1,4-Di-tert-butyl-1,4-cyclohexadiene (i) 1-Bromo-3-nitrobenzene 12.28 Write equations showing how you could prepare each of the following from anisole and any necessary organic or inorganic reagents. If an ortho, para mixture is formed in any step of your synthesis, assume that you can separate the two isomers. (a) p-Methoxybenzenesulfonic acid (c) 4-Bromo-2-nitroanisole (b) 2-Bromo-4-nitroanisole (d) p-Methoxystyrene 12.29 How many products are capable of being formed from toluene in each of the following reac- tions? (a) Mononitration (HNO 3 , H 2 SO 4 , 40°C). (b) Dinitration (HNO 3 , H 2 SO 4 , 80°C). (c) Trinitration (HNO 3 , H 2 SO 4 , 110°C). The explosive TNT (trinitrotoluene) is the major product obtained on trinitration of toluene. Which trinitrotoluene isomer is TNT? 12.30 Friedel–Crafts acylation of the individual isomers of xylene with acetyl chloride and alu- minum chloride yields a single product, different for each xylene isomer, in high yield in each case. Write the structures of the products of acetylation of o-, m-, and p-xylene. 12.31 Reaction of benzanilide with chlorine in acetic acid yields a mixture of two monochloro derivatives formed by electrophilic aromatic substitution. Suggest reasonable structures for these two isomers. 12.32 Each of the following reactions has been reported in the chemical literature and gives a pre- dominance of a single product in synthetically acceptable yield. Write the structure of the prod- uct. Only monosubstitution is involved in each case, unless otherwise indicated. (C 6 H 5 NHCC 6 H 5 ) O X 482 CHAPTER TWELVE Reactions of Arenes: Electrophilic Aromatic Substitution Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website (a) (h) (b) (i) (c) (j) (d) (k) (e) (l) (f) (m) (g) (n) 12.33 What combination of acyl chloride or acid anhydride and arene would you choose to pre- pare each of the following compounds by a Friedel–Crafts acylation reaction? (a) (c) (b) (d) C O H 3 C H 3 C H 3 C CH 3 CCH 2 CH 2 CO 2 H O O 2 N C O C 6 H 5 CCH 2 C 6 H 5 O Br 2 acetic acid CO 2 H S HNO 3 H 2 SO 4 CH(CH 3 ) 2 NO 2 Zn(Hg) HCl CH 3 CH 3 CCH 3 O H 3 C AlCl 3 OCH 3 F H11001 CH 3 COCCH 3 O O AlCl 3 CS 2 CH 2 CH 3 CH 3 CNH O H11001 CH 3 CCl O H 2 SO 4 5–15°C H11001 CH 2 CH(CH 2 ) 5 CH 3 AlCl 3 F H11001 CH 2 Cl HNO 3 acetic acid C(CH 3 ) 3 CH(CH 3 ) 2 H 2 NNH 2 , KOH triethylene glycol, 173°C C O Br 2 CHCl 3 OH Br 2 CHCl 3 CH 2 H 3 C OH CH 3 Br 2 acetic acid CF 3 NH 2 O 2 N H 2 SO 4 OCH 3 CH 3 H11001 (CH 3 ) 2 C CH 2 HNO 3 H 2 SO 4 , heat CO 2 H Cl CO 2 H Problems 483 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website (e) 12.34 Suggest a suitable series of reactions for carrying out each of the following synthetic trans- formations: (a) (b) (c) (d) 12.35 A standard synthetic sequence for building a six-membered cyclic ketone onto an existing aromatic ring is shown in outline as follows. Specify the reagents necessary for each step. CCH 2 CH 2 COH O O CH 2 CH 2 CH 2 COH O CH 2 CH 2 ClC O CH 2 O OCH 3 OCH 3 to OCH 3 OCH 3 C(CH 3 ) 3 O 2 N to O O CH 3 C CH 3 CH 3 to CO 2 H CO 2 H C(CH 3 ) 3 CH(CH 3 ) 2 to CO 2 H SO 3 H H 3 C C O HO 2 C 484 CHAPTER TWELVE Reactions of Arenes: Electrophilic Aromatic Substitution Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website 12.36 Each of the compounds indicated undergoes an intramolecular Friedel–Crafts acylation reac- tion to yield a cyclic ketone. Write the structure of the expected product in each case. (a) (c) (b) 12.37 The partial rate factors for chlorination of biphenyl are as shown. (a) What is the relative rate of chlorination of biphenyl compared with benzene? (b) If, in a particular chlorination reaction, 10 g of o-chlorobiphenyl was formed, how much p-chlorobiphenyl would you expect to find? 12.38 Partial rate factors may be used to estimate product distributions in disubstituted benzene derivatives. The reactivity of a particular position in o-bromotoluene, for example, is given by the product of the partial rate factors for the corresponding position in toluene and bromobenzene. On the basis of the partial rate factor data given here for Friedel–Crafts acylation, predict the major product of the reaction of o-bromotoluene with acetyl chloride and aluminum chloride. 12.39 When 2-isopropyl-1,3,5-trimethylbenzene is heated with aluminum chloride (trace of HCl present) at 50°C, the major material present after 4 h is 1-isopropyl-2,4,5-trimethylbenzene. Sug- gest a reasonable mechanism for this isomerization. 12.40 When a dilute solution of 6-phenylhexanoyl chloride in carbon disulfide was slowly added (over a period of 8 days!) to a suspension of aluminum chloride in the same solvent, it yielded a product A (C 12 H 14 O) in 67% yield. Oxidation of A gave benzene-1,2-dicarboxylic acid. HCl, AlCl 3 50°C CH 3 H 3 C CH(CH 3 ) 2 CH 3 CH 3 H 3 C CH(CH 3 ) 2 CH 3 CH 3 CCl, AlCl 3 O X Partial rate factors for reaction of toluene and bromobenzene with Br Very small 0.0003 Very small 0.0003 0.084 CH 3 4.5 4.8 4.5 4.8 750 0 250 790 0 250 250 250 0 0 790 CH 2 CCl O CH 3 O CH 2 CHCH 2 C CH 3 O OCl (CH 3 ) 3 C CCH 2 CCl CH 3 CH 3 O Problems 485 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website Formulate a reasonable structure for compound A. 12.41 Reaction of hexamethylbenzene with methyl chloride and aluminum chloride gave a salt A, which, on being treated with aqueous sodium bicarbonate solution, yielded compound B. Suggest a mechanism for the conversion of hexamethylbenzene to B by correctly inferring the structure of A. 12.42 The synthesis of compound C was achieved by using compounds A and B as the sources of all carbon atoms. Suggest a synthetic sequence involving no more than three steps by which A and B may be converted to C. 12.43 When styrene is refluxed with aqueous sulfuric acid, two “styrene dimers” are formed as the major products. One of these styrene dimers is 1,3-diphenyl-1-butene; the other is 1-methyl- 3-phenylindan. Suggest a reasonable mechanism for the formation of each of these compounds. 12.44 Treatment of the alcohol whose structure is shown here with sulfuric acid gave as the major organic product a tricyclic hydrocarbon of molecular formula C 16 H 16 . Suggest a reasonable struc- ture for this hydrocarbon. CH 2 C(CH 3 ) 2 OH C 6 H 5 CH CH 3 CHCHC 6 H 5 1,3-Diphenyl-1-butene CH 3 C 6 H 5 1-Methyl-3-phenylindan CH 3 O CH 3 O CH O Compound A CH 3 O CH 3 O CH 2 CCl O Compound B CH 3 O CH 3 O CH 3 CH 3 O CH 3 O Compound C A CH 3 Cl AlCl 3 H 2 O NaHCO 3 H 3 C H 3 C CH 3 CH 3 CH 3 CH 3 Hexamethylbenzene H 3 C H 3 C CH 3 CH 3 CH 3 CH 2 H 3 C Compound B AlCl 3 CS 2 Na 2 Cr 2 O 7 , H 2 O H 2 SO 4 , heat C 6 H 5 (CH 2 ) 5 CCl O 6-Phenylhexanoyl chloride C 12 H 14 O Compound A CO 2 H CO 2 H Benzene-1,2-dicarboxylic acid 486 CHAPTER TWELVE Reactions of Arenes: Electrophilic Aromatic Substitution Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website