CHAPTER TWELVE Reactions of Arenes: Electrophilic Aromatic Substitution 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 CBHg NO2 in high yield. What is this product? 12. 4 SULFONATION OF BENZENE The reaction of benzene with sulfuric acid to produce benzenesulfonic acid SO,OH O+ HOSO,OH2 HO Sulfuric acid Benzenesulfonic acid Water 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 SO,OH sO3 Benzene Sulfur Benzenesulfonic 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 C1oH14O3S Lin 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- ene in the presence of metallic iron(customarily a few carpet tacks) and the reaction mixture is heated H Brb> HBr Benzene Bromine Bromobenzene Hydrogen Back Forward Main MenuToc Study Guide ToC Student o 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 materials to products in aromatic nitration before continuing to the next section. PROBLEM 12.2 Nitration of 1,4-dimethylbenzene (p-xylene) gives a single product having the molecular formula C8H9NO2 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 virtually 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 displaced 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 represent 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 C10H14O3S 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 benzene in the presence of metallic iron (customarily a few carpet tacks) and the reaction mixture is heated. H Benzene Br2 Bromine Br Bromobenzene (65–75%) HBr Hydrogen bromide Fe heat Benzene SO3 Sulfur trioxide SO2OH Benzenesulfonic acid H2SO4 H Benzene HOSO2OH Sulfuric acid SO2OH Benzenesulfonic acid H2O Water heat 448 CHAPTER TWELVE Reactions of Arenes: Electrophilic Aromatic Substitution Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
12.5 Halogenation of Benzene Step 1: Sulfur trioxide attacks benzene in the rate-determining step FIGURE 12.3 The me- chanism of sulfonation of benzene. An electrostatic pc an be viewed on Learning By Modeling Benzene and sulfur trioxide Cyclohexadienyl cation intermediate Step 2: A proton is lost from the sp 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 HOSO,OH y OSO,OH Cyclohexadienyl Hydrogen Benzenesulfonate ion cation intermediate Step 3: A rapid proton transfer from the oxygen of sulfuric acid to the oxygen of benzenesulfonate completes the process. H-OSO,OH + OSO,OH Sulfuric acid 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(iD)bromide, formed by reaction of (Fe Br3)is ron and bromine 2Fe 3B 2Fe Br. Iron(lin bromide is a weak Lewis acid. It combines with bromine to form a Lewis acid Lewis base complex Lewis base Lewis acid Lewis acid-Lewis base Back Forward Main MenuToc Study Guide ToC Student o 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 acidLewis base complex. Br Br Lewis base FeBr3 Lewis acid FeBr3 Br Br Lewis acid-Lewis base complex 3Br2 Bromine 2Fe Iron 2FeBr3 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 sp3 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 H Cyclohexadienyl cation intermediate O O S O O Cyclohexadienyl cation intermediate fast H OSO2OH Hydrogen sulfate ion Benzenesulfonate ion HOSO2OH Sulfuric acid Benzenesulfonate ion H±OSO2OH Sulfuric acid fast OSO2OH Hydrogen sulfate ion Benzenesulfonic acid H O S O O O O O S O O O± S O O S O FIGURE 12.3 The mechanism of sulfonation of benzene. An electrostatic potential map of sulfur trioxide can be viewed on Learning By Modeling. Iron(III) bromide (FeBr3) is also called ferric bromide. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
CHAPTER TWELVE Reactions of Arenes: Electrophilic Aromatic Substitution Complexation of bromine with iron(in) bromide makes bromine more elec- trophilic, and it attacks benzene to give a cyclohexadienyl intermediate as shown in step I 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(I 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 read 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. lodination 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 C(CH3)3 +(Ch3)cCL Benzene tert-Butyl chloride tert-Butylbenzene Hydrogen Step 1: The bromine-iron(i) bromide complex is the active electrophile that attacks benzene. Two of the T electrons of benzene are used to form a bond to bromine and give a cyclohexadienyl cation intermediate B fe br 3 H Br-FeBr3 Benzene and bromine-iron(li) cation intermediate Step 2: Loss of a proton from the cyclohexadienyl cation yields bromobenzene Br-FeBr3 H—Br Tetrabromoferrate Bromobenzer Hydrogen cation intermediate FIGURE 12. 4 The mechanism of bromination of benzene Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
Complexation of bromine with iron(III) bromide makes bromine more electrophilic, 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 electrophilic 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 alkylbenzenes. H Benzene (CH3)3CCl tert-Butyl chloride C(CH3)3 tert-Butylbenzene (60%) HCl Hydrogen chloride AlCl3 0°C 450 CHAPTER TWELVE Reactions of Arenes: Electrophilic Aromatic Substitution H H Benzene and bromine–iron(III) bromide complex slow Br±Br±FeBr3 Cyclohexadienyl cation intermediate 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 Tetrabromoferrate ion H Cyclohexadienyl cation intermediate Tetrabromoferrate ion fast Bromobenzene Hydrogen bromide Iron(III) bromide Br±FeBr3 Br H±Br FeBr3 Br Br±FeBr3 FIGURE 12.4 The mechanism of bromination of benzene. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
12.6 Friedel-Crafts Alkylation of Benzene 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 Re 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. (CH3)3C--CI: AlCI3->(CH3)3C-CI-AICI tert-Butyl chloride Aluminum Lewis acid-Lewis base chloride complex (CH3)3CCI-AlCI3 (CH3)3C++ tert-Butyl chloride- tert-Butyl Tetrachloroaluminate 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 Step 1: Once generated by the reation of tert-butyl chloride and aluminum chloride, tert-butyl cation attacks the Tr electrons of benzene and a carbon-carbon bond is formed CH CH C(CH3)3 Benzene and tert-butyl cation Step 2: Loss of a proton from the cyclohexadienyl cation intermediate yields tert-butylbenzene C(CH3)3 +:C!1-A1Cl3 t HCI AlCl3 Tetrachloroalumina Aluminum cation intermediate boride chloride 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 MenuToc Study Guide ToC Student o MHHE Website
Alkylation of benzene with alkyl halides in the presence of aluminum chloride was discovered by Charles Friedel and James M. Crafts in 1877. Crafts, who later became president of the Massachusetts Institute of Technology, collaborated with Friedel at the Sorbonne 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 benzene. Aluminum chloride serves as a Lewis acid catalyst to enhance the electrophilicity of the alkylating agent. With tertiary and secondary alkyl halides, the addition 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. AlCl3 (CH Cl 3)3C tert-Butyl chloride– aluminum chloride complex tert-Butyl cation (CH3)3C AlCl4 Tetrachloroaluminate anion (CH3)3C Cl tert-Butyl chloride AlCl3 Aluminum chloride AlCl3 (CH Cl 3)3C 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 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 H Cyclohexadienyl cation intermediate C(CH3)3 C(CH3)3 C(CH3)3 Cyclohexadienyl cation intermediate fast H Cl Tetrachloroaluminate ion tert-Butylbenzene HCl Hydrogen chloride CH3 CH3 CH3 AlCl3 Aluminum chloride AlCl3 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
CHAPTER TWELVE Reactions of Arenes: Electrophilic Aromatic Substitution 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 AIX CH3,-X-AIX3 Methyl halide-aluminum Other limitations to One drawback to Friedel-Crafts alkylation is that rearrangements can occur, esp Friedel-Crafts will cially when primary alkyl halides are used. For example, Friedel-C be encountered in this chap- benzene with isobutyl chloride(a primary alkyl halide) yields only tert-butylbenzene Table 12.4 C(CH3)3 t(CH3),CHCH, CI Hcl Isobutyl chloride Here, the electrophile is tert-butyl cation formed by a hydride migration that accompa nies ionization of the carbon-chlorine bond CH3C—CH2Cl-AlCl3 CH3C一CH2+ sobutyl chloride- terl-Butyl cation Tetrachloroaluminate aluminum chloride complex 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 bocao 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 Cyclohexylbenzene(65-68%) 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(CH2-CHCI) do not form carbocations on treatment with aluminum chloride and so cannot be used in friedel-crafts reactions Back Forward Main MenuToc Study Guide ToC Student o 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, especially 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 accompanies 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 carbocation, other carbocation precursors can be used in place of alkyl halides. For example, alkenes, which are converted to carbocations by protonation, can be used to alkylate benzene. PROBLEM 12.5 Write a reasonable mechanism for the formation of cyclohexylbenzene from the reaction of benzene, cyclohexene, and sulfuric acid. Alkenyl halides such as vinyl chloride (CH2œCHCl) do not form carbocations on treatment with aluminum chloride and so cannot be used in Friedel–Crafts reactions. H2SO4 Benzene Cyclohexene Cyclohexylbenzene (65–68%) CH3 CH3 H C CH2 AlCl3 Cl Isobutyl chloride– aluminum chloride complex CH3 CH3 C H CH2 tert-Butyl cation AlCl4 Tetrachloroaluminate ion H Benzene (CH3)2CHCH2Cl Isobutyl chloride C(CH3)3 tert-Butylbenzene (66%) HCl Hydrogen chloride AlCl3 0°C CH3 X AlX3 Methyl halide–aluminum halide complex CH3CH2 X AlX3 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 chapter and are summarized in Table 12.4. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website