● CHAPTER 12 REACTIONS OF ARENES ELECTROPHILIC AROMATIC SUBSTITUTION 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 dd to alkenes C=C+ Alkene Electrophilic Product of reagent electrophilic addition 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 生y Arene Electrophilic Product of electrophilic aromatic substitution 443 Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
443 CHAPTER 12 REACTIONS OF ARENES: ELECTROPHILIC AROMATIC SUBSTITUTION I n the preceding chapter the special stability of benzene was described, along with reactions 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 E Y Electrophilic reagent Ar E H Y Product of electrophilic aromatic substitution C C Alkene E Y Electrophilic reagent E C C Y Product of electrophilic addition Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
CHAPTER TWELVE Reactions of Arenes: Electrophilic Aromatic Substitution call this reaction electrophilic aromatic substitution; it is one of the fundamental cesses 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 lectrophilic 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 +:Y Alkene and electrophile Carbocation E-C-C++:Y →E-C-C-Y Carbocation Nucleophile Product of electrophilic first step is rate-determining. It is the sharing of the pair of T 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 T system of benzene to form a carbocation: H +: Y Benzene and electrophile 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 Resonance forms of a cyclohexadienyl cation Back Forward Main MenuToc Study Guide ToC Student o 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 substitution 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 mechanism 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 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 system of benzene to form a carbocation: This particular carbocation is a resonance-stabilized one of the allylic type. It is a cyclohexadienyl cation (often referred to as an arenium ion). H E H E H E Resonance forms of a cyclohexadienyl cation slow Y H E Y Benzene and electrophile H E Carbocation slow Y E C C Alkene and electrophile E C C Carbocation Y fast E C C Y Product of electrophilic addition E C C Carbocation Y Nucleophile 444 CHAPTER TWELVE Reactions of Arenes: Electrophilic Aromatic Substitution Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
12.2 Mechanistic Principles of Electrophilic Aromatic Substitution TABLE 12.1 Representative Electrophilic Aromatic Substitution Reactions of Benzene Reaction and comment Equation 1. Nitration Warming benzene with a mix ture of nitric acid and nitrobenzene. a nitro H2o places one of the ring hydrogens Benzene Nitrobenzene(95%)Water 2. Sulfonation Treatment of benzene with H hot concentrated sulfuric acid gives ben- zenesulfonic acid. A sulfonic acid group HOSO2OH H2o (-SO2OH)replaces one of the ring hydro- gens. Sulfuric acid Benzenesulfonic acid Water (100%) 3. Halogenation Bromine reacts w zene in the presence of iron(Ill)bi FeBr a catalyst to give bromobenzene. chlorine HBr reacts similarly in the presence chloride to give chlorobenzene Benzene Bromine Bromobenzene Hydrogen bromide 4. Friedel-Crafts alkylation Alkyl halides H C(CH3)3 react with benzene in the presence of alu- minum chloride to yield alkylbenzenes CH3)aCCI HCl Benzene tert-Butyl chloride 5. Friedel-Crafts acylation An analogous reaction occurs when acyl halides react with benzene in the presence of alumi- H CCH2 CH3 num chloride. The products are acylben CH3 CH2 CCI + HCl Benzene Propanoyl 1-Phenyl-1 Hydroger anone chloride PROBLEM 12.1 In the simplest molecular orbital treatment of conjugated sys- tems, it is assumed that the system does not interact with the framework of g bonds. When this Mo method was used to calculate the charge distribution in A model showing the electrostatic potential of this yclohexadienyl cation, it gave the results indicated How does the charge at each irbocation can be viewed or carbon compare with that deduced by examining the most stable resonance struc-Learning ures for cyclohexadienyl cation +033 0.33 H Most of the resonance stabilization of benzene is lost when it is converted to the yclohexadienyl cation intermediate. In spite of being allylic, a cyclohexadienyl cation Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
PROBLEM 12.1 In the simplest molecular orbital treatment of conjugated systems, it is assumed that the system does not interact with the framework of 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 structures 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 H H H H H 0 0.33 0 H 0 0.33 0.33 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 mixture of nitric acid and sulfuric acid gives nitrobenzene. A nitro group (±NO2) replaces one of the ring hydrogens. 3. Halogenation Bromine reacts with benzene 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 aluminum chloride to yield alkylbenzenes. 5. Friedel-Crafts acylation An analogous reaction occurs when acyl halides react with benzene in the presence of aluminum chloride. The products are acylbenzenes. 2. Sulfonation Treatment of benzene with hot concentrated sulfuric acid gives benzenesulfonic acid. A sulfonic acid group (±SO2OH) replaces one of the ring hydrogens. Equation H Benzene Sulfuric acid HOSO2OH Benzenesulfonic acid (100%) SO2OH Water H2O heat H Benzene Bromine Br2 Bromobenzene (65–75%) Br Hydrogen bromide HBr FeBr3 H Benzene tert-Butyl chloride (CH3)3CCl tert-Butylbenzene (60%) C(CH3)3 Hydrogen chloride HCl AlCl3 0°C H Benzene Hydrogen chloride HCl Propanoyl chloride CH3CH2CCl O 1-Phenyl-1- propanone (88%) CCH2CH3 O AlCl3 40°C Nitric acid HNO3 Nitrobenzene (95%) NO2 Water H2O H2SO4 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
CHAPTER TWELVE Reactions of Arenes: Electrophilic Aromatic Substitution 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 H E Observed product of electrophilic H H E Not observed-not aromatic If the Lewis base (Y) 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 FIGURE 12.1 Energy two steps of electrophile aromatic substitution E H E -H--.yo- E H E-Y E H-Y Reaction coordinate Back Forward Main MenuToc Study Guide ToC Student o 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) had acted as a nucleophile and added to carbon, the product 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 reactions to overcome the high activation energy that characterizes the first step, the electrophile 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 Y H H E Cyclohexadienyl cation fast Observed product of electrophilic aromatic substitution E H 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 E±Y H±Y Yδ Yδ Y H δ δ 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
12.3 Nitration of benzene electrophiles stems from the substantial loss of resonance stabilization that accompanies transfer of a pair of its six T 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 +HONO,- Ha Benzene Nitric acid Nitrobenzene(95%) Wa The electrophile(e) that reacts with benzene is nitronium ion (NO2). The concentra- The role of nitronium ion in tion of nitronium ion in nitric acid alone is too low to nitrate benzene at a convenient the nitration of benzene was rate, but can be increased by adding sulfuric acid. demonstrated by Sir Christ her ingold-the same persol who suggested the Sn1 and HO- 2HOSO,OH n→-N- H3o 2HOSO,O collaborated with Cahn and elog on the R and Snot- tional system Nitric acid Sulfuric acid Nitronium i Hydronium Hyd Step 1: Attack of nitronium cation on the Tt system of the aromatic ring FIGURE 12.2 The me- chanism of benzene. An electrostatic po- tential map of nitronium ion can be viewed on Learning H Benzene and nitronium ion ation intermediate Step 2: Loss of a proton from the cyclohexadienyl cation HE +H-0 Cyclohexadienyl Water Nitrobenzene Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
electrophiles stems from the substantial loss of resonance stabilization that accompanies transfer of a pair of its six 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) that reacts with benzene is nitronium ion ( NO2). The concentration 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. HO N O O Nitric acid 2HOSO2OH Sulfuric acid O N O Nitronium ion H3O Hydronium ion 2HOSO2O Hydrogen sulfate ion H Benzene HONO2 Nitric acid NO2 Nitrobenzene (95%) H2O Water H2SO4 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 O Cyclohexadienyl cation intermediate O H Cyclohexadienyl cation intermediate O N O H H O Water fast Nitrobenzene O H H H O Hydronium ion O N N O FIGURE 12.2 The mechanism of the nitration of benzene. An electrostatic potential 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 Christopher Ingold–the same person who suggested the SN1 and SN2 mechanisms of nucleophilic substitution and who collaborated with Cahn and Prelog on the R and S notational system. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
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
