12.7 Friedel-Crafts Acylation of Benzene 453 Thus, the industrial preparation of styrene from benzene and ethylene does not involve vinyl chloride but proceeds by way of ethylbenzene + CH,CH HCL 一CH2CH3z0 CH=CH, 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 dehalogenation 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 gen- and AICI CH3CH,CCI t HCl Benzer Propanoyl chloride 1-Phenyl-1-propanone(88%) Hy 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 CH3CH2C=O:← CH3CH2C≡O Most stable resonance form oxygen and carbon have octets of electrons Acyl cations form by coordination of an acyl chloride with aluminum chloride, followed by cleavage of the carbon-chlorine bond CH3CH,: →CH3CH2C一C1一ACl3—>CH3CH2C≡O:+AlCl4 Lewis acid-Lewis base Tetrachloro- The electrophilic site of an acyl cation is its acyl carbon. An electrostatic po ( Figure 12.6) illustrates nic 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 ure12.7) Back Forward Main MenuToc Study Guide ToC Student o 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 dehydrohalogenation. 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 potential 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 (Figure 12.7). CH3CH2C O CH3CH2C O Most stable resonance form; oxygen and carbon have octets of electrons H Benzene CH3CH2CCl O Propanoyl chloride AlCl3 carbon disulfide 40°C CCH2CH3 O 1-Phenyl-1-propanone (88%) HCl Hydrogen chloride Benzene CH2 CH2 Ethylene HCl, AlCl3 630°C ZnO CH2CH3 Ethylbenzene CH CH2 Styrene 12.7 Friedel–Crafts Acylation of Benzene 453 CH3CH2C O Cl Propanoyl chloride AlCl3 Aluminum chloride Tetrachloroaluminate ion AlCl4 Propanoyl cation CH3CH2C CH3CH2C O O AlCl3 Cl Lewis acid-Lewis base complex An acyl group has the general formula RC± O X Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
CHAPTER TWELVE Reactions of Arenes: Electrophilic Aromatic Substitution FIGURE 12. 6 Electrostatic potential [(CH3CH2C=O)+. The re with the carbon of the c=o group. PROBLEM 12.7 The reaction shown gives a single product in 88% yield What is th OCH3 +(CH3)2 CHCH, CCI OCH Acyl chlorides are readily available. They are prepared from carboxylic acids by reaction with thionyl chloride RCOH SoCl2 RCCI SO, HCl FIGURE 12.7 The Carboxylic acid Thionyl Acyl chloride mechanism of friedel-Crafts chloride dioxid chloride Ition Step 1: The acyl cation attacks benzene. a pair of t electrons of benzene is used to form a covalent bond to the carbon of the acyl catic CCH,CH H Benzene and propanoyl cation Cyclohexadienyl cation intermediate Step 2: Aromaticity of the ring is restored when it loses a proton to give the acylbenzene CCH,CH CCH2CH3 + H-Ci: AICI - alCl3 Cyclohexadienyl Tetrachloroaluminate I-Phenyl-l-propanone cation intermediate chloride chloride Back Forward Main MenuToc Study Guide ToC Student o 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 SOCl2 Thionyl chloride Hydrogen chloride RCCl HCl O Acyl chloride Sulfur dioxide SO2 CH3O OCH3 OCH3 (CH3)2CHCH2CCl O AlCl3 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. Cyclohexadienyl cation intermediate fast H Cl Tetrachloroaluminate ion H Hydrogen chloride AlCl3 Aluminum chloride AlCl3 H H Benzene and propanoyl cation slow O C CH2CH3 Cyclohexadienyl cation intermediate 1-Phenyl-1-propanone P O X O X O X Cl W CCH2CH3 CCH2CH3 CCH2CH3 FIGURE 12.6 Electrostatic potential map of propanoyl cation [(CH3CH2CœO)]. The region of greatest positive charge (blue) is associated with the carbon of the CœO group. FIGURE 12.7 The mechanism of Friedel–Crafts acylation. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
12.8 Synthesis of Alkylbenzenes by acylation-Reduction Carboxylic acid anhydrides, compounds of the type RCOCR, 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 acetophenone of the t CH3 COCCH3 CCH ChacO zene derivatives listed in Benzene Acetic anhydride Acetophenone(76-83%) Acetic 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 ct 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. M ato ms ha e ocoe Less stable cation: six electrons at carbon of electrons 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 ArCH2R is desired, a two-step sequence used in which the first step is a Friedel-Crafts acylation -CR >CH,R Benzene Amylbenzene Alkylbenzene Back Forward Main MenuToc Study Guide ToC Student o 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 product 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 conceivably 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 ArCH2R is desired, a two-step sequence is used in which the first step is a Friedel–Crafts acylation. Benzene RCCl AlCl3 O X reduction Acylbenzene CH2R Alkylbenzene CR O C R C O More stable cation; all atoms have octets of electrons R O C C Less stable cation; six electrons at carbon O O O H Benzene CH3COCCH3 O O Acetic anhydride CH3COH O Acetic acid AlCl3 40°C CCH3 O Acetophenone (76–83%) RCOCR O O 12.8 Synthesis of Alkylbenzenes by Acylation–Reduction 455 Acetophenone is one of the commonly encountered benzene derivatives listed in Table 11.1. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
CHAPTER TWELVE Reactions of Arenes: Electrophilic Aromatic Substitution The second step is a reduction of the carbonyl group(C=O)to a methylene group (CH2) The most commonly used method for reducing an acy benzene 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 O t Ch3 CH,CH,CCl CCH2CH2CY HCR CH,CH,CH,C Benzen 1-Phenyl-1-butanone(86%) Butylbenzene(73%0) 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 CsHS CH2 CH(CH3)2 (b)Neopentylbenzene, CsHsCH2 C(CH3)3 SAMPLE SOLUTION (a)Friedel-Crafts alkylation of benzene with isobutyl chlo ide is not suitable, because it yields tert-butylbenzene by rearrangement. C(CH3)3 +(CH3)2 CHCH2CI Benzene Isobutyl chloride tert-Butylbenzene(66%) 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 +(CH3)2CHCCI CCH(CH3)2 CH2 CH(CH3)2 Benzene 2-Methylpropanoyl 2-Methyl-1-phenyl-1-propanone butylbenzene(80%) (84%) Another way to reduce aldehyde and ketone carbonyl groups is by Wolff-Kishner reduction. Heating an aldehyde or a ketone with hydrazine(H2NNH2) and sodium or potassium hydroxide in a high-boiling alcohol such as triethylene glycol (HOCH2 CH2OCH2CH2OCH2 CH2OH, bp 287C)converts the carbonyl to a CH2 group CCH, CH3 -CH,,CH glycol.175°C I-Phenyl-l-propanone Propylbenzene (82%) 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 Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
The second step is a reduction of the carbonyl group (CœO) to a methylene group (CH2). 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, C6H5CH2CH(CH3)2 (b) Neopentylbenzene, C6H5CH2C(CH3)3 SAMPLE SOLUTION (a) Friedel–Crafts alkylation of benzene with isobutyl chloride 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 reduction 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 (H2NNH2) and sodium or potassium hydroxide in a high-boiling alcohol such as triethylene glycol (HOCH2CH2OCH2CH2OCH2CH2OH, bp 287°C) converts the carbonyl to a CH2 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 H2NNH2, KOH triethylene glycol, 175°C CH2CH2CH3 1-Phenyl-1-propanone Propylbenzene (82%) CCH2CH3 O AlCl3 Benzene (CH3)2CHCH2Cl Isobutyl chloride C(CH3)3 tert-Butylbenzene (66%) 456 CHAPTER TWELVE Reactions of Arenes: Electrophilic Aromatic Substitution Benzene AlCl3 Zn(Hg) HCl CH2CH2CH2CH3 1-Phenyl-1-butanone (86%) Butylbenzene (73%) CCH2CH2CH3 O Butanoyl chloride CH3CH2CH2CCl O AlCl3 Zn(Hg) HCl Benzene 2-Methylpropanoyl chloride (CH3)2CHCCl O CCH(CH3)2 O 2-Methyl-1-phenyl-1-propanone (84%) CH2CH(CH3)2 Isobutylbenzene (80%) Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
12.9 Rate and Regioselectivity in Electrophilic Aromatic Substitution 457 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 weve 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. l. 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 To illustrate substituent effects on rate. consider the nitration of benzene toluene the molecula models of toluene and (trifluc By Modeling In which molecule is the electrostatic potential of the ring most negative? How should this affect the rate of (most reactive (least reactive) 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 bromethyl 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%0 NO Toluene o-Nitrotoluene m-Nitrotoluene Nitrotoluene 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 Back Forward Main MenuToc Study Guide ToC Student o 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 important 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 substitution? 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 trifluoromethyl 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-nitrotoluene, and p-nitrotoluene. All are formed, but not in equal amounts. Together, the orthoand 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. CH3 Toluene HNO3 Acetic anhydride CH3 NO2 o-Nitrotoluene (63%) CH3 NO2 m-Nitrotoluene (3%) NO2 CH3 p-Nitrotoluene (34%) CH3 Toluene (most reactive) Benzene CF3 (Trifluoromethyl)benzene (least reactive) 12.9 Rate and Regioselectivity in Electrophilic Aromatic Substitution 457 Examine the molecular models of toluene and (trifluoromethyl)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 nitration? Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website