279 CHAPTER 12 REACTIONS OF ARENES: ELECTROPHILIC AROMATIC SUBSTITUTION SOLUTIONS TO TEXT PROBLEMS 12.1 The three most stable resonance structures for cyclohexadienyl cation are The positive charge is shared equally by the three carbons indicated. Thus the two carbons ortho to the sp 3 -hybridized carbon and the one para to it each bear one third of a positive charge (H110010.33). None of the other carbons is charged. The resonance picture and the simple MO treatment agree with respect to the distribution of charge in cyclohexadienyl cation. 12.2 Electrophilic aromatic substitution leads to replacement of one of the hydrogens directly attached to the ring by the electrophile. All four of the ring hydrogens of p-xylene are equivalent; so it does not matter which one is replaced by the nitro group. CH 3 CH 3 p-Xylene HNO 3 H 2 SO 4 CH 3 CH 3 NO 2 1,4-Dimethyl-2- nitrobenzene HH H H H H H H11001 HH H H H H H H11001 HH H H H H H H11001 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website 280 REACTIONS OF ARENES: ELECTROPHILIC AROMATIC SUBSTITUTION 12.3 The aromatic ring of 1,2,4,5-tetramethylbenzene has two equivalent hydrogen substituents. Sul- fonation of the ring leads to replacement of one of them by @SO 3 H. 12.4 The major product is isopropylbenzene. Aluminum chloride coordinates with 1-chloropropane to give a Lewis acid/Lewis base complex, which can be attacked by benzene to yield propylbenzene or can undergo an intramolecular hydride shift to produce isopropyl cation. Isopropylbenzene arises by reaction of isopropyl cation with benzene. 12.5 The species that attacks the benzene ring is cyclohexyl cation, formed by protonation of cyclohexene. The mechanism for the reaction of cyclohexyl cation with benzene is analogous to the general mech- anism for electrophilic aromatic substitution. 12.6 The preparation of cyclohexylbenzene from cyclohexene and benzene was described in text Sec- tion 12.6. Cyclohexylbenzene is converted to 1-phenylcyclohexene by benzylic bromination, fol- lowed by dehydrohalogenation. H11001 Benzene Cyclohexene Cyclohexylbenzene H 2 SO 4 NaOCH 2 CH 3N-Bromosuccinimide (NBS), benzoyl peroxide, heat 1-Phenylcyclohexene1-Bromo-1- phenylcyclohexane Br H H H H H H H H H11002H H11001 H11001 H11001 Benzene Cyclohexyl cation Cyclohexadienyl cation intermediate Cyclohexylbenzene H H H H H11001 H HOSO 2 OH Cyclohexene Sulfuric acid Cyclohexyl cation Hydrogen sulfate ion OSO 2 OH H11002 H11001 CH 3 Isopropyl cation CH H CH 2 Cl AlCl 3 hydride migration H11002 H11001CH 3 CH CH 3 AlCl 4 H11002 H11001H11001 CH 3 CH 2 CH 2 Cl 1-Chloropropane H11001H11001 AlCl 3 Propylbenzene (20% yield) CH 2 CH 2 CH 3 Benzene Isopropylbenzene (40% yield) CH(CH 3 ) 2 H 3 C CH 3 CH 3 H 3 C 1,2,4,5-Tetramethylbenzene SO 3 H 2 SO 4 2,3,5,6-Tetramethylbenzene- sulfonic acid SO 3 H H 3 C CH 3 CH 3 H 3 C Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website 12.7 Treatment of 1,3,5-trimethoxybenzene with an acyl chloride and aluminum chloride brings about Friedel–Crafts acylation at one of the three equivalent positions available on the ring. 12.8 Because the anhydride is cyclic, its structural units are not incorporated into a ketone and a car- boxylic acid as two separate product molecules. Rather, they become part of a four-carbon unit attached to benzene by a ketone carbonyl. The acyl substituent terminates in a carboxylic acid func- tional group. 12.9 (b) A Friedel–Crafts alkylation of benzene using 1-chloro-2,2-dimethylpropane would not be a satisfactory method to prepare neopentylbenzene because of the likelihood of a carbocation rearrangement. The best way to prepare this compound is by Friedel–Crafts acylation fol- lowed by Clemmensen reduction. 12.10 (b) Partial rate factors for nitration of toluene and tert-butylbenzene, relative to a single position of benzene, are as shown: The sum of these partial rate factors is 147 for toluene, 90 for tert-butylbenzene. Toluene is 147H2086290, or 1.7, times more reactive than tert-butylbenzene. (c) The product distribution for nitration of tert-butylbenzene is determined from the partial rate factors. Ortho: H5007 2( 9 4 0 .5) H5007H11005 10% Meta: H5007 2 9 (3 0 ) H5007 H11005 6.7% Para: H5007 7 9 5 0 H5007 H11005 83.3% CH 3 4242 58 2.52.5 C(CH 3 ) 3 4.54.5 75 33 AlCl 3 Zn(Hg), HCl H11001 Benzene2,2-Dimethylpropanoyl chloride (CH 3 ) 3 CCCl O 2,2-Dimethyl-1- phenyl-1-propanone (CH 3 ) 3 CC O Neopentylbenzene (CH 3 ) 3 CCH 2 AlCl 3 H11001 Benzene 4-Oxo-4-phenylbutanoic acid CCH 2 CH 2 COH O O Succinic anhydride O O O AlCl 3 H11001 1,3,5-Trimethoxybenzene OCH 3 CH 3 O OCH 3 3-Methylbutanoyl chloride (CH 3 ) 2 CHCH 2 CCl O Isobutyl 1,3,5-trimethoxyphenyl ketone OCH 3 CH 3 O OCH 3 CCH 2 CH(CH 3 ) 2 O REACTIONS OF ARENES: ELECTROPHILIC AROMATIC SUBSTITUTION 281 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website 12.11 The compounds shown all undergo electrophilic aromatic substitution more slowly than benzene. Therefore, @CH 2 Cl, @CHCl 2 , and @CCl 3 are deactivating substituents. The electron-withdrawing power of these substituents, and their tendency to direct incoming elec- trophiles meta to themselves, will increase with the number of chlorines each contains. Thus, the substituent that gives 4% meta nitration (96% ortho H11001 para) contains the fewest chlorine atoms (GCH 2 Cl), and the one that gives 64% meta nitration contains the most (@CCl 3 ). 12.12 (b) Attack by bromine at the position meta to the amino group gives a cyclohexadienyl cation in- termediate in which delocalization of the nitrogen lone pair cannot participate in dispersal of the positive charge. (c) Attack at the position para to the amino group yields a cyclohexadienyl cation intermediate that is stabilized by delocalization of the electron pair of the amino group. 12.13 Electrophilic aromatic substitution in biphenyl is best understood by considering one ring as the functional group and the other as a substituent. An aryl substituent is ortho, para-directing. Nitration of biphenyl gives a mixture of o-nitrobiphenyl and p-nitrobiphenyl. 12.14 (b) The carbonyl group attached directly to the ring is a signal that the substituent is a meta- directing group. Nitration of methyl benzoate yields methyl m-nitrobenzoate. HNO 3 H 2 SO 4 Methyl benzoate COCH 3 O Methyl m-nitrobenzoate (isolated in 81–85% yield) O 2 N COCH 3 O HNO 3 H 2 SO 4 O 2 N o-Nitrobiphenyl (37%) Biphenyl NO 2 p-Nitrobiphenyl (63%) H11001 NH 2 H11001 H11001 NH 2 H11001 NH 2 H11001 NH 2 BrH BrH BrH BrH NH 2 H11001 Br H NH 2 H11001 NH 2 H11001 Br H Br H Deactivating, ortho, para-directing CH 2 Cl Deactivating, ortho, para-directing CHCl 2 Deactivating, meta-directing CCl 3 Benzyl chloride CH 2 Cl (Dichloromethyl)benzene CHCl 2 (Trichloromethyl)benzene CCl 3 282 REACTIONS OF ARENES: ELECTROPHILIC AROMATIC SUBSTITUTION Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website (c) The acyl group in 1-phenyl-1-propanone is meta-directing; the carbonyl is attached directly to the ring. The product is 1-(m-nitrophenyl)-1-propanone. 12.15 Writing the structures out in more detail reveals that the substituent G H11001 N(CH 3 ) 3 lacks the unshared electron pair of . This unshared pair is responsible for the powerful activating effect of an group. On the other hand, the nitrogen in G H11001 N(CH 3 ) 3 is positively charged and in that respect resembles the nitro- gen of a nitro group. We expect the substituent G H11001 N(CH 3 ) 3 to be deactivating and meta-directing. 12.16 The reaction is a Friedel–Crafts alkylation in which 4-chlorobenzyl chloride serves as the carboca- tion source and chlorobenzene is the aromatic substrate. Alkylation occurs at the positions ortho and para to the chlorine substituent of chlorobenzene. 12.17 (b) Halogen substituents are ortho, para-directing, and the disposition in m-dichlorobenzene is such that their effects reinforce each other. The major product is 2,4-dichloro-1-nitrobenzene. Substitution at the position between the two chlorines is slow because it is a sterically hin- dered position. (c) Nitro groups are meta-directing. Both nitro groups of m-dinitrobenzene direct an incoming substituent to the same position in an electrophilic aromatic substitution reaction. Nitration of m-nitrobenzene yields 1,3,5-trinitrobenzene. Both nitro groups of m-dinitrobenzene direct electrophile to same position. NO 2 NO 2 1,3,5-Trinitrobenzene (principal product of nitration of m-dinitrobenzene) NO 2 NO 2 O 2 N Most reactive positions in electrophilic aromatic substitution of m-dichlorobenzene Cl Cl 2,4-Dichloro-1-nitrobenzene (major product of nitration) Cl Cl NO 2 AlCl 3 Chlorobenzene Cl 4-Chlorobenzyl chloride ClCH 2 Cl 1-Chloro-4-(4H11032-chlorobenzyl)- benzene Cl CH 2 Cl 1-Chloro-2-(4H11032-chlorobenzyl)- benzene CH 2 Cl Cl H11001H11001 N(CH 3 ) 2 N O H11002 O H11001 CH 3 CH 3 CH 3 N H11001 N CH 3 CH 3 N(CH 3 ) 2 nitration 1-Phenyl-1-propanone CCH 2 CH 3 O 1-(m-Nitrophenyl)-1-propanone (isolated in 60% yield) O 2 N CCH 2 CH 3 O REACTIONS OF ARENES: ELECTROPHILIC AROMATIC SUBSTITUTION 283 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website (d) A methoxy group is ortho, para-directing, and a carbonyl group is meta-directing. The open positions of the ring that are activated by the methoxy group in p-methoxyacetophenone are also those that are meta to the carbonyl, so the directing effects of the two substituents reinforce each other. Nitration of p-methoxyacetophenone yields 4-methoxy-3-nitroacetophenone. (e) The methoxy group of p-methylanisole activates the positions that are ortho to it; the methyl activates those ortho to itself. Methoxy is a more powerful activating substituent than methyl, so nitration occurs ortho to the methoxy group. ( f ) All the substituents in 2,6-dibromoanisole are ortho, para-directing, and their effects are felt at different positions. The methoxy group, however, is a far more powerful activating substituent than bromine, so it controls the regioselectivity of nitration. 12.18 The product that is obtained when benzene is subjected to bromination and nitration depends on the order in which the reactions are carried out. A nitro group is meta-directing, and so if it is introduced prior to the bromination step, m-bromonitrobenzene is obtained. Bromine is an ortho, para-directing group. If it is introduced first, nitration of the resulting bromobenzene yields a mixture of o-bromonitrobenzene and p-bromonitrobenzene. Br 2 FeBr 3 HNO 3 H 2 SO 4 H11001 Benzene Br Bromobenzene Br NO 2 o-Bromonitrobenzene Br NO 2 p-Bromonitrobenzene Benzene m-BromonitrobenzeneNitrobenzene Br NO 2 NO 2 HNO 3 H 2 SO 4 Br 2 FeBr 3 OCH 3 Br Br 1 2 3 4 5 6 OCH 3 NO 2 Br Br Methoxy directs toward C-4; bromines direct toward C-3 and C-5. 2,6-Dibromo-4-nitroanisole (principal product of nitration) 4-Methyl-2-nitroanisole (principal product of nitration) CH 3 OCH 3 NO 2 Methyl activates C-3 and C-5; methoxy activates C-2 and C-6. CH 3 OCH 3 1 6 5 4 32 Positions ortho to the methoxy group are meta to the carbonyl. CH 3 C OCH 3 O 4-Methoxy-3-nitroacetophenone CH 3 C OCH 3 O NO 2 284 REACTIONS OF ARENES: ELECTROPHILIC AROMATIC SUBSTITUTION Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website 12.19 A straightforward approach to the synthesis of m-nitrobenzoic acid involves preparation of ben- zoic acid by oxidation of toluene, followed by nitration. The carboxyl group of benzoic acid is meta-directing. Nitration of toluene prior to oxidation would lead to a mixture of ortho and para products. 12.20 The text points out that C-1 of naphthalene is more reactive than C-2 toward electrophilic aromatic substitution. Thus, of the two possible products of sulfonation, naphthalene-1-sulfonic acid should be formed faster and should be the major product under conditions of kinetic control. Since the problem states that the product under conditions of thermodynamic control is the other isomer, naphthalene-2-sulfonic acid is the major product at elevated temperature. Naphthalene-2-sulfonic acid is the more stable isomer for steric reasons. The hydrogen at C-8 (the one shown in the equation) crowds the group in naphthalene-1-sulfonic acid. 12.21 The text states that electrophilic aromatic substitution in furan, thiophene, and pyrrole occurs at C-2. The sulfonation of thiophene gives thiophene-2-sulfonic acid. 12.22 (a) Nitration of benzene is the archetypical electrophilic aromatic substitution reaction. (b) Nitrobenzene is much less reactive than benzene toward electrophilic aromatic substitution. The nitro group on the ring is a meta director. HNO 3 H 2 SO 4 NO 2 Nitrobenzene NO 2 NO 2 m-Dinitrobenzene HNO 3 H 2 SO 4 Benzene NO 2 Nitrobenzene S S SO 3 H H 2 SO 4 Thiophene Thiophene-2- sulfonic acid SO 3 H H 2 SO 4 Naphthalene Naphthalene-1-sulfonic acid major product at 0H11034C; formed faster H 1 2 HSO 3 H Naphthalene-2-sulfonic acid major product at 160H11034C; more stable H SO 3 H H11001 Na 2 Cr 2 O 7 H 2 O, H 2 SO 4 , heat HNO 3 H 2 SO 4 CH 3 Toluene CO 2 H Benzoic acid CO 2 H NO 2 m-Nitrobenzoic acid REACTIONS OF ARENES: ELECTROPHILIC AROMATIC SUBSTITUTION 285 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website (c) Toluene is more reactive than benzene in electrophilic aromatic substitution. A methyl sub- stituent is an ortho, para director. (d)Trifluoromethyl is deactivating and meta-directing. (e) Anisole is ortho, para-directing, strongly activated toward electrophilic aromatic substitution, and readily sulfonated in sulfuric acid. Sulfur trioxide could be added to the sulfuric acid to facilitate reaction. The para isomer is the predominant product. ( f ) Acetanilide is quite similar to anisole in its behavior toward electrophilic aromatic substitution. (g) Bromobenzene is less reactive than benzene. A bromine substituent is ortho, para-directing. FeCl 3 Cl 2 H11001 Br Bromobenzene Br Cl o-Bromochloro- benzene Br Cl p-Bromochloro- benzene H 2 SO 4 H11001 HNCCH 3 O Acetanilide HNCCH 3 O SO 3 H o-Acetamidobenzene- sulfonic acid HNCCH 3 O SO 3 H p-Acetamidobenzene- sulfonic acid H 2 SO 4 OCH 3 Anisole OCH 3 SO 3 H o-Methoxybenzene- sulfonic acid p-Methoxybenzene- sulfonic acid OCH 3 SO 3 H H11001 Br 2 FeBr 3 CF 3 (Trifluoromethyl)- benzene CF 3 Br m-Bromo(trifluoromethyl)- benzene Br 2 FeBr 3 CH 3 Toluene CH 3 Br o-Bromotoluene p-Bromotoluene CH 3 Br H11001 286 REACTIONS OF ARENES: ELECTROPHILIC AROMATIC SUBSTITUTION Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website (h) Anisole is a reactive substrate toward Friedel–Crafts alkylation and yields a mixture of o- and p-benzylated products when treated with benzyl chloride and aluminum chloride. (i) Benzene will undergo acylation with benzoyl chloride and aluminum chloride. ( j) A benzoyl substituent is meta-directing and deactivating. (k) Clemmensen reduction conditions involve treating a ketone with zinc amalgam and concen- trated hydrochloric acid. (l) Wolff–Kishner reduction utilizes hydrazine, a base, and a high-boiling alcohol solvent to reduce ketone functions to methylene groups. 12.23 (a) There are three principal resonance forms of the cyclohexadienyl cation intermediate formed by attack of bromine on p-xylene. CH 3 H Br CH 3 H11001 CH 3 CH 3 H11001 CH 3 CH 3 H11001 H Br H Br H 2 NNH 2 KOH diethylene glycol C O Benzophenone Diphenylmethane CH 2 Zn(Hg) HCl C O Benzophenone Diphenylmethane CH 2 HNO 3 H 2 SO 4 C O Benzophenone m-Nitrobenzophenone C O NO 2 AlCl 3 H11001 Benzene CCl O Benzoyl chloride C O Benzophenone AlCl 3 H11001H11001 CH 2 Cl Benzyl chloride OCH 3 Anisole OCH 3 CH 2 C 6 H 5 o-Benzylanisole OCH 3 CH 2 C 6 H 5 p-Benzylanisole REACTIONS OF ARENES: ELECTROPHILIC AROMATIC SUBSTITUTION 287 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website Any one of these resonance forms is a satisfactory answer to the question. Because of its ter- tiary carbocation character, this carbocation is more stable than the corresponding intermedi- ate formed from benzene. (b) Chlorination of m-xylene will give predominantly 4-chloro-1,3-dimethylbenzene. The intermediate shown (or any of its resonance forms) is more stable for steric reasons than The cyclohexadienyl cation intermediate leading to 4-chloro-1,3-dimethylbenzene is more stable and is formed faster than the intermediate leading to chlorobenzene because of its ter- tiary carbocation character. (c) The most stable carbocation intermediate formed during nitration of acetophenone is the one corresponding to meta attack. An acyl group is electron-withdrawing and destabilizes a carbocation to which it is attached. The most stable carbocation intermediate in the nitration of acetophenone is less stable and is formed more slowly than is the corresponding carbocation formed during nitration of benzene. CCH 3 O H less stable than H11001H11001 H NO 2 H NO 2 CCH 3 O CCH 3 O CCH 3 O H O 2 N more stable than or H11001 H11001H11001 H NO 2 NO 2 H CH 3 CH 3 H11001 H H11001 more stable than ClH ClH CH 3 H Cl CH 3 H11001 Less stable cyclohexadienyl cation CH 3 CH 3 m-Xylene CH 3 Cl CH 3 4-Chloro-1,3- dimethylbenzene H11001 CH 3 ClH CH 3 More stable cyclohexadienyl cation Cl 2 via 288 REACTIONS OF ARENES: ELECTROPHILIC AROMATIC SUBSTITUTION Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website (d) The methoxy group in anisole is strongly activating and ortho, para-directing. For steric rea- sons and because of inductive electron withdrawal by oxygen, the intermediate leading to para substitution is the most stable. Of the various resonance forms for the most stable intermediate, the most stable one has eight electrons around each oxygen and carbon atom. This intermediate is much more stable than the corresponding intermediate from acylation of benzene. (e) An isopropyl group is an activating substituent and is ortho, para-directing. Attack at the ortho position is sterically hindered. The most stable intermediate is or any of its resonance forms. Because of its tertiary carbocation character, this cation is more stable than the corresponding cyclohexadienyl cation intermediate from benzene. ( f ) A nitro substituent is deactivating and meta-directing. The most stable cyclohexadienyl cation formed in the bromination of nitrobenzene is This ion is less stable than the cyclohexadienyl cation formed during bromination of benzene. (g) Sulfonation of furan takes place at C-2. The cationic intermediate is more stable than the cyclo- hexadienyl cation formed from benzene because it is stabilized by electron release from oxygen. O O SO 3 H O H11001 O H11001 H 2 SO 4 via Furan Furan-2- sulfonic acid SO 3 H H SO 3 H H N H Br H11001 H11002 H11001 O O CH(CH 3 ) 2 H NO 2 H11001 Most stable resonance form H O CCH 3 OCH 3 H11001 more stable thanslightly more stable than OCH 3 H CCH 3 H11001 O OCH 3 O H CCH 3 H11001 OCH 3 H CCH 3 H11001 O REACTIONS OF ARENES: ELECTROPHILIC AROMATIC SUBSTITUTION 289 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website (h) Pyridine reacts with electrophiles at C-3. It is less reactive than benzene, and the carbocation intermediate is less stable than the corresponding intermediate formed from benzene. 12.24 (a) Toluene is more reactive than chlorobenzene in electrophilic aromatic substitution reac- tions because a methyl substituent is activating but a halogen substituent is deactivating. Both are ortho, para-directing, however. Nitration of toluene is faster than nitration of chlorobenzene. Faster: Slower: (b)Afluorine substituent is not nearly as strongly deactivating as a trifluoromethyl group. The reaction that takes place is Friedel–Crafts alkylation of fluorobenzene. Strongly deactivated aromatic compounds do not undergo Friedel–Crafts reactions. (c) A carbonyl group directly bonded to a benzene ring strongly deactivates it toward elec- trophilic aromatic substitution. Methyl benzoate is much less reactive than benzene. COCH 3 O COCH 3 O H11002 H11001 CF 3 C 6 H 5 CH 2 Cl no reactionH11001 AlCl 3 F F CH 2 C 6 H 5 F CH 2 C 6 H 5 C 6 H 5 CH 2 Cl AlCl 3 H11001 o-Benzylfluorobenzene (15%) p-Benzylfluorobenzene (85%) Cl Cl NO 2 Cl NO 2 HNO 3 H 2 SO 4 H11001 Chlorobenzene o-Chloronitrobenzene p-Chloronitrobenzene CH 3 CH 3 NO 2 CH 3 NO 2 HNO 3 H 2 SO 4 H11001 Toluene o-Nitrotoluene p-Nitrotoluene N H11001 Br H 290 REACTIONS OF ARENES: ELECTROPHILIC AROMATIC SUBSTITUTION Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website An oxygen substituent directly attached to the ring strongly activates it toward electrophilic aromatic substitution. Phenyl acetate is much more reactive than benzene or methyl benzoate. Bromination of methyl benzoate requires more vigorous conditions; catalysis by iron(III) bro- mide is required for bromination of deactivated aromatic rings. (d) Acetanilide is strongly activated toward electrophilic aromatic substitution and reacts faster than nitrobenzene, which is strongly deactivated. (e) Both substrates are of the type and are activated toward Friedel–Crafts acylation. Since electronic effects are comparable, we look to differences in steric factors and conclude that reaction will be faster for R H11005 CH 3 than for R H11005 (CH 3 ) 3 CG. CH 3 CH 3 H11001 p-Xylene Acetyl chloride 2,5-Dimethylacetophenone CH 3 CCl O AlCl 3 CH 3 CH 3 C O CH 3 R R R H11005 alkyl HNCCH 3 O Acetanilide o-Acetamidobenzene- sulfonic acid HNCCH 3 O SO 3 H H11001 p-Acetamidobenzene- sulfonic acid HNCCH 3 O SO 3 H SO 3 H 2 SO 4 N O O H11002 H11001 Nitrobenzene (Nitrogen is positively charged and is electron-withdrawing.) HNCCH 3 O Acetanilide (Lone pair on nitrogen can stabilize cyclohexadienyl cation intermediate.) Br 2 acetic acid OCCH 3 O OCCH 3 Br O OCCH 3 Br O H11001 Phenyl acetate o-Bromophenyl acetate p-Bromophenyl acetate REACTIONS OF ARENES: ELECTROPHILIC AROMATIC SUBSTITUTION 291 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website ( f ) A phenyl substituent is activating and ortho, para-directing. Biphenyl will undergo chlorina- tion readily. Each benzene ring of benzophenone is deactivated by the carbonyl group. Benzophenone is much less reactive than biphenyl in electrophilic aromatic substitution reactions. 12.25 Reactivity toward electrophilic aromatic substitution increases with increasing number of electron- releasing substituents. Benzene, with no methyl substituents, is the least reactive, followed by toluene, with one methyl group. 1,3,5-Trimethylbenzene, with three methyl substituents, is the most reactive. o-Xylene and m-xylene are intermediate in reactivity between toluene and 1,3,5-trimethylben- zene. Of the two, m-xylene is more reactive than o-xylene because the activating effects of the two methyl groups reinforce each other. 12.26 (a) Chlorine is ortho, para-directing, carboxyl is meta-directing. The positions that are ortho to the chlorine are meta to the carboxyl, so that both substituents direct an incoming electrophile to the same position. Introduction of the second nitro group at the remaining CH 3 CH 3 CH 3 CH 3 m-Xylene (activating effects reinforce each other) 5 H11003 10 4 o-Xylene (all positions somewhat activated) Relative reactivity: 5 H11003 10 2 CH 3 CH 3 H 3 CCH 3 1,3,5-Trimethylbenzene 2 H11003 10 7 Toluene 60 Benzene Relative reactivity: 1 Benzophenone C O C O H11002 H11001 Biphenyl o-Chlorobiphenyl p-Chlorobiphenyl Cl 2 FeCl 3 C 6 H 5 C 6 H 5 ClH11001 Cl 292 REACTIONS OF ARENES: ELECTROPHILIC AROMATIC SUBSTITUTION Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website position that is ortho to the chlorine puts it meta to the carboxyl and meta to the first nitro group. (b) An amino group is one of the strongest activating substituents. The para and both ortho posi- tions are readily substituted in aniline. When aniline is treated with excess bromine, 2,4,6- tribromoaniline is formed in quantitative yield. (c) The positions ortho and para to the amino group in o-aminoacetophenone are the ones most activated toward electrophilic aromatic substitution. (d) The carboxyl group in benzoic acid is meta-directing, and so nitration gives m-nitrobenzoic acid. The second nitration step introduces a nitro group meta to both the carboxyl group and the first nitro group. (e) Both bromine substituents are introduced ortho to the strongly activating hydroxyl group in p-nitrophenol. p-Nitrophenol OH NO 2 2,6-Dibromo-4- nitrophenol (96–98%) OH BrBr NO 2 Br 2 CO 2 H Benzoic acid HNO 3 H 2 SO 4 HNO 3 H 2 SO 4 m-Nitrobenzoic acid CO 2 H NO 2 3,5-Dinitrobenzoic acid (54–58%) CO 2 H NO 2 O 2 N Br 2 o-Aminoacetophenone O CH 3 C H 2 N 2-Amino-3,5- dibromoacetophenone (65%) O CH 3 C H 2 NBr Br Aniline NH 2 2,4,6-Tribromoaniline (100%) NH 2 BrBr Br H11001 3Br 2 p-Chlorobenzoic acid Cl CO 2 H Cl NO 2 CO 2 H 4-Chloro-3,5- dinitrobenzoic acid (90%) Cl NO 2 O 2 N CO 2 H HNO 3 H 2 SO 4 , heat HNO 3 H 2 SO 4 , heat REACTIONS OF ARENES: ELECTROPHILIC AROMATIC SUBSTITUTION 293 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website ( f ) Friedel–Crafts alkylation occurs when biphenyl is treated with tert-butyl chloride and iron (III) chloride (a Lewis acid catalyst); the product of monosubstitution is p-tert-butylbiphenyl. All the positions of the ring that bears the tert-butyl group are sterically hindered, so the sec- ond alkylation step introduces a tert-butyl group at the para position of the second ring. (g) Disulfonation of phenol occurs at positions ortho and para to the hydroxyl group. The ortho, para product predominates over the ortho, ortho one. 12.27 When carrying out each of the following syntheses, evaluate how the structure of the product differs from that of benzene or toluene; that is, determine which groups have been substituted on the ben- zene ring or altered in some way. The sequence of reaction steps when multiple substitution is de- sired is important; recall that some groups direct ortho, para and others meta. (a) Isopropylbenzene may be prepared by a Friedel–Crafts alkylation of benzene with isopropyl chloride (or bromide, or iodide). It would not be appropriate to use propyl chloride and trust that a rearrangement would lead to isopropylbenzene, because a mixture of propylbenzene and isopropylbenzene would be obtained. Isopropylbenzene may also be prepared by alkylation of benzene with propene in the pres- ence of sulfuric acid. (b) Since the isopropyl and sulfonic acid groups are para to each other, the first group introduced on the ring must be the ortho, para director, that is, the isopropyl group. We may therefore use the product of part (a), isopropylbenzene, in this synthesis. An isopropyl group is a fairly H 2 SO 4 H11001 Benzene Isopropylbenzene CH(CH 3 ) 2 Propene CH 3 CH CH 2 AlCl 3 H11001 Benzene Isopropyl chloride (CH 3 ) 2 CHCl Isopropylbenzene CH(CH 3 ) 2 Phenol OH 2-Hydroxy-1,5- benzenedisulfonic acid OH SO 3 H SO 3 H H 2 SO 4 Biphenyl C(CH 3 ) 3 4,4H11032-Di-tert- butylbiphenyl (70%) C(CH 3 ) 3 C(CH 3 ) 3 (CH 3 ) 3 CCl FeCl 3 (CH 3 ) 3 CCl FeCl 3 294 REACTIONS OF ARENES: ELECTROPHILIC AROMATIC SUBSTITUTION Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website bulky ortho, para director, and so sulfonation of isopropylbenzene gives mainly p-isopropyl- benzenesulfonic acid. A sulfonic acid group is meta-directing, so that the order of steps must be alkylation followed by sulfonation rather than the reverse. (c) Free-radical halogenation of isopropylbenzene occurs with high regioselectivity at the ben- zylic position. N-Bromosuccinimide (NBS) is a good reagent to use for benzylic bromination reactions. (d) Toluene is an obvious starting material for the preparation of 4-tert-butyl-2-nitrotoluene. Two possibilities, both involving nitration and alkylation of toluene, present themselves; the prob- lem to be addressed is in what order to carry out the two steps. Friedel–Crafts alkylation must precede nitration. Introduction of the nitro group as the first step is an unsatisfactory approach since Friedel–Crafts reactions cannot be carried out on nitro-substituted aromatic compounds. (e) Two electrophilic aromatic substitution reactions need to be performed: chlorination and Friedel–Crafts acylation. The order in which the reactions are carried out is important; chlo- rine is an ortho, para director, and the acetyl group is a meta director. Since the groups are meta in the desired compound, introduce the acetyl group first. ( f ) Reverse the order of steps in part (e) to prepare p-chloroacetophenone. Friedel–Crafts reactions can be carried out on halobenzenes but not on arenes that are more strongly deactivated. Benzene Cl 2 FeCl 3 Chlorobenzene Cl p-Chloroacetophenone Cl O CCH 3 AlCl 3 CH 3 CCl O Benzene Cl 2 AlCl 3 AlCl 3 CH 3 CCl O Acetophenone O CCH 3 m-Chloroacetophenone O CCH 3 Cl CH 3 Toluene CH 3 C(CH 3 ) 3 p-tert-Butyltoluene (CH 3 ) 3 CCl AlCl 3 HNO 3 H 2 SO 4 4-tert-Butyl- 2-nitrotoluene CH 3 NO 2 C(CH 3 ) 3 Br 2 , light or NBS Isopropylbenzene CH(CH 3 ) 2 2-Bromo-2-phenylpropane CCH 3 Br CH 3 SO 3 H 2 SO 4 Isopropylbenzene (CH 3 ) 2 CH p-Isopropylbenzenesulfonic acid (CH 3 ) 2 CH SO 3 H REACTIONS OF ARENES: ELECTROPHILIC AROMATIC SUBSTITUTION 295 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website (g) Here again the problem involves two successive electrophilic aromatic substitution reactions, in this case using toluene as the initial substrate. The proper sequence is Friedel–Crafts acyla- tion first, followed by bromination of the ring. If the sequence of steps had been reversed, with halogenation preceding acylation, the first in- termediate would be o-bromotoluene, Friedel–Crafts acylation of which would give a com- plex mixture of products because both groups are ortho, para-directing. On the other hand, the orienting effects of the two groups in p-methylacetophenone reinforce each other, so that its bromination is highly regioselective and in the desired direction. (h) Recalling that alkyl groups attached to the benzene ring by CH 2 may be prepared by reduction of the appropriate ketone, we may reduce 3-bromo-4-methylacetophenone, as prepared in part (g), by the Clemmensen on Wolff–Kishner procedure to give 2-bromo-4-ethyltoluene. (i) This is a relatively straightforward synthetic problem. Bromine is an ortho, para-directing substituent; nitro is meta-directing. Nitrate first, and then brominate to give 1-bromo- 3-nitrobenzene. ( j) Take advantage of the ortho, para-directing properties of bromine to prepare 1-bromo-2,4- dinitrobenzene. Brominate first, and then nitrate under conditions that lead to disubstitution. The nitro groups are introduced at positions ortho and para to the bromine and meta to each other. Benzene Bromobenzene Br Br 2 , FeBr 3 HNO 3 H 2 SO 4 , heat 1-Bromo-2,4- dinitrobenzene Br NO 2 NO 2 Benzene Nitrobenzene NO 2 HNO 3 H 2 SO 4 Br 2 AlBr 3 1-Bromo-3-nitrobenzene NO 2 Br Zn(Hg), HCl or H 2 NNH 2 , KOH diethylene glycol, heat 3-Bromo-4- methylacetophenone CH 3 Br CCH 3 O 2-Bromo-4- ethyltoluene CH 3 Br CH 2 CH 3 CH 3 Toluene Br 2 AlBr 3 AlCl 3 CH 3 CCl O p-Methylacetophenone CH 3 CCH 3 O 3-Bromo-4- methylacetophenone CH 3 Br CCH 3 O 296 REACTIONS OF ARENES: ELECTROPHILIC AROMATIC SUBSTITUTION Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website (k) Although bromo and nitro substituents are readily introduced by electrophilic aromatic substi- tution, the only methods we have available so far to prepare carboxylic acids is by oxidation of alkyl side chains. Thus, use toluene as a starting material, planning to convert the methyl group to a carboxyl group by oxidation. Nitrate next; nitro and carboxyl are both meta-directing groups, so that the bromination in the last step occurs with the proper regioselectivity. If bromination is performed prior to nitration, the bromine substituent will direct an incoming electrophile to positions ortho and para to itself, giving the wrong orientation of substituents in the product. (l) Again toluene is a suitable starting material, with its methyl group serving as the source of the carboxyl substituent. The orientation of the substituents in the final product requires that the methyl group be retained until the final step. Nitration must precede bromination, as in the previous part, in order to prevent formation of an undesired mixture of isomers. (m) Friedel–Crafts alkylation of benzene with benzyl chloride (or benzyl bromide) is a satisfac- tory route to diphenylmethane. Benzyl chloride is prepared by free-radical chlorination of toluene. Alternatively, benzene could have been subjected to Friedel–Crafts acylation with benzoyl chloride to give benzophenone. Clemmensen or Wolff–Kishner reduction of benzophenone would then furnish diphenylmethane. (n) 1-Phenyloctane cannot be prepared efficiently by direct alkylation of benzene, because of the probability that rearrangement will occur. Indeed, a mixture of 1-phenyloctane and 2-phenyl- octane is formed under the usual Friedel–Crafts conditions, along with 3-phenyloctane. C 6 H 6 C 6 H 5 CH 2 (CH 2 ) 6 CH 3 1-Phenyloctane (40%) 2-Phenyloctane (30%) 3-Phenyloctane (30%)Benzene 1-Bromooctane CH 3 CH 2 CH 3 C 6 H 5 CH(CH 2 ) 5 CH 3 C 6 H 5 CH(CH 2 ) 4 CH 3 AlBr 3 H11001H11001H11001 CH 3 (CH 2 ) 6 CH 2 Br Benzyl chloride CH 3 CH 2 Cl Cl 2 Toluene light or heat DiphenylmethaneBenzene H11001 CH 2 Cl CH 2 AlCl 3 Benzyl chloride Toluene CH 3 p-Nitrotoluene CH 3 NO 2 HNO 3 H 2 SO 4 Na 2 Cr 2 O 7 H 2 O, H 2 SO 4 , heat 2-Bromo-4- nitrotoluene CH 3 NO 2 Br 2-Bromo-4- nitrobenzoic acid CO 2 H NO 2 Br Br 2 FeBr 3 Toluene CH 3 Benzoic acid CO 2 H Na 2 Cr 2 O 7 H 2 O, H 2 SO 4 , heat HNO 3 H 2 SO 4 Br 2 FeBr 3 3-Nitrobenzoic acid CO 2 H NO 2 3-Bromo-5- nitrobenzoic acid Br CO 2 H NO 2 REACTIONS OF ARENES: ELECTROPHILIC AROMATIC SUBSTITUTION 297 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website A method that permits the synthesis of 1-phenyloctane free of isomeric compounds is acyla- tion followed by reduction. Alternatively, Wolff–Kishner conditions (hydrazine, potassium hydroxide, diethylene glycol) could be used in the reduction step. (o) Direct alkenylation of benzene under Friedel–Crafts reaction conditions does not take place, and so 1-phenyl-1-octene cannot be prepared by the reaction Having already prepared 1-phenyloctane in part (n), however, we can functionalize the ben- zylic position by bromination and then carry out a dehydrohalogenation to obtain the target compound. (p) 1-Phenyl-1-octyne cannot be prepared in one step from benzene; 1-haloalkynes are unsuitable reactants for a Friedel–Crafts process. In Chapter 9, however, we learned that alkynes may be prepared from the corresponding alkene: Using the alkene prepared in part (o), (q) Nonconjugated cyclohexadienes are prepared by Birch reduction of arenes. Thus the last step in the synthesis of 1,4-di-tert-butyl-1,4-cyclohexadiene is the Birch reduction of 1,4-di-tert- butylbenzene. C(CH 3 ) 3 Benzene tert-Butylbenzene p-Di-tert- butylbenzene (CH 3 ) 3 CCl AlCl 3 (CH 3 ) 3 CCl AlCl 3 Na, NH 3 ethanol C(CH 3 ) 3 C(CH 3 ) 3 1,4-Di-tert-butyl-1,4- cyclohexadiene C(CH 3 ) 3 C(CH 3 ) 3 C 6 H 5 CH C 6 H 5 CHCH(CH 2 ) 5 CH 3 1,2-Dibromo-1-phenyloctane 1-Phenyl-1-octyne1-Phenyl-1-octene Br Br CH(CH 2 ) 5 CH 3 C 6 H 5 C C(CH 2 ) 5 CH 3 Br 2 NaNH 2 NH 3 RC RCH Br Br CR RCH CHRCHR obtained fromobtained from C 6 H 5 CH(CH 2 ) 6 CH 3 1-Bromo-1-phenyloctane 1-Phenyl-1-octene1-Phenyloctane C 6 H 5 CH Br 2 , light KOCH 3 CH 3 OH C 6 H 5 CH 2 (CH 2 ) 6 CH 3 or NBS CH(CH 2 ) 5 CH 3 Br C 6 H 6 Benzene 1-Chloro-1-octene AlCl 3 H11001 ClCH CH(CH 2 ) 5 CH 3 1-Phenyl-1-octene C 6 H 5 CH CH(CH 2 ) 5 CH 3 No! Reaction effective only with alkyl halides, not 1-haloalkenes. C 6 H 6 C 6 H 5 C(CH 2 ) 6 CH 3 1-Phenyl-1-octanone 1-PhenyloctaneBenzene Octanoyl chloride O C 6 H 5 CH 2 (CH 2 ) 6 CH 3 AlCl 3 Zn(Hg) HCl H11001 CH 3 (CH 2 ) 6 CCl O 298 REACTIONS OF ARENES: ELECTROPHILIC AROMATIC SUBSTITUTION Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website 12.28 (a) Methoxy is an ortho, para-directing substituent. All that is required to prepare p-methoxy- benzenesulfonic acid is to sulfonate anisole. (b) In reactions involving disubstitution of anisole, the better strategy is to introduce the para sub- stituent first. The methoxy group is ortho, para-directing, but para substitution predominates. (c) Reversing the order of the steps used in part (b) yields 4-bromo-2-nitroanisole. (d) Direct introduction of a vinyl substituent onto an aromatic ring is not a feasible reaction. p-Methoxystyrene must be prepared in an indirect way by adding an ethyl side chain and then taking advantage of the reactivity of the benzylic position by bromination (e.g., with N- bromosuccinimide) and dehydrohalogenation. 12.29 (a) Methyl is an ortho, para-directing substituent, and toluene yields mainly o-nitrotoluene and p-nitrotoluene on mononitration. Some m-nitrotoluene is also formed. CH 3 CH 3 Toluene o-Nitrotoluene HNO 3 40 O C CH 3 m-Nitrotoluene NO 2 NO 2 CH 3 NO 2 p-Nitrotoluene H11001H11001 OCH 3 OCH 3 CH 2 CH 3 Anisole p-Ethylanisole CH 3 CH 2 Cl AlCl 3 NBS peroxides, heat NaOCH 3 p-(1-Bromoethyl)anisole OCH 3 BrCHCH 3 p-Methoxystyrene OCH 3 CH CH 2 Br 2 FeBr 3 HNO 3 H 2 SO 4 Anisole OCH 3 p-Bromoanisole OCH 3 Br 4-Bromo-2- nitroanisole OCH 3 Br NO 2 OCH 3 OCH 3 NO 2 Anisole p-Nitroanisole HNO 3 H 2 SO 4 Br 2 FeBr 3 OCH 3 Br NO 2 2-Bromo-4- nitroanisole OCH 3 Anisole H 2 SO 4 p-Methoxybenzene- sulfonic acid OCH 3 SO 3 H REACTIONS OF ARENES: ELECTROPHILIC AROMATIC SUBSTITUTION 299 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website (b) There are six isomeric dinitrotoluenes: The least likely product is 3,5-dinitrotoluene because neither of its nitro groups is ortho or para to the methyl group. (c) There are six trinitrotoluene isomers: The most likely major product is 2,4,6-trinitrotoluene because all the positions activated by the methyl group are substituted. This is, in fact, the compound commonly known as TNT. 12.30 From o-xylene: o-Xylene CH 3 CH 3 Acetyl chloride AlCl 3 CH 3 CClH11001 O 3,4-Dimethyl- acetophenone (94%) CCH 3 CH 3 CH 3 O CH 3 NO 2 O 2 N 2,3,6-Trinitrotoluene NO 2 O 2 N 3,4,5-Trinitrotoluene NO 2 CH 3 NO 2 2,4,5-Trinitrotoluene CH 3 NO 2 NO 2 O 2 N 2,4,6-Trinitrotoluene CH 3 NO 2 O 2 N NO 2 2,3,4-Trinitrotoluene CH 3 NO 2 NO 2 NO 2 2,3,5-Trinitrotoluene O 2 N CH 3 NO 2 NO 2 3,4-Dinitrotoluene CH 3 NO 2 NO 2 3,5-Dinitrotoluene CH 3 NO 2 O 2 N 2,3-Dinitrotoluene CH 3 NO 2 NO 2 2,4-Dinitrotoluene CH 3 NO 2 NO 2 2,6-Dinitrotoluene CH 3 O 2 N NO 2 2,5-Dinitrotoluene O 2 N CH 3 NO 2 300 REACTIONS OF ARENES: ELECTROPHILIC AROMATIC SUBSTITUTION Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website From m-xylene: From p-xylene: 12.31 The ring that bears the nitrogen in benzanilide is activated toward electrophilic aromatic substitu- tion. The ring that bears the C?O is strongly deactivated. 12.32 (a) Nitration of the ring takes place para to the ortho, para-directing chlorine substituent; this position is also meta to the meta-directing carboxyl groups. (b) Bromination of the ring occurs at the only available position activated by the amino group, a powerful activating substituent and an ortho, para director. This position is meta to the meta- directing trifluoromethyl group and to the meta-directing nitro group. Br 2 acetic acid 2-Bromo-4-nitro-6- (trifluoromethyl)aniline (81%) 4-Nitro-2-(trifluoromethyl)- aniline NH 2 CF 3 O 2 N NH 2 Br CF 3 O 2 N HNO 3 H 2 SO 4 2-Chloro-1,3- benzenedicarboxylic acid Cl CO 2 H CO 2 H 2-Chloro-5-nitro-1,3- benzenedicarboxylic acid (86%) Cl CO 2 H CO 2 H O 2 N Benzanilide H11001NHC NHC NHCCl Cl 2 N-(o-Chlorophenyl)benzamide N-(p-Chlorophenyl)benzamide O Cl O O p-Xylene CH 3 CH 3 AlCl 3 H11001 CH 3 CCl O 2,5-Dimethyl- acetophenone (99%) CH 3 CH 3 CCH 3 O m-Xylene CCH 3 CH 3 2,4-Dimethyl- acetophenone (86%) AlCl 3 CH 3 CClH11001 O O CH 3 CH 3 CH 3 REACTIONS OF ARENES: ELECTROPHILIC AROMATIC SUBSTITUTION 301 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website (c) This may be approached as a problem in which there are two aromatic rings. One of them bears two activating substituents and so is more reactive than the other, which bears only one activating substituent. Of the two activating substituents (GOH and C 6 H 5 G), the hydroxyl substituent is the more powerful and controls the regioselectivity of substitution. (d) Both substituents are activating, nitration occurring readily even in the absence of sulfuric acid; both are ortho, para-directing and comparable in activating power. The position at which substitution takes place is therefore (e) Protonation of 1-octene yields a secondary carbocation, which attacks benzene. ( f ) The reaction that occurs with arenes and acid anhydrides in the presence of aluminum chloride is Friedel–Crafts acylation. The methoxy group is the more powerful activating substituent, so acylation occurs para to it. AlCl 3 H11001 o-Fluoroanisole OCH 3 F Acetic anhydride CH 3 COCCH 3 OO H11001 CH 3 CO 2 H 3-Fluoro-4-methoxyacetophenone (70–80%) OCH 3 CH 3 C O F H 2 SO 4 Benzene 1-Octene H11001 CH 3 CH(CH 2 ) 5 CH 3 2-Phenyloctane (84%) CH 2 CH(CH 2 ) 5 CH 3 HNO 3 acetic acid C(CH 3 ) 3 CH(CH 3 ) 2 1-tert-Butyl-3- isopropylbenzene C(CH 3 ) 3 NO 2 CH(CH 3 ) 2 4-tert-Butyl-2-isopropyl- 1-nitrobenzene (78%) Ortho to isopropyl, para to tert-butyl Not here; too hinderedNot here; too hindered C(CH 3 ) 3 CH(CH 3 ) 2 OH p-Phenylphenol 2-Bromo-4-phenylphenol Br 2 CHCl 3 OH Br 302 REACTIONS OF ARENES: ELECTROPHILIC AROMATIC SUBSTITUTION Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website (g) The isopropyl group is ortho, para-directing, and the nitro group is meta-directing. In this case their orientation effects reinforce each other. Electrophilic aromatic substitution takes place ortho to isopropyl and meta to nitro. (h) In the presence of an acid catalyst (H 2 SO 4 ), 2-methylpropene is converted to tert-butyl cation, which then attacks the aromatic ring ortho to the strongly activating methoxy group. In this particular example, 2-tert-butyl-4-methylanisole was isolated in 98% yield. (i) There are two things to consider in this problem: (1) In which ring does bromination occur, and (2) what is the orientation of substitution in that ring? All the substituents are activating groups, so substitution will take place in the ring that bears the greater number of sub- stituents. Orientation is governed by the most powerful activating substituent, the hydroxyl group. Both positions ortho to the hydroxyl group are already substituted, so that bromina- tion takes place para to it. The product shown was isolated from the bromination reaction in 100% yield. ( j) Wolff–Kishner reduction converts benzophenone to diphenylmethane. H 2 NNH 2 , KOH triethylene glycol, heat Benzophenone C O Diphenylmethane (83%) CH 2 Br 2 CHCl 3 3-Benzyl-2,6-dimethylphenol CH 2 CH 3 H 3 C OH 3-Benzyl-4-bromo-2, 6-dimethylphenol (100%) CH 3 CH 2 H 3 COH Br CH 3 OCH 3 CH 3 C(CH 3 ) 3 OCH 3 (CH 3 ) 3 C H11001 H11001 H H11001 H11001 (CH 3 ) 3 C H11001 (CH 3 ) 2 CCH 2 p-Nitroisopropyl- benzene NO 2 CH(CH 3 ) 2 2,4-Dinitroisopropyl- benzene (96%) NO 2 NO 2 CH(CH 3 ) 2 HNO 3 H 2 SO 4 REACTIONS OF ARENES: ELECTROPHILIC AROMATIC SUBSTITUTION 303 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website (k) Fluorine is an ortho, para-directing substituent. It undergoes Friedel–Crafts alkylation on being treated with benzyl chloride and aluminum chloride to give a mixture of o-fluoro- diphenylmethane and p-fluorodiphenylmethane. (l) The substituent is a more powerful activator than the ethyl group. It directs Friedel–Crafts acylation primarily to the position para to itself. (m) Clemmensen reduction converts the carbonyl group to a CH 2 unit. (n) Bromination occurs at C-5 on thiophene-3-carboxylic acid. Reaction does not occur at C-2 since substitution at this position would place a carbocation adjacent to the electron- withdrawing carboxyl group. 12.33 In a Friedel–Crafts acylation reaction an acyl chloride or acid anhydride reacts with an arene to yield an aryl ketone. H11001ArH AlCl 3 RCCl O ArCR O Br 2 acetic acid 2-Bromo-thiophene-4- carboxylic acid (69%) S Br CO 2 H 5 S CO 2 H 2 Thiophene-3- carboxylic acid Zn(Hg) HCl 2,4,6-Trimethylacetophenone CH 3 CH 3 H 3 C CCH 3 O 2-Ethyl-1,3,5-trimethylbenzene (74%) CH 3 CH 3 H 3 C CH 2 CH 3 o-Ethylacetanilide H11001H11001 AlCl 3 HCl Acetyl chloride CH 3 CCl O CH 3 CNH CH 2 CH 3 O 4-Acetamido-3- ethylacetophenone (57%) CH 3 CNH O CH 2 CH 3 CCH 3 O NHCCH 3 O Fluorobenzene F H11001H11001 Benzyl chloride C 6 H 5 CH 2 Cl p-Fluorodiphenylmethane (85%) F C 6 H 5 CH 2 AlCl 3 o-Fluorodiphenylmethane (15%) F C 6 H 5 CH 2 304 REACTIONS OF ARENES: ELECTROPHILIC AROMATIC SUBSTITUTION Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website or The ketone carbonyl is bonded directly to the ring. In each of these problems, therefore, you should identify the bond between the aromatic ring and the carbonyl group and realize that it arises as shown in this general reaction. (a) The compound is derived from benzene and . The observed yield in this reac- tion is 82%. (b) The presence of the unit suggests an acylation reaction using succinic anhydride. In practice, this reaction has been carried out in 55% yield. (c) Two methods seem possible here but only one actually works. The only effective combination is The alternative combination fails because it requires a Friedel–Crafts reaction on a strongly deactivated aromatic ring (nitrobenzene). (d) Here also two methods seem possible, but only one is successful in practice. The valid synthesis is H11001CCl O H 3 C H 3 C 3,5-Dimethylbenzoyl chloride Benzene H 3 C H 3 C C O 3,5-Dimethylbenzophenone (89%) AlCl 3 H11001O 2 N ClC O no reaction AlCl 3 H11001CCl O O 2 N p-Nitrobenzoyl chloride Benzene C O O 2 N p-Nitrobenzophenone (87%) AlCl 3 H 3 CCH 3 O H 3 CCH 3 CCH 2 CH 2 CO 2 H arises from and O OO Succinic anhydride O ArCCH 2 CH 2 CO 2 H ClCCH 2 O H O CCH 2 arises from and C 6 H 5 CH 2 CCl O H11001H11001ArH AlCl 3 RCOCR O O RCOH O ArCR O REACTIONS OF ARENES: ELECTROPHILIC AROMATIC SUBSTITUTION 305 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website The alternative combination will not give 3,5-dimethylbenzophenone, because of the ortho, para-directing properties of the methyl substituents in m-xylene. The product will be 2,4- dimethylbenzophenone. (e) The combination that follows is not effective, because it involves a Friedel–Crafts reaction on a deactivated aromatic ring. The following combination, utilizing toluene, therefore seems appropriate: The actual sequence used a cyclic anhydride, phthalic anhydride, in a reaction analogous to that seen in part (b). 12.34 (a) The problem to be confronted here is that two meta-directing groups are para to each other in the product. However, by recognizing that the carboxylic acid function can be prepared by oxidation of the isopropyl group we have a reasonable last step in the synthesis. The key intermediate has its sulfonic acid group para to the ortho, para-directing isopropyl group, which suggests the following CH(CH 3 ) 2 SO 3 H oxidize CO 2 H SO 3 H AlCl 3 H 3 CH 3 C HO 2 C O O H11001 O C Toluene Phthalic anhydride o-(4-Methylbenzoyl)benzoic acid (96%) O AlCl 3 H11001H 3 C HO 2 C ClC O C O H 3 C HO 2 C H11001 no reactionCCl O H 3 C p-Methylbenzoyl chloride HO 2 C Benzoic acid AlCl 3 H11001 H 3 C H 3 C m-Xylene ClC O Benzoyl chloride H 3 C H 3 C C O 2,4-Dimethylbenzophenone AlCl 3 306 REACTIONS OF ARENES: ELECTROPHILIC AROMATIC SUBSTITUTION Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website approach: (b) In this problem two methyl groups must be oxidized to carboxylic acid functions, and a tert- butyl group must be introduced, most likely by a Friedel–Crafts reaction. Since Friedel–Crafts alkylations cannot be performed on deactivated aromatic rings, oxidation must follow, not pre- cede, alkylation. The following reaction sequence therefore seems appropriate: In practice, zinc chloride was used as the Lewis acid to catalyze the Friedel–Crafts reaction (64% yield). Oxidation of the methyl groups occurs preferentially because the tert-butyl group has no benzylic hydrogens. (c) The carbonyl group is directly attached to the naphthalene unit in the starting material. Reduce it in the first step so that a Friedel–Crafts acylation can be accomplished on the naphthalene ring. An aromatic ring that bears a strongly electron-withdrawing group such as C?O does not undergo Friedel–Crafts reactions. (d) m-Dimethoxybenzene is a strongly activated aromatic compound and so will undergo elec- trophilic aromatic substitution readily. The ring position between the two methoxy groups is sterically hindered and less reactive than the other activated positions. Arrows indicate equivalent ring positions strongly activated by methoxy groups. OCH 3 OCH 3 CH 3 C Zn(Hg), HCl AlCl 3 CH 3 CCl O O O o-Xylene Na 2 Cr 2 O 7 H 2 O, H 2 SO 4 , heat 4-tert-Butyl-1,2- dimethylbenzene 4-tert-Butylbenzene-1,2- dicarboxylic acid CH 3 CH 3 C(CH 3 ) 3 CH 3 CH 3 CO 2 H CO 2 H C(CH 3 ) 3 (CH 3 ) 3 CClH11001 AlCl 3 CH(CH 3 ) 2 Isopropylbenzene SO 3 H 2 SO 4 Na 2 Cr 2 O 7 H 2 O, H 2 SO 4 , heat CH(CH 3 ) 2 SO 3 H p-Isopropylbenzene- sulfonic acid CO 2 H SO 3 H p-Carboxylbenzene- sulfonic acid REACTIONS OF ARENES: ELECTROPHILIC AROMATIC SUBSTITUTION 307 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website Because Friedel–Crafts reactions may not be performed on deactivated aromatic rings, the tert-butyl group must be introduced before the nitro group. The correct sequence is therefore This is essentially the procedure actually followed. Alkylation was effected, however, not with tert-butyl chloride and aluminum chloride but with 2-methylpropene and phosphoric acid. Nitration was carried out in the usual way. the orientation of nitration is controlled by the more powerfully activating methoxy groups rather than by the weakly activating tert-butyl. 12.35 The first step is a Friedel–Crafts acylation reaction. The use of a cyclic anhydride introduces both the acyl and carboxyl groups into the molecule. The second step is a reduction of the ketone carbonyl to a methylene group. A Clemmensen reduc- tion is normally used for this step. Zn(Hg) HCl 4-Phenylbutanoic acid CH 2 CH 2 CH 2 COH O 4-Oxo-4-phenylbutanoic acid CCH 2 CH 2 COH OO AlCl 3 Benzene 4-Oxo-4-phenylbutanoic acid CCH 2 CH 2 COH OO H11001 Succinic anhydride O O O OCH 3 C(CH 3 ) 3 OCH 3 HNO 3 H 2 SO 4 OCH 3 O 2 N C(CH 3 ) 3 OCH 3 1-tert-Butyl-2,4- dimethoxy-5-nitrobenzene OCH 3 OCH 3 m-Dimethoxybenzene 2-Methylpropene OCH 3 C(CH 3 ) 3 OCH 3 1-tert-Butyl-2,4- dimethoxybenzene (75%) (CH 3 ) 2 C H 3 PO 4 H11001 CH 2 OCH 3 OCH 3 C(CH 3 ) 3 OCH 3 C(CH 3 ) 3 OCH 3 OCH 3 OCH 3 O 2 N 308 REACTIONS OF ARENES: ELECTROPHILIC AROMATIC SUBSTITUTION Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website The cyclization phase of the process is an intramolecular Friedel–Crafts acylation reaction. It requires conversion of the carboxylic acid to the acyl chloride (thionyl chloride is a suitable reagent) followed by treatment with aluminum chloride. 12.36 Intramolecular Friedel–Crafts acylation reactions that produce five-membered or six-membered rings occur readily. Cyclization must take place at the position ortho to the reacting side chain. (a)Afive-membered cyclic ketone is formed here. (b) This intramolecular Friedel–Crafts acylation takes place to form a six-membered cyclic ketone in excellent yield. (c) In this case two aromatic rings are available for attack in the acylation reaction. The more reac- tive ring is the one that bears the two activating methoxy groups, and cyclization occurs on it. CH 3 O CH 3 O CH 2 O Only product (78% yield) CH 3 O CH 3 O CH 2 O (Not observed) CH 3 OCH 2 CHCH 2 CH 3 O CCl O faster slower CH 2 CCl O O AlCl 3 93% (CH 3 ) 3 CC CH 3 CH 3 CH 2 ClC O (CH 3 ) 3 C CH 3 CH 3 O AlCl 3 (46%) and AlCl 3 AlCl 3 O C O Cl C O Cl O 4-Phenylbutanoyl chloride CH 2 CH 2 CH 2 CCl O 4-Phenylbutanoic acid CH 2 CH 2 CH 2 COH O SOCl 2 AlCl 3 O REACTIONS OF ARENES: ELECTROPHILIC AROMATIC SUBSTITUTION 309 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website 12.37 (a) To determine the total rate of chlorination of biphenyl relative to that of benzene, we add up the partial rate factors for all the positions in each substrate and compare them. Relative rate of chlorination: H5007 B B i e p n h z e e n n y e l H5007H11005 H5007 25 6 80 H5007 H11005 H5007 43 1 0 H5007 (b) The relative rate of attack at the para position compared with the ortho positions is given by the ratio of their partial rate factors. H5007 O P r a t r h a o H5007H11005 H5007 1 1 5 0 8 0 0 0 H5007 H11005 H5007 1. 1 58 H5007 Therefore, 15.8 g of p-chlorobiphenyl is formed for every 10 g of o-chlorobiphenyl. 12.38 The problem stipulates that the reactivity of various positions in o-bromotoluene can be estimated by multiplying the partial rate factors for the corresponding positions in toluene and bromobenzene. Therefore, given the partial rate factors: the two are multiplied together to give the combined effects of the two substituents at the various ring positions. The most reactive position is the one that is para to bromine. The predicted product is therefore 4-bromo-3-methylacetophenone. Indeed, this is what is observed experimentally. This was first considered to be “anomalous” behavior on the part of o-bromotoluene, but, as can be seen, it is consistent with the individual directing properties of the two substituents. CH 3 Br H11001 CH 3 CCl O AlCl 3 CH 3 Br CH 3 C O 4-Bromo-3-methyl- acetophenone Acetyl chloride o-Bromotoluene CH 3 CH 3 4.5 H11003 0.0003 4.8 H11003 0.084 750 H11003 0.0003 Br Very small Br Very small 0.0013 0.403 0.225 or CH 3 4.5 4.8 4.5 4.8 750 Br Very small Very small 0.0003 0.084 0.0003 and 0 0 0 0 790 790 250 250 250 250 Biphenyl (sum H11005 2580) 1 1 11 1 1 Benzene (sum H11005 6) 310 REACTIONS OF ARENES: ELECTROPHILIC AROMATIC SUBSTITUTION Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website 12.39 The isomerization is triggered by protonation of the aromatic ring, an electrophilic attack by HCl catalyzed by AlCl 3 . The carbocation then rearranges by a methyl shift, and the rearranged cyclohexadienyl cation loses a proton to form the isomeric product The driving force for rearrangement is relief of steric strain between the isopropyl group and one of its adjacent methyl groups. Isomerization is acid-catalyzed. Protonation of the ring generates the necessary carbocation intermediate and rearomatization occurs by loss of a proton. 12.40 The relation of compound A to the starting material is The starting acyl chloride has lost the elements of HCl in the formation of A. Because A forms benzene-1,2-dicarboxylic acid on oxidation, it must have two carbon substituents ortho to each other. These facts suggest the following process: (CH 2 ) 5 CCl O O C H O CH 2 CH 2 CH 2 CH 2 H 2 C H11001 AlCl 3 (H11002Cl H11002 ) (H11002H H11001 ) A C C CO 2 H CO 2 H Na 2 Cr 2 O 7 H 2 O, H 2 SO 4 , heat H11001 HClAC 6 H 5 (CH 2 ) 5 CCl O (C 12 H 15 ClO) (C 12 H 14 O) CH 3 CH 3 H 3 C H H H CH(CH 3 ) 2 H11001 CH 3 CH 3 H 3 C CH(CH 3 ) 2 1-Isopropyl-2,4,5- trimethylbenzene CH 3 CH 3 H 3 C HH H CH(CH 3 ) 2 H11001 H11001 H H11001 HCl AlCl 3 CH 3 CH 3 H 3 C HH CH(CH 3 ) 2 H11001 CH 3 CH 3 H 3 C HH CH(CH 3 ) 2 2-Isopropyl-1,3,5- trimethylbenzene H REACTIONS OF ARENES: ELECTROPHILIC AROMATIC SUBSTITUTION 311 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website The reaction leading to compound A is an intramolecular Friedel–Crafts acylation. Since cyclization to form an eight-membered ring is difficult, it must be carried out in dilute solution to minimize competition with intermolecular acylation. 12.41 Although hexamethylbenzene has no positions available at which ordinary electrophilic aromatic substitution might occur, electrophilic attack on the ring can still take place to form a cyclohexadi- enyl cation. Compound A is the tetrachloroaluminate (AlCl 4 H11002 ) salt of the carbocation shown. It undergoes deprotonation on being treated with aqueous sodium bicarbonate. 12.42 By examining the structure of the target molecule, compound C, we see that the bond indicated in the following structure joins two fragments that are related to the given starting materials A and B: The bond connecting the two fragments can be made by a Friedel–Crafts acylation-reduction sequence using the acyl chloride B. CH 3 OCH 3 CH 3 O CH 3 O CH 3 O O CH 3 O CH 3 O Cl O CH 3 O CH 3 O CH 3 AlCl 3 Clemmensen or Wolff–Kishner reduction C CH 3 OCH 3 CH 3 O CH 3 O CH 3 O CH 3 O CH 3 O Cl O CH 3 O CH 3 O CH O Compound C A B H11001 CH 3 CH 3 H 3 C H 3 C CH 2 HOH H11002 CH 3 CH 3 H 3 C H11001 H 2 O H 3 C CH 2 B CH 3 H 3 C CH 3 H 3 C CH 3 Cl AlCl 3 CH 3 CH 3 CH 3 H 3 C H 3 C CH 3 H11001 CH 3 CH 3 CH 3 H 3 C H 3 C H 3 C CH 3 312 REACTIONS OF ARENES: ELECTROPHILIC AROMATIC SUBSTITUTION Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website The orientation is right; attack is para to one of the methoxy groups and ortho to the methyl. The substrate for the Friedel–Crafts acylation reaction, 3,4-dimethoxytoluene, is prepared from com- pound A by a Clemmensen or Wolff–Kishner reduction. Compound A cannot be acylated directly because it bears a strongly deactivating substituent. 12.43 In the presence of aqueous sulfuric acid, the side-chain double bond of styrene undergoes protona- tion to form a benzylic carbocation. This carbocation then reacts with a molecule of styrene in the manner we have seen earlier (Chap- ter 6) for alkene dimerization. The carbocation produced in this step can lose a proton to form 1,3-diphenyl-1-butene or it can undergo a cyclization reaction in what amounts to an intramolecular Friedel–Crafts alkylation 12.44 The alcohol is tertiary and benzylic. In the presence of sulfuric acid a carbocation is formed. An intramolecular Friedel–Crafts alkylation reaction follows, in which the carbocation attacks the adjacent aromatic ring. CH 2 CH 3 H 3 C C H11001 H11001 H 3 C H 3 C H C 16 H 16 H 3 C CH 3 CH 2 C(CH 3 ) 2 OH CH 2 CCH 3 CH 3 H11001 H 2 SO 4 CH 3 C 6 H 5 CH CH 3 C 6 H 5 CH 2 H H11001 H11001 CH H11001 1-Methyl-3-phenylindan C 6 H 5 CHCH 2 CHC 6 H 5 CH 3 CHCHC 6 H 5 C 6 H 5 CH H H11001 H11001 CH 3 H11001 1,3-Diphenyl-1-butene C 6 H 5 CH C 6 H 5 CHCH 2 CHC 6 H 5 CH 3 C 6 H 5 CHCH 3 CH 2 H11001 H11001H11001 C 6 H 5 CH C 6 H 5 CHCH 3 CH 2 H H11001 H11001 Styrene 1-Phenylethyl cation H11001 CH O REACTIONS OF ARENES: ELECTROPHILIC AROMATIC SUBSTITUTION 313 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website SELF-TEST PART A A-1. Write the three most stable resonance contributors to the cyclohexadienyl cation found in the ortho bromination of toluene. A-2. Give the major product(s) for each of the following reactions. Indicate whether the reaction proceeds faster or slower than the corresponding reaction of benzene. A-3. Write the formula of the electrophilic reagent species present in each reaction of the preced- ing problem. A-4. Provide the reactant, reagent, or product omitted from each of the following: (e) Cl 2 FeCl 3 ? S O (d) HNO 3 ? H 2 SO 4 OCH 3 (c) OCH 3 O CC 6 H 5 C 6 H 5 H11001 ? OCH 3 CO CH 2 CH 2 CH 2 C(CH 3 ) 2 (b) AlCl 3 ? Cl CH 2 CH(CH 3 ) 2 C(CH 3 ) 3 (a) Zn(Hg) HCl ? Cl (c) ? SO 3 H 2 SO 4 CH 2 CH 3 (b) Br 2 FeBr 3 ? NO 2 (a) ? HNO 3 H 2 SO 4 314 REACTIONS OF ARENES: ELECTROPHILIC AROMATIC SUBSTITUTION Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website A-5. Draw the structure(s) of the major product(s) formed by reaction of each of the following compounds with Cl 2 and FeCl 3 . If two products are formed in significant amounts, draw them both. A-6. Provide the necessary reagents for each of the following transformations. More than one step may be necessary. A-7. Outline a reasonable synthesis of each of the following from either benzene or toluene and any necessary organic or inorganic reagents. (a) (b) (c) CH 2 CH(CH 3 ) 2 CH 3 Cl C H 3 C CH 2 NO 2 CO 2 H NO 2 O 2 N NO 2 (CH 3 ) 2 CH(e) ? SO 3 H Br (d) ? CH CH 3 CH 3 C O O (c) ? CH 2 CH 2 C 6 H 5 Cl (b) ? CH(CH 3 ) 2 HO 3 SCO 2 H (a) ? CH 3 CH 2 OH(d)(b) OCH 3 CN (c) O NO 2 (a) CH 3 REACTIONS OF ARENES: ELECTROPHILIC AROMATIC SUBSTITUTION 315 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website A-8. Outline a reasonable synthesis of the compound shown using anisole (C 6 H 5 OCH 3 ) and any necessary inorganic reagents. PART B B-1. Consider the following statements concerning the effect of a trifluoromethyl group, GCF 3 , on an electrophilic aromatic substitution. 1. The CF 3 group will activate the ring. 2. The CF 3 group will deactivate the ring. 3. The CF 3 group will be a meta director. 4. The CF 3 group will be an ortho, para director. Which of these statements are correct? (a) 1, 3 (b) 1, 4 (c) 2, 3 (d) 2, 4 B-2. Which of the following resonance structures is not a contributor to the cyclohexadienyl cation intermediate in the nitration of benzene? B-3. All the following groups are activating ortho, para directors when attached to a benzene ring except (a) GOCH 3 (c) GCl (b)(d) GN(CH 3 ) 2 B-4. Rank the following in terms of increasing reactivity toward nitration with HNO 3 , H 2 SO 4 (least A most): (a)1H11021 2 H11021 3(c)3H11021 1 H11021 2 (b)2H11021 1 H11021 d)3H11021 2 H11021 1 B-5. For the reaction Br NO 2 ? 123 Cl NHCH 3 NHCCH 3 O H H H (a)(c) H11001 NO 2 H H11001 H11001 NO 2 NO 2 (b) CH 3 ONO 2 Br 316 REACTIONS OF ARENES: ELECTROPHILIC AROMATIC SUBSTITUTION (d) None of these (all are contributors) Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website the best reactants are: (a)C 6 H 5 Br H11001 HNO 3 , H 2 SO 4 (c)C 6 H 5 Br H11001 H 2 SO 4 , heat (b)C 6 H 5 NO 2 H11001 Br 2 , FeBr 3 (d)C 6 H 5 NO 2 H11001 HBr B-6. For the reaction the best reactants are (a)(c)C 6 H 5 CH 2 C 6 H 5 H11001 Cl 2 , FeCl 3 , followed by oxidation with chromic acid (b d) None of these yields the desired product. B-7. The reaction gives as the major product: (a)(c) (b d) B-8. Which one of the following compounds undergoes bromination of its aromatic ring (elec- trophilic aromatic substitution) at the fastest rate? (a)(b)(c)(d) B-9. Which one of the following is the most stable? (a)(b)(c)(d) Br H H H H H H11001 NH 2 H11001 NH 2 HBr H H H H H11001 Br H HH H H NH 2 Br H HH H H NH 2 H11001 O NHNH N H H 3 C NO 2 ClH 3 C O 2 N Cl H 3 C O 2 N ClH 3 C NO 2 Cl H 3 CCl HNO 3 H11408H 2 SO 4 H11001Cl 2 , FeCl 3 C 6 H 5 CC 6 H 5 O C 6 H 5 ClH11001C 6 H 5 CCl, AlCl 3 O Cl CC 6 H 5 O ? REACTIONS OF ARENES: ELECTROPHILIC AROMATIC SUBSTITUTION 317 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website B-10. The major product of the reaction is (a)(b) (c) An equal mixture of compound (a) and (b) would form. (d) None of these; substitution would not occur. B-11. What is the product of the following reaction? (a)(d) (b e) (c) B-12. Partial rate factors are shown for nitration of a particular aromatic compound. Based on these data, the most reasonable choice for substituent X is: (a) GN(CH 3 ) 2 (c) GBr (e) (b) GSO 3 H(d) GCH(CH 3 ) 2 B-13. Which reactants combine to give the species shown at the right as a reactive intermediate? (a) Benzene, isopropyl bromide, and HBr (b) Bromobenzene, isopropyl chloride, and AlCl 3 (c) Isopropylbenzene, Br 2 , and FeBr 3 (d) Isopropylbenzene, Br 2 , light, and heat (e) Isopropylbenzene, N-bromosuccinimide, benzoyl peroxide, and heat H CH(CH 3 ) 2 H HH HBr H11001 CH O X 0.003 0.001 0.1 0.003 0.001 OCH 3 (CH 3 ) 2 CH C CH 3 CH 3 OCH 3 CHCH 2 CH 3 OCH 3 OCH 3 (CH 3 ) 2 CHCHCH 2 CH 3 OCH 3 C CH 2 CH 3 H11001OCH 3 H 2 SO 4 S Br S Br S ? Br 2 FeBr 3 318 REACTIONS OF ARENES: ELECTROPHILIC AROMATIC SUBSTITUTION Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website B-14. Which sequence of steps describes the best synthesis of the compound shown? (a) (b) (c) (d) B-15. Which one of the following is the best synthesis of 2-chloro-4-nitrobenzoic acid? (a) 1. Heat benzoic acid with HNO 3 ,(d) 1. Treat nitrobenzene with Cl 2 , H 2 SO 4 FeCl 3 , heat 2. Cl 2 , FeCl 3 , heat 2. CH 3 Cl, AlCl 3 (b) 1. Treat toluene with HNO 3 ,3.K 2 Cr 2 O 7 , H 2 O, H 2 SO 4 , heat H 2 SO 4 (e) 1. Treat chlorobenzene with 2. K 2 Cr 2 O 7 , H 2 O, H 2 SO 4 , heat HNO 3 , H 2 SO 4 3. Cl 2 , FeCl 3 , heat 2. CH 3 Cl, AlCl 3 (c) 1. Treat toluene with HNO 3 ,3.K 2 Cr 2 O 7 , H 2 O, H 2 SO 4 , heat H 2 SO 4 2. Cl 2 , FeCl 3 , heat 3. K 2 Cr 2 O 7 , H 2 O, H 2 SO 4 , heat 2-Chloro-4- nitrobenzoic acid CO 2 H NO 2 Cl Br 2 FeBr 3 Zn(Hg) HClAlCl 3 C 6 H 5 CCl O Br 2 FeBr 3 Zn(Hg) HClAlCl 3 C 6 H 5 CCl O C 6 H 5 CH 2 Cl AlCl 3 Br 2 FeBr 3 C 6 H 5 CH 2 Cl AlCl 3 Br 2 FeBr 3 CH 2 Br REACTIONS OF ARENES: ELECTROPHILIC AROMATIC SUBSTITUTION 319 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website