(a) Draw a detailed mechanism for the FeBr3@catalyzed reaction of ethylbenzene with

Step 2 of the iodination of benzene shows water acting as a base and removing a proton from the sigma complex. We did not consider the possibility of water acting as a nucleophile and attacking the carbocation, as in an electrophilic addition to an alkene. Draw the reaction that would occur if water reacted as a nucleophile and added to the carbocation. Explain why this type of addition is rarely observed.

Propose a mechanism for the aluminum chloride–catalyzed reaction of benzene with chlorine.

p-Xylene undergoes nitration much faster than benzene. Use resonance forms of the sigma complex to explain this accelerated rate.

Use resonance forms to show that the dipolar sigma complex shown in the sulfonation of benzene has its positive charge delocalized over three carbon atoms and its negative charge delocalized over three oxygen atoms.

(a) Draw a detailed mechanism for the FeBr3@catalyzed reaction of ethylbenzene with bromine, and show why the sigma complex (and the transition state leading to it) is lower in energy for substitution at the ortho and para positions than it is for substitution at the meta position. (b) Explain why m-xylene undergoes nitration 100 times faster than p-xylene.

Styrene (vinylbenzene) undergoes electrophilic aromatic substitution much faster than benzene, and the products are found to be primarily ortho- and para-substituted styrenes. Use resonance forms of the intermediates to explain these results.

Propose a mechanism for the bromination of ethoxybenzene to give o- and p-bromoethoxybenzene.

Draw all the resonance forms for the sigma complexes corresponding to bromination of aniline at the ortho, meta, and para positions.

When bromine is added to two beakers, one containing phenyl isopropyl ether and the other containing cyclohexene, the bromine color in both beakers disappears. What observation could you make while performing this test that would allow you to distinguish the alkene from the aryl ether?

In an aqueous solution containing sodium bicarbonate, aniline reacts quickly with bromine to give 2,4,6-tribromoaniline. Nitration of aniline requires very strong conditions, however, and the yields (mostly m-nitroaniline) are poor. (a) What conditions are used for nitration, and what form of aniline is present under these conditions? (b) Explain why nitration of aniline is so sluggish and why it gives mostly meta substitution. *(c) Although nitration of aniline is slow and gives mostly meta substitution, nitration of acetanilide (PhNHCOCH3) goes quickly and gives mostly para substitution. Use resonance forms to explain this difference in reactivity

Draw all the resonance forms of the sigma complex for nitration of bromobenzene at the ortho, meta, and para positions. Point out why the intermediate for meta substitution is less stable than the other two.

Predict the mononitration products of the following compounds. (a) o-nitrotoluene (b) m-chlorotoluene (c) o-bromobenzoic acid (d) p-methoxybenzoic acid (e) m-cresol (m-methylphenol) (f) o-hydroxyacetophenone

Predict the mononitration products of the following aromatic compounds. (a) p-methylanisole (b) m-nitrochlorobenzene (c) p-chlorophenol (d) m-nitroanisole

Biphenyl is two benzene rings joined by a single bond. The site of substitution for a biphenyl is determined by (1) which phenyl ring is more activated (or less deactivated), and (2) which position on that ring is most reactive, using the fact that a phenyl substituent is activating and ortho, para-directing. (a) Use resonance forms of a sigma complex to show why a phenyl substituent should be ortho, para-directing. (b) Predict the mononitration products of the following compounds. biphenyl (i) (ii) OH C CH3 (iii) O NO2 (iv) O O

Propose products (if any) and mechanisms for the following AlCl3@catalyzed reactions: (a) chlorocyclohexane with benzene (b) methyl chloride with anisole *(c) 3-chloro-2,2-dimethylbutane with isopropylbenzene

For each reaction, show the generation of the electrophile and predict the products. (a) benzene + cyclohexene + HF (b) tert@butyl alcohol + benzene + BF3 (c) tert@butylbenzene + 2@methylpropene + HF (d) propan@2@ol + toluene + BF3

Predict the products (if any) of the following reactions. (a) (excess) benzene + isobutyl chloride + \(AlCl_3\) (b) (excess) toluene + butan-1-ol + \(BF_3\) (c) (excess) nitrobenzene + 2-chloropropane + \(AlCl_3\) (d) (excess) benzene + 3,3-dimethylbut-1@ene + HF

Which reactions will produce the desired product in good yield? You may assume that aluminum chloride is added as a catalyst in each case. For the reactions that will not give a good yield of the desired product, predict the major products. Reagents Desired Product (a) benzene + n-butyl bromide n-butylbenzene (b) ethylbenzene + tert-butyl chloride p-ethyl-tert-butylbenzene (c) bromobenzene + ethyl chloride p-bromoethylbenzene (d) benzamide (PhCONH2) + CH3CH2Cl p-ethylbenzamide (e) toluene + HNO3, H2SO4, heat 2,4,6-trinitrotoluene (TNT)

Show how you would synthesize the following aromatic derivatives from benzene. (a) p-tert-butylnitrobenzene (b) p-toluenesulfonic acid (c) p-chlorotoluene

Show how you would use the Friedel–Crafts acylation, Clemmensen reduction, and>or Gatterman–Koch synthesis to prepare the following compounds:

Fluoride ion is usually a poor leaving group because it is not very polarizable. Fluoride serves as the leaving group in the Sanger reagent (2,4-dinitrofluorobenzene), used in the determination of peptide structures (Chapter 24). Explain why fluoride works as a leaving group in this nucleophilic aromatic substitution, even though it is a poor leaving group in the SN1 and SN2 mechanisms.

Propose a mechanism that shows why p-chlorotoluene reacts with sodium hydroxide at 350 C to give a mixture of p-cresol and m-cresol.

Propose mechanisms and show the expected products of the following reactions. (a) 2,4@dinitrochlorobenzene + sodium methoxide (NaOCH3) (b) 2,4@dimethylchlorobenzene + sodium hydroxide, 350 C (c) p@nitrobromobenzene + methylamine (CH3 NH2) (d) 2,4@dinitrochlorobenzene + excess hydrazine (H2NNH2)

The highly reactive triple bond of benzyne is a powerful dienophile. Predict the product of the Diels–Alder reaction of benzyne (from chlorobenzene and NaOH, heated) with cyclopentadiene.

What products would you expect from the following reactions?

What organocuprate reagent would you use for the following substitutions? I (a) Br (b) O O

What products would you expect from the following reactions? Br O + (a) PdCl2 PPh3, Et3N OCH3 Br + (b) Pd(OAc)2 PPh3, Et3N

What substituted alkene would you use in the Heck reaction to make the following products?

What products would you expect from the following Suzuki coupling reactions?

Show how you would use Suzuki reactions to synthesize these products from the indicated starting materials. You may use any additional reagents you need.

Propose mechanisms for the Birch reductions of benzoic acid and anisole just shown. Show why the observed orientation of reduction is favored in each case.

Predict the major products of the following reactions. (a) toluene + excess Cl2 (heat, pressure) (b) benzamide (PhCONH2) + Na (liquid NH3, CH3CH2OH) (c) o@xylene + H2 (1000 psi, 100 C, Rh catalyst) (d) p@xylene + Na (liquid NH3, CH3CH2OH) (e) O 2,7-dimethoxynaphthalene CH3 OCH3 excess Li NH3(l)/THF (CH3) 3COH

Predict the major products of treating the following compounds with hot, concentrated potassium permanganate, followed by acidification with dilute HCl. (a) isopropylbenzene (b) p-xylene (tetralin) (c)

Propose a mechanism for the bromination of ethylbenzene shown above.

What would be the ratio of products in the reaction of chlorine with ethylbenzene if chlorine randomly abstracted a methyl or methylene proton? What is the reactivity ratio for the benzylic hydrogens compared with the methyl hydrogens?

Predict the major products when the following compounds are irradiated by light and treated with (1) 1 equivalent of Br2 and (2) excess Br2. (a) isopropylbenzene (tetralin)

Propose a mechanism for the reaction of benzyl bromide with ethanol to give benzyl ethyl ether (shown above).

(a) Based on what you know about the relative stabilities of alkyl cations and benzylic cations, predict the product of addition of HBr to 1-phenylpropene. (b) Propose a mechanism for this reaction. (c) Based on what you know about the relative stabilities of alkyl radicals and benzylic radicals, predict the product of addition of HBr to 1-phenylpropene in the presence of a free-radical initiator. (d) Propose a mechanism for this reaction.

Show how you would synthesize the following compounds, using the indicated starting materials. (a) 3-phenylbutan-1-ol from styrene OCH3 CH from anisole CH3 OCH3 (b) O2N CH2CN from toluene

The bombardier beetle defends itself by spraying a hot quinone solution from its abdomen (see photo). This solution is formed by the enzyme-catalyzed oxidation of hydroquinone by hydrogen peroxide. Write a balanced equation for this oxidation.

Predict the products formed when m-cresol (m-methylphenol) reacts with (a) NaOH and then ethyl bromide (b) CH3 acetyl chloride, (c) bromine in \(\mathrm{CCl}_{4}\) in the dark (d) excess bromine in \(\mathrm{CCl}_{4}\) in the light (e) sodium dichromate in \(\mathrm{H}_{2} \mathrm{SO}_{4}\) (f) two equivalents of tert-butyl chloride and \(\mathrm{AlCl}_{3}\)

1,4-Benzoquinone is a good DielsAlder dienophile. Predict the products of its reaction with (a) buta-1,3-diene (b) cyclopenta-1,3-diene

Predict the major product at the end of each sequence. Cl2 AlCl3 SO3 H2SO4 (a) SO3 H2SO4

Predict the site(s) of electophilic attack on these compounds.

Predict the products. Cl + AlCl3 (a) Cl + AlCl3 two rearranged products (Hint: hydride shift and ring expansion.)

To synthesize m-ethylbenzenesulfonic acid, a student attempted the Friedel–Crafts alkylation of benzenesulfonic acid with bromoethane. Do you predict that this reaction was successful? If not, propose an alternative synthesis.

Propose a synthetic sequence of this trisubstituted benzene starting from toluene. COOH NO2 Cl

Starting from toluene, propose syntheses for ortho-, meta-, and para-chlorobenzoic acid.

Starting from toluene, propose a synthesis of this trisubstituted benzene. Cl NH2 COOH

Predict products and propose mechanisms for the common electrophilic aromatic substitutions: halogenation, nitration, sulfonation, and Friedel–Crafts alkylation and acylation. (Problems 17-50, 53, 54, 57, 66, 71, and 77)

Draw resonance forms for the sigma complexes resulting from electrophilic attack on substituted aromatic rings. Explain which substituents are activating and which are deactivating, and show why they are ortho,para-directing, or meta-directing.

Predict the position(s) of electrophilic aromatic substitution on molecules containingsubstituents on one or more aromatic rings, and design syntheses thatusetheinfluence of substituents to generate the correct isomers.

Determine which nucleophilic aromatic substitutions are likely, and propose mechanisms for both the addition–elimination type and the benzyne type. (Problems 17-58, 68, 69, 70, and 73)

Predict the coupling products of the organocuprate, Heck, and Suzuki reactions, and use these reactions in syntheses.

Predict the products of the Birch reduction, hydrogenation, and chlorination of aromatic compounds, and use these reactions in syntheses. (Problems 17-51, 57, 59, and 74)

Explain how the reactions of side chains are affected by the presence of the aromatic ring, predict the products of side-chain reactions, and use these reactions in syntheses. (Problems 17-51, 53, and 74)

Predict the products of the reactions of phenols, and use these reactions in syntheses.

Predict the major products formed when benzene reacts (just once) with the following reagents. (a) tert-butyl bromide, AlCl3 (b) 1-chlorobutane, AlCl3 (c) isobutyl alcohol + BF3 (d) bromine + a nail (e) isobutylene + HF (f) fuming sulfuric acid (g) 1@chloro@2,2@dimethylpropane + AlCl3 (h) benzoyl chloride + AlCl3 (i) iodine + HNO3 (j) nitric acid + sulfuric acid (k) carbon monoxide, HCl, and AlCl3 >CuCl (l) CH2(COCl)2, AlCl3

Indane can undergo free-radical chlorination at any of the alkyl positions on the aliphatic ring. indane (a) Draw the possible monochlorinated products from this reaction. (b) Draw the possible dichlorinated products from this reaction. (c) What instrumental technique would be most helpful for determining how many products are formed, and how many of those products are monochlorinated and how many are dichlorinated? (d) Once the products have been separated, what instrumental technique would be most helpful for determining the structures of all the dichlorinated products?

Show how you would synthesize the following compounds, starting with benzene or toluene and any necessary acyclic reagents. Assume para is the major product (and separable from ortho) in ortho, para mixtures. (a) 1-phenyl-1-bromobutane (b) 1-phenyl-1-methoxybutane (c) 3-phenylpropan-1-ol (d) ethoxybenzene (e) 1,2-dichloro-4-nitrobenzene (f) 1-phenylpropan-2-ol (g) p-aminobenzoic acid (h) 2-methyl-1-phenylbutan-2-ol (i) 5-chloro-2-methylaniline (j) 3-nitro-4-bromobenzoic acid (k) 3-nitro-5-bromobenzoic acid (l) 4-butylphenol (m) 2-(4-methylphenyl)butan-2-ol

Predict the major products of the following reactions. (a) 2,4-dinitrochlorobenzene + \(NaOCH_3\) (b) phenol + tert-butyl chloride + \(AlCl_3\) (c) nitrobenzene + fuming sulfuric acid (d) nitrobenzene + acetyl chloride + \(AlCl_3\) (e) p-methylanisole + acetyl chloride + \(AlCl_3\) (f) p-methylanisole + \(Br_2\) , light (g) 1,2-dichloro-4-nitrobenzene + \(NaNH_2\) (h) p-nitrotoluene + Zn + dilute HCl (i) p-ethylbenzenesulfonic acid + steam/\(H^+\) (j) p-ethylbenzenesulfonic acid + \(HNO_3\), \(H_2SO_4\)

Predict the major products of bromination of the following compounds, using \(Br_2\) and \(FeBr_3\) in the dark.

What products would you expect from the following coupling reactions? Br CuLi 2 + (a) I O O OH + PdCl2 Na2CO3, H2O (b) Br Pd catalyst, base B OH OH (c) Br Pd catalyst, base OR B OR (d) Br NO2 + Pd(OAc)2 PPh3 Et3N (e)

A student added 3-phenylpropanoic acid (PhCH2CH2COOH) to a molten salt consisting of a 1:1 mixture of NaCl and AlCl3 maintained at 170 C. After 5 minutes, he poured the molten mixture into water and extracted it into dichloromethane. Evaporation of the dichloromethane gave a 96% yield of the product whose spectra follow. The mass spectrum of the product shows a molecular ion at m>z 132. What is the product?

Give the structures of compounds A through H in the following series of reactions. A B Zn(Hg) HCl C D E F G HBr H (excess) NH2 C Cl O AlCl3 NH3 NaOCH3 Br2 h (CH3) 3CO K+ H2SO4 KMnO4 HNO3 (hot, concd.)

The following compound reacts with a hot, concentrated solution of NaOH (in a sealed tube) to give a mixture of two products. Propose structures for these products, and give a mechanism to account for their formation. 2 products Cl NaOH, H2O 350 C

a@Tetralone undergoes Birch reduction to give an excellent yield of a single product. Predict the structure of the product, and propose a mechanism for its formation. O -tetralone Na, NH3(l) CH3CH2OH

Electrophilic aromatic substitution usually occurs at the 1-position of naphthalene, also called the a position. Predict the major products of the reactions of naphthalene with the following reagents. (a) HNO3, H2SO4 (b) Br2, FeBr3 (c) CH3CH2COCl, AlCl3 (d) isobutylene and HF (e) cyclohexanol and BF3 (f) fuming sulfuric acid 8 1 7 6 5 4 3 2

Nucleophilic aromatic substitution provides one of the common methods for making phenols. (Another method is discussed in Section 19-17.) Show how you would synthesize the following phenols, using benzene or toluene as your aromatic starting material, and explain why mixtures of products would be obtained in some cases. (a) p-nitrophenol (b) 2,4,6-tribromophenol (c) p-chlorophenol (d) m-cresol (e) p-n-butylphenol

Show how you would use a Suzuki reaction to synthesize Bombykol, the sex hormone of the silk moth, from cis-1-bromopent-1-ene and the acetylenic alcohol shown below. Br H C C (CH2 Bombykol )8 CH2OH (CH2)8 CH2OH

The most common selective herbicide for killing broadleaf weeds is 2,4-dichlorophenoxyacetic acid (2,4-D). Show how you would synthesize 2,4-D from benzene, chloroacetic acid (ClCH2COOH), and any necessary reagents and solvents. O Cl Cl 2,4-dichlorophenoxyacetic acid (2,4-D) CH2COOH

Furan undergoes electrophilic aromatic substitution more readily than benzene; mild reagents and conditions are sufficient. For example, furan reacts with bromine to give 2-bromofuran. (a) Propose mechanisms for the bromination of furan at the 2-position and at the 3-position. Draw the resonance forms of each sigma complex, and compare their stabilities. (b) Explain why furan undergoes bromination (and other electrophilic aromatic substitutions) primarily at the 2-position.

(a) Draw the three isomers of benzenedicarboxylic acid. (b) The isomers have melting points of \(210^{\circ}C\), \(343^{\circ}C\), and \(427^{\circ}C\). Nitration of the isomers at all possible positions was once used to determine their structures. The isomer that melts at \(210^{\circ}C\) gives two mononitro isomers. The isomer that melts at \(343^{\circ}C\) gives three mononitro isomers. The isomer that melts at \(427^{\circ}C\) gives only one mononitro isomer. Show which isomer has which melting point.

Bisphenol A is an important component of many polymers, including polycarbonates, polyurethanes, and epoxy resins. It is synthesized from phenol and acetone with HCl as a catalyst. Propose a mechanism for this reaction. phenol acetone bisphenol A OH HO C CH3 CH3 2 + O CH3 CH3 C HCl

Unlike most other electrophilic aromatic substitutions, sulfonation is often reversible (see Section 17-4). When one sample of toluene is sulfonated at \(0^{\circ}C\) and another sample is sulfonated at \(100^{\circ}C\), the following ratios of substitution products result: (a) Explain the change in the product ratios when the temperature is increased. (b) Predict what will happen when the product mixture from the reaction at \(0^{\circ}C\) is heated to \(100^{\circ}C\). (c) Because the \(SO_3H\) group can be added to a benzene ring and removed later, it is sometimes called a blocking group. Show how 2,6-dibromotoluene can be made from toluene using sulfonation and desulfonation as intermediate steps in the synthesis.

When 1,2-dibromo-3,5-dinitrobenzene is treated with excess NaOH at 50 C, only one of the bromine atoms is replaced. Draw an equation for this reaction, showing the product you expect. Give a mechanism to account for the formation of your proposed product.

When anthracene is added to the reaction of chlorobenzene with concentrated NaOH at 350 C, an interesting DielsAlder adduct of formula C20H14 results. The proton NMR spectrum of the product shows a singlet of area 2 around d 3 and a broad singlet of area 12 around d 7. Propose a structure for the product, and explain why one of the aromatic rings of anthracene reacted as a diene.

In Chapter 14, we saw that Agent Orange contains (2,4,5-trichlorophenoxy) acetic acid, called 2,4,5-T. This compound is synthesized by the partial reaction of 1,2,4,5-tetrachlorobenzene with sodium hydroxide, followed by reaction with sodium chloroacetate, ClCH2CO2Na. (a) Draw the structures of these compounds, and write equations for these reactions. (b) One of the impurities in the Agent Orange used in Vietnam was 2,3,7,8-tetrachlorodibenzodioxin (2,3,7,8-TCDD), often incorrectly called dioxin. Propose a mechanism to show how 2,3,7,8-TCDD is formed in the synthesis of 2,4,5-T. (c) Show how the TCDD contamination might be eliminated, both after the first step and on completion of the synthesis. Cl Cl Cl OCH2COOH 2,4,5-T O Cl Cl O 2,3,7,8-tetrachlorodibenzodioxin (TCDD)

Phenol reacts with three equivalents of bromine in CCl4 (in the dark) to give a product of formula C6H3OBr3. When this product is added to bromine water, a yellow solid of molecular formula C6H2OBr4 precipitates out of the solution. The IR spectrum of the yellow precipitate shows a strong absorption (much like that of a quinone) around 1680 cm-1 . Propose structures for the two products

Starting with benzene and any other reagents you need, show how you would synthesize the compound shown here. (Hint: Consider a Pd-catalyzed coupling for the final step.)

A graduate student tried to make o-fluorophenylmagnesium bromide by adding magnesium to an ether solution of o-fluorobromobenzene. After obtaining puzzling results with this reaction, she repeated the reaction by using as solvent some tetrahydrofuran that contained a small amount of furan. From this reaction, she isolated a fair yield of the compound that follows. Propose a mechanism for its formation.

A common illicit synthesis of methamphetamine involves an interesting variation of the Birch reduction. A solution of ephedrine in alcohol is added to liquid ammonia, followed by several pieces of lithium metal. The Birch reduction usually reduces the aromatic ring (Section 17-14C), but in this case it eliminates the hydroxy group of ephedrine to give methamphetamine. Propose a mechanism, similar to that for the Birch reduction, to explain this unusual course of the reaction.

Show how you would use a Suzuki reaction to synthesize the following biaryl compound. As starting materials, you may use the two indicated compounds, plus any additional reagents you need.

The antioxidants BHA and BHT are commonly used as food preservatives. Show how BHA and BHT can be made from phenol and hydroquinone. OH OCH3 BHA BHT C(CH3)3 OH CH3 C(CH3)3 (CH3)3C

Triphenylmethanol is insoluble in water, but when it is treated with concentrated sulfuric acid, a bright yellow solution results. As this yellow solution is diluted with water, its color disappears and a precipitate of triphenylmethanol reappears. Suggest a structure for the bright yellow species, and explain this unusual behavior.

Phenolphthalein, a common nonprescription laxative, is also an acidbase indicator that is colorless in acid and red in base. Phenolphthalein is synthesized by the acid-catalyzed reaction of phthalic anhydride with 2 equivalents of phenol. O O O + 2 OH H2SO4 heat O O HO OH OH H+ O O O C C O phenolphthalein red dianion