1559T_ch22_389-40810/19/0517:23Pa9e389 EQA 22 Chemistry of Benzene Substituents: Alkylbenzenes,Phenols,and Benzenamines atonr to a benzene nng (a benzy zene ring with the attached groups modifies their chemistry significantly. Outline of the Chapter 21-1 Benzylic Resonance Stabilization Carbons attached to benzene rings display enhanced reactivity 22-2 Benzylic Oxidations and Reductions Including one especially useful oxidation of alkyl side chains. 22-3 Naming and Properties of Phenols 22-4 Preparation of Phenols:Nucleophilic Aromatic Substitution Useful new methods for synthesizing benzene derivatives 22-5 Alcohol Chemistry of Phenols 22-6 Electrophilic Substitution of Phenols 22-7 Claisen and Cope Rearrangements 22-8 Oxidation of Phenols:Benzoquinones Aromatic alcohols:how the functional groups affect one another 22-9 Oxidation-Reduction Processes in Nature 22-10,22-11 Arenediazonium Salts and Diazo Coupling Using aromatic amines to synthesize substituted benzenes Keys to the Chapter 22-1.Benzylic Resonance Stabilization go back andtaethe ffor the perolmethl (ben nion.There are I forms for each one.lea stability and ase of formation. 389
22 Chemistry of Benzene Substituents: Alkylbenzenes, Phenols, and Benzenamines In this chapter you continue to study the chemistry of aromatic compounds. You find out about reactions at a carbon attached to a benzene ring (a “benzylic” carbon) and about more transformations of benzenes containing either hydroxy or amino groups connected directly to the ring. In all these cases the interaction of the benzene ring with the attached groups modifies their chemistry significantly. Outline of the Chapter 21-1 Benzylic Resonance Stabilization Carbons attached to benzene rings display enhanced reactivity. 22-2 Benzylic Oxidations and Reductions Including one especially useful oxidation of alkyl side chains. 22-3 Naming and Properties of Phenols 22-4 Preparation of Phenols: Nucleophilic Aromatic Substitution Useful new methods for synthesizing benzene derivatives. 22-5 Alcohol Chemistry of Phenols 22-6 Electrophilic Substitution of Phenols 22-7 Claisen and Cope Rearrangements 22-8 Oxidation of Phenols: Benzoquinones Aromatic alcohols: how the functional groups affect one another. 22-9 Oxidation–Reduction Processes in Nature 22-10, 22-11 Arenediazonium Salts and Diazo Coupling Using aromatic amines to synthesize substituted benzenes. Keys to the Chapter 22-1. Benzylic Resonance Stabilization Chemical reactivity at a saturated carbon atom attached to a benzene ring is greatly enhanced over that of ordinary alkyl carbons. Delocalization stabilizes both reaction transition states and intermediates. After reading this section once, go back and take a good look at the sets of resonance forms for the phenylmethyl (benzyl) radical, cation, and anion. There are four forms for each one, leading to increased stability and ease of formation. 389 1559T_ch22_389-408 10/19/05 17:23 Page 389
1559Tch22389-40810/19/0517:23Page390 ⊕ EQA 390 chapter 22 CHEMISTRY OF BENZENE SUBSTITUENTS:ALKYLBENZENES,PHENOLS,AND BENZENAMINES Most ofte encounte d is nucleophilic substitution on comp potential Ss2 mechanism are stabilized.so both pathways may be followed.Just as you saw a long time ago with sec ondary (Sectio) 4.h pounds.both free radical and anionie reactions take place at benzyli carbons as well.Notice.however.tha the products of these reactions ne er involve attachment of groups to the benzene ring itself:Double bond mi 22.2.Ben Of the several reactions in this section.the one you are most likely to encounter is the oxidation of alkyl side chains on benzene rings with KMnO to form benzoic acids.Notice two features:First,all carbons but the ben emmnCgC0oHpcreaecnnddapea.andocoad.anop-tirctimgaglgroupiscoanento 22-4.Pr ration of Phenols:Nucleophilic Aro The two nuceophilic aromatic (is)substitution reactions are useful synthetic processes.The addition- elimination version is a common reaction of be zees containing a leaving group together with good electron- withdr wing (ani 2 on ber Although these reactions are indeed useful you should keep them in perspective:the are encountered only rarely relative to the electrophil c reactions de cribed earlier You have a lready sen attack be likely to occur. 22-3,22-5 through 22-7.Reactions of Phenols The that of ordi ary alcohols that th zen.The immediate result is that phenols are more acidic and le ess ba asic than ordinary alcohols.The conjugate bases of phenols,phenox are much less much hd car 52 for ica coequence of thi),but they stll good nucleophiles,especially usefu in either synthesis via ce between phenol oxygen and the benzene ring also affects benzen activity.The extr electron density in the ing makes eptible to electrophilic attack by even rather weak electrophiles Reactions with formaldehyde and CO in the presence of base are examples. 22-8.Oxidation of Phenols:Benzoquinones The evers 22-9.Oxidation-Reduction Processes in Nature ucas lipids in cellm embrane neagm
Most often encountered is nucleophilic substitution on compounds containing potential leaving groups on the benzylic carbon. Both the carbocation intermediate for an SN1 mechanism and the transition state for the SN2 mechanism are stabilized, so both pathways may be followed. Just as you saw a long time ago with secondary haloalkanes (Section 7-5), and more recently with allylic systems (Sections 14-1 through 14-4), the choice of mechanism is determined by the specific conditions and reagents. Also, in analogy with allylic compounds, both free radical and anionic reactions take place at benzylic carbons as well. Notice, however, that the products of these reactions never involve attachment of groups to the benzene ring itself: Double bond migrations, which are often seen with allylic systems, do not occur with benzylic ones, because the aromaticity of the benzene ring would be lost (see Problem 35). 22-2. Benzylic Oxidations and Reductions Of the several reactions in this section, the one you are most likely to encounter is the oxidation of alkyl side chains on benzene rings with KMnO4 to form benzoic acids. Notice two features: First, all carbons but the benzylic carbon are chewed off by the reagent and disappear, and second, an o,p-directing alkyl group is converted into an m-directing COOH group. 22-4. Preparation of Phenols: Nucleophilic Aromatic Substitution The two nucleophilic aromatic (ipso) substitution reactions are useful synthetic processes. The addition– elimination version is a common reaction of benzenes containing a leaving group together with good electronwithdrawing (anion-stabilizing) groups like NO2. The elimination–addition (“benzyne”) mechanism occurs when benzenes containing a leaving group, but no other anion-stabilizing groups, are treated with strong bases. Although these nucleophilic substitution reactions are indeed useful, you should keep them in perspective; they are encountered only rarely relative to the electrophilic reactions described earlier. You have already seen the reasons for this: Arenes normally contain electron-rich systems and are naturally most easily attacked by electrophiles. Only in the presence of strong electron-withdrawing groups or very strong bases will nucleophilic attack be likely to occur. 22-3, 22-5 through 22-7. Reactions of Phenols The behavior of aromatic alcohols is so different from that of ordinary alcohols that the properties of the aromatic alcohols merit special coverage. Most of the differences are due to the ability of the benzene ring to delocalize a lone pair of electrons from the phenol oxygen. The immediate result is that phenols are more acidic and less basic than ordinary alcohols. The conjugate bases of phenols, phenoxide ions, are much less basic than alkoxide ions and can therefore be generated by reaction of phenols with HO. Being less basic, phenoxide ions are much better leaving groups than are hydroxide or alkoxide ions (see Problem 52 for a practical consequence of this), but they are still good nucleophiles, especially useful in either synthesis via SN2 reaction. The resonance between phenol oxygen and the benzene ring also affects benzene reactivity. The extra electron density in the ring makes it susceptible to electrophilic attack by even rather weak electrophiles: Reactions with formaldehyde and CO2 in the presence of base are examples. 22-8. Oxidation of Phenols: Benzoquinones The reversible redox relationship between 1,4-benzenediols and p-benzoquinones, or just quinones, is a special one because of its relative ease. Conjugate addition and Diels-Alder cycloaddition are common reactions of quinones; conjugate additions have biological importance. The isomeric but less stable 1,2-compounds are encountered much less frequently. 22-9. Oxidation–Reduction Processes in Nature After a discussion of types of reactions that can damage biological molecules such as lipids in cell membranes, this section illustrates the ways antioxidant molecules such as vitamin E inhibit these processes. These antioxidants share one property in common with 1,4-benzenediols: They are easily oxidized, although they usually 390 • Chapter 22 CHEMISTRY OF BENZENE SUBSTITUENTS: ALKYLBENZENES, PHENOLS, AND BENZENAMINES 1559T_ch22_389-408 10/19/05 17:23 Page 390
1559T_ch22_389-40810/19/0517:23Page39 EQA Solutions to Problems.391 carefully to find out about some 22-10 and 22-11.Arenediazonium Salts and Diazo Coupling 心如 Like aromatic alcoho lies in the ease of replacement of this group by any of the following (reagents are given in parentheses): Arenediazonium salts are als electrophilic enough to react with phenolsor benzenamines to form so-called azo dyes via the diazo coupling process. Solutions to Problems CICHCH H Br 31.a〔】 32.Radical chemistry:initiation,propagation,and termination(which we will ignore) INITIATION: :一+ PROPAGATION -奶 -0
aren’t oxidized to quinones (their structures don’t usually permit that). Read carefully to find out about some molecules that are good for you! 22-10 and 22-11. Arenediazonium Salts and Diazo Coupling Like aromatic alcohols, aromatic amines are also special. In particular, resonance delocalization of the lone pair on nitrogen into the benzene ring makes aromatic amines much less basic than their alkyl relatives. However, most of the reactions of aromatic amines are similar enough qualitatively to those of alkanamines that there’s really no need to rehash all that stuff. Instead, this section presents just one class of reactions of these compounds, chosen because of its special versatility in synthesis. Diazotization of a primary benzenamine produces an arenediazonium salt containing an ON2 substituent on the benzene ring. The value of these salts lies in the ease of replacement of this group by any of the following (reagents are given in parentheses): OH (H3PO2) OOH ( H2O, ) OCl, Br (CuX, ) OI (I, ) OCN (CuCN, CN, ) Arenediazonium salts are also electrophilic enough to react with phenols or benzenamines to form so-called azo dyes via the diazo coupling process. Solutions to Problems 31. (a) (b) 32. Radical chemistry: initiation, propagation, and termination (which we will ignore). INITIATION: PROPAGATION: O O N O O H H Br N Br NH O O N O O H H H N O O Br N O O Br ClCHCH3 H Br Solutions to Problems • 391 1559T_ch22_389-408 10/19/05 17:23 Page 391
1559Tch22389-40910/19/0517:23Page392 392 chapter 22 CHEMISTRY OF BENZENE SUBSTITUENTS:ALKYLBENZENES,PHENOLS,AND BENZENAMINES 33.Several reactions derive from fundamental material presented in earlier chapters. CICHCH CICHCH HOOCCHCH 8 CH=CHz CH.CH.OH ⊕ 6.8-6-6- 0-这-g-0-i-过 2-1-9-68 butor in which a lone pair on o
33. Several reactions derive from fundamental material presented in earlier chapters. (a) (b) (c) (d) 34. The cation derived from chloromethylbenzene (benzyl chloride, top) is stabilized by four resonance contributing forms. The cation from 1-(chloromethyl)-4-methoxybenzene (4-methoxybenzyl chloride, middle) is more stable because of the added contributor in which a lone pair on oxygen is delocalized into the ring (second Lewis structure from the right). The cation from 1-(chloromethyl)-4-nitrobenzene ClCH2 CH2 CH2 Cl CH2 CH2 NO2 NO2 NO2 NO2 NO2 Poor ClCH2 OCH3 OCH3 OCH3 OCH3 OCH3 OCH3 CH2 CH2 Cl CH2 CH2 CH2 ClCH2 CH2 CH2 Cl CH2 CH2 CH CH2 MCPBA O ClCHCH3 CH CH2 KOC(CH3)3 1. BH3, THF 2. NaOH, H2O2 CH2CH2OH ClCHCH3 HOOCCHCH3 1. KCN, DMSO 2. H3O, CH2CH3 ClCHCH3 Cl2 (1 equivalent), hv (Problem 30a) 392 • Chapter 22 CHEMISTRY OF BENZENE SUBSTITUENTS: ALKYLBENZENES, PHENOLS, AND BENZENAMINES 1559T_ch22_389-408 10/19/05 17:23 Page 392
1559T_ch22_389-40810/19/0517:23Page39 EQA Soutionso Problems393 one of its r the one with the +charge Not aromatic 36.In each cas umerous re sonance forms can be drawn.Both of these species are resonance hybrid ation)or the od in the radical 品品只 37.(a)BrCH,CH,CH〈 CH2OH Benzylic position is most ive in nucleophilic substitutio 0o-0-0
(4-nitrobenzyl chloride, bottom) is least stable because one of its resonance forms, the one with the charge next to the electron-withdrawing nitro group, is poor. 35. 36. In each case numerous resonance forms can be drawn. Both of these species are resonance hybrids strongly stabilized by delocalization of the charge (in the cation) or the odd electron (in the radical). Three of the resonance forms for the radical are shown below. How many more can you draw? 37. (a) Benzylic position is most reactive in nucleophilic substitution. (b) (c) 38. H H three others in right-hand benzene ring H H H Base H H2O H OH C6H5 product H C6H5 C6H5CHO H Li (E and Z), via CH2COOH BrCH2CH2CH2 CH2OH C C etc. C CH2Cl CH2 CH2 Product is aromatic Benzylic Cl Cl Para CH2 H Cl Not aromatic Solutions to Problems • 393 1559T_ch22_389-408 10/19/05 17:23 Page 393
1559rch22389-40810/19/0517:23Page394 394 chapter 22 CHEMISTRY OF BENZENE SUBSTITUENTS:ALKYLBENZENES,PHENOLS,AND BENZENAMINES 39.(a)One solution,perhaps a bit roundabout: 】CHa.A BrCHCHs NBS./wy K+-OC(CH: (CHaCOH CH=CH2 CH2CH2Br COOH B.a. 一-○-00 0
Seven resonance forms make this carbanion especially stable. It is also aromatic, having 14 electrons in an unbroken loop of p orbitals. 39. (a) One solution, perhaps a bit roundabout: (b) (c) (d) CH3 Br Br Na2Cr2O7, H2SO4 product CH3 CH3 SO3H SO3H CH3 Br Br SO3, H2SO4 2 Br2, FeBr3 H2O, C COOH CH3OH, H O product C CH3 Na2Cr2O7, H2SO4 O CH3 COOH COCl SOCl2 KMnO CH3, AlCl3 4, HO, CH3 CH3 Cl Cl2, FeCl3 Na2Cr2O7, H2SO4, COOH Cl 1. SOCl2 2. NH3 product CH2CH2Br HBr, ROOR (Anti-Markovnikov) CH CH2 BrCHCH3 NBS, hv CH2CH3 K OC(CH3)3 (CH3)3COH CH3CH2Cl, AlCl3 394 • Chapter 22 CHEMISTRY OF BENZENE SUBSTITUENTS: ALKYLBENZENES, PHENOLS, AND BENZENAMINES 1559T_ch22_389-408 10/19/05 17:23 Page 394
1559T_ch22_389-40810/19/0517:23Pa9e395 ⊕ EQA Solutions to Problems.395 40 ing group 41.The presence of strong electror CH:O. Cl ortho or para to no?'s No. is most easily displaced NO CH Benzyne mechanism N(CHCH N(CH2CH) 42.aCCCettmote2eatKoe mide metRmmmHoHad2a.aoka ,H0,△ CH,CH2CH2CH2-Li* 入CH,CH,CH,CH CH.O CH2O-Li* H.H0,product CH2CH2CH2CHs Strongly basic butyllithium s HE in the firs
40. Most reactive ones have NO2 groups ortho or para to the leaving group. So, 41. The presence of strong electron-withdrawing groups such as NO2 ortho or para to a potential leaving group favors nucleophilic aromatic substitution by the addition–elimination mechanism. Without such groups in these positions, the benzyne mechanism is favored. (a) (b) (c) 42. (a) 1. CH3COCl (forms amide, reduces ring activation so that bromination in the next step can be controlled to attach just one Br to the ring instead of three), 2. Br2, CHCl3, 3. KOH, H2O, (hydrolyzes amide back to benzenamine); (b) 1. CF3CO3H, CH2Cl2, 2. Cl2, FeCl3; (c) KCN (nucleophilic aromatic substitution); (d) H, H2O, 43. Strongly basic butyllithium removes HF in the first step, generating benzyne. A second mole of butyllithium adds to benzyne as a nucleophile. The reason for the direction of addition is explained in the answer to Exercise 22-12. CH3O CH2CH2CH2CH3 CH2O Li H, H2O product CH3O CH2CH2CH2CH3 CH3CH2CH2CH2 Li Li OCH3 OCH3 C O H H CH3CH2CH2CH2 Li LiF butane F H N(CH2CH3)2 CH3 N(CH2CH3)2 CH3 Benzyne mechanism NO2 CH3O NO2 Cl Cl ortho or para to NO2’s is most easily displaced NO2 NO2 NHNH2 NO2 NO2 Br NO2 Br NO2 NO2 Br NO2 Br NO2 Br (Closer, so greater inductive effect) Solutions to Problems • 395 1559T_ch22_389-408 10/19/05 17:23 Page 395
15597.ch22.389-40811/7/0515:40Page396 EQA 396 chapter 22 CHEMISTRY OF BENZENE SUBSTITUENTS:ALKYLBENZENES,PHENOLS,AND BENZENAMINES tion mechanism,the most of all the halogens.and stabilizes the resulting anion by an inductive effect to the greatest degree.While of the benzene ring.In Chapter 25 we will see even worse leaving groups than this expelled to generate aromatic rings. 45.The first step introd to give the final product. C:OH c人a OCHaCO2H(after acidification) 46.(a) 人COOH (b)The first step oxidizes the benzylic alcohol to an aldehyde.The molecule is then capable of an automer of a more stable phenol.Using equations,we have “ 及
44. In nucleophilic aromatic substitution reactions that proceed by the addition-elimination mechanism, the addition step is rate-limiting. Fluorine is the most electronegative and, therefore, the most electron-withdrawing of the halogens. Therefore, the presence of F lowers the transition-state energy for nucleophilic addition the most of all the halogens, and stabilizes the resulting anion by an inductive effect to the greatest degree. While it is true that F is by far the worst leaving group among halide ions, expulsion of the leaving groups takes place after the rate-determining addition and is fast because it benefits from reestablishment of the aromaticity of the benzene ring. In Chapter 25 we will see even worse leaving groups than this expelled to generate aromatic rings. 45. The first step introduces oxygen into the ring. Nucleophilic aromatic substitution is the most reasonable method. The resulting phenol must be used as a nucleophile itself to attack an appropriate substrate in order to give the final product. *Acidification is necessary because this phenolic hydroxy group will be deprotonated at the pH used for the initial nucleophilic aromatic substitution. 46. (a) (b) The first step oxidizes the benzylic alcohol to an aldehyde. The molecule is then capable of an intramolecular aldol condensation, forming a second six-membered ring that contains an , -unsaturated ketone. This ketone, in turn, is unusual in that it is a cyclohexadienone, the ketone tautomer of a more stable phenol. Using equations, we have H CH3 O O KOH Aldol Tautomerization O H H H OH CH2OH H O O O MnO2 COOH COOH HOOC HOOC Cl Cl Cl OCH2CO2H (after acidification) Cl Cl Cl Cl Cl Cl Cl O H Cl CH2CO2 OH O OH Cl Cl Cl Cl OH* Cl Cl Cl Cl Cl Cl Cl Cl OH 396 • Chapter 22 CHEMISTRY OF BENZENE SUBSTITUENTS: ALKYLBENZENES, PHENOLS, AND BENZENAMINES 1559T_ch22_389-408 11/7/05 15:40 Page 396
1559T_ch22_389-40811/7/0515:40Page397 EQA Soutionso Problems397 COOH COOH nost phenol wing groups increase the acidity of phenol 5ed O- OH OH OH NH
(c) 47. (c) (The SO3H group is very acidic) (b) (e) (f) (d) (a). Carboxylic acids are more acidic than most phenols, and electron-withdrawing groups increase the acidity of phenols. 48. (a) (b) product OH SO3H OH Br Br H2O, 1. H2SO4 2. excess Br2 CH3 CH3 SO3H SO3, H2SO4 NaOH, product COOH COOH NO2 Solutions to Problems • 397 (c) HNO3, H2SO4, 1. H2, Ni, CH3CH2OH 2. NaNO2, HCl, H2O NO2 NO2 NO2 OH OH NaNO2, HCl, H2O, OH OH OH NH2 OH OH OH OH SO3H NaOH, H2O, H2, Ni CH3CH2OH H2SO4 HNO3, H2SO4 OH NO2 SO3H OH NO2 1559T_ch22_389-408 11/7/05 15:40 Page 397
15597.eh22.389-40810/19/0517:23Pag0398 398 chapter 22 CHEMISTRY OF BENZENE SUBSTITUENTS:ALKYLBENZENES,PHENOLS,AND BENZENAMINES NO [From Problem 48(d)] OH OCH-COOCH 风 NOH.H:O 2.4-D OH OCH.CH OCH-CH CH:CH:OH NO: OH 00H Br
(d) 49. (a) (b) (c) CO2, pressure, KHCO3, H2O OH Br Br OH Br Br COOH CH3COCCH3, H, O O product 1. HNO3, H2SO4 2. Br2, FeBr3 1. Fe, HCl 2. NaNO2, HCl, 0 C 3. H2O, 4. Br2, CCl 4, 0 C NO2 Br 1. HNO3, H2SO4 2. H2, Ni CH3CH2OH OCH2CH3 OCH2CH3 CH3COCCH3, NH2 O O product 1. SO3, H2SO4 2. NaOH, 1. NaOH, CH3CH2OH 2. CH3CH2Br OH 1. NaOH, CH3CH2OH 2. ClCH2COOCH3 OH NaOH, H2O Cl Cl OCH2COOCH3 (Williamson ether synthesis) Cl Cl 2,4-D 1. NaNO2, HCl, H2O, 0 C 2. CuCl, NO2 OH NO2 NH2 NH2 OH H2, Ni, CH3CH2OH [From Problem 48(d)] Cl2, FeCl3 NO2 OH NO2 Cl NO2 NO2 OH Excess HNO3, H2SO4, NaOH, H2O, (Nucleophilic aromatic subst.) NO2 Cl Cl NO2 398 • Chapter 22 CHEMISTRY OF BENZENE SUBSTITUENTS: ALKYLBENZENES, PHENOLS, AND BENZENAMINES 1559T_ch22_389-408 10/19/05 17:23 Page 398