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1 CHAPTER 22 Chemistry of Benzene Substituents: Alkylbenzenes, Phenols and Benzenamines Reactivity at the Phenylmethyl (Benzyl) Carbon: Benzylic Resonance Stabilization 22-1 The methyl C-H bonds in methylbenzene are relatively weak with respect to homolytic and heterolytic cleavage. The phenylmethyl (benzyl) group may be viewed as a benzene ring whose π system overlaps with an extra p orbital on the attached alkyl carbon: Reactivity at the Phenylmethyl (Benzyl) Carbon: Benzylic Resonance Stabilization 22-1 Benzylic radicals are reactive intermediates in the halogenation of alkylbenzenes. Benzene will not react with Cl2 or Br2 unless a Lewis acid is added: Heat or light allows attack of Cl2 or Br2 on methylbenzene even in the absence of a catalyst, however, attack is at the methyl group, not the aromatic ring. Excess halogen leads to multiple substitution. The mechanism of benzylic halogenation proceeds through radical intermediates: The benzylic C-H bond is relatively weak (DHo=87 kcal mol-1) due to resonance stabilization of the intermediate radical formed. Subsequent halogen attack is always at the benzylic position because attack at an aromatic carbon would destroy the aromatic character of the ring
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2 Benzylic cations delocalize the positive charge. Benzylic resonance can strongly affect the reactivity of benzylic halides and sulfonates in nucleophilic displacements. For example, a primary benzylic tosylate rapidly reacts with ethanol via an SN1 reaction: Delocalization of positive charge into the aromatic ring facilitates the dissociation of the starting sulfonate: Several benzylic cations are stable enough to have been isolated. The X-ray structure of 2-phenyl-2-propyl cation (as its SbF6 - salt) was obtained in 1997. A para methoxy substituent on the benzene ring allows for extra stabilization of the benzylic positive charge. In its absence, the SN2 reaction may dominate due to the lack of steric interference and the stabilization of the SN2 transition state by overlap with the benzene π system. Resonance in benzylic anions makes benzylic hydrogens relatively acidic. The anion, radical and cation adjacent to a benzene ring are all stabilized by conjugation: The acidity of methylbenzene (pKa~41) is considerably greater than that of ethane (pKa~50) and comparable to that of propene (pKa~40) which can be deprotonated to form the resonancestabilized 2-propenyl anion. Consequently, methylbenzene can be deprotonated by butyllithium to generate phenylmethyllithium:
22-2 Benzvlic Oxidations and Reductions Bdasinaieatagadbenzenesleadstn u w8goa nzylic ethers are cleaved by hydrogenolysis H OH HOR 网 22-3 Names and Properties of Phenols ---5-d 中 3
3 22-2 Benzylic Oxidations and Reductions Oxidation of alkyl-substituted benzenes leads to aromatic ketones and acids. Hot KMnO4 and Na2Cr2O7 may oxidize alkylbenzenes all the way to benzoic acids. These reactions require at least one benzylic CH bond to be present in the starting materials (tertiary alkylbenzenes are inert). The oxidation reaction proceeds through the alcohol, the ketone and then the acid. It can be stopped at the ketone stage under milder conditions. Benzylic alcohols, in the presence of other non-benzylic hydroxy groups, can be oxidized to the corresponding carbonyl compounds under mild conditions. Benzylic ethers are cleaved by hydrogenolysis. Exposure of benzylic alcohols or ethers to hydrogen in the presence of a metal catalyst leads to cleavage of a σ-bond by catalytically activated hydrogen. Since hydrogenolysis is not possible for ordinary alcohols and ethers, the phenylmethyl substituent is a valuable protecting group for hydroxy functions. Protection by a tertiary butyl group would require acid to cleave, which might cause dehydration. 22-3 Names and Properties of Phenols In hydroxy-substituted arenes (phenols), the π system of the benzene ring overlaps an occupied p orbital on the oxygen atom. This results in delocalization similar to that found in benzylic anions. Enols are usually unstable and revert to their ketone forms. Phenols, however prefer the enol form which preserves the aromatic nature of the aromatic ring
22-3 Names and Properties of Phenols of phenol derivative)are gredphenehndnhotogrpy.yen9an H- 8 cal activity are: ally ac 脱o0 epnateoahenotsdetoresonmncestabtiatoncd 5aa 4
4 22-3 Names and Properties of Phenols Phenols are hydroxyarenes. Phenol was formerly known as “carbolic acid.” Aqueous solutions of phenol (or its derivatives) are used as disinfectants. Its main use is in the preparation of polymers (phenolic resins). Pure phenol is toxic and causes severe skin burns. Substituted phenols are named as phenols, benzenediols or benzenetriols. Some common names are accepted by IUPAC. Substituted phenols find uses in photography, dyeing and tanning. Bisphenol A is an important monomer in the synthesis of epoxyresins and polycarbonates. Phenols containing a carboxylic acid functionality (higher ranking) are called hydroxybenzoic acids. Phenyl ethers are named as alkoxybenzenes. As a substituent, C6H5O is called phenoxy. Examples of phenols possessing physiological activity are: Phenols are unusually acidic. The pKa values of phenols range from 8 to 10. They are less acidic than carboxylic acids (pKa=4-5) and stronger than alkanols (pKa=16-18). The acidic nature of phenols is due to resonance stabilization of the phenoxide ion: Substituents can affect the acidity of phenols: Multiple nitrations can increase the acidity to that of carboxylic or even mineral acids. Electron donating substituents have the opposite effect:
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5 Preparation of Phenols: Nucleophilic Aromatic Substitution 22-4 Nucleophilic aromatic substitution may follow an addition-elimination pathway. Displacement of a group (other than hydrogen) from an aromatic ring is called ipso substitution. The transformation is called nucleophilic aromatic substitution. Success of this reaction is dependent upon the presence of one or stronger electron-withdrawing groups located on the ring ortho or para to the leaving group. Electron-withdrawing groups stabilize the intermediate anion by resonance. Nucleophilic aromatic substitution reactions proceed by a twostep addition-elimination sequence. In the meta compound, 1-chloro-3,5-dinitrobenzene, ipso substitution does not occur: The reactivity of haloarenes in nucleophilic substitutions increases with the nucleophilicity of the reagent and the number of electron-withdrawing groups on the ring. Haloarenes may react through benzyne intermediates. Haloarenes without electron-withdrawing substituents can undergo nucleophilic substitution at highly elevated temperatures and pressures