Organic Chemistry III

Mohammad Jafarzadeh Faculty of Chemistry, Razi University

Organic Chemistry, Structure and Function (7th edition) By P. Vollhardt and N. Schore, Elsevier, 2014 1 22. Chemistry of Benzene Substituents

Alkylbenzenes, Phenols, and Benzenamines

22-1 REACTIVITY AT THE PHENYLMETHYL (BENZYL) CARBON:

Methylbenzene is readily metabolized because its methyl C–H bonds are relatively weak with respect to homolytic and heterolytic cleavage. 980 CHAPTER 22 Chemistry of Benzene Substituents When one of these methyl hydrogens has been removed, the resulting phenylmethyl (benzyl) group, C6H5CH2, may be viewed as a benzene ring whose � system overlaps with an extra p orbital located on an attached alkyl carbon. Sole site of reactivity 22-1 REACTIVITY AT THE PHENYLMETHYL (BENZYL) CARBON: BENZYLIC RESONANCE STABILIZATION

Methylbenzene is readily metabolized because its methyl C–H bonds are relatively weak with respect to homolytic and heterolytic cleavage. When one of these methyl hydrogens has been removed, the resulting phenylmethyl (benzyl) group, C6H5CH2 (see margin), may Phenylmethyl (benzyl) system 2be viewed as a benzene ring whose ␲ system overlaps with an extra p orbital located on an attached alkyl carbon. This interaction, generally called benzylic resonance, stabilizes Sites of reactivity adjacent radical, cationic, and anionic centers in much the same way that overlap of a ␲ bond and a third p orbital stabilizes 2-propenyl (allyl) intermediates (Section 14-1). However, unlike allylic systems, which may undergo transformations at either terminus and give product mixtures (in the case of unsymmetrical substrates), benzylic reactivity is regioselective and occurs only at the benzylic carbon. The reason for this selectivity lies in the disruption of aromaticity that goes with attack on the benzene ring. 2-Propenyl (allyl) system Benzylic radicals are reactive intermediates in the halogenation of alkylbenzenes We have seen that benzene will not react with chlorine or bromine unless a Lewis acid is added. The acid catalyzes halogenation of the ring (Section 15-9).

Br–Br Br–Br, FeBr No reaction 3 –HBr

In contrast, heat or light allows attack by chlorine or bromine on methylbenzene (toluene) even in the absence of a catalyst. Analysis of the products shows that reaction takes place at the methyl group, not at the aromatic ring, and that excess halogen leads to multiple substitution.

CH2H CH2Br

⌬ ReactionR ϩ Br2 ϩ HBr

(Bromomethyl)- benzene

CH3 CH2Cl CHCl2 CCl3

Cl2, hv Cl2, hv Cl2, hv ϪHCl ϪHCl ϪHCl

(Chloromethyl)- (Dichloromethyl)- (Trichloromethyl)- benzene benzene benzene

Each substitution yields one molecule of hydrogen halide as a by-product. As in the halogenation of alkanes (Sections 3-4 through 3-6) and the allylic halogenation of alkenes (Section 14-2), the mechanism of benzylic halogenation proceeds through radical intermediates. Heat or light induces dissociation of the halogen molecule into atoms. One of them abstracts a benzylic hydrogen, a reaction giving HX and a phenylmethyl (benzyl) radical. This intermediate reacts with another molecule of halogen to give the product, a (halomethyl)benzene, and another halogen atom, which propagates the chain process. 980 CHAPTER 22 Chemistry of Benzene Substituents

This interaction, generally called benzylic resonance, stabilizes adjacent radical, cationic, Sole site and anionic centers in much the same way that overlap of a � bond andof reactivitya third p orbital 22-1 REACTIVITY AT THE PHENYLMETHYL (BENZYL) CARBON: stabilizes 2-propenyl (allyl) intermediates. BENZYLIC RESONANCE STABILIZATION However, unlike allylic systems, which may undergo transformations at either terminus and give product mixtures (in the case of unsymmetrical substrates), benzylic reactivity is Methylbenzene is readily metabolized because its methyl C–H bonds are relatively weak regioselective and occurs only at the benzylic carbon. with respect to homolytic and heterolytic cleavage. When one of these methyl hydrogens has been removed, the resulting phenylmethyl (benzyl) group, C6H5CH2 (see margin), may The reason for this selectivity lies in the disruption of aromaticityPhenylmethylthat goes (benzyl)with systemattack on be viewed as a benzene ring whose ␲ system overlaps with an extra p orbital located on the benzene ring. an attached alkyl carbon. This interaction, generally called benzylic resonance, stabilizes Sites of reactivity adjacent radical, cationic, and anionic centers in much the same way that overlap of a ␲ bond and a third p orbital stabilizes 2-propenyl (allyl) intermediates (Section 14-1). However, unlike allylic systems, which may undergo transformations at either terminus and give product mixtures (in the case of unsymmetrical substrates), benzylic reactivity is regioselective and occurs only at the benzylic carbon. The reason for this selectivity lies in the disruption of aromaticity that goes with attack on the benzene ring. 2-Propenyl (allyl) system 3 Benzylic radicals are reactive intermediates in the halogenation of alkylbenzenes We have seen that benzene will not react with chlorine or bromine unless a Lewis acid is added. The acid catalyzes halogenation of the ring (Section 15-9).

Br–Br Br–Br, FeBr No reaction 3 –HBr

CH2H CH2Br

⌬ ReactionR ϩ Br2 ϩ HBr

(Bromomethyl)- benzene

CH3 CH2Cl CHCl2 CCl3

Cl2, hv Cl2, hv Cl2, hv ϪHCl ϪHCl ϪHCl

(Chloromethyl)- (Dichloromethyl)- (Trichloromethyl)- benzene benzene benzene

980 CHAPTER 22 Chemistry of Benzene Substituents Sole site Sole site of reactivity 22-1 of REACTIVITY reactivity AT THE22-1 PHENYLMETHYL REACTIVITY (BENZYL) AT THE CARBON: PHENYLMETHYL (BENZYL) CARBON: BENZYLIC RESONANCE STABILIZATIONBENZYLIC RESONANCE STABILIZATION Sole site of reactivity 22-1 REACTIVITY AT THE PHENYLMETHYL (BENZYL) CARBON: Methylbenzene is readily metabolizedMethylbenzene because its methyl is readily C–H bonds metabolizedBENZYLIC are relatively becauseRESONANCE weak its methyl STABILIZATION C–H bonds are relatively weak with respect to homolytic and heterolyticwith respect cleavage. to When homolytic one of and these heterolytic methyl hydrogens cleavage. When one of these methyl hydrogens has been removed, the resulting phenylmethylhas been removed,(benzyl) group, the resulting C6H5CH phenylmethyl2 (see margin), may (benzyl) group, C H CH (see margin), may be viewed as a benzene ring whose ␲ system overlapsMethylbenzene with an extra is p readily orbital metabolized located on because its methyl6 5 C–H2 bonds are relatively weak Phenylmethyl (benzyl) system be viewed as a benzene ring whose ␲ system overlaps with an extra p orbital located on Phenylmethylan attached alkyl (benzyl) carbon. system This interaction, generally with called respect benzylic to homolyticresonance, and stabilizes heterolytic cleavage. When one of these methyl hydrogens Sites of reactivity an attached alkylhas carbon. been removed, This interaction, the resulting generallyphenylmethyl called (benzyl) benzylic group, resonance, C H CH (see stabilizes margin), may adjacent radical,Sites of reactivitycationic, and anionic centers in much the same way that overlap of a ␲ bond 6 5 2 and a third p orbitalPhenylmethyl stabilizes 2-propenyl(benzyl)adjacent system (allyl) radical, intermediatesbe cationic, viewed and as (Section a anionic benzene 14-1). centers ring However, whose in much ␲ system the same overlaps way with that anoverlap extra pof orbital a ␲ bond located on an attached alkyl carbon. This interaction, generally called benzylic resonance, stabilizes unlike allylic systems, whichSites may of reactivity and undergo a third transformations p orbital stabilizes at either 2-propenyl terminus and (allyl) give intermediates (Section 14-1). However, product mixtures (in the case of unsymmetricalunlike allylic substrates), systems,adjacent benzylic radical, which reactivity cationic, may undergo isand regioselec- anionic transformations centers in much atthe either same way terminus that overlap and of give a ␲ bond and a third p orbital stabilizes 2-propenyl (allyl) intermediates (Section 14-1). However, tive and occurs only at the benzylicproduct carbon. mixturesThe reason (in for the this case selectivity of unsymmetrical lies in the dis- substrates), benzylic reactivity is regioselec- unlike allylic systems, which may undergo transformations at either terminus and give ruption of aromaticity that goes with attack on the benzene ring. tive and occurs productonly at mixtures the benzylic (in the carbon.case of unsymmetrical The reason forsubstrates), this selectivity benzylic liesreactivity in the is dis-regioselec- 2-Propenyl ruption of aromaticity that goes with attack on the benzene ring. (allyl) system tive and occurs only at the benzylic carbon. The reason for this selectivity lies in the dis- Benzylic2-Propenyl radicals are reactive intermediatesruption of in aromaticity the halogenation that goes with attack on the benzene ring. (allyl) system of alkylbenzenes 2-Propenyl (allyl) systemBenzylic radicals are reactive intermediates in the halogenation We have seen that benzene will not ofreact alkylbenzenes with chlorineBenzylic or bromine radicals unless a areLewis reactive acid is intermediates in the halogenation added. The acid catalyzes halogenation of the ring (Section 15-9). We have seen thatof alkylbenzenesbenzene will not react with chlorine or bromine unless a Lewis acid is We have seen that benzene will not react with chlorine or bromine unless a Lewis acid is added. The acid catalyzes halogenationBr of the ring (Section 15-9). Benzene will not react with chlorine oradded.bromine The acid unlesscatalyzes ahalogenationLewis acid of theis ringadded (Section. The15-9). acid Br–Br catalyzes halogenation of the ring. Br–Br, FeBr Br No reaction 3 Br –HBr Br–Br Br–Br Br–Br, FeBr3 Br–Br, FeBr No reaction No reaction 3 –HBr –HBr In contrast, heat or light allows attack by chlorine or bromine on methylbenzene (toluene) even in the absence of a catalyst. Analysis of the products shows that reaction takes place at the methyl group, not at the aromatic ring, and that excess halogen leads to multiple In contrast, heat or light allowsIn contrast,attack heatbyIn or chlorinecontrast, light allows heator or attack brominelight allows by chlorine attackon methylbenzene byor chlorinebromine or on bromine methylbenzene(toluene) on methylbenzene (toluene) (toluene) substitution. even in the absence of a catalysteven in the. absenceeven inof thea catalyst.absence ofAnalysis a catalyst. of Analysisthe products of the shows products that shows reaction that reactiontakes place takes place at the methyl group, not at the aromatic ring, and that excess halogen leads to multiple at the methyl group, not at the aromatic ring, and that excess halogen leads to multiple CH2H CHsubstitution.2Br The reaction takes placesubstitution.at the methyl group, not at the aromatic ring, and that excess halogen leads to multiple substitution⌬ . CH H CH Br ReactionR ϩ Br ϩ HBr 2 2 2 CH2H CH2Br ⌬ ReactionR (Bromomethyl)- ϩ Br2 ϩ HBr benzene ⌬ ReactionR ϩ Br2 ϩ HBr (Bromomethyl)- CH3 CH2Cl CHCl2 CCl3 benzene (Bromomethyl)- benzene Cl2, hv Cl2, hv CH3 Cl2, hv CH2Cl CHCl2 CCl3 ϪHCl ϪHCl ϪHCl CH3 CH2Cl CHCl2 CCl3 Cl2, hv Cl2, hv Cl2, hv (Chloromethyl)- (Dichloromethyl)- (Trichloromethyl)- ϪHCl ϪHCl ϪHCl 4 benzene benzene benzene Cl2, hv Cl2, hv Cl2, hv (Chloromethyl)- (Dichloromethyl)- (Trichloromethyl)- ϪHCl ϪHCl ϪHCl Each substitution yields one molecule of hydrogen halide as a by-product. benzene benzene benzene As in the halogenation of alkanes (Sections 3-4 through(Chloromethyl)- 3-6) and the allylic halogena-(Dichloromethyl)- (Trichloromethyl)- tion of alkenes (Section 14-2), the mechanism of benzylicEach substitution halogenationbenzene yields proceeds one molecule through ofbenzene hydrogen halide as a by-product.benzene radical intermediates. Heat or light induces dissociationAs ofin the the halogenation halogen molecule of alkanes into (Sections 3-4 through 3-6) and the allylic halogenation of alkenes (Section 14-2), the mechanism of benzylic halogenation proceeds through atoms. One of them abstracts a benzylicEach substitution hydrogen, a reactionyields one giving molecule HX and of ahydrogen phenyl- halide as a by-product. methyl (benzyl) radical. This intermediate reacts withradical another intermediates. molecule of halogen Heat or to light give induces dissociation of the halogen molecule into As in the halogenation of alkanes (Sections 3-4 through 3-6) and the allylic halogena- the product, a (halomethyl)benzene, and another halogenatoms. One atom, of which them abstracts propagates a benzylic the hydrogen, a reaction giving HX and a phenyl- chain process. tion of alkenes methyl(Section (benzyl) 14-2), radical. the mechanism This intermediate of benzylic reacts halogenationwith another molecule proceeds of halogenthrough to give radical intermediates.the product, Heat a or (halomethyl)benzene, light induces dissociation and another of halogen the halogen atom, moleculewhich propagates into the atoms. One of chain them process. abstracts a benzylic hydrogen, a reaction giving HX and a phenylmethyl (benzyl) radical. This intermediate reacts with another molecule of halogen to give the product, a (halomethyl)benzene, and another halogen atom, which propagates the chain process. As in the halogenation of alkanes and the allylic halogenation of alkenes, the mechanism of benzylic halogenation proceeds through radical intermediates.

Heat or light induces dissociation of the halogen molecule into atoms. One of them abstracts a benzylic hydrogen, a reaction giving HX and a benzyl radical.

This intermediate reacts with another molecule22-1 Benzylicof halogen Resonanceto Stabilizationgive the product,CHAPTERa 22 981 (halomethyl)benzene, and another halogen atom, which propagates the chain process.

Mechanism of Benzylic Halogenation

⌬ or h␯ Initiation: #šXO#šXðð 2ð#šXj Mechanism

CH2OH jCH2 CH2X Remember: Single-headed Xj XOX (“! shhook”) arrows denote Propagation: ϩ Xj ϪHX the movement of single electrons. Phenylmethyl (benzyl) radical 5

What explains the ease of benzylic halogenation? The answer lies in the stabilization of the phenylmethyl (benzyl) radical by the phenomenon called benzylic resonance (Figure 22-1). As a consequence, the benzylic C–H bond is relatively weak (DH8 5 87 kcal mol21, 364 kJ mol21); its cleavage is relatively favorable and proceeds with a low activation energy. Inspection of the resonance structures in Figure 22-1 reveals why the halogen attacks only the benzylic position and not an aromatic carbon: Reaction at any but the benzylic carbon would destroy the aromatic character of the benzene ring.

δ Figure 22-1 The benzene ␲ system of the phenylmethyl CH2 CH2 CH2 CH2 CH2 (benzyl) radical enters into δ δ resonance with the adjacent or radical center. The extent of delocalization may be depicted by (A) resonance structures, δ (B) dotted lines, or (C) orbitals. A B

H C H

Exercise 22-1 For each of the following compounds, draw the structure and indicate where radical halogenation is most likely to occur upon heating in the presence of Br 2. Then rank the compounds in approximate descending order of reactivity under bromination conditions. (a) Ethylbenzene; (b) 1,2-diphenylethane; (c) 1,3-diphenylpropane; (d) diphenylmethane; (e) (1-methylethyl)benzene.

Benzylic cations delocalize the positive charge Reminiscent of the effects encountered in the corresponding allylic systems (Section 14-3), benzylic resonance can affect strongly the reactivity of benzylic halides and sulfonates in nucleophilic displacements. For example, the 4-methylbenzenesulfonate (tosylate) of 4-methoxyphenylmethanol (4-methoxybenzyl alcohol) reacts with solvent ethanol rapidly via an SN1 mechanism. This reaction is an example of solvolysis, speci! cally ethanolysis, which we described in Chapter 7. 22-1 Benzylic Resonance Stabilization CHAPTER 22 981

Mechanism of Benzylic Halogenation

⌬ or h␯ Initiation: #šXO#šXðð 2ð#šXj Mechanism 22-1 Benzylic Resonance Stabilization CHAPTER 22 981

CH2OH jCH2 CH2X Mechanism of Benzylic Halogenation Remember: Single-headed Xj XOX (“! shhook”) arrows denote Propagation: ϩ Xj ϪHX the movement of single ⌬ or h␯ Initiation: šXOšXðð 2ðšXj electrons. # # # MechanismPhenylmethyl (benzyl) radical

CH OH jCH CH X 2 2 What explains2 the ease of benzylic halogenation? The answer lies in the stabilization of the phenylmethyl (benzyl) radical by theRemember: phenomenon Single-headed called benzylic resonance (Figure 22-1). Xj XAsOX a consequence, the benzylic C–H(“! shhook”) bond is arrows relatively denote weak (DH8 5 87 kcal mol21, Propagation: ϩ Xj the movement of single ϪHX 364 kJ mol21); its cleavage is relatively favorable and proceeds with a low activation energy. What explains the ease of benzylic halogenation? electrons. Phenylmethyl (benzyl) Inspection of the resonance structures in Figure 22-1 reveals why the halogen attacks radical only the benzylic position and not an aromatic carbon: Reaction at any but the benzylic The answer lies in the stabilization of the benzylcarbon radicalwould destroyby the the phenomenonaromatic charactercalled of the benzenebenzylic ring. resonance. As a consequence, the benzylic C–H bond is relatively weak (DHo = 87 kcal mol- What explains the ease of benzylic halogenation? The answer lies in the stabilization of 1 -1 the phenylmethyl, 364 kJ (benzyl)mol radical); its bycleavage the phenomenonis relatively called benzylicfavorable resonance and(Figureproceeds 22-1). with a low activation δ Figure 22-1 The benzene energy. 21 ␲ system of the phenylmethyl As a consequence, the benzylic C–H bond is relatively weak (DH8 5C H872 kcal mol CH, 2 CH2 CH2 CH2 364 kJ mol21); its cleavage is relatively favorable and proceeds with a low activation energy. (benzyl) radical enters into δ δ resonance with the adjacent InspectionInspection of theof resonancethe resonance structures instructures Figure 22-1 reveals reveals whywhy the the halogenhalogen attacks attacks only the benzylic or radical center. The extent of only theposition benzylicand positionnot andan aromatic not an aromaticcarbon carbon:: Reaction Reaction at at anyany butbut thethe benzylicbenzylic carbon would destroy delocalization may be depicted carbon would destroy the aromatic character of the benzene ring. by (A) resonance structures, the aromatic character of the benzene ring. δ (B) dotted lines, or (C) orbitals. A B

δ Figure 22-1 The benzene ␲ system of the phenylmethyl CH2 CH2 CH2 CH2 CH2 (benzyl) radical enters into resonance with the adjacent or δ δ H radical center. The extentC of delocalization may be depictedH by (A) resonance structures, δ (B) dotted lines, or (C) orbitals. A B C

6 Exercise 22-1 H C For each of the following compounds, draw the structure and indicate where radical H halogenation is most likely to occur upon heating in the presence of Br 2. Then rank the compounds in approximate descending order of reactivity under bromination conditions. C (a) Ethylbenzene; (b) 1,2-diphenylethane; (c) 1,3-diphenylpropane; (d) diphenylmethane; (e) (1-methylethyl)benzene.

Exercise 22-1 Benzylic cations delocalize the positive charge For each of the following compounds, draw the structure and indicate where radical Reminiscent of the effects encountered in the corresponding allylic systems (Section 14-3), halogenation is most likely to occur upon heating in the presence of Br 2. Then rank the compounds in approximate descending order of reactivity underbenzylic bromination resonance conditions. can affect strongly the reactivity of benzylic halides and sulfonates (a) Ethylbenzene; (b) 1,2-diphenylethane; (c) 1,3-diphenylpropane;in nucleophilic (d) diphenylmethane; displacements. For example, the 4-methylbenzenesulfonate (tosylate) of (e) (1-methylethyl)benzene. 4-methoxyphenylmethanol (4-methoxybenzyl alcohol) reacts with solvent ethanol rapidly via an SN1 mechanism. This reaction is an example of solvolysis, speci! cally ethanolysis, which we described in Chapter 7. Benzylic cations delocalize the positive charge Reminiscent of the effects encountered in the corresponding allylic systems (Section 14-3), benzylic resonance can affect strongly the reactivity of benzylic halides and sulfonates in nucleophilic displacements. For example, the 4-methylbenzenesulfonate (tosylate) of 4-methoxyphenylmethanol (4-methoxybenzyl alcohol) reacts with solvent ethanol rapidly via an SN1 mechanism. This reaction is an example of solvolysis, speci! cally ethanolysis, which we described in Chapter 7. Benzylic resonance can affect strongly the reactivity of benzylic halides and sulfonates in nucleophilic displacements.

For example, the 4-methylbenzenesulfonate (tosylate) of 4-methoxyphenylmethanol (4-

methoxybenzyl alcohol) reacts with solvent ethanol rapidly via an SN1 mechanism. 982 CHAPTER 22 Chemistry of Benzene Substituents This reaction is an example of solvolysis, specifically ethanolysis.

982 CHAPTER 22 OChemistry of Benzene Substituents The delocalization Bof the positive charge of the benzylic cation through the benzene ring, SN1 CHallows3OCfor relativelyH2OSfacile dissociationCH3 ϩof theCH3startingCH2OH sulfonate. B Ethanolysis O O B (4-Methoxyphenyl)methyl SN1 CH OC4-methylbenzenesulfonateH OS CH ϩ CH CH OH 3 2 3 3 2 Ethanolysis (A primary benzylic tosylate)B O ReactionR (4-Methoxyphenyl)methyl 4-methylbenzenesulfonate CH OCH OCH CH ϩ HO S CH (A primary benzylic tosylate) 3 2 2 3 3 3

ReactionR 1-(Ethoxymethyl)-4-methoxybenzene 7 CH3OCH2OCH2CH3 ϩ HO3S CH3 The reason is the delocalization of the positive charge of the benzylic cation through the 1-(Ethoxymethyl)-4-methoxybenzene benzene ring, allowing for relatively facile dissociation of the starting sulfonate. Mechanism MechanismThe reason of isBenzylic the delocalization Unimolecular of the Nucleophilic positive charge Substitution of the benzylic cation through the benzene ring, allowing for relatively facile dissociation of the starting sulfonate.

MechanismCH3šO CH2OL " MechanismϪLϪ of Benzylic Unimolecular Nucleophilic Substitution

ϩ CH3šO CH2OL C"H2 CH2 ϪLϪ CH2 CH2 CH2

ϩ ϩ CH CH OH ϩ 3 2 product CH2 CH2 CH2 CH2 CH2 ϩ ϩ ϩ ϩ CH3CH2OH CH3"Oð CH3"Oð CH3"Oð CH3"O CH3"Oð product

ϩ Octet form Benzylic cation ϩ CH3"Oð CH3"Oð CH3"Oð CH3"O CH3"Oð Animation Octet form Several benzylic cations are stable enough to be isolable. For example, the X-ray struc- Benzylic cation 2 ANIMATED MECHANISM: ture of the 2-phenyl-2-propyl cation (as its SbF6 salt) was obtained in 1997 and shows Benzylic nucleophilicAnimation the phenyl–C bond (1.41 Å) to be intermediate in length between those of pure single substitution (1.54Several Å) and benzylic double cations bonds are(1.33 stable Å), enoughin addition to be to isolable.the expected For example, planar framework the X-ray andstruc- 2 2 ANIMATED MECHANISM: trigonalture of arrangement the 2-phenyl-2-propyl of all sp cationcarbons (as (Figure its SbF 622-2), salt) aswas expected obtained for in 1997a delocalized and shows Benzylic nucleophilic benzylicthe phenyl–C system. bond (1.41 Å) to be intermediate in length between those of pure single substitution (1.54 Å) and double bonds (1.33 Å), in addition to the expected planar framework and trigonal arrangement of all sp2 carbons (Figure 22-2), as expected for a delocalized benzylic system. Exercise 22-2 Which one of the two chlorides will solvolyze more rapidly: (1-chloroethyl)benzene, C6H5CHCl, or chloro(diphenyl)methane, (C6H5)2CHCl? Explain your answer. Exercise A 22-2 CH Which3 one of the two chlorides will solvolyze more rapidly: (1-chloroethyl)benzene, C6H5CHCl, or chloro(diphenyl)methane, (C6H5)2CHCl? Explain your answer. A CH3 H C + The above S 1 reaction is facilitated by the presence of the para methoxy substituent, 3 123° 122° N which allows for extra stabilization of the positive charge. In the absence of this substituent, 114° 116° 1.41 Å SN2 processes may dominate. Thus, the parent phenylmethyl (benzyl) halides and sulfonates H C 1.40 Å + The above S 1 reaction is facilitated by the presence of the para methoxy substituent, H3C 3 123° 122° undergo preferentialN and unusually rapid SN2 displacements, even under solvolytic condi- 1.48 Å 1.43 Å 1.37 Å tions,which and allows particularly for extra in stabilization the presence of ofthe good positive nucleophiles. charge. In Asthe absence in allylic of S this2 reactionssubstituent, 114° 116° N 1.41 Å S 2 processes may dominate. Thus, the parent phenylmethyl (benzyl) halides and sulfonates Figure 22-2 Structure of the (SectionN 14-3), two factors contribute to this acceleration. One is that the benzylic carbon 1.40 Å 2 2-phenyl-2-propylH3C cation. is madeundergo relatively preferential more and electrophilic unusually rapidby the SN neighboring2 displacements, sp -hybridized even under phenyl solvolytic carbon condi- 1.48 Å 1.43 Å 1.37 Å tions, and particularly in the presence of good nucleophiles. As in allylic SN2 reactions Figure 22-2 Structure of the (Section 14-3), two factors contribute to this acceleration. One is that the benzylic carbon 2-phenyl-2-propyl cation. is made relatively more electrophilic by the neighboring sp2-hybridized phenyl carbon 982 CHAPTER 22 Chemistry of Benzene Substituents

O B SN1 CH3OCH2OS CH3 ϩ CH3CH2OH B Ethanolysis O (4-Methoxyphenyl)methyl 4-methylbenzenesulfonate (A primary benzylic tosylate) ReactionR

CH3OCH2OCH2CH3 ϩ HO3S CH3

1-(Ethoxymethyl)-4-methoxybenzene

The reason is the delocalization of the positive charge of the benzylic cation through the benzene ring, allowing for relatively facile dissociation of the starting sulfonate. Mechanism Mechanism of Benzylic Unimolecular Nucleophilic Substitution

CH3šO CH2OL " ϪLϪ

ϩ CH2 CH2 CH2 CH2 CH2

ϩ ϩ CH CH OH 3 2 product

ϩ ϩ CH3"Oð CH3"Oð CH3"Oð CH3"O CH3"Oð Octet form Benzylic cation

AnimationThe above SN1 reaction is facilitated by the presence of the para methoxy substituent, which Several benzylic cations are stable enough to be isolable. For example, the X-ray struc- allows for extra stabilization of the positive charge. 2 ANIMATED MECHANISM: ture of the 2-phenyl-2-propyl cation (as its SbF6 salt) was obtained in 1997 and shows Benzylic nucleophilic the phenyl–C bond (1.41 Å) to be intermediate in length between those of pure single substitution In the absence of this(1.54substituent, Å) and doubleS bondsN2 processes (1.33 Å), in mayadditiondominate to the expected. Thus, planarthe frameworkparent benzyland 2 halides and sulfonatestrigonalundergo arrangementpreferential of all sp andcarbonsunusually (Figure 22-2),rapid asS expectedN2 displacements, for a delocalizedeven under solvolytic conditions,benzylic system.and particularly in the presence of good nucleophiles. 8

Exercise 22-2 Which one of the two chlorides will solvolyze more rapidly: (1-chloroethyl)benzene, C6H5CHCl, or chloro(diphenyl)methane, (C6H5)2CHCl? Explain your answer. A CH3

H C + The above S 1 reaction is facilitated by the presence of the para methoxy substituent, 3 123° 122° N which allows for extra stabilization of the positive charge. In the absence of this substituent, 114° 116° 1.41 Å SN2 processes may dominate. Thus, the parent phenylmethyl (benzyl) halides and sulfonates 1.40 Å H3C undergo preferential and unusually rapid SN2 displacements, even under solvolytic condi- 1.48 Å 1.43 Å 1.37 Å tions, and particularly in the presence of good nucleophiles. As in allylic SN2 reactions Figure 22-2 Structure of the (Section 14-3), two factors contribute to this acceleration. One is that the benzylic carbon 2-phenyl-2-propyl cation. is made relatively more electrophilic by the neighboring sp2-hybridized phenyl carbon 982 CHAPTER 22 Chemistry of Benzene Substituents

O B SN1 CH3OCH2OS CH3 ϩ CH3CH2OH B Ethanolysis O (4-Methoxyphenyl)methyl 4-methylbenzenesulfonate (A primary benzylic tosylate) ReactionR

CH3OCH2OCH2CH3 ϩ HO3S CH3

1-(Ethoxymethyl)-4-methoxybenzene

CH3šO CH2OL " ϪLϪ

ϩ CH2 CH2 CH2 CH2 CH2

ϩ ϩ CH CH OH 3 2 product

ϩ ϩ CH3"Oð CH3"Oð CH3"Oð CH3"O CH3"Oð Octet form Benzylic cation Animation Several benzylic cations are stable enough to be isolable. For example, the X-ray struc- 2 ANIMATED MECHANISM: ture of the 2-phenyl-2-propyl cation (as its SbF6 salt) was obtained in 1997 and shows Benzylic nucleophilic the phenyl–C bond (1.41 Å) to be intermediate in length between those of pure single substitution (1.54 Å) and double bonds (1.33 Å), in addition to the expected planar framework and trigonal arrangement of all sp2 carbons (Figure 22-2), as expected for a delocalized benzylic system.

Several benzylic cations are stable enough to be isolable. Exercise 22-2 For example, the X-ray structure of the 2-phenyl-2-propyl cation (as its SbF - salt) was Which one 6 of the two chlorides will solvolyze more rapidly: (1-chloroethyl)benzene, obtained in 1997 and shows the phenyl–C bond (1.41 Å) to be intermediate in length C6H5CHCl, or chloro(diphenyl)methane, (C6H5)2CHCl? Explain your answer. between those of pure single (1.54 Å) and double bonds (1.33 Å ), inA addition to the expected planar framework and trigonal arrangement of all sp2 carbons, CHas3 expected for a delocalized benzylic system.

9 22-1 Benzylic Resonance Stabilization CHAPTER 22 983

Figure 22-3 The benzene X␦ − ‡ As in allylic SN2 reactions, two factors contribute to this acceleration. ␲ system overlaps with the orbitals of the SN2 transition state at a benzylic center. As a result, (1) benzylic carbon is made relatively more electrophilic byH the neighboring sp2-hybridizedthe transition state is stabilized, phenyl carbon (as opposed to sp3-hybridized ones). C thereby lowering the activation barrier toward S 2 reactions 22-1 Benzylic ResonanceH Stabilization CHAPTER 22 983 N of (halomethyl)benzenes. (2) stabilization of the SN2 transition state by overlap with the benzene � system. ␦ − Nu The benzene ␦ − ‡ Figure 22-3 X ␲ system overlaps with the orbitals of the SN2 transition state at a benzylic center. As a result, H the transition state is stabilized, 3 C thereby lowering the activation (as opposed to sp -hybridized ones; Section 13-2). TheH second is stabilization ofbarrier the toward SN2 SN2 reactions transition state by overlap with the benzene ␲ system (Figure 22-3). of (halomethyl)benzenes. Nu␦ −

CH2Br CH2CN (as opposed to sp3-hybridized ones; Section 13-2). The second is stabilization of the S 2 SN2 N transition state by overlap withϩ theϪ CNbenzene ␲ system (Figure 22-3). ϩ BrϪ Animation ANIMATED MECHANISM: CH2Br CH81%2CN S 2 Ϫ N Ϫ Animation Benzylic nucleophilic (Bromomethyl)benzene ϩ CN Phenylethanenitrileϩ Br substitution (Benzyl bromide) (Phenylacetonitrile) ANIMATED MECHANISM: 81% ( 100 times faster than SN2 reactions of primary bromoalkanes) Benzylic nucleophilic (Bromomethyl)benzene Phenylethanenitrile substitution 10 (Benzyl bromide) (Phenylacetonitrile)

( 100 times faster than SN2 reactions of primary bromoalkanes)

Exercise 22-3 Exercise 22-3 PhenylmethanolPhenylmethanol (benzyl (benzyl alcohol) alcohol) is convertedis converted into into (chloromethyl)benzene (chloromethyl)benzene in the presence in theof presence of hydrogen chloridehydrogen muchchloride moremuch more rapidly rapidly than than ethanol is convertedis converted into chloroethane. into chloroethane. Explain. Explain.

Phenylmethyl (benzyl) cation Resonance in benzylic anions makes benzylic hydrogens Phenylmethyl (benzyl) relatively acidic cation ResonanceA negative in benzylic charge adjacent anions to a benzene makes ring, as in the benzylic phenylmethyl (benzyl)hydrogens anion, is relativelystabilized acidic by conjugation in much the same way that the corresponding radical and cation are stabilized. The electrostatic potential maps of the three species (rendered in the margin A negative at charge an attenuated adjacent scale for to optimum a benzene contrast) ring, show asthe indelocalized the phenylmethyl positive (blue) and (benzyl) neg- anion, is stabilized byative conjugation (red) charges in in themuch cation the and same anion, way respectively, that the in additioncorresponding to the delocalized radical and cation are stabilized.electron The (yellow) electrostatic in the neutral potential radical. maps of the three species (rendered in the margin at an attenuated scale for optimum contrast) show the delocalized positive (blue) and neg- Resonance in Benzylic Anions ative (red) charges in the cation and anion, respectively, in addition to the delocalizedPhenylmethyl (benzyl) Ϫ radical electron (yellow)CH3 in the neutralðCH2 radical. CH2 CH2 CH2

Ϫ Ϫ k k ϩ Hϩ " Resonance in BenzylicϪ Anions pKa 41 Phenylmethyl (benzyl) Ϫ radical CH3 ðCH2 CH2 CH2 CH2

The acidity of methylbenzene (toluene; pKa Ϸ 41) is therefore considerably greater than that of ethane (pKa Ϸ 50) and comparableϪ to that of propene (pKa Ϸ 40), which is de- Ϫ protonated to produce the resonance-stabilizedk 2-propenyl (allyl) anion (Section 14-4). k ϩ Hϩ Consequently, methylbenzene (toluene) can be deprotonated by butyllithium to generate Phenylmethyl (benzyl) " anion phenylmethyllithium. Ϫ

pKa 41

The acidity of methylbenzene (toluene; pKa Ϸ 41) is therefore considerably greater than that of ethane (pKa Ϸ 50) and comparable to that of propene (pKa Ϸ 40), which is deprotonated to produce the resonance-stabilized 2-propenyl (allyl) anion (Section 14-4). Consequently, methylbenzene (toluene) can be deprotonated by butyllithium to generate Phenylmethyl (benzyl) phenylmethyllithium. anion 22-1 Benzylic Resonance Stabilization CHAPTER 22 983

The benzene ␦ − ‡ Figure 22-3 X ␲ system overlaps with the orbitals of the SN2 transition state at a benzylic center. As a result, H the transition state is stabilized, C thereby lowering the activation H barrier toward SN2 reactions of (halomethyl)benzenes.

Nu␦ −

3 (as opposed to sp -hybridized ones; Section 13-2). The second is stabilization of the SN2 transition state by overlap with the benzene ␲ system (Figure 22-3).

CH2Br CH2CN S 2 ϩ ϪCN N ϩ BrϪ Animation ANIMATED MECHANISM: 81% Benzylic nucleophilic (Bromomethyl)benzene Phenylethanenitrile substitution (Benzyl bromide) (Phenylacetonitrile)

( 100 times faster than SN2 reactions of primary bromoalkanes)

Exercise 22-3 Phenylmethanol (benzyl alcohol) is converted into (chloromethyl)benzene in the presence of hydrogen chloride much more rapidly than ethanol is converted into chloroethane. Explain.

Phenylmethyl (benzyl) Resonance in benzylic anions makes benzylic hydrogens cation relatively acidic ResonanceA negativein benzylic charge adjacentanions tomakes a benzenebenzylic ring, as inhydrogens the phenylmethylrelatively (benzyl)acidic anion, is stabilized by conjugation in much the same way that the corresponding radical and cation A negativeare stabilized.charge adjacentThe electrostaticto a potentialbenzene mapsring, of theas threein speciesthe benzyl(renderedanion, in the marginis stabilized by conjugationat an. attenuated scale for optimum contrast) show the delocalized positive (blue) and negative (red) charges in the cation and anion, respectively, in addition to the delocalized The acidityelectronof methylbenzene (yellow) in the neutral(toluene radical.; pKa ≈ 41) is considerably greater than that of ethane (pKa ≈ 50) and comparable to that of propene (pKa ≈ 40).

Toluene can be deprotonated by butyllithiumResonance in toBenzylicgenerate Anionsphenylmethyllithium. Phenylmethyl (benzyl) Ϫ radical CH3 ðCH2 CH2 CH2 CH2

Ϫ Ϫ 984 CHAPTER 22 Chemistry of Benzenek Substituents k ϩ Hϩ " Ϫ pK 41 a Deprotonation of Methylbenzene

CH3 CH2Li The acidity of methylbenzene (toluene; pKa Ϸ 41) is therefore considerably greater than that of ethane (pK 50) and comparable(CH3)2NCH2CH2N(CH to 3)that2, THF, of ⌬ propene (pK 40), which is de- ϩ CH CH aCHϷ CH Li a Ϸ ϩ CH CH CH CH H protonated to 3 produce2 2 the2 resonance-stabilized 2-propenyl (allyl) anion (Section 14-4).3 2 2 2 Consequently, methylbenzene (toluene) can be deprotonated by butyllithium to generate Phenylmethyl (benzyl) Methylbenzene Phenylmethyllithium 11 anion (Toluene)phenylmethyllithium. (Benzyllithium)

Exercise 22-4 Which molecule in each of the following pairs is more reactive with the indicated reagents, and why?

(a) (C6H5)2CH2 or C6H5CH3, with CH3CH2CH2CH2Li

CH2Br CH2Cl

(b) or , with NaOCH3 in CH3OH

OCH3 OCH3

CH3CHOH CH3CHOH

OH Reagents such as hot KMnO4 and Na2Cr2O7 may oxidize alkylbenzenes all the way to benzoic acids. Benzylic carbon–carbon bonds are cleaved in this process, which usually requires at least one benzylic C–H bond to be present in the starting material (i.e., tertiary O alkylbenzenes are inert).

Complete Benzylic Oxidations of Alkyl Chains

Benzylic Ϫ CH2CH2CH2CH3 1. KMnO4, HO , ⌬ COOH hydroxylation ϩ 2. H , H2O HO H Ϫ3 CO2 H C HOOC H 3 OCH3 80% Metoprolol 1-Butyl-4-methylbenzene 1,4-Benzenedicarboxylic acid (Terephthalic acid) 22-2 BENZYLIC OXIDATIONS AND REDUCTIONS

Because it is aromatic, the benzene ring is quite unreactive. While it does undergo electrophilic aromatic substitutions, reactions that dismantle the aromatic six-electron circuit, such as oxidations and reductions, are much more difficult to achieve.

In contrast, such transformations occur with comparative ease when taking place at benzylic positions.

Oxidation of alkyl-substituted benzenes leads to aromatic ketones and acids

Reagents such as hot KMnO4 and Na2Cr2O7 may oxidize alkylbenzenes all the way to benzoic acids.

Benzylic carbon–carbon bonds are cleaved in this process, which usually requires at least one benzylic C–H bond to be present in the starting material (i.e., tertiary alkylbenzenes are inert).

12 984 CHAPTER 22 Chemistry of Benzene Substituents

Deprotonation of Methylbenzene

CH3 CH2Li

(CH3)2NCH2CH2N(CH3)2, THF, ⌬ ϩ CH3CH2CH2CH2Li ϩ CH3CH2CH2CH2H

Methylbenzene Phenylmethyllithium (Toluene) (Benzyllithium)

Exercise 22-4 Which molecule in each of the following pairs is more reactive with the indicated reagents, and why?

(a) (C6H5)2CH2 or C6H5CH3, with CH3CH2CH2CH2Li

CH2Br CH2Cl

(b) or , with NaOCH3 in CH3OH

OCH3 OCH3

CH3CHOH CH3CHOH

Benzylic Metabolism NO2 of Drugs The lability of benzylic bonds makes them easy targets In Summary Benzylic radicals, cations, and anions are stabilized by resonance with the of drug metabolism. For benzene ring. This effect allows for relatively easy radical halogenations, SN1 and SN2 example, the antihypertensive reactions, and benzylic anion formation. metoprolol (Lopressor) works by blocking receptors for adrenaline in the heart 22-2 BENZYLIC OXIDATIONS AND REDUCTIONS muscles and other tissues. The ! rst step of its degradation in the body features cytochrome Because it is aromatic, the benzene ring is quite unreactive. While it does undergo electrophilic enzymes (see Real Life 8-1 aromatic substitutions (Chapters 15 and 16), reactions that dismantle the aromatic six-electron and Section 22-9), which circuit, such as oxidations and reductions, are much more dif! cult to achieve. In contrast, such hydroxylate the benzylic transformations occur with comparative ease when taking place at benzylic positions. This sec- positions. tion describes how certain reagents oxidize and reduce alkyl substituents on the benzene ring. Oxidation of alkyl-substituted benzenes leads to aromatic NH ketones and acids 22-2 Benzylic Oxidations and Reductions CHAPTER 22 985 OH Reagents such as hot KMnO4 and Na2Cr2O7 may oxidize alkylbenzenes all the way to benzoic acids. Benzylic carbon–carbon bonds are cleaved in this process, which usually requires atThe least reaction one benzylic proceeds C–Hthrough bond ! rst to the be benzylic present alcohol in the andstarting then materialthe ketone, (i.e., at which tertiary stage O alkylbenzenesit can are be inert).stopped under milder conditions (see margin and Section 16-5). The special reactivity of the benzylic position is also seen in the mild conditions required for the oxidationComplete of benzylic Benzylic alcohols Oxidations to the corresponding of Alkyl Chainscarbonyl compounds. For example, 1,2,3,4-Tetra- manganese dioxide, MnO , performs this oxidation selectively in the presence of other hydronaphthalene Benzylic 2 Ϫ CH2CH2CH2CH3 1. KMnO4, HO , ⌬ COOH (Tetralin) hydroxylation (nonbenzylic) hydroxy groups. (Recallϩ that MnO2 was used in the conversion of allylic 2. H , H2O HO H alcohols into ␣,␤-unsaturated aldehydes and ketones; see Section 17-4.) Ϫ3 CO2 CrO3, CH3COOH, H C HOOC H2O, 21°C H 3 OCH Selective Oxidation of a Benzylic Alcohol with Manganese80% Dioxide 3 OH Metoprolol 1-Butyl-4-methylbenzeneOHH 1,4-BenzenedicarboxylicO acid (Terephthalic acid) CH3O CH3O OH MnO2, acetone, 25°C, 5 h OH

CH3O CH3O Not isolated The reaction proceeds through first the benzylic alcohol94% and then the ketone, at which stage it can be stopped under milder conditions. Benzylic ethers are cleaved by hydrogenolysis O Exposure of benzylic alcohols, ethers, or esters to hydrogen in the presence of metal catalysts results in rupture of the reactive benzylic carbon–oxygen bond. This transformation is an example of hydrogenolysis, cleavage of a ␴ bond by catalytically activated hydrogen.

71% Cleavage of Benzylic Ethers by Hydrogenolysis 1-Oxo-1,2,3,4-tetrahydro- naphthalene (1-Tetralone) 13 CH2 CH2H OR H2, Pd–C, 25°C ϩ HOR

Exercise 22-5 Write synthetic schemes that would connect the following starting materials with their products.

CH2CH3 CH3 (a)

O O H3C CH3 (b) O O

H3C CH3 O O

O O (c) O Cl

Hydrogenolysis is not possible for ordinary alcohols, ethers, and esters. Therefore, the phenylmethyl (benzyl) substituent is a valuable protecting group for hydroxy functions. The following scheme shows its use in part of a synthesis of a compound in the eudesmane class of volatile plant oils, which includes substances of importance in both medicine and perfumery. 22-2 Benzylic Oxidations and Reductions CHAPTER 22 985 The special reactivity of the benzylic position is also seen in the mild conditions required for the oxidation of benzylic alcohols to the corresponding carbonyl compounds. The reaction proceeds through ! rst the benzylic alcohol and then the ketone, at which stage it can be stopped under milder conditions (see margin and Section 16-5). For example,Themanganese special reactivity dioxide,of the benzylicMnO position2, performsis also seen in thisthe mildoxidation conditions requiredselectively in the for the oxidation of benzylic alcohols to the corresponding carbonyl compounds. For example, 1,2,3,4-Tetra- presence of other (nonbenzylic) hydroxy groups. (Recall that MnO2 was used in the manganese dioxide, MnO2, performs this oxidation selectively in the presence of other hydronaphthalene conversion of allylic alcohols into �,�-unsaturated aldehydes and ketones.) (Tetralin) (nonbenzylic) hydroxy groups. (Recall that MnO2 was used in the conversion of allylic alcohols into ␣,␤-unsaturated aldehydes and ketones; see Section 17-4.) CrO3, CH3COOH, H2O, 21°C Selective Oxidation of a Benzylic Alcohol with Manganese Dioxide OH OHH O

CH3O CH3O OH MnO2, acetone, 25°C, 5 h OH

CH3O CH3O Not isolated 94%

Benzylic ethers are cleaved by hydrogenolysis O Exposure of benzylic alcohols, ethers, or esters to hydrogen in the presence of metal catalysts results in rupture of the reactive benzylic carbon–oxygen bond. This transformation is an example of hydrogenolysis, cleavage of a ␴ bond by catalytically activated hydrogen. 14

71% Cleavage of Benzylic Ethers by Hydrogenolysis 1-Oxo-1,2,3,4-tetrahydro- naphthalene (1-Tetralone) CH2 CH2H OR H2, Pd–C, 25°C ϩ HOR

Exercise 22-5 Write synthetic schemes that would connect the following starting materials with their products.

CH2CH3 CH3 (a)

O O H3C CH3 (b) O O

H3C CH3 O O

O O (c) O Cl

The reaction proceeds through ! rst the benzylic alcohol and then the ketone, at which stage it can be stopped under milder conditions (see margin and Section 16-5). The special reactivity of the benzylic position is also seen in the mild conditions required for the oxidation of benzylic alcohols to the corresponding carbonyl compounds. For example, 1,2,3,4-Tetra- manganese dioxide, MnO2, performs this oxidation selectively in the presence of other hydronaphthalene (Tetralin) (nonbenzylic) hydroxy groups. (Recall that MnO2 was used in the conversion of allylic alcohols into ␣,␤-unsaturated aldehydes and ketones; see Section 17-4.) CrO3, CH3COOH, H2O, 21°C Selective Oxidation of a Benzylic Alcohol with Manganese Dioxide OH OHH O CH O CH O 3 OH 3 OH Benzylic ethers are cleaved by hydrogenolysisMnO2, acetone, 25°C, 5 h

CH O CH O Exposure of 3benzylic alcohols, ethers, or esters to hydrogen3 in the presence of metal Not isolated 94% catalysts results in rupture of the reactive benzylic carbon–oxygen bond. Benzylic ethers are cleaved by hydrogenolysis This transformation is an example of hydrogenolysis, cleavage of a � bond by catalytically O activated hydrogenExposure of. benzylic alcohols, ethers, or esters to hydrogen in the presence of metal catalysts results in rupture of the reactive benzylic carbon–oxygen bond. This transformation is an example of hydrogenolysis, cleavage of a ␴ bond by catalytically activated hydrogen. Hydrogenolysis is not possible for ordinary alcohols, ethers, and esters. Therefore, the benzyl substituent is a valuable protecting group for hydroxy functions. 71% Cleavage of Benzylic Ethers by Hydrogenolysis 1-Oxo-1,2,3,4-tetrahydro- naphthalene (1-Tetralone) CH2 CH2H OR H2, Pd–C, 25°C ϩ HOR

The following scheme shows its use in part of a synthesis of a compound in the eudesmane class of volatile plant oils, which includes substances of importance in both medicine and perfumery. Exercise 22-5 15 Write synthetic schemes that would connect the following starting materials with their products.

CH2CH3 CH3 (a)

O O H3C CH3 (b) O O

H3C CH3 O O

O O (c) O Cl

Phenylmethyl Protection in a Complex Synthesis

HO RO % CH3 % CH3 % 1. NaH, THF % CH3COOH, 2. C6H5CH2Br H2O O O Protection of OH O Deprotection O ≥ (Section 9-6) ≥ of carbonyl group (Section 17-8) O H O H O 80%

(C6H5CH2 ؍ R)

RO RO RO 1. BH3, THF % CH3 % CH3 % CH3 CH3CHP P(C6H5)3, 2. Oxidation (to alcohol)

% DMSO % 3. Oxidation (to ketone) % Wittig reaction Hydroboration–oxidation* % ≥ O (Section 17-12) ≥ CHCH (Section 12-8) ≥ COCH H H 3 Oxidation (Section 8-6) H 3 93% 94% 99% (Mixture of E and Z isomers)

RO HO 1. CH3Li, % CH3 % CH3 (CH3CH2)2O H2, Pd–C, ϩ % % 2. H , H2O CH3CH2OH

CH3 CH3 %

(Section 8-8) % A Deprotection A O ≥ of OR ≥ CCH3 CCH3 H H A A O OH OH 16 98% 98%

2 *While the literature reports the use of special oxidizing agents, in principle 2. H2O2, OH and 3. CrO3 would have been satisfactory.

Because the hydrogenolysis of the phenylmethyl (benzyl) ether in the ! nal step occurs under neutral conditions, the tertiary alcohol function survives untouched. A tertiary butyl ether would have been a worse choice as a protecting group, because cleavage of its carbon–oxygen bond would have required acid (Section 9-8), which may cause dehydration (Section 9-2). In Summary Benzylic oxidations of alkyl groups take place in the presence of permanga- nate or chromate; benzylic alcohols are converted into the corresponding ketones by manganese dioxide. The benzylic ether function can be cleaved by hydrogenolysis in a transformation that allows the phenylmethyl (benzyl) substituent to be used as a protecting group for the hydroxy function in alcohols.

22-3 NAMES AND PROPERTIES OF PHENOLS

Arenes substituted by hydroxy groups are called phenols (Section 15-1). The ␲ system of the benzene ring overlaps with an occupied p orbital on the oxygen atom, a situation resulting in delocalization similar to that found in benzylic anions (Section 22-1). As one result of this extended conjugation, phenols possess an unusual, enolic structure. Recall that enols are usually unstable: They tautomerize easily to the corresponding ketones because of the relatively strong carbonyl bond (Section 18-2). Phenols, however, prefer the enol to the keto form because the aromatic character of the benzene ring is preserved. 22-2 Benzylic Oxidations and Reductions CHAPTER 22 985

CH3O CH3O OH MnO2, acetone, 25°C, 5 h OH

CH3O CH3O Not isolated 94%

71% Cleavage of Benzylic Ethers by Hydrogenolysis 1-Oxo-1,2,3,4-tetrahydro- naphthalene (1-Tetralone) CH2 CH2H OR H2, Pd–C, 25°C ϩ HOR

Exercise 22-5 Exercise 22-5 Write synthetic schemes that would connect the following starting materials with their products. Write synthetic schemes that would connect the following starting materials with their products.

CH2CH3 CH3 (a)

O O H3C CH3 (b) O O

H3C CH3 O O

O O (c) O Cl

Hydrogenolysis is not possible for ordinary alcohols, ethers, and esters. Therefore, the phenylmethyl (benzyl) substituent is a valuable protecting group for hydroxy functions. The following scheme shows its use in part of a synthesis of a compound in the eudesmane class of volatile plant oils, which includes substances of importance in both medicine and perfumery. 22-3 NAMES AND PROPERTIES OF PHENOLS Arenes substituted by hydroxy groups are called phenols. The � system of the benzene ring overlaps with an occupied p orbital on the oxygen atom, a situation resulting in delocalization similar to that found in benzylic anions. As one result of this extended conjugation, phenols possess an unusual, enolic structure. Enols are usually unstable, and tautomerize22-3 Nameseasily and toPropertiesthe corresponding of Phenols ketonesCHAPTERbecause 22 of 987 the relatively strong carbonyl bond. Phenols prefer the enol to theKetoketo andform Enol becauseForms of Acetonethe aromatic and Phenolcharacter of the benzene ring is preserved. Oðð ðšOH H Ϫ9 H3C CH2 K ~ 10 H3C CH2 Acetone 2-Propenol

ððO ðOšH ðOHš ϩšOH ϩšOH ϩšOH H Ϫ Ϫ H ð ð K ~ 1013 šϪ 2,4-Cyclohexadienone Phenol 18

Exercise 22-6 Many naturally occurring phenols are derived from nonaromatic precursors through rearrange- ments driven by the aromaticity of the ! nal product. For example, carvone (see Real Life 5-1) undergoes an acid-catalyzed reorganization to carvacrol [2-methyl-5-(1-methylethyl)phenol], a component of the herbs oregano, thyme, and marjoram that contributes to their characteristic odor. Formulate a mechanism.

O OH

H2SO4, H2O

Carvone Carvacrol

Phenols and their ethers are ubiquitous in nature; some derivatives have medicinal and herbicidal applications, whereas others are important industrial materials. This section ! rst explains the names of these compounds. It then describes an important difference between phenols and alkanols—phenols are stronger acids because of the neighboring aromatic ring.

Phenols are hydroxyarenes Phenol itself was formerly known as carbolic acid. It forms colorless needles (m.p. 418C), OH has a characteristic odor, and is somewhat soluble in water. Aqueous solutions of it (or its methyl-substituted derivatives) are applied as disinfectants, but its main use is for the preparation of polymers (phenolic resins; Section 22-6). Pure phenol causes severe skin burns and is toxic; deaths have been reported from the ingestion of as little as 1 g. Fatal poisoning may also result from absorption through the skin. CCH CH Substituted phenols are named as phenols, benzenediols, or benzenetriols, according to 3 OO 3 the system described in Section 15-1, although some common names are accepted by IUPAC (Section 22-8). These substances ! nd uses in the photography, dyeing, and tanning industries. The compound bisphenol A (shown in the margin; see also Real Life 22-1) is an important monomer in the synthesis of epoxyresins and polycarbonates, materials that are widely employed in the manufacture of durable plastic materials, food packaging, dental OH sealants, and coatings inside beverage cans (Real Life 22-1). Bisphenol A Phenols and their ethers are ubiquitous in nature; some derivatives have medicinal and herbicidal applications, whereas others are important industrial materials.

Phenols are hydroxyarenes

Phenol itself was formerly known as carbolic acid. It forms colorless needles (m.p. 41 oC), has a characteristic odor, and is somewhat soluble in water.

Aqueous solutions of it (or its methyl-substituted derivatives) are applied as disinfectants, but its main use is for the preparation of polymers (phenolic resins).

Pure phenol causes severe skin burns and is toxic; deaths have been reported from the ingestion of as little as 1 g. Fatal poisoning may also result from absorption through the skin.

Substituted phenols are named as phenols, benzenediols, or benzenetriols, although some common names are accepted by IUPAC. These substances find uses in the photography, dyeing, and tanning industries.

19 22-3 Names and Properties of Phenols CHAPTER 22 987

Keto and Enol Forms of Acetone and Phenol

Oðð ðšOH H Ϫ9 H3C CH2 K ~ 10 H3C CH2 Acetone 2-Propenol

ððO ðOšH ðOHš ϩšOH ϩšOH ϩšOH H Ϫ Ϫ H ð ð K ~ 1013 šϪ 2,4-Cyclohexadienone Phenol

O OH

H2SO4, H2O

Carvone Carvacrol

ThePhenolscompound and their ethersbisphenol are ubiquitousA is an inimportant nature; somemonomer derivativesin havethe medicinalsynthesis of epoxyresins and andpolycarbonates, herbicidal applications,materials whereas othersthat areare importantwidely employedindustrial materials.in the Thismanufacture section of durable plastic ! rst explains the names of these compounds. It then describes an important difference betweenmaterials, phenolsfood and packaging, alkanols—phenolsdental are sealants, stronger acidsand becausecoatings of theinside neighboringbeverage cans. 988 CHAPTER 22 Chemistry of Benzene Substituents aromatic ring. Phenols containing the higher-ranking carboxylic acid functionality are called hydroxybenzoic acids. Many have common names. Phenyl ethers are named as alkoxybenzenes. PhenolsPhenols are hydroxyarenes containing the higher-ranking carboxylic acid functionality are called hydroxy- As a substituent, C6H5O is called phenoxy. Phenol benzoicitself was acids. formerly Many known have as common carbolic names. acid. It Phenyl forms etherscolorless are needles named as(m.p. alkoxybenzenes. 418C), OH has a characteristicAs a substituent, odor, C and6H5 Ois issomewhat called phenoxy. soluble in water. Aqueous solutions of it (or its methyl-substitutedOH derivatives)OH are applied as COOHdisinfectants, but its mainOH use is for the prep-OH aration of polymers (phenolic resins; Section 22-6). Pure phenol causes severe skin burns and is toxic; deaths have been reported from the ingestion of as little as 1 g. Fatal poison- OH ing may also result from absorption through the skin. CCH CH Substituted phenols are named as phenols, benzenediols, or benzenetriols, according to 3 OO 3 OH the system described in SectionNO 15-1,2 although some OHcommon names are accepted by IUPAC OH (SectionCH 22-8).3 These Clsubstances ! nd uses in the photography, dyeing,OH and tanning industries.4-Methyl Thephen compoundol bisphenol4-Chloro- A (shown 3- inHydroxy the margin;benz- see also1,4-Benzene Real Lifediol 22-1)1,2,3-Benzene is an triol (p-Cresol) 3-nitrophenol oic acid (Hydroquinone) (Pyrogallol) important monomer in the synthesis of( mepoxyresins-Hydroxybenzoic and acid) polycarbonates, materials that are widely employed in the manufacture of durable plastic materials, food packaging, dental OH sealants, andMany coatings examples inside ofbeverage phenol cans derivatives, (Real Life particularly 22-1). those exhibiting physiological Bisphenol A

activity, are depicted in this book (e.g., see Real Life 5-4, 9-1, 21-1, 22-1, and 22-2, and 20 Sections 4-7, 9-11, 15-1, 22-9, 24-12, 25-8, and 26-1). You are very likely to have ingested without knowing it the four phenol derivatives shown here. O

EO HO OH H3C N Resveratrol A H (Cancer chemopreventive HO from grapes; see also Real Life 22-1) Capsaicin (Active ingredient in hot pepper, as in jalapeño or cayenne pepper; see margin note on the next page) OH OH

HO O OH

~O HO OH O

OH HO O OH Epigallocatechin-3 gallate 4-(4-Hydroxyphenyl)-2-butanone (Cancer chemopreventive from green tea) (Flavor of raspberries) A raspberry. Green tea. Phenols are unusually acidic

Phenols have pKa values that range from 8 to 10. Even though they are less acidic than carboxylic acids (pKa 5 3–5), they are stronger than alkanols (pKa 5 16–18). The reason is resonance: The negative charge in the conjugate base, called the phenoxide ion, is stabilized by delocalization into the ring. Acidity of Phenol

ðšOH ððšO Ϫ ððO ððO ððO

Ϫ Ϫ Hϩ ϩ k k # Ϫ

pKa 10 Phenoxide ion 988 988 CHAPTER 22 Chemistry of BenzeneCHAPTER Substituents 22 Chemistry of Benzene Substituents

Phenols containing the higher-ranking carboxylic acid functionality are called hydroxy- Phenols containing the higher-ranking carboxylic acid functionality are called hydroxybenzoic acids. Many have common names. Phenyl ethers are named as alkoxybenzenes. benzoic acids. Many have common names. Phenyl ethers are named as alkoxybenzenes. As a substituent, C6H5O is called phenoxy. As a substituent, C6H5O is called phenoxy. OH OH COOH OH OH OH OH COOH OH OH OH OH

NO2 OH OH NO OH OH OH 2 CH3 Cl OH OH CH3 Cl 4-Methylphenol 4-ChloroOH- 3-Hydroxybenz- 1,4-Benzenediol 1,2,3-Benzenetriol 4-Methylphenol 4-Chloro- 3-Hydroxy(p-Cresol)benz- 3-1,4-Benzenenitrophenoldiol 1,2,3-Benzeneoic acid triol (Hydroquinone) (Pyrogallol) (m-Hydroxybenzoic acid) (p-Cresol) 3-nitrophenol oic acid (Hydroquinone) (Pyrogallol) (m-Hydroxybenzoic acid) 988 CHAPTER 22 Chemistry ofMany Benzene examples Substituents of phenol derivatives, particularly those exhibiting physiological Many examples of phenol derivatives,activity, particularly are depicted those in exhibiting this book (e.g., physiological see Real Life 5-4, 9-1, 21-1, 22-1, and 22-2, and activity, are depicted in this book (e.g., seeSections Real Life 4-7, 5-4, 9-11, 9-1, 15-1, 21-1, 22-9, 22-1, 24-12, and 25-8, 22-2, and and 26-1). You are very likely to have ingested Sections 4-7, 9-11, 15-1, 22-9, 24-12,Phenols 25-8,without andcontaining 26-1). knowing You the higher-rankingare it thevery four likely phenol carboxylicto have derivatives ingested acid shownfunctionality here. are called hydroxy- Many withoutexamples knowingof phenol it the fourderivatives, phenolbenzoic derivativesparticularly acids. Manyshown those have here. commonexhibiting names.physiological Phenyl ethersO activity are named. as alkoxybenzenes. As a substituent, C H O is called phenoxy. O 6 5 O HO OH E N OH OH H3C COOH OH OH ResveratrolO A HO OH E N H (CancerH3C chemopreventive HO OH Resveratrol from grapes; see also A Real Life 22-1) H Capsaicin (Cancer chemopreventive HO from grapes; see also (Active ingredient in hot pepper, Capsaicin as in jalapeño or cayenne pepper; see margin note on the next page) Real Life 22-1) NO2 OH OH (Active ingredient in hot pepper, OH OH as in jalapeño or CHcayenne3 pepper; see Clmargin note on the next page) OH 4-Methylphenol 4-Chloro- 3-Hydroxybenz- OH 1,4-Benzenediol 1,2,3-Benzenetriol (p-Cresol)OH 3-nitrophenol oic acid (Hydroquinone) (Pyrogallol) (m-Hydroxybenzoic acid) OH HO O Many examples of phenol derivatives, particularlyOH those exhibiting physiological HO O activity, are depicted in this book (e.g., see Real Life 5-4, 9-1, 21-1, 22-1, and 22-2, and ~O Sections 4-7,OH 9-11, 15-1, 22-9, 24-12, 25-8, and 26-1). You are very likely to have ingested without knowing it the fourHO phenol derivatives shown here.OH ~O O O HO OH O OH EO HO OH H3C N OH HO O A Resveratrol OH Epigallocatechin-3 gallate (Cancer chemopreventive H 4-(4-Hydroxyphenyl)-2-butanoneHO (Cancer chemopreventive from grapes; see also O OH from green tea) HO Real Life 22-1) (Flavor of raspberries) Capsaicin 21 A raspberry. Epigallocatechin-3 gallate Green tea. (Active ingredient in hot pepper, 4-(4-Hydroxyphenyl)-2-butanone (Cancer chemopreventive as in jalapeño or cayenne pepper; see margin note on the next page) from greenPhenols tea) are unusually acidic (Flavor of raspberries) A raspberry. Green tea. OH Phenols have pKa values that range from 8 to 10. Even though they are less acidic than carboxylic acids (pKa 5 3–5), theyOH are stronger than alkanols (pKa 5 16–18). The reason Phenols are unusually acidic is resonance: The negative charge in the conjugate base, called the phenoxide ion, is stabilized Phenols have pK values that range from 8 to 10. Even though they are less acidic than a HOby delocalizationO into the ring. carboxylic acids (pKa 5 3–5), they are stronger than alkanols (pKa 5 16–18).OH The reason is resonance: The negative charge in the conjugate base, called the phenoxide ion,Acidity is stabilized of Phenol by delocalization into the ring. ~O ðšOH ððšO Ϫ ððO ððO ððO Acidity of PhenolHO OH O Ϫ Ϫ Hϩ ϩ k k ðšOH ððšO Ϫ ððO ððO ððO OH # Ϫ pKa Ϫ 10 OH Ϫ Phenoxide ion ϩ HO O H ϩ k Epigallocatechin-3 gallate k # 4-(4-Hydroxyphenyl)-2-butanone (Cancer chemopreventive Ϫ from green tea) (Flavor of raspberries) Ap Kraspberry.a 10 Phenoxide ion Green tea. Phenols are unusually acidic

ðšOH ððšO Ϫ ððO ððO ððO

Ϫ Ϫ Hϩ ϩ k k # Ϫ

pKa 10 Phenoxide ion 988 CHAPTER 22 Chemistry of Benzene Substituents

Phenols containing the higher-ranking carboxylic acid functionality are called hydroxybenzoic acids. Many have common names. Phenyl ethers are named as alkoxybenzenes. As a substituent, C6H5O is called phenoxy. OH OH COOH OH OH OH

NO2 OH OH OH CH3 Cl OH 4-Methylphenol 4-Chloro- 3-Hydroxybenz- 1,4-Benzenediol 1,2,3-Benzenetriol (p-Cresol) 3-nitrophenol oic acid (Hydroquinone) (Pyrogallol) (m-Hydroxybenzoic acid)

Many examples of phenol derivatives, particularly those exhibiting physiological activity, are depicted in this book (e.g., see Real Life 5-4, 9-1, 21-1, 22-1, and 22-2, and Sections 4-7, 9-11, 15-1, 22-9, 24-12, 25-8, and 26-1). You are very likely to have ingested without knowing it the four phenol derivatives shown here. O

HO O OH

~O HO OH O

OH HO O OH Epigallocatechin-3 gallate Phenols 4-(4-Hydroxyphenyl)-2-butanoneare unusually acidic (Cancer chemopreventive from green tea) (Flavor of raspberries) A raspberry. Green tea. Phenols have pKa values that range from 8 to 10. Even though they are less acidic than carboxylicPhenolsacids (p Karea = unusually3–5), they areacidicstronger than alkanols (pKa = 16–18). Phenols have pKa values that range from 8 to 10. Even though they are less acidic than The reasoncarboxylicis resonance acids (pKa 5: 3–5),The theynegative are strongercharge than alkanolsin the (pKa conjugate5 16–18). Thebase, reason called the is resonance: The negative charge in the conjugate base, called the phenoxide ion, is stabilized phenoxide ion, is stabilized by delocalization into the ring. by delocalization into the ring. Acidity of Phenol

ðšOH ððšO Ϫ ððO ððO ððO

Ϫ Ϫ Hϩ ϩ k k # Ϫ

pKa 10 Phenoxide ion

The acidity of phenols is greatly affected by substituents that are capable of resonance. 4-

Nitrophenol (p-nitrophenol), for example, has a pKa of 7.15.

22 22-3 Names and Properties of Phenols CHAPTER 22 989

The acidity of phenols is greatly affected by substituents that are capable of resonance. 22-3 Names and Properties of Phenols CHAPTER 22 989 4-Nitrophenol (p-nitrophenol), for example, has a pKa of 7.15.

The acidity of phenols is greatly affected by substituents that are capable of resonance. 4-Nitrophenol (p-nitrophenol), for example, has a pKa of 7.15. ðšOH ððšO Ϫ ððO ððO ððO

Ϫ ϩ k Ϫ H ϩ etc. ðšOH ððšO ððO ððO ððO # Ϫ Nϩ Ϫ Nϩ Nϩ Nϩ Nϩ Hϩ ϩ# K H k # K H # K H # H etc. E H O Ok Ϫ O Ok Ϫ Ok Ϫ O Ok Ϫ Ϫ ýO Ok Ϫ # Â½ # Â½ # O Â½ # Â½ Â½ Â½ Ϫ # 7.15Nϩ Nϩ Nϩ Nϩ Negative charge ؍ Nϩ pKa # K H # K H # K H # H E H delocalized into the O Ok Ϫ O Ok Ϫ O Ok Ϫ O Ok Ϫ Ϫ ýO Ok Ϫ # Â½ # Â½ # Â½ # Â½ Â½ Â½ nitro group

Negative charge 7.15 ؍ pKa delocalized into the nitro group Some Like it Hot The 2-isomer has similarTheacidity 2-isomer( phasKa similar= 7.22 acidity), whereas (pKa 5 7.22),nitrosubstitution whereas nitrosubstitutionat C3 results at C3 resultsin a p Kin aa of 8.39. Multiple nitrationpKaincreases of 8.39. Multiplethe acidity nitrationto increasesthat of thecarboxylic acidity to thator even of carboxylicmineral or acids even mineral. acids. Electron-donating substituents have the opposite effect, raising Somethe p LikeK . it Hot The 2-isomer has similar acidity (pKa 5 7.22), whereas nitrosubstitution at C3 results in a a ElectronpKa of 8.39.-donating Multiple substituents nitration increaseshave the aciditythe opposite to that of carboxyliceffect, raising or even mineralthe p Ka. acids. Electron-donating substituents have the opposite effect, raising the pKa. Chili peppers use capsaicin The oxygen in phenol and its ethers is also weakly basic, in the case of ethers giving rise to (see also Problem 60) as a acid-catalyzed cleavage. OH OH ChiliO Hpeppers use capsaicin chemical deterrent against NO O N NO (see also Problem 60) as a herbivores, as well as certain OH OH 2 O2H 2 chemical deterrent against invading fungi. Its burning herbivores, as well as certain (to some, painful) sensation NO2 O2N NO2 invading fungi. Its burning is the result of the activation (to some, painful) sensation of a protein that is involved is the result of the activation NO2 NO2 CH3 in the transmission of pain, of a protein that is involved NO NO2,4-Dinitrophenol CH2,4,6-Trinitrophenol 4-Methylphenol speci! cally that caused by 2 2 3 (Picric acid) ( inp-Cresol) the transmission of pain, 2,4-Dinitrophenol 2,4,6-Trinitrophenol 4-Methylphenol speci! cally that caused by 23 excessive heat, strong acid, 10.26 ؍ pK 0.25 ؍ pK 4.09 ؍ pK (Picric acid) a ( p-Cresol) a excessivea heat, strong acid, or abrasion. Thus, capsaicin or abrasion. Thus, capsaicin “tricks” our neurons into 10.26 ؍ pKa 0.25 ؍ pKa 4.09 ؍ pKa “tricks” our neurons into sending a pain signal to the sending a pain signal to the brain, when in fact there As Section 22-5 will show, the oxygen in phenol and its ethers isbrain, also when weakly in fact basic, there in the is no tissue damage. Real As Section 22-5 will show, thecase oxygen of ethers in phenol giving and rise its to ethers acid-catalyzed is also weakly cleavage. basic, in the is no tissue damage. Real in" ammation can ensue, case of ethers giving rise to acid-catalyzed cleavage. in" ammation can ensue, however, due to secondary however, due to secondary chemical reactions, not unlike chemical reactions, not unlike the effect of prostaglandins the effect of prostaglandins (Real Life 11-1 and Section (Real Life 11-1 and Section 19-13). Remarkably, prolonged Exercise 22-7 Exercise 22-7 19-13). Remarkably, prolonged exposure to capsaicin exposure to capsaicin (a) Why is 3-nitrophenol (m-nitrophenol)(a) Why lessis 3-nitrophenol acidic than its (2-m -nitrophenol)and 4-isomers, lessbut moreacidic acidic than than its 2- and 4-isomers,desensitizes but themore pain acidic response than desensitizes the pain response phenol itself? phenol itself? by chemical “overload” of by chemical “overload” of (b) Rank in order of increasing(b) acidity: Rank phenol, in order A; of 3,4-dimethylphenol, increasing acidity: B; phenol, 3-hydroxybenzoic A; 3,4-dimethylphenol, our nerves B; 3-hydroxybenzoic (sort of like a our nerves (sort of like a (m-hydroxybenzoic) acid, C; 4-((m" uoromethyl)phenol-hydroxybenzoic) [acid,p-(" uoromethyl)phenol], C; 4-(" uoromethyl)phenol D. [p-(" uoromethyl)phenol],neuroelectrical short), D. leading neuroelectrical short), leading to an analgesic effect. The drug to an analgesic effect. The drug Qutenza is a high-potency Qutenza is a high-potency capsaicin (8%) topical patch capsaicin (8%) topical patch for treating pain associated for treating pain associated In Summary Phenols existIn in Summary the enol form Phenols because exist of in aromatic the enol stabilization. form because They of aromaticwith a shingles stabilization. infection. They with a shingles infection. are named according to are the rules named for according naming aromatic to the rulescompounds for naming explained aromatic in compoundsThe pain of shingles explained may last in The pain of shingles may last for years, and a 30-minute Section 15-1. Those derivatives bearing carboxy groups on the ring are called hydroxy- for years, and a 30-minute Section 15-1. Those derivatives bearing carboxy groups on theapplication ring are ofcalled the drug hydroxy- is said benzoic acids. Phenols are acidic because the corresponding anions are resonance application of the drug is said s t a b i l i z e d . benzoic acids. Phenols are acidic because the correspondingto bring anions relief up are to 3 resonance months. s t a b i l i z e d . to bring relief up to 3 months.