CHAPTER 23 ARYL HALIDES he value of alkyl halides as starting materials for the preparation of a variety of organic functional groups has been stressed many times. In our earlier discussions, we noted that ary! halides are normally much less reactive than alkyl halides in reactions that involve carbon-halogen bond cleavage. In the present chapter you will see that aryl halides can exhibit their own patterns of chemical reactivity, and that these reac- tions are novel, useful, and mechanistically interesting 23.1 BONDING IN ARYL HALIDES Aryl halides are compounds in which a halogen substituent is attached directly to an aro- matic ring. Representative aryl halides include -CHOH Fluorobenzene 1-chloro- 1-Bromonaphthalene P-lodobenzyl alcohol 2-nitrobenzene Halogen-containing organic compounds in which the halogen substituent is not directly bonded to an aromatic ring, even though an aromatic ring may be present, are not aryl halides. Benzyl chloride( C6HsCH2 Ci), for example, is not an aryl halide. The carbon-halogen bonds of aryl halides are both shorter and stronger than the carbon-halogen bonds of alkyl halides, and in this respect as well as in their chemical behavior, they resemble vinyl halides more than alkyl halides. A hybridization effect 917 Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
917 CHAPTER 23 ARYL HALIDES The value of alkyl halides as starting materials for the preparation of a variety of organic functional groups has been stressed many times. In our earlier discussions, we noted that aryl halides are normally much less reactive than alkyl halides in reactions that involve carbon–halogen bond cleavage. In the present chapter you will see that aryl halides can exhibit their own patterns of chemical reactivity, and that these reactions are novel, useful, and mechanistically interesting. 23.1 BONDING IN ARYL HALIDES Aryl halides are compounds in which a halogen substituent is attached directly to an aromatic ring. Representative aryl halides include Halogen-containing organic compounds in which the halogen substituent is not directly bonded to an aromatic ring, even though an aromatic ring may be present, are not aryl halides. Benzyl chloride (C6H5CH2Cl), for example, is not an aryl halide. The carbon–halogen bonds of aryl halides are both shorter and stronger than the carbon–halogen bonds of alkyl halides, and in this respect as well as in their chemical behavior, they resemble vinyl halides more than alkyl halides. A hybridization effect F Fluorobenzene Cl NO2 1-Chloro- 2-nitrobenzene Br 1-Bromonaphthalene I CH2OH p-Iodobenzyl alcohol Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
918 CHAPTER TWENTY-THREE Aryl Halides TABLE 23.1 Carbon-Hydrogen and Carbon-Chlorine Bond Dissociation Energies of Selected Compounds Bond energy Hybridization of kJ/mol (kcal/mol) carbon to which Compound X is attached XEH X=C CH3CH2X 410(98) (81) CH2=CHX 452(108)368(88) X 469(112)406(97) ns to be responsible because, as the data in Table 23. 1 indicate, similar patterns are for both carbon-hydrogen bonds and carbon-halogen bonds. An increase in s char- acter from 25%(Sp hybridization)to 33.3%o s character(sp- hybridization)increases the tendency of carbon to attract electrons and strengthens the bond PROBLEM 23.1 Consider all the isomers of C,H,Cl containing a benzene ring and write the structure of the one that has the weakest carbon -chlorine bond as measured by its bond dissociation energy The strength of their carbon-halogen bonds causes aryl halides to react very slowly in reactions in which carbon-halogen bond cleavage is rate-determining, as in nucle- ophilic substitution, for example. Later in this chapter we will see examples of such reac- tions that do take place at reasonable rates but proceed by mechanisms distinctly differ- ent from the classical SNI and SN2 pathways 23.2 SOURCES OF ARYL HALIDES The two main methods for the preparation of aryl halides--halogenation of arenes by electrophilic aromatic substitution and preparation by way of aryl diazonium salts\ described earlier and are reviewed in Table 23. 2. A number of aryl halides occu rally, some of which are shown in Figure 23. 1 on page 920. 23.3 PHYSICAL PROPERTIES OF ARYL HALIDES Aryl halides resemble alkyl halides in many of their physical properties. All are practi- points for some representa cally insoluble in water and most are denser than water. tive aryl halides are listed in Aryl halides are polar molecules but are less polar than alkyl halides Chlorocyclohexane Chlorobenzene Compare the electro harges at chlorine in chlorocy. Since carbon is sp-hybridized in chlorobenzene, it is more electronegative than the sp zene hybridized carbon of chlorocyclohexane. Consequently, the withdrawal of electron den- more sity away from carbon by chlorine is less pronounced in aryl halides than in alkyl halides, and the molecular dipole moment is smaller. Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
seems to be responsible because, as the data in Table 23.1 indicate, similar patterns are seen for both carbon–hydrogen bonds and carbon–halogen bonds. An increase in s character from 25% (sp3 hybridization) to 33.3% s character (sp2 hybridization) increases the tendency of carbon to attract electrons and strengthens the bond. PROBLEM 23.1 Consider all the isomers of C7H7Cl containing a benzene ring and write the structure of the one that has the weakest carbon–chlorine bond as measured by its bond dissociation energy. The strength of their carbon–halogen bonds causes aryl halides to react very slowly in reactions in which carbon–halogen bond cleavage is rate-determining, as in nucleophilic substitution, for example. Later in this chapter we will see examples of such reactions that do take place at reasonable rates but proceed by mechanisms distinctly different from the classical SN1 and SN2 pathways. 23.2 SOURCES OF ARYL HALIDES The two main methods for the preparation of aryl halides—halogenation of arenes by electrophilic aromatic substitution and preparation by way of aryl diazonium salts—were described earlier and are reviewed in Table 23.2. A number of aryl halides occur naturally, some of which are shown in Figure 23.1 on page 920. 23.3 PHYSICAL PROPERTIES OF ARYL HALIDES Aryl halides resemble alkyl halides in many of their physical properties. All are practically insoluble in water and most are denser than water. Aryl halides are polar molecules but are less polar than alkyl halides. Since carbon is sp2 -hybridized in chlorobenzene, it is more electronegative than the sp3 - hybridized carbon of chlorocyclohexane. Consequently, the withdrawal of electron density away from carbon by chlorine is less pronounced in aryl halides than in alkyl halides, and the molecular dipole moment is smaller. Cl Chlorocyclohexane 2.2 D Cl Chlorobenzene 1.7 D 918 CHAPTER TWENTY-THREE Aryl Halides TABLE 23.1 Carbon–Hydrogen and Carbon–Chlorine Bond Dissociation Energies of Selected Compounds Compound CH3CH2X CH2œCHX Hybridization of carbon to which X is attached sp3 sp2 sp2 X H 410 (98) 452 (108) 469 (112) X Cl 339 (81) 368 (88) 406 (97) Bond energy, kJ/mol (kcal/mol) X Melting points and boiling points for some representative aryl halides are listed in Appendix 1. Compare the electronic charges at chlorine in chlorocyclohexane and chlorobenzene on Learning By Modeling to verify that the C±Cl bond is more polar in chlorocyclohexane. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
23.4 Reactions of Aryl Halides: A Review and a Preview TABLE 23.2 Summary of Reactions Discussed in Earlier Chapters That Yield Aryl Halides Reaction(section) and comments General equation and specific example Halogenation of arenes( Section 12.5) Aryl chlorides and bromides are con ArH X2 -> ArX HX niently prepared by electrophilic aro- Arene Halogen Fex, Aryl matic substitution the reaction is I ited to chlorination and bromination Fluorination is difficult to control: iodi nation is too slow to be useful 2 Nitrobenzene Bromine The Sandmeyer reaction(Section 22. 18) 1. NaNO2, HaO Diazotization of a primary arylamine ArNH2 →Arx 2. CUX followed by treatment of the diazo- Primary arylamine Aryl halide nium salt with copper()bromid copper()chloride yields the corre- CI NH2 sponding aryl bromide or aryl chloride 1-Amino-8-chloronaphthalene 1-Bromo-8-chloronaphth. Diazotization of an arylamine followed ArNH, 1. NaNO, H,o arN=N.f/heat The Schiemann reaction(Section 22. 18) ArF by treatment with fluoroboric acid Aryl diazonium gives an aryl diazonium fluoroborate arylami salt. Heating this salt converts it to an aryl fluoride ChS Aniline benzene (51-57%) Reaction of aryl diazonium salts with iodide ion(Section 22. 18)Adding ArNH2 Arl potassium iodide to a solution of an Primary arylamine Aryl iodide aryl diazonium ion leads to the forma- tion of an aryl iodide CsHSNH 23.4 REACTIONS OF ARYL HALIDES: A REVIEW AND A PREVIEW Table 23.3 summarizes the reactions of aryl halides that we have encountered to this Noticeably absent from Table 23.3 are nucleophilic substitutions. We have, to thi point, seen no nucleophilic substitution reactions of aryl halides in this text. Chloroben zene, for example, is essentially inert to aqueous sodium hydroxide at room temperature Reaction temperatures over 300C are required for nucleophilic substitution to proceed at a reasonable rate Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
23.4 Reactions of Aryl Halides: A Review and a Preview 919 TABLE 23.2 Summary of Reactions Discussed in Earlier Chapters That Yield Aryl Halides Reaction (section) and comments Halogenation of arenes (Section 12.5) Aryl chlorides and bromides are conveniently prepared by electrophilic aromatic substitution. The reaction is limited to chlorination and bromination. Fluorination is difficult to control; iodination is too slow to be useful. The Sandmeyer reaction (Section 22.18) Diazotization of a primary arylamine followed by treatment of the diazonium salt with copper(I) bromide or copper(I) chloride yields the corresponding aryl bromide or aryl chloride. Reaction of aryl diazonium salts with iodide ion (Section 22.18) Adding potassium iodide to a solution of an aryl diazonium ion leads to the formation of an aryl iodide. The Schiemann reaction (Section 22.18) Diazotization of an arylamine followed by treatment with fluoroboric acid gives an aryl diazonium fluoroborate salt. Heating this salt converts it to an aryl fluoride. General equation and specific example ArH Arene Halogen X2 Aryl halide ArX Hydrogen halide HX Fe or FeX3 Fe m-Bromonitrobenzene (85%) Br O2N O2N Nitrobenzene Bromine Br2 Primary arylamine ArNH2 Aryl halide ArX 1. NaNO2, H3O 2. CuX Primary arylamine ArNH2 Aryl iodide ArI 1. NaNO2, H3O 2. KI 1-Amino-8-chloronaphthalene Cl NH2 1-Bromo-8-chloronaphthalene (62%) Cl Br 1. NaNO2, HBr 2. CuBr Aryl diazonium fluoroborate BF4 ArNPN Primary arylamine ArNH2 Aryl fluoride ArF 1. NaNO2, H3O heat 2. HBF4 Fluorobenzene (51–57%) C6H5F Aniline C6H5NH2 1. NaNO2, H2O, HCl 2. HBF4 3. heat Iodobenzene (74–76%) C6H5I Aniline C6H5NH2 1. NaNO2, HCl, H2O 2. KI 23.4 REACTIONS OF ARYL HALIDES: A REVIEW AND A PREVIEW Table 23.3 summarizes the reactions of aryl halides that we have encountered to this point. Noticeably absent from Table 23.3 are nucleophilic substitutions. We have, to this point, seen no nucleophilic substitution reactions of aryl halides in this text. Chlorobenzene, for example, is essentially inert to aqueous sodium hydroxide at room temperature. Reaction temperatures over 300°C are required for nucleophilic substitution to proceed at a reasonable rate. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
CHAPTER TWENTY-THREE Aryl Halides CH2O OCH orally administered antifungal agent H3O B a dye known as Tyrian purple, which is isolated from a species of Mediterranean for its vivid color HO O OH CNH Chlortetracycline. an antibiotic OH Cl HO CH3 N(CH3h CHa o CH3 CH3O O、CH3CH3 Maytansine: a potent antitumor agent isolated from a bush native to Kenya; HO CHO H FIGURE 23. 1 Some naturally occurring aryl halides The mechanism of this read 1NaOH.H2O.370° tion is discussed in Section 23.8. Chlorobenzene Phenol (97%o) reactions. The carbon-halogen bonds of aryl halides are too strong, and aryl cations are too high in energy, to permit aryl halides to ionize readily in SNl-type processes. Fur thermore, as Figure 23.2 depicts, the optimal transition-state geometry required for SN2 processes cannot be achieved. Nucleophilic attack from the side opposite the nd is blocked by the Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
Aryl halides are much less reactive than alkyl halides in nucleophilic substitution reactions. The carbon–halogen bonds of aryl halides are too strong, and aryl cations are too high in energy, to permit aryl halides to ionize readily in SN1-type processes. Furthermore, as Figure 23.2 depicts, the optimal transition-state geometry required for SN2 processes cannot be achieved. Nucleophilic attack from the side opposite the carbon–halogen bond is blocked by the aromatic ring. Cl Chlorobenzene OH Phenol (97%) 1. NaOH, H2O, 370°C 2. H 920 CHAPTER TWENTY-THREE Aryl Halides N Cl Cl O Griseofulvin: biosynthetic product of a particular microorganism, used as an orally administered antifungal agent. O H O Br O Dibromoindigo: principal constituent of a dye known as Tyrian purple, which is isolated from a species of Mediterranean sea snail and was much prized by the ancients for its vivid color. H N N H N H O Br O OH CNH2 CH3 O N(CH3)2 O Chlortetracycline: an antibiotic. O O O O O O N O Maytansine: a potent antitumor agent isolated from a bush native to Kenya; 10 tons of plant yielded 6 g of maytansine. CH3O CH3O CH3O CH3O OCH3 H3C HO HO HO OH OH Cl CH3 CH3 CH3 CH3 CH3 CH3 CH3 The mechanism of this reaction is discussed in Section 23.8. FIGURE 23.1 Some naturally occurring aryl halides. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
23.4 Reactions of Aryl Halides: A Review and a Preview TABLE 23.3 Summary of Reactions of Aryl Halides Discussed in Earlier Chapters Reaction(section) and comments General equation and specific example Electrophilic aromatic substitution(Section 12. 14)Halo- gen substituents are slightly deactivating and ortho CHacOCcH CCH3 Formation of aryl Grignard reagents ( Section 14.4) Aryl alides react with magnesium to form the corresponding magnesium halide Aryl iodides are the most reac tive, aryl fluorides the least. A similar reaction occurs Aryl halide Magnesium with lithium to give aryllithium reagents( Section 14.3) Bromobenzene Magnesium Phenylmagnes bromide(95 (a) Hydroxide ion chloromethane (b)Hydroxide ion chlorobenzene FIGURE 23.2 Nucleophilic substitution, with inversion of configuration, is blocked by the benzene ring of an aryl halide. (a) Alkyl halide: the new bond is formed by attack of the nucle ophile at carbon from the side opposite the bond to the leaving group Inversion of configuration is observed. (b)Aryl halide: The aromatic ring blocks the approach of the nucleophile to carbon at the side opposite the bond to the leaving group. Inversion of configuration is impossible Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
23.4 Reactions of Aryl Halides: A Review and a Preview 921 TABLE 23.3 Summary of Reactions of Aryl Halides Discussed in Earlier Chapters Reaction (section) and comments Electrophilic aromatic substitution (Section 12.14) Halogen substituents are slightly deactivating and ortho, para-directing. Formation of aryl Grignard reagents (Section 14.4) Aryl halides react with magnesium to form the corresponding arylmagnesium halide. Aryl iodides are the most reactive, aryl fluorides the least. A similar reaction occurs with lithium to give aryllithium reagents (Section 14.3). General equation and specific example Arylmagnesium halide ArMgX Aryl halide ArX Magnesium Mg diethyl ether Bromobenzene Br p-Bromoacetophenone (69–79%) Br CCH3 O CH3COCCH3 AlCl3 O X O X Bromobenzene Br Phenylmagnesium bromide (95%) MgBr Magnesium Mg diethyl ether (a) Hydroxide ion + chloromethane (b) Hydroxide ion + chlorobenzene FIGURE 23.2 Nucleophilic substitution, with inversion of configuration, is blocked by the benzene ring of an aryl halide. (a) Alkyl halide: The new bond is formed by attack of the nucleophile at carbon from the side opposite the bond to the leaving group. Inversion of configuration is observed. (b) Aryl halide: The aromatic ring blocks the approach of the nucleophile to carbon at the side opposite the bond to the leaving group. Inversion of configuration is impossible. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
CHAPTER TWENTY-THREE Aryl Halides 23.5 NUCLEOPHILIC SUBSTITUTION IN NITRO-SUBSTITUTED ARYL HALIDES One group of aryl halides that do undergo nucleophilic substitution readily consists of those that bear a nitro group ortho or para to the halogen OCH NaoCH3 Nacl p-Nitroanisole(92%) Sodium chloride An ortho-nitro group exerts a comparable rate-enhancing effect. m-Chloronitrobenzene, although much more reactive than chlorobenzene itself, is thousands of times less reac- tive than either o-or p-chloronitrobenzene The effect of o- and p-nitro substituents is cumulative, as the following rate data demonstrate Increasing rate of reaction with sodium methoxide in methanol (50C O2N、 Chlorobenzene 1-chloro- 1-chloro- 2-chloro- 4-nitrobenzene 2. 4-dinitrobenzene 1.3, 5-trinitrobenzene Relative rate 1.0 7×10 24×1015 (too fast to measure) PROBLEM 23.2 Write the structure of the expected product from the reaction of 1-chloro-2, 4-dinitrobenzene with each of the following reagen (aCH3 CH2ON (b)CHSCH2 SNa ( d)CH SAMPLE SoLUTION (a)Sodium ethoxide is a source of the nucleophile CH3,O, which displaces chloride from 1-chloro-2, 4-dinitrobenzene OCHCH +CH3CH2O一 NO 1-Chloro-2 4-dinitrobenzene Ethoxide 1-Ethoxy-2, 4-dinitrobenzene Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
23.5 NUCLEOPHILIC SUBSTITUTION IN NITRO-SUBSTITUTED ARYL HALIDES One group of aryl halides that do undergo nucleophilic substitution readily consists of those that bear a nitro group ortho or para to the halogen. An ortho-nitro group exerts a comparable rate-enhancing effect. m-Chloronitrobenzene, although much more reactive than chlorobenzene itself, is thousands of times less reactive than either o- or p-chloronitrobenzene. The effect of o- and p-nitro substituents is cumulative, as the following rate data demonstrate: PROBLEM 23.2 Write the structure of the expected product from the reaction of 1-chloro-2,4-dinitrobenzene with each of the following reagents: (a) CH3CH2ONa (b) C6H5CH2SNa (c) NH3 (d) CH3NH2 SAMPLE SOLUTION (a) Sodium ethoxide is a source of the nucleophile CH3CH2O, which displaces chloride from 1-chloro-2,4-dinitrobenzene. Cl NO2 NO2 1-Chloro-2,4-dinitrobenzene CH3CH2O Ethoxide anion OCH2CH3 NO2 NO2 1-Ethoxy-2,4-dinitrobenzene Cl Increasing rate of reaction with sodium methoxide in methanol (50°C) Cl Chlorobenzene Relative rate: 1.0 Cl NO2 1-Chloro- 4-nitrobenzene 7 1010 NO2 Cl NO2 1-Chloro- 2,4-dinitrobenzene 2.4 1015 NO2 Cl O2N NO2 2-Chloro- 1,3,5-trinitrobenzene (too fast to measure) NO2 OCH3 p-Nitroanisole (92%) CH3OH 85°C Cl NO2 p-Chloronitrobenzene NaOCH3 Sodium methoxide NaCl Sodium chloride 922 CHAPTER TWENTY-THREE Aryl Halides Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
23.6 The Addition-Elimination Mechanism of Nucleophilic Aromatic Substitution In contrast to nucleophilic substitution in alkyl halides, where alkyl fluorides are exceedingly unreactive, aryl fluorides undergo nucleophilic substitution readily when the ring bears an o-or a p-nitro group The compound 1-fluoro-2,4- CH:OH gly reactive toward KOCH determination of the struG. p-Fluoronitrobenzene Potassium methoxide Nitroanisole (93%) Potassium fluoride ture of insulin Indeed, the order of leaving-group reactivity in nucleophilic aromatic substitution is the opposite of that seen in aliphatic substitution. Fluoride is the most reactive leaving group in nucleophilic aromatic substitution, iodide the least reactive. Relative reactivity toward sodium methoxide in methanol(50°C X=F 312 X= Br 0.8 0.4 Kinetic studies of these reactions reveal that they follow a second-order rate law Rate= k[Aryl halide] [Nucleophile] Second-order kinetics is usually interpreted in terms of a bimolecular rate-determinin step. In this case, then, we look for a mechanism in which both the aryl halide and the nucleophile are involved in the slowest step. Such a mechanism is described in the fol- 23.6 THE ADDITION-ELIMINATION MECHANISM OF NUCLEOPHILIC AROMATIC SUBSTITUTION The generally accepted mechanism for nucleophilic aromatic substitution in nitro- substituted aryl halides, illustrated for the reaction of p-fluoronitrobenzene with sodium methoxide, is outlined in Figure 23. 3. It is a two-step addition-elimination mechanism, in which addition of the nucleophile to the aryl halide is followed by elimination of the halide leaving group. Figure 23. 4 shows the structure of the key intermediate. The mech anism is consistent with the following experimental observations: 1. Kinetics: As the observation of second-order kinetics requires, the rate-determining step(step 1)involves both the aryl halide and the nucleophile. 2. Rate-enhancing effect of the nitro group: The nucleophilic addition step is rate- determining because the aromatic character of the ring must be sacrificed to form the cyclohexadienyl anion intermediate. Only when the anionic intermediate is sta- bilized by the presence of a strong electron-withdrawing substituent ortho or para to the leaving group will the activation energy for its formation be low enough to provide a reasonable reaction rate. We can illustrate the stabilization that a p-nitro group provides by examining the resonance structures for the cyclohexadienyl anion formed from methoxide and p-fluoronitrobenzene Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
In contrast to nucleophilic substitution in alkyl halides, where alkyl fluorides are exceedingly unreactive, aryl fluorides undergo nucleophilic substitution readily when the ring bears an o- or a p-nitro group. Indeed, the order of leaving-group reactivity in nucleophilic aromatic substitution is the opposite of that seen in aliphatic substitution. Fluoride is the most reactive leaving group in nucleophilic aromatic substitution, iodide the least reactive. Kinetic studies of these reactions reveal that they follow a second-order rate law: Rate k[Aryl halide] [Nucleophile] Second-order kinetics is usually interpreted in terms of a bimolecular rate-determining step. In this case, then, we look for a mechanism in which both the aryl halide and the nucleophile are involved in the slowest step. Such a mechanism is described in the following section. 23.6 THE ADDITION–ELIMINATION MECHANISM OF NUCLEOPHILIC AROMATIC SUBSTITUTION The generally accepted mechanism for nucleophilic aromatic substitution in nitrosubstituted aryl halides, illustrated for the reaction of p-fluoronitrobenzene with sodium methoxide, is outlined in Figure 23.3. It is a two-step addition–elimination mechanism, in which addition of the nucleophile to the aryl halide is followed by elimination of the halide leaving group. Figure 23.4 shows the structure of the key intermediate. The mechanism is consistent with the following experimental observations: 1. Kinetics: As the observation of second-order kinetics requires, the rate-determining step (step 1) involves both the aryl halide and the nucleophile. 2. Rate-enhancing effect of the nitro group: The nucleophilic addition step is ratedetermining because the aromatic character of the ring must be sacrificed to form the cyclohexadienyl anion intermediate. Only when the anionic intermediate is stabilized by the presence of a strong electron-withdrawing substituent ortho or para to the leaving group will the activation energy for its formation be low enough to provide a reasonable reaction rate. We can illustrate the stabilization that a p-nitro group provides by examining the resonance structures for the cyclohexadienyl anion formed from methoxide and p-fluoronitrobenzene: X NO2 Relative reactivity toward sodium methoxide in methanol (50°C): X F X Cl X Br X I 312 1.0 0.8 0.4 23.6 The Addition–Elimination Mechanism of Nucleophilic Aromatic Substitution 923 F NO2 p-Fluoronitrobenzene KOCH3 Potassium methoxide OCH3 NO2 p-Nitroanisole (93%) KF Potassium fluoride CH3OH 85°C The compound 1-fluoro-2,4- dinitrobenzene is exceedingly reactive toward nucleophilic aromatic substitution and was used in an imaginative way by Frederick Sanger (Section 27.10) in his determination of the structure of insulin. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
CHAPTER TWENTY-THREE Aryl Halides Overall reaction NaOCH3 p-Fluoronitrobenzene Sodium methoxide Sodium fluoride Step 1: Addition stage. The nucleophile, in this case methoxide ion, adds to the carbon atom that bears the leaving group to give a cyclohexadienyl anion intermediate OCH3 H O2 O, p-Fluoronitrobenzene Methoxide ion Cyclohexadienyl Step 2: Elimination stage. Loss of halide from the cyclohexadienyl intermediate restores the aromaticity of the ring and gives the product of nucleophilic aromatic substitution OCI H H O N p-Nitroanisole FIGURE 23. 3 The addition-elimination mechanism of nucleophilic aromatic substitution FIGURE 23. 4 Stru ture of the rate-dete ntermediate in the of 1-fluoro-4-nitrobenzene Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
924 CHAPTER TWENTY-THREE Aryl Halides FIGURE 23.4 Structure of the rate-determining intermediate in the reaction of 1-fluoro-4-nitrobenzene with methoxide ion. Overall reaction: Step 1: Addition stage. The nucleophile, in this case methoxide ion, adds to the carbon atom that bears the leaving group to give a cyclohexadienyl anion intermediate. NO2 NO2 NO2 NO2 F p-Fluoronitrobenzene NaOCH3 Sodium methoxide OCH3 OCH3 OCH3 OCH3 OCH3 p-Nitroanisole NaF Sodium fluoride H H H H F F p-Fluoronitrobenzene Methoxide ion slow H H H H Step 2: Elimination stage. Loss of halide from the cyclohexadienyl intermediate restores the aromaticity of the ring and gives the product of nucleophilic aromatic substitution. fast H H H H NO2 F H H H H NO2 p-Nitroanisole F Fluoride ion Cyclohexadienyl anion intermediate Cyclohexadienyl anion intermediate FIGURE 23.3 The addition–elimination mechanism of nucleophilic aromatic substitution. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
23.6 The Addition-Elimination Mechanism of Nucleophilic Aromatic Substitution F OCH F OCH3 H Most stable resonance structure: negative charge is on oxygen PROBLEM 23.3 Write the most stable resonance structure for the cyclohexa- dienyl anion formed by reaction of methoxide ion with o-fluoronitrobenzene m-Fluoronitrobenzene reacts with sodium methoxide 10 times more slowly than its ortho and para isomers. According to the resonance description, direct conjugation of the negatively charged carbon with the nitro group is not possible in the cyclohexa- dienyl anion intermediate from m-fluoronitrobenzene, and the decreased read reflects the decreased stabilization afforded this intermediate OCH OCH3 F OCH H (Negative charge is restricted to carbon in all resonance forms PROBLEM 23. 4 Reaction of 1.2 3-tribromo-5-nitrobenzene with sodium ethox ide in ethanol gave a single product, CH,Br2 NO3, in quantitative yield Suggest a reasonable structure for this compound 3. Leaving-group effects: Since aryl fluorides have the strongest carbon-halogen bond and react fastest, the rate-determining step cannot involve carbon-halogen bond cleavage. According to the mechanism in Figure 23. 3 the carbon-halogen bond breaks in the rapid elimination step that follows the rate-determining addition step. The unusually high reactivity of aryl fluorides arises because fluorine is the most electronegative of the halogens, and its greater ability to attract electrons increases the rate of formation of the cyclohexadienyl anion intermediate in the first step of the mechanism. CH3O CI is more stable than NO, Fluorine stabilizes Chlorine is less electronegative cyclohexadienyl anion than fluorine and does no by withdrawing electrons. stabilize cyclohexadienyl anion to as great an extent Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
PROBLEM 23.3 Write the most stable resonance structure for the cyclohexadienyl anion formed by reaction of methoxide ion with o-fluoronitrobenzene. m-Fluoronitrobenzene reacts with sodium methoxide 105 times more slowly than its ortho and para isomers. According to the resonance description, direct conjugation of the negatively charged carbon with the nitro group is not possible in the cyclohexadienyl anion intermediate from m-fluoronitrobenzene, and the decreased reaction rate reflects the decreased stabilization afforded this intermediate. PROBLEM 23.4 Reaction of 1,2,3-tribromo-5-nitrobenzene with sodium ethoxide in ethanol gave a single product, C8H7Br2NO3, in quantitative yield. Suggest a reasonable structure for this compound. 3. Leaving-group effects: Since aryl fluorides have the strongest carbon–halogen bond and react fastest, the rate-determining step cannot involve carbon–halogen bond cleavage. According to the mechanism in Figure 23.3 the carbon–halogen bond breaks in the rapid elimination step that follows the rate-determining addition step. The unusually high reactivity of aryl fluorides arises because fluorine is the most electronegative of the halogens, and its greater ability to attract electrons increases the rate of formation of the cyclohexadienyl anion intermediate in the first step of the mechanism. CH3O H Cl H H H NO2 Chlorine is less electronegative than fluorine and does not stabilize cyclohexadienyl anion to as great an extent. is more stable than CH3O H F H H H NO2 Fluorine stabilizes cyclohexadienyl anion by withdrawing electrons. (Negative charge is restricted to carbon in all resonance forms) OCH3 H F H H N H O O N O O OCH3 H F H H H OCH3 H F H H N H O O OCH3 H F H H H N O O OCH3 H F H H H N O O OCH3 H F H H H N O O Most stable resonance structure; negative charge is on oxygen 23.6 The Addition–Elimination Mechanism of Nucleophilic Aromatic Substitution 925 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
CHAPTER TWENTY-THREE Aryl Halides Before leaving this mechanistic discussion, we should mention that the addition- elimination mechanism for nucleophilic aromatic substitution illustrates a principle worth remembering. The words"activating"and"deactivating "as applied to substituent effects in organic chemistry are without meaning when they stand alone. When we say that a group is activating or deactivating, we need to specify the reaction type that is being considered. A nitro group is a strongly deactivating substituent in electrophilic aromatic substitution, where it markedly destabilizes the key cyclohexadienyl cation intermediate: N NO NO E Nitrobenzene and cation Product of electrophile intermediate; nitro group electrophilic is destabilizing A nitro group is a strongly activating substituent in nucleophilic aromatic substitution where it stabilizes the key cyclohexadienyl anion int O-Halonitrobenzene Cyclohexadienyl anion Product of (X= F, Cl. Br, or D) intermediate; nitro group and a nucleophile is stabilizing aromatic substitution A nitro group behaves the same way in both reactions: it attracts electrons Reaction is retarded when electrons flow from the aromatic ring to the attacking species(electrophilic aromatic substitution). Reaction is facilitated when electrons flow from the attacking pecies to the aromatic ring(nucleophilic aromatic substitution). By being aware of the connection between reactivity and substituent effects, you will sharpen your appreciation of how chemical reactions occur 23.7 RELATED NUCLEOPHILIC AROMATIC SUBSTITUTION REACTIONS The most common types of aryl halides in nucleophilic aromatic substitutions are those that bear o-or p-nitro substituents. Among other classes of reactive aryl halides, a few nerit special consideration. One class includes highly fluorinated aromatic compounds such as hexafluorobenzene, which undergoes substitution of one of its fluorines on reac- tion with nucleophiles such as sodium methoxide F F CH:OH, 65 OCH3 Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
Before leaving this mechanistic discussion, we should mention that the addition– elimination mechanism for nucleophilic aromatic substitution illustrates a principle worth remembering. The words “activating” and “deactivating” as applied to substituent effects in organic chemistry are without meaning when they stand alone. When we say that a group is activating or deactivating, we need to specify the reaction type that is being considered. A nitro group is a strongly deactivating substituent in electrophilic aromatic substitution, where it markedly destabilizes the key cyclohexadienyl cation intermediate: A nitro group is a strongly activating substituent in nucleophilic aromatic substitution, where it stabilizes the key cyclohexadienyl anion intermediate: A nitro group behaves the same way in both reactions: it attracts electrons. Reaction is retarded when electrons flow from the aromatic ring to the attacking species (electrophilic aromatic substitution). Reaction is facilitated when electrons flow from the attacking species to the aromatic ring (nucleophilic aromatic substitution). By being aware of the connection between reactivity and substituent effects, you will sharpen your appreciation of how chemical reactions occur. 23.7 RELATED NUCLEOPHILIC AROMATIC SUBSTITUTION REACTIONS The most common types of aryl halides in nucleophilic aromatic substitutions are those that bear o- or p-nitro substituents. Among other classes of reactive aryl halides, a few merit special consideration. One class includes highly fluorinated aromatic compounds such as hexafluorobenzene, which undergoes substitution of one of its fluorines on reaction with nucleophiles such as sodium methoxide. NaOCH3 CH3OH, 65°C F F F F F F Hexafluorobenzene F OCH3 F F F F 2,3,4,5,6-Pentafluoroanisole (72%) slow addition fast elimination NO2 X Y o-Halonitrobenzene (X F, Cl, Br, or I) and a nucleophile NO2 X Y Cyclohexadienyl anion intermediate; nitro group is stabilizing NO2 Y Product of nucleophilic aromatic substitution X very slow H fast NO2 H E Nitrobenzene and an electrophile NO2 H E Cyclohexadienyl cation intermediate; nitro group is destabilizing NO2 E Product of electrophilic aromatic substitution 926 CHAPTER TWENTY-THREE Aryl Halides Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
