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