Carey - Organic Chemistry - chapt23

Carey - Organic Chemistry - chapt23

(Parte 1 de 3)


The value of alkyl halidesas 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 halidesare 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.


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. Ahybridization effect


Cl NO2

1-Chloro- 2-nitrobenzene

1-Bromonaphthalene I CH2OH p-Iodobenzyl alcohol

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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 scharacter from 25% (sp3hybridization) to 3.3% scharacter (sp2hybridization) increases the tendency of carbon to attract electrons and strengthens the bond.

PROBLEM 23.1Consider 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 differ- ent from the classical SN1 and SSN2 pathways.


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. Anumber of aryl halides occur naturally, some of which are shown in Figure 23.1 on page 920.


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.

Chlorocyclohexane 2.2 D

Chlorobenzene 1.7 D


TABLE 23.1Carbon–Hydrogen and Carbon–Chlorine Bond Dissociation Energies of Selected Compounds


Hybridization of carbon to which X is attached sp3 sp2 sp2

410 (98) 452 (108)

469 (112)

339 (81) 368 (8)

406 (97)

Bond energy, kJ/mol (kcal/mol)

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 Modelingto verify that the C±Cl bond is more polar in chlorocyclohexane.

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TABLE 23.2Summary 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 2.18) 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 2.18) Adding potassium iodide to a solution of an aryl diazonium ion leads to the formation of an aryl iodide.

The Schiemann reaction (Section 2.18) 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


Arene Halogen X2

Aryl halide

Hydrogen halide

HX Fe or FeX3

Primary arylamine ArNH2Aryl halide

Primary arylamine ArNH2Aryl iodide


Cl NH2

1-Bromo-8-chloronaphthalene (62%)

Cl Br

1. NaNO2, HBr 2. CuBr

Aryl diazonium fluoroborate

Primary arylamine


Aryl fluoride

2. HBF4

2. HBF4 3. heat

2. KI


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.

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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. 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 carbon–halogen bond is blocked by the aromatic ring.

ClChlorobenzene OHPhenol (97%)


N Cl

O Griseofulvin: biosynthetic product of a particular microorganism, used as an orally administered antifungal agent.

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.

O Br



O Chlortetracycline: an antibiotic.

Maytansine: a potent antitumor agent isolated from a bush native to Kenya; 10 tons of plant yielded 6 g of maytansine.

Cl CH3





The mechanism of this reaction is discussed in Section 23.8.

FIGURE 23.1 Some naturally occurring aryl halides.

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TABLE 23.3Summary 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 halideArX Magnesium diethyl ether

BromobenzeneBr p-Bromoacetophenone



BromobenzeneBr Phenylmagnesium bromide (95%) MgBr Magnesium diethyl ether

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.

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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 23.2Write 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.



Ethoxide anion



1-Ethoxy-2,4-dinitrobenzene Cl

Increasing rate of reaction with sodium methoxide in methanol (50°C)

Chlorobenzene Relative rate: 1.0


1-Chloro- 4-nitrobenzene 7 1010


Cl NO2

1-Chloro- 2,4-dinitrobenzene 2.4 1015


2-Chloro- 1,3,5-trinitrobenzene (too fast to measure)

NO2 OCH3 p-Nitroanisole (92%)

NO2 p-Chloronitrobenzene

NaOCH3Sodium methoxide NaCl Sodium chloride


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In contrast to nucleophilic substitution in alkyl halides, where alkyl fluoridesare exceedingly unreactive, aryl fluoridesundergo 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.


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:

Relative reactivity toward sodium methoxide in methanol (50°C): X F X Cl X Br X I

NO2 p-Fluoronitrobenzene

KOCH3 Potassium methoxide


NO2 p-Nitroanisole (93%) KFPotassium fluoride

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.

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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 p-Fluoronitrobenzene

NaOCH3 Sodium methoxide



OCH3 p-Nitroanisole

NaF Sodium fluoride p-Fluoronitrobenzene Methoxide ion slow 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

NO2 p-Nitroanisole F Fluoride ion

Cyclohexadienyl anion intermediate

Cyclohexadienyl anion intermediate

FIGURE 23.3 The addition–elimination mechanism of nucleophilic aromatic substitution.

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PROBLEM 23.3Write the most stable resonance structure for the cyclohexadienyl anion formed by reaction of methoxide ion with o-fluoronitrobenzene.

m-Fluoronitrobenzene reacts with sodium methoxide 105times 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 23.4Reaction of 1,2,3-tribromo-5-nitrobenzene with sodium ethox- ide 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.



Chlorine is less electronegative than fluorine and does not stabilize cyclohexadienyl anion to as great an extent.

is more stable than



Fluorine stabilizes cyclohexadienyl anion by withdrawing electrons.

(Negative charge is restricted to carbon in all resonance forms)







Most stable resonance structure; negative charge is on oxygen

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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. Anitro group is a strongly deactivatingsubstituent in electrophilicaromatic substitution, where it markedly destabilizes the key cyclohexadienyl cation intermediate:

(Parte 1 de 3)