23_BRCLoudon_pgs5-0.qxd 12/8/08 1:22 PM Page 1138

1138 CHAPTER 23 • THE CHEMISTRY OF

AROMATIC SUBSTITUTION REACTIONS 23.9 OF DERIVATIVES

Aromatic amines can undergo electrophilic aromatic substitution reactions on the ring (Sec. 16.4). The amino group is one of the most powerful ortho, para-directing groups in elec- trophilic substitution. If the conditions of the reaction are not too acidic, aniline and its deriv- atives undergo rapid ring substitution. For example, aniline, like , brominates three

times under mild conditions.

% NH2 NH2% Br Br " " 3Br2 3HBr (23.36) i + i +

"Br

When aniline is nitrated with a mixture of nitric and , a mixture of meta and para products is obtained.

NH2 NH2 NH2

" HNO " " 3 ( 2% o-isomer) H SO , 20 °C (23.37) i 2 4 i + i + %NO2 "NO2 (51%) (47%)

(95% yield)

The formation of m-nitroaniline as one of the products is understandable because the major form of the starting material in the strongly acidic solution is the conjugate-acid ammonium ion. Because the ammonium ion has no unshared electron pair on , it cannot donate electrons by a effect; consequently, its electron-withdrawing polar effect makes it a meta-directing group. It is likely that the p-nitroaniline product arises by the rapid nitration of STUDY GUIDE LINK 23.1 the minuscule amount of highly reactive unprotonated aniline in the reaction mixture. As the Nitration of Aniline unprotonated aniline reacts, it is replenished, by Le Châtelier’s principle. Aniline can be nitrated regioselectively at the para position if the nitrogen is first protected from protonation. (The general idea of a protecting group was introduced in Sec. 19.10B.) This strategy is used in the solution to Study Problem 23.4.

Study Problem 23.4 Outline a preparation of p-nitroaniline from aniline and any other reagents.

Solution An group is much less basic than an amino group. Hence, acylation of the amino group of aniline with to give N-phenylacetamide () will protect the nitro- gen from protonation. The acetamido group, although much less activating than a free amino group, is nevertheless an activating, ortho, para-directing group in aromatic substitution (Table 16.2 on p. 763). Following nitration of acetanilide, the acetyl group is removed to give p-nitroaniline, the target compound. 23_BRCLoudon_pgs5-0.qxd 12/8/08 1:22 PM Page 1139

23.10 DIAZOTIZATION; REACTIONS OF DIAZONIUM IONS 1139

O O S S NH2 H3CCNH H3CCNH O L L L L " S " " H3C C Cl HNO3 L L H SO , 20 C i i 2 4 ° i

anilineprotection of acetanilide "NO2 the nitrogen p-nitroacetanilide

NH2 O " S H2O, _OH H3CCO_ i + L L removal of the protecting group "NO2 p-nitroaniline

Because the acetamido group is considerably less basic than an amino group, it is only partially protonated under the acidic reaction conditions of nitration. Because the acetamido group is less activating than a free amino group (why?), nitration occurs only once.

PROBLEMS 23.22 Outline a preparation of , a sulfa drug, from aniline and any other reagents. (Hint: See Eq. 20.27, p. 971; also note that sulfonyl chlorides react with amines to form in much the same manner as carboxylic acid chlorides.) O S H2NSNH2 LLc LS O sulfanilamide

23.23 Outline a preparation of each of the following compounds from aniline and any other reagents. (a) 2,4- (b) sulfathiazole, a sulfa drug. (Hint: 2-Aminothiazole is a readily available .) O S N N H2NSNH H2N LLLc LS S L S O 2-aminothiazole sulfathiazole

23.10 DIAZOTIZATION; REACTIONS OF DIAZONIUM IONS

A. Formation and Substitution Reactions of Diazonium Salts The reactions considered in previous sections show that the chemistry of the amino group vaguely resembles that of the . Amino groups, like hydroxy groups, can both