Preparation of Substituted Anilines

For the preparation of o-nitroaniline the method outlined above may be used. Nitration at a temperature of 40° is employed so as to increase the proportion of the o-nitroacetanilide to 25 per cent. Another variation is to treat aniline with excess of acetic anhydride and then with nitric acid. Acetanilide is first formed, which in the presence of acetic anhydride nitrates to give a larger proportion of the ortho isomer. The nitrating agent is assumed to be acetyl nitrate, CHaCOONOs. Finally, a number of indirect methods are 

These reactions depend on the inductive effect of the nitro group on the other groups in the ring, which results in easier replacement. The sulfonic acid used in the last equation is obtained by first sul-fonating acetanilide and then nitrating. 

For the preparation of OT-nitroaniline, nitrobenzene is nitrated to give m-dinitrobenzene. When this compound is reduced by an alkaline sulfide, the reduction can be controlled so that only one of the two nitro groups is reduced to form m-nitroaniline. 

Somewhat similar methods are used in the preparation of bromo-anilines. Consider, for example, the preparation of p-bromoaniline. The action of bromine on aniline gives quantitatively 2, 4, 6-tribro-moaniline. If aniline is first acetylated and then brominated, ortho-and poro-bromoacetanilides are formed with the para isomer predominating. The ortho compound is more soluble in alcohol than the para isomer, and thus can be removed by crystallization. The p-bromoacetanilide is then hydrolyzed. A variation of this method is to add bromine very slowly to aniline dissolved in a large excess of glacial acetic acid, when p-bromoaniline is directly formed, thereby eliminating acylation and hydrolysis. 

Nitration. Pulverize the crystals of acetanilide and place 5 g in a 250-ml beaker. Add 5 ml of glacial acetic acid and then, with stirring, 10 ml of concentrated sulfuric acid. Cool in an ice-salt mixture, and add through a dropper 2 ml of fuming nitric acid. 

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The prevalence of the aniline functional group in alkaloid natural products of medicinal interest has inspired a number of metal-catalyzed strategies for the preparation of substituted anilines. One classical method, a variation of the Ullman aryl ether synthesis, features copper catalysis. This method generally suffers from harsh reaction conditions and limited substrate scope. Nonetheless, the simplicity of the transformation and the inexpensiveness of copper catalysis has prompted additional development of this strategy. For instance, cyclohexylphenylamine is formed in excellent yield from the copper(I) iodide-catalyzed amination of iodobenzene. ... 

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