organic chemistry II

A.    AMIDES

1.      Introducing Amides

Amides, like ester, are abundant in all living organisms-protein, nucleic acids, and many pharmaceuticals have amide finctional groups. The reason for this abundance of amides, of course, is that they are stable on the conditions found in living organisms. Amide are the least reactive of the common acid derivatives and undergo reatively few necleophilic acyl substitution reactions.

2.      Preparation of Amides

Amides are usually prepared by reaction of an acid chloride with an amine. Ammonia, monosubstituted amines, and disubstituted amines all undergo the reaction.

3.      Reactions of Amides

a.      Conversion of Amides into Carboxylic Acid

Hydrolysis Amides undergo hydrolysis to yield carboxylic acids plus ammoniua or an amine on heating in either equeous acid or aqueous base. The conditions required for amide hydrilysis are more severe than those required for the hydrilysis of acid chlorides or ester, but the mechanisms are similar. Acidic hydrolysis reaction occur by necleophilic addition of water to the protonated amide, followed by transfer of a proton from oxygen to nitrogen to make the nitrogen a better leaving group and subsequent elimination. The step are revesible, with the equilibrium shifted toward product by protonation of NH₃ in the final step.

Basic hydrolysis accur by necleophilic addition of OH^- to the amide carbonyl group, followed by elimination of amide ion (-NH₂) and subsequent deprotonation of initially formed carboxylic acid by amide ion. The steps are reversible, with the equilibrium shifted toward pruduct by the final deprotonation of the carboxylic acid. Basic hydrilysis is substantially more difficult than the analogous acid-catalyzed reaction because amide ion is very poor leaving group, making the elimination step difficult.

Amide hydrolysis is common in biological chemisrty. Just as the hydrolysis of ester is the initial step in digestion of dietary fats, the hydrolysis of amides is the initial step in the digestion of dietary proteins. The reaction catalyzed by protease enzymes and occur by a mechanism almost identical to that we just saw for fat hydrolysis. That is, an intial necleophilic acyl substitution of an alcohol group in the enzyme on an amide linkage in the protein gives an acyl enzyme intermediate that them undergoes hydrolysis.

b.      Conversion of Amides into Amine

Reduction Like other carboxylic acid derivatives, amide can be reduced by LiAlH₄. The product of the reduction, however, is an amine rather that an alcohol. The net effect of an amide reduction reaction is thus the conversion of the amide carbonyl group into a methylene group (C=O àCH₂). This kind of reaction is specific for amides and doesn’t occur with other carboxylic acid derivatives.

Amide reduction occurs by necleophilic addition of hydride ion the amide carbonyl group, followed by expulsion of the oxygen atom as an aluminate anion leaving group to give an iminium ion intermediate. The intermediate iminium ion is then further reduced by LiAlH₄ to yield the amine.

The reaction is effective with both acylic and cyclic amides, or Lactams, and is a good method for preparing cyclic amines.