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 Ã CH2).
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.
