Amides

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Chapter: Organic Chemistry : Functional Group Synthesis

Amides are usually obtained from carboxylic acids or their derivatives. The tradi-tional method of preparation of amides is to react the corresponding acid chloride with an amine.


AMIDES

Amides are usually obtained from carboxylic acids or their derivatives. The tradi-tional method of preparation of amides is to react the corresponding acid chloride with an amine.


This substitution process replaces the chloride with an amine without a change in the oxidation level. This remains an excellent and efficient method. However, excess amine or another base is required to neutralize the equivalent of HCl produced by the substitution.

In this approach, formation of an acid chloride is required to activate the car-bonyl group and make it more electrophilic. This activation is required in most transformations of carboxylic acids because carboxylic acids themselves are not sufficiently electrophilic to react with most nucleophiles. Furthermore, since many nucleophiles are also basic, they can react with carboxylic acids to give the car-boxylate ion, which is an even poorer electrophile than the carboxylic acid itself.

Carbodiimides are increasingly being used to promote the conversion of car-boxylic acids to amides. This method was originally developed for creating the amide bonds in peptides. In this method the carboxylic acid is treated with a carbodiimide [a very common one is dicyclohexylcarbodiimide (DCC), although many others have been developed]. An activated acylating agent is produced which reacts with the amine present in the mixture to produce an amide. The advantage of this approach is that the acid is activated to a reactive electrophile in situ so the activated species need not be isolated. Yields are normally high and the urea by-product from the carbodiimide can be separated and removed from the amide by one of several methods.


Amides are also available from nitriles, which have the same oxidation level. Direct acid or base hydrolysis of a nitrile usually requires fairly severe conditions and often does not stop at the amide stage but goes on the carboxylic acid. Treatment of nitriles with a solution of HCl in ethanol furnishes an imidate ester which is hydrolyzed in aqueous acid to the amide. Because a nitrile is the starting material, only primary amides can be produced by this process.



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