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Carboxylic Acid Derivatives

Formation of Carboxamides

Carboxylic acids may be converted into carboxamides by treating them with amines. However, the reaction does not proceed rapidly. First of all, the amine (base) is protonated by the carboxylic acid, thus yielding an ammonium carboxylate. The salt is then heated to eliminate water. As a result, the carboxamide is formed.

Formation of a carboxamide by treating with an amine and subsequent heating of the ammonium salt.

Water is a relatively poor leaving group. Thus, several reagents needed to be developed in order to convert the carboxylic acid's hydroxyl oxygen into a more efficient leaving group. An example of such a reagent is dicyclohexylcarbodiimide (DCC).

3D animation

In the Fischer esterification, the electrophilicity and, thus, the reactivity of the carboxylic acid in regard to a nucleophilic attack are increased by acid catalysis. In contrast, acid catalysis cannot be introduced into carboxamide formation, as the amine would then be protonated. As a result, the ammonium ion that has been produced would no longer be able to attack the carboxylic acid nucleophilically, as it does not contain a lone electron pair. Reagents like DCC are therefore necessary in increasing the reactivity of the carboxylic acid in carboxamide synthesis.

Example of a carboxamide synthesis with DCC.

As a result of activation through DCC, the carboxylic acid's hydroxy group is converted into dicyclohexylurea, which is an effective leaving group.

Activation of carboxylic acids by DCC.

The DCC-activated carboxylic acid may either be nucleophilically attacked by the amine or by another carboxylic acid. In the first case (mechanism 1, click on "Mechanism" below), the carboxamide is directly formed by a tetrahedral intermediate through the elimination of dicyclohexylurea. In the second case (mechanism 2, click on "Mechanism" below), an intermediate carboxylic acid anhydride is formed which is subsequently attacked by the amine that yields a carboxamide and a carboxylic acid molecule.


Exercise: Formation of carboxamides

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