Direct Amide Formation Between Carboxylic Acids and Amines: Mechanism and Development of Novel Catalytic Solutions

Abstract

Despite the amide formation reaction being a key reaction in organic chemistry, the direct amide formation reaction is both little used and little explored. Acceptance of the feasibility and general applicability of this reaction depends upon the development of both an understanding of the mechanism of the reaction, and the design of catalysts, which can promote the reaction on a wide range of substrates and under ambient conditions.

Investigations into uncatalysed direct amide formation began with calorimetric studies of the mixing of a series of carboxylic acids and amines in order to measure heat output, which has been compared with their ability to react to form carboxylate ammonium salts and amides. In order to identify which species (salt or H-bonded species) were formed, 1H NMR studies were also carried out by mixing the substrates in d8-toluene and monitoring the resulting reactions. These experiments were also compared to DFT computational studies, from which the relative merits of different mechanistic schemes for direct amide formation could be assessed. A neutral intermediate pathway, involving carboxylic acid dimerisation via mutual hydrogen bonding was found to be accessible and may explain how the direct amide formation reaction occurs.

The synthesis of novel boronic acid compounds, which display the potential to act as catalysts for direct amide formation, has been attempted. Although the formation and purification of a reasonable amount of material for catalytic screening proved to be extremely difficult, progress towards the synthesis of these potential catalysts has been made.

The application of direct amide formation to the synthesis of key intermediates for some economically important, commercial syntheses has been assessed. The results of these reactions display a varying degree of success and largely depend on the properties of the substrates used. Further investigations are therefore required to ensure that direct amide formation becomes a general tool for a wide range of carboxylic acid and amine partners.