Mechanistic insights into boron-catalysed direct amidation reactions

Abstract

The generally accepted 'mechanism' of boron-catalysed direct amidation is brought into question in this study and new alternatives considered. The interactions of borinic acids and boronic acids separately with amines, carboxylic acids and mixutres of both have resulted in a number of novel complexes, many characterised by X-ray crystallography in addition to spectroscopic techniques. Rapid reaction between amines and the various boron compounds was observed in all cases, and it is proposed that such boron-nitrogen interactions are highly likely to take place in catalytic amidation reactions. These studies also clearly show that whilst boronic acids are capable of catalysing amidation reactions, borinic acids are not and that protodeboroation occurs in preference, or unreactive amino-carboxylate complexes are formed, which are readily isolated and characterised by X-ray crystallography. The catalytic activity of boronic acids can be explained by the need for at least three free coordination sites on the boron atom for amidation to occur which is seemingly necessary for catalytic activity. However, these observations are not consistent with the currently accepted 'mechanism' for boron-mediated amidation reactions involving nucleophilic attack of an amine onto a monomeric acyloxyboron intermediate, and as a result of these observations and theroetical modelling, alternative proposed mechanisms are presented for the boron-mediated amidation reactions. These are likely to proceed via the formation of the important structural motif of a dimeric B-X-B species, which is uniquely able to provide sufficient activation of the carboxylic acid, whilst orchestrating the delivery of the amine nucleophile to the activated carbonyl group. Quantum mechanical calculations have enabled the proposal of several closely related potential pathways for amidation, all of which are likely to be lower in energy than the currently accepted mechanism.