Reductive Amination - Reaction Process

Reaction Process

In this organic reaction, the amine first reacts with the carbonyl group to form a hemiaminal species, which subsequently loses one molecule of water in a reversible manner by alkylimino-de-oxo-bisubstitution, to form the imine. The equilibrium between aldehyde/ketone and imine can be shifted toward imine formation by removal of the formed water through physical or chemical means. This intermediate imine can then be isolated and reduced with a suitable reducing agent (e.g., sodium borohydride). This is indirect reductive amination.

However, it is also possible to carry out the same reaction simultaneously, with the imine formation and reduction occurring concurrently. This is known as direct reductive amination, and is carried out with reducing agents that are more reactive toward protonated imines than ketones, and that are stable under moderately acidic conditions. These include sodium cyanoborohydride (NaBH₃CN) and sodium triacetoxyborohydride (NaBH(OCOCH₃)₃). This reaction has in recent years been performed in an aqueous environment casting doubt on the necessity of forming the imine. This is because the loss of the water molecule is thermodynamically disfavoured by the presence of a large amount of water in its environment, as seen in the work of Turner et al. Therefore, this suggests that in some cases the reaction proceeds via direct reduction of the hemiaminal species.