Definitions

direct ex amination

Reductive amination

Reductive amination (also known as reductive alkylation) is a chemical reaction which involves the conversion of a carbonyl group to an amine, via an intermediate imine. The carbonyl group is most commonly a ketone or an aldehyde.

Reaction mechanism

In organic synthesis

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 all in one pot, 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 which 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. This therefore, suggests that in some cases the reaction proceeds via direct reduction of the hemiaminal species.

This reaction is related to the Eschweiler-Clarke reaction in which amines are methylated to tertiary amines, the Leuckart-Wallach reaction with formic acid and to other amine alkylation methods as the Mannich reaction and the Petasis reaction.

Scope

A classic named reaction is the Mignonac Reaction (1921) involving reaction of a ketone with ammonia over a nickel catalyst for example in a synthesis of alpha-phenylethylamine starting from acetophenone.

In industry, tertiary amines such as triethylamine and Hunig's base, are formed directly from ketones with a gasmixture of ammonia and hydrogen and a suitable catalyst .

The reaction depicted below is an example of an asymmetric reductive amination of an aryl ketone and an aniline.

The formation of only one enantiomer from the racemic reactant is attributed to dynamic kinetic resolution because both enantiomers in the racemic imine intermediate interconvert through their common enamine.

Biochemistry

A step in the biosynthesis of many α-amino acids is the reductive amination of an α-ketoacid, usually by a transaminase enzyme. The process is catalyzed by pyridoxal phosphate and the ammonia source is glutamate. The initial step entails formation of an imine, but the hydride equivalents are supplied by a reduced pyridine to give an aldimine, which hydrolyzes to the amine. The sequence from keto-acid to amino acid can be summarized as follows:
HO2CC(O)R → HO2CC(=NCH2-X)R → HO2CCH(N=CH-X)R → HO2CCH(NH2)R

External links

References

See also

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