Reductive Amination

Reductive amination (also known as reductive alkylation) is a form of amination that 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. It is considered the most important way to make amines, and a majority of amines made in the pharmaceutical industry are made this way.

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 method is sometimes called indirect reductive amination.

In a separate approach, imine formation and reduction can occur sequentially in one pot. This approach, known as direct reductive amination (Borch reaction), employs reducing agents that only react slowly (or not at all) with the ketone/aldehyde precursors. These hydride reagents also must tolerate moderately acidic conditions. Typical reagents that meet these criteria include sodium cyanoborohydride (NaBH₃CN) and sodium triacetoxyborohydride (NaBH(OCOCH₃)₃). These reactions are generally conducted at pH ~ 5, typically using a weak acid (e.g., acetic acid) as a catalyst. Under these conditions, the reaction of the carbonyl and amine results in formation of a small amount of the iminium ion (R₁R₂C=N⁺R₃R₄), which is reduced much more readily than the carbonyl starting material. As a result, the selective reduction of the iminium takes place to give the amine (rather than direct reduction of the carbonyl to form the alcohol).

Variations and related reactions

This reaction is related to the Eschweiler–Clarke reaction, in which amines are methylated to tertiary amines, the Leuckart–Wallach reaction, or by other amine alkylation methods such as the Mannich reaction and Petasis reaction.

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 1-phenylethylamine starting from acetophenone:
:
Nowadays, one-pot reductive amination fulfil by acid-metal catalysts that act as a hydride transfer. Much research study on this kind of reaction show high efficiency.

In industry, tertiary amines such as triethylamine and diisopropylethylamine are formed directly from ketones with a gaseous mixture of ammonia and hydrogen and a suitable catalyst.

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 pyridoxamine phosphate, which is converted into pyridoxal phosphate after the reaction. 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.Nelson, D. L.; Cox, M. M. "Lehninger, Principles of Biochemistry" 3rd Ed. Worth Publishing: New York, 2000. . 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.

In popular culture

In the critically acclaimed drama Breaking Bad, main character Walter White uses the reductive amination reaction to produce his high purity methamphetamine, relying on phenyl-2-propanone and methylamine. The phenyl-2-propanone (otherwise known as phenylacetone or P2P) is produced from phenylacetic acid and acetic acid using a tube furnace and thorium dioxide (ThO₂) as a catalyst.

See also

* Forster–Decker method
* Leuckart reaction

References

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External links

Current methods for reductive amination
* Industrial reductive amination a


Organic redox reactions