Reductive amination (also known as reductive alkylation) is a form of amination that converts a carbonyl group to an amine via an intermediate imine. The carbonyl group is most commonly a ketone or an aldehyde. It is a common method to make amines and is widely used in green chemistry since it can be done catalytically in one-pot under mild conditions. In biochemistry, dehydrogenase enzymes use reductive amination to produce the amino acid glutamate. Additionally, there is ongoing research on alternative synthesis mechanisms with various metal catalysts which allow the reaction to be less energy taxing, and require milder reaction conditions. Investigation into biocatalysts, such as imine reductases, have allowed for higher selectivity in the reduction of chiral amines which is an important factor in pharmaceutical synthesis.

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Reaction process

Reductive amination occurs between a carbonyl such as an aldehyde or ketone and an amine in the presence of a reducing agent. The reaction conditions are neutral or weakly acidic. The equilibrium between aldehyde/ketone and imine is shifted toward imine formation by dehydration.

There are two ways to conduct a reductive amination reaction: direct and indirect.

  1. Chemoselectivity issues may arise since the carbonyl group can also be reduced.
  2. The reaction between the carbonyl and amine are in equilibrium, favouring the carbonyl unless water is removed from the system.
  3. reduction-sensitive intermediates may form in the reaction which can affect chemoselectivity.
  4. The amine substrate, imine intermediate, or amine product might deactivate the catalyst.
  5. Acyclic imines have E/Z isomers. This makes it difficult to create enantiopure chiral compounds through stereoselective reductions.

To solve the last issue, asymmetric reductive amination reactions can be used to synthesize an enantiopure product of chiral amines. The carbonyl undergoes condensation with an amine in the presence of H<sub>2</sub> and a chiral catalyst to form the imine intermediate, which is then reduced to form the amine. As the pH increases, the reduction rate slows and instead, the imine intermediate becomes preferential for reduction. STAB is a weaker reductant than NaBH<sub>4</sub>, and can preferentially reduce the imine group in the presence of other reduction-sensitive functional groups. While STAB has also been reported as a selective reducing agent for aldehydes in the presence of keto groups, standard reductive amination reaction conditions greatly favour imine reduction to form an amine.

{| class="wikitable"

|+Physical and Chemical Characteristics of Common Reducing Agents

|

|H<sub>2</sub>/Pd

|NaBH<sub>4</sub>

|NaBH(OAc) <sub>3</sub>

|NaBH<sub>3</sub>CN

|CO/Rh

|-

|Selectivity

|Low

|Low

|High

|High

|High

|-

|Atom economy

|High

|Solid wastes

|Solid wastes

|Solid wastes

|High

|-

|Work up

|Required

|Not required

|Not required

|Not required

|Required

|-

|Flammability

|High

|Low

|High

|High

|High

|-

|Sensitivity to H<sub>2</sub>O, O<sub>2</sub>

|Low

|High

|High

|High

|Low

|-

|Toxicity

|None

|High, Carcinogen

|Low

|High

|High

|}

The reductive amination reaction is related to the Eschweiler–Clarke reaction, in which amines are methylated to tertiary amines, the Leuckart–Wallach reaction, and 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. An example of this reaction is the synthesis of 1-phenylethylamine from acetophenone:

:center|Reductive amination acetophenone ammonia

Additionally, many systems catalyze reductive aminations with hydrogenation catalysts. Generally, catalysis is preferred to stoichiometric reactions as they may improve reaction efficiency and atom economy, and produce less waste. These reactions can utilize homogeneous or heterogeneous catalyst systems. As well, this method can be used in the reduction of alcohols, along with aldehydes and ketones to form the amine product. Nickel is commonly used as a catalyst for reductive amination because of its abundance and relatively good catalytic activity.

alt=Figure of a reaction scheme of Ni-catalyzed reductive amination: First, the nickel metal dehydrogenates the alcohol to form a ketone and Ni-H complex. Then, the ketone reacts with ammonia to form an imine. Finally, the imine reacts with Ni-H to regenerate catalyst and form primary amine.|center|frameless|485x485px|First, the nickel metal dehydrogenates the alcohol to form a ketone and Ni-H complex. Then, the ketone reacts with ammonia to form an imine. Finally, the imine reacts with Ni-H to regenerate catalyst and form primary amine.

An example of a homogeneous catalytic system is the reductive amination of ketones done with an iridium catalyst. Homogenous Iridium (III) catalysts have been shown to be effective in the reductive amination of carboxylic acids, which in the past has been more difficult than aldehydes and ketones. Reductive amination can occur sequentially in one-pot reactions, which eliminates the need for intermediate purifications and reduces waste. The use of enzymes as a catalyst is advantageous because the enzyme active sites are often stereospecific and have the ability to selectively synthesize a certain enantiomer. This is useful in the pharmaceutical industry, particularly for drug-development, because enantiomer pairs can have different reactivities in the body. Additionally, enzyme biocatalysts are often quite selective in reactivity so they can be used in the presence of other functional groups, without the use of protecting groups. For instance a class of enzymes called imine reductases, IREDs, can be used to catalyze direct asymmetric reductive amination to form chiral amines.