Reductive amination (also known asreductive alkylation) is a form ofamination that converts acarbonyl group to anamine via an intermediateimine. The carbonyl group is most commonly aketone or analdehyde. It is a common method to make amines and is widely used ingreen chemistry since it can be done catalytically inone-pot under mild conditions. In biochemistry,dehydrogenase enzymes use reductive amination to produce the amino acidglutamate. 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 asimine reductases, have allowed for higher selectivity in the reduction of chiral amines which is an important factor in pharmaceutical synthesis.^[1]

Reductive amination occurs between a carbonyl such as an aldehyde or ketone and an amine in the presence of areducing agent.^[2] The reaction conditions are neutral or weakly acidic.^[2]

1. The nucleophilic amine reacts at the carbon of the carbonyl group to form ahemiaminal species
2. reversible loss of one molecule of water from the hemiaminal species byalkylimino-de-oxo-bisubstitution to form the imine intermediate.^[3] The equilibrium between aldehyde/ketone and imine is shifted toward imine formation by dehydration.^[2]
3. The intermediate imine can be isolated or reacted in-situ with a suitable reducing agent (e.g.,sodium borohydride) to produce the amine product.^[2] Intramolecular reductive amination can also occur to afford a cyclic amine product if the amine and carbonyl are on the same molecule of starting material.^[4]

There are two ways to conduct a reductive amination reaction: direct and indirect.^[2]

In a direct reaction, the carbonyl and amine starting materials and the reducing agent are combined and the reductions are done sequentially.^[2] These are often one-pot reactions since the imine intermediate is not isolated before the final reduction to the product.^[2] Instead, as the reaction proceeds, the imine becomes favoured for reduction over the carbonyl starting material.^[2] The two most common methods for direct reductive amination arehydrogenation with catalytic platinum, palladium, or nickel catalysts and the use of hydride reducing agents likecyanoborohydride (NaBH₃CN).^[2]

Indirect reductive amination, also called a stepwise reduction, isolates the imine intermediate.^[2] In a separate step, the isolated imine intermediate is reduced to form the amine product.^[2]

There are many considerations to be made when designing a reductive amination reaction.^[5]

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 enantiopurechiral compounds through stereoselective reductions.

To solve the last issue,asymmetric reductive amination reactions can be used to synthesize an enantiopure product of chiral amines.^[5] In asymmetric reductive amination, a carbonyl that can be converted from achiral to chiral is used.^[6] The carbonyl undergoescondensation with an amine in the presence of H₂ and a chiral catalyst to form the imine intermediate, which is then reduced to form the amine.^[6] However, this method is still limiting to synthesize primary amines which are non-selective and prone to overalkylation.^[6]

Palladium hydride (H₂/Pd) is a versatile reducing agent commonly used in reductive amination reactions. Its catalytic efficiency stems from the ability of palladium to adsorb hydrogen gas, forming active hydride species. These hydrides facilitate the reduction of imines or iminium ions—key intermediates in reductive amination—into secondary or tertiary amines. This reaction typically occurs under mild conditions with excellent selectivity, which often makes H₂/Pd the first choice for synthesizing amines in pharmaceuticals and fine chemicals. Additionally, H₂/Pd is compatible with a wide range of functional groups, further enhancing its utility in complex organic synthesis.

Sodium borohydride (NaBH₄₎ reduces both imines and carbonyl groups.^[3] However, it is not very selective and can reduce other reducible functional groups present in the reaction.^[3] To ensure that this does not occur, reagents with weakelectrophilic carbonyl groups, poornucleophilic amines and sterically hindered reactive centres should not be used, as these properties do not favour the reduction of the carbonyl to form an imine and increases the chance that other functional groups will be reduced instead.^[3]

Sodium cyanoborohydride (NaBH₃CN) is soluble in hydroxylic solvents, stable in acidic solutions, and has different selectivities depending on the pH.^[2] At low pH values, it efficiently reduces aldehydes and ketones.^[7] As the pH increases, the reduction rate slows and instead, the imine intermediate becomes preferential for reduction.^[7] For this reason, NaBH₃CN is an ideal reducing agent for one-pot direct reductive amination reactions that don't isolate the intermediate imine.^[2]

When used as a reducing agent, NaBH₃CN can release toxic by-products like HCN and NaCN during work up.^[2]

Sodium triacetoxyborohydride (STAB, NaBH(OAc)₃) is a common reducing agent for reductive aminations. STAB selectively reduces the imine intermediate formed through dehydration of the molecule.^[8] STAB is a weaker reductant than NaBH₄, 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.^[9][10]

The reductive amination reaction is related to theEschweiler–Clarke reaction, in which amines are methylated to tertiary amines, theLeuckart–Wallach reaction,^[12] and otheramine alkylation methods such as theMannich reaction andPetasis reaction.

A classicnamed reaction is theMignonac reaction (1921)^[13] involving reaction of aketone withammonia over a nickel catalyst. An example of this reaction is the synthesis of1-phenylethylamine fromacetophenone:^[14]

Additionally, many systems catalyze reductive aminations withhydrogenation catalysts.^[15] Generally,catalysis is preferred to stoichiometric reactions as they may improve reaction efficiency andatom economy, and produce less waste.^[16] These reactions can utilize homogeneous or heterogeneous catalyst systems.^[15] These systems provide alternative synthesis routes which are efficient, require fewer volatile reagents and are redox-economical.^[15][17] As well, this method can be used in the reduction ofalcohols, along withaldehydes andketones to form theamine product.^[15] One example of a heterogeneous catalytic system is the Ni-catalyzed reductive amination of alcohols.^[15][18]Nickel is commonly used as a catalyst for reductive amination because of its abundance and relatively good catalytic activity.^[15][19]

An example of a homogeneous catalytic system is the reductive amination of ketones done with aniridium catalyst.^[20] Homogenous Iridium (III) catalysts have been shown to be effective in the reductive amination ofcarboxylic acids, which in the past has been more difficult than aldehydes and ketones.^[16] Homogeneous catalysts are often favored because they are more environmentally and economically friendly compared to most heterogeneous systems.^[15]

In industry, tertiary amines such astriethylamine anddiisopropylethylamine are formed directly from ketones with a gaseous mixture of ammonia andhydrogen and a suitable catalyst.

Reductive amination is commonly used over other methods for introducing amines to alkyl substrates, such asSN2-type reactions withhalides, since it can be done in mild conditions and has high selectivity for nitrogen-containing compounds.^[21][22] Reductive amination can occur sequentially in one-pot reactions, which eliminates the need for intermediate purifications and reduces waste.^[21] Some multistep synthetic pathways have been reduced to one step through one-pot reductive amination.^[21] This makes it a highly appealing method to produce amines in green chemistry.

In biochemistry,dehydrogenase enzymes can catalyze the reductive amination of α-keto acids and ammonia to yield α-amino acids. Reductive amination is predominantly used for the synthesis of the amino acidglutamate starting from α-ketoglutarate, while biochemistry largely relies ontransamination to introduce nitrogen in the other amino acids.^[23] The use ofenzymes as a catalyst is advantageous because the enzymeactive sites are oftenstereospecific and have the ability to selectively synthesize a certainenantiomer.^[24] This is useful in the pharmaceutical industry, particularly fordrug-development, because enantiomer pairs can have different reactivities in the body.^[1][25] Additionally, enzymebiocatalysts are often quite selective in reactivity so they can be used in the presence of other functional groups, without the use ofprotecting groups.^[24][26] For instance a class of enzymes calledimine reductases, IREDs, can be used to catalyze direct asymmetric reductive amination to form chiral amines.^[1][26]

In the critically acclaimed dramaBreaking Bad, main character Walter White uses the reductive amination reaction to produce his high puritymethamphetamine, relying onphenyl-2-propanone andmethylamine.

• Forster–Decker method
• Leuckart reaction

• Current methods for reductive amination

• Organic redox reactions

• CS1 errors: ISBN date
• CS1 French-language sources (fr)
• Articles with short description
• Short description is different from Wikidata
• Use dmy dates from April 2023