Reductive amination

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. Direct reductive amination In a direct reaction, the carbonyl and amine starting materials and the reducing agent are combined and the reductions are done sequentially. These are often one-pot reactions since the imine intermediate is not isolated before the final reduction to the product. Instead, as the reaction proceeds, the imine becomes favoured for reduction over the carbonyl starting material. The two most common methods for direct reductive amination are hydrogenation with catalytic platinum, palladium, or nickel catalysts and the use of hydride reducing agents like cyanoborohydride (NaBH3CN). Indirect reductive amination Indirect reductive amination, also called a stepwise reduction, isolates the imine intermediate. In a separate step, the isolated imine intermediate is reduced to form the amine product. == Designing a reductive amination reaction ==

There are many considerations to be made when designing a reductive amination reaction. • Chemoselectivity issues may arise since the carbonyl group can also be reduced. • The reaction between the carbonyl and amine are in equilibrium, favouring the carbonyl unless water is removed from the system. • reduction-sensitive intermediates may form in the reaction which can affect chemoselectivity. • The amine substrate, imine intermediate, or amine product might deactivate the catalyst. • 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 H2 and a chiral catalyst to form the imine intermediate, which is then reduced to form the amine. However, this method is still limiting to synthesize primary amines which are non-selective and prone to overalkylation. == Common reducing agents ==

Sodium borohydride Sodium borohydride (NaBH4) reduces both imines and carbonyl groups. As the pH increases, the reduction rate slows and instead, the imine intermediate becomes preferential for reduction. 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. == Variations and related reactions ==

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: : 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. 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. Homogeneous catalysts are often favored because they are more environmentally and economically friendly compared to most heterogeneous systems. 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. == In green chemistry ==

Reductive amination is commonly used over other methods for introducing amines to alkyl substrates, such as SN2-type reactions with halides, since it can be done in mild conditions and has high selectivity for nitrogen-containing compounds. Reductive amination can occur sequentially in one-pot reactions, which eliminates the need for intermediate purifications and reduces waste. Some multistep synthetic pathways have been reduced to one step through one-pot reductive amination. This makes it a highly appealing method to produce amines in green chemistry. == Biochemistry ==

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 acid glutamate starting from α-ketoglutarate, while biochemistry largely relies on transamination to introduce nitrogen in the other amino acids. 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. ==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. ==See also==