User:Ezpzii/Reductive amination

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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 usually 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 which various metal catalysts which require more mild reaction conditions, allowing the reaction to be less energy taxing. Investigation into biocatalysts, such as lRED, have allowed for the reduction of chiral amines which is an important factor in pharmaceutical synthesis.

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 intermediates of a reductive amination 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 intermediate. The equilibrium between aldehyde/ketone and imine is shifted toward imine formation by dehydration. This intermediate imine can then be isolated and reduced with a suitable reducing agent (e.g., sodium borohydride) to produce the final amine product. Intramolecular reductive amination can also occur to afford a cyclic amine product if the amine and the carbonyl are on the same molecule of the starting material.

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.

1. Chemoselectivity issues may arise since the carbonyl group is also reducible.
2. The reaction between the carbonyl and amine are in equilibrium, with favouring for the carbonyl side unless water is removed from the system.
3. Reducible intermediates may appear 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. In asymmetric reductive amination, a carbonyl that can be converted from achiral to chiral is used. 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

NaBH₄ reduces both imines and carbonyl groups. However, it is not very selective and can reduce other reducible functional groups present in the reaction. To ensure that this does not occur, reagents with weak electrophilic carbonyl groups, poor nucleophilic 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.

Sodium Cyanoborohydride

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

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

H₂/metal Catalyst

H₂/Pt and H₂/Pd are the two most common hydrogen/metal catalysts, but other metals such as Raney Nickel, Cobalt, Copper and Iron are also used. H₂/metal catalysts are a greener method compared to sodium cyanoborohydride since borate by-products are not produced and the metal catalysts can be recovered and reused.

In green chemistry

Reductive amination is commonly used over other methods such as SN2 type reactions with halides to produce an alkylamines 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.

Variations and related reactions

Additionally, there exists many systems which catalyze reductive amination with a hydrogenation catalyst. Generally, catalysis is preferred to stoichiometric reactions to enable the reaction to be more efficient, more atom economic, and to produce less waste. This can be either a homogeneous catalytic system or heterogeneous system. These systems provide an alternative method which is efficient, requires fewer volatile reagents and is redox economic. As well, this method can be used in the reduction of alcohols, along with aldehydes and ketones to form the amine product. One example of a heterogeneous catalytic system is the reductive amination of alcohols using the Ni-catalyzed system.

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.

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. Additionally, it has been shown to be effective to use a homogeneous Iridium (III) catalyst system to reductively aminate 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.

Ketone reacting with ammonium formate, catalyzed by iridium catalyst, to form primary amine.

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 reductase, IRED, can be used to catalyze direct asymmetric reductive amination to form chiral amines.