Reductive Amination of Aldehydes and Ketones

The addition of the amine group into any organic compounds is called amination. Introducing an amine in an organic compound is termed amination. Because organonitrogen compounds are inevitable, this type of reaction is significant. An aldehyde is an organic molecule with a carbonyl group linked to a carbon atom at the carbon chain terminus. A ketone is an organic molecule that has a carbonyl group linked to one of the carbon atoms in the carbon chain.

Basic method reactions

• Aminase enzyme

Aminases are enzymes that are used to catalyse this process. Amination can take place in a variety of methods, alkylation with the help of ammonia or any different amine, reductive amination, and the Mannich reaction are some of them.

• Hydrobromination using acid catalyst

Industrially, in large amounts production of alkylamines is done by the amination of alcohols, in which solid acid acts as a catalyst in the presence of ammonia.

• Miscellaneous methods

Aqueous ammonia solution, hydrogen gas, and a heterogeneous metallic ruthenium catalyst are utilised to convert alpha-hydroxy acid chains into amino acids.

• Reductive amination

Reductive amination is also known as reductive alkylation, one of the types of amination in which an amine is formed by converting the carbonyl group through the use of an intermediate imine. A ketone or an aldehyde is the most frequent carbonyl group. It is the most important method for producing amines, and it produces the majority of amines produced in the pharmaceutical sector. 

• Reaction process

For reductive amination of aldehydes and ketones, sodium triacetoxyborohydride is utilised as a reducing agent. Acyclic and cyclic aliphatic ketones, aliphatic and aromatic aldehydes, and 1° and 2° amines, along with a range of weakly basic and non-basic amines, are all included in this sort of reaction. Aromatic and unsaturated ketones reactions, as well as several sterically hindered ketones and amines, are restricted. 1,2-dichloroethane (DCE), but reactions could be performed in tetrahydrofuran (THF) also and, on rare occasions, acetonitrile preferred solvents. In the case of ketone reactions, acetic acid acts as a catalyst but is rarely required in aldehyde reactions. The approach works well for acid-sensitive functional groups like acetals and ketals, as well as reducible functional groups like C-C multiple bonds and CN- and NO2 groups. THF reactions are slower than DCR reactions, but in the case of both solvents, in case of AcOH reactions are faster. Various reductive amination procedures, such as NaBH3CN/MeOH, borane pyridine, and catalytic hydrogenation, generate higher yields and fewer side products than NaBH(OAc)3. We used a stepwise process including imine production in MeOH after that reduction is done with the help of NaBH4 to reductive amination of certain aldehydes with primary amines when dialkylation was an issue.

• Reductive amination of aldehydes and ketones

In this type of chemical reaction, the amine reacts with the carbonyl group to generate a hemiaminal species, then removal of one water molecule is done reversibly via alkyliminodeoxo-bi substitution. The balance between aldehyde/ketone and imine creation can be changed toward imine formation by physically or chemically removing the generated water. After that, the intermediate formed in the reaction can be separated and it can be reduced with the help of appropriate reducing agents such as sodium borohydride. Indirect reductive amination is a term used to describe this technique.

Imine synthesis and reduction can be done in one pot using a different method. Direct reductive amination also known as Borch reaction, in this method slowly reacting reducing agents are used with ketone/aldehyde precursors. The reagents must be tolerant to moderate acidity. Sodium cyanoborohydride is a common reagent that meets these requirements. These reactions are normally carried out at pH 3 to 7, with weak acid like acetic acid acting as a catalyst. Under this kind of condition, small amounts of iminium ions can be produced by combining carbonyl and amine, which can be reduced more easily than the carbonyl starting material. As a result, the amine is formed by the selective reduction of iminium.

General reaction for Reductive amination of Aldehyde:

R2N–H  +  CH2=O  →  R2N–CH2  +  H2O

• Role in biochemistry

The step used in the biosynthesis of numerous amino acids is reductive amination of alpha-keto acid, commonly done by a transaminase enzyme. Pyridoxamine phosphate, which is transformed to pyridoxal phosphate following the reaction, catalyses the reaction. The imine is formed first; reduced pyridine supplies the hydride counterparts, resulting in an aldimine, subsequently hydrolyzes to the amine.

Conclusion

Reductive amination or reductive alkylation is a type of amination in which an amine is formed by the change in the carbonyl group, through the use of an intermediate imine.

Acid-metal catalysts that operate as hydride transfer are being used to perform one-pot reductive amination. This kind of reaction has been studied extensively, and the results reveal that it is extremely efficient. For such reductive amination of aldehydes and ketones, a universal reducing agent has been used namely sodium triacetoxyborohydride.