Transfer hydrogenation

Transfer Hydrogenation

Transfer hydrogenation intermediate

Transfer hydrogenation is a chemical reaction that involves the addition of hydrogen to a substrate from a donor molecule, rather than from molecular hydrogen (H₂). This process is widely used in organic synthesis for the reduction of various functional groups, such as carbonyls, imines, and alkenes. Transfer hydrogenation is often preferred over direct hydrogenation due to its operational simplicity and the avoidance of high-pressure hydrogen gas.

Mechanism

The mechanism of transfer hydrogenation typically involves the use of a catalyst that facilitates the transfer of hydrogen from a donor molecule to the substrate. Common hydrogen donors include alcohols, formic acid, and hydrazine. The catalyst often contains a transition metal, such as ruthenium, palladium, or iridium.

Ikariya-style transfer hydrogenation

In a typical catalytic cycle, the hydrogen donor first coordinates to the metal center, followed by the formation of a metal-hydride intermediate. The substrate then coordinates to the metal, and hydrogen is transferred from the metal to the substrate, resulting in the reduced product and regeneration of the catalyst.

Applications

Transfer hydrogenation is used in the synthesis of a wide range of chemical compounds, including pharmaceuticals, agrochemicals, and fine chemicals. It is particularly valuable in the reduction of carbonyl compounds to alcohols and imines to amines.

Pharmaceutical Synthesis

Reduction step in Asenapine synthesis

In the pharmaceutical industry, transfer hydrogenation is employed in the synthesis of active pharmaceutical ingredients (APIs). For example, the reduction step in the synthesis of asenapine, an atypical antipsychotic, involves transfer hydrogenation.

Asymmetric Transfer Hydrogenation

Asymmetric organocatalytic transfer hydrogenation

Asymmetric transfer hydrogenation is a variant of the reaction that allows for the enantioselective reduction of prochiral substrates. This is achieved by using chiral catalysts, which induce asymmetry in the product. Asymmetric transfer hydrogenation is a powerful tool in the synthesis of chiral molecules, which are important in the production of enantiomerically pure pharmaceuticals.

Organocatalytic Transfer Hydrogenation

Organocatalytic transfer hydrogenation

Organocatalytic transfer hydrogenation involves the use of organic molecules as catalysts, rather than metal-based catalysts. This approach is advantageous due to the lower toxicity and environmental impact of organocatalysts. Organocatalytic methods have been developed for the reduction of a variety of functional groups, including enones and imines.

MacMillan asymmetric organocatalytic transfer hydrogenation

Related Pages

• Hydrogenation
• Catalysis
• Asymmetric synthesis
• Organocatalysis