Leuckart reaction

History

The Leuckart reaction is named in honor of its developer, the German chemist Rudolf Leuckart (1854–1899). He discovered that heating benzaldehyde with formamide does not produce benzylidenediformamide as anticipated, but benzylamine. In 1891, a colleague of Leuckart at the University of Göttingen, Otto Wallach, performed further reactions using alicyclic and terpenoid ketones as well as aldehydes, demonstrating the general application. However, using just ammonium formate as the reagent produces the best yields.

Mechanism

Ammonium formate as reagent

Ammonium formate is a source of formic acid and ammonia. Starting with nucleophilic attack on the carbonyl by the ammonia, the carbonyl is converted to the iminium ion:

: : The iminium is then reduced by the formate: :

Formamide as reagent

Formamide first nucleophilically attacks the carbonyl carbon. The oxygen is protonated by abstracting hydrogen from the nitrogen atom, subsequently forming a water molecule that leaves, forming N-formyl derivative, which is resonance stabilized. Water hydrolyzes formamide to give ammonium formate, which acts as a reducing agent and adds on to the N-formyl derivative. Hydride shift occurs, resulting in loss of carbon dioxide. An ammonium ion is added forming an imine and releasing ammonia. The imine goes through hydrolysis to form the amine, which is depicted in the scheme below.

Applications

An example of the Leuckart reaction is its use in the synthesis of tetrahydro-1,4 benzodiazepin-5-one, a molecule that is part of the benzodiazepine family.

References

References

1. (2011). "Organic Reactions".
2. Crossley, Frank S.. (1944). "Studies on the Leuckart Reaction". Journal of Organic Chemistry.
3. Pollard, C.B.. (1951). "The Mechanism of the Leuckart Reaction". Journal of Organic Chemistry.
4. Alexander, Elliot. (1948). "Studies on the Mechanism of the Leuckart Reaction". Journal of the American Chemical Society.
5. Webers, Vincent J.. (1948). "The Leuckart Reaction: A study of the Mechanism". Journal of the American Chemical Society.
6. (1937). "α-Phenylethylamine". Organic Syntheses.
7. Lee, Sung-Chan. (2007). "Novel application of Leuckart–Wallach reaction for synthesis of tetrahydro-1,4-benzodiazepin-5-ones library". Chemical Communications.