Leuckart reaction

The Leuckart reaction is the chemical reaction that converts aldehydes or ketones to amines by reductive amination. The reaction, named after Rudolf Leuckart, proceeds via two mechanisms: one using ammonium formate and the other using formamide.

The ketone is converted to an amine via reductive amination using ammonium formate

History

The Leuckart reaction is named in honor of its developer, the German chemist Rudolf Leuckart (1854–1899). The son of the renowned zoologist, Karl Georg Friedrich Rudolf Leuckart, Rudolf Leuckart received his PhD from the University of Leipzig in 1879, and later became a professor at the University of Göttingen. He stumbled upon this reaction when he discovered that heating benzaldehyde with formamide didn't produce benzylidenediformamide as he anticipated, but benzylamine. In 1891, a colleague of Leuckart at the University of Göttingen, Otto Wallach, performed further reactions alicyclic and terpenoid ketones as well as aldehydes, demonstrating the general application. Over the course of the past century, chemists have discovered several methods to improve the yield of the reaction and carry it out under less strenuous conditions. Pollard and Young summarized various ways in which amines can be formed: using either formamide or ammonium formate, or both, or adding formic acid to formamide. However, using just ammonium formate as reagent produces the best yields. Using formamide produces low yields compared to ammonium formate but yields can be increased by using large amount of formamide, or using ammonium formate, ammonium sulfate, and magnesium chloride as catalysts.

Mechanism

Ammonium formate as reagent:

Ammonium formate first dissociates into formic acid and ammonia. Ammonia then performs a nucleophilic attack on the carbonyl carbon. The Oxygen deprotonates Hydrogen from Nitrogen to form a hydroxyl. The hydroxyl is protonated using Hydrogen from formic acid, which allows for water molecule to leave. This forms a carbocation, and is resonance stabilized. The compound attacks hydrogen from the deprotonated formic acid from previous step, forming a carbon dioxide and an amine.

Formamide as reagent:

Formamide 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 reducing agent and adds on to the N-formyl derivative. Hydride shifts occurs, resulting in loss of carbon dioxide. Ammonium ion is added forming an imine and releasing ammonia. The imine goes through hydrolysis to form amine.

Applications

A notable example of the Leuckart reaction is its use the synthesis of tetrahydro-1,4 benzodiazepin-5-ones, a molecule that is part of the benzodiazepine family. Many compounds in this family of molecules are central nervous system suppressants and are associated with therapeutic uses and a variety of medications, such as antibiotics, antiulcer, and anti-HIV agents. Researchers were able to synthesize tetrahydro-1,4-benzodiazepines with excellent yields and purities by utilizing the Leuckart Reaction.

See also

• Eschweiler–Clarke reaction