The Leuckart reaction is the

chemical reaction A chemical reaction is a process that leads to the chemistry, chemical transformation of one set of chemical substances to another. When chemical reactions occur, the atoms are rearranged and the reaction is accompanied by an Gibbs free energy, ...

that converts aldehydes or

ketones In organic chemistry, a ketone is an organic compound with the structure , where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group (a carbon-oxygen double bond C=O). The simplest ketone is acetone ( ...

amines In chemistry, amines (, ) are organic compounds that contain carbon-nitrogen bonds. Amines are formed when one or more hydrogen atoms in ammonia are replaced by alkyl or aryl groups. The nitrogen atom in an amine possesses a lone pair of elec ...

. The reaction is an example of

reductive amination Reductive amination (also known as reductive alkylation) is a form of amination that converts a carbonyl group to an amine via an intermediate imine. The carbonyl group is most commonly a ketone or an aldehyde. It is a common method to make amine ...

. The reaction, named after

Rudolf Leuckart Karl Georg Friedrich Rudolf Leuckart (7 October 1822 – 22 February 1898) was a German zoologist born in Helmstedt. He was a pioneer of parasitology research and was widely known for developing a series of illustrated wall charts for use in zo ...

, uses either

ammonium formate Ammonium formate, NH4HCO2, is the ammonium salt of formic acid. It is a colorless, hygroscopic, crystalline solid. Reductive amination Acetone can be transformed into isopropylamine as follows: :CH3C(O)CH3 + 2 HCO2− +NH4 → (CH3)2CHNHCHO + 2 ...

formamide Formamide is an amide derived from formic acid. It is a colorless liquid which is miscible with water and has an ammonia-like odor. It is chemical feedstock for the manufacture of sulfa drugs and other pharmaceuticals, herbicides and pesticides, ...

as the nitrogen donor and

reducing agent In chemistry, a reducing agent (also known as a reductant, reducer, or electron donor) is a chemical species that "donates" an electron to an (called the , , , or ). Examples of substances that are common reducing agents include hydrogen, carbon ...

. It requires high temperatures, usually between 120 and 130 °C; for the formamide variant, the temperature can be greater than 165 °C. Leuckart Reaction Scheme

History

The Leuckart reaction is named in honor of its developer, the German chemist

(1854–1899). He discovered that heating

benzaldehyde Benzaldehyde (C6H5CHO) is an organic compound consisting of a benzene ring with a formyl substituent. It is among the simplest aromatic aldehydes and one of the most industrially useful. It is a colorless liquid with a characteristic almond-li ...

with formamide does not produce benzylidenediformamide as anticipated, but

benzylamine Benzylamine, also known as phenylmethylamine, is an Organic chemistry, organic chemical compound with the Structural formula#Condensed formulas, condensed structural formula C6H5CH2NH2 (sometimes abbreviated as Phenyl group#Nomenclature, PhCH2NH2 ...

. 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. 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 the 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 Catalysis () is the increase in reaction rate, rate of a chemical reaction due to an added substance known as a catalyst (). Catalysts are not consumed by the reaction and remain unchanged after it. If the reaction is rapid and the catalyst ...

Mechanism

Ammonium formate as reagent

Ammonium formate is a source of

formic acid Formic acid (), systematically named methanoic acid, is the simplest carboxylic acid. It has the chemical formula HCOOH and structure . This acid is an important intermediate in chemical synthesis and occurs naturally, most notably in some an ...

and

ammonia Ammonia is an inorganic chemical compound of nitrogen and hydrogen with the chemical formula, formula . A Binary compounds of hydrogen, stable binary hydride and the simplest pnictogen hydride, ammonia is a colourless gas with a distinctive pu ...

. Starting with

nucleophilic attack In chemistry, a nucleophile is a chemical species that forms bonds by donating an electron pair. All molecules and ions with a free pair of electrons or at least one pi bond can act as nucleophiles. Because nucleophiles donate electrons, they a ...

on the

carbonyl In organic chemistry, a carbonyl group is a functional group with the formula , composed of a carbon atom double bond, double-bonded to an oxygen atom, and it is divalent at the C atom. It is common to several classes of organic compounds (such a ...

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 In organic chemistry, an imine ( or ) is a functional group or organic compound containing a carbon–nitrogen double bond (). The nitrogen atom can be attached to a hydrogen or an organic group (R). The carbon atom has two additional single bon ...

and releasing ammonia. The imine goes through hydrolysis to form the amine, which is depicted in the scheme below. Imine hydrolysis

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 Benzodiazepines (BZD, BDZ, BZs), colloquially known as "benzos", are a class of central nervous system (CNS) depressant, depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed t ...

family.

References

{{Authority control Substitution reactions Organic redox reactions Name reactions