Leuckart reaction

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.{{cite journal|last=Crossley|first=Frank S.|author2=Maurice L. Moore |title=Studies on the Leuckart Reaction|journal=Journal of Organic Chemistry|year=1944|volume=9|issue=6|pages=529–536| doi=10.1021/jo01188a006}} 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.{{cite journal|last=Pollard|first=C.B.|author2=David C. Young |title=The Mechanism of the Leuckart Reaction|journal=Journal of Organic Chemistry|year=1951|volume=16|issue=5|pages=661–672| doi=10.1021/jo01145a001}} However, using just ammonium formate as the reagent produces the best yields.{{cite journal|last=Alexander|first=Elliot|author2=Ruth Bowman Wildman |title=Studies on the Mechanism of the Leuckart Reaction|journal=Journal of the American Chemical Society|year=1948|volume=70|issue=3|pages=1187–1189| doi=10.1021/ja01183a091|pmid=18909189}} 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.{{cite journal|last=Webers|first=Vincent J.|author2=William F. Bruce |title=The Leuckart Reaction: A study of the Mechanism|journal=Journal of the American Chemical Society|year=1948|volume=70|issue=4|pages=1422–1424 |doi=10.1021/ja01184a038|pmid=18915755}}

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:{{cite journal|last1=Ingersoll|first1=A. W.|title=α-Phenylethylamine|journal=Organic Syntheses|date=1937|volume=17|page=76|doi=10.15227/orgsyn.017.0076}}

:{{chem2|NH4HCO2 <-> NH3 + HCO2H}}

:{{chem2|NH3 + R2C\dO + HCO2H -> R2C\dNH2+ + HCO2-}}

The iminium is then reduced by the formate:

:{{chem2|R2C\dNH2+ + HCO2- -> R2CH\sNH2 + CO2}}

File:Leuckart mechanism 2.jpg

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.

File:Imine hydrolysis.jpg

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.{{cite journal|last=Lee|first=Sung-Chan|author2=Seung Bum Park |title=Novel application of Leuckart–Wallach reaction for synthesis of tetrahydro-1,4-benzodiazepin-5-ones library|journal=Chemical Communications|year=2007|issue=36|pages=3714–3716|pmid=17851604|doi=10.1039/B709768A |url=https://www.researchgate.net/publication/5988189}}

• Eschweiler–Clarke reaction

• Leuchart's finding that benzaldehyde and acetamide react to give tribenzylamine:{{cite journal |doi=10.1002/cber.188501802113 |title=Ueber eine neue Bildungsweise von Tribenzylamin |date=1885 |last1=Leuckart |first1=R. |journal=Berichte der Deutschen Chemischen Gesellschaft |volume=18 |issue=2 |pages=2341–2344 }}
• Leuchart's use of ammonium formate:{{cite journal |doi=10.1002/cber.188601902105 |title=Ueber die Einwirkung von Ammoniumformiat auf Benzaldehyd und Benzophenon |date=1886 |last1=Leuckart |first1=R. |last2=Bach |first2=E. |journal=Berichte der Deutschen Chemischen Gesellschaft |volume=19 |issue=2 |pages=2128–2131 }}

{{reflist}}

{{Authority control}}

Category:Substitution reactions

Category:Organic redox reactions

Category:Name reactions