Reductive amination
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'''Reductive amination''' (also known as [[reductive alkylation]]) is a [[chemical reaction]] which involves the conversion of a [[carbonyl]] group to an [[amine]], via an intermediate [[imine]]. The carbonyl group is most commonly a [[ketone]] or an [[aldehyde]].
[[Image:ReductiveaminationOverview.png|500px|center|Reductive amination]]
==Reaction mechanism==
===In organic synthesis===
In this [[organic reaction]], the amine first reacts with the carbonyl group to form a [[hydroxylamine]] species, which subsequently loses one molecule of water in a [[reversible reaction|reversible]] manner by [[alkylimino-de-oxo-bisubstitution]], to form the [[imine]]. The equilibrium between aldehyde/ketone and imine can be shifted toward imine formation by removal of the formed water through physical or chemical means. This intermediate [[imine]] can then be isolated and reduced with a suitable reducing agent (e.g. [[sodium borohydride]]). This is '''indirect reductive amination'''.
However, it is also possible to carry out the same reaction all in one pot, with the imine formation and reduction occurring concurrently. This is known as direct reductive amination and is carried out with reducing agents that are more reactive toward imines than ketones, such as [[sodium cyanoborohydride]] (NaBH<sub>3</sub>CN) or sodium [[triacetoxyborohydride]] (NaBH(OCOCH<sub>3</sub>)<sub>3</sub>). This reaction has in recent years been performed in an aqueous environment casting doubt on the necessity of forming the imine.<ref>Shinya Sato, Takeshi Sakamoto, Etsuko Miyazawa and Yasuo Kikugawa, One-Pot Reductive Amination of Aldehydes and Ketones with $\alpha$-Picoline Borane in Methanol, in Water, and in Neat Conditions, Tetrahedron, 7899-7906, 60, 2004</ref> This is because the loss of the water molecule is thermodynamically disfavoured by the presence of a large amount of water in its environment, as seen in the work of Turner ''et al''.<ref>Colin J. Dunsmore, Reuben Carr, Toni Fleming and Nicholas J. Turner, A Chemo-Enzymatic Route to Enantiomerically Pure Cyclic Tertiary Amines, J Am Chem Soc, 2224-2225, 128(7), 2006</ref> This therefore, suggests that in some cases the reaction proceeds via direct reduction of the hydroxylamine species.<ref>V. A. Tarasevich and N. G. Kozloz, Reductive Amination of Oxygen-Containing Organic Compounds, Russian Chemical Reviews, 68(1), 55-72, 1999</ref>
This reaction is related to the [[Eschweiler-Clarke reaction]] in which amines are methylated to tertiary amines, the [[Leuckart-Wallach reaction]] with formic acid and to other amine alkylation methods as the [[Mannich reaction]] and the [[Petasis reaction]].
====Scope====
A classic [[named reaction]] is the '''Mignonac Reaction''' (1921) <ref>
[http://gallica.bnf.fr/ark:/12148/bpt6k3125x/f37.chemindefer Nouvelle méthodegénérale de préparation des amines à partir des aldéhydes ou des cétones.] M. Georges Mignonac, Compt. rend., 172, 223 (1921).</ref> involving reaction of a [[ketone]] with [[ammonia]] over a [[nickel]] catalyst for example in a synthesis of alpha-phenylethylamine <ref>[[Organic Syntheses]], Coll. Vol. 3, p.717 (1955); Vol. 23, p.68 (1943). http://www.orgsynth.org/orgsyn/pdfs/CV3P0717.pdf</ref> starting from [[acetophenone]].
In industry, tertiary amines such as [[triethylamine]] and [[Hunig's base]], are formed directly from ketones with a gasmixture of [[ammonia]] and [[hydrogen]] and a suitable catalyst .
The reaction depicted below is an example of an [[asymmetric reaction|asymmetric]] reductive amination of an aryl ketone and an [[aniline]].<ref>''Catalytic Asymmetric Reductive Amination of Aldehydes via Dynamic Kinetic Resolution'' Sebastian Hoffmann, Marcello Nicoletti, and Benjamin List ''[[J. Am. Chem. Soc.]]'' '''2006''', ''128(40)'', 13074 - 13075. ({{DOI|10.1021/ja065404r}})</ref><ref>In this reaction the [[reducing agent]] is an [[Hantzsch ester]] and the chiral catalyst a [[hydrogen phosphate]] of the [[BINAP]] family. [[Molecular sieve]]s remove formed water. The [[enantiomeric ratio]] is 99:1.</ref>
[[Image:AsymmetricReductiveAmination.png|400px|center|Asymmetric Reductive Amination Hoffmann 2006]]
The formation of only one enantiomer from the racemic reactant is attributed to [[dynamic kinetic resolution]] because both enantiomers in the racemic imine intermediate interconvert through their common [[enamine]].
===Biochemistry===
A step in the biosynthesis of many α-[[amino acid]]s is the reductive amination of an α-ketoacid, usually by a transaminase enzyme. The process is catalyzed by [[pyridoxal phosphate]] and the ammonia source is [[glutamate]]. The initial step entails formation of an imine, but the hydride equivalents are supplied by a reduced pyridine to give an aldimine, which hydrolyzes to the amine.<ref>Nelson, D. L.; Cox, M. M. "Lehninger, Principles of Biochemistry" 3rd Ed. Worth Publishing: New York, 2000. ISNB 1-57259-153-6.</ref> The sequence from keto-acid to amino acid can be summarized as follows:
:HO<sub>2</sub>CC(O)R → HO<sub>2</sub>CC(=NCH<sub>2</sub>-X)R → HO<sub>2</sub>CCH(N=CH-X)R → HO<sub>2</sub>CCH(NH<sub>2</sub>)R
== External links ==
* [http://www.organic-chemistry.org/synthesis/C1N/amines/reductiveamination.shtm Current methods for reductive amination]
* Industrial Reductive amination at [http://www2.basf.de/en/intermed/nbd/technology/amination.htm?id=V00-mR-a29Q3ebw20L7 BASF]
==References==
<references/>
==See also==
* [[Forster-Decker method]]
[[category:Organic redox reactions]]
[[es:Aminación reductora]]
[[fr:Amination réductrice]]
[[ja:還元的アミノ化]]
[[zh:还原胺化反应]]