Reductive amination

Reductive amination (also known as

reductive alkylation) is a form of
amination that 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.
It is considered the most important way to
make amines, and a majority of amines
made in the pharmaceutical industry are
made this way.[1][2]
 Reductive

Reaction amination

process Reaction Coupling

type reaction
In this organic
Identifiers
reaction, the amine
first reacts with the RSC RXNO:0000
ontology (https://ww
carbonyl group to
ID bi.ac.uk/ols
form a hemiaminal
tologies/rxn
species, which
erms?iri=htt
subsequently loses 3A%2F%2Fp
one molecule of obolibrary.o
water in a reversible 2Fobo%2FR
manner by O_0000335
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 method is
sometimes called indirect reductive
amination.

In a separate approach, imine formation

and reduction can occur sequentially in
one pot. This approach, known as direct
reductive amination (Borch reaction),
employs reducing agents that only react
slowly (or not at all) with the
ketone/aldehyde precursors. These
hydride reagents also must tolerate
moderately acidic conditions. Typical
reagents that meet these criteria include
sodium cyanoborohydride (NaBH3CN) and
sodium triacetoxyborohydride
(NaBH(OCOCH3)3).[3] These reactions are
generally conducted at pH ~ 5, typically
using a weak acid (e.g., acetic acid) as a
catalyst. Under these conditions, the
reaction of the carbonyl and amine results
in formation of a small amount of the
iminium ion (R1R2C=N+R3R4), which is
reduced much more readily than the
carbonyl starting material. As a result, the
selective reduction of the iminium takes
place to give the amine (rather than direct
reduction of the carbonyl to form the
alcohol).[4]

Variations and related

reactions
This reaction is related to the Eschweiler–
Clarke reaction, in which amines are
methylated to tertiary amines, the
Leuckart–Wallach reaction,[5] or by other
amine alkylation methods such as the
Mannich reaction and Petasis reaction.

A classic named reaction is the Mignonac

reaction (1921)[6] involving reaction of a
ketone with ammonia over a nickel
catalyst for example in a synthesis of 1-
phenylethylamine starting from
acetophenone:[7]

Nowadays, one-pot reductive amination

fulfil by acid-metal catalysts that act as a
hydride transfer. Much research study on
this kind of reaction show high efficiency.[8]

In industry, tertiary amines such as

triethylamine and diisopropylethylamine
are formed directly from ketones with a
gaseous mixture of ammonia and
hydrogen and a suitable catalyst.
Biochemistry
In biochemistry, dehydrogenase enzymes
can catalyze the reductive amination of α-
keto acids and ammonia to yield α-amino
acids. Reductive amination is
predominantly used for the synthesis of
the amino acid glutamate starting from α-
ketoglutarate, while biochemistry largely
relies on transamination to introduce
nitrogen in the other amino acids.[9]

In popular culture
In the critically acclaimed drama Breaking
Bad, main character Walter White uses the
reductive amination reaction to produce
his high purity methamphetamine, relying
on phenyl-2-propanone and methylamine.
The phenyl-2-propanone (otherwise known
as phenylacetone or P2P) is produced
from phenylacetic acid and acetic acid
using a tube furnace and thorium dioxide
(ThO2) as a catalyst.

See also
Forster–Decker method
Leuckart reaction

References
1. Warren, Stuart & Wyatt, Paul (2008).
Organic Synthesis : the disconnection
 approach (2nd ed.). Oxford: Wiley-
Blackwell. p. 54. ISBN 978-0-470-71236-8.
2. Afanasyev, Oleg I.; Kuchuk, Ekaterina;
Usanov, Dmitry L.; Chusov, Denis (21
October 2019). "Reductive Amination in the
Synthesis of Pharmaceuticals". Chemical
Reviews. 119 (23): 11857–11911.
doi:10.1021/acs.chemrev.9b00383 (http
s://doi.org/10.1021%2Facs.chemrev.9b003
83) . PMID 31633341 (https://pubmed.ncb
i.nlm.nih.gov/31633341) .
S2CID 204814584 (https://api.semanticsch
olar.org/CorpusID:204814584) .
3. Baxter, Ellen W.; Reitz, Allen B. (2004).
"Reductive Aminations of Carbonyl
Compounds with Borohydride and Borane
Reducing Agents". In Overman, Larry E.
 (ed.). Organic Reactions. pp. 1–714.
doi:10.1002/0471264180.or059.01 (http
s://doi.org/10.1002%2F0471264180.or05
9.01) . ISBN 978-0-471-17655-8.
4. Vollhardt, K. Peter C. (2018). Organic
chemistry : structure and function (https://
www.worldcat.org/oclc/1007924903) .
Neil Eric Schore (8th ed.). New York.
pp. 1036–1037. ISBN 978-1-319-07945-1.
OCLC 1007924903 (https://www.worldcat.
org/oclc/1007924903) .
5. George, Frederick & Saunders, Bernard
(1960). Practical Organic Chemistry, 4th Ed
(https://www.scribd.com/doc/46973684/P
ractical-Organic-Chemistry-Frederick-Georg
e-Mann) . London: Longman. p. 223.
ISBN 9780582444072.
6. Mignonac, Georges (1921). "Nouvelle
méthode générale de préparation des
amines à partir des aldéhydes ou des
cétones" (http://gallica.bnf.fr/ark:/12148/b
pt6k3125x/f37.chemindefer) [New general
method for preparation of amines from
aldehydes or ketones]. Comptes rendus (in
French). 172: 223.
7. Robinson, John C.; Snyder, H. R. (1955). "α-
Phenylethylamine" (http://www.orgsyn.org/
demo.aspx?prep=cv3p0717) . Organic
Syntheses.
doi:10.1002/0471264180.os023.27 (http
s://doi.org/10.1002%2F0471264180.os02
3.27) .; Collective Volume, vol. 3, p. 717
8. Kalbasi, Roozbeh Javad; Mazaheri, Omid
(2015). "Synthesis and characterization of
 hierarchical ZSM-5 zeolite containing Ni
nanoparticles for one-pot reductive
amination of aldehydes with nitroarenes" (h
ttps://zenodo.org/record/6616124) .
Catalysis Communications. 69: 86–91.
doi:10.1016/j.catcom.2015.05.016 (https://
doi.org/10.1016%2Fj.catcom.2015.05.01
6) .
9. Metzler, D. E. "Biochemistry—The Chemical
Reactions of Living Cells, Vol. 2" 2nd Ed.
Academic Press: San Diego, 2003.

External links
Current methods for reductive amination
(https://www.organic-chemistry.org/synt
hesis/C1N/amines/reductiveamination.s
htm)
 Industrial reductive amination at BASF (h
ttp://www2.basf.us/amines/bcaminesra
minati.html)

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