It was first produced accidentally by Rudolf Leuckart in the reaction of benzaldehyde with formamide in a process now known as the Leuckart reaction,[5] a general process in which reductive amination of aldehydes or ketones yields the corresponding amine.[6][7]
Biochemistry
Benzylamine occurs biologically from the action of the N-substituted formamide deformylase enzyme, which is produced by Arthrobacter pascens bacteria.[8] This hydrolase catalyses the conversion of N-benzylformamide into benzylamine with formate as a by-product.[9] Benzylamine is degraded biologically by the action of the monoamine oxidase Benzyme,[10] resulting in benzaldehyde.[11]
Uses
Benzylamine is used as a masked source of ammonia, since after N-alkylation, the benzyl group can be removed by hydrogenolysis:[12]
C6H5CH2NH2 + 2 RBr → C6H5CH2NR2 + 2 HBr
C6H5CH2NR2 + H2 → C6H5CH3 + R2NH
Typically a base is employed in the first step to absorb the HBr (or related acid for other kinds of alkylating agents).
Benzylamine reacts with acetyl chloride to form N-benzylacetamide, an exemplar of the Schotten–Baumann reaction[13] first described in the 1880s.[14][15] The reaction takes place in a two-phase solvent system (here water and diethyl ether) so that the hydrogen chloride by-product is sequestered in the aqueous phase (and sometimes neutralised with a dissolved base) and thus prevented from protonating the amine and impeding the progress of the reaction. These conditions are often called Schotten-Baumann reaction conditions and are applicable more generally.[16] This particular example is useful as a model for the mechanism of interfacial polymerisation of a diamine with a diacid chloride.[17]
Benzylamine is used in the manufacture of numerous pharmaceuticals, including alniditan,[19]lacosamide,[20][21]moxifloxacin,[22] and nebivolol.[23] It is also used to manufacture the military explosive hexanitrohexaazaisowurtzitane (HNIW) which is superior to older nitroaminehigh explosives like HMX and RDX, though it is less stable. The US Navy is testing HNIW for use in rocket propellants, such as for missiles, as it has lower observability characteristics such as less visible smoke.[24] HNIW is prepared by first condensing benzylamine with glyoxal in acetonitrile under acidic and dehydrating conditions.[25] Four of the benzyl groups are removed from hexabenzylhexaazaisowurtzitane by hydrogenolysis catalysed by palladium on carbon and the resulting secondary amine groups are acetylated in acetic anhydride.[25] The resulting dibenzyl-substituted intermediate is then reacted with nitronium tetrafluoroborate and nitrosonium tetrafluoroborate in sulfolane to produce HNIW.[25]
Salts
The hydrochloride salt of benzylamine, C6H5CH2NH3Cl or C6H5CH2NH2·HCl,[26] is prepared by reacting benzylamine with hydrochloric acid, and can be used in treating motion sickness. NASA astronaut John Glenn was issued with benzylamine hydrochloride for this purpose for the Mercury-Atlas 6 mission.[27] The cation in this salt is called benzylammonium and is a moiety found in pharmaceuticals such as the anthelmintic agent bephenium hydroxynaphthoate, used in treating ascariasis.[28]
Other derivatives of benzylamine and its salts have been shown to have anti-emetic properties, including those with the N-(3,4,5-trimethoxybenzoyl)benzylamine moiety.[29] Commercially available motion-sickness agents including cinnarizine and meclizine are derivatives of benzylamine.
Other benzylamines
1-Phenylethylamine is a methylated benzylamine derivative that is chiral; enantiopure forms are obtained by resolvingracemates. Its racemic form is sometimes known as (±)-α-methylbenzylamine.[30] Both benzylamine and 1-phenylethylamine form stable ammonium salts and imines due to their relatively high basicity.
Safety and environment
Benzylamine exhibits modest oral toxicity in rats with LD50 of 1130 mg/kg. It is readily biodegraded.[4]
References
^ a b"Benzylamine". Sigma-Aldrich. Retrieved 28 December 2015.
^Hall, H. K. (1957). "Correlation of the Base Strengths of Amines". J. Am. Chem. Soc.79 (20): 5441–5444. doi:10.1021/ja01577a030.
^ a bHeuer, L. (2006). "Benzylamines". Ullmann's Encyclopedia of Industrial Chemistry. Wiley-VCH. doi:10.1002/14356007.a04_009.pub2. ISBN 3527306730.
^Crossley, F. S.; Moore, M. L. (1944). "Studies on the Leuckart Reaction". J. Org. Chem.9 (6): 529–536. doi:10.1021/jo01188a006.
^Webers, V. J.; Bruce, W. F. (1948). "The Leuckart Reaction: A study of the Mechanism". J. Am. Chem. Soc.70 (4): 1422–1424. doi:10.1021/ja01184a038. PMID 18915755.
^Pollard, C. B.; Young, D. C. (1951). "The Mechanism of the Leuckart Reaction". J. Org. Chem.16 (5): 661–672. doi:10.1021/jo01145a001.
^Schomburg, D.; Schomburg, I.; Chang, A., eds. (2009). "3.5.1.91 N-substituted formamide deformylase". Class 3 Hydrolases: EC 3.4.22–3.13. Springer Handbook of Enzymes (2nd ed.). Springer Science & Business Media. pp. 376–378. ISBN 9783540857051.
^Fukatsu, H.; Hashimoto, Y.; Goda, M.; Higashibata, H.; Kobayashi, M. (2004). "Amine-synthesizing enzyme N-substituted formamide deformylase: screening, purification, characterization, and gene cloning". Proc. Natl. Acad. Sci.101 (38): 13726–13731. Bibcode:2004PNAS..10113726F. doi:10.1073/pnas.0405082101. PMC 518824. PMID 15358859.
^Tipton, K. F.; Boyce, S.; O'Sullivan, J.; Davey, G. P.; Healy, J. (2004). "Monoamine oxidases: Certainties and uncertainties". Curr. Med. Chem.11 (15): 1965–1982. doi:10.2174/0929867043364810. PMID 15279561.
^Gatto, V. J.; Miller, S. R.; Gokel, G. W. (1993). "4,13-Diaza-18-Crown-6". Organic Syntheses; Collected Volumes, vol. 8, p. 152. (example of alklylation of benzylamine followed by hydrogenolysis).
^Li, J. J. (2014). "Schotten–Baumann reaction". Name Reactions: A Collection of Detailed Mechanisms and Synthetic Applications (5th ed.). Springer. p. 362. ISBN 9783319039794.
^Schotten, C. (1884). "Ueber die Oxydation des Piperidins". Ber. Dtsch. Chem. Ges. (in German). 17 (2): 2544–2547. doi:10.1002/cber.188401702178.
^Baumann, E. (1886). "Ueber eine einfache Methode der Darstellung von Benzoësäureäthern". Ber. Dtsch. Chem. Ges.19 (2): 3218–3222. doi:10.1002/cber.188601902348.
^Anderson, N. G. (2012). "5. Solvent Selection". Practical Process Research and Development – A guide for Organic Chemists (2nd ed.). Academic Press. pp. 121–168. ISBN 9780123865380.
^Odian, G. (2004). "2.8c – Interfacial Polymerization". Principles of Polymerization (4th ed.). John Wiley & Sons. pp. 90–92. ISBN 9780471274001.
^Li, J. J. (2014). "Schlittler–Müller modification". Name Reactions: A Collection of Detailed Mechanisms and Synthetic Applications (5th ed.). Springer. p. 492. ISBN 9783319039794.
^Lommen, G.; De Bruyn, M.; Schroven, M.; Verschueren, W.; Janssens, W.; Verrelst, J.; Leysen, J. (1995). "The discovery of a series of new non-indole 5HT1D agonists". Bioorg. Med. Chem. Lett.5 (22): 2649–2654. doi:10.1016/0960-894X(95)00473-7.
^Choi, D.; Stables, J. P.; Kohn, H. (1996). "Synthesis and anticonvulsant activities of N-Benzyl-2-acetamidopropionamide derivatives". J. Med. Chem.39 (9): 1907–1916. doi:10.1021/jm9508705. PMID 8627614.
^Morieux, P.; Stables, J. P.; Kohn, H. (2008). "Synthesis and anticonvulsant activities of N-benzyl-(2R)-2-acetamido-3-oxysubstituted propionamide derivatives". Bioorg. Med. Chem.16 (19): 8968–8975. doi:10.1016/j.bmc.2008.08.055. PMC 2701728. PMID 18789868.
^Peterson, U. (2006). "Quinolone Antibiotics: The Development of Moxifloxacin". In IUPAC; Fischer, J.; Ganellin, C. R. (eds.). Analogue-based Drug Discovery. John Wiley & Sons. pp. 338–342. ISBN 9783527607495.
^US patent 4654362, Van Lommen, G. R. E.; De Bruyn, M. F. L. & Schroven, M. F. J., "Derivatives of 2,2'-iminobisethanol", published 1987-03-31, assigned to Janssen Pharmaceutica, N.V.. Full text
^Yirka, B. (9 September 2011). "University chemists devise means to stabilize explosive CL-20". Phys.org. Retrieved 28 December 2015.
^ a b cNair, U. R.; Sivabalan, R.; Gore, G. M.; Geetha, M.; Asthana, S. N.; Singh, H. (2005). "Hexanitrohexaazaisowurtzitane (CL-20) and CL-20-based formulations (review)". Combust. Explos. Shock Waves. 41 (2): 121–132. doi:10.1007/s10573-005-0014-2. S2CID 95545484.
^"Benzylamine hydrochloride". Sigma-Aldrich. Retrieved 28 December 2015.
^Swenson, L. S.; Grimwood, J. M.; Alexander, C. C. "13: Mercury Mission Accomplished (13.1 Preparing a Man to Orbit)". This New Ocean: A History of Project Mercury. nasa.gov. pp. 413–418.
^Hellgren, U.; Ericsson, Ö.; Aden Abdi, Y.; Gustafsson, L. L. (2003). "Bephenium hydroxynaphthoate". Handbook of Drugs for Tropical Parasitic Infections (2nd ed.). CRC Press. pp. 33–35. ISBN 9780203211519.
^US patent 2879293, Sidney, T. & Goldberg, M. W., "Benzylamine derivatives", published 1959-03-24, issued 1959-03-24, assigned to Hoffmann La Roche. Full text