Benzylamine

Benzylamine is an organic chemical compound with the condensed structural formula C₆H₅CH₂NH₂ (sometimes abbreviated as PhCH₂NH₂ or BnNH₂). It consists of a benzyl group, C₆H₅CH_2, attached to an amine functional group, NH₂. This colorless water-soluble liquid is a common precursor in organic chemistry and used in the industrial production of many pharmaceuticals. The hydrochloride salt was used to treat motion sickness on the Mercury-Atlas 6 mission in which NASA astronaut John Glenn became the first American to orbit the Earth.

Benzylamine

Names
Preferred IUPAC name Phenylmethanamine
Other names α-Aminotoluene Benzyl amine Phenylmethylamine
Identifiers
CAS Number	100-46-9 Y
3D model (JSmol)	Interactive image
Beilstein Reference	741984
ChEBI	CHEBI:40538 Y
ChEMBL	ChEMBL522 Y
ChemSpider	7223 Y
DrugBank	DB02464 Y
ECHA InfoCard	100.002.595
EC Number	202-854-1
Gmelin Reference	49783
KEGG	C15562 Y
PubChem CID	7504
RTECS number	DP1488500
UNII	A1O31ROR09 Y
UN number	2735
CompTox Dashboard (EPA)	DTXSID5021839
InChI InChI=1S/C7H9N/c8-6-7-4-2-1-3-5-7/h1-5H,6,8H2 Y Key: WGQKYBSKWIADBV-UHFFFAOYSA-N Y InChI=1/C7H9N/c8-6-7-4-2-1-3-5-7/h1-5H,6,8H2 Key: WGQKYBSKWIADBV-UHFFFAOYAL
SMILES c1ccc(cc1)CN
Properties
Chemical formula	C7H9N
Molar mass	107.156 g·mol−1
Appearance	Colorless liquid
Odor	weak, ammonia-like
Density	0.981 g/mL[1]
Melting point	10 °C (50 °F; 283 K)[2]
Boiling point	185 °C (365 °F; 458 K)[2]
Solubility in water	Miscible[2]
Solubility	miscible in ethanol, diethyl ether very soluble in acetone soluble in benzene, chloroform
Acidity (pKa)	9.34[3]
Basicity (pKb)	4.66
Magnetic susceptibility (χ)	-75.26·10−6 cm3/mol
Refractive index (nD)	1.543
Structure
Dipole moment	1.38 D
Hazards
Occupational safety and health (OHS/OSH):
Main hazards	Flammable and corrosive
GHS labelling:
Pictograms
Signal word	Danger
Hazard statements	H302, H312, H314
Precautionary statements	P260, P264, P270, P280, P301+P312, P301+P330+P331, P302+P352, P303+P361+P353, P304+P340, P305+P351+P338, P310, P312, P321, P322, P330, P363, P405, P501
NFPA 704 (fire diamond)	3 2 0
Flash point	65 °C (149 °F; 338 K)[2][1]
Safety data sheet (SDS)	Fischer Scientific
Related compounds
Related amines	aniline
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). N verify (what is YN ?) Infobox references

Manufacturing

Benzylamine can be produced by several methods, the main industrial route being the reaction of benzyl chloride and ammonia. It is also produced by the reduction of benzonitrile and reductive amination of benzaldehyde, both done over Raney nickel.^[4]

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 B enzyme,^[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.

Isoquinolines can be prepared from benzylamine and glyoxal acetal by an analogous approach known as the Schlittler-Müller modification to the Pomeranz–Fritsch reaction. This modification can also be used for preparing substituted isoquinolines.^[13]

Synthesis of HNIW from benzylamine

Benzylamine is used in the manufacture of other pharmaceuticals, including alniditan,^[14] lacosamide,^[15][16] moxifloxacin,^[17] and nebivolol.^[18]

Benzylamine is also used to manufacture the military explosive hexanitrohexaazaisowurtzitane (HNIW), which is superior to older nitroamine high explosives like HMX and RDX. Illustrating the debenzylation tendency of benzylamines, four of the benzyl groups are removed from hexabenzylhexaazaisowurtzitane by hydrogenolysis catalysed by palladium on carbon.^[19]

Salts

The hydrochloride salt of benzylamine, C₆H₅CH₂NH₃Cl or C₆H₅CH₂NH₂·HCl,^[20] 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.^[21] 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.^[22]

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.^[23] 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 resolving racemates. Its racemic form is sometimes known as (±)-α-methylbenzylamine.^[24] 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

1. "Benzylamine". Sigma-Aldrich. Retrieved 28 December 2015.
2. Record in the GESTIS Substance Database of the Institute for Occupational Safety and Health
3. Hall, H. K. (1957). "Correlation of the Base Strengths of Amines". J. Am. Chem. Soc. 79 (20): 5441–5444. doi:10.1021/ja01577a030.
4. Heuer, L. (2006). "Benzylamines". Ullmann's Encyclopedia of Industrial Chemistry. Wiley-VCH. doi:10.1002/14356007.a04_009.pub2. ISBN 3527306730.
5. Crossley, F. S.; Moore, M. L. (1944). "Studies on the Leuckart Reaction". J. Org. Chem. 9 (6): 529–536. doi:10.1021/jo01188a006.
6. 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.
7. Pollard, C. B.; Young, D. C. (1951). "The Mechanism of the Leuckart Reaction". J. Org. Chem. 16 (5): 661–672. doi:10.1021/jo01145a001.
8. 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.
9. 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.
10. "MAOB: Monoamine oxidase B – Homo sapiens". National Center for Biotechnology Information. 6 December 2015. Retrieved 29 December 2015.
11. 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.
12. 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).
13. Li, J. J. (2014). "Schlittler–Müller modification". Name Reactions: A Collection of Detailed Mechanisms and Synthetic Applications (5th ed.). Springer. p. 492. ISBN 9783319039794.
14. 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 5HT_1D agonists". Bioorg. Med. Chem. Lett. 5 (22): 2649–2654. doi:10.1016/0960-894X(95)00473-7.
15. 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.
16. 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.
17. 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.
18. 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
19. Nair, 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.
20. "Benzylamine hydrochloride". Sigma-Aldrich. Retrieved 28 December 2015.
21. 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.
22. 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.
23. 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
24. PubChem Public Chemical Database (26 December 2015). "1-Phenylethylamine". National Center for Biotechnology Information. Retrieved 29 December 2015.