Benzylamine

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Benzylamine
Skeletal formula of benzylamine
Space-filling model of the benzylamine molecule
Names
IUPAC name
1-Phenylmethanamine
Other names
α-Aminotoluene
Benzyl amine
Phenylmethylamine
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
DrugBank
ECHA InfoCard 100.002.595
KEGG
RTECS number DP1488500
UNII
Properties
C7H9N
Molar mass 107.16 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]
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
-75.26·10−6 cm3/mol
1.543
Structure
1.38 D
Hazards
Main hazards Flammable
Safety data sheet Fischer Scientific
R-phrases (outdated) R21/22 R34[1]
S-phrases (outdated) S26 S36/37/39 S45[1]
NFPA 704
Flammability code 2: Must be moderately heated or exposed to relatively high ambient temperature before ignition can occur. Flash point between 38 and 93 °C (100 and 200 °F). E.g., diesel fuel Health code 3: Short exposure could cause serious temporary or residual injury. E.g., chlorine gas Reactivity code 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g., liquid nitrogen Special hazards (white): no codeNFPA 704 four-colored diamond
Flash point 65 °C (149 °F; 338 K)[2][1]
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).
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Infobox references

Benzylamine is an organic chemical compound with the condensed structural formula C6H5CH2NH2 (sometimes abbreviated as PhCH2NH2 or BnNH2). It consists of a benzyl group, C6H5CH2, attached to an amine functional group, NH2. This colorless liquid is a common precursor in organic synthesis 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.

Manufacturing[edit]

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 over Raney nickel.[4]

Benzonitrile hydrogenation.svg

It was 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[edit]

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[edit]

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]

Schotten-Baumann.png

Isoquinolines are a class of compounds (benzopyridines) which are used in medical contexts (such as the anesthetic dimethisoquin, the antihypertensive debrisoquine, and the vasodilator papaverine) and in other areas (such as disinfectant N-laurylisoquinolinium bromide). Isoquinoline itself is efficiently prepared using the Pomeranz–Fritsch reaction, but can also 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.[18]

Synthesis of HNIW from benzylamine

The aza-Diels–Alder reaction converts imines and dienes to tetrahydropyridines in which the nitrogen atom can be part of the diene or the dienophile.[19] The imine is often generated in situ from an amine and formaldehyde. An example is the reaction of cyclopentadiene with benzylamine to form an aza-norbornene.[20]

Aza-Diels-Alder phenylmethylamine.png

Benzylamine is used in the industrial manufacturer of numerous pharmaceuticals, including alniditan,[21] lacosamide,[22][23] moxifloxacin,[24] and nebivolol.[25] It is also used to manufacture the military explosive hexanitrohexaazaisowurtzitane (HNIW) which is superior to older nitroamine high 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.[26] HNIW is prepared by first condensing benzylamine with glyoxal in acetonitrile under acidic and dehydrating conditions.[27] 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.[27] The resulting dibenzyl-substituted intermediate is then reacted with nitronium tetrafluoroborate and nitrosonium tetrafluoroborate in sulfolane to produce HNIW.[27]

Salts[edit]

The hydrochloride salt of benzylamine, C6H5CH2NH3Cl or C6H5CH2NH2·HCl,[28] 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.[29] 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.[30]

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.[31] Commercially available motion-sickness agents including cinnarizine and meclizine are derivatives of benzylamine.

Other benzylamines[edit]

1-Phenylethylamine is a methylated benzylamine derivative which is chiral; enantiopure forms are obtained by resolving racemates. Its racemic form is sometimes known as (±)-α-methylbenzylamine.[32] Both benzylamine and 1-phenylethylamine form stable ammonium salts and imines due to their relatively high basicity.

Safety and environment[edit]

Benzylamine exhibits modest oral toxicity in rats with LD50 of 1130 mg/kg. It is readily biodegraded.[4]

References[edit]

  1. ^ a b c d "Benzylamine". Sigma-Aldrich. Retrieved 28 December 2015. 
  2. ^ a b c d 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. ^ a b Heuer, L. (2006). "Benzylamines". Ullmann's Encyclopedia of Industrial Chemistry. Wiley-VCH. doi:10.1002/14356007.a04_009.pub2. 
  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. Amer. Chem. Soc. 70 (4): 1422–1424. doi:10.1021/ja01184a038. 
  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. doi:10.1073/pnas.0405082101. PMC 518824Freely accessible. 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. ; Collective Volume, 8, p. 152  (example of alklylation of benzylamine followed by hydrogenolysis).
  13. ^ Li, J. J. (2014). "Schotten–Baumann reaction". Name Reactions: A Collection of Detailed Mechanisms and Synthetic Applications (5th ed.). Springer. p. 362. ISBN 9783319039794. 
  14. ^ Schotten, C. (1884). "Ueber die Oxydation des Piperidins". Ber. Dtsch. Chem. Ges. (in German). 17 (2): 2544–2547. doi:10.1002/cber.188401702178. 
  15. ^ Baumann, E. (1886). "Ueber eine einfache Methode der Darstellung von Benzoësäureäthern". Ber. Dtsch. Chem. Ges. 19 (2): 3218–3222. doi:10.1002/cber.188601902348. 
  16. ^ 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. 
  17. ^ Odian, G. (2004). "2.8c – Interfacial Polymerization". Principles of Polymerization (4th ed.). John Wiley & Sons. pp. 90–92. ISBN 9780471274001. 
  18. ^ Li, J. J. (2014). "Schlittler–Müller modification". Name Reactions: A Collection of Detailed Mechanisms and Synthetic Applications (5th ed.). Springer. p. 492. ISBN 9783319039794. 
  19. ^ Kobayashi, S. (2002). "Catalytic Enantioselective Aza Diels-Alder Reactions". In Kobayashi, S.; Jørgensen, K. A. Cycloaddition Reactions in Organic Synthesis. John Wiley & Sons. pp. 187–210. ISBN 9783527301591. 
  20. ^ Grieco, P. A.; Larsen, S. D. (1990). "N-benzyl-2-azanorbornene". Organic Syntheses. 68: 206. doi:10.15227/orgsyn.068.0206. 
  21. ^ 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. 
  22. ^ 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. 
  23. ^ 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 2701728Freely accessible. PMID 18789868. 
  24. ^ Peterson, U. (2006). "Quinolone Antibiotics: The Development of Moxifloxacin". In IUPAC; Fischer, J.; Ganellin, C. R. Analogue-based Drug Discovery. John Wiley & Sons. pp. 338–342. ISBN 9783527607495. 
  25. ^ 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
  26. ^ Yirka, B. (9 September 2011). "University chemists devise means to stabilize explosive CL-20". Phys.org. Retrieved 28 December 2015. 
  27. ^ a b c 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. 
  28. ^ "Benzylamine hydrochloride". Sigma-Aldrich. Retrieved 28 December 2015. 
  29. ^ 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. 
  30. ^ 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. 
  31. ^ 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
  32. ^ PubChem Public Chemical Database (26 December 2015). "1-Phenylethylamine". National Center for Biotechnology Information. Retrieved 29 December 2015.