Benzylamine

Last updated
Benzylamine
Benzylamine2DCSD.svg
Benzylamine-from-xtal-3D-bs-17.png
Names
Preferred IUPAC name
Phenylmethanamine
Other names
α-Aminotoluene
Benzyl amine
Phenylmethylamine
Identifiers
3D model (JSmol)
741984
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.002.595 OOjs UI icon edit-ltr-progressive.svg
EC Number
  • 202-854-1
49783
KEGG
PubChem CID
RTECS number
  • DP1488500
UNII
UN number 2735
  • InChI=1S/C7H9N/c8-6-7-4-2-1-3-5-7/h1-5H,6,8H2 Yes check.svgY
    Key: WGQKYBSKWIADBV-UHFFFAOYSA-N Yes check.svgY
  • InChI=1/C7H9N/c8-6-7-4-2-1-3-5-7/h1-5H,6,8H2
    Key: WGQKYBSKWIADBV-UHFFFAOYAL
  • c1ccc(cc1)CN
Properties
C7H9N
Molar mass 107.156 g·mol−1
AppearanceColorless 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
Occupational safety and health (OHS/OSH):
Main hazards
Flammable and corrosive
GHS labelling:
GHS-pictogram-acid.svg GHS-pictogram-exclam.svg
Danger
H302, H312, H314
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)
NFPA 704.svgHealth 3: Short exposure could cause serious temporary or residual injury. E.g. chlorine gasFlammability 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 fuelInstability 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g. liquid nitrogenSpecial hazards (white): no code
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).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

Benzylamine, also known as phenylmethylamine, 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 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.

Contents

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]

Benzonitrile hydrogenation.svg

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]

Biochemistry

Benzylamine occurs biologically from the action of the N-substituted formamide deformylase enzyme, which is produced by Arthrobacter pascens bacteria. [6] This hydrolase catalyses the conversion of N-benzylformamide into benzylamine with formate as a by-product. [7] Benzylamine is degraded biologically by the action of the monoamine oxidase B enzyme, [8] resulting in benzaldehyde. [9]

Uses

Benzylamine is used as a masked source of ammonia, since after N-alkylation, the benzyl group can be removed by hydrogenolysis: [10]

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. [11]

Synthesis of HNIW from benzylamine Synthesis CL20.svg
Synthesis of HNIW from benzylamine

Benzylamine is used in the manufacture of other pharmaceuticals, including alniditan, [12] lacosamide, [13] [14] moxifloxacin, [15] and nebivolol. [16]

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. [17]

Pharmacology and derivatives

Benzylamine has been found to act as a monoamine oxidase inhibitor (MAOI), including of both monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B). [18]

A derivative, pargyline (N-Methyl-N-propargylbenzylamine), is an MAOI that has been used pharmaceutically as an antihypertensive agent and antidepressant. [19] α-Methylbenzylamine is an MAOI, inhibiting both MAO-A and MAO-B, as well. [18]

Another derivative, α,N-DMMDBA (MDM1EA; α,N-dimethyl-3,4-methylenedioxybenzylamine), partially substitutes for MDMA at high doses in drug discrimination tests in rats. [20] [21] Benzylamine is also similar in structure to benzylpiperazine (BZP), which is a monoamine releasing agent and psychostimulant. [22] However, both benzylamine and α-methylbenzylamine have been found to be inactive as norepinephrine releasing agents. [23]

Salts

The hydrochloride salt of benzylamine, C6H5CH2NH3Cl or C6H5CH2NH2·HCl, [24] 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. [25] 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. [26]

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. [27] 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. [28] 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]

Related Research Articles

<span class="mw-page-title-main">Monoamine oxidase</span> Family of enzymes

Monoamine oxidases (MAO) are a family of enzymes that catalyze the oxidation of monoamines, employing oxygen to clip off their amine group. They are found bound to the outer membrane of mitochondria in most cell types of the body. The first such enzyme was discovered in 1928 by Mary Bernheim in the liver and was named tyramine oxidase. The MAOs belong to the protein family of flavin-containing amine oxidoreductases.

<span class="mw-page-title-main">Phenelzine</span> Antidepressant

Phenelzine, sold under the brand name Nardil among others, is a non-selective and irreversible monoamine oxidase inhibitor (MAOI) of the hydrazine family which is primarily used as an antidepressant and anxiolytic to treat depression and anxiety. Along with tranylcypromine and isocarboxazid, phenelzine is one of the few non-selective and irreversible MAOIs still in widespread clinical use.

<span class="mw-page-title-main">Phenethylamine</span> Organic compound, a stimulant in humans

Phenethylamine (PEA) is an organic compound, natural monoamine alkaloid, and trace amine, which acts as a central nervous system stimulant in humans. In the brain, phenethylamine regulates monoamine neurotransmission by binding to trace amine-associated receptor 1 (TAAR1) and inhibiting vesicular monoamine transporter 2 (VMAT2) in monoamine neurons. To a lesser extent, it also acts as a neurotransmitter in the human central nervous system. In mammals, phenethylamine is produced from the amino acid L-phenylalanine by the enzyme aromatic L-amino acid decarboxylase via enzymatic decarboxylation. In addition to its presence in mammals, phenethylamine is found in many other organisms and foods, such as chocolate, especially after microbial fermentation.

<span class="mw-page-title-main">Tryptamine</span> Metabolite of the amino acid tryptophan

Tryptamine is an indolamine metabolite of the essential amino acid tryptophan. The chemical structure is defined by an indole—a fused benzene and pyrrole ring, and a 2-aminoethyl group at the second carbon. The structure of tryptamine is a shared feature of certain aminergic neuromodulators including melatonin, serotonin, bufotenin and psychedelic derivatives such as dimethyltryptamine (DMT), psilocybin, psilocin and others.

<span class="mw-page-title-main">Tyramine</span> Chemical compound

Tyramine, also known under several other names, is a naturally occurring trace amine derived from the amino acid tyrosine. Tyramine acts as a catecholamine releasing agent. Notably, it is unable to cross the blood-brain barrier, resulting in only non-psychoactive peripheral sympathomimetic effects following ingestion. A hypertensive crisis can result, however, from ingestion of tyramine-rich foods in conjunction with the use of monoamine oxidase inhibitors (MAOIs).

<span class="mw-page-title-main">Selegiline</span> Monoamine oxidase inhibitor

Selegiline, also known as L-deprenyl and sold under the brand names Eldepryl, Zelapar, and Emsam among others, is a medication which is used in the treatment of Parkinson's disease and major depressive disorder. It has also been studied and used off-label for a variety of other indications, but has not been formally approved for any other use. The medication, in the form licensed for depression, has modest effectiveness for this condition that is similar to that of other antidepressants. Selegiline is provided as a swallowed tablet or capsule or an orally disintegrating tablet (ODT) for Parkinson's disease and as a patch applied to skin for depression.

<span class="mw-page-title-main">Phentermine</span> Weight loss medication

Phentermine, sold under the brand name Adipex-P among others, is a medication used together with diet and exercise to treat obesity. It is available by itself or as the combination phentermine/topiramate. Phentermine is taken by mouth.

<span class="mw-page-title-main">Clorgiline</span> Chemical compound

Clorgiline (INN), or clorgyline (BAN), is a monoamine oxidase inhibitor (MAOI) structurally related to pargyline which is described as an antidepressant. Specifically, it is an irreversible and selective inhibitor of monoamine oxidase A (MAO-A). Clorgiline was never marketed, but it has found use in scientific research. It has been found to bind with high affinity to the σ1 receptor (Ki = 3.2 nM) and with very high affinity to the I2 imidazoline receptor (Ki = 40 pM).

<span class="mw-page-title-main">Rasagiline</span> Chemical compound

Rasagiline, sold under the brand name Azilect among others, is a medication which is used in the treatment of Parkinson's disease. It is used as a monotherapy to treat symptoms in early Parkinson's disease or as an adjunct therapy in more advanced cases. The drug is taken by mouth.

The Leuckart reaction is the chemical reaction that converts aldehydes or ketones to amines. The reaction is an example of reductive amination. The reaction, named after Rudolf Leuckart, uses either ammonium formate or formamide as the nitrogen donor and reducing agent. It requires high temperatures, usually between 120 and 130 °C; for the formamide variant, the temperature can be greater than 165 °C.

<span class="mw-page-title-main">Pargyline</span> Chemical compound

Pargyline, sold under the brand name Eutonyl among others, is a monoamine oxidase inhibitor (MAOI) medication which has been used to treat hypertension but is no longer marketed. It has also been studied as an antidepressant, but was never licensed for use in the treatment of depression. The drug is taken by mouth.

<span class="mw-page-title-main">5-Methoxytryptamine</span> Chemical compound

5-Methoxytryptamine, also known as serotonin methyl ether or O-methylserotonin and as mexamine, is a tryptamine derivative closely related to the neurotransmitters serotonin and melatonin. It has been shown to occur naturally in the body in low levels, especially in the pineal gland. It is formed via O-methylation of serotonin or N-deacetylation of melatonin.

<i>N</i>-Methylphenethylamine Chemical compound

N-Methylphenethylamine (NMPEA) is a naturally occurring trace amine neuromodulator in humans that is derived from the trace amine, phenethylamine (PEA). It has been detected in human urine and is produced by phenylethanolamine N-methyltransferase with phenethylamine as a substrate, which significantly increases PEA's effects. PEA breaks down into phenylacetaldehyde which is further broken down into phenylacetic acid by monoamine oxidase. When this is inhibited by monoamine oxidase inhibitors, it allows more of the PEA to be metabolized into nymphetamine (NMPEA) and not wasted on the weaker inactive metabolites.

<span class="mw-page-title-main">Benzofuranylpropylaminopentane</span> Chemical compound

(–)-Benzofuranylpropylaminopentane is an experimental drug related to selegiline which acts as a monoaminergic activity enhancer (MAE). It is orally active in animals.

<span class="mw-page-title-main">Phenylpropylaminopentane</span> Stimulant drug of the substituted phenethylamine class

1-Phenyl-2-propylaminopentane is an experimental drug related to selegiline which acts as a catecholaminergic activity enhancer (CAE).

<span class="mw-page-title-main">Monoamine oxidase B</span> Protein-coding gene in the species Homo sapiens

Monoamine oxidase B (MAO-B) is an enzyme that in humans is encoded by the MAOB gene.

<span class="mw-page-title-main">Pheniprazine</span> Chemical compound

Pheniprazine, formerly sold under the brand names Catron and Cavodil, is an irreversible and non-selective monoamine oxidase inhibitor (MAOI) of the hydrazine group that was used as an antidepressant to treat depression in the 1960s. It was also used in the treatment of angina pectoris and schizophrenia. Pheniprazine has been largely discontinued due to toxicity concerns such as jaundice, amblyopia, and optic neuritis.

<span class="mw-page-title-main">4-Benzylpiperidine</span> Chemical compound

4-Benzylpiperidine is a drug and research chemical used in scientific studies. It has been encountered as a designer drug.

<span class="mw-page-title-main">Phenylpropylamine</span> Pharmaceutical compound

Phenylpropylamine, also known as 3-phenylpropylamine, is a monoamine releasing agent (MRA) related to phenethylamine (2-phenylethylamine). It is the analogue of phenethylamine in which the ethylamine side chain has been lengthened by one carbon atom to instead be a propylamine chain.

<span class="mw-page-title-main">SU-11739</span> Monoamine oxidase inhibitor

SU-11739 is an experimental monoamine oxidase inhibitor (MAOI) that was never marketed.

References

  1. 1 2 "Benzylamine". Sigma-Aldrich . Retrieved 28 December 2015.
  2. 1 2 3 4 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. 1 2 Heuer, L. (2006). "Benzylamines". Ullmann's Encyclopedia of Industrial Chemistry. Wiley-VCH. doi:10.1002/14356007.a04_009.pub2. ISBN   3527306730.
  5. ↑ Moore, Maurice L. (2011). "The Leuckart Reaction". Organic Reactions. pp. 301–330. doi:10.1002/0471264180.or005.07. ISBN   978-0-471-26418-7.
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ "MAOB: Monoamine oxidase B – Homo sapiens". National Center for Biotechnology Information. 6 December 2015. Retrieved 29 December 2015.
  9. ↑ 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.
  10. ↑ 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).
  11. ↑ Li, J. J. (2014). "Schlittler–Müller modification". Name Reactions: A Collection of Detailed Mechanisms and Synthetic Applications (5th ed.). Springer. p. 492. ISBN   9783319039794.
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ 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.
  16. ↑ USpatent 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
  17. ↑ 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.
  18. 1 2 Nakagawasai O, Arai Y, Satoh SE, Satoh N, Neda M, Hozumi M, Oka R, Hiraga H, Tadano T (January 2004). "Monoamine oxidase and head-twitch response in mice. Mechanisms of alpha-methylated substrate derivatives". Neurotoxicology. 25 (1–2): 223–232. Bibcode:2004NeuTx..25..223N. doi:10.1016/S0161-813X(03)00101-3. PMID   14697897.
  19. ↑ Ho BT (June 1972). "Monoamine oxidase inhibitors". J Pharm Sci. 61 (6): 821–837. doi:10.1002/jps.2600610602. PMID   4558257.
  20. ↑ Shulgin, A.; Manning, T.; Daley, P.F. (2011). The Shulgin Index, Volume One: Psychedelic Phenethylamines and Related Compounds . Vol. 1. Berkeley: Transform Press. ISBN   978-0-9630096-3-0.
  21. ↑ Bronson ME, Barrios-Zambrano L, Jiang W, Clark CR, DeRuiter J, Newland MC (December 1994). "Behavioral and developmental effects of two 3,4-methylenedioxymethamphetamine (MDMA) derivatives". Drug Alcohol Depend. 36 (3): 161–166. doi:10.1016/0376-8716(94)90141-4. PMID   7889806.
  22. ↑ Gee, Paul; Schep, Leo J. (2022). "1-Benzylpiperazine and other piperazine-based stimulants". Novel Psychoactive Substances. Elsevier. pp. 301–332. doi:10.1016/b978-0-12-818788-3.00009-7. ISBN   978-0-12-818788-3.
  23. ↑ Biel, J. H.; Bopp, B. A. (1978). "Amphetamines: Structure-Activity Relationships". Stimulants. Boston, MA: Springer US. p. 1–39. doi:10.1007/978-1-4757-0510-2_1. ISBN   978-1-4757-0512-6. The β-phenethylamine skeleton is a critical feature of the molecule since either increasing or decreasing the number of carbons between the phenyl ring and the nitrogen reduced or abolished the activity. Both the γ-phenylpropylamines (e.g., 1-phenyl-3-aminobutane, γ-phenylpropylamine, γ-phenyl-N,N-dimethylpropylamine) and the benzylamines (e.g., α-methylbenzylamine, N,N-diethylbenzylamine, benzylamine) were found to be inactive as releasers of norepinephrine (Daly et al., 1966).
  24. ↑ "Benzylamine hydrochloride". Sigma-Aldrich . Retrieved 28 December 2015.
  25. ↑ 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.
  26. ↑ 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.
  27. ↑ USpatent 2879293,Sidney, T.& Goldberg, M. W.,"Benzylamine derivatives",published 1959-03-24,issued 1959-03-24, assigned to Hoffmann La Roche . Full text
  28. ↑ PubChem Public Chemical Database (26 December 2015). "1-Phenylethylamine". National Center for Biotechnology Information . Retrieved 29 December 2015.
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