Benzylamine#Salt

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.{{cite book |last= Heuer |first= L. |date= 2006|chapter= Benzylamines |title= Ullmann's Encyclopedia of Industrial Chemistry |publisher= Wiley-VCH |doi= 10.1002/14356007.a04_009.pub2 |isbn= 3527306730 }}

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It was first produced accidentally by Rudolf Leuckart in the reaction of benzaldehyde with formamide in a process now known as the Leuckart reaction.{{cite book |doi=10.1002/0471264180.or005.07 |chapter=The Leuckart Reaction |title=Organic Reactions |date=2011 |last1=Moore |first1=Maurice L. |pages=301–330 |isbn=978-0-471-26418-7 }}

Benzylamine occurs biologically from the action of the N-substituted formamide deformylase enzyme, which is produced by Arthrobacter pascens bacteria.{{cite book|chapter-url = https://books.google.com/books?id=hN38HsVK5HgC&q=benzylformamide&pg=PA376|chapter = 3.5.1.91 N-substituted formamide deformylase|pages = 376–378|title = Class 3 Hydrolases: EC 3.4.22–3.13|series = Springer Handbook of Enzymes|editor1-first = D.|editor1-last = Schomburg|editor2-first = I.|editor2-last = Schomburg|editor3-last = Chang|editor3-first = A.|edition = 2nd|publisher = Springer Science & Business Media|year = 2009|isbn = 9783540857051}} This hydrolase catalyses the conversion of N-benzylformamide into benzylamine with formate as a by-product.{{cite journal|last1 = Fukatsu|first1 = H.|last2 = Hashimoto|first2 = Y.|last3 = Goda|first3 = M.|last4 = Higashibata|first4 = H.|last5 = Kobayashi|first5 = M.|year = 2004|title = Amine-synthesizing enzyme N-substituted formamide deformylase: screening, purification, characterization, and gene cloning|journal = Proc. Natl. Acad. Sci.|volume = 101|pages = 13726–13731|pmid = 15358859|doi = 10.1073/pnas.0405082101|issue = 38|pmc=518824|bibcode = 2004PNAS..10113726F|doi-access = free}} Benzylamine is degraded biologically by the action of the monoamine oxidase B enzyme,{{cite web|title = MAOB: Monoamine oxidase B – Homo sapiens|url = https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=4129|publisher = National Center for Biotechnology Information|access-date = 29 December 2015|date = 6 December 2015}} resulting in benzaldehyde.{{cite journal|last1 = Tipton|first1 = K. F.|last2 = Boyce|first2 = S.|last3 = O'Sullivan|first3 = J.|last4 = Davey|first4 = G. P.|last5 = Healy|first5 = J.|year = 2004|title = Monoamine oxidases: Certainties and uncertainties|journal = Curr. Med. Chem.|volume = 11|issue = 15|pages = 1965–1982|doi = 10.2174/0929867043364810| doi-broken-date=16 April 2025 |pmid = 15279561}}

Benzylamine is used as a masked source of ammonia, since after N-alkylation, the benzyl group can be removed by hydrogenolysis:{{OrgSynth | author = Gatto, V. J. |author2=Miller, S. R. |author3=Gokel, G. W. | title = 4,13-Diaza-18-Crown-6 | collvol = 8 | collvolpages = 152 | year = 1993 | prep = cv8p0152}} (example of alklylation of benzylamine followed by hydrogenolysis).

: 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.{{cite book|last = Li|first = J. J.|title = Name Reactions: A Collection of Detailed Mechanisms and Synthetic Applications|year = 2014|chapter = Schlittler–Müller modification|publisher = Springer|isbn = 9783319039794|pages = 492|edition = 5th|url = https://books.google.com/books?id=HoXBBAAAQBAJ&q=Name+reactions:+A+collection+of+detailed+reaction+mechanisms}}

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Benzylamine is used in the manufacture of other pharmaceuticals, including alniditan,{{Cite journal|title = The discovery of a series of new non-indole 5HT_1D agonists|year = 1995|last1 = Lommen| first1 = G.|last2 = De Bruyn|first2 = M.|last3 = Schroven|first3 = M.|last4 = Verschueren|first4 = W.|last5 = Janssens|first5 = W.|last6 = Verrelst|first6 = J.|last7 = Leysen|first7 = J.|journal = Bioorg. Med. Chem. Lett.|volume = 5|issue = 22|pages = 2649–2654|doi = 10.1016/0960-894X(95)00473-7}} lacosamide,{{cite journal|last1 = Choi|first1 = D.|last2 = Stables|first2 = J. P.|last3 = Kohn|first3 = H.|title = Synthesis and anticonvulsant activities of N-Benzyl-2-acetamidopropionamide derivatives|journal = J. Med. Chem.|year = 1996|volume = 39|issue = 9|pages = 1907–1916|pmid = 8627614|doi = 10.1021/jm9508705}}{{cite journal|last1 = Morieux|first1 = P.|last2 = Stables|first2 = J. P.|last3 = Kohn|first3 = H.|title = Synthesis and anticonvulsant activities of N-benzyl-(2R)-2-acetamido-3-oxysubstituted propionamide derivatives|journal = Bioorg. Med. Chem.|year = 2008|volume = 16|issue = 19|pages = 8968–8975|pmid = 18789868|doi = 10.1016/j.bmc.2008.08.055|pmc = 2701728}} moxifloxacin,{{cite book|chapter-url = https://books.google.com/books?id=FjKfqkaKkAAC&q=discovery+benzylamine&pg=PA338|pages = 338–342|chapter = Quinolone Antibiotics: The Development of Moxifloxacin|title = Analogue-based Drug Discovery|editor1 = IUPAC|editor-link = IUPAC|editor2-first = J.|editor2-last = Fischer|editor3-first = C. R.|editor3-last = Ganellin|publisher = John Wiley & Sons|isbn = 9783527607495|year = 2006|first = U.|last = Peterson}} and nebivolol.{{cite patent|country = US|number = 4654362|status = patent|title = Derivatives of 2,2'-iminobisethanol|pubdate = 1987-03-31|fdate = 1984-10-12|pridate = 1983-12-05|invent1 = Van Lommen, G. R. E.|invent2 = De Bruyn, M. F. L.|invent3 = Schroven, M. F. J.|assign1 = Janssen Pharmaceutica, N.V.|class = }}. {{US patent|4654362|Full text}}

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.{{cite journal|journal = Combust. Explos. Shock Waves|year = 2005|volume = 41|issue = 2|pages = 121–132|title = Hexanitrohexaazaisowurtzitane (CL-20) and CL-20-based formulations (review)|first1 = U. R.|last1 = Nair|first2 = R.|last2 = Sivabalan|first3 = G. M.|last3 = Gore|first4 = M.|last4 = Geetha|first5 = S. N.|last5 = Asthana|first6 = H.|last6 = Singh|doi = 10.1007/s10573-005-0014-2| bibcode=2005CESW...41..121N |s2cid = 95545484}}

{{See also|Phenylpropylamine}}

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).{{cite journal | vauthors = Nakagawasai O, Arai Y, Satoh SE, Satoh N, Neda M, Hozumi M, Oka R, Hiraga H, Tadano T | title = Monoamine oxidase and head-twitch response in mice. Mechanisms of alpha-methylated substrate derivatives | journal = Neurotoxicology | volume = 25 | issue = 1–2 | pages = 223–232 | date = January 2004 | pmid = 14697897 | doi = 10.1016/S0161-813X(03)00101-3 | bibcode = 2004NeuTx..25..223N | url = }}

A derivative, pargyline (N-methyl-N-propargylbenzylamine), is an MAOI that has been used pharmaceutically as an antihypertensive agent and antidepressant.{{cite journal | vauthors = Ho BT | title = Monoamine oxidase inhibitors | journal = J Pharm Sci | volume = 61 | issue = 6 | pages = 821–837 | date = June 1972 | pmid = 4558257 | doi = 10.1002/jps.2600610602 | url = | pmc = 1991462 }} α-Methylbenzylamine (1-phenylethylamine) is an MAOI, inhibiting both MAO-A and MAO-B, as well.{{cite journal | vauthors = Nakagawasai O, Arai Y, Satoh SE, Satoh N, Neda M, Hozumi M, Oka R, Hiraga H, Tadano T | title = Monoamine oxidase and head-twitch response in mice. Mechanisms of alpha-methylated substrate derivatives | journal = Neurotoxicology | volume = 25 | issue = 1–2 | pages = 223–232 | date = January 2004 | pmid = 14697897 | doi = 10.1016/S0161-813X(03)00101-3 | bibcode = 2004NeuTx..25..223N | url = }}

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.{{cite book | last1=Shulgin | first1=A. | last2=Manning | first2=T. | last3=Daley | first3=P.F. | title=The Shulgin Index, Volume One: Psychedelic Phenethylamines and Related Compounds | publisher=Transform Press | location=Berkeley | volume=1 | year=2011 | isbn=978-0-9630096-3-0 }}{{cite journal | vauthors = Bronson ME, Barrios-Zambrano L, Jiang W, Clark CR, DeRuiter J, Newland MC | title = Behavioral and developmental effects of two 3,4-methylenedioxymethamphetamine (MDMA) derivatives | journal = Drug Alcohol Depend | volume = 36 | issue = 3 | pages = 161–166 | date = December 1994 | pmid = 7889806 | doi = 10.1016/0376-8716(94)90141-4 | url = }} Benzylamine is also similar in structure to benzylpiperazine (BZP), which is a monoamine releasing agent and psychostimulant.{{cite book | last1=Gee | first1=Paul | last2=Schep | first2=Leo J. | title=Novel Psychoactive Substances | chapter=1-Benzylpiperazine and other piperazine-based stimulants | publisher=Elsevier | date=2022 | isbn=978-0-12-818788-3 | doi=10.1016/b978-0-12-818788-3.00009-7 | pages=301–332}} However, both benzylamine and α-methylbenzylamine have been found to be inactive as norepinephrine releasing agents.{{cite book | last1=Biel | first1=J. H. | last2=Bopp | first2=B. A. | title=Stimulants | chapter=Amphetamines: Structure-Activity Relationships | publisher=Springer US | publication-place=Boston, MA | date=1978 | isbn=978-1-4757-0512-6 | doi=10.1007/978-1-4757-0510-2_1 | page=1–39 | quote = 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).}}

The hydrochloride salt of benzylamine, C₆H₅CH₂NH₃Cl or C₆H₅CH₂NH₂·HCl,{{cite web|url = http://www.sigmaaldrich.com/catalog/product/aldrich/b5136?lang=en|title = Benzylamine hydrochloride|publisher = Sigma-Aldrich|access-date = 28 December 2015}} 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.{{cite book|chapter-url = https://history.nasa.gov/SP-4201/ch13-2.htm|title = This New Ocean: A History of Project Mercury|last1 = Swenson|first1 = L. S.|first2 = J. M.|last2 = Grimwood|first3 = C. C.|last3 = Alexander|chapter = 13: Mercury Mission Accomplished (13.1 Preparing a Man to Orbit)|pages = 413–418|publisher = nasa.gov}} 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.{{cite book|chapter-url = https://books.google.com/books?id=DYc7bY-egLEC&q=Bephenium&pg=PA35|pages = 33–35|title = Handbook of Drugs for Tropical Parasitic Infections|first1 = U.|last1 = Hellgren|first2 = Ö.|last2 = Ericsson|first3 = Y.|last3 = Aden Abdi|first4 = L. L.|last4 = Gustafsson|chapter = Bephenium hydroxynaphthoate|edition = 2nd|year = 2003|publisher = CRC Press|isbn = 9780203211519}}

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.{{cite patent|country = US|number = 2879293|status = patent|title = Benzylamine derivatives|pubdate = 1959-03-24|gdate = 1959-03-24|fdate = 1957-02-19|pridate = 1957-02-19|invent1 = Sidney, T.|invent2 = Goldberg, M. W.|assign1 = Hoffmann La Roche|class = }}. {{US patent|2879293|Full text}} Commercially available motion-sickness agents including cinnarizine and meclizine are derivatives of benzylamine.

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.{{cite web|url = https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=7408|title = 1-Phenylethylamine|author = PubChem Public Chemical Database|publisher = National Center for Biotechnology Information|access-date = 29 December 2015|date = 26 December 2015|author-link = PubChem}} Both benzylamine and 1-phenylethylamine form stable ammonium salts and imines due to their relatively high basicity.

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

{{Reflist|30em}}

Category:Aldehyde dehydrogenase inhibitors

Category:Arylalkylamines

Category:Benzylamines

Category:Human drug metabolites

Category:Aminomethyl compounds