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 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] 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, 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 Synthesis CL20.svg
Synthesis of HNIW from benzylamine

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 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. [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 resolving racemates. 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]

Related Research Articles

<span class="mw-page-title-main">Amide</span> Organic compounds of the form RC(=O)NR′R″

In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a compound with the general formula R−C(=O)−NR′R″, where R, R', and R″ represent any group, typically organyl groups or hydrogen atoms. The amide group is called a peptide bond when it is part of the main chain of a protein, and an isopeptide bond when it occurs in a side chain, as in asparagine and glutamine. It can be viewed as a derivative of a carboxylic acid with the hydroxyl group replaced by an amine group ; or, equivalently, an acyl (alkanoyl) group joined to an amine group.

<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">Protecting group</span> Group of atoms introduced into a compound to prevent subsequent reactions

A protecting group or protective group is introduced into a molecule by chemical modification of a functional group to obtain chemoselectivity in a subsequent chemical reaction. It plays an important role in multistep organic synthesis.

Hydrogenolysis is a chemical reaction whereby a carbon–carbon or carbon–heteroatom single bond is cleaved or undergoes lysis (breakdown) by hydrogen. The heteroatom may vary, but it usually is oxygen, nitrogen, or sulfur. A related reaction is hydrogenation, where hydrogen is added to the molecule, without cleaving bonds. Usually hydrogenolysis is conducted catalytically using hydrogen gas.

<span class="mw-page-title-main">Benzyl group</span> Chemical group (–CH₂–C₆H₅)

In organic chemistry, benzyl is the substituent or molecular fragment possessing the structure R−CH2−C6H5. Benzyl features a benzene ring attached to a methylene group group.

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

Formamide is an amide derived from formic acid. It is a colorless liquid which is miscible with water and has an ammonia-like odor. It is chemical feedstock for the manufacture of sulfa drugs and other pharmaceuticals, herbicides and pesticides, and in the manufacture of hydrocyanic acid. It has been used as a softener for paper and fiber. It is a solvent for many ionic compounds. It has also been used as a solvent for resins and plasticizers. Some astrobiologists suggest that it may be an alternative to water as the main solvent in other forms of life.

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

Isoquinoline is an individual chemical specimen - a heterocyclic aromatic organic compound - as well as the name of a family of many thousands of natural plant alkaloids, any one of which might be referred to as "an isoquinoline". It is a structural isomer of quinoline. Isoquinoline and quinoline are benzopyridines, which are composed of a benzene ring fused to a pyridine ring. In a broader sense, the term isoquinoline is used to make reference to isoquinoline derivatives. 1-Benzylisoquinoline is the structural backbone in many naturally occurring alkaloids such as papaverine. The isoquinoline ring in these natural compound derives from the aromatic amino acid tyrosine.

An isocyanide is an organic compound with the functional group –N+≡C−. It is the isomer of the related nitrile (–C≡N), hence the prefix is isocyano. The organic fragment is connected to the isocyanide group through the nitrogen atom, not via the carbon. They are used as building blocks for the synthesis of other compounds.

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

Benzyl chloroformate, also known as benzyl chlorocarbonate or Z-chloride, is the benzyl ester of chloroformic acid. It can be also described as the chloride of the benzyloxycarbonyl group. In its pure form it is a water-sensitive oily colorless liquid, although impure samples usually appear yellow. It possesses a characteristic pungent odor and degrades in contact with water.

In organic chemistry, the Menshutkin reaction converts a tertiary amine into a quaternary ammonium salt by reaction with an alkyl halide. Similar reactions occur when tertiary phosphines are treated with alkyl halides.

The Bischler–Napieralski reaction is an intramolecular electrophilic aromatic substitution reaction that allows for the cyclization of β-arylethylamides or β-arylethylcarbamates. It was first discovered in 1893 by August Bischler and Bernard Napieralski, in affiliation with Basel Chemical Works and the University of Zurich. The reaction is most notably used in the synthesis of dihydroisoquinolines, which can be subsequently oxidized to isoquinolines.

The Leuckart reaction is the chemical reaction that converts aldehydes or ketones to amines by reductive amination in the presence of heat. 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">Fencamfamin</span> Chemical compound

Fencamfamin (INN), also known as fencamfamine or by the brand names Glucoenergan and Reactivan, is a stimulant which was developed by Merck in the 1960s.

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

The Ojima lactam is an organic compound of some importance in the commercial production of Taxol. This lactam was first synthesized by Iwao Ojima. The organic synthesis is an illustration of asymmetric synthesis via a chiral auxiliary.

The Schotten–Baumann reaction is a method to synthesize amides from amines and acid chlorides:

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

Ammonium formate, NH4HCO2, is the ammonium salt of formic acid. It is a colorless, hygroscopic, crystalline solid.

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

Monoamine oxidase B, also known as MAO-B, is an enzyme that in humans is encoded by the MAOB gene.

In enzymology, a N-substituted formamide deformylase (EC 3.5.1.91) is an enzyme that catalyzes the chemical reaction

In nitrile reduction a nitrile is reduced to either an amine or an aldehyde with a suitable chemical reagent.

<i>N</i>-<i>tert</i>-Butylbenzenesulfinimidoyl chloride Chemical compound

N-tert-Butylbenzenesulfinimidoyl chloride is a useful oxidant for organic synthesis reactions. It is a good electrophile, and the sulfimide S=N bond can be attacked by nucleophiles, such as alkoxides, enolates, and amide ions. The nitrogen atom in the resulting intermediate is basic, and can abstract an α-hydrogen to create a new double bond.

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. ↑ 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). "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. ↑ 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.
  20. ↑ 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.
  21. ↑ 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.
  22. ↑ 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.
  23. ↑ 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
  24. ↑ Yirka, B. (9 September 2011). "University chemists devise means to stabilize explosive CL-20". Phys.org . Retrieved 28 December 2015.
  25. 1 2 3 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.
  26. ↑ "Benzylamine hydrochloride". Sigma-Aldrich . Retrieved 28 December 2015.
  27. ↑ 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.
  28. ↑ 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.
  29. ↑ USpatent 2879293,Sidney, T.& Goldberg, M. W.,"Benzylamine derivatives",published 1959-03-24,issued 1959-03-24, assigned to Hoffmann La Roche . Full text
  30. ↑ PubChem Public Chemical Database (26 December 2015). "1-Phenylethylamine". National Center for Biotechnology Information . Retrieved 29 December 2015.
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