Trimethylamine - Wikipedia

Chemical compound responsible for rotten fish odor Trimethylamine[1]

Names
Preferred IUPAC name N,N-Dimethylmethanamine
Other names (Trimethyl)amine (The name trimethylamine is deprecated.)[2]
Identifiers
CAS Number	75-50-3 Y
3D model (JSmol)	Interactive image
3DMet	B00133
Beilstein Reference	956566
ChEBI	CHEBI:18139 Y
ChEMBL	ChEMBL439723 Y
ChemSpider	1114 Y
ECHA InfoCard	100.000.796
EC Number	200-875-0
KEGG	C00565 N
PubChem CID	1146
RTECS number	PA0350000
UNII	LHH7G8O305 Y
UN number	1083
CompTox Dashboard (EPA)	DTXSID2026238
InChI InChI=1S/C3H9N/c1-4(2)3/h1-3H3 YKey: GETQZCLCWQTVFV-UHFFFAOYSA-N Y
SMILES CN(C)C
Properties
Chemical formula	C3H9N
Molar mass	59.112 g·mol−1
Appearance	Colorless gas
Odor	Fishy, ammoniacal
Density	670 kg m−3 (at 0 °C)627.0 kg m−3 (at 25 °C)
Melting point	−117.20 °C; −178.96 °F; 155.95 K
Boiling point	3 to 7 °C; 37 to 44 °F; 276 to 280 K
Solubility in water	Miscible
log P	0.119
Vapor pressure	188.7 kPa (at 20 °C)[3]
Henry's lawconstant (kH)	95 μmol Pa−1 kg−1
Basicity (pKb)	4.19
Dipole moment	0.612 D
Thermochemistry
Std enthalpy offormation (ΔfH⦵298)	−24.5 to −23.0 kJ mol−1
Hazards
GHS labelling:
Pictograms
Signal word	Danger
Hazard statements	H220, H315, H318, H332, H335
Precautionary statements	P210, P261, P280, P305+P351+P338
NFPA 704 (fire diamond)	2 4 0
Flash point	−7 °C (19 °F; 266 K)
Autoignitiontemperature	190 °C (374 °F; 463 K)
Explosive limits	2–11.6%
Lethal dose or concentration (LD, LC):
LD50 (median dose)	500 mg kg−1 (oral, rat)
NIOSH (US health exposure limits):
PEL (Permissible)	none[4]
REL (Recommended)	TWA 10 ppm (24 mg/m3) ST 15 ppm (36 mg/m3)[4]
IDLH (Immediate danger)	N.D.[4]
Related compounds
Related amines	Dimethylamine N-Nitrosodimethylamine Diethylamine Triethylamine Diisopropylamine Dimethylaminopropylamine Diethylenetriamine N,N-Diisopropylethylamine Triisopropylamine Tris(2-aminoethyl)amine Mechlorethamine HN1 (nitrogen mustard) HN3 (nitrogen mustard)
Related compounds	Unsymmetrical dimethylhydrazine Biguanide Dithiobiuret
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

Chemical compound

Trimethylamine (TMA) is an organic compound with the formula N(CH3)3. It is a trimethylated derivative of ammonia. TMA is widely used in industry.[5][6] At higher concentrations it has an ammonia-like odor, and can cause necrosis of mucous membranes on contact.[7] At lower concentrations, it has a "fishy" odor, the odor associated with rotting fish.

Physical and chemical properties

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TMA is a colorless, hygroscopic, and flammable tertiary amine. It is a gas at room temperature but is usually sold as a 40% solution in water. It is also sold in pressurized gas cylinders.

TMA protonates to give the trimethylammonium cation. Trimethylamine is a good nucleophile, and this reactivity underpins most of its applications. Trimethylamine is a Lewis base that forms adducts with a variety of Lewis acids.[8]

Production

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Industry and laboratory

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Trimethylamine is prepared by the reaction of ammonia and methanol employing a catalyst:[5]

3 CH3OH + NH3 → (CH3)3N + 3 H2O

This reaction coproduces the other methylamines, dimethylamine (CH3)2NH and methylamine CH3NH2.

Trimethylammonium chloride has been prepared by a reaction of ammonium chloride and paraformaldehyde:[9]

9 (CH2=O)n + 2n NH4Cl → 2n (CH3)3N•HCl + 3n H2O + 3n CO2

Biosynthesis

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Trimethylamine is produced by several routes in nature. Well studied are the degradation of choline and carnitine.[10]

Applications

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Trimethylamine is used in the synthesis of choline, tetramethylammonium hydroxide, plant growth regulators, herbicides, strongly basic anion exchange resins, dye leveling agents and a number of basic dyes.[5][6] Gas sensors to test for fish freshness detect trimethylamine.

Toxicity

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In humans, ingestion of certain plant and animal (e.g., red meat, egg yolk) food containing lecithin, choline, and L-carnitine provides certain gut microbiota with the substrate to synthesize TMA, which is then absorbed into the bloodstream.[11][12] High levels of trimethylamine in the body are associated with the development of trimethylaminuria, or fish odor syndrome, caused by a genetic defect in the enzyme which degrades TMA; or by taking large doses of supplements containing choline or L-carnitine.[11][12] TMA is metabolized by the liver to trimethylamine N-oxide (TMAO); TMAO is being investigated as a possible proatherogenic substance which may accelerate atherosclerosis in those eating foods with a high content of TMA precursors.[12] TMA also causes the odor of some human infections, bad breath, and bacterial vaginosis.

Trimethylamine is a full agonist of human TAAR5,[13][14][15] a trace amine-associated receptor that is expressed in the olfactory epithelium and functions as an olfactory receptor for tertiary amines.[15][16] One or more additional odorant receptors appear to be involved in trimethylamine olfaction in humans as well.[16]

Acute and chronic toxic effects of TMA were suggested in medical literature as early as the 19th century. TMA causes eye and skin irritation, and it is suggested to be a uremic toxin.[17] In patients, trimethylamine caused stomach ache, vomiting, diarrhoea, lacrimation, greying of the skin and agitation.[18] Apart from that, reproductive/developmental toxicity has been reported.[7] Some experimental studies suggested that TMA may be involved in etiology of cardiovascular diseases.[19][20]

Guidelines with exposure limit for workers are available e.g. the Recommendation from the Scientific Committee on Occupational Exposure Limits by the European Union Commission.[21]

Trimethylaminuria

[edit] Main article: Trimethylaminuria

Trimethylaminuria is an autosomal recessive genetic disorder involving a defect in the function or expression of flavin-containing monooxygenase 3 (FMO3) which results in poor trimethylamine metabolism. Individuals with trimethylaminuria develop a characteristic fish odor—the smell of trimethylamine—in their sweat, urine, and breath after the consumption of choline-rich foods. A condition similar to trimethylaminuria has also been observed in a certain breed of Rhode Island Red chicken that produces eggs with a fishy smell, especially after eating food containing a high proportion of rapeseed.[22][23]

In the history of psychoanalysis

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The first dream of his own which Sigmund Freud tried to analyse in detail, when he was developing his theories about the interpretation of dreams, involved a patient of Freud's who had to have an injection of trimethylamine, and the chemical formula of the substance, written in bold letters on the bottle, jumping out at Freud.[24]

See also

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• Ammonia, NH3
• Ammonium, NH4+
• Methylamine, (CH3)NH2
• Triethylamine (TEA)

References

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1. ^ Merck Index, 11th Edition, 9625.
2. ^ IUPAC Chemical Nomenclature and Structure Representation Division (2013). "P-62.2.2.1". In Favre, Henri A.; Powell, Warren H. (eds.). Nomenclature of Organic Chemistry: IUPAC Recommendations and Preferred Names 2013. IUPAC–RSC. ISBN 978-0-85404-182-4.
3. ^ Swift, Elijah; Hochanadel, Helen Phillips (May 1945). "The Vapor Pressure of Trimethylamine from 0 to 40°". Journal of the American Chemical Society. 67 (5): 880–881. doi:10.1021/ja01221a508.
4. ^ a b c NIOSH Pocket Guide to Chemical Hazards. "#0636". National Institute for Occupational Safety and Health (NIOSH).
5. ^ a b c Van Gysel, August B.; Musin, Willy (2000). "Methylamines". Ullmann's Encyclopedia of Industrial Chemistry. Weinheim: Wiley-VCH. doi:10.1002/14356007.a16_535. ISBN 3527306730.
6. ^ a b Ashford, Robert D. (2011). Ashford's Dictionary of Industrial Chemicals (3rd ed.). Wavelength. p. 9362. ISBN 978-0-9522674-3-0.
7. ^ a b "Trimethylamine [MAK Value Documentation, 1983]", The MAK-Collection for Occupational Health and Safety, Wiley-VCH Verlag GmbH & Co. KGaA, 27 October 2014, pp. 1–9, doi:10.1002/3527600418.mb7550e0914, ISBN 978-3527600410
8. ^ Cramer, R. E.; Bopp, T. T. (1977). "Graphical display of the enthalpies of adduct formation for Lewis acids and bases". Journal of Chemical Education. 54: 612–613. doi:10.1021/ed054p612.
9. ^ Adams, Roger; Marvel, C. S. (1921). "Trimethylamine Hydrochloride". Organic Syntheses. 1: 79. doi:10.15227/orgsyn.001.0079.
10. ^ Craciun, Smaranda; Balskus, Emily P. (2012). "Microbial conversion of choline to trimethylamine requires a glycyl radical enzyme". Proceedings of the National Academy of Sciences. 109 (52): 21307–21312. doi:10.1073/pnas.1215689109. PMC 3535645. PMID 23151509.
11. ^ a b Falony G, Vieira-Silva S, Raes J (2015). "Microbiology Meets Big Data: The Case of Gut Microbiota-Derived Trimethylamine". Annu. Rev. Microbiol. 69: 305–321. doi:10.1146/annurev-micro-091014-104422. PMID 26274026. we review literature on trimethylamine (TMA), a microbiota-generated metabolite linked to atherosclerosis development.
12. ^ a b c Gaci N, Borrel G, Tottey W, O'Toole PW, Brugère JF (November 2014). "Archaea and the human gut: new beginning of an old story". World J. Gastroenterol. 20 (43): 16062–16078. doi:10.3748/wjg.v20.i43.16062. PMC 4239492. PMID 25473158. Trimethylamine is exclusively a microbiota-derived product of nutrients (lecithin, choline, TMAO, L-carnitine) from normal diet, from which seems originate two diseases, trimethylaminuria (or Fish-Odor Syndrome) and cardiovascular disease through the proatherogenic property of its oxidized liver-derived form.
13. ^ Wallrabenstein I, Kuklan J, Weber L, Zborala S, Werner M, Altmüller J, Becker C, Schmidt A, Hatt H, Hummel T, Gisselmann G (2013). "Human trace amine-associated receptor TAAR5 can be activated by trimethylamine". PLOS ONE. 8 (2): e54950. Bibcode:2013PLoSO...854950W. doi:10.1371/journal.pone.0054950. PMC 3564852. PMID 23393561.
14. ^ Zhang J, Pacifico R, Cawley D, Feinstein P, Bozza T (February 2013). "Ultrasensitive detection of amines by a trace amine-associated receptor". J. Neurosci. 33 (7): 3228–39. doi:10.1523/JNEUROSCI.4299-12.2013. PMC 3711460. PMID 23407976. We show that [human TAAR5] responds to the tertiary amine N,N-dimethylethylamine and to a lesser extent to trimethylamine, a structurally related agonist for mouse and rat TAAR5 (Liberles and Buck, 2006; Staubert et al., 2010; Ferrero et al., 2012)
15. ^ a b Zhang LS, Davies SS (April 2016). "Microbial metabolism of dietary components to bioactive metabolites: opportunities for new therapeutic interventions". Genome Med. 8 (1): 46. doi:10.1186/s13073-016-0296-x. PMC 4840492. PMID 27102537.Table 2: Microbial metabolites: their synthesis, mechanisms of action, and effects on health and diseaseFigure 1: Molecular mechanisms of action of indole and its metabolites on host physiology and disease
16. ^ a b Liberles SD (October 2015). "Trace amine-associated receptors: ligands, neural circuits, and behaviors". Curr. Opin. Neurobiol. 34: 1–7. doi:10.1016/j.conb.2015.01.001. PMC 4508243. PMID 25616211.
17. ^ Wills, M. R.; Savory, J. (1981). "Biochemistry of renal failure". Annals of Clinical and Laboratory Science. 11 (4): 292–9. PMID 7023344.
18. ^ "Gifte und Vergiftungen. Vierte Ausgabe des Lehrbuches der Toxikologie. Von Prof. Louis Lewin. Mit 41 Figuren und einer farbigen Spektraltafel. Berlin 1929. Verlag von Georg Stilke. 1087 Seiten. Preis geh. 50,— Mark, geb. 55,— Mark". Archiv der Pharmazie. 267 (4): 322–323. 1929. doi:10.1002/ardp.19292670410. ISSN 0365-6233. S2CID 221459303.
19. ^ Jaworska, Kinga; Bielinska, Klaudia; Gawrys-Kopczynska, Marta; Ufnal, Marcin (27 August 2019). "TMA (trimethylamine), but not its oxide TMAO (trimethylamine-oxide), exerts hemodynamic effects - implications for interpretation of cardiovascular actions of gut microbiome". Cardiovascular Research. 115 (14): 1948–1949. doi:10.1093/cvr/cvz231. ISSN 0008-6363. PMID 31504256.
20. ^ Jaworska, Kinga; Hering, Dagmara; Mosieniak, Grażyna; Bielak-Zmijewska, Anna; Pilz, Marta; Konwerski, Michał; Gasecka, Aleksandra; Kapłon-Cieślicka, Agnieszka; Filipiak, Krzysztof (26 August 2019). "TMA, A Forgotten Uremic Toxin, but Not TMAO, Is Involved in Cardiovascular Pathology". Toxins. 11 (9): 490. doi:10.3390/toxins11090490. ISSN 2072-6651. PMC 6784008. PMID 31454905.
21. ^ Directorate-General for Employment, Social Affairs and Inclusion (European Commission); Scientific Committee on Occupational Exposure Limits; Nielsen, G. D.; Pospischil, E.; Johanson, G.; Klein, C. L.; Papameletiou, D. (2017). SCOEL/REC/179 trimethylamine: recommendation from the Scientific Committee on Occupational Exposure Limits. LU: Publications Office of the European Union. doi:10.2767/440659. ISBN 978-92-79-66627-8. OCLC 1032584642.
22. ^ Pearson, Arthur W.; Butler, Edward J.; Curtis, R. Frank; Fenwick, G. Roger; Hobson-Frohock, Anthony; Land, Derek G. (1979). "Effect of rapeseed meal on trimethylamine metabolism in the domestic fowl in relation to egg taint". Journal of the Science of Food and Agriculture. 30 (8): 799–804. Bibcode:1979JSFA...30..799P. doi:10.1002/jsfa.2740300809.
23. ^ Lichovníková, M.; Zeman, L.; Jandásek, J. (2008). "The effect of feeding untreated rapeseed and iodine supplement on egg quality" (PDF). Czech Journal of Animal Science. 53 (2): 77–82. doi:10.17221/330-CJAS. Retrieved 19 December 2016.
24. ^ Sigmund Freud, Standard Ed., 4:116-119.

External links

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• Molecule of the Month: Trimethylamine
• NIST Webbook data
• CDC - NIOSH Pocket Guide to Chemical Hazards

Wikimedia Commons has media related to Trimethylamine.

v t e Human trace amine-associated receptor ligands
TAAR1	Agonists Endogenous† Classical monoamine neurotransmitters Dopamine Histamine Epinephrine (adrenaline) Norepinephrine (noradrenaline) Serotonin Trace amines 3-Iodothyronamine 3-Methoxytyramine N-Methylphenethylamine N-Methyltyramine m-Octopamine p-Octopamine Phenethylamine Phenylethanolamine Synephrine Tryptamine m-Tyramine p-Tyramine Synthetic and natural‡ Amphetamine DOB DOET N,N-Dimethylphenethylamine Guanfacine Halostachine Higenamine Hordenine 4-Hydroxyamphetamine Isopropyloctopamine Isoprenaline MDA (tenamfetamine) MDMA (midomafetamine) 2-Methylphenethylamine 3-Methylphenethylamine 4-Methylphenethylamine β-Methylphenethylamine Methamphetamine 3-MMA Norfenfluramine Phentermine o-PIT Propylhexedrine Ralmitaront (RG-7906, RO-6889450) RG-7351 RG-7410 RO-5166017 RO-5256390 RO-5263397 Selegiline Solriamfetol Ulotaront (SEP-363856) Neutral antagonists RTI-7470-44 Inverse agonists EPPTB (RO-5212773)
TAAR2	Agonists‡   Neutral antagonists
TAAR5	Agonists‡ N,N-Dimethylethylamine Trimethylamine Neutral antagonists   Inverse agonists‡ 3-Iodothyronamine
† References for all endogenous human TAAR1 ligands are provided at List of trace amines ‡ References for synthetic TAAR1 agonists can be found at TAAR1 or in the associated compound articles. For TAAR2 and TAAR5 agonists and inverse agonists, see TAAR for references. See also: Receptor/signaling modulators

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