Trimethylamine Explained

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.[1] At higher concentrations it has an ammonia-like odor, and can cause necrosis of mucous membranes on contact. At lower concentrations, it has a "fishy" odor, the odor associated with rotting fish.

Physical and chemical properties

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.[2]

Production

Industry and laboratory

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

3 CH3OH + NH3 → (CH3)3N + 3 H2OThis reaction coproduces the other methylamines, dimethylamine (CH3)2NH and methylamine CH3NH2.

Trimethylammonium chloride has been prepared by a reaction of ammonium chloride and paraformaldehyde:[3]

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

Biosynthesis

Trimethylamine is produced by several routes in nature. Well studied are the degradation of choline and carnitine.[4]

Applications

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. Gas sensors to test for fish freshness detect trimethylamine.

Toxicity

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.[5] [6] 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. 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. TMA also causes the odor of some human infections, bad breath, and bacterial vaginosis.

Trimethylamine is a full agonist of human TAAR5,[7] [8] [9] a trace amine-associated receptor that is expressed in the olfactory epithelium and functions as an olfactory receptor for tertiary amines.[10] One or more additional odorant receptors appear to be involved in trimethylamine olfaction in humans as well.

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.[11] In patients, trimethylamine caused stomach ache, vomiting, diarrhoea, lacrimation, greying of the skin and agitation.[12] Apart from that, reproductive/developmental toxicity has been reported. Some experimental studies suggested that TMA may be involved in etiology of cardiovascular diseases.[13] [14]

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.[15]

Trimethylaminuria

See 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.[16] [17]

In the history of psychoanalysis

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.[18]

See also

External links

Notes and References

  1. Book: Ashford's Dictionary of Industrial Chemicals. 3rd. 2011. 9362. 978-0-9522674-3-0. Ashford. Robert D.. Wavelength .
  2. 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 . 10.1021/ed054p612.
  3. Roger. Adams. C. S.. Marvel. 10.15227/orgsyn.001.0079. Trimethylamine Hydrochloride. Organic Syntheses. 1921. 1. 79.
  4. 10.1073/pnas.1215689109 . Microbial conversion of choline to trimethylamine requires a glycyl radical enzyme . 2012 . Craciun . Smaranda . Balskus . Emily P. . Proceedings of the National Academy of Sciences . 109 . 52 . 21307–21312 . 23151509 . free . 3535645 .
  5. 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 . 10.1146/annurev-micro-091014-104422 . 26274026 . we review literature on trimethylamine (TMA), a microbiota-generated metabolite linked to atherosclerosis development.. free .
  6. 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 . 10.3748/wjg.v20.i43.16062 . 4239492 . 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. . free .
  7. Wallrabenstein I, Kuklan J, Weber L, Zborala S, Werner M, Altmüller J, Becker C, Schmidt A, Hatt H, Hummel T, Gisselmann G . Human trace amine-associated receptor TAAR5 can be activated by trimethylamine . PLOS ONE. 8 . 2 . e54950 . 2013 . 23393561 . 3564852 . 10.1371/journal.pone.0054950 . 2013PLoSO...854950W . free.
  8. Zhang J, Pacifico R, Cawley D, Feinstein P, Bozza T . Ultrasensitive detection of amines by a trace amine-associated receptor . J. Neurosci. . 33 . 7 . 3228–39 . February 2013 . 23407976 . 3711460 . 10.1523/JNEUROSCI.4299-12.2013 . 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).
  9. Zhang LS, Davies SS . Microbial metabolism of dietary components to bioactive metabolites: opportunities for new therapeutic interventions . Genome Med . 8 . 1 . 46 . April 2016 . 27102537 . 4840492 . 10.1186/s13073-016-0296-x . free .
    Table 2: Microbial metabolites: their synthesis, mechanisms of action, and effects on health and disease
    Figure 1: Molecular mechanisms of action of indole and its metabolites on host physiology and disease
  10. Liberles SD . Trace amine-associated receptors: ligands, neural circuits, and behaviors . Curr. Opin. Neurobiol. . 34 . 1–7 . October 2015 . 25616211 . 10.1016/j.conb.2015.01.001 . 4508243 .
  11. 7023344. 1981. Wills. M. R.. Biochemistry of renal failure. Annals of Clinical and Laboratory Science. 11. 4. 292–9. Savory. J..
  12. 1929. 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. 10.1002/ardp.19292670410. 221459303. 0365-6233.
  13. Jaworska . Kinga . Bielinska . Klaudia . Gawrys-Kopczynska . Marta . Ufnal . Marcin . 2019-08-27 . 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 . 10.1093/cvr/cvz231 . 0008-6363 . 31504256 . free.
  14. Jaworska . Kinga . Hering . Dagmara . Mosieniak . Grażyna . Bielak-Zmijewska . Anna . Pilz . Marta . Konwerski . Michał . Gasecka . Aleksandra . Kapłon-Cieślicka . Agnieszka . Filipiak . Krzysztof . 2019-08-26 . TMA, A Forgotten Uremic Toxin, but Not TMAO, Is Involved in Cardiovascular Pathology . Toxins . 11 . 9 . 490 . 10.3390/toxins11090490 . 2072-6651 . 6784008 . 31454905 . free.
  15. Book: Directorate-General for Employment . Social Affairs and Inclusion (European Commission) . SCOEL/REC/179 trimethylamine: recommendation from the Scientific Committee on Occupational Exposure Limits . Scientific Committee on Occupational Exposure Limits . Nielsen . G. D. . Pospischil . E. . Johanson . G. . Klein . C. L. . Papameletiou . D. . 2017 . Publications Office of the European Union . 978-92-79-66627-8 . LU . 10.2767/440659 . 1032584642.
  16. 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 . 10.1002/jsfa.2740300809 . 1979JSFA...30..799P .
  17. Lichovníková . M. . Zeman . L. . Jandásek . J. . 2008 . The effect of feeding untreated rapeseed and iodine supplement on egg quality . Czech Journal of Animal Science . 53 . 2 . 77–82 . 19 December 2016. 10.17221/330-CJAS . free .
  18. Sigmund Freud, Standard Ed., 4:116-119.

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