Trimethylamine

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Trimethylamine [1]
Me3N showing pyramidal-ness.svg
Ball and stick model of trimethylamine Trimethylamine-3D-balls.png
Ball and stick model of trimethylamine
Spacefill model of trimethylamine Trimethylamine-3D-vdW.png
Spacefill model of trimethylamine
Names
Preferred IUPAC name
N,N-Dimethylmethanamine
Other names
(Trimethyl)amine (The name trimethylamine is deprecated.) [2]
Identifiers
3D model (JSmol)
3DMet
956566
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.000.796 OOjs UI icon edit-ltr-progressive.svg
EC Number
  • 200-875-0
KEGG
PubChem CID
RTECS number
  • PA0350000
UNII
UN number 1083
  • InChI=1S/C3H9N/c1-4(2)3/h1-3H3 Yes check.svgY
    Key: GETQZCLCWQTVFV-UHFFFAOYSA-N Yes check.svgY
  • CN(C)C
Properties
C3H9N
Molar mass 59.112 g·mol−1
AppearanceColorless 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
Miscible
log P 0.119
Vapor pressure 188.7 kPa (at 20 °C) [3]
95 μmol Pa−1 kg−1
Basicity (pKb)4.19
0.612 D
Thermochemistry
−24.5 to −23.0 kJ mol−1
Hazards
GHS labelling:
GHS-pictogram-flamme.svg GHS-pictogram-acid.svg GHS-pictogram-exclam.svg
Danger
H220, H315, H318, H332, H335
P210, P261, P280, P305+P351+P338
NFPA 704 (fire diamond)
NFPA 704.svgHealth 2: Intense or continued but not chronic exposure could cause temporary incapacitation or possible residual injury. E.g. chloroformFlammability 4: Will rapidly or completely vaporize at normal atmospheric pressure and temperature, or is readily dispersed in air and will burn readily. Flash point below 23 °C (73 °F). E.g. propaneInstability 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g. liquid nitrogenSpecial hazards (white): no code
2
4
0
Flash point −7 °C (19 °F; 266 K)
190 °C (374 °F; 463 K)
Explosive limits 2–11.6%
Lethal dose or concentration (LD, LC):
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
Related compounds
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 ?)

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

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

Industry and laboratory

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

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

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. [5] [6] 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. [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

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

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

Related Research Articles

<span class="mw-page-title-main">Choline</span> Chemical compound and essential nutrient

Choline ( KOH-leen) is an essential nutrient for humans and many other animals, which was formerly classified as a B vitamin (vitamin B4). It is a structural part of phospholipids and a methyl donor in metabolic one-carbon chemistry. The compound is related to trimethylglycine in the latter respect. It is a cation with the chemical formula [(CH3)3NCH2CH2OH]+. Choline forms various salts, for example choline chloride and choline bitartrate.

<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">Ethanolamine</span> Chemical compound

Ethanolamine is a naturally occurring organic chemical compound with the formula HOCH
2CH
2NH
2 or C
2H
7NO. The molecule is bifunctional, containing both a primary amine and a primary alcohol. Ethanolamine is a colorless, viscous liquid with an odor reminiscent of ammonia.

<span class="mw-page-title-main">Methylamine</span> Organic chemical compound

Methylamine is an organic compound with a formula of CH3NH2. This colorless gas is a derivative of ammonia, but with one hydrogen atom being replaced by a methyl group. It is the simplest primary amine.

<span class="mw-page-title-main">Trimethylaminuria</span> Medical condition

Trimethylaminuria (TMAU), also known as fish odor syndrome or fish malodor syndrome, is a rare metabolic disorder that causes a defect in the normal production of an enzyme named flavin-containing monooxygenase 3 (FMO3). When FMO3 is not working correctly or if not enough enzyme is produced, the body loses the ability to properly convert the fishy-smelling chemical trimethylamine (TMA) from precursor compounds in food digestion into trimethylamine oxide (TMAO), through a process called N-oxidation.

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

Dimethylamine is an organic compound with the formula (CH3)2NH. This secondary amine is a colorless, flammable gas with an ammonia-like odor. Dimethylamine is commonly encountered commercially as a solution in water at concentrations up to around 40%. An estimated 270,000 tons were produced in 2005.

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

Ethylamine, also known as ethanamine, is an organic compound with the formula CH3CH2NH2. This colourless gas has a strong ammonia-like odor. It condenses just below room temperature to a liquid miscible with virtually all solvents. It is a nucleophilic base, as is typical for amines. Ethylamine is widely used in chemical industry and organic synthesis.

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

Ammonia borane, also called borazane, is the chemical compound with the formula H3NBH3. The colourless or white solid is the simplest molecular boron-nitrogen-hydride compound. It has attracted attention as a source of hydrogen fuel, but is otherwise primarily of academic interest.

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

Diethylamine is an organic compound with the formula (CH3CH2)2NH. It is a secondary amine. It is a flammable, weakly alkaline liquid that is miscible with most solvents. It is a colorless liquid, but commercial samples often appear brown due to impurities. It has a strong ammonia-like odor.

Trace amine-associated receptors (TAARs), sometimes referred to as trace amine receptors, are a class of G protein-coupled receptors that were discovered in 2001. TAAR1, the first of six functional human TAARs, has gained considerable interest in academic and proprietary pharmaceutical research due to its role as the endogenous receptor for the trace amines phenethylamine, tyramine, and tryptamine – metabolic derivatives of the amino acids phenylalanine, tyrosine and tryptophan, respectively – ephedrine, as well as the synthetic psychostimulants, amphetamine, methamphetamine and methylenedioxymethamphetamine. In 2004, it was shown that mammalian TAAR1 is also a receptor for thyronamines, decarboxylated and deiodinated relatives of thyroid hormones. TAAR2–TAAR9 function as olfactory receptors for volatile amine odorants in vertebrates.

<i>n</i>-Butylamine Chemical compound

n-Butylamine is an organic compound (specifically, an amine) with the formula CH3(CH2)3NH2. This colourless liquid is one of the four isomeric amines of butane, the others being sec-butylamine, tert-butylamine, and isobutylamine. It is a liquid having the fishy, ammonia-like odor common to amines. The liquid acquires a yellow color upon storage in air. It is soluble in all organic solvents. Its vapours are heavier than air and it produces toxic oxides of nitrogen during combustion.

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

Isopropylamine is an organic compound, an amine. It is a hygroscopic colorless liquid with ammonia-like odor. It is miscible with water and flammable. It is a valuable intermediate in chemical industry.

Trimethylamine <i>N</i>-oxide Chemical compound

Trimethylamine N-oxide (TMAO) is an organic compound with the formula (CH3)3NO. It is in the class of amine oxides. Although the anhydrous compound is known, trimethylamine N-oxide is usually encountered as the dihydrate. Both the anhydrous and hydrated materials are white, water-soluble solids.

<span class="mw-page-title-main">Flavin-containing monooxygenase 3</span> Protein-coding gene in the species Homo sapiens

Flavin-containing monooxygenase 3 (FMO3), also known as dimethylaniline monooxygenase [N-oxide-forming] 3 and trimethylamine monooxygenase, is a flavoprotein enzyme (EC 1.14.13.148) that in humans is encoded by the FMO3 gene. This enzyme catalyzes the following chemical reaction, among others:

Trimethylamine N-oxide reductase is a microbial enzyme that can reduce trimethylamine N-oxide (TMAO) into trimethylamine (TMA), as part of the electron transport chain. The enzyme has been purified from E. coli and the photosynthetic bacteria Roseobacter denitrificans.

<span class="mw-page-title-main">TAAR5</span> Protein-coding gene in the species Homo sapiens

Trace amine-associated receptor 5 is a protein that in humans is encoded by the TAAR5 gene. In vertebrates, TAAR5 is expressed in the olfactory epithelium.

<i>N</i>,<i>N</i>-Dimethylethylamine Chemical compound

N,N-Dimethylethylamine (DMEA), sometimes referred to as dimethylethylamine, is an organic compound with formula (CH3)2NC2H5. It is an industrial chemical that is mainly used in foundries as a catalyst for epoxy resins and polyurethane as well as sand core production. Dimethylethylamine is a malodorous, volatile liquid at room temperature that is excreted at greater concentrations with larger dietary intake of trimethylamine.

<span class="mw-page-title-main">Flavin-containing monooxygenase</span> Class of enzymes

The flavin-containing monooxygenase (FMO) protein family specializes in the oxidation of xeno-substrates in order to facilitate the excretion of these compounds from living organisms. These enzymes can oxidize a wide array of heteroatoms, particularly soft nucleophiles, such as amines, sulfides, and phosphites. This reaction requires an oxygen, an NADPH cofactor, and an FAD prosthetic group. FMOs share several structural features, such as a NADPH binding domain, FAD binding domain, and a conserved arginine residue present in the active site. Recently, FMO enzymes have received a great deal of attention from the pharmaceutical industry both as a drug target for various diseases and as a means to metabolize pro-drug compounds into active pharmaceuticals. These monooxygenases are often misclassified because they share activity profiles similar to those of cytochrome P450 (CYP450), which is the major contributor to oxidative xenobiotic metabolism. However, a key difference between the two enzymes lies in how they proceed to oxidize their respective substrates; CYP enzymes make use of an oxygenated heme prosthetic group, while the FMO family utilizes FAD to oxidize its substrates.

<span class="mw-page-title-main">3,3-Dimethyl-1-butanol</span> Chemical compound

3,3-Dimethyl-1-butanol (DMB) is a structural analog of choline.

Intestinal metabolic bromhidrosis syndrome (IMBS) is a disorder, that is characterized by bromhidrosis and halitosis symptoms that are caused by odorous intestinal metabolites passing through the intestinal wall and by the liver to be excreted by skin glands and the lung gas exchange.

References

  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. 1 2 3 NIOSH Pocket Guide to Chemical Hazards. "#0636". National Institute for Occupational Safety and Health (NIOSH).
  5. 1 2 3 Van Gysel, August B.; Musin, Willy (2000). "Methylamines". Ullmann's Encyclopedia of Industrial Chemistry . Weinheim: Wiley-VCH. doi:10.1002/14356007.a16_535. ISBN   978-3527306732.
  6. 1 2 Ashford, Robert D. (2011). Ashford's Dictionary of Industrial Chemicals (3rd ed.). Wavelength. p. 9362. ISBN   978-0-9522674-3-0.
  7. 1 2 "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. 1 2 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. 1 2 3 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. 1 2 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 disease
    Figure 1: Molecular mechanisms of action of indole and its metabolites on host physiology and disease
  16. 1 2 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.
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