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Trimethylamine (TMA) is an
organic compound In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen or carbon-carbon bonds. Due to carbon's ability to catenate (form chains with other carbon atoms), millions of organic compounds are known. T ...
with the formula N(CH3)3. It is a colorless,
hygroscopic Hygroscopy is the phenomenon of attracting and holding water molecules via either absorption or adsorption from the surrounding environment, which is usually at normal or room temperature. If water molecules become suspended among the substan ...
, and flammable
tertiary amine In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituent such ...
. It is a gas at room temperature but is usually sold as a 40% solution in
water Water (chemical formula ) is an Inorganic compound, inorganic, transparent, tasteless, odorless, and Color of water, nearly colorless chemical substance, which is the main constituent of Earth's hydrosphere and the fluids of all known living ...
. (It is also sold in pressurized gas cylinders.) TMA is a
nitrogenous base Nucleobases, also known as ''nitrogenous bases'' or often simply ''bases'', are nitrogen-containing biological compounds that form nucleosides, which, in turn, are components of nucleotides, with all of these monomers constituting the basic b ...
and can be readily
protonated In chemistry, protonation (or hydronation) is the adding of a proton (or hydron, or hydrogen cation), (H+) to an atom, molecule, or ion, forming a conjugate acid. (The complementary process, when a proton is removed from a Brønsted–Lowry acid, ...
to give the trimethylammonium cation. Trimethylammonium chloride is a hygroscopic colorless solid prepared from
hydrochloric acid Hydrochloric acid, also known as muriatic acid, is an aqueous solution of hydrogen chloride. It is a colorless solution with a distinctive pungent smell. It is classified as a strong acid Acid strength is the tendency of an acid, symbol ...
. Trimethylamine is a good nucleophile, and this reaction is the basis of most of its applications. TMA is widely used in industry: it is used in the synthesis of
choline Choline is an essential nutrient for humans and many other animals. Choline occurs as a cation that forms various salts (X− in the depicted formula is an undefined counteranion). Humans are capable of some ''de novo synthesis'' of choline but r ...
, tetramethylammonium hydroxide,
plant growth regulator Plant hormone (or phytohormones) are signal molecules, produced within plants, that occur in extremely low concentrations. Plant hormones control all aspects of plant growth and development, from embryogenesis, the regulation of organ size, ...
s or herbicides, strongly basic anion exchange resins, dye leveling agents, and a number of basic dyes. At higher concentrations it has an
ammonia Ammonia is an inorganic compound of nitrogen and hydrogen with the formula . A stable binary hydride, and the simplest pnictogen hydride, ammonia is a colourless gas with a distinct pungent smell. Biologically, it is a common nitrogenous wa ...
-like odor, and can cause necrosis of
mucous membrane A mucous membrane or mucosa is a membrane that lines various cavities in the body of an organism and covers the surface of internal organs. It consists of one or more layers of epithelial cells overlying a layer of loose connective tissue. It i ...
s on contact. At lower concentrations, it has a "fishy" odor, the odor associated with rotting
fish Fish are aquatic, craniate, gill-bearing animals that lack limbs with digits. Included in this definition are the living hagfish, lampreys, and cartilaginous and bony fish as well as various extinct related groups. Approximately 95% of ...
. In humans, ingestion of certain plant and animal (e.g., red meat, egg yolk) food containing lecithin,
choline Choline is an essential nutrient for humans and many other animals. Choline occurs as a cation that forms various salts (X− in the depicted formula is an undefined counteranion). Humans are capable of some ''de novo synthesis'' of choline but r ...
and
L-carnitine Carnitine is a quaternary ammonium compound involved in metabolism in most mammals, plants, and some bacteria. In support of energy metabolism, carnitine transports long-chain fatty acids into mitochondria to be oxidized for energy production, ...
provides certain gut microbiota with the substrate to synthesize TMA, which is then absorbed into the bloodstream. 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 Choline is an essential nutrient for humans and many other animals. Choline occurs as a cation that forms various salts (X− in the depicted formula is an undefined counteranion). Humans are capable of some ''de novo synthesis'' of choline but r ...
or
L-carnitine Carnitine is a quaternary ammonium compound involved in metabolism in most mammals, plants, and some bacteria. In support of energy metabolism, carnitine transports long-chain fatty acids into mitochondria to be oxidized for energy production, ...
. TMA is metabolized by the liver to
trimethylamine N-oxide 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 anhydr ...
(TMAO); TMAO is being investigated as a possible pro
atherogenic Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheroma, atheromatous plaque. At onset there are usu ...
substance which may accelerate
atherosclerosis Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheromatous plaque. At onset there are usually no s ...
in those eating foods with a high content of TMA precursors. TMA also causes the odor of some human
infection An infection is the invasion of tissues by pathogens, their multiplication, and the reaction of host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmissible disease or communicable dis ...
s,
bad breath Bad breath, also known as halitosis, is a symptom in which a noticeably unpleasant breath odour is present. It can result in anxiety among those affected. It is also associated with depression and symptoms of obsessive compulsive disorder. Th ...
, and bacterial vaginosis. Trimethylamine is a
full agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the a ...
of human TAAR5,
Table 2: Microbial metabolites: their synthesis, mechanisms of action, and effects on health and disease
br
Figure 1: Molecular mechanisms of action of indole and its metabolites on host physiology and disease
/ref> a
trace amine-associated receptor Trace amine-associated receptors (TAARs), sometimes referred to as trace amine receptors (TAs or TARs), are a class of G protein-coupled receptors that were discovered in 2001. TAAR1, the first of six functional human TAARs, has gained considerab ...
that is expressed in the
olfactory epithelium The olfactory epithelium is a specialized epithelial tissue inside the nasal cavity that is involved in smell. In humans, it measures 9 cm2 and lies on the roof of the nasal cavity about 7 cm above and behind the nostrils. The olfactory ...
and functions as an
olfactory receptor Olfactory receptors (ORs), also known as odorant receptors, are chemoreceptors expressed in the cell membranes of olfactory receptor neurons and are responsible for the detection of odorants (for example, compounds that have an odor) which give r ...
for
tertiary amine In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituent such ...
s. One or more additional odorant receptors appear to be involved in trimethylamine olfaction in humans as well.


Production

Trimethylamine is prepared by the reaction of
ammonia Ammonia is an inorganic compound of nitrogen and hydrogen with the formula . A stable binary hydride, and the simplest pnictogen hydride, ammonia is a colourless gas with a distinct pungent smell. Biologically, it is a common nitrogenous wa ...
and methanol employing a catalyst: :3 CH3OH + NH3 → (CH3)3N + 3 H2O This reaction coproduces the other methylamines,
dimethylamine 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 aroun ...
(CH3)2NH and methylamine CH3NH2. Trimethylamine has also been prepared by a reaction of ammonium chloride and
paraformaldehyde Paraformaldehyde (PFA) is the smallest polyoxymethylene, the polymerization product of formaldehyde with a typical degree of polymerization of 8–100 units. Paraformaldehyde commonly has a slight odor of formaldehyde due to decomposition. Paraf ...
: : 9 (CH2=O)n + 2n NH4Cl → 2n (CH3)3N•HCl + 3n H2O + 3n CO2


Toxicity

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


Applications

Trimethylamine is used in the synthesis of
choline Choline is an essential nutrient for humans and many other animals. Choline occurs as a cation that forms various salts (X− in the depicted formula is an undefined counteranion). Humans are capable of some ''de novo synthesis'' of choline but r ...
, tetramethylammonium hydroxide,
plant growth regulator Plant hormone (or phytohormones) are signal molecules, produced within plants, that occur in extremely low concentrations. Plant hormones control all aspects of plant growth and development, from embryogenesis, the regulation of organ size, ...
s, herbicides, strongly basic anion exchange resins, dye leveling agents and a number of basic dyes. Gas sensors to test for fish freshness detect trimethylamine.


Reactions

Trimethylamine is a Lewis base that forms
adducts An adduct (from the Latin ''adductus'', "drawn toward" alternatively, a contraction of "addition product") is a product of a direct addition of two or more distinct molecules, resulting in a single reaction product containing all atoms of all co ...
with a variety of
Lewis acids A Lewis acid (named for the American physical chemist Gilbert N. Lewis) is a chemical species that contains an empty orbital which is capable of accepting an electron pair from a Lewis base to form a Lewis adduct. A Lewis base, then, is any spe ...
.


Trimethylaminuria

Trimethylaminuria is an
autosomal An autosome is any chromosome that is not a sex chromosome. The members of an autosome pair in a diploid cell have the same morphology, unlike those in allosomal (sex chromosome) pairs, which may have different structures. The DNA in autosom ...
recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...
genetic disorder A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic disorders ...
involving a defect in the function or expression of
flavin-containing monooxygenase 3 Flavin-containing monooxygenase 3 (FMO3), also known as dimethylaniline monooxygenase -oxide-forming3 and trimethylamine monooxygenase, is a flavoprotein enzyme () that in humans is encoded by the ''FMO3'' gene. This enzyme catalyzes the foll ...
(FMO3) which results in poor trimethylamine
metabolism Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run c ...
. Individuals with trimethylaminuria develop a characteristic fish odor—the smell of trimethylamine—in their
sweat Perspiration, also known as sweating, is the production of fluids secreted by the sweat glands in the skin of mammals. Two types of sweat glands can be found in humans: eccrine glands and apocrine glands. The eccrine sweat glands are distrib ...
,
urine Urine is a liquid by-product of metabolism in humans and in many other animals. Urine flows from the kidneys through the ureters to the urinary bladder. Urination results in urine being excreted from the body through the urethra. Cellular ...
, and
breath Breathing (or ventilation) is the process of moving air into and from the lungs to facilitate gas exchange with the internal environment, mostly to flush out carbon dioxide and bring in oxygen. All aerobic creatures need oxygen for cell ...
after the consumption of
choline Choline is an essential nutrient for humans and many other animals. Choline occurs as a cation that forms various salts (X− in the depicted formula is an undefined counteranion). Humans are capable of some ''de novo synthesis'' of choline but r ...
-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 Rapeseed (''Brassica napus ''subsp.'' napus''), also known as rape, or oilseed rape, is a bright-yellow flowering member of the family Brassicaceae (mustard or cabbage family), cultivated mainly for its oil-rich seed, which naturally contains a ...
.


See also

*
Ammonia Ammonia is an inorganic compound of nitrogen and hydrogen with the formula . A stable binary hydride, and the simplest pnictogen hydride, ammonia is a colourless gas with a distinct pungent smell. Biologically, it is a common nitrogenous wa ...
, NH3 * Ammonium, NH4+ * Methylamine, (CH3)NH2 *
Triethylamine Triethylamine is the chemical compound with the formula N(CH2CH3)3, commonly abbreviated Et3N. It is also abbreviated TEA, yet this abbreviation must be used carefully to avoid confusion with triethanolamine or tetraethylammonium, for which TEA ...
(TEA)


References


External links


Molecule of the Month: Trimethylamine

NIST Webbook data


{{Authority control Pesticides Dimethylamino compounds Foul-smelling chemicals