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. Th ...

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 substance ...

, 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 Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituent such ...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 Solution may refer to: * Solution (chemistry), a mixture where one substance is dissolved in another * Solution (equation), in mathematics ** Numerical solution, in numerical analysis, approximate solutions within specified error bounds * Solutio ...

water Water (chemical formula ) is an inorganic, transparent, tasteless, odorless, and nearly colorless chemical substance, which is the main constituent of Earth's hydrosphere and the fluids of all known living organisms (in which it acts as ...

. (It is also sold in pressurized

gas cylinder A gas cylinder is a pressure vessel for storage and containment of gases at above atmospheric pressure. High-pressure gas cylinders are also called ''bottles''. Inside the cylinder the stored contents may be in a state of compressed gas, vapo ...

s.) 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 ...

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. It is a component of the gastric acid in the dig ...

. Trimethylamine is a good

nucleophile In chemistry, a nucleophile is a chemical species that forms bonds by donating an electron pair. All molecules and ions with a free pair of electrons or at least one pi bond can act as nucleophiles. Because nucleophiles donate electrons, they a ...

, 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 ...

tetramethylammonium hydroxide Tetramethylammonium hydroxide (TMAH or TMAOH) is a quaternary ammonium salt with molecular formula N(CH3)4+ OH−. It is commonly encountered in form of concentrated solutions in water or methanol. TMAH in solid state and its aqueous solut ...

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, pa ...

s or herbicides, strongly basic

anion exchange resins An ion-exchange resin or ion-exchange polymer is a resin or polymer that acts as a medium for ion exchange. It is an insoluble matrix (or support structure) normally in the form of small (0.25–1.43 mm radius) microbeads, usually white ...

dye A dye is a colored substance that chemically bonds to the substrate to which it is being applied. This distinguishes dyes from pigments which do not chemically bind to the material they color. Dye is generally applied in an aqueous solution and ...

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 nitrogeno ...

-like odor, and can cause

necrosis Necrosis () is a form of cell injury which results in the premature death of cells in living tissue by autolysis. Necrosis is caused by factors external to the cell or tissue, such as infection, or trauma which result in the unregulated dig ...

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% ...

. In humans, ingestion of certain plant and animal (e.g., red meat, egg yolk) food containing

lecithin Lecithin (, from the Greek ''lekithos'' "yolk") is a generic term to designate any group of yellow-brownish fatty substances occurring in animal and plant tissues which are amphiphilic – they attract both water and fatty substances (and so a ...

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 Gut microbiota, gut microbiome, or gut flora, are the microorganisms, including bacteria, archaea, fungi, and viruses that live in the digestive tracts of animals. The gastrointestinal metagenome is the aggregate of all the genomes of the gut ...

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

. 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 anhyd ...

(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 ...

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 d ...

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 Bacterial vaginosis (BV) is a disease of the vagina caused by excessive growth of bacteria. Common symptoms include increased vaginal discharge that often smells like fish. The discharge is usually white or gray in color. Burning with urinatio ...

. 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 ag ...

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 ri ...

for

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

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 Methylamine is an organic compound with a formula of . 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. Methylamine is sold as a solution in methanol, ...

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 Uremia is the term for high levels of urea in the blood. Urea is one of the primary components of urine. It can be defined as an excess of amino acid and protein metabolism end products, such as urea and creatinine, in the blood that would be no ...

. In patients, trimethylamine caused stomach ache, vomiting, diarrhoea, lacrimation, greying of the skin and agitation. Apart from that,

reproductive The reproductive system of an organism, also known as the genital system, is the biological system made up of all the anatomical organs involved in sexual reproduction. Many non-living substances such as fluids, hormones, and pheromones are al ...

developmental toxicity Development of the human body is the process of growth to maturity. The process begins with fertilization, where an egg released from the ovary of a female is penetrated by a sperm cell from a male. The resulting zygote develops through mit ...

has been reported. Guidelines with exposure limit for workers are available e.g. the Recommendation from the

Scientific Committee on Occupational Exposure Limits The Scientific Committee on Occupational Exposure Limit Values (SCOEL) is a committee of the European Commission established in 1995 to advise on occupational exposure limits for chemicals in the workplace within the framework of: * Directive 98/2 ...

by the European Union Commission. Some experimental studies suggested that TMA may be involved in etiology of

cardiovascular disease Cardiovascular disease (CVD) is a class of diseases that involve the heart or blood vessels. CVD includes coronary artery diseases (CAD) such as angina and myocardial infarction (commonly known as a heart attack). Other CVDs include stroke, ...

Applications

Trimethylamine is used in the synthesis of

s, herbicides, strongly basic

leveling agents and a number of basic dyes. Gas sensors to test for fish freshness detect trimethylamine.

Reactions

Trimethylamine is a

Lewis base 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 sp ...

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 sp ...

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 autosomes ...

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 ...

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 disorde ...

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 followin ...

(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 dist ...

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

-rich foods. A condition similar to trimethylaminuria has also been observed in a certain breed of

Rhode Island Red The Rhode Island Red is an American breed of domestic chicken. It is the state bird of Rhode Island. It was developed there and in Massachusetts in the late nineteenth century, by cross-breeding birds of Oriental origin such as the Malay wit ...

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 ...

References

External links

Molecule of the Month: Trimethylamine

NIST Webbook data

{{Authority control Pesticides Dimethylamino compounds Foul-smelling chemicals