Tetramethylammonium (TMA) is the simplest

quaternary ammonium cation In organic chemistry, quaternary ammonium cations, also known as quats, are positively-charged polyatomic ions of the structure , where R is an alkyl group, an aryl group or organyl group. Unlike the ammonium ion () and the primary, secondary, ...

. It has the

chemical formula A chemical formula is a way of presenting information about the chemical proportions of atoms that constitute a particular chemical compound or molecule, using chemical element symbols, numbers, and sometimes also other symbols, such as pare ...

and consists of four

methyl group In organic chemistry, a methyl group is an alkyl derived from methane, containing one carbon atom bonded to three hydrogen atoms, having chemical formula (whereas normal methane has the formula ). In formulas, the group is often abbreviated a ...

s (, denoted Me) attached to a central

nitrogen Nitrogen is a chemical element; it has Symbol (chemistry), symbol N and atomic number 7. Nitrogen is a Nonmetal (chemistry), nonmetal and the lightest member of pnictogen, group 15 of the periodic table, often called the Pnictogen, pnictogens. ...

atom. The cation is

isoelectronic Isoelectronicity is a phenomenon observed when two or more molecules have the same structure (positions and connectivities among atoms) and the same electronic configurations, but differ by what specific elements are at certain locations in th ...

with

neopentane Neopentane, also called 2,2-dimethylpropane, is a double-branched-chain alkane with five carbon atoms. Neopentane is a flammable gas at room temperature and pressure which can condense into a highly volatile liquid on a cold day, in an ice bat ...

(). It is positively-charged and can only be isolated in association with a counter-ion. Common

salts In chemistry, a salt or ionic compound is a chemical compound consisting of an assembly of positively charged ions ( cations) and negatively charged ions (anions), which results in a compound with no net electric charge (electrically neutral). ...

include tetramethylammonium chloride and

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 soluti ...

. Tetramethylammonium salts are used in

chemical synthesis Chemical synthesis (chemical combination) is the artificial execution of chemical reactions to obtain one or several products. This occurs by physical and chemical manipulations usually involving one or more reactions. In modern laboratory uses ...

and in pharmacological research. It confers no color to its salts.

Common nomenclature

In the toxicological literature, ''naturally occurring'' tetramethylammonium (anion unspecified) is often referred to by the name "tetramine". Unfortunately, this non-systematic or "trivial" name is also used for other chemical entities, including a toxic rodenticide ( Tetramethylenedisulfotetramine). Similarly, the acronym "TMA", which is frequently used for tetramethylammonium in the pharmacological literature, may also refer to the investigational drug 3,4,5-trimethoxyamphetamine, which, being a close structural analog of

mescaline Mescaline, also known as mescalin or mezcalin, and in chemical terms 3,4,5-trimethoxyphenethylamine, is a natural product, naturally occurring psychedelic drug, psychedelic alkaloid, protoalkaloid of the substituted phenethylamine class, found ...

, has been the subject of numerous publications.

Occurrence

TMA has been detected in or isolated from a number of marine organisms, mostly amongst the

Cnidaria Cnidaria ( ) is a phylum under kingdom Animalia containing over 11,000 species of aquatic invertebrates found both in fresh water, freshwater and marine environments (predominantly the latter), including jellyfish, hydroid (zoology), hydroids, ...

and

Mollusca Mollusca is a phylum of protostome, protostomic invertebrate animals, whose members are known as molluscs or mollusks (). Around 76,000 extant taxon, extant species of molluscs are recognized, making it the second-largest animal phylum ...

, notably in some species of '' Neptunea'' (commonly called whelks) that are eaten by humans. It has also been found in one plant, the African '' Courbonia virgata'' (Cappariaceae). TMA also occurs within the crystal structure Tsaregorodtsevite, a rare Sodalite group mineral with the formula N(CH₃)₄AlSi₅O₁₂ found on Gora Yaruta Mountain, Khanty-Mansi Autonomous Okrug, Russia.

Preparation, reactions, solution properties

Tetramethylammonium ion is typically prepared by the reaction between

trimethylamine 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. At higher concentrations it has an ammonia-like odor, and can cause necrosis of mucous membranes ...

and a

methyl chloride Chloromethane, also called methyl chloride, Refrigerant-40, R-40 or HCC 40, is an organic compound with the chemical formula . One of the haloalkanes, it is a colorless, sweet-smelling, flammable gas. Methyl chloride is a crucial reagent in indus ...

: : -labeled TMA has been made by this method. Although this reaction is suitable for the common halides, tetramethylammonium salts with more complex anions may be prepared by

salt metathesis A salt metathesis reaction (also called a double displacement reaction, double replacement reaction, or double decomposition) is a type of chemical reaction in which two ionic compounds in aqueous solution exchange their component ions to form two ...

reactions, e.g. tetramethylammonium borohydride has been made from

as shown: : Although TMA salts do possess some of the phase-transfer catalytic properties that are characteristic of

quaternary ammonium compounds In organic chemistry, quaternary ammonium cations, also known as quats, are positively-charged polyatomic ions of the structure , where R is an alkyl group, an aryl group or organyl group. Unlike the ammonium ion () and the primary, secondary, o ...

, they tend to behave atypically because of the relatively high '' hydrophilicity'' of the TMA cation. TMA cation is

hydrophilic A hydrophile is a molecule or other molecular entity that is attracted to water molecules and tends to be dissolved by water.Liddell, H.G. & Scott, R. (1940). ''A Greek-English Lexicon'' Oxford: Clarendon Press. In contrast, hydrophobes are n ...

. The octanol-water partition coefficient of TMA iodide, ''P''_o-w, is (or ). In the TMA cation, the methyl groups are tetrahedrally arranged around the central N atom, as is evident from X-ray crystallographic studies of various of its salts. From measurements taken on molecular models, it has been estimated that the diameter of the TMA ion is ~0.6 nm; From more accurate physico-chemical measurements, the

ionic radius Ionic radius, ''r''ion, is the radius of a monatomic ion in an ionic crystal structure. Although neither atoms nor ions have sharp boundaries, they are treated as if they were hard spheres with radii such that the sum of ionic radii of the cati ...

for TMA is given as 0.322 nm; several thermodynamic parameters for the TMA ion are also recorded. The paper by Aue et al. gives a good discussion of the methods by which the ionic radius was determined.

Pharmacology

The pharmacological literature on tetramethylammonium is extensive. In general, TMA is a

cholinomimetic A parasympathomimetic drug, sometimes called a cholinomimetic drug or cholinergic receptor stimulating agent, is a substance that stimulates the parasympathetic nervous system (PSNS). These chemicals are also called cholinergic drugs becaus ...

whose effects mimic most of those produced by exogenous

acetylcholine Acetylcholine (ACh) is an organic compound that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Par ...

. Pharmacological experiments with TMA have been performed using one of its salts, typically the chloride, bromide or iodide, since these anions were not expected to interfere with the actions of the TMA cation. In the early pharmacological literature, however, there are references to the use of "

" or "tetramethylammonium hydrate", which were meant to facilitate comparison between weight-based dosages of different TMA salts, but did not involve the actual use of tetramethylammonium hydroxide, whose strong basicity would have been incompatible with physiological conditions. A thorough review of the pharmacology of TMA from a toxicological perspective, and current up to 1989, has been given by Anthoni and co-workers. Thus, the effects of TMA on nicotinic and

muscarinic A muscarinic acetylcholine receptor agonist, also simply known as a muscarinic agonist or as a muscarinic agent, is an agent that activates the activity of the muscarinic acetylcholine receptor. The muscarinic receptor has different subtypes, lab ...

ACh receptors first stimulate, then block neurotransmission in sympathetic and parasympathetic ganglia, with

depolarization In biology, depolarization or hypopolarization is a change within a cell (biology), cell, during which the cell undergoes a shift in electric charge distribution, resulting in less negative charge inside the cell compared to the outside. Depolar ...

. TMA also acts as an

agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

at muscarinic receptors in post-ganglionic nerve endings in

smooth muscle Smooth muscle is one of the three major types of vertebrate muscle tissue, the others being skeletal and cardiac muscle. It can also be found in invertebrates and is controlled by the autonomic nervous system. It is non- striated, so-called bec ...

s, cardiac muscle, and

exocrine Exocrine glands are glands that secrete substances onto an epithelial surface by way of a duct. Examples of exocrine glands include sweat, salivary, mammary, ceruminous, lacrimal, sebaceous, prostate and mucous. Exocrine glands are one of t ...

glands. In

skeletal muscle Skeletal muscle (commonly referred to as muscle) is one of the three types of vertebrate muscle tissue, the others being cardiac muscle and smooth muscle. They are part of the somatic nervous system, voluntary muscular system and typically are a ...

, TMA initially causes

fasciculation A fasciculation, or muscle twitch, is a spontaneous, involuntary muscle contraction and relaxation, involving fine muscle fibers. They are common, with as many as 70% of people experiencing them. They can be benign, or associated with more seriou ...

s, then paralysis, as a result of the depolarization from stimulation of nicotinic ACh receptors.

Absorption; distribution; metabolism; excretion (ADME)

Absorption: TMA is readily absorbed from the gastro-intestinal tract. Studies on the rat

jejunum The jejunum is the second part of the small intestine in humans and most higher vertebrates, including mammals, reptiles, and birds. Its lining is specialized for the absorption by enterocytes of small nutrient molecules which have been pr ...

indicated that TMA absorption involved a combination of simple diffusion and carrier-mediated transport, with nearly 100% absorption occurring within 60 to 90 minutes. By comparison,

tetraethylammonium Tetraethylammonium (TEA) is a quaternary ammonium cation with the chemical formula , consisting of four ethyl groups (, denoted Et) attached to a central nitrogen atom. It is a counterion used in the research laboratory to prepare lipophilic salt ...

and tetrapropylammonium ions were only absorbed to the extent of ~30%. Distribution:

Intraperitoneal The peritoneum is the serous membrane forming the lining of the abdominal cavity or coelom in amniotes and some invertebrates, such as annelids. It covers most of the intra-abdominal (or coelomic) organs, and is composed of a layer of mesothe ...

administration of radio-labeled tetramethylammonium iodide to mice showed that TMA was rapidly distributed to all parts of the body, with the highest concentrations being in the kidney and liver. Similar results were reported by Neef and co-workers using rats. Metabolism and excretion: Parenteral administration of radio-labeled tetramethylammonium iodide to rats resulted in almost the whole dose being excreted in urine, without any evidence of metabolic transformation.

Toxicology

The human toxicology of TMA (under the name "tetramine") has been studied primarily in the context of accidental poisoning after ingestion of '' Neptunea'' species. Symptoms include the following: nausea, vomiting, headache, vertigo/dizziness, impaired vision/temporary blindness,

diplopia Diplopia is the simultaneous perception of two images of a single object that may be displaced in relation to each other. Also called double vision, it is a loss of visual focus under regular conditions, and is often voluntary. However, when occ ...

photophobia Photophobia is a medical symptom of abnormal intolerance to visual perception of light. As a medical symptom, photophobia is not a morbid fear or phobia, but an experience of discomfort or pain to the eyes due to light exposure or by presence o ...

, lack of balance, feeling of intoxication and

urticaria Hives, also known as urticaria, is a kind of skin rash with red or flesh-colored, raised, itchy bumps. Hives may burn or sting. The patches of rash may appear on different body parts, with variable duration from minutes to days, and typically ...

. These symptoms appear within 30 minutes but recovery is usually complete after a few hours. Only one account of human death following ingestion of TMA (from the plant ''Courbonia virgata'') has been recorded. Although many of these symptoms can be accounted for on the basis of impairment of neurotransmission in the

autonomic nervous system The autonomic nervous system (ANS), sometimes called the visceral nervous system and formerly the vegetative nervous system, is a division of the nervous system that operates viscera, internal organs, smooth muscle and glands. The autonomic nervo ...

, there also seem to be distinct indications of central effects. In animal studies, parenteral administration of TMA-containing extracts from ''Neptunea'' to mice, cats and fish mainly show effects involving skeletal muscles: there are muscular

s, convulsions, loss of balance, motor paralysis and ultimately cessation of respiration. The lethal oral dose of TMA for humans has been estimated at 3–4 mg/kg. The lethal dose for rats was estimated to be ~45–50 mg/kg, p.o., and ~15 mg/kg, i.p.

Acute toxicity

LD₅₀ for TMA chloride: 25 mg/kg (mouse, i.p.); 40 mg/kg (mouse, s.c.). LC₅₀ for TMA chloride: 462 mg/L for 96 hrs. (Fathead minnow, ''Pimephales promelas'').

References

{{reflist Quaternary ammonium compounds Cations Tetramethylammonium salts