:Tetraethylammonium

The halide salt is prepared by the reaction of triethylamine and an ethyl halide:

:{{chem2 | Et3N + EtX -> Et4N+X- }}

This method works well for the preparation of tetraethylammonium iodide (where X = I).A. A. Vernon and J. L. Sheard (1948). "The solubility of tetraethylammonium iodide in benzene-ethylene dichloride mixtures." J. Am. Chem. Soc. 70 2035-2036. https://doi.org/10.1021/ja01186a015

Most tetraethylammonium salts are prepared by salt metathesis reactions. For example, the synthesis of tetraethylammonium perchlorate, a salt that has been useful as a supporting electrolyte for polarographic studies in non-aqueous solvents, is carried out by mixing the water-soluble salts tetraethylammonium bromide and sodium perchlorate in water, from which the water-insoluble tetraethylammonium perchlorate precipitates:I. M. Kolthoff and J. F. Coetzee (1957). "Polarography in acetonitrile. I. Metal ions which have comparable polarographic properties in acetonitrile and in water." J. Am. Chem. Soc. 79 870-874.

:{{chem2 | Et4N+Br-_{(aq)} + Na+[ClO4]-_{(aq)} -> Na+Br-_{(aq)} + Et4N+[ClO4]-_{(s)} }}

Other examples include tetraethylammonium cyanide ({{chem2|Et4NCN}}),{{cite book | doi = 10.1002/9780470132470.ch36 | chapter = Tetraethylammonium, Tetraphenylarsonium, and Ammonium Cyanates and Cyanides | title = Inorganic Syntheses | date = 1976 | last1 = Dieck | first1 = R. L. | last2 = Peterson | first2 = E. J. | last3 = Galliart | first3 = A. | last4 = Brown | first4 = T. M. | last5 = Moeller | first5 = T. | last6 = Ruckenstein | first6 = A. | last7 = Burmeister | first7 = J. L. | volume = 16 | pages = 131–137 | isbn = 978-0-470-13178-7 }} and trichlorostannate ({{chem2|Et4NSnCl3}}).{{cite book | doi = 10.1002/9780470132463.ch48 | chapter = Tetraethylammonium Trichlorogermanate(l-) and Trichlorostannate(l-) | title = Inorganic Syntheses | date = 1974 | last1 = Parshall | first1 = G. W. | last2 = Jolly | first2 = W. L. | last3 = Iannone | first3 = M. | last4 = Koo | first4 = P. | volume = 15 | pages = 222–225 | isbn = 978-0-470-13176-3 }} In some cases, salts are produced of anions that cannot be generated in water, such as the tetrahedral {{chem2|[NiCl4](2-)}} salt.{{cite book | doi = 10.1002/9780470132401.ch37 | chapter = Tetrahalo Complexes of Dipositive Metals in the First Transition Series | title = Inorganic Syntheses | date = 1967 | last1 = Gill | first1 = Naida S. | last2 = Taylor | first2 = F. B. | last3 = Hatfield | first3 = W. E. | last4 = Parker | first4 = W. E. | last5 = Fountain | first5 = Carol S. | last6 = Bunger | first6 = Fred L. | volume = 9 | pages = 136–142 | isbn = 978-0-470-13168-8 }}

The principal chemical characteristic of tetraethylammonium salts is their ability to engage in processes involving phase-transfer, such as phase-transfer catalysis.C. M. Starks, C. L. Liotta and M. Halpern (1994). "Phase-Transfer Catalysis: Fundamentals, Applications, and Industrial Perspectives." Springer. Typically, the four ethyl groups surrounding the nitrogen are too small to facilitate efficient ion transfer between aqueous and organic phases, but tetraethylammonium salts have been found to be effective in a number of such applications, and these are exemplified under the headings of the individual salts.

TEA salts such as tetraethylammonium tetrafluoroborate and tetraethylammonium methylsulfonate are used in supercapacitors as organic electrolytes.{{cite journal | doi = 10.1002/chem.200800639 | title = A Universal Model for Nanoporous Carbon Supercapacitors Applicable to Diverse Pore Regimes, Carbon Materials, and Electrolytes | date = 2008 | last1 = Huang | first1 = Jingsong | last2 = Sumpter | first2 = Bobby G. | last3 = Meunier | first3 = Vincent | journal = Chemistry – A European Journal | volume = 14 | issue = 22 | pages = 6614–6626 | pmid = 18576455 }}

TEA halide and its hydroxide are used for the synthesis of high-silica zeolite, especially for the zeolite beta.{{Ref patent|country=US|number=5139759A|status=patent|gdate=1992-08-18|title = Synthesis of zeolite beta}} TEA can act as a template for micropore of zeolites under hydrothermal conditions during crystallization processes.

The effective radius of the tetraethylammonium ion is reported as ~0.45 nm, which is comparable in size to that of the hydrated {{chem2|K+}} ion.C. M. Armstrong (1971). "Interaction of tetraethylammonium ion derivatives with the potassium channels of giant axons." J. Gen. Physiol. 58 413-437. The ionic radius for TEA is given as 0.385 nm; several thermodynamic parameters for the TEA ion are also recorded.D. H. Aue, H. M. Webb and M. T. Bowers (1976). "A thermodynamic analysis of solvation effects on the basicities of alkylamines. An electrostatic analysis of substituent effects." J. Am. Chem. Soc. 98 318–329.J. Palomo and P. N. Pintauro (2003). "Competitive absorption of quaternary ammonium and alkali metal cations into a Nafion cation-exchange membrane." J. Membrane Sci. 215 103-114.

The octanol-water partition coefficient of TEA iodide, P_o-w was determined experimentally to be {{val|6.9e-4}} (or {{nowrap|log P ≈ −3.16}}).H. Tsubaki, E. Nakajima, T. Komai and H. Shindo (1986). "The relation between structure and distribution of quaternary ammonium ions in mice and rats. Simple tetraalkylammonium and a series of m-substituted trimethylphenylammonium ions." J. Pharmacobio-Dyn. 9 737-746.

The literature dealing with the pharmacologically-related properties of tetraethylammonium is vast, and research continues.There are over 8500 citations in PubMed, as of October 2012. It is clear that TEASince tetraethylammonium is always paired with an anion, the TEA salts, TEA chloride, TEA bromide, or TEA iodide have actually been used, but not always specified as such. Here, the term "TEA" is written for convenience. blocks autonomic ganglia - it was the first "ganglionic blocker" drug to be introduced into clinical practice.Drill's Pharmacology in Medicine, 4th Ed. (1971). J. R. DiPalma (Ed.), pp. 723-724, New York: McGraw-Hill.G. K. Moe and W. A. Freyburger (1950). "Ganglionic blocking agents." Pharmacol. Rev. 2 61-95. However, TEA also produces effects at the neuromuscular junctionR. C. Elliott (1982). "The action of tetraethylammonium at the neuromuscular junction." Gen. Pharmacol. 13 11-14. and at sympathetic nerve terminals.V. Ceña, A. G. García, C. Gonzalez-Garcia, and S. M. Kirpekar (1985). "Ion dependence of the release of noradrenaline by tetraethylammonium and 4-aminopyridine from cat splenic slices." Br. J. Pharmacol. 84 299–308.

At the mechanistic level, TEA has long been known to block voltage-dependent K⁺ channels in nerve,B. Hille (1967). "The selective inhibition of delayed potassium currents in nerve by tetraethylammonium ions." J. Gen. Physiol. 50 1287-1302. and it is thought that this action is involved in the effects of TEA at sympathetic nerve terminals. With respect to activity at the neuromuscular junction, TEA has been found to be a competitive inhibitor at nicotinic acetylcholine receptors, although the details of its effect on these receptor proteins are complex.G. Akk and J. H. Steinbach (2003). "Activation and block of mouse muscle-type nicotinic receptors by tetraethylammonium." J. Physiol. 551 155-168. TEA also blocks Ca²⁺ - activated K⁺ channels, such as those found in skeletal muscleR. Latorre, C. Vergara, and C. Hidalgo (1982). "Reconstitution in planar lipid bilayers of a Ca²⁺-dependent K⁺ channel from transverse tubule membranes isolated from rabbit skeletal muscle." Proc. Natl. Acad. Sci. 79 805-809. and pituitary cells.D. G. Lang and A. K. Ritchie (1990. "Tetraethylammonium blockade of apamin-sensitive and insensitive Ca²⁺-activated K⁺ channels in a pituitary cell line." J. Physiol. 425 117-132. It has also been reported that TEA inhibits aquaporin (APQ) channels,E. M. Müller, J. S. Hub, H. Grubmüller, and B. L. de Groot (2008). "Is TEA an inhibitor for human Aquaporin-1?" Pflügers Arch. 456 663–669, and references herein. but this still seems to be a disputed issue.R. Søgaard and T. Zeuthen (2008). "Test of blockers of AQP1 water permeability by a high-resolution method: no effects of tetraethylammonium ions or acetazolamide." Pflügers Arch. 456 285-292

A partial effect of these voltage-dependent and permeability properties within each system mentioned above is not only due to the aforementioned inhibitory properties of TEA, but also its ability to inhibit Na,K-ATPase. Acting on the extracellular vestibule of the Na,K-ATPase, inhibiting K+ access similar to ouabain, TEA further accentuates the disrupted K, and Na, gradients within each of these systems.1988. Inhibition of the electrogenic Na,K pump and Na,K-ATPase activity by tetraethylammonium, tetrabutylammonium, and apamin. Zemková H, Teisinger J, Vyskocil F. J Neurosci Res. Apr;19(4):497-503

Although TEA (sometimes under the name "Etamon"J. P. Hendrix (1949. "Neostigmine as antidote to Etamon®." JAMA 139(11) 733-734.) was explored in a number of different clinical applications, including the treatment of hypertension,S. W. Hoobler, G. K. Moe and R. H. Lyons (1949). "The cardiovascular effects of tetraethylammonium in animals and man with special reference to hypertension." Med. Clin. N. Amer. 33 805-832. its major use seems to have been as a probe to assess the capacity for vasodilation in cases of peripheral vascular disease.A. J. P. Graham (1950). "Toxic effects in animals and man after tetraethylammonium bromide." Br. Med. J. 2 321-322. Because of dangerous, even fatal reactions in some patients, as well as inconsistent cardiovascular responses, TEA was soon replaced by other drugs.

TEA is not orally active.A. M. Boyd et al. (1948). "Action of tetraethylammonium bromide." Lancet 251 15-18. Typical symptoms produced in humans include the following: dry mouth, suppression of gastric secretion, drastic reduction of gastric motility, paralysis of urinary bladder, and relief of some forms of pain. Most studies with TEA seem to have been performed using either its chloride or bromide salt without comment as to any distinctions in effect, but Birchall and his co-workers preferred the use of TEA chloride in order to avoid the sedative effects of the bromide ion.R. Birchall et al. (1947). "Clinical studies of the pharmacological effects of tetraethyl ammonium chloride in hypertensive persons made in an attempt to select patients suitable for lumbodorsal sympathectomy and ganglioectomy." Am. J. Med. Sci. 213 572-578

An extensive study of the toxicology of tetraethylammonium chloride in mice, rats and dogs was published by Gruhzit and co-workers in 1948. These workers reported the following symptoms in mice and rats receiving toxic parenteral doses: tremors, incoordination, flaccid prostration, and death from respiratory failure within 10–30 minutes; dogs exhibited similar symptoms, including incoordination, flaccid prostration, respiratory and cardiac depression, ptosis, mydriasis, erythema, and death from respiratory paralysis and circulatory collapse. After non-lethal doses, symptoms abated within 15–60 minutes. There was little evidence of toxicity from chronic administration of non-lethal doses.O. M. Gruhzit, R. A. Fisken and B. J. Cooper (1948). "Tetraethylammonium chloride [(C₂H₅)₄NCl]. Acute and chronic toxicity in experimental animals." J. Pharmacol. Exp. Ther. 92 103-107. These investigators recorded the following acute toxicities, as LD₅₀s for TEA chloride (error ranges not shown):

:Mouse: 65 mg/kg, i.p.; 900 mg/kg, p.o.

:Rat: ~56 mg/kg, i.v.; 110 mg/kg, i.m.; 2630 mg/kg, p.o.

:Dog: ~36 mg/kg, i.v.; 58 mg/kg, i.m.

Another research group, working at about the same time, but using tetraethylammonium bromide, published the following LD₅₀ data:L. O. Randall, W. G. Peterson and G. Lehmann (1949). "The ganglionic blocking actions of thiophanium derivatives." J. Pharmacol. Exp. Ther. 97 48-57.

:Mouse: 38 mg/kg, i.v.; 60 mg/kg, i.p.; >2000 mg/kg, p.o.

:Rat: 63 mg/kg, i.v.; 115 mg/kg, i.p.

:Dog: 55 mg/kg, i.v.

:Rabbit: 72 mg/kg, i.v.

Writing in 1950, Graham made some observations on the toxic effects of tetraethylammonium bromide in humans. In one subject, described as a "healthy woman", 300 mg of tetraethylammonium bromide, i.v., produced incapacitating "curariform" (i.e., resembling the effects of tubocurarine) paralysis of the skeletal muscles, as well as marked drowsiness. These effects were largely dissipated within 2 hours. Citing the work of other investigators, Graham noted that Birchall had also produced "alarming curariform effects" in humans with i.v. doses of 32 mg/kg of tetraethylammonium chloride.

• Tetraethylammonium bromide
• Tetraethylammonium chloride
• Tetraethylammonium iodide

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{{Potassium channel blockers}}

Category:Neurotoxins

Category:Quaternary ammonium compounds

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