Tetraethylammonium

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Tetraethylammonium
Tetraethylammonium.svg
Tetraethylammonium-cation-3D-balls.png
Names
IUPAC name
tetraethylazanium
Other names
N,N,N-triethylethanaminium
Identifiers
66-40-0 N
ChEBI CHEBI:44296 YesY
ChEMBL ChEMBL9324 YesY
ChemSpider 5220 YesY
Jmol-3D images Image
PubChem 5413
Properties
C8H20N+
Molar mass 130.25 g/mol
Except where noted otherwise, data is given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
 N verify (what isYesY/N?)
Infobox references

Tetraethylammonium (TEA) or (Et4N+) is a quaternary ammonium cation consisting of four ethyl groups attached to a central nitrogen atom, and is positively charged. It must exist in association with a counter-ion, and is most commonly found in simple salts such as tetraethylammonium chloride, tetraethylammonium bromide, tetraethylammonium iodide and tetraethylammonium hydroxide. Tetraethylammonium salts are used in chemical synthesis, have briefly been used in clinical applications, and are widely employed in pharmacological research. The identity of the anion associated with the tetraethylammonium cation frequently has little or no bearing on a particular chemical or biological type of action, but this is not invariably so.

Chemistry[edit]

Preparation[edit]

One of the most straightforward methods of preparing a simple salt containing the tetraethylammonium ion is by the reaction between triethylamine and an ethyl halide:

Et3N + Et-X → Et4N+X

This method works well for the preparation of tetraethylammonium iodide (where X = I).[1] However, the tetraethylammonium cation can exist in association with a large variety of different anions, some of which may be quite complex, and the preparations of such salts often involve a salt metathesis reaction. For example, the synthesis of tetraethylammonium perchlorate, a salt that has been useful as a supporting electrolyte for polarographic studies in non-aqueous solvents, was carried out by mixing the water-soluble salts tetraethylammonium bromide and sodium perchlorate in water, from which the water-insoluble tetraethylammonium perchlorate precipitated:[2]

Et4N+Br + Na+[ClO4] → Na+Br + Et4N+[ClO4]

Uses[edit]

The principal chemical characteristic of tetraethylammonium salts is their ability to engage in processes involving phase-transfer, such as phase-transfer catalysis.[3] 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.[4]

Properties[edit]

The effective radius of the tetraethylammonium ion is reported as ~ 0.45 nm, which is comparable in size to that of the hydrated K+ ion.[5] In more recent studies, the ionic radius for TEA is given as 0.385 nm; several thermodynamic parameters for the TEA ion are also recorded.[6][7]

The partition coefficient of TEA iodide in octanol-water, Po-w was determined experimentally to be 0.69 x 10−3 (or log P ≅ -3.16).[8]

Biology[edit]

Pharmacology[edit]

The literature dealing with the pharmacologically-related properties of tetraethylammonium is vast, and research continues.[9] It is clear that TEA[10] blocks autonomic ganglia - it was the first "ganglionic blocker" drug to be introduced into clinical practice.[11][12] However, TEA also produces effects at the neuromuscular junction[13] and at sympathetic nerve terminals.[14]

At the mechanistic level, TEA has long been known to block voltage-dependent K+ channels in nerve,[5][15] and it is thought that this action is involved in the effects of TEA at sympathetic nerve terminals.[14] 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.[16] TEA also blocks Ca2+ - activated K+ channels, such as those found in skeletal muscle[17] and pituitary cells.[18] It has also been reported that TEA inhibits aquaporin (APQ) channels,[19] but this still seems to be a disputed issue.[20]

Clinical Considerations[edit]

Although TEA (sometimes under the name "Etamon"[21]) was explored in a number of different clinical applications,[12] including the treatment of hypertension,[22] its major use seems to have been as a probe to assess the capacity for vasodilation in cases of peripheral vascular disease.[23] Because of dangerous, even fatal reactions in some patients,[23] as well as inconsistent cardiovascular responses, TEA was soon replaced by other drugs.[11]

TEA is not orally active.[24] 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.[12] 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 it is noteworthy that Birchall and his co-workers preferred the use of TEA chloride in order to avoid the sedative effects of the bromide ion.[25]

Toxicology[edit]

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.[26] 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:[27]

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.[23] Citing the work of other investigators, Graham noted that Birchall[25] had also produced "alarming curariform effects" in humans with i.v. doses of 32 mg/kg of tetraethylammonium chloride.

See also[edit]

References[edit]

  1. ^ 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.
  2. ^ 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.
  3. ^ C. M. Starks, C. L. Liotta and M. Halpern (1994). "Phase-Transfer Catalysis: Fundamentals, Applications, and Industrial Perspectives." Springer.
  4. ^ J. Huang, B. G. Sumpter and V. Meunier (2008). "A universal model for nanoporous carbon supercapacitors applicable to diverse pore regimes, carbon materials, and electrolytes." Chem. Eur. J. 14 6614-6626.
  5. ^ a b C. M. Armstrong (1971). "Interaction of tetraethylammonium ion derivatives with the potassium channels of giant axons." J. Gen. Physiol. 58 413-437.
  6. ^ 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.
  7. ^ 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.
  8. ^ 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.
  9. ^ There are over 8500 citations in PubMed, as of October 2012.
  10. ^ Since 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.
  11. ^ a b Drill's Pharmacology in Medicine, 4th Ed. (1971). J. R. DiPalma (Ed.), pp. 723-724, New York: McGraw-Hill.
  12. ^ a b c G. K. Moe and W. A. Freyburger (1950). "Ganglionic blocking agents." Pharmacol. Rev. 2 61-95.
  13. ^ R. C. Elliott (1982). "The action of tetraethylammonium at the neuromuscular junction." Gen. Pharmacol. 13 11-14.
  14. ^ a b 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.
  15. ^ B. Hille (1967). "The selective inhibition of delayed potassium currents in nerve by tetraethylammonium ions." J. Gen. Physiol. 50 1287-1302.
  16. ^ G. Akk and J. H. Steinbach (2003). "Activation and block of mouse muscle-type nicotinic receptors by tetraethylammonium." J. Physiol. 551 155-168.
  17. ^ R. 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.
  18. ^ 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.
  19. ^ E. M. Müller, J. S. Hub, H. Grubmüller, and B. L. de Groot (2008). "Is TEA an inhibitor for human Aquaporin-1?" Pflugers Arch. 456 663–669, and references herein.
  20. ^ 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." Pflugers Arch. 456 285-92.
  21. ^ J. P. Hendrix (1949. "Neostigmine as antidote to Etamon®." JAMA 139(11) 733-734.
  22. ^ 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.
  23. ^ a b c A. J. P. Graham (1950). "Toxic effects in animals and man after tetraethylammonium bromide." Br. Med. J. 2 321-322.
  24. ^ A. M. Boyd et al. (1948). "Action of tetraethylammonium bromide." Lancet 251 15-18.
  25. ^ a b 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.
  26. ^ 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.
  27. ^ L. O. Randall, W. G. Peterson and G. Lehmann (1949). "The ganglionic blocking actions of thiophanium derivatives." J. Pharmacol. Exp. Ther. 97 48-57.