Tetraethyl pyrophosphate

Tetraethyl pyrophosphate, abbreviated TEPP, is an organophosphate compound with the formula [(C2H5O)2P(O)]2O. It is the tetraethyl derivative of pyrophosphate (P2O74-). It is a colorless oil that solidifies near room temperature. It is used as an insecticide. The compound hydrolyzes rapidly.[3]

Tetraethyl pyrophosphate
Names
IUPAC name
tetraethyl diphosphate
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.003.179
EC Number
  • 203-495-3
KEGG
RTECS number
  • UX6825000
UNII
UN number 3018 2783
Properties
C8H20O7P2
Molar mass 290.189 g·mol−1
Appearance colorless to amber liquid[1]
Odor faint, fruity[1]
Density 1.19 g/mL (20°C)[1]
Melting point 0 °C; 32 °F; 273 K [1]
Boiling point decomposes[1]
miscible[1]
Vapor pressure 0.0002 mmHg (20°C)[1]
Hazards
GHS pictograms
GHS Signal word Danger
GHS hazard statements
 H300, H310, H400
P262, P264, P270, P273, P280, P301+310, P302+350, P310, P321, P322, P330, P361, P363, P391, P405, P501
NFPA 704 (fire diamond)
Flammability code 1: Must be pre-heated before ignition can occur. Flash point over 93 °C (200 °F). E.g. canola oilHealth code 4: Very short exposure could cause death or major residual injury. E.g. VX gasReactivity code 1: Normally stable, but can become unstable at elevated temperatures and pressures. E.g. calciumSpecial hazards (white): no code
1
4
1
Lethal dose or concentration (LD, LC):
0.5 mg/kg (rat, oral)
2.3 mg/kg (guinea pig, oral)
3 mg/kg (mouse, oral)[2]
NIOSH (US health exposure limits):
PEL (Permissible)
 TWA 0.05 mg/m3 [skin][1]
REL (Recommended)
 TWA 0.05 mg/m3 [skin][1]
IDLH (Immediate danger)
 5 mg/m3[1]
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
N verify (what is YN ?)
Infobox references

Applications

TEPP is a very good insecticide to aphids, mites, spiders, mealybugs, leafhoppers, lygus bugs, thrips, leafminers, and many other pests.[4] TEPP and other organophosphates are the most widely used pesticides in the U.S. due to their effectiveness and relative small impact on the environment.[5] Organophosphates are hydrolyzed and broken down so easily, that the residual period is approximately 48 hours for TEPP.[4] That is enough time for TEPP to do its work, since TEPP is mostly acute toxic with nerve gas-like properties.[5]

TEPP has been used for treatment for myasthenia gravis, an autoimmune disease. The treatment would deliver an increase in strength.[6]

Synthesis

The synthesis by De Clermont and Moschnin was based on the earlier work by Alexander Williamson (who is well known for the Williamson-synthesis of ethers).[7] Their synthesis made use of ethyl iodide and silver salts to form esters in combination with pyrophosphate.[8]

Ag4P2O7 + 4 EtI → [(EtO)2P(O)]2O + 4 AgI

Commercial routes to TEPP often use methods developed by Schrader, Woodstock, and Toy. Triethyl phosphate reacts with phosphorus oxychloride (Schrader-method) or phosphorus pentoxide (Woodstock-method).[9][10] Alternatively, controlled hydrolysis of diethyl phosphorochloridate delivers the compound:[11][12]

2 (EtO)2P(O)Cl + H2O → [(EtO)2P(O)]2O + 2 HCl

The related tetrabenzylpyrophosphate is prepared by dehydration of dibenzylphosphoric acid:[13]

2 (RO)2P(O)OH → [(EtO)2P(O)]2O + H2O

Hydrolysis

Hydrolysis follows first order kinetic, with t1/2 = 7.5 hours at 25 °C and 3.1 hours at 40 °C.[4]

TEPP and most of the other organophosphates are detoxified by hydrolysis.[14] Due to this oxidation and hydrolysis the compound gets more polar, which makes it much easier to excrete via the urine. Note that TEPP is a lipophilic compound, so it can diffuse through tissues easily. This makes it hard to excrete TEPP.

Many enzymes hydrolyze TEPP, especially the phosphotriesterases (PTEs). In the serum and the liver, there is a significant higher PTE activity found than in other tissues of mammals.[14]

PTEs are responsible for the cleavage of the bond between the phosphorus atom and the leaving group. When TEPP is hydrolyzes, the products is diethyl phosphate.[14][15][15]

Toxicity

TEPP is bioactive as an acetylcholinesterase inhibitor. It binds strongly to a serine hydroxyl group at the active site, preventing this enzyme from acting on its normal substrate, the neurotransmitter acetyl choline.

TEPP is highly toxic for all warm-blooded animals, including humans. This includes direct contact and inhalation of the vapors.[16] There are three types of effects on these animals that have come forward during laboratory studies.

  • DERMAL: LD50 = 2.4 mg/kg (male rat)
  • ORAL: LD50 = 1.12 mg/kg (rat)[4]

Death is mostly due to either respiratory failure and in some cases cardiac arrest. The route of absorption might be responsible for the range of effect on certain systems.[17]

For cold-blooded animals the effects are slightly different. In a study with frogs, acute exposure caused a depression in the amount of erythocytes in the blood. There was also a reduction of white bloodcells, especially the neutrophil granulocytes and lymphocytes. There was no visible damage to the bloodvessels to explain the loss of blood cells. Further there were no signs like hypersalivation or tears like in warm-blooded animals, though there was hypotonia leading to paralysis.[18]

History

It was first synthesized by Wladimir Moschnin in 1854 while working with Adolphe Wurtz. A fellow student Philippe de Clermont is often incorrectly credited as the discoverer of TEPP despite his recognition of the Moschnin primacy in two publications.[19]

The ignorance about the potential toxicity of TEPP is evidenced by De Clermont himself, who described the taste of TEPP as having a burning taste and a peculiar odor ("un liquide visqueux d’une saveur brulante(et) d’une odeur particuliere").[7] Even though TEPP has repeatedly been synthesized by other chemists during the years that followed, not until the 1930s had any adverse effects been observed. Furthermore, Philippe de Clermont has never been reported ill by his family up to his passing at the age of 90. In the meantime, organophosphorus chemistry has really started developing with the help of A. W. von Hofmann, Carl Arnold August Michaelis and Aleksandr Arbuzov.[20]

It was not until 1932 before the first adverse effects of compounds similar to TEPP had been recognized. Willy Lange and Gerda von Krueger were the first to report such effects, about which the following statement was published in their article (in German):[21]

"Interestingly, we report the strong effect of monofluorophosphate phosphoric acid alkyl esters on the human organism. The vapor of these compounds have a pleasant odor and sharply aromatic. After only a few minutes of inhaling the vapor, there is a strong pressure on the larynx, associated with shortness of breath. Then comes decreased awareness, opacities, and dazzling phenomena causing painful sensitivity of the eye to light. Only after several hours is there relief from these phenomena. They are apparently not caused by acidic decomposition products of the ester, but they are probably due to the Dialkyl monofluorophosphates themselves. The effects are exerted by very small amounts."

Starting in 1935 the German government started gathering information about new toxic substances, of which some were to be classified as secret by the German Ministry of Defence.[20] Gerhard Schrader, who has become famous for his studies into organophosphorus insecticides and nerve gases, was one of the chemists who was also studying TEPP. In his studies, in particular his studies into the biological aspects, he noticed that this reagent could possibly be used as an insecticide. This would make the classification of the compound as secret disadvantageous for commercial firms .[20]

Around the beginning of the Second World War, TEPP was discovered to be an inhibitor of cholinesterases.[7] Schrader referred to the studies by Eberhard Gross, who was the first to recognize the mechanism of action for TEPP in 1939. More experiments were conducted including those of Hans Gremels, who confirmed Gross’s work.[20] Gremels was also involved in the development of nerve gases at that time. His studies involved several species of animals and human volunteers. Around that same time, atropine was discovered as a possible antidote for the anticholinesterase activity of TEPP.

After the Second World War, Schrader was among many German scientists who were interrogated by English scientists, among others. During the war, the English had been developing chemical weapons of their own to surprise their enemies. In these interrogations the existence of TEPP and other insecticides were disclosed. The existence of nerve gases, however also being disclosed by Schrader, was kept secret by the military.[11]

gollark: Audiovisual stuff is quite high-bandwidth.
gollark: So is basically any internet-connected device.
gollark: A desktop computer (with peripherals) is great cognitive expansion and has decent IO.
gollark: And calculators, notepads, etc.
gollark: I've seen one which said it detected level of focus or something.

References
  1. NIOSH Pocket Guide to Chemical Hazards. "#0590". National Institute for Occupational Safety and Health (NIOSH).
  2. "TEPP". Immediately Dangerous to Life and Health Concentrations (IDLH). National Institute for Occupational Safety and Health (NIOSH).
  3. Robert L. Metcalf. "Insect Control". Ullmann's Encyclopedia of Industrial Chemistry. Weinheim: Wiley-VCH. doi:10.1002/14356007.a14_263.
  4. "TEPP (Kilmite 40) - Chemical Profile 3/85". pmep.cce.cornell.edu. Retrieved 2016-03-08.
  5. "Organophosphates". Toxipedia. Gilbert, S. Retrieved 2016-02-28.
  6. "TEPP | C8H20O7P2 - PubChem". pubchem.ncbi.nlm.nih.gov. Retrieved 2016-03-08.
  7. Petroianu, G. A. (2009-04-01). "The synthesis of phosphor ethers: who was Franz Anton Voegeli?". Die Pharmazie. 64 (4): 269–271. doi:10.1691/ph.2009.8244. ISSN 0031-7144. PMID 19435147.
  8. Petroianu, Georg (2015). "History of organophosphorus cholinesterase inhibitors & reactivators". Military Medical Science Letters. 84 (4): 182–185. doi:10.31482/mmsl.2015.023.
  9. Sherma, Joseph; Zweig, Gunter (1973). Thin-Layer and Liquid Chromatography and Pesticides of International Importance: Analytical Methods for Pesticides and Plant Growth Regulators. 7. Academic Press. pp. 471–477. ISBN 978-1-4832-2084-0.
  10. National Research Council (U S. ) Pesticide Residues Committee (1965). Report on "no Residue" and "zero Tolerance". National Academies. pp. 3–4.
  11. Toy, A. D. F. (1948). "The Preparation of Tetraethyl Pyrophosphate and Other Tetraalkyl Pyrophosphates". J. Am. Chem. Soc. 70 (11): 3882–3886. doi:10.1021/ja01191a104. PMID 18102975.
  12. Steinberg, Geo. M. (1950). "Reactions of Dialkyl Phosphites. Synthesis of Dialkyl Chlorophosphates, Tetraalkyl Pyrophosphates, and Mixed Orthophosphate Esters". Journal of Organic Chemistry. 15 (3): 637–47. doi:10.1021/jo01149a031.
  13. Todd D. Nelson, Jonathan D. Rosen, M. Bhupathy, James McNamara, Michael J. Sowa, Chad Rush, Louis S. Crocker (2003). "Tetrabenzyl Pyrophosphate". Org. Synth. 80: 219. doi:10.15227/orgsyn.080.0219.CS1 maint: uses authors parameter (link)
  14. Sogorb, Miguel A; Vilanova, Eugenio (2002-03-10). "Enzymes involved in the detoxification of organophosphorus, carbamate and pyrethroid insecticides through hydrolysis". Toxicology Letters. 128 (1–3): 215–228. doi:10.1016/S0378-4274(01)00543-4. PMID 11869832.
  15. Jokanović, Milan (2001-09-25). "Biotransformation of organophosphorus compounds". Toxicology. 166 (3): 139–160. doi:10.1016/S0300-483X(01)00463-2. PMID 11543910.
  16. "BENFLURALIN - National Library of Medicine HSDB Database". toxnet.nlm.nih.gov. Retrieved 2016-03-08.
  17. Clarke, Myra L.; Harvey, Douglas Graham; Humphreys, David John (1988). Veterinary Toxicology (2 ed.). London, England: Bailliere Tindal. p. 157.
  18. Kaplan, Harold M.; Glaczenski, Sheila S. (1965-06-01). "Hematological effects of organophosphate insecticides in the frog (Rana pipiens)". Life Sciences. 4 (12): 1213–1219. doi:10.1016/0024-3205(65)90335-8. PMID 4284682.
  19. Fest, Christa; Schmidt, Karl-Julius (1982). The Chemistry of Organophosphorus Pesticides - Springer. doi:10.1007/978-3-642-68441-8. ISBN 978-3-642-68443-2.The history of cholinesterase inhibitors: who was Moschnin(e)?
  20. "9: "Structure-Activity Relationships of the Organophosphorus Anticholinesterase Agents, Historical development of organophosphorus cholinesterase inhibitors." Handbook of Experimental Pharmacology.". Cholinesterases and Anticholinesterase Agents. 15. Springer Science & Business Media. 1963. pp. 434–437. ISBN 978-3-642-99875-1.
  21. Petroianu, G. A. (2010-10-01). "Toxicity of phosphor esters: Willy Lange (1900-1976) and Gerda von Krueger (1907-after 1970)". Die Pharmazie. 65 (10): 776–780. ISSN 0031-7144. PMID 21105582.
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