Organophosphate

An organophosphate (sometimes abbreviated OP) is the general name for esters of phosphoric acid. Phosphates are probably the most pervasive organophosphorus compounds. Many of the most important biochemicals are organophosphates, including DNA and RNA as well as many cofactors that are essential for life. Organophosphates are also the basis of many insecticides, herbicides, and nerve gases. Organophosphates are widely used as solvents, plasticizers, and EP additives.

Organophosphates are widely employed both in natural and synthetic applications because of the ease with which organic groups can be linked together. Being a triprotic acid, phosphoric acid can form triesters whereas carboxylic acids only form monoesters. Esterification entails the attachment of organic groups to phosphorus through oxygen linkers. The precursors to such esters are alcohols. Encompassing many thousands of natural and synthetic compounds, alcohols are diverse and widespread.

OP(OH)₃ + ROH → OP(OH)₂(OR) + H₂O

OP(OH)₂(OR) + R'OH → OP(OH)(OR)(OR') + H₂O

OP(OH)(OR)(OR') + R"OH → OP(OR)(OR')(OR") + H₂O

The phosphate esters bearing OH groups are acidic and partially deprotonated in aqueous solution. For example DNA and RNA are polymers of the type [PO₂(OR)(OR')^-]_n. Polyphosphates also form esters. An important example of an ester of a polyphosphate is ATP, which is the monoester of triphosphoric acid (H₅P₃O₁₀).

Alcohols can be detached from phosphate esters by hydrolysis, which is the reverse of the above reactions. For this reason, phosphate esters are common carriers of organic groups in biosynthesis.

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Organophosphate pesticides

In health, agriculture, and government, the word "organophosphates" refers to a group of insecticides or nerve agents acting on the enzyme acetylcholinesterase (the pesticide group Carbamates also act on this enzyme, but through a different mechanism). The term is used often to describe virtually any organic phosphorus(V)-containing compound, especially when dealing with neurotoxins. Many of the so called organophosphates contain C-P bonds. For instance, sarin is O-isopropyl methylphosphonofluoridate, which is formally derived from HP(O)(OH)₂, not phosphoric acid. Also many compounds which are derivatives of phosphinic acid are used as organic phosphorus containing neurotoxin.

Organophosphate pesticides (as well as Sarin and VX nerve gas) irreversibly inactivate acetylcholinesterase, which is essential to nerve function in insects, humans, and many other animals. Organophosphate pesticides affect this enzyme in varied ways, and thus in their potential for poisoning. For instance, parathion, one of the first OPs commercialized, is many times more potent than malathion, an insecticide used in combatting the Mediterranean fruit fly (Med-fly) and West Nile Virus-transmitting mosquitoes.

Organophosphate pesticides degrade rapidly by hydrolysis on exposure to sunlight, air, and soil, although small amounts can be detected in food and drinking water. Their ability to degrade made them an attractive alternative to the persistent organochlorine pesticides, such as DDT, aldrin and dieldrin. Although organophosphates degrade faster than the organochlorines, they have greater acute toxicity, posing risks to people who may be exposed to large amounts (see the Toxicity section below).

Commonly used organophosphates have included Parathion, Malathion, Methyl parathion, Chlorpyrifos, Diazinon, Dichlorvos, Phosmet, Tetrachlorvinphos, Azinphos methyl.

Organophosphate neurotoxins

History of nerve gases

Early pioneers in the field include Jean Louis Lassaigne (early 1800s) and Philip de Clermount (1854). In 1932, German chemist Willy Lange and his graduate student, Gerde von Krueger, first described the cholinergic nervous system effects of organophosphates, noting a choking sensation and a dimming of vision after exposure. This discovery later inspired German chemist Gerhard Schrader at company I.G. Farben in the 1930s to experiment with these compounds as insecticides. Their potential use as chemical warfare agents soon became apparent, and the Nazi government put Schrader in charge of developing organophosphate (in the broader sense of the word) nerve gases. Schrader's laboratory discovered the G series of weapons, which included Sarin, Tabun, and Soman. The Nazis produced large quantities of these compounds, though did not use them during World War II (likely because they feared the Allies possessed similar weapons). British scientists experimented with an cholinergic organophosphate of their own, called diisopropylfluorophosphate (DFP), during the war. The British later produced VX nerve gas, which was many times more potent than the G series, in the early 1950s.

After World War II, American companies gained access to some information from Schrader's laboratory, and began synthesizing organophosphate pesticides in large quantities. Parathion was among the first marketed, followed later by malathion and azinphosmethyl. The popularity of these insecticides increased after many of the organochlorine insecticides like DDT, dieldrin, and heptachlor were banned in the 1970s.

Structural features of organophosphate neurotoxins

Effective organophosphate neurotoxins have the following structural features:

• A terminal oxygen connected to phosphorus by a double bond, i.e. a phosphoryl group
• Two lipophilic groups bonded to the phosphorus
• A leaving group bonded to the phosphorus, often a halide

Terminal oxygen vs. terminal sulfur

Thiophosphoryl compounds, those bearing the P=S functionality, are much less toxic than related phosphoryl derivatives, which includes as sarin, VX and tetraethyl pyrophosphate. Thiophosphoryl compound is not active inhibitor acetylcholinesterase in either mammals or insects, in mammals the animals metabolism tends to remove lipophilic side groups from the phosphorus atom while an insect tends to oxidise the compound so removing the terminal sulfur and replacing it with a terminal oxygen which causes the compound to be more able to act as an acetylcholinesterase inhibitor.

Fine tuning

Within these requirements, a large number of different lipophilic and leaving groups have been used. The variation of these groups is one means of fine tuning the toxicity of the compound. A good example of this chemistry are the P-thiocyanate compounds which use an aryl (or alkyl) group and an alkylamino group as the lipophilic groups. The thiocyanate is the leaving group.  

It was claimed in a German patent that the reaction of 1,3,2,4-dithiadiphosphetane 2,4-disulfides with dialkyl cyanamides formed plant protection agents which contained six membered (P-N=C-N=C-S-) rings. It has been proven in recent times by the reaction of diferrocenyl 1,3,2,4-dithiadiphosphetane 2,4-disulfide (and Lawesson's reagent) with dimethyl cyanamide that, in fact, a mixture of several different phosphorus-containing compounds is formed. Depending on the concentration of the dimethyl cyanamide in the reaction mixture, either a different six membered ring compound (P-N=C-S-C=N-) or a nonheterocylic compound (FcP(S)(NR2)(NCS)) is formed as the major product; the other compound is formed as a minor product.

In addition, small traces of other compounds are also formed in the reaction. It is unlikely that the ring compound (P-N=C-S-C=N-) {or its isomer} would act as a plant protection agent, but (FcP(S)(NR2)(NCS)) compounds can act as nerve poisons in insects.

Organophosphate poisoning

Main article: Organophosphate poisoning

Many organophosphates are potent neurotoxins, functioning by inhibiting the action of acetylcholinesterase (AChE) in nerve cells. They are one of the most common causes of poisoning worldwide, and are frequently intentionally used in suicides in agricultural areas. Their toxicity is not limited to the acute phase, however, and chronic effects have long been noted. Neurotransmitters such as acetylcholine (which is affected by organophosphate pesticides) are profoundly important in the brain's development, and many OPs have neurotoxic effects on developing organisms even from low levels of exposure.

See also

• Activity based protein profiling using organophosphate-containing activity based probes
• Mark Purdey
• Pesticide toxicity to bees

References

• Costa LG. Current issues in organophosphate toxicology. Clin Chim Acta. 2006 Apr;366(1-2):1-13. Epub 2005 December 6. Review. PMID: 16337171.