Organophosphate

Source: Wikipedia, the free encyclopedia.
This article is about the organic derivatives of the phosphate ion. For the inorganic ion, see phosphate. For all organic compounds incorporating phosphorus, see organophosphorus chemistry.
General chemical structure of the organophosphate functional group

In

aromatic substituents.[1] They can be considered as esters of phosphoric acid. Organophosphates are best known for their use as pesticides
.

Like most functional groups, organophosphates occur in a diverse range of forms,[2] with important examples including key biomolecules such as DNA, RNA and ATP, as well as many insecticides, herbicides, nerve agents and flame retardants. OPEs have been widely used in various products as flame retardants, plasticizers, and performance additives to engine oil. The low cost of production and compatibility to diverse polymers made OPEs to be widely used in industry including textile, furniture, electronics as plasticizers and flame retardants. These compounds are added to the final product physically rather than by chemical bond.[3] Due to this, OPEs leak into the environment more readily through volatilization, leaching, and abrasion.[4] OPEs have been detected in diverse environmental compartments such as air, dust, water, sediment, soil and biota samples at higher frequency and concentration.[1][4]

The popularity of OPEs as flame retardants came as a substitution for the highly regulated brominated flame retardants.[5]

Forms

Organophosphates are a class of compounds encompassing a number of distinct but closely related

function groups. These are primarily the esters of phosphoric acid and can be mono‑esters, di‑esters or tri‑esters depending on the number of attached organic groups (abbreviated as 'R' in the image below). In general man‑made organophosphates are most often triesters, while biological organophosphates are usually mono- or di-esters. The hydolysis of triesters can form diesters and monoesters.[6]

In the context of pesticides, derivatives of organophosphates such as

phosphorodiamidates
(P-N) are included as being organophosphates. The reason is that these compound are converted into organophosphates biologically.

In biology the esters of

diphosphoric acid and triphosphoric acid are generally included as organophosphates. The reason is again a practical one, as many cellular processes involve the mono- di and tri- phosphates of the same compound. For instance, the phosphates of adenosine (AMP, ADP, ATP
) play a key role in many metabolic processes.

Synthesis

Alcoholysis of POCl3

alcohols
to give organophosphates. This is the dominate industrial route and is responsible for almost all organophosphate production.

O=PCl3 + 3 ROH → O=P(OR)3 + 3 HCl

When aliphatic alcohols are used the HCl by-product can react with the phosphate esters to give

organochlorides
and a lower ester.

O=P(OR)3 + HCl → O=P(OR)2OH + RCl

This reaction is usually undesirable and is exacerbated by high reaction temperatures. It can be inhibited by the use of a base or the removal of HCl through sparging.

Esterification of phosphoric acid and P2O5

Esterifications of phosphoric acid with alcohols proceed less readily than the more common carboxylic acid esterifications, with the reactions rarely proceeding much further than the phosphate mono-ester. The reaction requires high temperatures, under which the phosphoric acid can dehydrate to form poly-phosphoric acids. These are exceedingly viscous and their linear polymeric structure renders them less reactive than phosphoric acid.[7] Despite these limitations the reaction does see industrial use for the formation of monoalkyl phosphates, which are used as surfactants.[8]
A major appeal of this route is the low cost of phosphoric acid compared to phosphorus oxychloride.

OP(OH)3 + ROH → OP(OH)2(OR) + H2O

P2O5 is the anhydride of phosphoric acid and acts similarly. The reaction yields equimolar amounts of di- and monoesters with no phosphoric acid. The process is mostly limited to primary alcohols, as secondary alcohols are prone to undesirable side reactions such as dehydration.[9]

Oxidation of phosphite esters

stabilisers for plastics, with their gradual oxidation forming organophosphates in the human environment.[10][11]

P(OR)3 + [O] → OP(OR)3
Phosphorylation
Main article: Phosphorylation

The formation of organophosphates is an important part of biochemistry and living systems achieve this using a variety of

aerobic respiration, which involve the production of adenosine triphosphate
(ATP), the "high-energy" exchange medium in the cell.

Properties

Bonding

The bonding in organophosphates has been a matter of prolonged debate; the phosphorus atom is classically

phosphites. The bonding in penta-coordinate phosphoranes (i.e. P(OR)5) is entirely different and involves three-center four-electron bonds
.

Acidity

Phosphate esters bearing P-OH groups are acidic. The pKa of the first OH group is typically between 1-2, with the second OH deprotonating at a pKa of 6-7.[20] This is great practical importance as it means that phosphate mono- and di-esters are negatively charged at physiological pH (due to deprotonation).[21] This includes biomolecules such as DNA and RNA. The presence of this negative charge makes these compound much more water soluble, and also more resistant to degradation by hydrolysis or other forms of nucleophilic attack.[22]

Water solubility

The water solubility of organophosphates is an important factor in biological, industrial and environmental settings. The wide variety of substitutes used in organophosphate esters results in great variations in physical properties. OPEs exhibit a wide range of octanol/water

hydrophobicity.[5][23][4][24] Hydrophobic OPEs are more likely to be bioaccumulated and biomagnified in aquatic ecosystems.[3] Halogenated organophosphates tend to be denser than water and sink, causing them to accumulate in sediments.[25]

Industrial materials

Pesticides

Malathion, one of the first organophosphate insecticides. It remains important as a Vector control agent.

Organophosphates are best known for their use as pesticides. The vast majority are

insecticides and are used either to protect crops, or as vector control agents to reduce the transmission of diseases spread by insects, such as mosquitoes. Health concerns have seen their use significantly decrease since the turn of the century.[26][27] Glyphosate is sometimes called an organophosphate, but is in-fact a phosphonate
. Its chemistry, mechanism of toxicity and end-use as a herbicide are different from the organophosphate insecticides.

The development of organophosphate insecticides dates back to the 1930s and is generally credited to

organochlorine insecticides such as DDT, dieldrin, and heptachlor. When many of the organochlorines were banned in the 1970s, following the publishing of Silent Spring
, organophosphates became the most important class of insecticides globally. Nearly 100 were commercialised, with the following being a varied selection:

Organophosphate insecticides are acetylcholinesterase inhibitors, and when introduced to an organism they act to fatally disrupt the transmission of nerve signals. The risk of human death through organophosphate poisoning[32] was obvious from the start and let to efforts to lower toxicity against mammals while not reducing efficacy against insects.[33][34]

The majority of organophosphate insecticides are

phosphorodiamidates (P-N), both of which are significantly weaker acetylcholinesterase inhibitors than the corresponding phosphates (P=O). They are 'activated' biologically by the exposed organism, via oxidative conversion of P=S to P=O,[35] hydroxylation,[36][37] or other related process which see them transformed into organophosphates. In mammals these transformations occur almost exclusively in the liver,[38] while in insects they take place in the gut and fat body.[39][40][41] As the transformations are handled by different enzymes
in different classes of organism it is possible to find compounds which activate more rapidly and completely in insects, and thus display more targeted lethal action.

This selectivity is far from perfect and organophosphate insecticides remain acutely toxic to humans, with many thousands estimated to be killed each year due to intentional (suicide)[42] or unintentional poisoning. Beyond their acute toxicity, exposure to organophosphates is associated with a number of heath risks, including organophosphate-induced delayed neuropathy (muscle weakness) and developmental neurotoxicity.[28][43][44] There is limited evidence that certain compounds cause cancer, including malathion and diazinon.[45] Children[46] and farmworkers[47] are considered to be at greater risk.

Pesticide regulation in the United States and the regulation of pesticides in the European Union have both been increasing restrictions on organophosphate pesticides since the 1990s, particularly when used for crop protection. The use of organophosphates has decreased considerably since that time, having been replaced by pyrethroids and neonicotinoids, which are effective a much lower levels.[48] Reported cases of organophosphate poisoning in the US have reduced during this period.[49][50] Regulation in the global south can be less extensive.[51][52]

In 2015, only 3 of the 50 most common crop-specific pesticides used in the US were organophosphates (

insecticide resistance.[57]

Flame retardants

Bisphenol A diphenyl phosphate
, a common organophosphate flame retardant
Main article:
flame retardants

Flame retardants are added to materials to prevent combustion and to delay the spread of fire after ignition. Organophosphate flame retardants are part of a wider family of phosphorus-based agents which include organic phosphonate and phosphinate esters, in addition to inorganic salts.[58][59] When some prominent brominated flame retardant were banned in the early 2000s phosphorus-based agents were promoted as safer replacements. This has led to a large increase in their use, with an estimated 1 million tonnes of organophosphate flame retardants produced in 2018.[60] Safety concerns have subsequently been raised about some of these reagents,[61][62] with several under regulatory scrutiny.[63][64]

Organophosphate flame retardants were first developed in the first half of the twentieth century in the from of

HIPS and PC/ABS,[66]
which are commonly used to make casing for electrical items like TVs, computers and home appliances.

Organophosphates act multifunctionally to retard fire in both the gas phase and condensed (solid) phase. Halogenated organophosphates are more active overall as their degradation products interfere with combustion directly in the gas phase. All organophosphates have activity in the condensed phase, by forming phosphorus acids which promote char formation, insulating the surface from heat and air.

Organophosphates were originally thought to be a safe replacements for brominated flame retardants, however many are now coming under regulatory pressure due to their apparent health risks.[64][67][68] The chlorinated organophosphates may be carcinogenic, while others such as tricresyl phosphate have necrotoxic properties.[69] Bisphenol-A bis(diphenyl phosphate) can hydrolyse to form

endocrine-disrupting chemical. Although their names imply that they are a single chemical, many are actually produced as complex mixtures. For instance, commercial grade TCPP can contain 7 different isomers,[70] while tricresyl phosphate can contain up to 10.[71] This makes their safety profiles harder to ascertain, as material from different producers can have different compositions.[72]

Plasticisers

Main article: Plasticizer
2-Ethylhexyl diphenyl phosphate an alkyl diaryl organophosphate used as both a plasticizer and flame retardant in PVC

Plasticisers are added to polymers and plastics to improve their flexibility and processability, giving a softer more easily deformable material. In this way brittle polymers can be made more durable. Organophosphates find use because they are multifunctional; primarily plasticising but also imparting flame resistance. The most frequently plasticised polymers are the vinyls (

PVA and PVCA), as well as cellulose plastics (cellulose acetate, nitrocellulose and cellulose acetate butyrate).[73] PVC dominates the market, consuming 80-90% of global plasticiser production.[73][74] PVC can accept large amounts of plasticiser; a PVC item may be 70-80% plasticiser by mass in extreme cases, but loadings of between 0-50% are more common.[75] The main applications of these products are in wire and cable insulation, flexible pipe, automotive interiors, plastic sheeting, vinyl flooring
, and toys.

Pure PVC is more than 60% chlorine by mass and difficult to burn, but its flammability increases the more it is plasticised.

2-ethylhexyl diphenyl phosphate being important respective example.[77] These are both liquids with high boiling points. Organophosphates are more expensive than traditional plasticisers and so tend be used in combination with other plasticisers and flame retardants.[78]

Hydraulic fluids and lubricant additives

Similar to their use as plastisiers, organophosphates are well suited to use as hydraulic fluids due to their low freezing points and high boiling points, fire-resistance, non-corrosiveness, excellent boundary lubrication properties and good general chemical stability. The triaryl phosphates are the most important group, with tricresyl phosphate being the first to be commercialised in the 1940s, with trixylyl phosphate following shortly after. Butylphenyl diphenyl phosphate and propylphenyl diphenyl phosphate became available after 1960.[79]

In addition to their use as hydraulic base-stock, organophosphates (tricresyl phosphate) and metal organothiophosphates (zinc dithiophosphate) are used as both an antiwear additives and extreme pressure additives in lubricants, where they remain effective even at high temperatures.[80][81][82]

Metal extractants

Organophosphates have long been used in the field of extractive metallurgy to liberate valuable rare earths from their ores.[83] Di(2-ethylhexyl)phosphoric acid and tributyl phosphate are used for the liquid–liquid extraction of these elements from the acidic mixtures form by the leaching of mineral deposits.[84] These compounds are also used for the PUREX (plutonium uranium reduction extraction) process, which is used for nuclear reprocessing.[85]

Surfactants

Mono- and di- phosphate esters of alcohols or alcohol

LAS or SLES), phosphate ester surfactants are more expensive and generate less foam.[86] Benefits include stability over a broad pH range, low skin irritation and a high tolerance to dissolved salts.[87]
In agricultural settings monoesters of fatty alcohol ethoxylates are used, which are able to disperse poorly miscible or insoluble pesticides into water. As they are low-foaming these mixtures can be sprayed effectively onto fields, while a high salt tolerance allows co-spraying of pesticides and inorganic fertilisers.[88] Low-levels of phosphate mono-esters, such as
anti-foaming agent
in paints and concrete.

Nerve agents

Main article:
Nerve agents

Although the first phosphorus compounds observed to act as cholinesterase inhibitors were organophosphates,

Novichok agents.[91] Some of these can be considered organophosphates (in a broad sense), being derivatives of fluorophosphoric acid. Examples include A-232, A-234, A-262, C01-A035 and C01-A039. The most notable of these is A-234, which was claimed to be responsible for the poisoning of Sergei and Yulia Skripal in Salisbury (UK) 2018.[92]

In nature

The detection of OPEs in the air as far away as Antarctica at concentrations around 1 ng/m3 suggests their persistence in air, and their potential for long-range transport.[24] OPEs were measured in high frequency in air and water and widely distributed in northern hemisphere.[93][94] The chlorinated OPEs (TCEP, TCIPP, TDCIPP) in urban sampling sites and non-halogenated like TBOEP in rural areas respectively were frequently measured in the environment across multiple sites. In the Laurentian Great Lakes total OPEs concentrations were found to be 2–3 orders of magnitude higher than concentrations of brominated flame retardants measured in similar air.[94] Waters from rivers in Germany, Austria, and Spain have been consistently recorded for TBOEP and TCIPP at highest concentrations.[24] From these studies, it is clear that OPE concentrations in both air and water samples are often orders of magnitude higher than other flame retardants, and that concentrations are largely dependent on sampling location, with higher concentrations in more urban, polluted locations.

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