This article is about the organic derivatives of the phosphate ion. For the inorganic ion, see
phosphate. For all organic compound incorporating phosphorus, see
organophosphorus chemistry.
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
organothiophosphates (P=S) or
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
Phosphorus oxychloride reacts readily with
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
Organophosphites can be easily oxidised to give organophosphates. This might ordinarily be considered a specialised method, however large quantities of organophosphites are produced as antioxidant
stabilisers for plastics, with their gradual oxidation forming organophosphates in the human environment.[10][11]
The formation of organophosphates is an important part of biochemistry and living systems achieve this using a variety of
enzymes. Phosphorylation is essential to the processes of both
anaerobic and
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
hypervalent, as it possesses more bonds than the
octet rule should allow.[12] The focus of debate is usually on the nature of the
phosphoryl P=O bond, which displays (in spite of the common depiction) non-classical bonding, with a
bond order somewhere between 1 and 2. Early papers explained the hypervalence in terms of d-
orbital hybridisation, with the energy penalty of promoting electrons into the higher energy orbitals being off-set by the stabilisation of additional bonding.[13] Later advances in computational chemistry showed that d-orbitals played little significant role in bonding.[14][15] Current models rely on either
negative hyperconjugation,[16] or a more complex arraignment with a
dative-type bond from P to O, combined with back-donation from a 2p orbital on the oxygen.[15][17] These models agree with the experimental observations of the phosphoryl as being shorter than P-OR bonds[18] and much more polarised. It has been argued that a more accurate depiction is dipolar (i.e. (RO)3P+-O-),[19] which is similar to the depiction
phosphorus ylides such as
methylenetriphenylphosphorane. However in contrast to ylides, the phosphoryl group is unreactive and organophosphates are poor nucleophiles, despite the high concentration of charge on the phosphoryl oxygen. The polarisation accounts in part for the higher melting points of phosphates when compared to their corresponding
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
partition coefficients where log Kow values range from -0.98 up to 10.6.[5] Mono- and di- esters are usually water soluble, particularity biomolecules. Tri-esters such as flame retardants and plasticisers have positive log Kow values ranging between 1.44 and 9.49, signifying
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
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
Gerhard Schrader.[28] At the time pesticides were largely limited to arsenic salts (
calcium arsenate,
lead arsenate and
Paris green)[29] or
pyrethrin plant extracts, all of which had major problems.[30] Schrader was seeking more effective agents, however while some organophosphates were found to be far more dangerous to insects than higher animals,[31] the potential effectiveness of others as
chemical weapons did not go unnoticed. The development of organophosphate insecticides and the earliest
nerve agents was conjoined, with Schrader also developing the nerve agents
tabun and
sarin. Organophosphate pesticides were not commercialised until after WWII.
Parathion was among the first marketed, followed by
malathion and
azinphosmethyl . Although organophosphates were used in considerable qualities they were originally less important than
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, which disrupt the transmission of nerve signals in exposed organisms, with fatal results. 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
organothiophosphates (P=S) or
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 (
Chlorpyrifos,
Bensulide,
Acephate),[53] of these
Chlorpyrifos was banned in 2021.[54] No new organophosphate pesticides have been commercialised in the 21st century.[55] The situation in
vector control is fairly similar, despite different risk trade-offs,[56] with the global use of organophosphate insecticides falling by nearly half between 2010 and 2019.[27]Pirimiphos-methyl,
Malathion and
Temefos are still important, primarily for the control of
malaria in the Asia-Pacific region.[27] The continued use of these agents is being challenged by the emergence of
insecticide resistance.[57]
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
triphenyl phosphate,
tricresyl phosphate and
tributyl phosphate for use in plastics like
cellulose nitrate and
cellulose acetate.[65] Use in cellulose products is still significant, but the largest area of application is now in plasticized vinyl polymers, principally
PVC. The more modern organophosphate flame retardants come in 2 major types;
chlorinated aliphatic compounds or aromatic diphosphates.[58] The chlorinated compounds
TDCPP,
TCPP and
TCEP are all involatile liquids, of which TCPP is perhaps the most important. They are used in
polyurethane (insulation, soft furnishings),
PVC (wire and cable)
phenolic resins and
epoxy resins (varnishes, coatings and adhesives). The most important of the diphosphates is
bisphenol-A bis(diphenyl phosphate), with related analogues based around
resorcinol and
hydroquinone. These are used in
polymer blends of
engineering plastics, such as
PPO/
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
Bisphenol-A which is under significant scrutiny as potential
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 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 (
PVC,
PVB,
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.[76] Organophosphates can act as both plasticisers and flame retarders. Compounds used are typically triaryl or alkyl diaryl phosphates, with
cresyl diphenyl phosphate and
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]
Mono- and di- phosphate esters of alcohols or alcohol
ethoxylates are used as
surfactants (detergents).[86] Compared to the more common sulfur-based anionic surfactants (such as
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
potassium cetyl phosphate, find use in cosmetic creams and lotions.[89] These in oil-in-water formulations are primarily based on non-ionic surfactants, with the anionic phosphate acting as emulsion-stabilisers. Phosphate tri-esters such as
tributyl phosphate are used as
anti-foaming agent in paints and concrete.
Although the first phosphorus compounds observed to act as cholinesterase inhibitors were organophosphates,[90] the vast majority of nerve agents are instead
phosphonates containing a P-C bond. Only a handful of organophosphate nerve agents were developed between the 1930s and 1960s, including
diisopropylfluorophosphate,
VG and
NPF. Between 1971 and 1993 the
Soviet Union developed many new potential nerve agents, commonly known as the
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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