Preparation of Organophosphorus Insecticides

The synthesis of organophosphorus insecticides involves numerous different reactions. In most cases, the preparation starts by treating phosphorous with sulfur or chlorine to give diphosphorus pentasulfide or phosphorus trichloride, respectively. Subsequently, they are transformed into the main intermediates 58-64 depicted in Scheme 2.4.97 As an example, phenyl phosphorothionates 65 can be made by treatment of dialkyl phosphorochloridothionates 64 with phenols in basic medium (see Scheme 2.4). This is the approach used for the

Preparation Insecticides
Figure 2.3 Main commercially available OP insecticides of vinyl phosphate and aliphatic phosphorothioate/phosphorodithioate families.
Organophosphurs Insecticide Structure
Figure 2.4 Main commercially available OP insecticides of aryl phosphorothioate and heteroaryl phosphorothioate families.
Synthesis Malathion
Figure 2.5 Main commercially available OP insecticides of heteroarylmethyl phos-phorodithioate family. Miscellaneous structures.
Synthesis Malathion
Scheme 2.4 General intermediates for the synthesis of OP insecticides

synthesis of parathion 46. Furthermore, O,O-dialkyl phosphorodithioic acids 63 are used to yield phosphorodithioate esters. For example, malathion 42 is prepared by reaction with diethyl maleate.97 Classification of Organophosphorus Insecticides Vinyl Phosphates. Substituted vinyl phosphates (R1CH=CR2) P(=O)(OR3)(OR4) have shown excellent insecticidal activity and desirable stability properties. Due to their volatility and biological instability, certain substituted vinyl phosphates are suitable for use on food crops near harvest time, as it is advantageous to have an insecticide with little persistence to alleviate the danger of toxic residues.98,99 The phosphate esters are more reactive in organisms than the corresponding phosphorothioate esters, as a phosphorus atom doubly bounded to oxygen (P=O) is more electrophilic that its P=S counterpart. As significant examples of insecticides belonging to this group, chlorfenvinphos 33, dichlorvos 34 and monocrotophos 35 should be mentioned (see Figure 2.3). The three examples considered in this family were classified in the group Ib (highly hazardous) by the WHO (World Health Organization).100 102

Chlorfenvinphos 33 is a hydrolysable insecticide, applied in soil to control root-flies, rootworms and other soil pests, although it was also used to control household pests such as flies, fleas and mites. It was banned by the US EPA in 1991,103 and in the EU in 2006.104

Dichlorvos 34 is a rapid-acting insecticide, used in aerosols against flies and mosquitoes. It has also been incorporated in pet collars against ectoparasites. It was reregistered by EPA in was re-evaluated and it was not included in Annex I to Directive 91/414/EEC in 20 06,106 and in 2010 virtually all use was prohibited.107

Monocrotophos 35 is a systemic broad spectrum insecticide, with stomach and contact action. It is used to control sucking, chewing pests and common mites, ticks and spiders, typically on cotton, citrus and olives. In the USA, this substance was voluntarily withdrawn by the registrant in 1989, and banned in the EU in 2003.104 No remaining uses are currently allowed.108 Monocrotophos is one of the most toxic pesticides to birds (LD50 0.9-6.7 mgkg-1) and is highly toxic to bees (3384 mgbee-1), as well as to humans.108 Monocrotophos was also identified as the cause of paralysis in children in a cotton-growing area.109 Aliphatic Phosphorothioates and Phosphorodithioates. Phosphorothioate esters have two general formulae: R1OP(=S)(OR2)(OR3) for phosphoro-thionates and R1SP(=O)(OR2)(OR3) for phosphorothiolates. Phosphorodithioate esters have the two following general formulae: R1SP(=S)(OR2)(OR3) for phosphorothiolthionates and R1SP(=O)(SR2)(OR3) for phosphorodithiolates (see Figure 2.3).

Demeton-S 36 is used as a mixture with its thiono isomer as a systemic insecticide to control aphids and other sucking insects, sawflies and spider mites on a range of crops. This mixture is classified by WHO as Ib, highly hazar-dous,110 and as a result, all products containing this insecticide were banned in the USA by 1989.111

Demeton-S-methyl 37 is the O,O-dimethyl ester analogous to demeton-S, used to control aphids and other sucking insects, sawflies and spider mites on a range of crops as a systemic insecticide with contact and stomach action, manufactured by Bayer Cropscience. It is classified by WHO as Ib, highly hazardous,110 with a LD50 of 30mgkg_1 (oral, rat). In the EU, its registration was withdrawn in 2002.112

Dimethoate 38 is a systemic broad spectrum insecticide with contact and stomach action, used against sucking insects such as aphids, and against fruit flies. It can also be used for a postharvest dip treatment. The US EPA revoked certain tolerance of its use in 2008.113 It is classified II by WHO, moderately hazardous, LD50 of 150mgkg-1 (oral, rat).114 In the EU, it was re-evaluated and included in Annex I to Directive 91/414/EEC in 2006, allowing its use.115

Dioxathion 39 was used as a livestock insecticide and acaricide for the control of insects and mites on grapes, walnuts, ornamentals, apples, pears and quince. It is now considered obsolete and its use as a pesticide has been discontinued by WHO,116 and is no longer allowed to be sold in the USA.

Disulfoton 40 was approved as a systemic insecticide, registered for use to control aphids, thrips, and other sucking insects, as well as spider mites on a variety of crops (frequently asparagus, beans, broccoli, Brussels sprouts, cabbage, cauliflower, lettuce, coffee, cotton and Christmas trees). It is also registered in the USA117 for residential uses including flowers, shrubs and ornamentals, although it was classified by WHO in the group Ia, extremely hazardous.116 Dioxathion and disulfoton registration in the EU were discontinued in 2002.112 This insecticide is translocated through plant tissue, and activated by microsomal oxidation. This oxidation also takes place in the mammalian liver, making this insecticide extremely toxic to humans.

Ethion 41 is an acaricide and insecticide used on fruit trees, fiber and ornamental crops, including greenhouse crops, lawns and turf. It may also be used on cattle. It is efficient against aphids, mites, scales, thrips, leafhoppers, maggots and foliar feeding larvae. It is mixed with oil and sprayed on dormant trees to kill eggs and scales. WHO classification is II, moderately hazardous, exhibiting a LD50 of 208mgkg-1 (oral, rat). It was withdrawn from the EU in 2003.118

Malathion 42, the most commonly used organophosphate insecticide119 in the USA, is a persistent general-purpose insecticide. It is used in household, home garden, vegetable and fruit insect control, as well as in the control of insects affecting public health (e.g. flies, mosquitoes120 and lice). Malathion is also sprayed, aerially, over cities, suburbs and farmland to control mosquitoes and Mediterranean fruit flies.121 As a result of the emergence of pyrethroid-resistant head lice, malathion (0.5% formulation) has been approved by the FDA for the treatment of pediculosis.122,123 However, oral ivermectin has been shown to be more efficient than malathion lotion for difficult-to-treat head lice.124 Although malathion itself is of low toxicity, absorption or ingestion into the human body readily results in its metabolization to malaoxon, via oxidation of the P=S moiety to P=O, which is substantially (61 times) more toxic.125 High levels of malathion metabolites in children's urine seem to be related to an increased risk of attention deficit hyperactivity disorder (ADHD).126 Aryl Phosphorothioates. The aryl OPs (see Figure 2.4) are generally more stable than the aliphatic analogues, therefore their residues are longer lasting. Famphur 43 is used as an insecticide for the lice and grubs of reindeer and cattle. WHO classification is Ib, highly hazardous, with a LD50 of 48 mg kg-1 (oral, rat),116 and it is quite toxic to birds.127 In the US EPA its registration was cancelled in 1989.128

Fenitrothion 44 is a contact insecticide effective against penetrating, chewing and sucking insect pests on cereals, cotton, fruits, vegetables and forests, as well as against household insects (flies, mosquitoes and cockroaches). WHO classification is II, moderately hazardous, with a LD50 of 503mgkg-1 (oral, rat).116 In the USA, fenitrothion is registered and formulated for use only in indoor and outdoor bait stations, the target species being ants and roaches.129 In the EU fenitrothion is severely restricted for pesticide use, and virtually all use is prohibited.130

Fenthion 45 is a persistent contact and stomach insecticide used against sucking and biting pests,131 for veterinary hygiene purposes and as a mosquito larvicide. It has also been used for bird pest control, especially weaver birds. WHO classification is II, moderately hazardous, with a LD50 of 586mgkg-1 (oral, rat). Fenthion exposure to the general population is quite limited based on its bioavailability. The EPA classified fenthion as a Restricted Use Pesticide because is very highly toxic to birds and estuarine/marine invertebrates.132 In the EU general uses of fenthion were withdrawn in 2005, although, in the absence of efficient alternatives for certain uses in citrus, peaches and olives, it can be used with severe restrictions.135

Parathion 46 is highly toxic to non-target organisms and humans by inhalation, oral and dermal exposures. It is among the most highly toxic chemicals registered by the US EPA. WHO classification is Ia, extremely hazardous, with a LD50 of 13mgkg-1,116 and it is in the PAN "dirty dozen'' list.133 The US EPA and the manufacturer, Cheminova, signed an agreement in 2000 to cancel all remaining uses of parathion.134 From 2006, it was no longer included in formulations in the EU.135

Methyl parathion 47 is a non-systemic pesticide that kills pests by acting as a stomach poison. It has similar properties to parathion, but hydrolyzes more readily. It has similar acute toxicity to parathion, with a LD50 of 14mgkg-1.116 WHO classification is Ia, extremely hazardous, and it is in the PAN "dirty dozen'' list.136 In 2010, the US EPA cancelled all methyl parathion product registration, and all use of stocks shall be prohibited at the end of 2013.137

Temephos 48 is used as a larvicide to treat water infested with mosquito and black fly larvae. It is widely used against the mosquito, Aedes aegypti, the most important vector of both yellow fever and dengue viruses (see Chapter 1). Up to date, reduction in the population density of the vector mosquitoes is the only option for controlling the transmission of dengue virus, which infects 50-100 million people annually, with 500 000 people being admitted to hospital.138 Temephos is applied in areas of standing water, shallow ponds, swamps and marshes, and water storage containers in tropical and subtropical urban and semi-urban areas.139 WHO classification is III, slightly hazardous, with a LD50 of 4000 mgkg-1 (oral, rat).116 It is currently registered by the US EPA, confirming temephos as the only organo-phosphate with any appreciable mosquito larvicidal use.140 Heteroaryl Phosphorothioates. The most significant examples of heteroaryl phosphorothioates are depicted in Figure 2.4. Chlorpyrifos 49 is used widely as a broad spectrum soil insecticide. Today it is the best-selling organophosphorus insecticide and one of the most widely-used pest control products in the world for both agricultural (more than 50 different crops) and non-agricultural pests. For home applications, chlorpyrifos is used to control cockroaches, fleas and termites. It is also used in some pet flea and tick collars. In farms, it is used to control ticks on cattle. In 2005, agricultural uses of chlorpyrifos received the EU approval (Annex I of the European Commission's Plant Protection Products Directive 91/414), allowing the EU members to renew their registrations of chlorpyrifos products.141 In 2006, the US EPA completed the reregistration eligibility for agricultural use of chlorpyrifos, although its use in homes and other places where children could be exposed is not allowed, and its use on crops is severely restricted.142 WHO classification is II, moderately hazardous, with a LD50 of 135mgkg_1 (oral, rat).116 Chronic exposure has been linked to neurological effects and developmental disorders, and prenatal chlorpyrifos exposure can lead to an increased risk of delays in mental and motor development at the age of three.143 Chlorpyrifos-methyl 50 is much safer than chloryphos, and is used to control a range of insect pests in different crops and ornamentals. It is also used to control household pests and stored grain pests. WHO classification is U, unlikely to be hazardous, with a LD50 >3000mgkg_1 (oral, rat). The US EPA registered chlorpyrifos-methyl for use only as an indoor treatment for small grains (wheat, oats and barley) in storage bins and warehouses to control a variety of insects (including beetles, weevils, moths and grain borers).144 In 2005, agricultural uses of chlorpyrifos-methyl were included in Annex I of the European Commission's Plant Protection Products Directive 91/414.141 Concerning its environmental behaviour, the hydrolysis rate of chlorpyrifos-methyl was found to be approximately twice that of chlorpyrifos.145

Diazinon 51 is a non-systemic insecticide used to control pest insects in soil, on ornamental plants, and on fruit and vegetable field crops. In the USA, all residential uses of diazinon were cancelled in 2004, and agricultural uses on a variety of fruit, vegetable and field crops have been restricted. It is allowed on non-lactating cattle as an ear-tag.146 WHO classification is II, moderately hazardous, with a LD50 of 300mgkg_1 (oral, rat).116 In the EU, authorisations for plant protection products containing diazinon were withdrawn in 2007.147 Heteroarylmethyl Phosphorodithioates. Commercially-available insecticides belonging to this group are included in Figure 2.5. Azinphos-ethyl 53 is a persistent broad spectrum insecticide, effective in the control of chewing and sucking insects of fruits, vegetables, cotton and ornamentals. It is no longer registered for use in many countries due to its extreme acute toxicity in humans. WHO classification is Ib, highly hazardous, with a LD50 of 12mgkg_1 (oral, rat).116 The US EPA reregistered the insecticide in 2006, but decided to phase out the remaining uses of the pesticide in 2007, with all uses ending in 2012. It has been banned in the EU since 2002.104 Azinphos-ethyl is dangerous to bees, fish and harmful to livestock, wild birds and animals. It has a lifetime of hours in the atmosphere, but relatively long persistence (months) in water and in soil where it is biodegraded slowly.148

Azinphos-methyl 52, a broad spectrum persistent insecticide, is used extensively as a foliar application against leaf feeding insects. It works both as a contact insecticide and as a stomach poison. WHO classification is Ib, highly hazardous, with a LD50 of 16mgkg-1 (oral, rat).116 The US EPA reregistered this insecticide in 2006 and it was decided to phase out the remaining uses in 2007, with all uses ending in 2012.149 It has been banned in the EU since 2002, because it was not approved for inclusion in Annex I to Directive 91/414/EEC.150 Phosmet 54 is used to control pests of deciduous fruit. It is a phthali-mide-derived, non-systemic insecticide, used on a wide range of fruit trees, ornamentals and vines for the control of aphids, suckers and fruit flies. The compound is also an active ingredient in some dog collars.151 WHO classification is II, moderately hazardous, with a LD50 of 113mgkg~1 (oral, rat). The US EPA issued in 2007 its final decision on the restricted-entry intervals (the time after a pesticide application during which entry into the treated area is restricted) for nine uses of phosmet: apples, apricots, highbush blueberries, grapes, nectarines, peaches, pears, plums and prunes, in order to protect workers and bystanders.152 In the EU, phosmet was reevaluated (2007), and its uses as an insecticide and acaricide were authorised.153 Miscellaneous Organophosphorus Esters. Some other different structures of organophosphorus insecticides are included in Figure 2.5. Ace-phate 55 is a phosphoramidothioate insecticide, with residual systemic activity of about 10-15 days. It kills the insects by direct contact or by ingestion. Therefore, it is used for controlling biting and sucking insects, especially aphids, in vegetables and in horticulture. It also controls leaf miners, lepi-dopterous larvae (caterpillars), mole crickets, chinch bugs, ants, lacebugs and lawn pests. Used as a turf insecticide, it must be applied 48 hours before irrigation. Wetting the lawn with a 2% soap solution pulls mole crickets and chinch bugs up to the top of the thatch and improves the eradication after spraying. Acephate affects the migratory orientation of adult white-throated sparrows, by affecting the memory of the migratory route.154 WHO classification is III, slightly hazardous, with a LD50 of 945mgkg-1 (oral, rat). In the EU the authorisations for products containing acephate were withdrawn in March, 20 03,155 whereas in 2008 the US EPA imposed new restrictions.156 Phoxim 56 is an oxime phosphorothioate insecticide with stomach and contact action, especially useful for controlling stored product pests. WHO classification is II, moderately hazardous, with a LD50 of 1975mgkg 1 (oral, rat).116 It has not been registered in the US EPA, while it is allowed in the EU for use in veterinary medicine for the control of mites, lice and other ectoparasites of pigs and sheep.157 However, it is banned for use on crops since December 2007.158

Trichlorfon 57 is a non-systemic phosphonate insecticide with contact and stomach action, used on golf course turfs, home lawns, food processing plants, ornamental plants and fish ponds, to control arthropod pests such as fleas, flies, ants, cockroaches, water scavenger beetle, water scorpions and giant water bugs, among others. It is a curative grub insecticide, playing an important role in IPM programs for white grubs in turf, allowing turf managers to reduce preventative treatments. WHO classification is II, moderately hazardous, with a LD50 of 250 mg kg-1 (oral, rat).116 Trichlorfon is under registration review by the US EPA,159 while the EU authorisations for plant protection products containing trichlorfon were withdrawn by November 2007.160 Mode of Action

Organophosphorus insecticides are able to phosphorylate the active site of acetylcholinesterase AChE (EC, an enzyme widely distributed in excitable membranes of nerves and muscles, throughout the animal king-dom.161,162 This enzyme works at the neural synapses to rapidly hydrolyze the neurotransmitter acetylcholine to acetate and choline. When AChE is phos-phorylated, acetylcholine accumulates, the nerve remains polarized and there is an over-stimulation at the neuromuscular junctions.163,164

AChE is located primarily in the central nervous system of insects, whereas in mammals AChE is found in both the central and peripheral nervous systems. Therefore, differences exist in the symptoms of poisoning by anticholinesterases between the two groups. Those effects (nausea, lacrimation, salivation, sweating and abnormal constriction of the pupil of the eye), associated with poisoning of the parasympathetic nervous system in mammals,165 are not observed in insects since they do not have a parasympathetic nervous system.166 Central nervous system poisoning effects (tremors, hyperactivity, ataxia, convulsions paralysis and death) occur in both groups.167

The reaction between acetylcholine and AChE takes place in three stages, as shown in Scheme 2.5: (1) formation of the Michaelis complex between the substrate, acetylcholine and AChE; (2) acetylation of the enzyme and formation of choline; and (3) hydrolysis of the acetylated enzyme to give free enzyme and acetic acid. These reactions take place rapidly, so there is no accumulation of acetylcholine across the synapse.168

The reaction between the organophosphorus compounds and AChE is analogous, as seen in Scheme 2.5: (1) formation of the complex; (2) phos-phorylation of a serine hydroxyl group at the active site of AChE; and

Preparation Insecticides
Scheme 2.5 Mode of action of OP insecticides.

(3) dephosphorylation, although this step occurs at an extremely slow rate: from hours (O,O-dimethyl phosphates) to days (O,O-diethyl phosphates).90

The reactivity of organophosphorus insecticides is determined by the electrophilicity of the phosphorus atom; the phosphate esters being much more reactive than the phosphorothionate esters (P=S). The latter are unreactive with acetylcholinesterase, and are active only after in vivo oxidation to the phosphate analogues by a microsomal oxidase in the insect gut and in the mammalian liver. For example, parathion 46 is converted into paraoxon by oxidation. The time required for this oxidation (hours), allows treatment with atropine before severe effects are developed. This explains why phosphoro-thionates are less hazardous and have less fatal consequences than their equivalent phosphates.

One of the main drawbacks associated with organophosphorus insecticides is their high toxicity in non-target organisms. Acute poisoning of humans can occur by inhalation, ingestion or dermal exposure. As an example, 120 mg of parathion is known to kill an adult human, and children of five- to six-years old were killed by ingestion of only 2 mg of parathion 46 (about 0.1mgkg-1). Repeated chronic exposure of agricultural workers is also quite dangerous due to the irreversible inhibition of acetylcholinesterase and the need for the enzyme to be resynthesized in the organism. Improper storage, handling and use have caused many cases of poisoning with thousands of deaths occurring each year.169,170

In spite of the hazards associated with the use of highly toxic organopho-sphorus compounds, they are still used in great quantities throughout the world. In the USA, OPs account for about half of all insecticides used (by amount sold).171 In the search for safer OPs, malathion 42 was shown to be about one-hundredth as toxic to humans and higher animals, compared with parathion 46.172

The introduction of a methyl group in the 3-position of the aryl ring of parathion increases the affinity for the insect AChE and decreases it for the mammalian enzyme, due to the stereochemical interaction of the methyl group with the enzyme. This increases the selectivity of insecticides such as feni-trothion or fenthion, which are widely, and safely, used in the control of household and public health pests and animal ectoparasites.

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