Cyclodiene Insecticides

Cyclodiene insecticides are comprised of compounds obtained by a Diels-Alder reaction, and were first marketed after World War II. The key synthetic intermediate is hexachlorocyclopentadiene 26 that can be obtained by chlorination of cyclopentadiene 25, but also from pentane, cyclopentane or neopentane (see Scheme 2.2).68 A Diels-Alder cycloaddition between cyclopentadiene and 26 gave an intermediate called chlordene 27, whose chlorination afforded mainly a mixture of cis- and trans- isomers on 1 and 2 positions. These isomers are called a- and b-chlordane (6 and 7, respectively), which are the oldest cyclodiene insecticides (1944),68 and whose technical product is a mixture of up to 14 compounds.54 Chlordane was used against sucking and blowing insects and soil pests, and also as an acaricide as a contact, respiratory and stomach poison.43

Chlordane is roughly 300 times more active than its precursor chlordene 27. Furthermore, b-chlordane is much more active than its a-isomer, whereas the toxicity against mammals is reversed.43 These data suggest that for insecticidal activity, not only the number of chlorine atoms, but the stereochemistry of the compound is important.

A related compound that is also present in chlordane formulations is hepta-chlor 8, whose synthesis also involves 27, followed by chlorination with sulfuryl chloride or chlorine in the presence of a peroxide (see Scheme 2.2). Heptachlor has been used against termites and soil insects, and apparently undergoes epoxidation upon metabolization by the insect. The resulting epoxide has been proved to exhibit greater insecticidal activity than heptachlor itself.54

Another very popular organochlorine insecticide of the cyclodiene family is aldrin 9, which can be obtained by Diels-Alder reaction between

Synthesis Aldrin Insecticide

Aldrin (9) Dieldrin (10)

Scheme 2.2 Synthesis of chlordane, heptachlor, aldrin and dieldrin.

Aldrin (9) Dieldrin (10)

Scheme 2.2 Synthesis of chlordane, heptachlor, aldrin and dieldrin.

hexachlorocyclopentadiene 26 and norbornadiene68 (available by another Diels-Alder cycloaddition between cyclopentadiene and acetylene) under solventless conditions (see Scheme 2.2), and the endo-exo isomer was obtained. This insecticide was especially useful for controlling soil-dwelling insects, due to its chemical stability and high vapor pressure,43 with better results than DDT. Epoxidation of aldrin with a peracid (e.g. peracetic acid, perbenzoic acid), or alternatively with hydrogen peroxide and tungstic oxide, yielded dieldrin 10 (exo-epoxide), quite commonly used in the past on crops, soil and seed dressing applications,68 and also for wood preservation in buildings.69

In a similar fashion, a Diels-Alder reaction between hexachlorocyclopentadiene as the diene and acetylene as the dienophile (see Scheme 2.3),68 followed again by a cycloaddition reaction of the intermediate with cyclopentadiene, afforded isodrin 11, an isomer of aldrin. Alternatively, isodrin was also prepared by a Diels-Alder reaction of 26 with vinyl chloride, followed by heating in the presence of cyclopentadiene.43 Epoxidation of 11 with peracetic acid yielded endrin 12,68 of interest against insects affecting cotton. Endrin undergoes much faster biodegradation than isomeric dieldrin 10, mainly by a hydroxylation reaction followed by biosynthesis of glucuronides or sulfates which are excreted via urine in mammals.68

Another derivative of commercial importance obtained via a Diels-Alder reaction is endosulfan, prepared as depicted in Scheme 2.3 by a cycloaddition reaction between hexachlorocyclopentadiene 26 and cis-pent-2-en-1,4-diol, followed by treatment with thionyl chloride.70 Endosulfan exists as a mixture of a- and b-isomers 13 and 14, respectively, resulting from chirality in the sulfur atom, although it has been demonstrated that on storage an irreversible conversion into the a-isomer can take place.71 Endosulfan has been used in a 7 : 3 ratio for commercial purposes71 for pests affecting cereals, fruits, vegetable, cotton and tobacco (e.g. chewing insects and mite pests), although it was found

Preparation Reaction Heptachlor
Scheme 2.3 Synthesis of isodrin, endrin, endosulfan, mirex and chlordecone.

to be quite toxic to mammals (LD50 = 2mgkg~1 in cats) and highly toxic to aquatic organisms, especially fishes (LD50 = 0.005-0.0010 mgl-1).43 Endo-sulfan is quickly excreted by initial hydrolysis of the sulfite moiety or by its oxidation to the corresponding sulfate.

Alternatively, another synthetic route used for the preparation of cyclodiene insecticides is dimerization of hexachlorocyclopentadiene (see Scheme 2.3). If such dimerization is carried out in the presence of AlCl3, mirex 15 is obtained.68 Mirex was widely used for the control of fire ants, but also as a flame retardant. Remarkably, mirex exhibits a worse toxicological profile than other related organochlorine insecticides, due to its high environmental stability and biomagnification, and toxic effects have been reported for occupational exposure.68 Treatment of 26 with SO3 in the presence of SbCl5 furnished chlordecone (KeponeĀ®) 29.

Cyclodiene insecticides, like DDT, are also nerve poisons, acting in ganglia. In this case, they cause disruption of the normal functioning of the chloride channel, activated by neurotransmitter GABA (g-aminobutyric acid). Cyclo-diene insecticides are non-competitive inhibitors (antagonists) of post-synaptic binding of GABA to its receptor,72 causing increased nerve activity and high-frequency discharges. As a result, the insect undergoes hyperactivity, hyper-excitability and convulsions.73 Mutations leading to a modified GABA receptor have been reported to be responsible for cyclodiene insecticide resistance.73

In most cases, cyclodiene insecticides are more toxic than DDT, exhibiting lower LD50 values against mammals. In some cases, a cyclodiene insecticide dose of only 10mgkg_1 is sufficient to cause toxic effects in humans.58

In general, cyclodiene derivatives are quite persistent in the environment. Although SN1 or E1 reactions on the chlorine atoms located on the bridgehead positions would lead to stabilized tertiary carbocations, such reactions are not possible due to strain restrictions for the planar conformation of the carboca-tion.48 Instead, cyclodiene insecticides are slowly degraded in the environment.

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