Organophosphorus esters

The organophosphorus esters represent another class of environmental chemicals that are hydrolyzed by nucleophilic substitution reactions. These chemicals comprise one of the most important classes of agrochemicals with insecticidal activity (Fest and Schmidt, 1983). The organophosphorus esters also have important industrial uses such as oil additives, flame retardants, and plasticizers (Muir, 1988). The wide range of biological activity that this class of chemicals exhibits is due to the variety of substituents that can be attached to the central phosphorus atom. 

The organophosphorus esters that have the greatest environmental significance because of their extensive use as insecticides have the general structure  

As a result, hydrolysis mechanisms and product distribution for the organophos-phorus esters will be pH dependent. The diesters, the initial products formed from the hydrolysis of the triesters (2.50 and 2.51) will be further hydrolyzed to monoesters, but at a much slower rate than the parent compound. Little information exists to determine if formation of the more persistent diesters has deleterious effects on the health of environmental systems. 

The structural features of organophosphorus esters, which are very similar to those of the carboxylic acid esters, suggest that nucleophilic displacement at the central phosphorus atom will occur by an addition-elimination mechanism. Mechanistic studies, however, have demonstrated that hydrolysis occurs through direct nucleophilic displacement at phosphorus and does not involve formation of a pen-tavalent intermediate with H2O or OH (Hudson, 1965 Kirby and Warren, 1967). Accordingly, hydrolysis rates for phosphorus esters will be sensitive to electronic factors that alter the electrophilicity of the central phosphorus atom and steric interaetions that impede nucleophilic attack. 

The hydrolytic stability, as well as the biological activity, also can be affeeted by modifying other substituents at the phosphorus atom. For example, substitution of sulfur (P = S) for oxygen (P = O) in the ester moiety will reduce the electrophilicity of the phosphorus center because of the weaker electron withdrawing effect of sulfur. Accordingly, phosphorothioate esters (P = S) will exhibit greater stability toward 

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All the enzymes discussed above belong to the class of dimetalloenzymes. In this context, it should be mentioned that serine-type hydrolases are irreversibly inhibited by organophosphorus esters, among them highly toxic chemical warfare agents. However, in some cases, for example of human butyrylcholi-noesterase, the inhibited enzyme could be reactivated by proper mutations." Moreover, such mutahons were found to confer phosphotriesterase activity in this... 

Organophosphorus esters are known to react with a serine hydroxyl group in the active site of the acetylcholinesterase protein (Ecobichon 1991 Murphy 1986). Some organophosphorus esters (e.g., diisopropyl fluorophosphate, [DFP]) bind irreversibly, while others bind in a slowly reversible fashion, thereby leading to a slow reactivation (dephosphorylation) of the enzyme. A process known as "aging" has also been described in which reversibly bound compounds are changed with time to moieties that are essentially irreversibly... 

Organophosphate Ester Hydraulic Fluids. Very little is known about the bioavailability of organophosphorus esters. In fish, organophosphate esters appear to be more bioavailable when sediments are not present (Huckins et al. 1991), but chronomids appear to be able to bioaccumulate organophosphate esters from the sediments (Muir et al. 1983b, 1985). Because of this wide variation and the lack of any information in mammalian species, it is difficult to estimate bioavailability to humans. Development of bioavailability information in mammalian species will allow a better understanding of this complex process. Given the concerns over the toxicity of this class of hydraulic fluids, further research on this topic would be useful. 

Abou-Donia MB, Lapadula DM. 1990. Mechanisms of organophosphorus ester-induced delayed neurotoxicity Type I and Type II. Ann Rev Pharmacol Toxicol 30 405-440. 

JohnsonMK. 1975. The delayed neuropathy caused by some organophosphorus esters Mechanism and challenge. Crit Rev Toxicol 3 289-316. 

Johnson MK. 1982. The target for initiation of delayed neurotoxicity by organophosphorus esters biochemical studies and toxicological applications. In Hodgson E, Bend JR, Philpot, RM, eds. Reviews of biochemical toxicology, Vol 4. New York Elsevier, 141-212. 

Schwab BW, Richardson RJ. 1986. Lymphocyte and brain neurotoxic esterase Dose and time dependence of inhibition in the hen examined with three organophosphorus esters. Toxicol Appl Pharmacol 83 1-9. 

Thermal degradation occurs when heat causes compounds to undergo structural changes, leading to the formation of simpler species. For example, many organophosphorus esters isomerize when heated... 

Metal-catalyzed alcoholysis reactions of carboxylate and organophosphorus esters... 

Metal-catalyzed alcoholysis reactions of carboxylate and organophosphorus esters, 42, 271 Metal complexes, the nucleophilicity of towards organic molecules, 23, 1 Methyl transfer reactions, 16, 87... 

Mammalian esterases have been classified into three groups according to specificity for substates and inhibitors (110). In terms of overall hydrolytic activity in mammals, the most important class of esterases is that of the B-esterases, which are principally active with aliphatic esters and amides. A-Esterases are important for aromatic esters and organophosphorus esters, and C-esterases are active with acetyl esters. In general, the specificity of mammalian esterases is determined by the nature of substituent groups (acetyl, alkyl, or aryl) rather than the heteroatom (O, N, or S) that is adjacent to the carboxy group. That is, the same esterase would likely catalyze hydrolysis of an ester, amide, or thioester as long as the substituents were identical except for the heteroatom (110). 

A. Pla, M. K. Johnson, Degradation by Rat Tissues in vitro of Organophosphorus Esters Which Inhibit Cholinesterase , Biochem. Pharmacol. 1989, 38, 1527-1533. 

M. B. Abou-Donia, D. M. Lapadula, Mechanisms of Organophosphorus Ester-Induced Delayed Neurotoxicity Type I and Type II , Ann. Rev. Pharmacol. Toxicol. 1990, 30, 405-440. 

Reaction of Sodium Perborate with Organophosphorus Esters... 

The objective of this work Is to establish a reaction mechanism between sodium perborate and several organophosphorus esters. By analogy we can then describe Its probable effects upon other phosphorus-based Insecticides. We conclude that the reactivity of sodium perborate toward five model compounds Is attributable to the nucleophilic reactions of hydroperoxyl anion, HO2 , produced by perborate dissociation In water. On this basis we predict that sodium perborate solutions will be effective chemical detoxicants for phosphorus ester Insecticides. 

Insect resistance and environmental pollution due to the repeated application of persistent synthetic chemical insecticides have led to an Increased interest in the discovery of new chemicals with which to control Insect pests. Synthetic insecticides, including chlorinated hydrocarbons, organophosphorus esters, carbamates, and synthetic pyrethroids, will continue to contribute greatly to the increases in the world food production realized over the past few decades. The dollar benefit of these chemicals has been estimated at about 4 per 1 cost (JJ. Nevertheless, the repeated and continuous annual use in the United States of almost 400 million pounds of these chemicals, predominantly in the mass agricultural insecticide market (2), has become problematic. Many key species of insect pests have become resistant to these chemicals, while a number of secondary species now thrive due to the decimation of their natural enemies by these nonspecific neurotoxic insecticides. Additionally, these compounds sometimes persist in the environment as toxic residues, well beyond the time of their Intended use. New chemicals are therefore needed which are not only effective pest... 

Studies of the in vitro reaction between the alkaline oximes and sarin (isopropyl methylphosphonofluoridate, GB) revealed that 2-PAM reacted rapidly with the organophosphorus ester in solution at physiologic pH and temperature (Figure 2-2)... 

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