Phosphorus esters hydrolysis

The most common chemical reaction of the organophosphate class is hydrolysis because they are all phosphorus esters. Hydrolysis is catalyzed by H20 and esterases, as shown in Figure 4.6. 

There has been controversy over the mechanism of hydrolysis of ethylene methyl phosphate and investigations into the nature of metaphosphate and its role in the hydrolysis of phosphorus esters have continued. Elegant experiments relating to each of these problems have been reported. 

The mechanism of phosphate ester hydrolysis by hydroxide is shown in Figure 1 for a phosphodiester substrate. A SN2 mechanism with a trigonal-bipyramidal transition state is generally accepted for the uncatalyzed cleavage of phosphodiesters and phosphotriesters by nucleophilic attack at phosphorus. In uncatalyzed phosphate monoester hydrolysis, a SN1 mechanism with formation of a (POj) intermediate competes with the SN2 mechanism. For alkyl phosphates, nucleophilic attack at the carbon atom is also relevant. In contrast, all enzymatic cleavage reactions of mono-, di-, and triesters seem to follow an SN2... 

Vanadium is beneficial and possibly essential for humans. It is certainly essential for a number of organisms. Vanadate (oxidation state V) and its derivatives are phosphate analogues, showing both ground state and transition state analogy (both structural and electronic) with phosphorus compounds. The analogy of five-coordinate vanadium compounds with the transition state of phosphate ester hydrolysis is well documented, and explains why so many vanadium compounds are potent inhibitors of phosphatases, ribonucleases and ATPases. 

Aromatic substituent effects due to phosphorus groups have been studied for a number of reactions.47 Thus ester hydrolysis and fluoride-displacement rates, for (56) and (57) respectively, are enhanced by phosphorus substituents (X = O or ), while the rate of hydrolysis of the halide (58) is enhanced for X = , but slowed for X = O.47 A perturbation M.O. analysis of these observations has been presented.48... 

The first suggestion of a practical form of antidotal therapy came in 1949 from Hestrin, who found that acetylcholinesterase (AChE) catalyzed the formation of acetohydroxamlc acid when incubated with sodium acetate and hydroxylamine. Critical in vitro studies in the next decade led to the development of a practical approach to therapy. The crucial concept in these studies was the recognition that the compound formed when AChE reacted with a phosphorus ester was a covalent phosphoryl-enzyme Intermediate similar to that formed in the hydrolysis of acetylcholine. 3 Wilson and colleagues, beginning in 1951, demonstrated that AChE inhibited by alkyl phosphate esters (tetraethyl pyrophosphate, TEPP) could be reactivated by water, but that free enzyme formed much more rapidly in the presence of hydroxylamine. 0 21 Similar results... 

FIGURE 13. Fundamental pathways for the hydrolysis of a phosphorus ester bond... 

The phosphonamide bond is fairly labile to acid-catalyzed hydrolysis, although this is not normally a serious problem unless the phosphorus ester is hydrolyzed to produce the phosphonamidic acid (see Section 10.10.3). Nevertheless, it is prudent to use a mild aqueous acid solution (e.g., sat. KH2P04 or 2% KHS04) during reaction workups, rather than dilute mineral acids (e.g., 5% HC1 or 5% H2S04). 

Aminolysis of phenyl dithioacetates,8 pyridinolysis of O-ethyl dithiocarbonates,9 reaction of pyrrolidine with O-ethyl 5-aryl dithiocarbonates,10 aminolysis of chlorothionformates,11 pyridinolysis of alkyl aryl thioncarbonates,12 reaction of anionic nucleophiles with nitrophenyl benzoate and its sulfur analogues,36 hydrolysis of methyl benzoate and phenyl acetate containing SMe, SOMe and S02Me substituents,42 solvolysis of phenyl chlorothioformate,79 synthesis of new thiadiazoles,124 examination of a neighbouring sulfonium group in ester hydrolysis,136 hydrolysis of V-type nerve agents,250 and the reactions of peroxymonosulfate ion with phosphorus(V) esters have all been looked at previously in this review. 

Much of the splitting of the phosphorus ester bonds in organophosphorus insecticides, which was formerly believed to be due entirely to hydrolysis, is now known also to be due to oxidative dearylation catalyzed by CYP. 

Tissue esterases have been divided into two classes the A-type esterases, which are insensitive, and the B-type esterases, which are sensitive to inhibition by organo-phosphorus esters. The A esterases include the arylesterases, whereas the B esterases include cholinesterases of plasma, acetylcholinesterases of erythrocytes and nervous tissue, carboxylesterases, lipases, and so on. The nonspecific arylesterases that hydrolyze short-chain aromatic esters are activated by Ca2+ ions and are responsible for the hydrolysis of certain organophosphate triesters such as paraoxon (Figure 10.10B). 

The current review is of necessity selective. Over the two year period covered, there has been impressive advances in several areas of P(V) chemistry. For example, biological aspects of quinquevalent phosphorus acids chemistry continue to increase in importance. A wide variety of natural and unnatural phosphates including inositols, lipids, some carbohydrates and their phospho-nates, phosphinates and fluorinated analogues has been synthesized. Special attention has been paid to the synthesis of phosphorus analogues of all types of amino acids and some peptides. Numerous investigations of phosphate ester hydrolysis and related reactions continue to be reported. Interest in approaches to easier detoxification of insecticides continues. A number of new and improved stereoselective synthetic procedures have been elaborated. The importance of enantioselective and dynamic kinetic asymmetric transformations is illustrated in many publications. 

There have been a number of developments worthy of special mention in chemistry involving pentaco-ordinated compounds and intermediates. These include reports of molecular mechanics calculations to study the hydrolysis of cyclic phosphorus esters, further detailed studies of the reactions of tervalent phosphorus compounds with acetylene carboxylates and the first synthesis of a pentaco-ordinated phosphorus compound containing a three-membered (phosphirene) ring. There has also been further elegant work in the area of phosphatrane chemistry. 

The completely uncatalysed reaction involves nucleophilic attack by the OH group on the P=0 bond to form a five-covalent intermediate much like the tetrahedral intermediate in carboxylate ester hydrolysis. There is a difference. Phosphorus prefers five-membered rings to any other... 

Formation of sulfide with concurrent ester hydrolysis was achieved when various Cj cyclopropyl cephalosporin 5-oxide 2,2,2-trichloroethyl esters were treated with phosphorus trichloride followed by zinc under acidic conditions. Sulfoxide reduction also occurred on treatment of cyclopropyl phenyl sulfoxide with a mixture of benzenethiol and chlorotrimethylsilane in chloroform to give cyclopropyl phenyl sulfide in 76% yield and on reaction of various substituted cyclopropyl phenyl sulfoxides with diisobutylaluminum hydride. ... 

Katritzky, A.R., Duell, B.L., Durst, H.D., and Knier, B.L. 1988. Substituted o-iodoso- and o-iodoxybenzoic acids s3mthesis and catalytic activity in the hydrolysis of active phosphorus esters and related systems. Journal of Organic Chemistry, 53 3972-3978. 

The phosphorus ester molecule, blocking the activity of acetylcholinesterase, first takes up a steric orientation determined by the anionic and acidic groups of the enzyme, and this is then followed by hydrolysis of the phosphorus ester and by phosphorylation of the hydroxyl group of serine at the esteratic site of the enzyme ... 

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