Phosphate monoesters solvolysis

As noted previously, studies of the mechanisms of phosphate monoester solvolysis have been extended to the mechanisms of the analogous phosphorothioate ester solvolysis because the thiometaphosphate anion is believed to be more stable than the metaphosphate anion. Thus, a general method based upon P NMR spectroscopy for the configurational analysis of chiral thiophosphate monoesters (see Fig. 10) was described recently by Cullis and co-workers (38). 

Hoff RH, Hengge AC. Entropy and enthApy contributions to solvent effects on phosphate monoester solvolysis. The importance of entropy effects in the dissociative transition state. J Org Chem. 1998 63 6680-6688. 

Other workers have concluded that, for the solvolysis of phosphate monoesters, the bonding between nucleophile and mecaphosphate is not far developed in the transition state and... 

Solvolysis studies of meta- and para-substituted phenyl phosphates (240) in anhydrous Bu OH and in Am OH have revealed that generally reactions of dianions are much faster in alcohols than in water. For example, the dianion of p-nitrophenyl phosphate (240 X = 4-NO2) reacts 7500- and 8750-fold faster in Bu OH and Am OH, respectively, than in water." The results of a theoretical study of the reactivity of phosphate monoester anions in aqueous solution do not support the generally accepted view that Brpnsted coefficients fhg = —1.23 and jSnuc = 0.13 determined more than 30 years ago for the uncatalysed reaction of water and a monophosphate dianion (241) represent conclusive evidence for the dissociative mechanism. It is suggested that, instead, the observed LFERs could correspond to a late transition state in the associative mechanism." ... 

Converging lines of evidence have led to a general acceptance of the monomeric metaphosphate mechanism for the hydrolysis of phosphate monoester monoanions. The pH rate profile for aryl and alkyl phosphate monoester hydrolyses commonly exhibits a rate maximum near pH 4. where the concentration of the monoanion is at a maximum. The proposed mechanism is based on these principal points of evidence (a) a general observation of P-O bond cleavage (b) the entropies of activation for a series of monoester monoanions are all close to zero, which is consistent with a unimolecular rather than a bi-molecular solvolysis where entropies of activation are usually more negative by 20 eu7 (c) the molar product composition (methyl phosphate inorganic phosphate) arising from the solvolysis of the monoester monoanion in a mixed methanol-water solvent usually approximates the molar ratio of methanol ... 

In contrast, the acid-catalyzed hydrolysis of alkyl selenates is A-2158. The actual species which undergoes decomposition to alcohol and sulfur trioxide is probably the zwitterion as in the case of phosphate monoester monoanions. Evidence for sulfur trioxide as the reactive initial product of the A-1 solvolysis is obtained from the product compositions arising with mixed alcohol-water solvents. The product distribution is identical to that found for sulfur trioxide solvolysis, with the latter exhibiting a three-fold selectivity for methanol. Although the above entropies of activation and solvent deuterium isotope effects do not distinguish between the conventional A-l mechanism and one involving rate-limiting proton transfer, a simple calculation, based on the pKa of the sulfate moiety and the fact that its deprotonation is diffusion controlled. 

Many mechanistic aspects of the hydrolysis of phosphate esters in protic media remain uncertain. In spite of predictions that racemization at phosphorus should be the final outcome if indeed the (hypothetical) metaphosphate intermediate is involved in the solvolysis of monoesters, the results of several studies on the methanolysis of appropriately O-isotopically labelled compounds are consistent with reactions proceeding with inversion of configuration, as observed for all enzymic and non-enzymic systems so far examined this has resulted in the suggestion that if metaphosphate is actually formed, then it must be in a masked form. 

A detailed study of the specific rates of solvolysis of N,N,N, N -tetra-methyldiamidophosphorochloridate (80) (TMDAPC) with analysis in terms of the extended Grunwald-Winstein equation has been reported (Scheme 19). The stereochemistry of nucleophilic attack at tetracoordinate phosphorus was also discussed." The initial reaction of bis (2,4-dinitrophenyl) phosphate (BDNPP) (81) with hydroxylamine involves release of 1 mol 2,4-dinitrophen-oxide ion and formation of a phosphorylated hydroxylamine (82), which reacts readily with further NH2OH, giving the monoester (83). The intermediate (82) also breaks down by two other independent reactions one involves intramolecular displacement of aryloxide ion (83) and the other involves migration of the 2,4-dinitrophenyl group from O to N and formation of phosphorylated 2,4-dinitrophenylhydroxylamine (84) (Scheme 20)." ... 

Very little is known about the transition states for enzymic nucleotidyl and phospho transfer reactions. Inasmuch as the mechanisms of the nonenzymic sol-volyses of phosphate esters establish the possibilities for comparable enzymic reactions, either associative or dissociative mechanisms can be considered. However, the dissociative mechanism is thought to be possible only for phospho transfer reactions and not for nucleotidyl transfers, because metaphosphate cannot be formed from diesters. A dissociative mechanism for a diester would entail the formation of a monomeric metaphosphate monoester, a species that can exist but which has not been observed in solvolysis reactions. The difficulty with the dissociative mechanism for phosphodiesters may be that a monoanion cannot provide enough driving force to expel a leaving group under solvolytic conditions. 

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