Methyl phosphate, hydrolysis

The factors involved and mechanistic pathways in the hydrolysis of phosphate esters, particularly those of a cyclic nature, continue to be the source of much speculation. A further study of the simplest cyclic triester, ethylene methyl phosphate, seems only to have served to consolidate already polarized views. The original, experiments of Westheimer s group employed gc and H nmr spectroscopy and demonstrated that ethylene methyl phosphate (26) hydrolyses under alkaline conditions by... 

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. 

As is apparent from Fig. 1, the dianions of monoalkyl phosphates normally resist hydrolysis. However, for leaving groups whose conjugate acids exhibit a pKa < 5 in water, hydrolysis of the dianion becomes faster than that of the monoanion. Fig. 2 shows a pH profile characteristic of this situation. Whereas the hydrolysis rate of 2,4,6-trichlorophenyl phosphate (pKa of the phenol 6.1) still shows the typical monoanion preference as seen for methyl phosphates (Fig. 1), the dianion of 2,4-dinitrophenyl phosphate (pKa of the phenol 4.09) is hydrolyzed far faster than the monoanion 2-chloro-4-nitrophenyl phosphate represents an intermediate case (pKa of the phenol 5.45)6S). 

Fig. 9.7. a) Mechanism of activation of (phenytoin-3-yl)methyl phosphate (9.25) to release phenytoin. Phosphoric acid ester hydrolysis is mediated by alkaline phosphatase, b) (Phospho-ryloxy)methyl prodrugs of tertiary amines, whose activation occurs by the same two-step mechanism shown in a [79]. 

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 ... 

Proton transfer may proceed directly or via a six-membered cyclic transition state involving a molecule of water. A calculation of the intermediate zwitter-ionic concentration for the hydrolysis of methyl phosphate monoanion, based on the pKa values for methanol and methyl phosphate dianion, predicts the first-order rate coefficient for zwitterion decomposition to be ca. 10 sec-1 at 100°C. This value is in good agreement with the observed rate of hydrolysis and, considering the assumptions involved, with the rate of P-O bond fission of the presumed zwitterionic intermediate (2) formed in the Hg(II) catalyzed solvolysis of phosphoenolpyruvic acid, a model reaction for pyruvate kinase10. 

At this point it is profitable to consider the hydrolysis or alcoholyses of the cyclic oxyphosphoranes themselves. The trimethoxyphospholene (37) undergoes a nearly instantaneous reaction with one molar equivalent of water in benzene solution at 0°C101. The products of this reaction are mainly dimethyl phosphoracetoin and the cyclic methyl phosphate of acetoinenediol, viz-... 

The data and mechanistic conclusions summarized above come from work with aryl phosphomonoesters as predicted by the steep jSlg value, alkyl ester dianions react at very slow rates. A recent study of methyl phosphate found the rate of the dianion hydrolysis to be below the threshold of detectability, with an estimated rate constant of 2 x 10 20 s 1 at 25 °C.3 Since this value is close to the rate predicted from an extrapolation of the Bronsted plot of aryl phosphomonoester dianions, a similar mechanism is likely to be followed for alkyl and aryl esters. 

P-O bond fission is the usual mode of attack by nucleophiles on phosphodiesters, although there are exceptions. The labile diester methyl-2,4-dinitrophenyl phosphate shows significant amounts of attack at aromatic carbon (nucleophilic aromatic substitution, with loss of methyl phosphate) in competition with attack at phosphorus, most notably with hydroxide and with primary amines.46 Due to the small size of the methyl group it is sterically susceptible to nucleophilic attack in phosphate esters the hydrolysis of the dimethyl phosphate anion occurs almost exclusively by C-O bond fission.4 With larger or less labile leaving groups, even... 

TFA, FDT, TIS, H2O. These conditions readily cleave the benzyl phosphate but also result in some methyl ester hydrolysis of a cyclic peptide. The problem was avoided by using hydrogenolysis to affect cleavage, but this also reduced an olefin in the molecule. 

Condensation of 2-amino-3-bromo-l,6-naphthyridines 81 with potassium O-ethyl xanthate in A-methylpyrrolidone afforded thiazolo[4,5-6][l,6]naphthyridine-2(3//)-thiones 303 whose subsequent methylation and hydrolysis in the presence of sodium methoxide afforded thiazolonaphthyridones 304 inhibiting adenosine-3, 5 -cyclo-phosphate phosphodiesterase (cAMP PDE III) (1995JMC2546). 

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