Mu-monothiopyrophosphate (MTP) is millions of times more reactive than pyrophosphate as a phosphoryl group donor to water. Addition of nucleophiles, including alpha-effect nucleophiles, at high concentrations to aqueous solutions of MTP does not increase the rate at which MTP is cleaved to thiophosphate. However, tris(hydroxymethyl)aminomethane (Tris) and ethylenediamine capture phosphoryl groups from MTP in competition with water. Phosphoryl capture by 3.0 M Tris at pH 9.9 partitions the phosphoryl group into N-phospho-Tris (53%) and O-phospho-Tris (47%). Fluoride and acetohydroxamate anion do not capture phosphoryl groups from MTP, despite being excellent nucleophiles for the phosphoryl group in highly reactive phosphoric esters such as acetyl phosphate and N-phosphopyridines. The results are interpreted in terms of a mechanism in which MTP undergoes cleavage into thiophosphate and discrete monomeric metaphosphate within a solvation sphere, from which metaphosphate cannot escape before being captured by a solvating nucleophile. Nucleophiles such as Tris can enter the solvation sphere by displacing water molecules in a preliminary equilibrium step; however, solvating Tris has little or no effect on the rate at which MTP undergoes cleavage into metaphosphate, and metaphosphate is captured by solvating water or Tris. Negatively charged nucleophiles such as fluoride and acetohydroxamate anion cannot solvate MTP, owing to electrostatic repulsion, and cannot capture metaphosphate. MTP differs from phosphoric esters, acyl phosphates, and phosphoramidates as a phosphoryl group donor in that its P-S bonds are weaker than P-O or P-N bonds. Phosphoric esters and anhydrides donate phosphoryl groups to nucleophiles within dissociative transition states that include the nucleophile (Herschlag, D.; Jencks, W. P. J. Am. Chem. Soc. 1989, 111, 7579-7586). In the case of the trianion of MTP, the P-S bond is very weak and undergoes cleavage to metaphosphate and thiophosphate dianion without nucleophilic participation. Metaphosphate monoanion is so reactive with nucleophiles that it cannot escape from its solvation sphere; it is captured by water or another nucleophile that competes with water in solvating MTP.
