Phosphoryl transfer from phosphomonoesters in aprotic and protic solvents

The "addition-elimination" mechanism of nucleophilic displacements on phosphotriesters and phosphodiesters via oxyphosphorane intermediates is reviewed. Recent data on nucleophilic catalysis of this mechanism in aprotic and protic solvents is summarized. The implications of positional exchange of ligands in the phosphorane intermediate with respect to the stereochemistry of the product are emphasized. The "elimination-addition" mechanism of displacements on phosphomonoesters via a monomeric metaphosphate anion intermediate is considered, first from earlier data obtained in aqueous solutions, and then from the results of the present work in both aprotic and protic solvents. Evidence is provided for the operation of the additionelimination and the elimination-addition mechanisms in nonenzymatic phosphoryl transfer from aryl phosphomonoesters, ArOPO3FL,, as a function of the structure of the nucleofugic group, ArOH, and ofthe state of ionizatjon of the ester, i .e • , neutral acid, monoanion, ArOPO3H , or dianion , ArOPO3 . The medium is very important in controlling the acidity of the phosphomonoester and, hence, its state of ionization, and in determining relative solvation of the more polar ground states vs the less polar transition state in both mechanisms. Only monoanions are susceptible to nucleophilic catalysis in displacement reactions of phosphomonoesters, and the catalysis is exerted via ox>rphosphorane intermediates. Dianions are not su.sceptible to nucleophilic catalysis due to their relatively low phosphorus electrophilicity. A very slight rate acceleration of dianion displacements observed in the presence of most types of anilnes is attributed to medium effects not associated with nucleophilic catalysis. The first direct observation of the monomeric metaphosphate anion and metaphosphoric acid in the gas phase is described. Monomeric alkyl metaphosphates are also generated by purely thermal reactions in the gas phase at temperatures as low as 200°C. It is concluded that the characteristics of the elimination-addition mechanism of phosphoryl-transfer are such that this mechanism is unlikely to be involved in enzymatic reactions of phosphorus compounds with two ionizable hydrogens on the same phosphate group, phosphomonoesters, acyl phosphates and the terminal (P1) group of ATP. These enzymatic reactions probably involve the monoprotonated species, XPO3H , and proceed via oxyphosphorane intermediates, without or with assistance of nucleoph]iTc catalysis. The essential role of Mg2 ions in most of the enzymatic reactions is probably associated with the simultaneous binding of the metal ion to the phosphate and to amino acid residues of the enzyme, which reinforces the direct binding of the phosphate to enzyme at the active site pocket. Magnesium ions do not increase significantly the electrophilicity of the phosphorus in nonenzymatic phosphoryl transfer.