Mechanistic studies of thiophosphoryl transfer reactions.

Nucleophilic displacement reactions of monosubstituted thiophosphate esters have been studied. A general synthesis of isotopically chiral O-substituted [16O, 18O] thiophosphate monoesters has been developed. A new and general method for the configurational analysis of these labelled thiophosphates using high-field 31P n.m.r. spectroscopy has been developed. The thiophosphate is S-alkylated with myrtenyl bromide (10-bromopin-2-ene) followed by O-derivatisation either with dimethyl sulphate, diphenyldiazomethane or benzoyl chloride. Using the above analysis, it was found that the ethanolysis of the monoanion of (Rp)-4- nitrophenyl [16O, 18O] thiophosphate proceeds with a high degree of racemisation (ca. 80%) and the dianion with complete racemisation, the corresponding solvolysis of the monoanion in aqueous ethanol gives ethyl thiophosphate with ca. 70% racemisation; these data provide the first direct support of a freely-solvated monomeric thiometaphosphate intermediate in the case of the solvolysis of the dianion in ethanol and a relatively long-lived intermediate for the monoanion in ethanol and in aqueous ethanol. A kinetic study has also been undertaken to investigate the nature of thiophosphoryl transfer reactions in aqueous solution. The rate of hydrolysis of 2,4-dinitrophenyl thiophosphate was observed to be reduced by increased pressure with a volume of activation (?V+) of +11 cm3 mol-1. This result indicates that the thiophosphoryl transfer to water is essentially dissociative in nature involving the intermediacy of thiometaphosphate. Thiophosphoryl transfer reactions involving "front-side" displacement has also been studied. It is found that the formally intramolecular thiophosphoryl transfer reaction of (Rp)-2-(hydroxymethyl)-4-nitrophenyl [16O, 18O] thiophosphate proceeds with 65% race misation and 35% excess retention of configuration. This observation shows that a dissociative mechanism can occur with retention of configuration if the nucleophile is constrained to attack the phosphorus centre on the same side as the leaving group.