Hydrolysis of phosphonoformate triesters: rate acceleration of a millionfold in nucleophilic substitution at phosphorus

Abstract

The base-catalysed hydrolysis of triesters of phosphonoformic acid via P–O bond cleavage proceeds at rates at least 10⁴ times greater than diethyl difluoromethylphosphonate and 10⁶ times greater than diphenyl methylphosphonate. Buffer catalysis and isotope labelling studies suggest the mechanism of rate acceleration by the ethoxycarbonyl group to involve either intramolecular nucleophilic catalyses via a three-membered ring or stereoelectronic assistance, both of which are unprecedented.