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A detailed analysis of the alkylation of phosphodiesters with a p-quinone methide under aqueous conditions has been accomplished. The relative rates of phosphodiester alkylation and hydrolysis have been examined by (1)H NMR analysis of the reaction of 2,6-dimethyl-p-quinone methide in a buffered diethyl phosphate/acetonitrile solution (1:9 v/v, pH 4.0). The rate of hydrolysis of the quinone methide was confirmed by UV analysis in 28.5% solutions of aqueous inorganic phosphate in acetonitrile at pH 4.0 and 7.0. Similarly, the rate of phosphodiester alkylations by the quinone methide was also confirmed by UV analysis in 28.5% solutions of aqueous dibenzyl, dibutyl, or diethyl phosphate in acetonitrile at pH 4.0 and 7.0. These kinetic studies further establish that the phosphodiester alkylation reactions are acid-catalyzed, second-order processes. The rate constant for phosphodiester alkylation was found to range from approximately 370-3700 times the rate constant of quinone methide hydrolysis with diethyl and dibenzyl phosphate, respectively (pH 4.0, 28.5% aqueous acetonitrile).

Despite the wide array of studies involving DNA alkylation and cleavage with quinone methide generating compounds, there have been no reports on the alkylation of phosphodiesters with quinone methides. We have investigated the reaction of dialkyl phosphates with a p-quinone methide in order to determine the potential for alkylation to produce trialkyphosphates. These studies have revealed that a phosphodiester can be alkylated with a p-quinone methide when promoted by a Brønsted acid. The role of the Brønsted acid is to sufficiently activate the p-quinone methide to allow phosphodiester addition to occur. The alkyl substituents of the phosphodiester have been found to effect the reactivity of the dialkyl phosphate under the reaction conditions examined. Equilibrium conversions up to 83% trialkyl phosphate formation have been achieved.