The acid-catalyzed solvolysis of dehydroepiandrosterone sulfate and its significance in the examination of urinary 17-ketosteroids.

Burstein and Lieberman (1) have reported a procedure for the examination of urinary ketosteroid sulfates which involves the extraction of an acidified urine with ethyl acetate followed by solvolysis of the sulfates in the organic phase at 39” for 24 hours. Although the previous authors (1) recognized that this technique partitions water and mineral acid into the ethyl acetate, they did not report a detailed examination of these factors on the rate of reaction. From kinetic evidence presented (2) for a variety of other solvents, one could expect that water would markedly inhibit the reaction, and we have obtained quantitative information in support of this. On the other hand, the role of acid is not clear. Conflicting results have been published (2) ; p-toluenesulfonic acid was found to increase the rate of solvolysis of dehydroepiandrosterone sulfate in tetrahydrofuran-6% HzO, but the same acid had no effect in tetrahydrofuran-10% ethanol. Unfortunately, it is not obvious how these results can be extrapolated to a different solvent system and a different acid, viz. sulfuric acid in ethyl acetate equilibrated with water. In fact, Burstein and Lieberman (1) have reported that, when dehydroepiandrosterone sulfate is solvolyzed in a two phase system containing sulfuric acid, water, and diethyl ether, the rate of reaction is enhanced by the acid merely by increasing the extractability of the steroid sulfate from the aqueous to the organic phase. This seems to be at variance with their study (2) in tetrahydrofuran in which acid in the presence of water increased the rate of reaction itself. Finally, mechanistic considerations (2,3) do not lead to an unequivocal prediction of the influence of acid. Both a dipolar ion (RO+(H)S03 and an anion (ROSOz-) have been suggested as reactive intermediates. In the latter case, acid should decrease the rate of reaction, whereas with the former intermediate, either an increase or a decrease in the solvolysis rate might occur, depending on the quantitative aspects of Equation 1 which have not been evaluated. Furthermore,