Hydrolytic Stabilization of Protected p-Hydroxybenzyl Halides Designed as Latent Quinone Methide Precursors

The hydrolysis rates of a series of protected p-hydroxybenzyl halides designed to generate a p-quinone methide through 1,6-elimination following photolytic deprotection have been investigated in order to optimize hydrolytic stability. A number of p-hydroxybenzyl halides containing an ether- or carbonate-linked photolabile hydroxy protecting group and a fluoride, chloride, or bromide benzylic leaving group have been synthesized. The hydrolysis rates of these derivatives in different water/acetonitrile mixtures and temperatures have been determined. The hydrolysis half-life of the benzyl bromide with the p-hydroxy protected as the carbonate-linked α-methylnitroveratryl (18c) is more than 750 times that of the ether-linked analogue (16c). These studies afford a Hammett σp+ of +0.28 for the carbonate-linked derivatives compared to a σp+ of −0.39 for the ether-linked derivatives. The theoretical hydrolysis half-life of the most stable benzyl fluoride in 100% water was sufficiently long so as to preclude extrap...