The Impact of Electronic Effects on Photolysis: A Model Study on the 4,5-Dimethoxy-2-nitrobenzyl Caged N-Phenylpyrimidine-2-amine Scaffold

Abstract

Caging of pharmacologically active compounds is an interesting approach in biological chemistry and such photoactivatable compounds are also being developed towards novel therapeutic prodrug concepts. In this study we investigated the photolysis of the commonly used 4,5-dimethoxy-2-nitrobenzyl (DMNB) caging moiety attached to the NH-nitrogen of the pharmacologically relevant N-phenylpyrimidine-2-amine scaffold. Based on this concept, a small set of para-phenyl substituted derivatives with varying I/M effects (inductive/mesomeric electron-donating/withdrawing effects) was designed, synthesized and parameters of the photolysis were determined. Hammett constants were related to photokinetic measurements, revealing electron donating effects to be unfavorable for the photolysis reaction. Our findings suggest electronic features of the entire molecule should be taken into account when considering its suitability for the caging concept. The results may also serve as a guideline to make relevant choices for DMNB applications in classical protecting group chemistry.