Biological and Medicinal Chemistry

A Strategy for Engineering High Photolysis Efficiency of Photocleavable Protecting Groups Through Cation Stabilization

Authors

Abstract

Photolabile protecting groups (PPGs) enable the precise activation of molecular function with light in many research areas, such as photopharmacology, where remote spatiotemporal control over the release of a molecule is needed. The design and application of PPGs in recent years has particularly focused on the development of molecules with high molar absorptivity at long irradiation wavelengths. However, a crucial and until now mostly neglected parameter, pivotal to the efficiency of uncaging, is the photolysis quantum yield (QY). Here, we describe a novel and general approach to greatly increase the photolysis QY of heterolytic PPGs through stabilization of an intermediate chromophore cation. When applied to coumarin PPGs, our strategy resulted in systems possessing an up to 35-fold increase in QY and a convenient fluorescent readout during their uncaging, all while requiring the same number of synthetic steps for their preparation as the usual coumarin systems. We demonstrate that the same QY-engineering strategy applies to different photolysis payloads and even different classes of PPGs. Furthermore, analysis of the DFT-calculated energy barriers in the first singlet excited state have revealed valuable insights into the important factors that determine photolysis efficiency. The strategy reported herein will enable the development of efficient PPGs tailored for many applications.

Content

Thumbnail image of PPG Engineering QY Manuscript.pdf

Supplementary material

Thumbnail image of PPG Engineering QY ChemRxiv SI Final.pdf
Supporting Information
Synthetic methods, photochemical evaluation methods, and computational chemistry data.