Direct hydrogen selenide (H2Se) release from activatable selenocarbamates

Abstract

Hydrogen selenide (H₂Se) is a possible bioregulator, potential gasotransmitter, and important precursor in biological organoselenium compound synthesis. Early tools for H₂Se research have benefitted from available mechanistic understanding of analogous small molecules developed for detecting or delivering H₂S. A now common approach for H₂S delivery is the use of small molecule thiocarbamates that can be engineered to release COS, which is quickly converted to H₂S by carbonic anhydrase. To expand our understanding of the chemical underpinnings that enable H₂Se delivery, we investigated whether selenocarbamates undergo similar chemistry to release carbonyl selenide (COSe). Using both light- and hydrolysis-activated systems, we demonstrate that unlike their lighter thiocarbamate congeners, selenocarbamates release H₂Se directly with concomitant isocyanate formation rather than by the intermediate release of COSe. This reaction mechanism for direct H₂Se release is further supported by computational investigations that identify a ΔΔG^‡ ∼ 25 kcal mol⁻¹ between the H₂Se and COSe release pathways in the absence of protic solvent. This work highlights fundamentally new approaches for H₂Se release from small molecules and advances the understanding of reactivity differences between reactive sulfur and selenium species.