Computational analysis of modular diazotransfer reactions for the development of predictive reactivity models and diazotransfer reagents

Abstract

The development of the sulfur(VI)–fluoride exchange (SuFEx) and modular diazotransfer (MoDAT) reactions represent important milestones in the evolution of click chemistry. However, their reactivity profiles, chemoselectivity origins and underlying mechanisms remain unclear. Here we report a computational study of the MoDAT and SuFEx pathways, focusing on the reaction between the diazotransfer reagent fluorosulfuryl azide and primary amines. Our calculations reveal that the MoDAT reaction possesses a small kinetic barrier and a strong driving force, making it kinetically and thermodynamically more favourable than the SuFEx reaction. Through mechanistic scrutiny and structure–activity relationship studies, we have formulated predictive models for the reactivity and selectivity of the MoDAT reaction. Leveraging these insights, an easy-to-prepare and easily handled diazotransfer reagent with excellent reactivity has been developed, which holds broad promise for applications in chemistry and biology. Computational analysis of competing sulfur(VI)–fluoride exchange and modular diazotransfer pathways in the reaction between primary amines and fluorosulfuryl azide reveals that diazotransfer is more kinetically and thermodynamically favoured. Predictive models are formulated by combining mechanistic analysis and structure–activity relationship studies, enabling the development of an easy-to-prepare and highly reactive diazotransfer reagent.