Stretching the Bisalkyne Raman Spectral Palette Reveals a New Electrophilic Covalent Motif

Abstract

AbstractSmall heteroaryl‐diyne (Het‐DY) tags with distinct vibrational frequencies, and physiologically relevant cLog P were designed for multiplexed bioorthogonal Raman imaging. Pd−Cu catalyzed coupling, combined with the use of Lei ligand, was shown to improve overall yields of the desired heterocoupled Het‐DY tags, minimizing the production of homocoupled side‐products. Spectral data were in agreement with the trends predicted by DFT calculations and systematic introduction of electron‐ rich/poor rings stretched the frequency limit of aryl‐capped diynes (2209–2243 cm−1). The improved Log P of these Het‐DY tags was evident from their diffuse distribution in cellular uptake studies and functionalizing tags with organelle markers allowed the acquisition of location‐specific biological images. LC–MS‐ and NMR‐based assays showed that some heteroaryl‐capped internal alkynes are potential nucleophile traps with structure‐dependent reactivity. These biocompatible Het‐DY tags, equipped with covalent reactivity, open up new avenues for Raman bioorthogonal imaging.