Abstract
Despite the frequent use of alcohols as solvents in GBB (Groebke-Blackburn-Bienaymé) protocols, the mechanistic reasons for their preference remain poorly understood. In this work, we combined experimental and theoretical investigations to elucidate the roles of solvents and reagents in the GBB reaction, revealing their noninnocent behavior. Kinetic experiments, high-resolution ESI-(+)-MS-(/MS), and DFT calculations demonstrated that methanol not only acts as a solvent but also as a cocatalyst, significantly influencing the reaction mechanism and accelerating key steps. We proposed both uncatalyzed and PTSA-catalyzed pathways, including alternative mechanisms involving solvent-participating intermediates. The reaction scope confirmed the method's robustness, and selected fluorescent products were successfully applied as bioimaging probes in live cells. These findings contribute to a deeper understanding of MCR mechanisms and highlight the critical impact of solvent and reagent effects on their efficiency.