Dongyeon Ro (POSTECH)

Jongcheol Seo (POSTECH)

Dongyeon Ro (POSTECH)

Jongcheol Seo (POSTECH)

The identification and control of enantiomeric, regio-, and chemoselectivity are key indicators for evaluating the efficiency and scientific value of chemical reactions. These forms of selectivity are governed by a variety of physicochemical factors, including the structure of the reactants, the nature of catalysts and reagents, reaction conditions, and the balance between kinetic and thermodynamic control. In micro- and nano-droplets, where a high surface-to-volume ratio arises from the extensive air–solvent interface, the extent to which this unique interfacial environment influences chemical selectivity remains largely unexplored.

In this study, we investigated the regioselective outcome of the thermal Huisgen azide–alkyne cycloaddition between benzyl azide and phenyl acetylene, which generates 1,4- and 1,5-substituted triazole regioisomers. Using reverse-phase HPLC, we achieved clear chromatographic separation of the two isomers based on differences in dipole–stationary phase interactions. Ion mobility spectrometry (IM-MS) further resolved the isomers by their distinct collision cross sections (CCS), yielding statistically significant differences in arrival time distributions. Analysis of chromatographic peak areas provided semi-quantitative insights into the relative formation ratios of the regioisomers, while IM-MS enabled confident assignment of each peak to a specific structure.

To probe the impact of droplet-phase environments, we employed a home-built electrospray setup to generate charged micro- and nano-droplets in which the reaction proceeds spontaneously. Comparison with bulk-phase results revealed a marked shift in regioisomer distribution, indicating that the unique physicochemical conditions in droplets can influence both reaction kinetics and selectivity. These findings highlight the ability of microdroplet environments to modulate chemical reactivity, and further demonstrate the potential of HPLC–IM–MS as a rapid and precise analytical tool for evaluating selectivity in droplet-phase reactions.