Nanophase Structuring in Simple Ternary Solvents Mediates Reaction Kinetics

Solvents play a critical role in chemical reactivity. Ternary solvent systems—such as combinations of water, a water-miscible polar organic solvent, and a water-immiscible oil—have been shown to organize into nanophase-structured domains. However, the influence of these nanophases on reaction kinetics remains largely unexplored. In this study, we investigate how nanophase structuring within ternary solvents impacts the kinetics of strain-promoted azide-alkyne click reactions. Ternary solvents were designed to either promote or suppress nanophase structuring, with dynamic light scattering being used to assess nanoscale domain formation. High-throughput UV-Vis kinetic analysis revealed that hydrophobic reactants exhibited significantly enhanced reaction rates within ternary solvents, beyond the hydrophobic effects induced within water-containing binary solvents. Rates were elevated for ternary compositions within a small, specific region of the ternary phase diagram expected to contain oil-in-water nanophases. This kinetic enhancement effect was removed when hydrophilic reactants were used or when nanophase stability was reduced. These findings suggest that the structure of ternary solvent nanophases can be harnessed to modulate reaction kinetics and have influence beyond that of the bulk solvent properties like the polarity or water-induced hydrophobic interactions between reagents. This insight has broad implications for solvent design in synthetic chemistry, biocatalysis, and prebiotic chemistry, offering insight into controlling chemical reactivity in complex, multicomponent solvent systems.