Rationalizing and Adapting Water-Accelerated Reactions for Sustainable Flow Organic Processes.

Abstract

Water-accelerated reactions, wherein at least one organic reactant is not soluble in water, are an important class of organic reactions, with a potentially pivotal impact on sustainability of chemical manufacturing processes. However, mechanistic understanding of the factors controlling the acceleration effect has been limited, due to the complex and varied physical and chemical nature of these processes. In this study, a theoretical framework has been established to calculate the rate acceleration of known water-accelerated reactions, giving computational estimations of the change to ΔG‡ which correlate with experimental data. In-depth study of a Henry reaction between N-methylisatin and nitromethane using our framework led to rationalization of the reaction kinetics, its lack of dependence on mixing, kinetic isotope effect, and different salt effects with NaCl and Na2SO4. Based on these findings, a multiphase flow process which includes continuous phase separation and recycling of the aqueous phase was developed, and its superior green metrics (PMI-reaction = 4 and STY = 0.64 kg L-1 h-1) were demonstrated. These findings form the essential basis for further in silico discovery and development of water-accelerated reactions for sustainable manufacturing.