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
betweenN-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–1h–1) were demonstrated. These findings form the
essential basis for further in silico discovery and development of
water-accelerated reactions for sustainable manufacturing.