A molecular dynamics strategy to investigate the effect of liquid additives in liquid-assisted mechanochemistry

We describe a computational modeling strategy to investigate the dynamics and mobility of molecules in systems that compositionally correspond to the liquid-assisted environments, which are of importance to increasingly popular mechanochemical and other solvent-limited systems in which the amount of a liquid phase is tens or hundreds of times smaller compared to conventional solution environments. This work investigates how the presence of minute quantities of intimately mixed-in small-molecule solvents can influence the rigidity and mobility of an initially crystalline molecular solid, offering a starting point towards the understanding and modelling of liquid-assisted reactivity of relevance in mechanochemistry, as well as to a wide range of aging transformations relevant to, for example, the environmental stability of molecular solids such as pharmaceuticals. In effect, this study allowed us to evaluate changes to the molecular and structural dynamics with increasing amounts of a liquid additive, providing a nanoscopic view of the liquid-assisted environment, based on the number and choice of the additive and their nature, contextualized in the macroscopic and experimentally relevant η parameter. This represents, to our knowledge, the first attempt at an in silico modelling study to understand the fundamental aspects of the liquid-assisted environments found in a wide range of mechanochemical and mechanically-activated reactions. The herein presented theoretical modelling approach should be seen as a step towards detailed, quantitative studies of how the liquid-assisted environments might compare to bulk-solution environments characteristic of traditional solvent-based chemistry.