Predicting when precipitation-driven synthesis is feasible: application to biocatalysis

Precipitation-driven synthesis offers the possibility of obtaining high reaction yields using very low volume reactors and is finding increasing applications in biocatalysis. Here, a model that allows straightforward prediction of when such a precipitation-driven reaction will be thermodynamically feasible is presented. This requires comparison of the equilibrium constant, K-eq,with the saturated mass action ratio, Z(sat), defined as the ratio of product solubilities to reactant solubilities. A hypothetical thermodynamic cycle that can be used to accurately predict Z(sat) in water is described. The cycle involves three main processes: fusion of a solid to a supercooled liquid, ideal mixing of the liquid with octanol, and partitioning from octanol to water. To obtain the saturated mass action ratio using this cycle, only the melting points of the reactants and products, and in certain cases the pK(a) of ionisable groups, are required as input parameters. The model was tested on a range of enzyme-catalysed peptide syntheses from the literature and found to predict accurately when precipitation-driver reaction was possible. The methodology employed is quite general and the model is therefore expected to be applicable to a wide range of other (bio)-catalysed reactions.