This work provides a detailed study of an example SNAr reaction as these transformations are widely used in the synthesis of pharmaceutical drugs. The specific reaction we are considering is that of 2,4-difluoroacetophenone and pyrrolidine which has not previously been reported in the literature. We focus on elucidating the effect of solvent on the reaction mechanism and kinetics with a subsequent solvent design study to optimise both the reaction rate constant and selectivity. The solvent effect on the mechanism of the competing ortho- and
para-substitution pathways is investigated using 1H NMR spectroscopy and density functional
theory calculations. The reaction rate constants for the two reaction pathways are then determined
by measuring reaction component concentrations in a set of diverse solvents using in situ 1H NMR spectroscopy followed by parameter estimation to extract the reaction rate constants.
A hybrid empirical computer-aided methodology to design optimal solvents for the ortho-substitution reaction, incorporating both selectivity and reaction rate constant, is then presented. A surrogate model is built in which the reaction kinetics are correlated with a selection of solvent properties via linear regression. The surrogate model is then employed in a computer-aided molecular design formulation using multi-objective optimisation to identify solvents with improved performance compared with the initial solvent set. Safety, environmental
impact and toxicity constraints are introduced which gives the possibility of designing solvents
that simultaneously optimise the performance of the reaction whilst keeping in line with industrial
guidelines. A set of Pareto-optimal solutions is obtained, highlighting the trade-off between reaction rate constant and selectivity.