Conformational Effects on Physical-Organic Descriptors – the Case of Sterimol Steric Parameters

Mathematical relationships which relate chemical structure with selectivity have provided quantitative insights underlying catalyst design and informing mechanistic studies. Flexible compounds, however, can adopt several distinct geometries and so can be challenging to describe using a single structure-based descriptor. How best to quantify the structural characteristics of an ensemble of structure poses both practical and technical difficulties. In this work we introduce an automated computational workflow which can be used to obtain multidimensional Sterimol parameters for a conformational ensemble of a given substituent from a single command. The Boltzmann-weighted Sterimol parameters obtained from this approach are shown to be useful in multivariate models of enantioselectivity, while the range of values from conformers within 3 kcal/mol of the most stable structure provides a visual way to capture a possible source of uncertainty arising in the resulting models. Implementing our approach requires no programming expertise and can be executed from within a graphical user interface using open-source programs.