Conformational Effects on Physical-Organic Descriptors: The Case of Sterimol Steric Parameters

Mathematical
relationships that relate chemical structure with
selectivity have provided quantitative insights underlying catalyst
design and informing mechanistic studies. However, flexible compounds
can adopt several distinct geometries and 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 that 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 for enantioselectivity. Our approach improves the model performance
in cases where particularly flexible substituents have been studied.
In all cases, this approach enables the impact of conformational effects
on model performance to be quickly diagnosed: in particular, these
effects may be more significant than statistical model error such
that selectivity prediction should be performed more cautiously. Implementing
our approach requires no programming expertise and can be executed
from within a graphical user interface using open-source programs.