Computational Library Enables Pattern Recognition of Noncovalent Interactions and Application as a Modern Linear Free Energy Relationship

A quantitative
and predictive understanding of how attractive
noncovalent
interactions (NCIs) influence functional outcomes is a long-standing
goal in mechanistic chemistry. In that context, better comprehension
of how substituent effects influence NCI strengths, and the origin
of those effects, is still needed. We sought to build a resource capable
of elucidating fundamental origins of substituent effects in NCIs
and diagnosing NCIs in chemical systems. To accomplish this, a library
of 893 NCI energies was calculated encompassing cation−π,
anion−π, CH−π, and π–π
interactions across 60 different arenes and heteroarenes. The interaction
energies (IEs) were calculated using symmetry-adapted perturbation
theory (SAPT), which identifies electrostatic, inductive, exchange-repulsive,
and dispersive contributions to total IE. This descriptor library
provides a comprehensive platform for evaluating substituent effect
trends beyond traditional molecular descriptors such as Hammett values,
frontier molecular orbital energies, and electrostatic potential,
thereby expanding the tools available to analyze modern chemical processes
that involve NCIs. To demonstrate the application of this library,
three case studies in asymmetric catalysis and supramolecular chemistry
are presented. These case studies informed the development of an automated
NCI analysis tool, which employs statistical analyses to diagnose
a particular NCI in a chemical system of interest.