Statistical Analysis of $\sigma$-Holes: A Novel Complementary View on Halogen Bonding

TL;DR

This paper analyzes electrostatic potential maps of over 2,500 compounds to better understand $\sigma$-holes, enhancing the intuition about halogen bonding in drug-like molecules through a simplified and trend-based approach.

Contribution

It introduces a simplified view of $\sigma$-holes and provides general electrostatic trends in organic drug-like molecules, aligning with crystallographic data.

Findings

$\sigma$-holes are consistent with crystallographic data

Electrostatic potential maps reveal general trends in halogen bonding

Simplified models improve chemists' intuition on halogenated compounds

Abstract

To contribute to the understanding of noncovalent binding of halogenated molecules with a biological activity, electrostatic potential (ESP) maps of more than 2,500 compounds were thoroughly analysed. A peculiar region of positive ESP, called $\sigma$-hole, is a concept of central importance for halogen bonding. We aim at simplifying the view on $\sigma$-holes and provide general trends in organic drug-like molecules. The results are in fair agreement with crystallographic surveys of small molecules as well as of biomolecular complexes and attempt to improve the intuition of chemists when dealing with halogenated compounds.