Halogen bonding in drug-like molecules: a computational and systematic study of the substituent effect

Abstract

Halogen bonding (XB) is a noncovalent interaction that has been increasingly used in molecular recognition, and more recently, in protein–ligand binding. We have studied and quantified, using density functional theory (DFT) calculations, the substituent effect of fourteen chemical groups in the chloro-, bromo- and iodobenzene⋯N-methylacetamide (NMA) complexes, which serve as a model of a common arrangement of XB in biological systems. A total of 126 halobenzene⋯NMA complexes have been optimized and examined regarding their relative energy, molecular electrostatic potential, topological analysis of electron density and charge transfer. The extent of substituent effect was found to be up to 1.5 kcal mol⁻¹, where electron-withdrawing groups increase the XB strength while electron-donating substituents reduce it. Excellent statistical correlations (R² > 0.9) were obtained for the comparison between XB interaction energy and the computed electronic properties (electron density, molecular electrostatic potential, and NBO charges), suggesting that the substituent effect was mainly due to the electrostatic interaction, and resonance effects were negligible. Furthermore, a positive cooperativity effect, in the strengthening of the XB, was observed in NMA complexes with di-, tri- and tetrafluoro-iodobenzenes.