Three-DimensionalDescriptions of π/π,CH/π, and Halogen/π Interactions Formed between PhenylSubstructures

Abstract π/π, CH/π, and halogen/π interactions are key intermolecular interactions in molecular design for drug discovery and materials science. Three-dimensional (3D) characterization of these interactions is essential for rational molecular design, as molecules typically form noncovalent interactions in multiple directions within complex systems. Accordingly, 3D descriptions of π/π, CH/π, and halogen/π interactions provide valuable insights for rational molecular design. In this study, we present experimentally and theoretically validated 3D descriptions of interaction-formable regions for π/π, CH/π, and halogen/π interactions around phenyl and halogenated phenyl substructures, based on quantum mechanical molecular interaction field (MIF(QM)) calculations and database analyses. O-shaped or C-shaped π/π interaction regions are observed above and below the aromatic rings of benzene and halobenzene molecules. Halogen substitution enhances the stability of π/π interactions by 1.0–2.5 kcal/mol. Spherical CH/π interaction regions are located beyond the π/π interaction regions, which are more spatially extended than those of CH/π interactions. In addition, halogen/π and CH/π interaction regions are distributed along the extension lines of C–X (X = Cl, Br, I) and C–H bonds, respectively. The proposed 3D descriptions of π/π, CH/π, and halogen/π interactions provide a framework for understanding and predicting molecular recognition in protein–ligand systems.