Orthogonal dipolar interactions between amide carbonyl groups

Orthogonal dipolar interactions between amide C=O bond dipoles are commonly found in crystal structures of small molecules, proteins, and protein–ligand complexes. We herein present the experimental quantification of such interactions by employing a model system based on a molecular torsion balance. Application of a thermodynamic double-mutant cycle allows for the determination of the incremental energetic contributions attributed to the dipolar contact between 2 amide C=O groups. The stabilizing free interaction enthalpies in various apolar and polar solvents amount to −2.73 kJ mol−1 and lie in the same range as aromatic-aromatic C–H⋯π and π–π interactions. High-level intermolecular perturbation theory (IMPT) calculations on an orthogonal acetamide/N-acetylpyrrole complex in the gas phase at optimized contact distance predict a favorable interaction energy of −9.71 kJ mol−1. The attractive dipolar contacts reported herein provide a promising tool for small-molecule crystal design and the enhancement of ligand–protein interactions during lead optimization in medicinal chemistry.

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