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...pi and pi-pi 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.
Fischer
Felix R
FR
Laboratory of Organic Chemistry, Department of Chemistry and Applied Biosciences, ETH-Hönggerberg, HCI, CH-8093 Zurich, Switzerland.
Wood
Peter A
PA
Allen
Frank H
FH
Diederich
François
F
D000577:Amides / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D008956:Models, Chemical; D050050:Protein Carbonylation; D013816:Thermodynamics
D000577:Amides