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Do Sulfonamides Interact with Aromatic Rings? |
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| Authors: | Jie Jian Dr Roel Hammink Prof Dr Christine J McKenzie Prof Dr F Matthias Bickelhaupt Prof Dr Jordi Poater Prof Dr Jasmin Mecinović |
| Institution: | 1. Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej, 55, 5230 Odense, Denmark
These authors contributed equally to this work.;2. Division of Immunotherapy, Oncode Institute, Radboud University Medical Center, Nijmegen, The Netherlands Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein 26, 6525 GA Nijmegen, The Netherlands These authors contributed equally to this work.;3. Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej, 55, 5230 Odense, Denmark;4. Institute for Molecules and Materials, Radboud University, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands;5. ICREA, Passeig Lluís Companys 23, 08010 Barcelona, Spain |
| Abstract: | Aromatic rings form energetically favorable interactions with many polar groups in chemical and biological systems. Recent molecular studies have shown that sulfonamides can chelate metal ions and form hydrogen bonds, however, it is presently not established whether the polar sulfonamide functionality also interacts with aromatic rings. Here, synthetic, spectroscopic, structural, and quantum chemical analyses on 2,6-diarylbenzenesulfonamides are reported, in which two flanking aromatic rings are positioned close to the central sulfonamide moiety. Fine-tuning the aromatic character by substituents on the flanking rings leads to linear trends in acidity and proton affinity of sulfonamides. This physical-organic chemistry study demonstrates that aromatic rings have a capacity to stabilize sulfonamides via through-space NH–π interactions. These results have implications in rational drug design targeting electron-rich aromatic rings in proteins. |
| Keywords: | aromatic compounds molecular recognition noncovalent interactions polar–pi interactions sulfonamides |