Illuminating a Solvent-Dependent Hierarchy for Aromatic CH/π Complexes with Dynamic Covalent Glyco-Balances.

CH/π interactions are prevalent among aromatic complexes and represent invaluable tools for stabilizing well-defined molecular architectures. Their energy contributions are exceptionally sensitive to various structural and environmental factors, resulting in a context-dependent nature that has led to conflicting findings in the scientific literature. Consequently, a universally accepted hierarchy for aromatic CH/π interactions has remained elusive. Herein, we present a comprehensive experimental investigation of aromatic CH/π complexes, employing a novel approach that involves isotopically labeled glyco-balances generated in situ. This innovative strategy not only allows us to uncover thermodynamic insights but also delves into the often less-accessible domain of kinetic information. Our analyses have yielded more than 180 new free energy values while considering key factors such as solvent properties, the interaction geometry, and the presence and nature of accompanying counterions. Remarkably, the obtained results challenge conventional wisdom regarding the stability order of common aromatic complexes. While it was believed that cationic CH/π interactions held the highest strength, followed by polarized CH/π, nonpolarized CH/π, and finally anionic CH/π interactions, our study reveals that this hierarchy can be subverted depending on the environment. Indeed, the performance of polarized CH/π interactions can match or even outcompete that of cationic CH/π interactions making them a more reliable stabilization strategy across the entire spectrum of solvent polarity. Overall, our results provide valuable guidelines for the selection of optimal interacting partners in every chemical environment, allowing the design of tailored aromatic complexes with applications in supramolecular chemistry, organocatalysis, and/or material sciences.

Binding-driven reactivity attenuation enables NMR identification of selective drug candidates for nucleic acid targets.

NMR methods, and in particular ligand-based approaches, are among the most robust and reliable alternatives for binding detection and consequently, they have become highly popular in the context of hit identification and drug discovery. However, when dealing with DNA/RNA targets, these techniques face limitations that have precluded widespread application in medicinal chemistry. In order to expand the arsenal of spectroscopic tools for binding detection and to overcome the existing difficulties, herein we explore the scope and limitations of a strategy that makes use of a binding indicator previously unexploited by NMR: the perturbation of the ligand reactivity caused by complex formation. The obtained results indicate that ligand reactivity can be utilised to reveal association processes and identify the best binders within mixtures of significant complexity, providing a conceptually different reactivity-based alternative within NMR screening methods.