The role of cleft flexibility in tetracationic oxacalixarenes-paraquat recognition revealed by experimental and ab initio molecular dynamics investigations

Molecular recognition in aqueous environments depends on a subtle interplay of non-covalent interactions, solvent effects, and entropic contributions. Herein, we report a combined 1H NMR and ab initio molecular dynamics (AIMD) study on paraquat (PQT²⁺) recognition by two isomeric tetraoxacalix[4]arenes bearing four ammonium groups. Despite their comparable charge and cavity architecture, only the more flexible all-meta-bridged 4,6,16,18-tetraammonium-2,8,14,20-tetraoxacalix[4]arene (1·H44+) isomer forms a stable complex with PQT²⁺ in water, whereas the more rigid, ortho-meta-ortho-meta-bridged 4,6,17,19-tetraammonium-2,8,15,21-tetraoxacalix[4]arene (3·H44+) ejects the dication from its cleft. Our ab initio simulations reveal that cavity adaptability and solvent-mediated effects dictate the binding behavior, with correlation analyses highlighting stronger angular-distance anticorrelations in the 3·H44+/PQT²⁺system, revealing that host-guest complexation is largely entropy driven.