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

• NMR and AIMD reveal cleft flexibility drives oxacalix[4]arene–paraquat binding in water. • ⁠All-meta isomer adapts to bind; rigid ortho–meta rejects paraquat binding. • Complexation depends on solvent-mediated interactions and entropic contributions. Molecular recognition in aqueous environments depends on a subtle interplay of non-covalent interactions, solvent effects, and entropic contributions. Herein, we report a combined 1 H NMR and ab initio molecular dynamics (AIMD) study on paraquat ( PQT ²⁺) 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 ·H 4 4+ ) isomer forms a stable complex with PQT ²⁺ in water, whereas the more rigid, ortho-meta-ortho-meta -bridged 4,6,17,19-tetraammonium-2,8,15,21-tetraoxacalix[4]arene ( 3 ·H 4 4+ ) 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 ·H 4 4+ / PQT ²⁺system, revealing that host-guest complexation is largely entropy driven. A combined 1 H NMR and ab initio molecular dynamics (AIMD) study reveals that cavity adaptability and solvent-mediated effects determine the affinity between tetracationic oxacalix[4]arenes and the paraquat dication in aqueous medium.