Synergy-Promoted Specific Alkyltriphenylphosphonium Binding to CB[8]

Abstract

Biological substrate specificity ensures that organisms interact accurately with biomolecular receptors, crucial for key functions such as signaling and immunity. Nevertheless, this phenomenon is still poorly understood, with host–guest chemistry offering a suitable platform for studying simplified models. Herein, we report an in-depth study of the host–guest chemistry of alkyltriphenylphosphonium cations with cucurbit[8]uril (CB[8]), initiated by the serendipitous discovery of salt forming a tightly bound pseudoheteroternary 1:1 complex with CB[8]. A first generation of model substrates was designed to explore an unusual binding mode characterized by the simultaneous introduction of two distinct guest fragments within the host cavity. Structural features of the complexes were elucidated using ESI-MS and NMR 1D/2D techniques; thermodynamic properties were assessed by isothermal titration calorimetry, and kinetic parameters were derived from selective inversion–recovery NMR. Experimental results aligned well with electronic structure calculations, revealing a reproducible binding motif with submicromolar affinities. This peculiar complexation mode involves a synergistic effect caused by steric crowding around the P⁺ atom, facilitating the insertion of two aromatic units into CB[8] while hindering association with CB[7]. Based on these findings, a second generation of minimalistic substrates was developed, preserving the synergistic interaction mode and exhibiting specific binding to CB[8].