Counteranions at Peripheral Sites Tune Guest Affinity for a Protonated Hemicryptophane

[Image: see text] The affinity of small molecules for biomolecular cavities is tuned through a combination of primary and secondary interactions. It has been challenging to mimic these features in organic synthetic host molecules, however, where the cavities tend to be highly symmetric and nonpolar, and less amenable to chemical manipulation. Here, a host molecule composed of a TREN ligand and cyclotriveratrylene moiety was investigated. Size-matched polar guests were encapsulated within the cavity via triple protonation of the TREN moiety with various sulfonic acids. X-ray crystallography confirmed guest encapsulation and identified three methanesulfonates, p-toluenesulfonates, or 2-naphthalenesulfonates hydrogen-bonded with H(3)TREN at the periphery of the cavity. These structurally diverse counteranions were shown by (1)H NMR spectroscopy to differentially regulate guest access at the three portals, and to undergo competitive displacement in solution. This work reveals “counteranion tuning” to be a simple and powerful strategy for modulating host–guest affinity, as applied here in a TREN-hemicryptophane.