The affinity of small molecules for biomolecular cavities is modulated by a combination of primary and secondary interactions. Mimicking these features in organic synthetic host molecules has proven challenging due to their highly symmetric and nonpolar cavities, which are less amenable to chemical manipulation. Inspired by the host-guest properties of calix[6]arenes, the initial objective was to enhance the binding affinity of a hemicryptophane host L1. By protonating the TREN moiety of L1 with various sulfonic acids, the cavity was polarized. Interestingly, the sulfonate counteranions form hydrogen bonds at the apertures of the cavity, thereby regulating small-molecule access and binding affinity in organic solution. TREN protonation provides a versatile method for installing counteranions with widely varying stereoelectronic properties. This work reveals ‘counteranion tuning’ to be a simple and powerful strategy for modulating host-guest affinity. Further investigation revealed that the triply protonated hemicryptophane [3H-L1]3+ is also suitable for studying anion binding in aqueous solution. Selective fluoride encapsulation was evidenced by 1H NMR and 19F NMR. XRD analysis also confirmed that a fluoride anion binds in the small cavity above the protonated TREN; the three phenylene linkers point inwards towards the fluoride and this geometry precludes binding of larger anions. Notably, the protonated capsule exhibited an exclusive ‘turn-on’ fluorescence signal upon fluoride addition. An ‘apparent’ association constant of 4.0 × 105 M–1 and a detection limit of 100 nM were extracted from fluorescence titration experiments in H2O. Additionally, the protonated capsule was supported on silica gel, which enabled adsorptive removal of stoichiometric fluoride from water. Finally, hemicryptophane L1 was complexed with Cu(I) to produce Cu(I)-hemicryptophane, which remained stable in air for weeks. Cyclic voltammetry indicated that oxidation is thermodynamically favorable, whereas X-ray structural analysis revealed that the capsule provides a kinetic barrier to Cu+ oxidation. Preliminary experiments indicate that [Cu+-L1]+ can encapsulate carbon monoxide selectively within the cavity. The corresponding [Cu2+-L1]2+ complex adopts more open structures while binding various small molecules.