A Cyclopeptide‐Derived Molecular Cage for Sulfate Ions That Closes with a Click

The 2:1 sandwich‐type complexes formed between a cyclopeptide with alternating L ‐proline and 6‐aminopicolinic acid subunits and inorganic anions can be stabilized by covalently linking a tris‐alkyne and a tris‐azide derivative of this peptide through copper‐catalyzed azide–alkyne cycloaddition. The resulting triply linked bis‐cyclopeptide can interact with anions such as sulfate ions in aqueous solution by including them into the cavity between the two cyclopeptide rings, where they can form hydrogen bonds to amide NH groups, distributed along the inner surface. The binding kinetics of this system differ significantly from those of a bis‐cyclopeptide that contains only one linker because the rate of guest exchange is considerably slower. Thermodynamically, the stability of the sulfate complex of the triply linked bis‐cyclopeptide approaches a log K_a value of 6 in H₂O/CH₃OH 1:1 (v/v) which is, however, only approximately one order of magnitude larger than affinity of the more flexible monolinked analogue. Titration calorimetry revealed that this behavior is mainly due to the change in the binding enthalpy from exothermic to endothermic upon increasing the number of linkers. Results from NMR spectroscopy and X‐ray crystallography indicate that the mono‐ and triply linked bis‐cyclopeptides adopt similar conformations in their complexes with sulfate ions, but the complex formation is enthalpically unfavorable for the cage. The substantial entropic contribution to sulfate complexation of this receptor more than compensates for this disadvantage, so that the overall sulfate affinity of both bis‐cyclopeptides ends up in the same range. These investigations provide important insight into the structure–property relationships of such receptors, thus leading the way to further structural improvement.