Eugenia Eugenieva-Ilieva

• The research presented in this PhD thesis is a contribution to the field of anion recognition in competitive aqueous solvent mixtures. Neutral anion receptors having a cage-type architecture have been developed on the basis of triply-linked bis(cyclopeptides) and their binding properties toward various inorganic anions have been studied. The synthetic approaches chosen to assemble the targeted container molecules rely on dynamic chemistry under the template effects of anions such as sulfate and halides. As reversible reactions metal-ligand exchange and thiol-disulfide exchange were used. Disulfide exchange has previously provided singly- and doubly-linked bis(cyclopeptide) receptors whose anion affinities in 2:1 acetonitrile/water mixtures approached the nanomolar range. Metal-ligand interactions have so far not been used to assemble bis(cyclopeptides) in our group. The cyclopeptide building blocks required for both approaches, namely cyclic hexapeptides containing alternating 6-aminopicolinic acid and either (2S,4S)-4-cyanoproline or (2S,4S)-4-thioproline subunits could be synthesized successfully. Self-assembly of the bis(cyclopeptide) held together by coordinative interactions has been attempted by treating the cyclopeptide trinitrile with square-planar palladium (II) complexes. The reaction was followed with different NMR spectroscopic techniques. Unfortunately, none of the experiments provides conclusive evidence that the targeted triply-linked cage was indeed formed. Bis(cyclopeptides) containing three dithiol derived linkers between the cyclopeptide rings could be synthesizes successfully. Two complexes were isolated, albeit in small amounts, one containing linkers derived from 1,2-ethanedithiol and the other one from 1,3-benzenedithiol that contain a sulfate anion incorporated in the cavity between the cyclopeptide rings. Formation of triply-linked bis(cyclopeptides) containing different types of linkers could be achieved by performing the synthesis in the presence of different dithiols. Unfortunately, the two C3 symmetrical bis(cyclopeptides) containing a single linker type could not be isolated in analytically pure form so that only qualitative binding studies could be performed. Investigations in this context indicate extraordinary sulfate affinity for these bis(cyclopeptides). In particular, affinity of the receptor containing the 1,2-ethanedithiol linkers for sulfate anions is so high that is even able to dissolve barium sulfate under appropriate conditions and presumably exceeds the sulfate affinity of the doubly-linked bis(cyclopeptides). The sulfate anion present in the cavity of this bis(cyclopeptide) can be replaced by a large number of other anions, i.e. by selenate, perrhenate, nitrate, tetrafluoroborate, hexafluorophosphate and halides. None of these complexes proved to be as stable as the corresponding sulfate complex. In addition, 1H-NMR spectroscopic investigations provided information about the solution structure of the bis(cyclopeptide) anion complexes. Sulfate release from the cavity of the receptor is a slow process while exchange of other anions is significantly faster. Another interesting feature that has been observed for sulfate and selenate complexes of the 1,2-ethanedithiol-containing bis(cyclopeptide) is the very slow H/D rate with which protons on amide groups located inside the cavity of the cage are replaced by deuterium atoms in protic deuterated solvents. This effect in combination with the observation that the different deuterated bis(cyclopeptide) species exhibit individual amide NH signals in the 1H-NMR spectrum are indicative for well defined complex geometries with strong hydrogen-bonding interactions between the anion and the amide NH groups of the receptor. Following the H/D exchange rate in the presence of various salts indicated that anion exchange proceeds via the dissociated complex and not by direct replacement of one anion by another one.