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Fluorinated bambusurils as anion receptors and transmembrane transporters

par Chvojka, Matúš
Président du jury Marek, Radek
Promoteur Valkenier, Hennie ;Šindelář, Vladimír
Publication Non publié, 2025-05-15

Thèse de doctorat

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Résumé :

Bambusurils (BUs) are macrocycles that excel in their ability to bind inorganic anions. Previous studies have shown that attaching fluorinated substituents to the structure of BUs significantly enhances the anion-binding capabilities of these macrocycles. Moreover, one of the macrocycles developed so far is the most potent Cl⁻/HCO₃⁻ transporter known. In general, anion receptors with highly organized structures and electron-accepting groups at their binding sites tend to exhibit strong anion affinity. These groups often contain fluorine atoms and are commonly used in mobile synthetic anion transporters (anionophores), where they enhance both lipophilicity and anion-binding strength. Only a few fluorinated substituents used for the preparation of fluorinated anion receptors and transporters have been described in the literature. Moreover, there is only limited amount of macrocycles that incorporate multiple fluorinated substituents within a single molecule.Therefore, this thesis focuses on the preparation of a library of fluorinated BU derivatives and to investigate how different substituents influence the ability of these macrocycles to bind anions and transport them across lipid bilayers.In this thesis, new BU derivatives bearing benzyl substituents with fluoroalkylthio groups and their oxidized forms were synthesized. These structural motifs have not been previously reported, and their synthesis was designed and successfully carried out as part of this research. The anion-binding abilities of the new BUs were studied in acetonitrile using 1H and 19F NMR spectroscopy. The determination of the association constant (Kₐ) for the individual BU–halide complexes was complicated by their strong binding affinities. Therefore, competitive titration methods were employed to determine these Kₐ values. The results revealed that increasing the electron-withdrawing strength of the substituents leads to a decrease in the electron density within the BU cavity, and consequently, to stronger anion binding. This is attributed to the unique structure of the macrocycle, which allows for electron density redistribution, even though the fluorinated groups are spatially distant from the binding sites. Using this strategy, a BU was developed that forms the most stable 1:1 complex with iodide (I⁻) in solution reported to date.The ability of the synthesized BUs to transport anions across lipid membranes was also investigated.The experiments focused particularly on Cl⁻/HCO₃⁻ exchange. It was found that an excessive increase in lipophilicity, caused by attaching longer perfluoroalkyl chains to the BUs, negatively affects anion transport. In some cases, cholesterol present in the membrane significantly influenced transport, suggesting that more complex membrane compositions can strongly impact the performance of these anionophores. Experiments with monofunctionalized BUs showed that different groups attached to the BU (e.g., cholic acid or crown ether) do not substantially affect their anion transport ability. However, introducing six cholate-derived units at the portals of the BU resulted in the formation of a unique unimolecular channel.