Synthesis of 6-mono-6-deoxy-beta-cyclodextrins substituted with isomeric aminobenzoic acids. Structural characterization, conformational preferences, and self-inclusion as studied by NMR spectroscopy in aqueous solution and by X-ray crystallography in the solid state.

The synthesis, purification, and characterization of mono-6-modified-beta-cyclodextrins bearing N-attached o-, m-, and p-aminobenzoic acids (2, 3, and 4, respectively) are presented. The structures in aqueous solution were investigated using one- and two-dimensional NMR spectroscopy. Detailed assignment of the spectra together with intramolecular NOE correlations revealed the way each of the isomeric appendages is positioned relative to the macrocyclic cavity. No self-inclusion is observed. The o-isomer 2 turns inward over the top of the primary side and interacts with specific protons of the substituted glucopyranose unit A and those of a neighboring unit. The m-isomer 3 displays two conformations, where the substituent resides above the primary side in a tilted manner and interacts either with the previous or the next unit. We propose that the carboxyl groups in both 2 and 3 are localized through H-bonding with one or two, respectively, primary hydroxyl groups of the neighboring glucopyranose units. In a similar positioning of the aromatic ring of the p-isomer 4, the hydrophilic carboxyl end is fully exposed to the aqueous environment. The X-ray structure of 4 shows that the solution conformation has evolved such that in the crystalline state, the aromatic moiety is inserted through its carboxyl part inside another CD where it establishes intermolecular H-bonds with inward-turned primary OH groups. Besides this stabilization, 4 forms parallel and antiparallel supramolecular chains in the crystal that are additionally stabilized by direct H-bonds.