Interaction of 5‐fluorouracil with β‐cyclodextrin: A density functional theory study with dispersion correction

Detailed studies on the stability, interaction, and microstructure of host-guest complexes in the vacuum of 5-fluorouracil (5FU) with β-cyclodextrin (βCD) were performed using B3LYP with the inclusion of Grimme's dispersion correction GD3 term and 6-31+G(d,p) basis set. Among several studied 1:1 5FU-βCD complexes, the one placing the keto tautomer of 5FU vertically in the host cavity and forming N-H···O _CD and C=O···H-O _CD hydrogen bonds with hydroxyl groups of the smaller rim of βCD has the highest stability (E _int = −195 kJ/mol). Interestingly, there are no interactions with the inner hydrophobic part of the βCD host cavity. The strength of the intermolecular H-bonds to the smaller rim of βCD is comparable to those in 5FU-water and 5FU-methanol clusters, used as model systems characterizing the noncovalent interactions. Of several studied host-guest complexes, the inner ones are more stable than the outer systems. Our results reveal that taking dispersion interaction in DFT into account is essential for reliable modeling of the structure, interaction, and stability of 5FU-βCD complexes. This study is crucial for understanding the interaction of 5FU with βCD in the solid state and additionally suggests the presence of equilibrium between 5FU-βCD complex and solvated 5FU.