Abstract

Inclusion complexes formed by cyclodextrins (CDs) and cucurbit[n]urils (CB[n]) have been shown to be efficient platforms to modulate the reactivity of substrates confined in their cavities. In this study, a conceptual density functional theory (cDFT)-based model has been developed to describe the electrophilic and nucleophilic activation and deactivation of Aristotelin in inclusion complexes with CDs and CB[n]. For this purpose, electronic structure and molecular docking calculations were employed, analyzing global and regional reactivity indices, such as the Fukui function and the Dual Descriptor. The results indicate that the interaction of the substrate with the host cavity induces significant changes in its reactivity. In complexes with cyclodextrins, the A-ring of Aristotelin undergoes electrophilic deactivation accompanied by nucleophilic activation. In contrast, in complexes with cucurbit[n]urils, the observed increase in overall reactivity cannot be attributed to the high polarizability of the cavity, which is inherently limited due to the absence of inward-facing bonds or lone electron pairs, as well as the strong polarization of the ureido ? system toward oxygen atoms. This effect seems to be more related to the structural rigidity of the host and the electronic influence of carbonyl portals, which could induce a redistribution of electron density in the guest. These effects can be attributed to both conformational changes and non-covalent interactions with the supramolecular environment. The developed model provides a sound theoretical framework for understanding the modulation of reactivity in confined spaces and can be extended to biological systems such as enzymes. © 2025 American Chemical Society.