Halogenated N-phenylpiperazine and 2-(piperazin-1-yl)pyrimidine as novel cucurbit[7]uril guests: experimental and computational insights into supramolecular binding

Abstract

This study presents a new class of halogenated N-phenylpiperazine and 2-(piperazin-1-yl)pyrimidine derivatives as guests for cucurbit[7]uril (CB[7]), expanding the space of CB[7]-binding ligands. Combining isothermal titration calorimetry (ITC), X-ray crystallography, and computation (attach–pull–release, APR; symmetry-adapted perturbation theory, SAPT), we quantify how halogen identity and position modulate host–guest binding. We find that halogenation provides two position-specific levers for tuning affinity. At the ortho position, both F and Cl enhance dispersion (Cl more strongly), while ortho-F additionally confers pre-organization (intramolecular C–H⋯F) that reduces the entropic penalty. Across the series, the lowest free energies of binding (ΔG) are observed for ligands with ortho-F, consistent with entropy reduction via pre-organization. By contrast, para-substituent effects become significant mainly for larger halogens (Br, I), which can engage the carbonyl-lined portal and enhance enthalpic stabilization. These findings provide a rational strategy for optimizing ligand properties via supramolecular recognition, offering new perspectives for host–guest chemistry.