Revealing Pathway Complexity in Host–Guest Binding: Allosteric Regulation and Temporal Chiral Inversion During Complexation of Naphtho[2,2]urils

Studies on pathway complexity in supramolecular polymerization have uncovered intriguing kinetic behaviors, though these are not directly transferable to host-guest systems. Here, we report unprecedented chiral inversion kinetics in a host-guest complexation process, arising from the coupling of sequential binding and conformational interconversion. Naphtho[n,n]urils (NGU[n,n]), constructed by alternating glycoluril and naphthyl units, were synthesized via a one-pot three-component condensation, yielding hybrid architectures with well-defined cavities. In NGU[2,2], the two naphthyl units adopt either S_P or R_P planar chiral conformations, giving rise to interconvertible racemic and meso conformers. NGU[2,2] binds chiral amino acid derivatives stepwise through hydrogen bonding and cation-dipole interactions, forming 1:1 and 1:2 complexes. Complexation shifts the equilibrium between racemic and meso conformers, inducing a circular dichroism (CD) response. Notably, the transition from the 1:1 to the 1:2 complex triggers an inversion of conformational preference in NGU[2,2], representing a unique case of chiral allosteric regulation. Furthermore, temporal inversion of the CD signal was observed upon mixing NGU[2,2] with the guest, displaying a transient overshoot and sign reversal. This kinetic behavior originates from the interplay between binding dynamics and conformational interconversion, with the meso conformer playing a central role.