Phenacetin[3]Arenes: Mannich-Type Macrocyclization, Unique Structure, Versatile Functionalization, and Strong Allosteric Binding.

This work introduces a novel N-CH₂-C macrocyclization pathway, diverging from the conventional C-CH₂-C linkages prevalent in macrocyclic arenes. This approach involves a one-pot condensation of - Phenacetin and its homologs with formaldehyde, yielding phenacetin[3]arenes (Ph[3]s) in yields up to 25.9%. Ph[3] exhibits an unsymmetrical hourglass-shaped architecture, featuring an upper rim adorned with amide groups and a lower rim comprising an alkoxylbenzene cavity. This unique structure facilitates reversible equilibrium between conformers via benzene ring flipping, which simultaneously reverses the orientation of amide groups, establishing equilibrium between C and F conformers. Increasing concentrations of organic ammonium guests lead to a transition from a predominantly 1:1 to 1:2 host-guest complexation. The estimated binding constants for the 1:1 complexes are in the order of 10-10 M, the overall binding constants for the 1:2 complexes are greater than 10 M. This stepwise complexation triggers a conformational shift from the C to F conformer, demonstrating intriguing allosteric behavior. Furthermore, interactions with chiral guests selectively influence the equilibrium of planar chiral conformers, generating chiroptical responses suitable for chirality sensing applications. The distinct functional groups on the two rims facilitate diverse chemical modifications, including reduction, deprotection, and condensation, providing synthetic flexibility for post-chemical modifications.