Phenacetin[3]arenes: Mannich-type Macrocyclization, Unique Structure, Versatile Functionalization, and Strong Allosteric Binding

This work introduces a novel NAm-CH₂-CAr macrocyclization pathway, diverging from the conventional CAr-CH₂-CAr linkages prevalent in macrocyclic arenes. This approach involves a one-pot condensation of readily available Phenacetin and its homologs with formaldehyde, yielding phenacetin[3]arenes (Ph[3]) 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 the amide groups, establishing equilibrium between C3 and F conformers. Increasing concentrations of organic ammonium guests lead to a transition from a predominantly 1:1 to a 1:2 host–guest complexation. The estimated binding constants for the 1:1 complexes are in the order of 104-105 M-1, the overall binding constants for the 1:2 complexes are greater than 106 M-2. This stepwise complexation triggers a conformational shift from the C3 to the 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—amides and alkoxyl groups—facilitate diverse chemical modifications, including reduction, deprotection, and condensation, …