An Adaptable Porous Metal–Organic Framework for Structural Visualization of Beyond Rule of 5 Molecules on the Microgram Scale

Abstract

Beyond rule of 5 (bRo5) pharmaceutical compounds represent major structural challenges due to their large size and complexity. Here, we show that a metal–organic framework, APF-40, enables encapsulation and structural visualization of bRo5 molecules. It comprises a new benzoate-substituted hexaazaphenalene ligand and Zn8 clusters forming a doubly interpenetrated framework. The dynamic movement of the two nets facilitates adaptive behavior, efficiently immobilizing molecules along with their solvation spheres. Structures of 12 guests, including eight bRo5 compounds with subtly differing substituent modifications─ methyl-to-ethyl, methoxy-to-hydroxy, and alkane-to-alkene─were precisely elucidated. Significantly, one compound, isolated from a commercially available sample, was identified as a novel ivermectin derivative. This work demonstrates μg-order structure determination of molecules larger than 500 Da, offering new possibilities for characterizing compounds previously intractable for established analytical techniques.