Acetylation-Tagging-Assisted Cocrystallization of Stubborn Molecules with Trinuclear Complexes

Crystallographic analysis has become the most reliable method for elucidating the chemical structures and absolute configurations of natural products. In this study, we present an <i>in situ</i> acetylation-tagging approach to enable the cocrystallization of difficult-to-crystallize molecules bearing hydroxyl or amino groups with cyclic trinuclear complexes (<b>Ag</b>_<b>3</b><b>Pz</b>_<b>3</b>). Single crystals are readily obtained upon slow evaporation after adding acetylating reagents and then <b>Ag</b>_<b>3</b><b>Pz</b>_<b>3</b> into an NMR tube. This acetylation tagging procedure introduces electron-rich acetyl groups with conformational flexibility that serve as beacons for electron-deficient <b>Ag</b>_<b>3</b><b>Pz</b>_<b>3</b>, leading to effective π-acid···base supramolecular interactions. Using this NMR tube protocol, we have successfully determined the structures of over 40 difficult-to-crystallize molecules, including flexible long-chain alcohols, macrocyclic alcohols, and aliphatic amines. These molecules, if not acetylated, would not cocrystallize with <b>Ag</b>_<b>3</b><b>Pz</b>_<b>3</b>. Further applications demonstrate the effectiveness of this protocol in determining the chemical structures and absolute configurations of highly complex natural glycosides and pharmaceutical molecules, showcasing broad substrate compatibility and its potential for analyzing difficult-to-crystallize molecules containing hydroxyl or amino groups.