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

Area of Science:

• Crystallography
• Supramolecular Chemistry
• Organic Chemistry

Background:

• Crystallographic analysis is crucial for determining chemical structures and absolute configurations.
• Cocrystallization of difficult-to-crystallize molecules, especially those with hydroxyl or amino groups, remains a significant challenge in structural elucidation.

Purpose of the Study:

• To develop a novel in situ acetylation-tagging approach for enabling the cocrystallization of challenging molecules.
• To facilitate the structural determination of natural products and pharmaceuticals that are otherwise difficult to crystallize.

Main Methods:

• An in situ acetylation-tagging protocol was employed using acetylating reagents and cyclic trinuclear complexes (Ag3Pz3).
• The method involves slow evaporation in an NMR tube after adding reagents to promote single crystal formation.
• Supramolecular interactions between electron-rich acetyl groups and electron-deficient Ag3Pz3 complexes drive cocrystallization.

Main Results:

• Successfully cocrystallized and determined the structures of over 40 difficult-to-crystallize molecules, including alcohols and amines.
• Demonstrated the protocol's effectiveness for complex natural glycosides and pharmaceutical molecules.
• Confirmed that acetylation is essential for cocrystallization with Ag3Pz3 for these specific molecules.

Conclusions:

• The in situ acetylation-tagging approach provides a reliable method for cocrystallizing and analyzing molecules with hydroxyl or amino groups.
• This protocol broadens the scope of crystallographic analysis for complex natural products and pharmaceuticals.
• The method offers a powerful tool for structural elucidation of challenging compounds.