Halogen Bonding in Sulphonamide Co-Crystals: X···π Preferred over X···O/N?

Area of Science:

• Crystallography
• Supramolecular Chemistry
• Medicinal Chemistry

Background:

• Sulphonamides are a significant pharmaceutical class since the 1930s.
• Co-crystallisation offers potential for new pharmaceutical co-crystals.
• Halogen bonding (XB) is explored as a supramolecular interaction for sulphonamide co-crystallisation.

Purpose of the Study:

• To synthesise and structurally analyse new co-crystals of sulphonamides with halogen bonding donors.
• To investigate the role of halogen bonding in the crystal packing of sulphonamide co-crystals.
• To compare interaction patterns between model sulphonamides and Chlorpropamide (CPA).

Main Methods:

• Synthesis of seven new co-crystals.
• Structural analysis using X-ray crystallography.
• Statistical analysis of the Cambridge Structural Database (CSD).

Main Results:

• Co-crystals of N-methylbenzenesulphonamide (NMBSA), N-phenylmethanesulphonamide (NPMSA), N-phenylbenzenesulphonamide (BSA), and Chlorpropamide (CPA) were successfully synthesised.
• X···π interactions were found to dominate crystal packing, contrary to design expectations.
• Halogen bonding (X···O/N) was not the predominant interaction.
• Differences in interaction patterns were observed between model sulphonamides and CPA due to hydrogen bonding.

Conclusions:

• Rational design based on halogen bonding (XB) for sulphonamide co-crystals may be challenged by dominant X···π interactions.
• The crystal packing of sulphonamides is influenced by the interplay of hydrogen bonding and halogen bonding.
• Further research is needed to understand and control co-crystal formation for pharmaceutical applications.