Pseudopolymorphs of chelidamic acid and its dimethyl ester

Area of Science:

• Crystal Engineering and Supramolecular Chemistry
• Organic Chemistry
• Physical Chemistry

Background:

• Chelidamic acid (4-hydroxypyridine-2,6-dicarboxylic acid) exists in various tautomeric and zwitterionic forms.
• Understanding these forms is crucial for predicting molecular interactions and crystal packing.
• Previous studies have relied on pKa values to explain observed protonation states.

Purpose of the Study:

• To investigate the diverse tautomeric and zwitterionic forms of chelidamic acid and its dimethyl ester in various crystalline environments.
• To analyze the factors influencing the protonation state of the hydroxy and carboxylic acid groups.
• To compare the conformational stabilities of the ester derivatives using computational methods.

Main Methods:

• X-ray crystallography was employed to determine the crystal structures of chelidamic acid solvates and its dimethyl ester.
• Analysis of hydrogen bonding networks and molecular conformations within the crystal lattices.
• Database studies and ab initio energy calculations were performed to assess the relative stabilities of different conformations.

Main Results:

• Observed unexpected deprotonation of the hydroxy group in dimethylammonium chelidamate and chelidamic acid dimethyl sulfoxide solvate.
• The dimethyl ester exists as a monohydrate and a solvent-free form, exhibiting different carbonyl conformations.
• Water molecules in the monohydrate stabilize a specific conformation via hydrogen bonding, unlike the solvent-free structure.

Conclusions:

• The crystal structures reveal tautomeric and zwitterionic forms of chelidamic acid that are not fully explained by simple pKa considerations.
• Solvent molecules and crystal packing significantly influence the observed protonation states and molecular conformations.
• Computational analysis provides insights into the energetic preferences of different conformations for the chelidamic acid dimethyl ester.