syn and anti polymorphs of 2,6-dimethoxy benzoic acid and its molecular and ionic cocrystals: Structural analysis and energetic perspective

Abstract The conformational polymorphism in 2,6-dimethoxy benzoic acid in which the acidic hydrogen atom can be either in an anti or a syn conformation with respect to the carbonyl oxygen atom has been studied. The compound crystallizes in two conformational polymorphic forms, anti and syn. The COOH group lies out of the phenyl ring plane due to steric repulsion with the ortho-methoxy substituents. The acidic O–H bond in the COOH carboxyl group in anti appears to be more polar/ionic compared to the syn form. Both polymorphs were characterized by single-crystal X-ray diffraction and for the anti form a neutron diffraction measurement was carried out. In addition, a new molecular co-crystal (MCC) and a new ionic cocrystal (ICC) form were also obtained and characterized by single crystal X-ray diffraction in which the protonated 2,6-dimethoxy benzoic acid units adopt syn configuration. The crystal packing, hydrogen bonding and intermolecular interactions are discussed in terms of Hirshfeld surface analysis and derived properties such as the contact enrichment ratio and energy frameworks. Cohesive energies based on fully periodic DFT calculations as well as based on the sum of dimeric interaction energies were estimated for both syn and anti forms. They reveal the higher stability of the crystal structure in the anti form while the syn form is more stable in the isolated state. Room temperature Raman spectra were collected on the single crystals of the anti and ionic cocrystal forms and compared with both isolated-molecule and periodic calculations.