Multicomponent Solids of DL-2-Hydroxy-2-phenylacetic Acid and Pyridinecarboxamides

Abstract

We prepared cocrystals of DL-2-Hydroxy-2-phenylacetic acid (D, L-H2ma) with the pyridinecarboxamide isomers, picolinamide (pic) and isonicotinamide (inam). They were characterized by elemental analysis, single crystal and powder X-ray, IR spectroscopy and 1H and 13C NMR. The crystal and molecular structures of (pic)-(D-H2ma) (1), (nam)-(L-H2ma) (2) and (inam)-(L-H2ma) (3) were studied. The crystal packing is stabilized primarily by hydrogen bonding and in some cases through π-π stacking interactions. The analysis of crystal structures reveals the existence of the characteristic heterosynthons with the binding motif R22(8) (primary amide–carboxilic acid) between pyridinecarboxamide molecules and the acid. Other synthons involve hydrogen bonds such as O-H(carboxyl)···N(pyridine) and O-H(hydroxyl)···N(pyridine) depending on the isomer. The packing of 1 and 3 is formed by tetramers, for whose formation a crystallization mechanism based on two stages is proposed, involving an amide–acid (1) or amide–amide (3) molecular recognition in the first stage and the formation of others, and interdimeric hydrogen bonding interactions in the second. The thermal stability of the cocrystals was studied by differential scanning calorimetry and thermogravimetry. Further studies were conducted to evaluate other physicochemical properties of the cocrystals in comparison to the pure coformers. Density-functional theory (DFT) calculations (including NCIplot and QTAIM analyses) were performed to further characterize and rationalize the noncovalent interactions.

Keywords

• pyridinecarboxamides
• cocrystals
• mandelic acid
• X-ray structure
• DFT calculations