Unraveling the Crystal Structures of Picolinic Acid Derivatives: Synthesis, Packing, Interactions, and Conformational Flexibility

Picolinic acid and its derivatives are widely used as pendant arms in ligands for metal ion complexation, with possible biomedical applications, when exploited in the preparation of magnetic resonance imaging contrast agents and radioisotope labeling for α- and β-therapy. Its structural and electronic characteristics make picolinic acid versatile and able to form stable complexes with various metal ions. The present study reports the synthesis of four picolinic acid derivatives useful for both coordination and bioconjugation, featuring a benzyl-protected hydroxy group removable via palladium-catalyzed hydrogenolysis. Chromatography and magnetic resonance assessed the purity, identity, and structural features of the synthesized compounds, ensuring their suitability for the said applications. Single-crystal X-ray diffraction was exploited for structure solution of three of them, revealing that the introduction of specific substituents induces changes in both the molecular structure and the crystal packing, driven by a balance between π-stacking and weak nonbonding contacts. Small changes in the pyridine substituents can induce conformational changes in the opposite benzyl ring orientation, spanning from a planar to a perpendicular orientation. The structural analysis, including Hirshfeld surfaces and energetic frameworks calculations, clarified intermolecular interactions contributing to a better understanding of the solid state behavior of the title compounds.