2024/12/16 by A. García‐Raso, Ángel Terrón, J.J. Fiol +7 · 1 voice
Chemistry · Pharmacology, Toxicology and Pharmaceutics · #Chemical Reaction Mechanisms #Fluorine in Organic Chemistry #Organic Chemistry Cycloaddition Reactions
paper · doi:10.1016/j.molstruc.2024.141123
openalex publication_date 2024/12/16 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/23
• Synthesis and X-ray characterization of six novel deferiprone analogues in neutral and zwitterionic forms. • The formation of the zwitterionic or neutral forms depends significantly on the crystallization solvent. • Theoretical analyses (QTAIM, NCIplot) were performed to study hydrogen bonding and π-stacking interactions. • The nitrate salt of one analogue exhibits unique anion–π interactions characterized via computational methods. This study reports the synthesis, X-ray characterization, and density functional theory (DFT) analysis of six deferiprone analogues: 4-(3‑hydroxy-2-methyl-4-oxopyridin-1(4H)-yl) acetic acid ( 1 ), 4-(3‑hydroxy-2-methyl-4-oxopyridin-1(4H)-yl) propanoic acid in its neutral ( 2a ) and zwitterionic ( 2b ) forms, 4-(3‑hydroxy-2-methyl-4-oxopyridin-1(4H)-yl) butanoic acid in its neutral ( 3a ), zwitterionic ( 3b ) and polymorphic ( 3c ) forms, and 4-(3‑hydroxy-2-methyl-4-oxopyridin-1(4H)-yl) hexanoic acid in its neutral ( 4a ) and zwitterionic ( 4b ) forms. All three pairs ( 2a and 2b, 3a and 3b, 4a and 4b ) are examples of prototropic tautomers. Notably, compounds 2a, 3a and 4a were previously synthesized but lacked X-ray characterization until this study. The solid-state behavior of these compounds, particularly the formation of neutral versus zwitterionic forms, is highly dependent on the solvent used for crystallization. Additionally, the nitrate salt of compound 2 ( 2c ) was obtained during an attempt to synthesize a Zn(II) complex. The solid-state structures of these compounds are primarily dominated by hydrogen bonding (H-bonding) interactions, which have been thoroughly analysed using theoretical calculations. For the nitrate salt, anion–π interactions were also observed and characterized using computational tools such as Quantum Theory of Atoms in Molecules (QTAIM) and Non-Covalent Interaction (NCI) plot analyses. The H-bonding interactions were evaluated using potential energy density values derived from the QTAIM analysis. This study provides new insights into the structural and electronic properties of deferiprone derivatives, highlighting their potential applications in various fields. This study presents the synthesis, X-ray characterization, and density functional theory (DFT) analysis of six novel deferiprone analogues. The research highlights the significant influence of solvents on the formation of neutral and zwitterionic forms.