Solid-State Acid−Base Interactions in Complexes of Heterocyclic Bases with Dicarboxylic Acids:  Crystallography, Hydrogen Bond Analysis, and 15N NMR Spectroscopy

• Published in: Journal of the American Chemical Society Vol. 128; no. 25; pp. 8199 - 8210
• Main Authors: Li, Z. Jane, Abramov, Yuriy, Bordner, Jon, Leonard, Jason, Medek, Ales, Trask, Andrew V
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 28.06.2006
• Subjects: Amines - chemistry; Chemical and knight shifts; Condensed matter: electronic structure, electrical, magnetic, and optical properties; Condensed matter: structure, mechanical and thermal properties; Crystal binding; cohesive energy; Crystalline state (including molecular motions in solids); Crystallography, X-Ray; Dicarboxylic Acids - chemistry; Drug Design; Exact sciences and technology; Heterocyclic Compounds - chemistry; Hydrogen Bonding; Hydrogen-Ion Concentration; Macromolecular Substances - chemistry; Magnetic Resonance Spectroscopy; Magnetic resonances and relaxations in condensed matter, mössbauer effect; Molecular Structure; Nitrogen Isotopes; Nuclear magnetic resonance and relaxation; Physics; Receptor, ErbB-2 - antagonists & inhibitors; Solubility; Structure of solids and liquids; crystallography; Nitrogen 15; Dicarboxylic acids; Proton transfer; Theoretical study; Molecular interaction; Crystal binding; Experimental study; Lattice parameters; Atomic orbital calculations; Solid state; Hydrogen bonds; Density functional method; Organic amide; Molecular complex; NMR spectroscopy; Organic compounds
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja0541332

A cancer candidate, compound 1, is a weak base with two heterocyclic basic nitrogens and five hydrogen-bonding functional groups, and is sparingly soluble in water rendering it unsuitable for pharmaceutical development. The crystalline acid−base pairs of 1, collectively termed solid acid−base complexes, provide significant increases in the solubility and bioavailability compared to the free base, 1. Three dicarboxylic acid−base complexes, sesquisuccinate 2, dimalonate 3, and dimaleate 4, show the most favorable physicochemical profiles and are studied in greater detail. The structural analyses of the three complexes using crystal structure and solid-state NMR reveal that the proton-transfer behavior in these organic acid−base complexes vary successively correlating with ΔpK a. As a result, 2 is a neutral complex, 3 is a mixed ionic and zwitterionic complex and 4 is an ionic salt. The addition of the acidic components leads to maximized hydrogen bond interactions forming extended three-dimensional networks. Although structurally similar, the packing arrangements of the three complexes are considerably different due to the presence of multiple functional groups and the flexible backbone of 1. The findings in this study provide insight into the structural characteristics of complexes involving heterocyclic bases and carboxylic acids, and demonstrate that X-ray crystallography and 15N solid-state NMR are truly complementary in elucidating hydrogen bonding interactions and the degree of proton transfer of these complexes.