Synthesis, Conformational Polymorphism, and Construction of a G − T Diagram of 2-[(2-Nitrophenyl)amino]-3-thiophenecarbonitrile

• Published in: Crystal growth & design Vol. 6; no. 11; pp. 2469 - 2474
• Main Authors: Li, Hui, Stowell, Joseph G, Borchardt, Thomas B, Byrn, Stephen R
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 01.11.2006; Amer Chemical Soc
• Subjects: Chemistry; Chemistry, Multidisciplinary; Condensed matter: structure, mechanical and thermal properties; Cross-disciplinary physics: materials science; rheology; Crystallography; Exact sciences and technology; Materials Science; Materials Science, Multidisciplinary; Methods of crystal growth; physics of crystal growth; Organic compounds; Physical Sciences; Physics; Science & Technology; Structure of solids and liquids; crystallography; Structure of specific crystalline solids; Technology; SYSTEM; SULFATHIAZOLE; DISAPPEARING POLYMORPHS; PHARMACEUTICAL APPLICATIONS; SOLIDS; Crystal growth; Differential scanning calorimetry; Temperature dependence; Transition temperature; Purification; Stability; Ethanol; Crystallization; Solubility; XRD; Melting points; Free energy; Solid state; Monocrystals; Lattice energy; Thermal analysis; Conformation; Polymorphism; Crystal structure
• DOI: 10.1021/cg050608p
• ISSN: 1528-7483

5-Nor-Me was prepared by a two-step synthesis. A disappearing polymorph, the yellow form (Y), was observed during synthesis, but pure Y could not be obtained with further purification by crystallization. The other two forms, red (R) and orange (O), were prepared by crystallization from tetrohydrofuran (THF) and absolute ethanol, respectively. Single-crystal structure data show that the 5-Nor-Me molecules in R and O have significantly different conformations; the thiophene ring and phenyl ring in 5-Nor-Me R are more planar than those in 5-Nor-Me O. The physical stabilities of 5-Nor-Me O and R were determined using X-ray powder diffraction (XRPD), thermal analysis, hot-stage microscopy, solubility determination, and calculation of lattice energy. DSC shows no difference for the R and O forms. The equilibrium melting point of R is shown to be 0.6 °C higher than O, and the lattice energy of R is lower than O. Slurry conversion studies indicate that R is more stable than O in the investigated temperature range (25−80 °C). Solubility data fit the van't Hoff equation for both forms; the transition temperature from O to R was determined to be above both melting points, indicating that O and R are monotropically related, with R being more stable in the solid state. The free-energy difference was small (∼200 J/mol) according to the normalized G − T diagram. Transformation from 5-Nor-Me O to R occurred only when R seeds (0.2%) were added, accompanied by grinding in Wig-L-Bug. Therefore, seeding could play a very important role in the crystallization process; the Y form could not be obtained once the more stable R or O seeds appeared in the lab.