Substituent Electronegativity and Isostructurality in the Polymorphism of Clonixin Analogues

Meng Liu, Guowen Shen, Zhong Yuan, Sean Parkin, Faquan Yu, Mingtao Zhang, Sihui Long, Tonglei Li

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8 Scopus citations


To gain understanding of how the variation in local weak interactions influences intermolecular interactions and subsequent crystal packing, four analogues of 2-(3-chloro-2-methyl-phenylamino)-nicotinic acid [clonixin] were synthesized by replacing the chlorine with fluorine (1), bromine (2), iodine (3), and hydrogen (4). Compounds 1, 2, and 3 were found to be polymorphic as shown by the discovery of two forms for each (1-I, 1-II; 2-I, 2-II; and 3-I, 3-II, respectively), while compound 4 has only a single identified form. Similar to clonixin, the analogue molecules in their crystals are associated either by the acid-acid dimer homosynthon or the acid-pyridine heterosynthon, depending on the dihedral angle between the two aromatic rings. Moreover, forms 2-I, 2-II, 3-I, and 3-II are isostructural to clonixin forms I and IV, compound 4 is isostructural to compound 1 form I, and 2-II is structurally similar to clonixin form II. The phase behaviors of these polymorphic systems were studied by differential scanning calorimetry, and it was found that 2-II converted into 2-I when heated, 3-II transformed into 3-I upon heating, and 1-II underwent transition into 1-I. Quantum mechanical calculations including conformational energy, hydrogen-bonding strength, lattice energy, and molecular contact were performed to provide further insight into the polymorphism. Given that all halogen derivatives are polymorphic, while the hydrogen analogue (4) is not, our study highlights the importance of intermolecular interactions in determining crystal packing.

Original languageEnglish
Pages (from-to)7006-7014
Number of pages9
JournalCrystal Growth and Design
Issue number11
StatePublished - Nov 7 2018

Bibliographical note

Funding Information:
S.L. thanks Natural Science Foundation of Hubei Province for financial support (2014CFB787). T.L. is grateful to NSF for supporting the work (DMR1006364).

Publisher Copyright:
© 2018 American Chemical Society.

ASJC Scopus subject areas

  • Chemistry (all)
  • Materials Science (all)
  • Condensed Matter Physics


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