Substituent Electronegativity and Isostructurality in the Polymorphism of Clonixin Analogues

Abstract

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.

A new solvate of clonixin and a comparison of the two clonixin solvates

“…Quench cooling was initially employed for the solvate screening, and slow evaporation was performed in order to confirm the result and obtain quality crystals suitable for structure determination by the single-crystal X-ray diffraction. 38 All crystals were harvested directly from their mother liquor.…”

Effect of Substituent Size and Isomerization on the Polymorphism of 2-(Naphthalenylamino)-benzoic Acids

“…Differential scanning calorimetry (DSC) experiments were performed on TA Instruments DSCQ20-1250 to study the phase behavior of the solid forms. The procedure is the same as the one used before …”

“…IR and Raman spectra were recorded using a PerkinElmer FT-IR spectrometer and a Thermo Raman confocal microscope, respectively. A literature procedure was applied …”

“…The polymorphism of FAs is mainly attributed to their conformational flexibility and sometimes the participation of other weak intermolecular interactions. , The isosteric compounds of FAs, i.e., phenylaminonicotinic acids (PNAs), are also prone to exist in multiple forms in the solid state, as suggested by the polymorphism of a series of compounds including clonixin (CLX), niflumic acid (NFA), , 2-phenylaminonicotinic acid (2-PNA), − 2-(methyl-phenyl-amino)-nicotinic acid (2-MPNA), and other compounds, , due to both conformational flexibility and synthon variation (Scheme ). Recently, CLX was found to form solvates with N , N -dimethylformamide and its analogues. Polymorphism as a phenomenon is widely observed in molecular compounds and is of particular significance in pharmaceuticals because different forms of the same active pharmaceutical ingredient (API) may have different properties, e.g., kinetic, thermodynamic, surface, mechanical, and packaging, which can affect clinical formulation and eventual bioavailability. Meanwhile, polymorphism is also important theoretically, as demonstrated by a series of crystal structure prediction (CSP) tests. …”

Isomorphous Series of PdII-Containing Halogen-Bond Donors Exhibiting Cl/Br/I Triple Halogen Isostructural Exchange

“…Current applications of these methods are primarily focused on design of novel solids with controllable structures and tunable physicochemical properties. − In construction of new compositions crystal engineering, in particular, deals with polymorphism and isostructuralitytwo phenomena that reflect connection between structure and molecular arrangement. The isostructurality is applied for the prediction of crystal structures, and it can be used for making similar arrangements based on the geometry of the known structures, insofar as different substituents may be changed in the parent molecule without substantial changes of the crystal lattice. − The isostructural halogen (X) exchange specifically might lead to tunable physicochemical properties depending on identity and strength of halogen bonding (XB), and thus, for instance, XB affects solubility, , melting point, thermal expansion, − color, , and also luminescence-, − sensing-, , biological-, or magnetic properties.…”