Conformational Polymorphism in N‐(4′‐methoxyphenyl)‐ 3‐bromothiobenzamide

Abstract

Three conformational polymorphs of N-(4'-methoxyphenyl)-3-bromothiobenzamide, yellow alpha, orange beta, and yellow gamma, have been identified by single-crystal X-ray diffraction. The properties and structure of the polymorphs were examined with FT Raman, FTIR (ATR), and UV/Vis spectroscopy, as well as differential scanning calorimetry. Computational data on rotational barriers in the isolated gas-phase molecule indicate that the molecular conformation found in the alpha form is energetically preferred, but only by around 2 kJ mol(-1) over the gamma conformation. The planar molecular structure found in the beta form is destabilized by 10-14 kJ mol(-1), depending on the calculation method. However, experimental evidence suggests that the beta polymorph is the most stable crystalline phase at room temperature. This is attributed to the relative planarity of this structure, which allows more and stronger intermolecular interactions, that is, more energetically effective packing. Calculated electronic-absorption maxima were in agreement with experimental spectra.

Insight to the Thermodynamic Stability of Molecular Crystals through Crystallographic Studies of a Multipolymorph System

“…This coincides with the few π–π interactions and intermolecular distances too far apart for CH···π interactions observed in N2 . A similar observation has been made by Bashkirava et al for a case in which a polymorph with a lower degree of conformational planarity leads to a lower crystal density than the opposite case. The aforementioned factors probably contribute to N2 being one of the polymorphs with the lowest calculated crystal density alongside N1 .…”

“…The Gibbs free energy curve of N3 ( G N3 ) does not depress exponentially with temperature as quickly as the G N1/N4 curve of N1 / N4 , and this can be explained by the entropy ( S ) effect based on observations made on their crystal structures. A closely packed solid form is expected to have low molecular motion and lattice vibration due to stronger intermolecular forces and greater steric hindrance, which lead to a low entropy that is less affected by temperature . The opposite is true for loosely packed structure that has more space for movement and weaker intermolecular forces, which result in higher vibrational entropy .…”

“…However, insight into the characteristics that make one polymorph more stable than another has to come from examination of their respective crystal structures, which offer a wealth of information about intermolecular interactions, bonding preferences, lattice energy, and molecular conformations. In fact, there have been many publications that attempt to qualitatively assess the stability of a crystal form based on crystallographic information, such as the number of molecules per asymmetric unit ( Z ′), crystal density, packing fraction or efficiency, and types of intermolecular interactions . Similarly, this work applies a qualitative approach to gain an understanding of H‐bonding contributions to three‐dimensional molecular packing compared with van der Waals forces and/or stacking interactions, and how these differences are translated into thermodynamic stability of a polymorph.…”

Conformational Polymorphism

“…Drug molecules in the CSD with at least three different conformers in multiple polymorphs include chlorpropamide, − aripiprazole, axitinib, furosemide, N -(4′-methoxyphenyl)-3-bromothiobenzamide, diflorasone diacetate, acitretin, and tolbutamide. − The conformational polymorphism of the HIV drug ritonavir − has attracted particular attention because of the spontaneous appearance of the stable polymorph, which compromised the drug bioavailability, approximately 2 years after the drug had been launched. The polymorphic appearance resulted in the drug being removed from the market in 1998 for a year for reformulation to overcome the seriously lower bioavailability of the new, more stable form.…”

trans-β2,3-Amino Acid-Based Supramolecular Synthons for Probing the Interrelationships between Structure, Torsion-Directed Assembly, and Isomorphism

“…The study of conformational preferences in molecules, their tendency to exist in polymorphic crystalline states, and its effect on molecular properties is an expanding area of science that has importance in material science and pharmaceutics alike. − Conformational isomers can organize into different crystalline forms to give conformational polymorphs or coexist in the same lattice as isomorphs . , Understandably, apart from the energy state of the individual conformer, contributions from inter- and intramolecular interactions and overall molecular packing in the lattice dictate the preference for one crystalline form over the other . Despite a large number of reports and detailed investigations, our current ability to accurately predict the three-dimensional packing propensities of molecules is in its infancy. , An analysis of the literature suggested that studies on structure−polymorphism relationships represent one of the hottest areas in crystal engineering and can be extremely important in building predictive models to foresee polymorphism and lattice arrangements. − …”