Effect of Homologation on the Polymorphism of Anthranilic Acids

Abstract

A series of homologues (1–4) of fenamic acid have been synthesized by varying the length of the linker between the two aromatic rings, and their polymorphism has been investigated. Under the same crystallization conditions, each of the newly synthesized compounds leads to two forms, except for compound 1, which indicates that additional flexibility due to homologation does not necessarily lead to more polymorphs. The molecules in each polymorphic system show different conformations due to the rotation about specific sigma bonds. Phase transitions are observed between the polymorphs of each system. Conformational analysis and Hirshfeld surface analysis were applied to investigate the effect of conformational flexibility on the polymorphism of these compounds.

anti/gauche Conformations Lead to Polymorphism in Homologous Phenylalkylamino-Nicotinic Acids

“…This could be a norm in polymorphic systems with long alkyl chains. But conformational flexibility is not the only driving force of polymorphism, and the number of polymorphs of a given compound is not even remotely proportional to the rotatable bonds . Phase transitions were observed between the polymorphs of each system.…”

“…The polymorphism was indeed caused by the rotation about specific sigma bonds. For example, two polymorphs were discovered for 2-PTA-BA, and although the two forms have the same acid–acid homodimer synthon in the crystal structures, the C2–C1 sigma bond in each form has a different conformation: anti in form I vs gauche in form II (Figure ). No higher probability of polymorphism was found for compounds with longer chains, despite conformational flexibility being a function of chain length.…”