Dissecting the Conformational and Interaction Topological Landscape of N-ethynylphenylbenzamide by the Device of Polymorphic Diversity

Abstract

The modern day crystal engineering approach aims at the exploration of the structural landscape of a molecule to perceive the phenomenon of the crystallization event for that molecule. The present study focuses on thorough experimental and computational investigations of the crystal landscape in the conformationally flexible N-ethynylphenylbenzamide molecule. We have performed the chemical modification of the parent unsubstituted N-ethynylphenylbenzamide molecule on the benzoyl ring by different halogen substitutions (monofluoro/difluoro/trifluoromethyl/chloro/bromo) at ortho/meta/para positions and employed the device of the polymorphophore concept to access a large number of experimentally viable structures in the landscape. In a total of 11 substituents as variants in molecules, the parent molecule displays monomorphic behavior, and in the remaining 10 molecules, each exists in several polymorphic forms resulting in a total of 28 single-component crystal structures. Through the systematic analysis of their conformational preferences in the conformational landscape and classification of the prevalent supramolecular recognition patterns, the interaction topologies of all substituent modified polymorphic structures have been mapped by the quantification of interaction energies of supramolecular synthons followed by a crystal structure prediction study. The combination of all studies demonstrates the robustness of primary synthon topology (formed by N–H···O═C/ π···π stacking interaction) and local variation of structures by different secondary interaction preferences (weak C–H···O, C–H···π, C–H···F/Cl/Br, and π···π interactions) to construct a nearly similar global interaction topology of molecules in all crystal structures and represents a general interaction topological landscape.