Role of halogen-involved intermolecular interactions and existence of isostructurality in the crystal packing of —CF₃ and halogen (Cl or Br or I) substituted benzamides

Abstract

A total of 23 benzamides are obtained through a simple reaction between chloro-/bromo-/iodoaniline and trifluoromethylbenzoyl chloride and characterized using single-crystal X-ray diffraction. Crystal structures of three series of benzamides based on N-chlorophenyl-trifluoromethyl-benzamide (nine compounds), N-bromophenyl-trifluoromethyl-benzamide (six compounds), and N-iodophenyl-trifluoromethyl-benzamide (eight compounds) are prepared to analyse the halogen-mediated noncovalent interactions. The influences of Cl/Br/I and trifluoromethyl substituents on the respective interactions are examined in the presence of a strong N-HÁ Á ÁO hydrogen bond. This exercise has resulted in the documentation of frequently occurring supramolecular synthons involving halogen atoms in the crystal packing of benzamide molecules in the solid state. In the present study, a detailed quantitative evaluation has been performed on the nature, energetics, electrostatic contributions, and topological properties of short and directional intermolecular interactions derived from the electron density on halogenated benzamides in the solid state. Besides these, the occurrence of three-, two-and one-dimensional isostructurality in halogen (Cl or Br or I) substituted benzamide analogues is also investigated. A 'region of co-existence' involving halogen-based intermolecular interactions in the vicinity of the sum of the van der Waals radii has been identified. Thus, the nature of the halogen (effective size), type of interaction and the packing characteristics via presence of additional interactions establish the subtle, yet important, role of cooperativity in intermolecular interactions in crystal packing.

New Theoretical Insight into Fluorination and Fluorine–Fluorine Interactions as a Driving Force in Crystal Structures

“…Bader’s QTAIM theory has been recognized as a very successful theory for analyzing the physical nature of intermolecular interactions with organic fluorine. − An important feature of QTAIM is that it can be applied on experimentally obtained electron densities (through the high resolution X-ray data) − and on theoretically calculated electron densities. − QTAIM characterization of intermolecular interactions is based on the examination of values of local properties at the bond critical points (BCPs). BCP is the point with the minimum of electron density (ρ) in the bond direction and the maximum in the directions perpendicular to the bond direction.…”

Investigation of crystal structures, energetics and isostructurality in halogen-substituted phosphoramidates

“…Decades of research in the field of crystal engineering have brought forward some significant achievements in desired features utilizing the various non-covalent intermolecular interactions through molecular assembly in the crystal structure (Bolla et al, 2015;Ranjan et al, 2020). These intermolecular interactions are classified primarily into hydrogen bonds, halogen bonds (XÁ Á ÁY, where X, Y = F, Cl, Br, I) (Desiraju et al, 2013) and other supporting interactions (Dey & Chopra, 2017;Mondal et al, 2018;Chakraborty & Desiraju, 2018). The quantitative and qualitative investigation of these interactions highlights the similarities and dissimilarities in the crystalline assembly (Dey et al, 2016;Shukla et al, 2018).…”

Insight into the Formation of Heteromolecular Hydrogen Bonds between Dasatinib and GRAS Molecules

“…Co-crystals, − salts, eutectic mixtures, and co-amorphous solids , of Biopharmaceutics Classification System (BCS) class II and class IV drugs with the Food and Drug Administration (FDA) approval generally recognized as safe (GRAS) substances have received attention as one of the promising methods to enhance the solubility, dissolution rate, and stability of solid active pharmaceutical ingredient (API). − The design approach for multicomponent crystal formation is often based on the concept of crystal engineering. − Noncovalent interactions , (namely, hydrogen-bonding, halogen-bonding, and van der Waals interactions) between an API molecule and a coformer facilitate the crystallization as a co-crystal or salt with a specific stoichiometric ratio. Multicomponent crystals of two components (API and coformer) can be achieved using mechanochemical grinding in a mortar and pestle or a ball mill. − Co-amorphous and eutectic mixtures are the byproducts of such co-crystallization events, which can also enhance the dissolution and bioavailability of an API in the aqueous medium …”

“…8−12 The design approach for multicomponent crystal formation is often based on the concept of crystal engineering. 13−15 Noncovalent interactions 16,17 (namely, hydrogen-bonding, halogen-bonding, and van der Waals interactions) between an API molecule and a coformer facilitate the crystallization as a co-crystal or salt with a specific stoichiometric ratio. Multicomponent crystals of two components (API and coformer) can be achieved using mechanochemical grinding in a mortar and pestle or a ball mill.…”