Structural systematics and conformational analyses of a 3 × 3 isomer grid of fluoro-N-(pyridyl)benzamides: physicochemical correlations, polymorphism and isomorphous relationships

Abstract

An isomer grid of nine fluoro-N-(pyridyl)benzamides (Fxx) (x = para-/meta-/ortho-) has been examined to correlate structural relationships between the experimental crystal structure and ab initio calculations, based on the effect of fluorine (Fx) and pyridine N-atom (x) substitution patterns on molecular conformation. Eight isomers form N-H⋅⋅⋅N hydrogen bonds, and only one (Fom) aggregates via intermolecular N-H⋅⋅⋅O=C interactions exclusively. The Fpm and Fom isomers both crystallize as two polymorphs with Fpm_O (N-H⋅⋅⋅O=C chains, P-syn) and Fpm_N (N-H⋅⋅⋅N chains, P-anti) both in P2(1)/n (Z' = 1) differing by their meta-N atom locations (P-syn, P-anti; N(pyridine) referenced to N-H), whereas the disordered Fom_O is mostly P-syn (Z' = 6) compared with Fom_F (P-anti) (Z' = 1). In the Fxo triad twisted dimers form cyclic R(2)(2)(8) rings via N-H⋅⋅⋅N interactions. Computational modelling and conformational preferences of the isomer grid demonstrate that the solid-state conformations generally conform with the most stable calculated conformations except for the Fxm triad, while calculations of the Fox triad predict the intramolecular N-H⋅⋅⋅F interaction established by spectroscopic and crystallographic data. Comparisons of Fxx with related isomer grids reveal a high degree of similarity in solid-state aggregation and physicochemical properties, while correlation of the melting point behaviour indicates the significance of the substituent position on melting point behaviour rather than the nature of the substituent.

Understanding of Noncovalent Interactions Involving Organic Fluorine

“…The free energy for C-H···F hydrogen bond in CCl 4 was computed to be 6 kJ/mol which was higher than other halogens and the value increases with the change in hybridization of C-atom connected to the fluorine atom (from sp 3 to sp 2 to sp). -5-22 Furthermore, the relevance of C-H···F-C interactions were observed in the formation of different motifs such as dimer, chain, chains of dimers, etc., in the presence of strong N-H···O=C hydrogen bond and other related weak interactions like C-H···O, C-H···π, π···π, halogen-halogen interactions in the crystal packing studies of halogenated benzanilides [88][89][90][91][92]. The significance of these studies was to acquire the systematic analysis of interactions involving organic fluorine when the molecular skeleton was fixed and the position of fluorine atoms were varied, thus an isomeric series was obtained.…”

“…The importance of such C-H···F interactions being weak and cooperative in nature has been realized in the crystal structure analysis of fluorinated N-(2-Chloropyridin-4-yl)-N′-phenylureas ( Fig. 2.11) [87], halogenated benzanilides (fluorinated [88] and hetero halogenated with at least one side of the phenyl ring contains fluorine [88][89][90]), trifluoromethyl (-CF 3 ) substituted benzanilides [91], fluoro-N-(pyridyl)benzamides [92], fluorine-substituted benzimidazoles [93]. In the crystal packing of a series of fluorinated N-(2-Chloropyridin-4-yl)-N′-phenylureas (Fig.…”

Short C–H⋯F interactions involving the 2,5-difluorobenzene group: understanding the role of fluorine in aggregation and complex C–F/C–H disorder in a 2 × 6 isomer grid

“…1820 Our interest in fluorine chemistry arising from isomer grids e.g. NxxF, 14 Fxx, 16 is to examine relationships between H/F atoms in systematic analyses and probe fluorine in unusual, short interactions and environments.…”

“…14, 16 We now extend the original series, 14,16 to twelve difluorobenzanilides and report on their chemistry and crystal structures (Scheme 1). Typically amide…amide C(4) chains serve as the primary hydrogen bonding interaction, usually with … stacking and C-H… interactions and in a few cases augmented by short, directional C-HF contacts.…”

“…An understanding of the relationships between F/H atom permutations in substituted difluorobenzenes is realised with the influence of fluorine substitution patterns on molecular aggregation rationalised in a series of twelve isomers. 16 Scheme 1 The (26) F 2 -xx and xx-F 2 isomer grids. …”