Assembling an isomer grid: the isomorphous 4-, 3- and 2-fluoro-N′-(4-pyridyl)benzamides

Abstract

The three title isomers, 4‐, (I), 3‐, (II), and 2‐fluoro‐N′‐(4‐pyridyl)benzamide, (III), all C12H9FN2O, crystallize in the P21/c space group (No. 14) with similar unit‐cell parameters and are isomorphous and isostructural at the primary hydrogen‐bonding level. An intramolecular C—H...O=C interaction is present in all three isomers [C...O = 2.8681 (17)–2.884 (2) Å and C—H...O117–118°], with an additional N—H...F [N...F = 2.7544 (15) Å] interaction in (III). Intermolecular amide–pyridine N—H...N hydrogen bonds link molecules into one‐dimensional zigzag chains [graph set C(6)] along the [010] direction as the primary hydrogen bond [N...N = 3.022 (2), 3.049 (2) and 3.0213 (17) Å]. These are augmented in (I) by C—H...π(arene) and cyclic C—F...π(arene) contacts about inversion centres, in (II) by C—F...F—C interactions [C...F = 3.037 (2) Å] and weaker C—H...π(arene)/C—H...F contacts, and in (III) by C—H...π(arene) and C=O...O=C interactions, linking the alternating chains into two‐dimensional sheets. Typical amide N—H...O=C hydrogen bonds [as C(4) chains] are not present [N...O = 3.438 (2) Å in (I), 3.562 (2) Å in (II) and 3.7854 (16) Å in (III)]; the C=O group is effectively shielded and only participates in weaker interactions/contacts. This series is unusual as the three isomers are isomorphous (having similar unit‐cell parameters, packing and alignment), but they differ in their interactions and contacts at the secondary level.

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

“…Single crystals of the Fxx isomers including the three Fxp compounds (Donnelly et al, 2008) were obtained by slow evaporation of solutions at 277 or 294 K and typically from ethyl acetate, while Fmo was grown from CDCl 3 . The only Fxx isomer that proved difficult to crystallize as diffraction quality crystals was Fom: decent quality crystals were only obtained after a series of crystal growth experiments from mixtures of methanol and diethyl ether.…”

“…All nine Fxx isomers were synthesized using standard nucleophilic acyl substitution reactions (Schö tten-Baumann reaction) between the 4-/3-/2-aminopyridines and 4-/3-/2fluorobenzoyl chlorides at 294 K. The general procedure is as described for the Fxp triad of compounds (Donnelly et al, 2008): an alternative route is reported by Lu et al (2003). The Fxm isomers were prepared by the condensation reaction of 3aminopyridine (3-AP) with 4-/3-/2-fluorobenzoyl chlorides in CH 2 Cl 2 in the presence of 1 equiv of triethylamine (Et 3 N).…”

“…Optimized feature in the Fxx NMR spectra is the splitting of the N-H peak into a broad doublet in the Fox triad (Fop, Fom, Foo) when using aprotic solvents such as CDCl 3 (supplementary material, x2;Donnelly et al, 2008). This splitting results from the strong through-space nuclear spin-spin couplings ( 1h J N-HÁ Á ÁF = 13-15.5 Hz), caused by the formation of a strong N-HÁ Á ÁF interaction between the ortho-F atom and amide proton (Manjunatha Reddy et al, 2010).…”

“…Isomorphous relationships have been noted in a series of benzamides where H/F atoms have been swopped in an aromatic ring (Donnelly et al, 2008). Given the isosteric relationship that fluorine has with the H atom and the ability of fluorine to participate in weak interactions (Berger et al, 2011), there is ample evidence that a wealth of interesting structural motifs involving 'organic fluorine' will be revealed in systematic studies (n  m isomer grids).…”

At the Interface of Isomorphous Behavior in a 3 × 3 Isomer Grid of Monochlorobenzamides: Analyses of the Interaction Landscapes via Contact Enrichment Studies

“…Subtle differences at the molecular level do not impact on the overall molecular aggregation (isomorphous series) and differences between the crystal structures are noted at the secondary level. [40][41][42][65][66][67][68][69][70][71][72] Why is there such a considerable overlap between Clxx, Brxx but not with Fxx or Mxx?…”