Molecular Structure and Crystal Packing of Monofluoromethoxyarenes

Abstract

X‐ray crystal structures of monofluoromethoxy aryl compounds are presented for the first time. In fluoromethoxybenzene derivatives with at least one unsubstituted ortho‐position, the fluoromethoxy group adopts a twisted anisole conformation. The twist is most pronounced in derivatives with the least electron‐demanding phenyl unit. The observed structural features in the crystalline state are in good agreement with theoretical predictions for prototypical monofluoromethoxybenzene. In contrast, a 5‐fluoromethoxyindole derivative exhibits a conformation differing from that by theoretical predictions. Such a difference may be due to crystal packing, in which the fluorine atom is trapped in a hydrophobic pocket lined with aliphatic C–H bonds. The crystal structures of the simple α‐monofluorinated anisoles exhibit a variety of linear and cyclic interaction motifs for the monofluoromethoxy group. Similar motifs are also observed in the crystals of other monofluoromethyl‐containing compounds. In all these crystal structures the geometrical characteristics of mutual close contacts between monofluoromethoxy or between monofluoromethyl units are dependent on their surrounding environment in the crystal structure, an observation consistent with relatively weak interactions. A survey of all close C–F···H–C contacts in these crystals and in crystal structures of CH2F‐containing compounds from the CSD reveals little evidence for significant H‐bonding character in these interactions.

Conformational Diversity in Partially Fluorinated N‐Alkyl Pipecolic Acid Amide Derivatives

“…The substantial conformational deviation of 12 facilitated by crystal packing is reminiscent of a case observed recently, [18] where the theoretically predicted and generally observed conformation of a monofluoromethoxy group was found in an aberrant orientation, but stabilized by accommodation of the CÀ F unit in a cavity lined with weakly polarized CÀ H units. In the current case of 12, the CÀ F unit is embedded in a hydrophobic pocket formed by three different neighboring molecules with major interactions (green dotted lines in Figure 23) to an aromatic CÀ H unit and two methyl groups, stabilizing a higherenergy conformation predicted for the free molecule.…”

“…The polar interactions are then the combined effects from both CÀ F units. Assuming small stabilizing energy contributions of À 0.1 to À 0.3 kcal/ mol per polar non-bonded CÀ F•••HÀ C interaction, [18] we may anticipate stabilization energies between ca. 0.5 and 2 kcal/mol from the combined effects of both CÀ F units.…”

Fluoroalkoxylating Reagents in Organic Synthesis: Recent Advances

“…[9] Furthermore, the OCH 2 F unit of monofluoromethoxyarenes adopted a gauche conformation in which the C−F bond was anti‐periplanar to the oxygen lone pair that was less involved in π‐conjugation with the phenyl unit (Figure 1c). [10] Therefore, fluoroalkoxy groups have garnered increasing attention for the further refinement of the physicochemical properties of drug candidates.…”

An Influence of Fluorinated Alkyl Substituents on Structure and Magnetic Properties of Mn(II) Complexes with Pyrazolyl-Substituted Nitronyl Nitroxides

“…The motivation was that the introduction of fluorine atom(s) into molecules alters physical and chemical properties of the compounds because of fluorine's electronegativity, its low polarisability and high bond strength [17]. In addition, there are many examples of the influence of substitution with fluorine on inter-molecular interactions and the use of 'organic fluorine' in crystal engineering or in the systematic design of functional materials [18][19][20]. Many research groups have performed comprehensive analyses of crystal structures of fluorinecontaining compounds and published excellent reviews on the specific role of fluorine in crystal packing [21].…”