Organofluorine chemistry: Difluoromethylene motifs spaced 1,3 to each other imparts facial polarity to a cyclohexane ring

Abstract

2,2-Dimethyl-5-phenyl-1,1,3,3-tetrafluororocyclohexane has been prepared and characterised as an example of a facially polarised cyclohexane containing 1,3 related CF2 groups. The dipolar nature of the ring arises from the axial orientation of two of the C–F bonds pointing in the same direction, and set by the chair conformation of the cyclohexane. This electrostatic profile is revealed experimentally both in the solid-state (X-ray) packing of the rings and by solution (NMR) in different solvents. A computationally derived electrostatic profile of this compound is consistent with a more electronegative and a more electropositive face of the cyclohexane ring. This placing of CF2 groups 1,3 to each other in a cyclohexane ring is introduced as a new design strategy which could be applicable to the preparation of polar hydrophobic cyclohexane motifs.

Last of the gem‐Difluorocycloalkanes 2: Synthesis of Fluorinated Cycloheptane Building Blocks

“…The decreased conformational flexibility of cycloalkane scaffolds can be used to fix the spatial orientation of the dipole moments of both fluorinated fragments and additional functional groups. For example, O'Hagan and colleagues implemented this approach into the design of facially‐polarized ‘Janus face’ all‐ cis trifluorocyclopropanes 1 , [15] tetrafluorocyclohexanes 2 (and their penta‐ and hexa‐fluorinated analogs), [16–19] as well as tetrafluorocyclohexane derivatives 3 [20] containing two gem ‐difluoromethylene moieties (Figure 1A).…”

Synthesis of a Hominal Bis(difluoromethyl) Fragment

“…Jones et al synthesized 2,2-dimethyl-5-phenyl-1,1,3,3-tetrafluorocyclohexane by means of the direct deoxofluorination of a diketone precursor. 41 Attempts to use the same approach in the case of diketones, which did not have dimethyl-substituted methylene between keto groups, were unsuccessful, yielding only complex and intractable products, which could be attributed to the high degree of enolization of such diketones. This behavior of diketones was also noted previously in the work by Singh et al 42 In both works by Stepanov et al 36 and Wang et al, 40 the route to compounds containing the hominal bis( gem -CF 2 ) fragment included the formation of 3,3-difluoroketones as intermediates.…”

“…The conversion to the CF 2 group occurred in modest yields and required neat DAST at elevated temperature. Jones et al synthesized 2,2-dimethyl-5-phenyl-1,1,3,3-tetrafluorocyclohexane by means of the direct deoxofluorination of a diketone precursor . Attempts to use the same approach in the case of diketones, which did not have dimethyl-substituted methylene between keto groups, were unsuccessful, yielding only complex and intractable products, which could be attributed to the high degree of enolization of such diketones.…”

Synthesis of a Hominal Bis(difluoromethyl) Fragments

“…Jones et al synthesized 2,2-dimethyl-5-phenyl-1,1,3,3tetrafluorocyclohexane by means of the direct deoxofluorination of a diketone precursor. 41 Attempts to use the same approach in the case of diketones, which did not have dimethylsubstituted methylene between keto groups were unsuccessful, yielding only complex and intractable products, which could be attributed to the high degree of enolization of such diketones. In both works by Stepanov et al 36 and Wang et al, 40 propargylic gem-difluorides.…”