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

Article abstract of DOI:10.3762/bjoc.12.281

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

Full text of DOI:10.3762/bjoc.12.281

Organofluorine chemistry: Difluoromethylene motifs spaced
1,3 to each other imparts facial polarity to a cyclohexane ring
Mathew J. Jones, Ricardo Callejo, Alexandra M. Z. Slawin, Michael Bühl
and David O'Hagan*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2016, 12, 2823–2827.
EaStCHEM School of Chemistry, University of St. Andrews, St.
Andrews, Fife KY16 9ST, UK
doi:10.3762/bjoc.12.281
Received: 07 September 2016
Accepted: 30 November 2016
Published: 22 December 2016
Email:
David O'Hagan* - do1@st-andrews.ac.uk
* Corresponding author
Associate Editor: V. Gouverneur
Keywords:
© 2016 Jones et al.; licensee Beilstein-Institut.
License and terms: see end of document.
aliphatic rings; C–F bond; cyclohexane conformation;
difluoromethylene group; organofluorine chemistry
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 ex-
perimentally 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 cyclo-
hexane 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.
Introduction
Selective incorporation of fluorine atoms is a powerful strategy nation and CF3 incorporation have had wide currency, the
for modulating the properties of organic compounds [1-3]. For difluoromethylene (CF2) motif has received relatively less
instance, the replacement of hydrogen by fluorine is commonly attention despite possessing unique properties [11-14]. For ex-
practised in medicinal [4,5] and agrochemical [6,7] research ample CH2F2 shows the highest molecular dipole (1.97 D) of
programmes. The dipole moment associated with the C–F bond the fluoromethane series, relative to CH3F (1.87 D) or CHF3
has also rendered fluorine containing compounds important in (1.65 D) [15,16]. Also (poly)vinylidine fluoride (~CF2CH2~) is
the development of organic materials such as liquid crystals the prototypical piezoelectric polymer, when the CF2 group are
[8,9]. Strategic fluorination can add polarity to a molecule, orientated (poled) in the melt [17].
however, such compounds do not generally increase in their
hydrophilic capacity, thus selective fluorination leads to polar- The search for new and more diverse polar hydrophobic scaf-
hydrophobic properties [10]. Although selective mono-fluori- folds is attractive for drug discovery research and new materi-
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als [18]. In our own lab we have been exploring the synthesis ported so far. It was prepared in an eight step synthesis [22]. At
and properties of differently fluorinated aliphatic structures the outset we explored a more direct synthesis of this arrange-
based on the cyclopentane (1) and cyclohexane (2 and 3) rings, ment based on deoxofluorination of 1,3-diketones 5 with DAST
compounds which can show quite large dipole moments or Deoxo-Fluor® [23] (Scheme 1). An alternative route envis-
depending on the stereochemistry [19,20] (Figure 1). All-syn aged a fluorodesulfurisation using 1,3-bis-dithianes 6 as sub-
1,2,3,4,5,6-hexafluorocyclohexane, which was prepared strates [24] (Scheme 1). Both synthetic approaches have been
recently, emerges as among the most polar aliphatic com- widely used for the introduction of the CF2 group in open-chain
pounds reported in the literature [21]. The specific arrangement and (macro)cyclic systems [23,24], but not in a 1,3 relationship.
with all of the fluorines “up” induces a facial polarisation to the
cyclohexane, a unique phenomenon which may have unex-
plored utility in organic chemistry. For example derivatives of
these compounds could be potentially useful as polar hydro-
phobic substituents in drug discovery that will simultaneously
contact both electropositive and electronegative domains within
a target protein.
Scheme 1: Retrosynthetic plan to the preparation of 1,1,3,3-tetra-
fluorocyclohexane structures.
Results and Discussion
The preparation of diketones 5a–c and bis-dithianes 6a–c was
carried out by previously described methods. The dimethyl-
Figure 1: Selected fluorinated polar alicyclic scaffolds.
diketone 5c was prepared by double methylation of 5b [25]
(Scheme 2). Two different O-alkylated products 7 and 8 were
In this paper, we now report the design, synthesis and character- also obtained as significant byproducts.
isation of a novel tetrafluorocyclohexane structure 4, rendered
polar by placing two CF2 groups located 1,3 from each other The reaction of ketones 5a–c with 1,2-ethanedithiol in the pres-
(Scheme 1). This forces two C–F bonds to lie 1,3-diaxial to ence of catalytic BF3·OEt2 afforded the corresponding bis-dithi-
each other while the cyclohexane adopts the classic chair con- anes 6a–c in moderate to good yields [26] (Scheme 2). The
formation. To the best of our knowledge, 2,2,6,6-tetrafluoro- reaction of diketone 5c also afforded the monoderivatised ke-
cyclohexanol is the only derivative containing this feature re- tone 9 as a minor product.
Scheme 2: Preparation of starting materials 5c and 6a–c.
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Direct fluorination of diketones 5a–c was explored with DAST
or Deoxo-Fluor® (Scheme 3). When diketones 5a and 5b were
treated with DAST or Deoxo-Fluor®, either neat or in DCM as
a solvent, only complex and intractable products were obtained.
These highly enolisable diketones [27,28] were incompatible
with deoxyfluorination. In order to block enolisation, diketone
5c containing two methyl groups α to the ketones was subject to
fluorination with DAST and Deoxo-Fluor®. In this case the
reaction was successful and the desired tetrafluorocyclohexane
4c could be obtained, most preferably with DAST although in a
low overall yield (Scheme 3). The presence of the gem-dimethyl
motif renders the carbonyl groups independent of each other
Scheme 4: Fluorodesulfurisation of bis-dithianes 6. Reagents and
conditions: a) NIS, HF·Py, DCM, −78 °C to rt, overnight.
and this facilitates the difluorination process relative to 5a and Tetrafluorocyclohexane 4c was a crystalline solid (mp 70 ºC).
5b. Nevertheless, other unidentified byproducts were also ob- The structure of this compound was established by NMR,
tained, which made purification of 4c by column chromatogra- showing a characteristic AB system in 19F NMR for axial/equa-
phy difficult and compromised the yield.
torial fluorines, and a triplet (1JCF = 250 Hz) in 13C NMR for
the CF2 group. In addition, single crystal X-ray diffraction data
were obtained for 4c which confirmed the structure (Figure 2).
The C–CF2–C angles in the cyclohexane ring are considerably
wider (≈116°) than that of the C–CH2–C angles (≈112°), which
is now recognised as a general phenomenon of the CF2 group in
an aliphatic chain/ring [10-13]. The two axial fluorines flex
away from each other with widened right angles of 96.3°, dis-
torting a co-parallel orientation. This distortion is also observed
for the 1,3-diaxial C–F bonds in the solid state structures of 2
[20] and 3 [21] consistent with electrostatic dipolar repulsion
between these C–F bonds and indicative of the origin of the
polarity of these molecules. In terms of intermolecular packing
in the solid state there are interactions between the non-fluorine
face of the cyclohexyl ring and the phenyl group of a neigh-
Scheme 3: Deoxofluorination of diketones 5. Reagents and conditions:
a) DAST, DCM, rt, overnight, 4a (traces), 4b (traces), 4c (14%);
b) Deoxo-Fluor®, DCM, rt, overnight, 4a (traces), 4b (traces), 4c
(10%).
Treatment of bis-dithianes 6 with NIS and HF·Py as previously bouring molecule (Figure 2). These C-H···π interactions are a
described for linear systems [28] proved unsuccessful feature of the solid state packing found in phenyl derivatives of
(Scheme 4) and did not offer a way forward.
2 [29].
Figure 2: X-ray structure of compound 4c. The image shows two molecules stacked with the non-fluorine face pointing to an adjacent phenyl ring
consistent with an electrostatic ordering. The structure has been deposited in the Cambridge Crystallographic Data Centre (CCDC) 1502954.
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Beilstein J. Org. Chem. 2016, 12, 2823–2827.
This electrostatic ordering was reinforced by an NMR shift ex-
periment in different solvents. Selected 1H NMR signals of 4c
showed a very clear upfield shift in [2H8]-toluene when com-
pared with the spectrum obtained in chloroform (CDCl3)
(Figure 3). In particular, the two axial protons H-3 and the axial
methyl group at C-4 display higher upfield shifts in toluene
(Δδ ≈ 0.5 ppm and Δδ ≈ 0.3 ppm, respectively), whereas that of
the equatorial protons H-2, the equatorial methyl group at C-5
and the axial proton H-1 do not experience shifts of the same
magnitude (Δδ ≈ 0.2 ppm, Δδ ≈ −0.1 ppm and Δδ ≈ 0.1 ppm, re-
spectively). These observations are consistent with the
anisotropic influence of the electronegative aromatic solvent
(toluene) interacting with the more electropositive (non-fluo-
rine) face of the cyclohexane ring (Figure 3).
Figure 4: Electrostatic potential map for 4c calculated at the B3LYP/6-
311G(d,p) level for an optimised structure calculated at the B3LYP-D3/
6-311+G(d,p) level. The image is plotted on a colour scale from
−0.003 a.u. (red) to +0.003 a.u. (blue) and mapped onto an isodensity
surface (ρ = 4 × 10−4 a.u.); hydrogen atoms are omitted for clarity.
To extend these experimental observations, a DFT computa-
tional study, at the B3LYP-D3/6-311+G(d,p) level, was carried
out in order to obtain an electrostatic potential map of cyclo- Conclusion
hexane 4c. The profile confirms the presence of an electronega- In this study we have prepared a novel polar aliphatic structure
tive face (in red) determined by the two 1,3-diaxial C–F bonds 4c based on the 1,1,3,3-tetrafluorocyclohexyl motif. The com-
and an electropositive face (dark blue), which is most intense at pound was prepared by direct difluorination of the correspond-
the hydrogens of the diaxial C–H bonds pointing antiperiplanar ing α,α-dimethylated 1,3-diketone with DAST. The presence of
to the diaxial C–F bonds (Figure 4). A molecular dipole the two 1,3-diaxial fluorine atoms in structure 4c is responsible
moment for compound 4c was calculated at 3.1 D and can be for the facial polarisation on the cyclohexane ring. We have
compared for example to 1,2,4,5-tetrafluorocyclohexane (2, demonstrated the intermolecular electrostatic interaction of the
5.2 D) [18].
positive non-fluorous face with the π-system of an aromatic ring
Figure 3: 1H NMR spectra of 4c. A) shows the spectrum in [2H8]-toluene, and B) shows the spectrum in chloroform (CDCl3). There are significant
upfield-shifted proton signals in toluene, consistent with an electrostatic interaction between toluene and the electropositive hydrogen face of 1,1,3,3-
tetrafluorocyclohexyl 4c.
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Beilstein J. Org. Chem. 2016, 12, 2823–2827.
14.O’Hagan, D.; Wang, Y.; Skibinski, M.; Slawin, A. M. Z.
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tional optimisations. It follows that functionalised cyclo-
hexanes containing the 1,3-di-CF2 motif would offer new possi-
bilities for the design of performance molecules extending from
organic materials research to medicinal chemistry.
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Supporting Information
Supporting Information File 1
Experimental part and NMR spectra of new synthesised
compounds.
doi:10.1002/anie.201508249
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This work was supported by the Engineering and Physical
Sciences Research Council (EPSRC) and the European
Research Council (ERC). The authors acknowledge the EPSRC
National Mass Spectrometry Facility (Swansea) and Mrs Caro-
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