Fluorocyclohexanes: Synthesis and structure of all-syn-1,2,4,5- tetrafluorocyclohexane

Article abstract of DOI:10.1039/c2cc34679f

The all-syn isomer of 1,2,4,5-tetrafluorocyclohexane is prepared and characterised by NMR and X-ray crystallography. It emerges to be a particularly polar cyclohexane analogue with differentially polarised faces.

Full text of DOI:10.1039/c2cc34679f

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COMMUNICATION
Fluorocyclohexanes: synthesis and structure of
all-syn-1,2,4,5-tetrafluorocyclohexanew
Alastair J. Durie,a Alexandra M. Z. Slawin,a Tomas Lebl,a Peer Kirschb and
David O’Hagan*a
Received 29th June 2012, Accepted 3rd August 2012
DOI: 10.1039/c2cc34679f
The all-syn isomer of 1,2,4,5-tetrafluorocyclohexane is prepared
and characterised by NMR and X-ray crystallography. It
emerges to be a particularly polar cyclohexane analogue with
differentially polarised faces.
Scheme 1 Synthesis of 2; (i) mCPBA, CH2Cl2, ꢀ15 - ꢀ10 1C, 52%.
Recently we reported the synthesis of the all-syn isomer of
1,2,3,4-tetrafluorocyclohexane 1.1 This was the first example
of a tetrafluorocyclohexane to be prepared and unexpectedly it
was a solid material at room temperature. X-ray crystallography
revealed a chair conformation for cyclohexane 1 in the solid
state with two C–F bonds orientated 1,3-diaxial (Fig. 1).
Although formally non-chiral, cyclohexane 1 crystallised as a
set of enantiomeric dimers. The two polar axial C–F bonds
running parallel to each other contribute to a large molecular
dipole (4.91 Dy).
(ii) DAST, 70 1C, 24%.
by treatment of diepoxide 4 with DAST, at 70 1C as illustrated
in Scheme 1.4 The tetrafluorocyclohexane was isolated after
repeated chromatography in 24% yield. Although a modest
recovery the stereospecific incorporation of four C–F bonds
makes this a useful reaction.
The 19F{1H}-NMR spectrum of 2 was recorded at ambient
temperature, however this was featureless and broad (Fig. 2A).
When the 19F{1H}-NMR spectrum of 2 was recorded at a low
temperature (193 K in [2H8]-toluene) two signals resolved
corresponding to an equivalent set of axial and equatorial
C–F bonds (Fig. 2B). The signals show an expected second
order AA0XX0 pattern. The 1H-NMR spectrum recorded at
193 K in both [2H8]-toluene (Fig. 3A) or [2H2]-dichloromethane
(Fig. 3B) resolved into six individual proton signals due
to relatively slow ring interconversion. On examination the
signals for the three axial (red) protons 1Ha and 3Ha on the
lower face of 2 are significantly shielded (D + 1.69 and D +
1.31 ppm), and the axial proton on the top face 4Ha is
deshielded, (D ꢀ 0.15 ppm) in [2H8]-toluene relative to the
As part of a general programme aimed at preparing aliphatic
organic molecules containing vicinal C–F bonds of defined
relative stereochemistry,2 we now report a second example of
an all-syn-tetrafluorocyclohexane, with the synthesis of isomer 2.
Diethylsulfur trifluoride (DAST) has been shown to react with
epoxides at high temperature (50–70 1C) to yield syn-difluorides.3
Therefore we decided to attempt this reaction with a diepoxide.
Thus syn-1,2,4,5,-tetrafluorocyclohexane 2 was prepared directly
Fig. 1 Ring interconversion of 1 generates conformational enantio-
mers, with the fluorine atoms on one face of the molecule.
a University of St Andrews, School of Chemistry and Centre for
Biomolecular Sciences, North Haugh, St Andrews, Fife, KY16 9ST,
UK. E-mail: do1@st-andrews.ac.uk; Fax: +44 (0)1334 463800;
Tel: +44 (0)1334 467171
Fig. 2 (A) 19F-NMR (282 MHz) of 2 at 298 K, in [2H8]-toluene.
(B) 19F-NMR (282 MHz) of 2 at 193 K, in [2H8]-toluene. The peak in
the upper spectrum is over 3000 Hz wide, which resolves to an
axial (ꢀ188.7 ppm) and an equatorial (ꢀ201.0 ppm) signal at low
temperature.
b Merck KGaA, Frankfurter Str. 250, D 64293 Darmstadt, Germany
w Electronic supplementary information (ESI) available. See http://
dx.doi.org/10.1039/c2cc34679f
c
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Fig. 4 Calculated electrostatic surface potential maps of 2 (geometry
optimization: B3LYP/6-311+G(2d,p) level of theory; red corresponds
to a partial charge of ꢀ0.043 e, blue to +0.097 e).6 (A) A view of the
lower ‘hydrogen’ face of 2 showing three axial and two equatorial
(blue) hydrogens. (B) A side view of 2 showing the upper ꢀve (red)
face and a lower +ve (blue) face. (C) A view of the upper ‘fluorine’
face of 2 with two axial (central) and two equatorial fluorine (red)
atoms. The axial hydrogen is neutral (green).
Fig. 5 Top: X-Ray structure and drawing of 2 showing a pair of
1,3-diaxial and 1,3-diequatorial C–F bonds. Bottom: Packing of three
molecules of 2 in the X-ray structure showing intermolecular contacts
between the positive and negative faces of the molecules. The distances
are the shorter intermolecular CFꢁ ꢁ ꢁHC contacts.
Fig. 3 (A) Low temp 1H-NMR (300 MHz) of 2 at 193 K, in
[2H2]-dichloromethane. (B) Low temp 1H-NMR (300 MHz) of 2 at
193 K, in [2H8]-toluene. The upfield shifted peaks at 3.22 ppm (3Ha)
and ꢀ0.06 ppm (1Ha) correspond to the lower face axial hydrogens
which are shielded by C–H/p electrostatic interactions with toluene at
low temperature.
bonds are splayed 5.61 from perpendicular, presumably to
minimise dipolar repulsion. The crystal packing arrangements
between molecules of 2 reinforces the electrostatic analysis
illustrated in Fig. 4 where the upper ‘fluorine’ faces contact the
lower ‘hydrogen’ faces in the solid state (Fig. 5). Consistent
with this are some relatively short CFꢁ ꢁ ꢁHC contacts (B2.49 A)
indicating weak electrostatic hydrogen to fluorine contacts.7
In order to explore how close the experimental structure
was to a theory determined (MP2/6-311+G(2d,p)//B3LYP/
6-311+G(2d,p) + ZPE level of theory)6 minimum gas phase
structure, the X-ray coordinates were used as the starting
point and the Fꢁ ꢁ ꢁF distance was varied around 2.80 A. The
changes in energy (blue) and dipole moment (red) relative to
the Fꢁ ꢁ ꢁF distance are presented in a graphical form in Fig. 6.
The lowest energy structure which emerged from this study
had the intramolecular Fꢁ ꢁ ꢁF distance at 2.81 A similar to the
experimental observation (2.80 A). The calculated molecular
dipole moment for 2 is 5.24 Dy, a higher value than that
determined for isomer 1 (4.91 Dy).
spectrum recorded in [2H2]-dichloromethane (Fig. 3A). Most
striking is the unusually high field signal at ꢀ0.06 ppm (dt),
assigned to the axial 1Ha proton, on the lower face of 2 lying
antiperiplanar to the two axial C–F bonds. The observed shifts
in toluene are indicative of a C–H/p electrostatic interaction
between the lower face axial protons and the p system of the
aromatic ring.5 This suggests that the two faces of the molecule
are differently polarised. To explore this further an electrostatic
surface potential map of 2 was calculated. This confirms that
the two faces of the molecule are differentially polarised as
illustrated in Fig. 4 with the upper ‘fluorine’ face electronegative
and the lower ‘hydrogen’ face electropositive.
A suitable crystal (mp = 107–109 1C) of 2 was submitted
for X-ray structure analysis and the resultant structure is
shown in Fig. 5.
The high polarity is consistent with the electrostatic surface
potential map illustrated in Fig. 4. Increased splaying of
the diaxial C–F bonds reduces the overall molecular dipole
moment (Fig. 6), however the relative energy begins to
increase due to emerging eclipsing interactions including those
between vicinal C–F bonds. Thus the equilibrium structure is
The structure of 2 posesses a set of axial and a set of
equatorial C–F bonds each located 1,3 to each other. Ring
interconversion generates an identical structure, unlike 1
which is enantiomeric. The intramolecular Fꢁ ꢁ ꢁF distance
between the two diaxial fluorines in 2 is 2.80 A, and the C–F
c
9644 Chem. Commun., 2012, 48, 9643–9645
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for EPSRC National Mass Spectrometry Swansea for Mass
Spectrometry Analysis.
References
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3 M. Hudlicky, J. Fluorine Chem., 1987, 36, 373–384.
Fig. 6 Calculated structures of
2 (MP2/6-311+G(2d,p)//B3LYP/
6-311+G(2d,p) + ZPE level of theory) varying the Fꢁ ꢁ ꢁF distance.6
The relative energy change (blue) in kcal molꢀ1, generates a minimum
structure at 2.81 A and a dipole moment of 5.24 Dy.
4 DAST is unstable at 70 1C and is potentially explosive.
5 G. Dombi, J. Mattinen, K. Pihaja and J. Czombos, Tetrahedron,
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tensioned between C–F/C–F eclipsing and C–F/C–F diaxial
interactions.
In summary all-syn 1,2,4,5-tetrafluorocyclohexane 2 has
been prepared and analysed both by solution and X-ray
structure analysis. It is calculated to have a large dipole
moment (5.18 Dy) for an aliphatic organic compound arising
largely due to the 1,3-diaxial C–F bonds in the equilibrium
structure. This leads to a polarisation with an electropositive
and an electronegative face of the molecule. The structural
motifs of 1 and 2 suggest design features for the incorporation
of these moieties into liquid crystalline materials which demand
molecular species with low viscosity but high polarity.
We are grateful to an Advanced Investigator Grant from
the European Research Council (GO802567) and EPSRC
(BB/F007426/1) for financial support. We are also grateful
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 9643–9645 9645