The synthesis of I·-1,2,3,4,5,6-hexafluorocyclohexane (benzene hexafluoride) from benzene

Article abstract of DOI:10.1002/anie.201205577

Six of the best: Benzene had been used by Faraday and Mitscherlich in their respective synthesis of hexachloro- and hexabromocyclohexane in the early 19th century. Also starting from benzene, I·-1,2,3,4,5,6- hexafluorocyclohexane (benzene hexafluoride; se

Full text of DOI:10.1002/anie.201205577

Angewandte
Chemie
DOI: 10.1002/anie.201205577
Benzene Hexafluoride
The Synthesis of h-1,2,3,4,5,6-Hexafluorocyclohexane (Benzene
Hexafluoride) from Benzene**
Alastair J. Durie, Alexandra M. Z. Slawin, Tomas Lebl, and David OꢀHagan*
In 1825 Michael Faraday reported the preparation and
isolation of hexachlorocyclohexane (HCCH), also known as
benzene hexachloride, after a photochemical reaction of
chlorine gas with benzene.[1] The reaction generates up to five
stereoisomers of hexachlorocyclohexane, a combination that
was subsequently marketed in the 1940s as Lindane, and
became an important insecticide.[2] The active constituent is
stereoisomer 1 (g-HCCH), and Lindane has been used as an
insecticide for over 50 years, until it was widely banned due to
a parent ion of 192 and a cracking pattern which indicated the
1
presence of CHF groups only. The H and 19F NMR spectra
also indicated that only CHF groups were present. The
compound was resistant to oxidation and could not be
dehydrofluorinated under a variety of conditions. These facts
suggest that compound (VII) is a 1,2,3,4,5,6-hexafluorocyclo-
hexane very probably with the trans structure.”[6]
The only other commentary in the literature on HFCH is
a theory study[7] which calculated the relative energies of the
thirteen possible chair conformers from the nine possible
configurational isomers of 3. The relative energies are
reproduced in the histogram in Figure 1. The different
isomers have different energies. The all-syn isomer 3b is
calculated to be of highest energy, and isomer 3c of lowest
energy, not the trans structure (all equatorial 3d, Figure 1)
which might be intuitively predicted.[6]
its persistence in the environment.[3] A decade after Faradayꢀs
chlorine experiment, Eilhard Mitscherlich working in Berlin
in 1835, reported the isolation of hexabromocyclohexane 2
(HBCH)[4] after combining bromine and benzene to give
a white solid. It was subsequently shown that the reaction
generates two major stereoisomers the predominant one
being the b-isomer 2.[5] The analogous hexaiodocyclohexane
is an unknown compound. There is only one report in the
literature, from 1969,[6] suggesting an identification of an
analagous hexafluorocyclohexane (HFCH) 3. The reaction
involved direct fluorination of benzene with CoF3/KF/F2. A
range of fluorinated products resulted and a minor compo-
nent (ca. 2%) of the product mixture was isolated as a solid
(m.p. 123-1248C). The authors proposed the all-trans (b-
HFCH) structure of 3 based on analytical data and empirical
logic, although the structure and stereochemistry was never
established. Their account stated: “When set aside, fraction 6
gave a crystalline solid (VII), which was filtered off. …
Analysis of (VII) indicated that it had an empirical formula
corresponding to C6H6F6. The mass spectrum of (VII) gave
Figure 1. Calculated relative energies of the thirteen possible stereoiso-
mers of the chair forms of the nine configurational isomers of HFCH.
The highest-energy structure is all-syn 3b and the lowest-energy
structure is isomer 3c.[7]
Here we report the first unambiguous synthesis of
a HFCH 3 stereoisomer. The route begins from benzene.
AgF2 has previously been reported[8] as a reagent for the
conversion of benzene to fluorobenzene 4 (Scheme 1). The
major product is fluorobenzene (ca. 45%), although there are
also a number of side-products with higher levels of fluori-
[*] A. J. Durie, Prof. A. M. Z. Slawin, Dr. T. Lebl, Prof. D. O’Hagan
EaStChem School of Chemistry, University of St. Andrews
North Haugh, St. Andrews, Fife KY16 9ST (UK)
E-mail: do1@st-andrews.ac.uk
Homepage: http://chemistry.st-and.ac.uk/staff/doh/group
[**] D.O’H. thanks the EPSRC and the ERC for an Advanced Investigator
Grant to support this research. We thank the EPSRC for a research
grant and for financial support through a DTG Studentship (A.J.D.).
nation including tetrafluorocyclohexenes
5 and 6 and
unreacted benzene. Although these compounds were not
isolated in the original report, their structure and stereo-
chemistry was deduced by NMR analysis. In our hands this
conversion was reproducible but the isolation of 5 or 6 proved
Supporting information for this article (full experimental procedures
and characterization data for all compounds, 19F NMR spectrum of
3a, and crystallographic data for 3a, 8, and 9) is available on the
WWW under http://dx.doi.org/10.1002/anie.201205577.
Angew. Chem. Int. Ed. 2012, 51, 1 – 4
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!

.
Angewandte
Communications
Figure 3. X-ray structure of HFCH 3a showing an enantiomer dimer
within the unit cell. The shortest CF···HC contact in the solid state is
shown.[20]
ambient temperature revealed two relatively sharp signals
and one almost imperceptible broad, base-line signal (Fig-
ure 4A). A more informative spectrum was revealed at
ꢀ708C (CD2Cl2) where the ring interconversion is slowed
Scheme 1. Reagents and conditions: a) AgF2, CH2Cl2, RT; b) KMnO4,
MgSO4, EtOAc, EtOH, H2O, 08C!RT; c) SO2Cl2, Et3N, EtOAc, 2.3%
from 3 steps; d) Et3N·3HF, 1208C, 86%; e) Deoxofluor, THF, 55%.
difficult due to a complex mixture of related organofluorines
and product volatility. Therefore, the product mixture was
oxidized directly with permanganate, to generate vicinal diol
7, a reaction we have used to advantage in the preparation of
acyclic vicinal fluorinated alkanes.[9] By using a modification
of a Sharpless protocol,[10,11] diol 7 was converted to the
corresponding cyclic sulfate 8. Although this compound was
isolated in a low overall yield from benzene, it was the first
tractable compound of the route and it could be secured by
chromatography. The structure and relative stereochemistry
of 8 was confirmed at this stage by X-ray structure analysis of
a suitable crystal (Figure 2). Hydrogen fluoride treatment of 8
then gave the pentafluoroalcohol 9 in an efficient conversion.
This alcohol was also a crystalline solid and X-ray analysis
(Figure 2) confirmed the relative stereochemistry and that an
inversion of configuration has occurred during the substitu-
tion reaction. Finally a high-temperature dehydroxyfluorina-
tion reaction of 9, by using Deoxofluor,[12] generated HFCH
3a.
Figure 2. X-ray structures which confirm structure and relative stereo-
chemistry of intermediates 8 and 9.[20]
HFCH 3a is a white solid (m.p. 99–1008C), and a suitable
crystal was subjected to X-ray crystallography. The structure
is shown in Figure 3, confirming the sterochemistry and
consistent with an inversion of configuration during the final
fluorination reaction. The structure reveals two 1,3-diaxial
Figure 4. 19F{1H} NMR spectrum of 3a at A) room temperature and
B) ꢀ708C in CD2Cl2. At room temperature there are two peaks and
a broad featureless peak, the latter arising due to the relatively large
chemical shift difference between F5 and F6. Six unique peaks resolve
on cooling to ꢀ708C. C) 2D-19F-EXSY correlation spectroscopy (mixing
time 100 ms) at ꢀ708C with three sets of correlating peaks indicating
the axial/equatorial interconversions with ring inversion. A 2D-19F-EXSY
with overlaid 19F-COSY spectrum (see Figure S1 in the Supporting
Information) illustrates additional correlations between the individual
fluorines in the chair conformation.
ꢀ
C F bonds. Although formally a meso compound, the chair
conformation of 3a is chiral and the X-ray structure is
composed of alternating enantiomers within the unit cell. The
enantiomers interconvert with ring inversion. The shortest
CF···HC contact within the unit cell is 2.44 ꢁ, suggesting
a weak CF···HC hydrogen bond.[13] 19F NMR analysis at
2
www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1 – 4
These are not the final page numbers!

Angewandte
Chemie
sufficiently such that all of the six fluorine atoms of 3a are
resolved (Figure 4B). The individual signals were assigned by
19F NMR 2D-EXSY correlation spectroscopy.[14,15] This anal-
[1] M. Faraday, Ann. Chem. Phys. 1825, 274 – 291.
[2] K. L. Willett, E. M. Ulrich, R. A. Hines, Environ. Sci. Technol.
1998, 32, 2197 – 2207.
[3] K. Walker, D. A. Vallero, R. G. Lewis, Environ. Sci. Technol.
1999, 33, 4373 – 4378.
[4] E. Mitscherlich, Ann. Phys. 1835, 111, 370 – 374.
[5] F. E. Matthews, J. Chem. Soc. 1892, 61, 103 – 114.
[6] P. L. Coe, R. G. Plevey, J. C. Tatlow, J. Chem. Soc. C 1969, 1060 –
1063.
[7] Z. Zdravkovski, Bull. Chem. Technol. Maced. 2004, 23, 131 – 137.
[8] Z. Zweig, R. G. Fischer, J. E. Lancaster, J. Org. Chem. 1980, 45,
3597 – 3603.
[9] D. OꢀHagan, J. Org. Chem. 2012, 77, 3689 – 3699; L. Hunter, P.
Kirsch, A. M. Z. Slawin, D. OꢀHagan, Angew. Chem. 2009, 121,
5565 – 5568; Angew. Chem. Int. Ed. 2009, 48, 5457 – 5460.
[10] Y. Gao, K. B. Sharpless, J. Am. Chem. Soc. 1988, 110, 7538 –
7539.
[11] M. Alonso, A. Riera, Tetrahedron: Asymmetry 2005, 16, 3908 –
3912.
[12] Y. Chang, A. Tewari, A.-I. Adi, C. Bae, Tetrahedron 2008, 64,
9837 – 9842.
ꢀ
ysis reveals that the two 1,3-diaxial C F bonds show a large
through-space coupling (4JHF = 30.6 Hz) confirming their
close proximity in space. The F···F distance in the X-ray
structure is 2.8 ꢁ which is at the van der Waalꢀs contact
distance. Through-space F···F couplings of this magnitude are
rarely observed except in rigid molecular systems,[16] although
they have been observed recently in the structurally related
all-syn 1,2,3,4-tetrafluorinated cyclohexane[15] and a difluori-
nated hexose.[17] Rate constants were determined by complete
lineshape analysis of the 19F NMR spectra recorded across the
temperature range 200–242 K. Fitting the experimental data
to the Eyring equation[18] allowed the activation parameters
for cyclohexane ring interconversion to be determined as
DG°298 = 11.5 kcalmolꢀ1, DH° = 10.6 kcalmolꢀ1, and DS° =
ꢀ2.9 kcalmolꢀ1 (see Supporting Information). The enthalpy
difference is very similar to cyclohexane itself (DH° =
10.8 kcalmolꢀ1).[19] It might be expected that eclipsing C F
ꢀ
[13] R. Frçhlich, T. C. Rosen, O. G. J. Meyer, K. Rissanen, G. Haufe,
J. Mol. Struct. 2006, 787, 50 – 62; J. D. Dunitz, R. Taylor, Chem.
Eur. J. 1997, 3, 89 – 98; J. A. K. Howard, V. J. Hoy, D. OꢀHagan,
G. T. Smith, Tetrahedron 1996, 52, 12613 – 12622.
[14] S. Bresciani, T. Lebl, A. M. Z. Slawin, D. OꢀHagan, Chem.
Commun. 2010, 46, 5434 – 5437; C. L. Perrin, T. J. Dwyer, Chem.
Rev. 1990, 90, 935 – 967.
interactions would raise this barrier during ring interconver-
sion transition states of 3a relative to cyclohexane, however
the ground-state energy of 3a is also raised, presumably by
a similar magnitude, such that the relative differences are
similar.
In conclusion, HFCH 3a, was prepared as a single
stereoisomer from benzene by a five-step route. Benzene
was also used by Faraday and Mitscherlich for their respective
syntheses of the hexachloro and hexabromo analogues in the
early 19th century. Coe et al.[6] suggested in 1969 that a HFCH
3 may have formed after direct fluorination of benzene with
CoF3 although this was never confirmed, thus the synthesis of
3a is the first unambiguous preparation of a HFCH 3
stereoisomer.
[15] A. J. Durie, A. M. Z. Slawin, T. Lebl, P. Kirsch, D. OꢀHagan,
Chem. Commun. 2011, 47, 8265 – 8267.
[16] C. F. Matta, N. Castillo, R. J. Boyd, J. Phys. Chem. A 2005, 109,
3669 – 3681.
[17] G. T. Giuffredi, L. E. Jennings, B. Bernet, V. Gouverneur, J.
Fluorine Chem. 2011, 132, 772 – 778.
[18] H. Eyring, J. Chem. Phys. 1935, 3, 107 – 115.
[19] E. L. Eliel, S. H. Wilen, Stereochemistry of Organic Compounds,
Wiley, New York, 1994.
[20] CCDC 899837 (3c), 899838 (8), and 899839 (9) contain the
supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Received: July 13, 2012
Published online: && &&, &&&&
Keywords: benzene hexafluoride · conformational analysis ·
.
hexafluorocyclohexane · organofluorine chemistry
Angew. Chem. Int. Ed. 2012, 51, 1 – 4
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3
These are not the final page numbers!

.
Angewandte
Communications
Communications
Benzene Hexafluoride
Six of the best: Benzene had been used by
Faraday and Mitscherlich in their respec-
tive synthesis of hexachloro- and hexa-
bromocyclohexane in the early 19th cen-
tury. Also starting from benzene, h-
1,2,3,4,5,6-hexafluorocyclohexane (ben-
zene hexafluoride; see X-ray structure of
a dimer) was now synthesized in five
steps.
A. J. Durie, A. M. Z. Slawin, T. Lebl,
D. O’Hagan*
&&&& — &&&&
The Synthesis of h-1,2,3,4,5,6-
Hexafluorocyclohexane (Benzene
Hexafluoride) from Benzene
4
www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1 – 4
These are not the final page numbers!