Synthesis and structure of all-syn-1,2,3,4-tetrafluorocyclohexane

Article abstract of DOI:10.1039/c1cc13016a

Preparation of the all-syn isomer of 1,2,3,4-tetrafluorocyclohexane is reported; X-ray structural studies shows a conformation with two of the C-F bonds oriented 1,3-diaxial to each other and ¹⁹F-NMR reveals a through space diaxial ⁴J_FF coupling constant of 29 Hz.

Full text of DOI:10.1039/c1cc13016a

View Article Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
ChemComm
Cite this: Chem. Commun., 2011, 47, 8265–8267
www.rsc.org/chemcomm
COMMUNICATION
Synthesis and structure of all-syn-1,2,3,4-tetrafluorocyclohexanew
Alastair J. Durie,a Alexandra M. Z. Slawin,a Tomas Lebl,a Peer Kirschb and
David O’Hagan*a
Received 23rd May 2011, Accepted 14th June 2011
DOI: 10.1039/c1cc13016a
Preparation of the all-syn isomer of 1,2,3,4-tetrafluorocyclohexane
is reported; X-ray structural studies shows a conformation with
two of the C–F bonds oriented 1,3-diaxial to each other and
19F-NMR reveals a through space diaxial 4JFF coupling constant
of 29 Hz.
moment with a value of 4.91 Dy. Ring inversion generates
iso-energetic enantiomeric chair (eaea to aeae) conformers,
(Scheme 1). The synthetic route developed to prepare 1,2,3,4-
tetrafluorocyclohexane 1 is illustrated in Scheme 2. A key
intermediate is the endoperoxide 3, which was prepared by a
singlet oxygen reaction on cyclohexadiene 2 as previously
reported by Murray and Kaplan.13 Disproportionation to
diepoxide 4 was catalysed by Ru(PPh3)3Cl2.14 In order to
introduce the first fluorine atoms, a double epoxide ring
opening with HFÁEt3N was investigated. This gave the
difluorodiol 5 as a single regio- and stereo-isomer. Diol 5
was converted to cyclic sulfate 6, as an activated precursor for
the introduction of the third fluorine, which was accomplished
by treatment with HFÁEt3N. This resulted in trifluoroalcohol
7. The final fluorine atom was introduced after triflation of
alcohol 7 and then treatment of 8 with HFÁEt3N. This resulted
in fluoride ion substitution with an inversion of configuration.
The 19F-NMR spectrum of 1,2,3,4-tetrafluorocyclohexane 1
at RT (298 K) displays two particularly broad signals
corresponding to the two sets of non-equivalent fluorines
(Fig. 1b). Such broad signals do not indicate a particularly
slow ring interconversion, but rather arise as a consequence of
the large chemical shift difference between the fluorine signals.
Warming well above RT (353 K) sharpened these two signals,
consistent with speeding up the rate of ring interconversion
(Fig. 1a). When the 19F-NMR spectrum was recorded at low
temperature (200 K in CD2Cl2) all four of the fluorine atoms
gave resolved signals, as they are non equivalent in the chair
conformation and the interconversion is slow on the NMR
The C–F bond is the most polar in organic chemistry and as
a consequence fluorine can influence the conformation and
reactivity of molecules based largely on stereoelectronic effects
and dipole–dipole interactions, rather than through steric
repulsion.1,2 We have had a programme preparing single stereo-
isomers of alkanes carrying multiple vicinal fluoromethylene
groups (B[CHF]nB) and have reported the synthesis and
conformation of straight chain alkanes with three,3 four,4 five5
and six6 vicinal fluorines. In these acyclic studies it emerges that
the all syn-vicinal fluorine stereoisomers adopt helical structures,
as a mechanism to avoid aligned 1,3-C–F bonds. In this
Communication we report the synthesis of 1, a cyclohexane ring
carrying four sequential vicinal fluorines in the ring, with the
all-syn stereochemistry. In this case the ring conformation
overrides repulsive 1,3-C–F bond interactions generating a highly
polar molecule. In 1969 Barton and Hassel received the Nobel
Prize for their studies on conformational analysis based on
cyclohexane7 and the motif is among the most common
in organic chemistry. None the less, selectively fluorinated
cyclohexanes are rare and only the mono-8 and some difluoro-
representatives have been prepared,9,10 with no syntheses
described of cyclohexanes containing three or more vicinal
fluorine atoms.11 The all-syn-tetrafluorocyclohexane 1 became
a synthetic target as it is anticipated to be a polar organic
molecule because the ground state chair conformation is forced
to have two 1,3-diaxial C–F bonds, a unique aspect of a
fluorinated cyclohexane to date. This interaction is anticipated
to raise the ground state energy by B3.0 kcal molÀ1 due to
dipolar repulsion.12 Indeed the calculated (MP2/6-311+G(2d,p)//
B3LYP/6-311+G(2d,p)) minimised chair conformer had all of
the fluorines on one face of the molecule and molecular dipole
timescale (Fig. 1c).
A
2D19F-EXSY-NMR experiment15
recorded at this low temperature (200 K) enabled the four
distinct fluorine signals arising from the chair conformation,
to be assigned (Fig. 1d).
4
Of particular interest was a large through space JFF
coupling of 29 Hz, between the two 1,3-diaxial fluorine atoms,
a value around twice the magnitude of each of the vicinal
gauche F–F coupling constants (B14 Hz). Through space F–F
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: 01334 463800;
Tel: 01334 467171
b Merck KGaA, Frankfurter Str. 250, D 64293 Darmstadt, Germany
w Electronic supplementary information (ESI) available. CCDC
829481. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c1cc13016a
Scheme 1 Ring interconversion of
1 generates conformational
enantiomers, with the fluorine atoms on one face of the molecule.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 8265–8267 8265

View Article Online
to a theory study (MP2/6-311+G(2d,p)//B3LYP/6-311+
G(2d,p)+ZPE level of theory).19 Real transition structures
could not be located, but the energies of the four possible boat
structures which could be involved in the ring inversion were
calculated. These had energies between 7.90 and 9.47 kcal molÀ1
above the ground state aeae chair conformation (See Supple-
mentary Material) and below the experimentally determined
transition energy of 10.9 kcal molÀ1. The experimental NMR
value indicates a ring inversion barrier very close to that of
cyclohexane itself (B10.8 kcal molÀ1). However in the case of
1 it can be assumed that both the ground state and transition
state energies are raised relative to cyclohexane due to
diaxial and eclipsing C–F bond interactions in the ground
and transition state structures.
Scheme 2 Synthesis of 1; (i) (PhO)3P, O3, CH2Cl2, À78 1C then 2,
CH2Cl2, À78 - À25 1C; (ii) Ru(PPh3)3Cl2, CH2Cl2, 0 1C - RT, 46%
from 2 steps; (iii) Et3NÁ3HF, 90 1C; (iv) Thionyl chloride, pyridine,
CH2Cl2, 0 1C; (v) NaIO4, RuCl3ÁxH2O, MeCN, H2O, 35% from
3 steps; (vi) Et3NÁ3HF, 120 1C, 70%; (vii) Tf2O, pyridine, RT;
(viii) Et3NÁ3HF, 120 1C, 35% over 2 steps.
Compound 1 was a relatively high melting solid (mp = 83 1C),
perhaps surprisingly so given that carbon bound fluorine
forms only weak hydrogen bonds.20 A suitable crystal was
selected for X-ray structure analysis and the resultant structure is
shown in Fig. 2. Cyclohexane 1 adopts the classical chair
conformation, and all three of the vicinal C–F relationships
are gauche. The chair structure demands that two of the C–F
bonds adopt 1,3-diaxial orientations, consistent with the
4
19F-NMR, through space JFF-coupling. Repulsion between
these axial C–F bonds is evinced in the X-ray structure by the
fact that they splay from each other each by B51 from the
perpendicular. The molecules of achiral 1 form pairs of
enantiomeric chair conformers within the unit cell, with an
axial fluorine and hydrogen pairing with a mirror image
hydrogen and fluorine respectively. The HÁ Á ÁF contact
distances are 2.77 A and 2.70 A, too long to represent
stabilising hydrogen bonds,20 but the orientation allows the
enantiomer pair to maintain a spatial symmetry. Stability from
this pairing may arise by attenuation of polarity in the solid
state, as both of the fluorinated faces of each enantiomer
Fig. 1 (a) 19F-NMR of 1 at 353 K. (b) 19F-NMR of 1 at 298 K.
(c) 19F-NMR of 1 at 200 K. (d) 2D19F-EXSY-NMR (mixing time 100 ms)
of 1 at 200 K. The cross-peaks indicate exchange between axial and
equatorial fluorines and facilitate assignment of the resonances.
couplings have been observed in rigid molecular frameworks,16
however it is unusual to observe such a large coupling constant
in a system which displays conformational freedom.17 The
through space coupling indicates the anticipated close proximity
of the axial fluorines. Rate constants for the ring interconversion
were determined by complete line shape analysis of the 19F NMR
spectra recorded across the temperature range 200–242 K. Fitting
the experimental data to the Eyring equation18 was used to
Fig. 2 X-Ray structure of 1 showing the pairing of enantiomer
dimers. The antiparallel nature of the highlighted C–FÁ Á ÁH–C contacts
enables the enantiomeric conformers to maintain spatial symmetry
within the unit cell. See Supplementary Information for full crystallo-
graphic details.
determine the activation parameters DG# = 10.9 kcal molÀ1
,
298
DH# = 9.1 kcal molÀ1 and DS# = À6.3 cal KÀ1 molÀ1 (See
Supplementary material). This experimental data was compared
c
8266 Chem. Commun., 2011, 47, 8265–8267
This journal is The Royal Society of Chemistry 2011

View Article Online
approach each other, and thus their molecular dipoles are
opposed.
Trans-1,4-difluorocyclohexane; L.-G. Hammarstrom, U. Berg and
¨
T. Liljefors, Tetrahedron Lett., 1987, 41, 4883–4886.
11 A hexafluorocyclohexane was tentatively reported as a low yielding
component of the product mixture after treatment of benzene with
CoF3, P. L. Coe, R. G. Plevey and J. C. Tatlow, J. Chem. Soc.,
1969, 1060–1063.
12 L. Hunter, P. Kirsch, J. T. G. Hamilton and D. O’Hagan, Org.
Biomol. Chem., 2008, 6, 3105; D. Wu, A. Tian and H. Sun, J. Phys.
Chem. A, 1998, 102, 9901.
13 R. W. Murray and M. L. Kaplan, J. Am. Chem. Soc., 1969,
91, 5358.
14 M. Suzuki, H. Ohtake, Y. Kameya, N. Hamanaka and R. Noyori,
J. Org. Chem., 1989, 54, 5292.
15 S. Bresciani, T. Lebl, A. M. Z. Slawin and D. O’Hagan, Chem.
Commun., 2010, 5434; C. L. Perrin and T. J. Dwyer, Chem. Rev.,
1990, 90, 935.
16 C. F. Matta, N. Castillo and R. J. Boyd, J. Phys. Chem. A, 2005,
109, 3669.
In summary 1,2,3,4-tetrafluorocyclohexane 1 has been
prepared, the first example of a cyclohexane with more than
two vicinal fluorine atoms. The all-syn stereochemistry forces a
ground state 1,3 diaxial fluorine-fluorine interaction, which is
clearly observed both via a through space coupling by low
temperature 19F-NMR and in the solid state by X-ray crystallo-
graphy. The polar nature of 1, due to this 1,3 diaxial interaction is
a unique aspect, which suggests prospects as a novel polar
structural motif for organic materials.
We are grateful to an Advanced Investigator Grant from
the European Research Council (GO802567) and EPSRC
(BB/F007426/1) for financial support.
17 During the review process we became aware of a paper in press
reporting a 4JFF coupling constant of 25 Hz resulting from 1,3 diaxial
Notes and references
fluorines in
a 2,4-dideoxy-2,4-difluoro-a–D-talopyranoside sugar;
1 L. Hunter, Beilstein J. Org. Chem., 2010, 6, 38; D. O’Hagan, Chem.
Soc. Rev., 2008, 37, 308–319.
2 C. Bucher and R. Gilmour, Angew. Chem., Int. Ed., 2010, 49,
8724–8728.
G. T. Giuffredi, L. E. Jennings, B. Bernet and V. Gouverneur,
J. Fluorine Chem., 2011, in press.
18 H. Eyring, J. Chem. Phys., 1935, 3, 107.
19 M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria,
M. A. Robb, J. R. Cheeseman, J. A. Montgomery, Jr., T. Vreven,
K. N. Kudin, J. C. Burant, J. M. Millam, S. S. Iyengar, J. Tomasi,
V. Barone, B. Mennucci, M. Cossi, G. Scalmani, N. Rega,
G. A. Petersson, H. Nakatsuji, M. Hada, M. Ehara, K. Toyota,
R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda,
O. Kitao, H. Nakai, M. Klene, X. Li, J. E. Knox, H. P. Hratchian,
J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts,
R. E. Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli,
J. W. Ochterski, P. Y. Ayala, K. Morokuma, G. A. Voth, P. Salvador,
J. J. Dannenberg, V. G. Zakrzewski, S. Dapprich, A. D. Daniels,
M. C. Strain, O. Farkas, D. K. Malick, A. D. Rabuck,
K. Raghavachari, J. B. Foresman, J. V. Ortiz, Q. Cui,
A. G. Baboul, S. Clifford, J. Cioslowski, B. B. Stefanov, G. Liu,
A. Liashenko, P. Piskorz, I. Komaromi, R. L. Martin, D. J. Fox,
T. Keith, M. A. Al-Laham, C. Y. Peng, A. Nanayakkara,
M. Challacombe, P. M. W. Gill, B. Johnson, W. Chen,
M. W. Wong, C. Gonzalez and J. A. Pople, Gaussian 03, Revision
D.01, Gaussian, Inc., Wallingford CT, 2004.
3 M. Nicoletti, M. Bremer, P. Kirsch and D. O’Hagan, Chem.
Commun., 2007, 47, 5075; M. Nicoletti, D. O’Hagan and
A. M. Z. Slawin, J. Am. Chem. Soc., 2005, 127, 482.
4 L. Hunter, D. O’Hagan and A. M. Z. Slawin, J. Am. Chem. Soc.,
2006, 128, 16422; L. Hunter, A. M. Z. Slawin, P. Kirsch and
D. O’Hagan, Angew. Chem., Int. Ed., 2007, 46, 7887.
5 D. Farran, A. M. Z. Slawin, P. Kirsch and D. O’Hagan, J. Org.
Chem., 2009, 74, 7168–7171.
6 L. Hunter, P. Kirsch, A. M. Z. Slawin and D. O’Hagan, Angew.
Chem., Int. Ed., 2009, 48, 5457–5460.
7 D.
Rogers,
Nobel
Laureate
Contributions
Century Chemistry, RSC Publishing, Cambridge, 2006.
to
20th
8 1,2-difluorocyclohexanes: A. D. Richardson, K. Hedberg, K. Utzat,
R. K. Bohn, J.-X. Duan and W. R. Dolbier Jr., J. Phys. Chem., 2006,
110, 2053.
9 K. B. Wiberg, W. Hinz, R. M. Jarret and K. B. Aubrecht, J. Org.
Chem., 2005, 70, 8381–8384; K. B. Wiberg, J. Org. Chem., 1999,
64, 6387–6393.
10 Cis/trans mixtures only of 1,3-difluorocyclohexane as a minor
component with other regioisomers; D. F. Shellhamer, M. J. Horney,
A. L. Toth and V. L. Heasley, Tetrahedron Lett., 1992, 46, 6903–6909.
20 J. D. Dunitz and R. Taylor, Chem.–Eur. J., 1997, 3, 89; J. A.
K. Howard, V. J. Hoy, D. O’Hagan and G. T. Smith, Tetrahedron,
1996, 52, 12613.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 8265–8267 8267