New entry for fluorinated carbocycles: Unprecedented 3,6-disubstituted 1,1,2,2-tetrafluorocyclohexane derivatives

Article abstract of DOI:10.1016/j.jfluchem.2017.05.013

The synthetic protocols for symmetrical/unsymmetrical 3,6-disubstituted 1,1,2,2-tetrafluorocyclohexane molecules were successfully established for the first time. Some of thus obtained tetrafluorinated cyclohexanes underwent recrystallization to afford trans-configured products preferentially. One of the unsymmetrical trans-disubstituted tetrafluorocyclohexanes, trans-1-ethyl-2,2,3,3-tetrafluoro-4-[4-(trans-4-n-propylcyclohex-1-yl)phenyl]cyclohexane, was found to possess a low birefringence Δn (0.073) and a large negative dielectric anisotropy Δε (–9.4) in a binary mixture system, which were very prominent as characteristics of LC molecules in VA-mode driving LC displays.

Full text of DOI:10.1016/j.jfluchem.2017.05.013

Accepted Manuscript
Title: New entry for fluorinated carbocycles: Unprecedented
3,6-disubstituted 1,1,2,2-tetrafluorocyclohexane derivatives
Authors: Shigeyuki Yamada, Shohei Hashishita, Hideaki
Konishi, Yuji Nishi, Toshio Kubota, Tomoyuki Asai, Takashi
Ishihara, Tsutomu Konno
PII:
S0022-1139(17)30170-7
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.jfluchem.2017.05.013
FLUOR 8990
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FLUOR
Received date:
Revised date:
Accepted date:
26-4-2017
30-5-2017
30-5-2017
Please cite this article as: Shigeyuki Yamada, Shohei Hashishita, Hideaki
Konishi, Yuji Nishi, Toshio Kubota, Tomoyuki Asai, Takashi Ishihara,
Tsutomu Konno, New entry for fluorinated carbocycles: Unprecedented 3,6-
disubstituted 1,1,2,2-tetrafluorocyclohexane derivatives, Journal of Fluorine
Chemistryhttp://dx.doi.org/10.1016/j.jfluchem.2017.05.013
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New entry for fluorinated carbocycles: Unprecedented 3,6-disubstituted
1,1,2,2-tetrafluorocyclohexane derivatives
Shigeyuki Yamada,a Shohei Hashishita,a Hideaki Konishi,a Yuji Nishi,a Toshio Kubota,b Tomoyuki
Asai,c Takashi Ishihara,a and Tsutomu Konno* a
aFaculty of Molecular Chemistry and Engineering, Kyoto Institute of Technology
Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan
Tel/Fax: +81-75-724-7504; E-mail: konno@kit.ac.jp
bDepartment of Materials Science, Ibaraki University, 4-12-1 Nakanarusawa,
Hitachi 316-8511, Japan
cAGC Seimi Chemical Co., Ltd., Chigasaki 3-2-10, Chigasaki-city, Kanagawa 253-0041, Japan
Graphical abstarct

Graphical Abstract
CF3CO2Et
or
F
F
R1
F
R2
F
F
F
F
F
F F
Tetrafluorinated liquid crystal
Δn 0.073, Δε −9.4
R1, R2 = Ph, p-Tol,
Et, etc
Br
F F

Highlight
1. Synthetic methods for the preparation of tetrafluorinated cyclohexanes were
established.
2. The methods involve a Pd-catalyzed formate reduction or a Barton-McCombie radical
reduction as a key reaction
3. The tetrafluorinated cyclohexanes were found to have a large negative dielectric
anisotropy.
Abstract:
The synthetic
protocols
for
symmetrical/unsymmetrical
3,6-disubstituted
1,1,2,2-tetrafluorocyclohexane molecules were successfully established for the first time. Some of
thus obtained tetrafluorinated cyclohexanes underwent recrystallization to afford trans-configured
products preferentially. One of the unsymmetrical trans-disubstituted tetrafluorocyclohexanes,
trans-1-ethyl-2,2,3,3-tetrafluoro-4-[4-(trans-4-n-propylcyclohex-1-yl)phenyl]cyclohexane,
was
found to possess a low birefringence n (0.073) and a large negative dielectric anisotropy  (–9.4)
in a binary mixture system, which were very prominent as characteristics of LC molecules in
VA-mode driving LC displays.
Keyword: Tetrafluoroethylenated cyclohexane, Homo-coupling, Pd-catalyzed regioselective
formate reduction, Barton-McCombie radical reduction

1. Introduction
Many efforts have been devoted to the development of novel and efficient synthetic protocols for
fluoroorganic molecules because introduction of a fluorine atom into organic substances can often
bring about a significant improvement of their chemical and physical properties owing to the potent
unique nature,1 such as the largest electronegativity, the smallest van der Waals radius (147 pm)
next to a hydrogen atom, and strong C–F bond energy (484 kJ mol–1), etc. Among various
organofluorine compounds, lowly fluorinated (≤ 3 fluorines) or highly fluorinated molecules (> 6
fluorines) have attracted an enormous interest due to their versatile utility in medicinal as well as in
material fields so far, whereas little attention has been paid to the development of semi-fluorinated
organic molecules containing 46 fluorine atoms. As the pioneering work, DiMagno et al.
reported the first synthesis of hexafluoropropylene-containing (-CF2CF2CF2- group) pyranose 1 in
1998 and found that the six fluorine atoms in the structure brought about drastic enhancement of
cell membrane permeability, which was explained by a strong interaction with transport proteins,
rather than non-fluorinated counterparts (Figure 1).2
Since the epoch-making report, extensive studies for the semi-fluorinated cyclic molecules, in
particular cyclic molecules have been carried out in the world and several synthetic approaches
have already been developed so far. For instance, Linclau and co-workers reported efficient and
enantioselective synthetic methods for tetrafluoroethylene-containing (-CF2CF2- group) pyranose 2
and franoses 3, 4.3 Also, Gouverneur et al. successfully developed new CF2CF2-containing
C-nucleosides 5.4 As promising candidates for the sensitive photoswitching devices,
CF2CF2CF2-containing cyclopentene derivatives 6 have also been worthy of remark.5
Owing to the potent utility of such semi-fluorinated cyclic compounds,6 our research group has also
devoted a great deal of attention to the exploitation of the synthetic protocols for novel
semi-fluorinated cyclic compounds. As novel synthetic applications of such cyclic compounds, we
have also focused on the development of unprecedented liquid crystalline (LC) molecules having
the cyclic fragments in the mesogenic core. Very recently, we succeeded in the synthesis of novel
semi-fluorinated carbocycles7 and it was proved that tricyclic organic molecules with the
CF2CF2-containing cyclohexadiene scaffold as a part of mesogen possessed a large negative
dielectric anisotropy in a host liquid-crystal, which would be one of the most desirable properties
for the prominent vertical alignment (VA)-mode liquid-crystalline (LC) display devices.8
In order to further expand our research project on the development of much more efficient liquid

crystals having an unprecedented semi-fluorinated carbocycle fragment, our attention was
subsequently directed towards novel CF2CF2-containing cyclohexane derivatives 7 and 8 that can be
derived from commercially available fluorinated substances (Scheme 1): symmetrical
3,6-disubstituted 1,1,2,2-tetrafluorocyclohexane derivatives 7 can be synthesized from ethyl
trifluoroacetate 9 (Path A) and the unsymmetrical derivatives 8 can be accessed from
4-bromo-3,3,4,4-tetrafluorobut-1-ene 10 (Path B). In this article, we would describe two types of
novel synthetic approaches for unprecedented 3,6-disubstituted 1,1,2,2-tetrafluorocyclohexane
derivatives as new entry for fluorinated carbocycles. In addition, results on the evaluation of LC
properties, such as a birefringence (n) and dielectric anisotropy (), of tricyclic mesogenic
molecules with a 1,1,2,2-tetrafluorocyclohexane moiety, would also be disclosed.
2. Results and discussion
2.1. Synthesis of symmetrical 3,6-disubstituted 1,1,2,2-tetrafluorocyclohexane (Path A)
Initially,
we
designed
a
synthetic
pathway
to
symmetrical
3,6-disubstituted
1,1,2,2-tetrafluorocyclohexane derivatives (Scheme 2). To establish the synthetic approach, we
started with a synthesis of 1,1,2,2-tetrafluoro-3,6-diphenylcyclohexane (7a), where Ar was phenyl
(Ph) group in Scheme 2. Thus, reaction of ethyl trifluoroacetate (9) with phenylmagnesium bromide
in THF at –78 °C during overnight, followed by acidic treatment, gave -trifluoroacetophenone
(11a) in 49% yield (Table 1).9 Subsequent Mg(0)-promoted C–F bond cleavage of 11a, which has
been reported by Amii and Uneyama et al., successfully gave rise to -difluoro enol silane 12a in
good yield.10 Mixing with Cu(OTf)2 in acetonitrile at room temperature, the 12a smoothly
underwent homo-coupling reaction to afford 2,2,3,3-tetrafluoro-1,4-diphenylbutan-1,4-dione (13a)
in 66% yield.11 Exposing the 13a under conditions of Horner-Wadsworth-Emmons reaction, the
carbonyl functionality in 13a was converted to -unsaturated diester, e.g. 14a, in 55% yield as a
single (2E,6E)-isomer.12 The diester moiety in 14a were easily reduced by treating 14a with
diisobutylaluminium hydride (DIBAL-H) in CH2Cl2 at 0 °C for 3 h, leading to the tetrafluorinated
2,6-dien-1,8-diol derivative 15a (66% yield), which was converted to the corresponding dicarbonate
16a in 95% yield after the reaction with ethyl chloroformate (ClCO2Et).
According to our previous report,13 the allyl dicarbonate 16a was subjected to Pd(0)-catalyzed
–
formate reduction with HCO2 NEt3H+, in situ prepared from HCO2H and Et3N, in DMF at 80 °C for
2 h, leading to the desired terminal diene 17a, the internal diene 18a, and other isomers in an
excellent yield as an inseparable mixture. Analyzing the diastereoselectivity (d.r.) of 17a by NMR
measurements, it was found to be approximately 1:1 ratio. Based on the results obtained, possible

reaction mechanism for the Pd(0)-catalyzed formate reduction of tetrafluorinated dicarbonate 16
can be explained as shown in Scheme 3. Thus, the reaction can be initiated by oxidative addition
of 16 to a Pd center to generate -allylpalladium species, which undergoes nucleophilic attack from
formate towards the Pd center, giving rise to the corresponding -allylpalladium complex, Int-A or
Int-B. The Int-B having a large steric repulsion between an aryl group (Ar) and a phosphine ligand,
may be easily interconverted to more stable Int-A with trans-configured ligands. It is also possible
that a Pd metal would be closer to the -carbon attached with an Rf group than the -carbon, like
Int-C, owing to an extremely electron-withdrawing Rf group, though the -position is somewhat
sterically hindered. Accordingly, subsequent evolution of CO2 from the preferentially formed Int-A
or Int-C, followed by hydride migration to -carbon and immediate reductive elimination of Pd(0),
yields the corresponding -product 17 in a regioselective fashion.
With the obtained terminal diene 17a in hand, we examined ring-closing metathesis (RCM)14 using
a Grubbs 2nd generation catalyst. On treating the mixture of 17a, 18a, and other isomers with a
catalytic amount of Grubbs catalyst (5 mol%) in CH2Cl2 at room temperature for 5 days, only 17a
was subjected to the RCM reaction to provide the desired 4,4,5,5-tetrafluoro-
3,6-diphenylcyclohex-1-ene (19a) in high yield as an inseparable diastereomeric mixture (cis/trans
= 56/44). Finally, hydrogenation of 19a under the standard reaction conditions proceeded smoothly
to give the desired 1,1,2,2-tetrafluoro-3,6-diphenylcyclohexane 7a in 83% yield. The NMR
measurements made us note that 7a was structurally well-characterized but still a mixture of
diastereomers in a ratio of cis/trans = 56/44.
With this established synthetic protocol, we carried out the synthesis of novel tetrafluorinated
carbocycles having other aromatic substituents, such as 4-CH3C6H4 and 4-n-C3H7C6H4 group, as
shown in Table 1. As a result, it was proved that the desired CF2CF2-containing cyclohexane
derivatives 7b and 7c were successfully yielded in moderate efficiency. However, the 7b and 7c
was also found to be a mixture of cis/trans isomers (ca. 1/1). To our great delight, it was proved
that the trans isomers of 7b and 7c could be easily obtained in a pure form (cis/trans = <1/>99)
after several recrystallization processes from hexane.
Fortunately, the trans-7b gave a single crystal suitable for X-ray crystallography, which was found
to be monoclinic crystal with P 1 21/a 1 space group and to contain twelve formula units in a unit

cell. The crystal structure and packing structures observed are shown in Fig. 2. The relative
configuration of the preferentially crystalized 7b was proved to be obviously trans-configuration at
3 and 6-positions (Fig. 2a). Viewing the packing structure of 7b, the twelve molecules in a unit
cell were tightly packed with multiple short contact between F···F with 290 pm as well as F···H of
260 pm, both of which are below the sum of van der Waals radii (Fig. 2b).15
Consequently, the synthetic approach for the unprecedented symmetrical 3,6-disubstituted
1,1,2,2-tetrafluorocyclohexane derivatives starting from commercially available fluorinated
substance was successfully developed.
2.2. Synthesis of unsymmetrical 3,6-disubstituted 1,1,2,2-tetrafluorocyclohexane derivatives (Path
B)
Our motivation was subsequently directed towards the development of unsymmetrical
3,6-disubstituted 1,1,2,2-tetrafluorocyclohexane derivatives, which would be more promising
entries for versatile applications, like liquid crystals, etc. It is unfortunate, however, that the
synthetic protocol shown in Scheme 2 is not applicable for construction of the unsymmetrical
derivatives: it is necessary to exploit alternative synthetic approach to the unsymmetrical
CF2CF2-containing cyclohexane derivatives.
As shown in Scheme 4, very recently, our group successfully developed the eight-step synthetic
approach to unsymmetrical 1,4-disubstituted 5,5,6,6-tetrafluorocyclohexa-1,3-diene derivatives 21
through reductive coupling of 10 with aldehyde,16 ozonolysis, Grignard reaction, Oxone®
oxidation,17 allylation, ring closing metathesis, hydrogenation, and the last dehydration of 20.8 To
fulfill our goal, which is novel exploitation of synthetic route to the unsymmetrical 3,6-disubstituted
1,1,2,2-tetrafluorocyclohexane derivatives, we further examined a catalytic hydrogenation of
cyclohexadiene derivative 21 as an initial attempt.
Thus, the 21a dissolved in methanol was exposed under hydrogen atmosphere in the presence of a
catalytic amount of Pd/C (10 mol%) and stirred at room temperature for 1 day. The catalytic
hydrogenation underwent very smoothly to afford the desired unsymmetrical
1,1,2,2-tetrafluorocyclohexane derivatives 8a in 96% yield. After NMR analyses, the 8a was
found to be obtained as a cis/trans-mixture (cis/trans = 70/30).
Several attempts to improve the ratio of cis/trans isomers, such as changing the reaction conditions

of hydrogenation, did not lead to a satisfactory result at all. This undesired stereoselectivity can be
explained on the basis of the coordination pattern of alkene moieties to the Pd center. As
illustrated in Scheme 5, the trans-8a can be obtained when two alkene moieties in 21a coordinate to
the different metal center of the Pd catalyst form an opposite direction, while the cis-8a can be
produced in the hydrogen addition form the same direction via the simultaneous coordination of
both alkenes to Pd center. Apparently, the former reaction is thermodynamicallly unfavorable than
the latter, strongly indicating that a catalytic hydrogenation smoothly afforded 8a with a cis
selectivity.
In order to preferentially obtain the trans-isomers, we next designed an alternative approach, i.e.
Barton-McCombie radical reduction of diol 20 (Scheme 6).
Thus, reaction of tetrafluorinated cyclohexan-1,4-diols 20a–c, which were derived from the same
starting substrate 10,8 with CS2 in the presence of NaH in THF at room temperature, followed by
the treatment of MeI, afforded the corresponding S,S-dimethyl bisxanthates. When the
bisxanthates were submitted under reaction conditions of Barton-McCombie radical reduction,18
they were smoothly converted to the corresponding reduction product, e.g. unsymmetrical
3,6-disubstituted tetrafluorocyclohexane derivatives 8a–c, in good to high yields. In the radical
reaction, the 8 were also found to obtain as a mixture of cis and trans isomers. After detailed
investigations, the ratio of cis-/trans-8 was proved to drastically change, depending on the
substituents at 3 and 6 positions of 8: the ratio of 8a having two aryl substituents at the 3 and 6
positions was cis/trans = 74/26, while the ratio of the others, e.g. 8b and 8c, bearing one alkyl and
one aryl substituents were cis/trans = 28/72 for 8b and cis/trans = 13/87 for 8c, respectively.
The cis/trans-selectivity in the radical reduction can be rationally understood by considering the
reaction mechanism. Scheme 7 shows the possible reaction mechanism. Tributylstannyl radical
(Sn•), generated from n-Bu3SnH and Et3B/O2, attacks thiocarbonyl moiety in a bisxanthate to form
a radical species T1. In all bisxanthates, a thiocarbonyl moieties neighboring aromatic substituent
is preferentially subjected to a radical reaction, resulting in the formation of thermally stable benzyl
radical T1. Subsequent H radical abstraction of the T1 from n-Bu3SnH gives the corresponding
mono-reduction intermediate (Int-D), along with a generation of Sn•. The Sn• generated or
remained in the mixture successively reacts with another xanthate moieties in Int-D to generate
tertiary carbon radical T2. When R2 is an aryl substituent, the radical intermediate is a
resonance-stabilized radical T2-Ar, in which the radical carbon is sp2-hybridized. Therefore, tin
hydride (SnH) preferentially comes close to the equatorial side, avoiding a large steric repulsion
with axial substituents, to afford 3,6-disubstituted tetrafluorocyclohexanes in a cis-selective manner.
In the case of R2 = Et, on the other hand, the radical intermediate is not so stabilized because of the
lack of resonance effect. Accordingly, T2-Eteq, in which the ethyl group occupies the equatorial
position, is more stable than T2-Etax with the ethyl group at the axial position, because of a steric

repulsion between the ethyl and axial substituents in T2-Etax. Therefore the radical reduction
preferentially proceeds via T2-Eteq, resulting in the preferential formation of a thermally stable
trans-8.
In order to further prove the stereoselection in the reaction mechanism, we carried out density
functional theory calculations at the B3LYP/6-311+G(d,p) levels of theory19 for
3,6-diphenyl-1,1,2,2-tetrafluorocyclohexyl
radical
T2-Ar
and
3-ethyl-6-phenyl-1,1,2,2-
tetrafluorocyclohexyl radical T2-Et. In Fig 3-(a) and (b) are shown the most stable conformers for
the above two radicals, and in addition their SOMOs are shown. As shown in (a), the unpaired
electron at the benzylic position is delocalized along with the  electrons on the benzene ring, and
electron clouds are equally oriented in both the benzene ring and the benzylic carbon. Electron
lobes at the benzylic position are also equally oriented on the both equatorial and axial sides.
Consequently, tin hydride preferentially approaches the radical from the equatorial side, avoiding
the large repulsion between tin hydride and axial substituents, to produce cis isomer in a selective
manner.
In sharp contrast, electron lobes at the tertiary radicalic carbon of two conformers in Fig (b), which
are at almost the same energy level, is oriented more largely on the axial side rather than on the
equatorial side. Then, the electron lobe of the tin hydride can overlap with the axially-oriented
lobe more effectively than the equatorially-oriented one, resulting in the preferential formation of
trans isomers.
Among the 8a–c in hand, 8b and 8c were found to be successfully recrystallized from Et2O/MeOH
system, furnishing the trans-isomer in a pure form. The relative structures of trans-8b and
trans-8c were determined by comparing not only their molecular polarity but also their spectral data
to a structure-identified trans-7b.
Consequently, we successfully developed new fluorinated carbocycles, e.g. unsymmetrical
3,6-disubstituted 1,1,2,2-tetrafluorocyclohexane derivatives 8.
The unsymmetrical
trans-configured cyclohexane scaffolds are widely known to be popular mesogenic structures,
which are one of the most important segments in liquid-crystalline (LC) materials.20
2.3. Evaluation of LC properties of unsymmetrical 3,6-disubstituted
1,1,2,2-tetrafluoro-trans-cyclohexane derivatives
In our previous study,8 we have disclosed tricyclic molecules 21b and 21c with
5,5,6,6-tetrafluorocyclohexa-1,3-diene motif exhibited a large negative dielectric anisotropy (),
which is an important characteristic for the application to a vertical alignment (VA)-mode LC
display. From the structural similarity, we envisioned that the present 3,6-disubstituted
trans-1,1,2,2-tetrafluorocyclohexanes, e.g. trans-8b and trans-8c, presented here would become

novel structural motif with a large .
Measuring the thermodynamic behavior of trans-8b and trans-8c using differential scanning
calorimeter and polarizing optical microscope, they did not exhibit any LC phase by direct phase
transition from the crystalline to isotropic phase (Table 2), though the reported 21b and 21c showed
nematic phase with a range of 4–12 °C.21 However, it is in general that binary or multicomponent
mixture systems with a host-material are employed in LC devices in a real world, meaning that the
trans-8b and trans-8c without LC phases in a single molecule can be still candidates for a guest
material. Therefore, we subsequently attempted evaluation of their physical properties, such as
birefringence (n), and dielectric anisotropy (), in a binary mixture system containing trans-8b
and trans-8c (10 wt%) and host material (90 wt%, MLC-6608 (Merck)). To estimate the
properties for a single molecule, we calculated using an extrapolation technique from the results of
a binary mixture system. In Table 3 are shown the observed n and  for the present trans-8b
and trans-8c as well as the data for previously reported cyclohexa-1,3-diene analogues 21b and 21c
as a comparison.
Measuring the n for the binary mixture of trans-8b and trans-8c using Abbe's refractometer,
equipped with a polarizer, the n were 0.13 for trans-8b and 0.073 for trans-8c, respectively.
Indeed, the n values of trans-8b and trans-8c were much lower than those of 21b and 21c, which
indicates that the switching partial mesogenic structure from tetrafluorocyclohexa-1,3-diene to
tetrafluorocyclohexane moiety is significantly attributable to increasing the ordinary refractive
indice. To ensure the change of the birefringence (n) depended on the mesogenic structure,
therefore, we performed quantum chemical calculation19 with a density functional theory at the
B3LYP/6-311+G(d,p) levels of theory for trans-8b, c, together with the reported 21b, c. It has
been known that the n of the molecule mostly depends on the polarizability anisotropy (),
which can explain the numerical relationship of the n for the most molecules.22 The , obtained
from DFT calculations, of 21b, c were 47.16 Å3 for 21b and 35.00 Å3 for 21c, whereas the values
for trans-8b, c were 32.41 Å3 for trans-8b and 23.75 Å3 for trans-8c. The results from DFT
calculations clearly indicate that the changing mesogenic structure to tetrafluorocyclohexane unit
contributes to effective decrease of the polarizability anisotropy. Moreover, comparing the n as
well as  values between trans-8b and trans-8c, the both values for trans-8c were obviously
smaller than those for trans-8b. Judging from these results, as a consequence, introducing less
polar structures in a mesogenic core caused a decrease of the , resulting in a drastic decrease of
the birefringence.
Similarly, the computational studies can be a powerful tool to expect dielectric anisotropy () as
well, since the  strongly depends on the molecular dipole moment ().22 The dipole moment in
short molecular axis (⊥) obtained from DFT calculation led us to figure out that trans-8b, c
possessed a larger molecular dipole ⊥, rather than the ⊥ for the corresponding 21b, c.

Comparing the values of ⊥, it can be easily estimated a larger dielectric anisotropy () in the
present trans-8b, c than the corresponding 21. In fact, the reported  for 21b, c were –6.2 and –
7.3, respectively, whilst more negative  were obtained in trans-8b, c (trans-8b: –7.9, trans-8c: –
9.4).
These results suggest that change of a partial structure in the mesogen, from
5,5,6,6-tetrafluorocyclohexa-1,3-diene to 1,1,2,2-cyclohexane structure, induced a drastic
enhancement of ⊥, resulting in a larger . Comparing the  between trans-8b and trans-8c, it
is likely to be important structural design that existence of less polar cyclohexane moiety in order to
exploit larger negative dielectric molecules. Finally, It can be concluded that the switching the
mesogenic structure from previously reported tetrafluorinated cyclohexadiene to the present
tetrafluorocyclohexane moiety would be effective modification to give rise to the prominent LC
molecules with a low birefringence and a large negative dielectric anisotropy,23 which would be
promising materials to produce LC display devices equipped with both a wide-viewing angle and a
fast response properties.
3. Conclusions
In conclusion, we successfully developed unprecedented fluorinated carbocycles thus far, i.e.
3,6-disubstituted 1,1,2,2-tetrafluorocyclohexane derivatives, starting from commercially available
fluorinated substances. Especially, we realized the development of effective synthetic protocols
for symmetrical disubstituted derivatives 7 as well as unsymmetrical ones 8. It was successful that,
at first time, a determination of relative structure of 3,6-disubstituted tetrafluorocyclohexane moiety
by single X-ray crystallography: it became clear that the disubstituted cyclohexane with
trans-configuration. Similarly, among unsymmetrical tetrafluorocyclohexane derivatives 8
developed in this study, tetrafluorocyclohexane derivatives 8b and 8c with both ethyl and aromatic
substituents were resolved into a single configuration by recrystallization processes, which were
identified as a trans-configuration by comparing with spectral data of purely trans-analogue.
It was notable that the unsymmetrical trans-8b and 8c were found to exhibit a low birefringence
and a large negative dielectric anisotropy, which were evaluated by using extrapolation technique
for the binary mixture with a host material. Comparing to the physical properties of the similar
structure reported before, it was made clear that the present tetrafluorocyclohexane moiety in a
mesogenic structure contributed to the lower birefringence as well as the larger dielectric anisotropy.
We believe that these results and understandings obtained in this study would offer a rational design
of novel LC molecules with a low birefringence as well as a large negative dielectric anisotropy,
and be attributable to development of high-performance VA-mode LC display materials.

4. Experimental
4.1. General information
Infrared spectra (IR) were taken on a JASCO FT/IR 4100 type A spectrometer as a film on a NaCl
plate. 1H NMR (500.13 MHz, 400.13 MHz, 399.65 MHz) and 13C NMR (125.75 MHz, 100.62 MHz,
100.40 MHz) spectra were measured with a Bruker DRX-500 NMR spectrometer, a Bruker
AVANCE III 400 NMR spectrometer, and a JEOL JNM-AL400 NMR spectrometer in a
chloroform-d (CDCl3) solution with a tetramethylsilane (Me4Si) as an internal standard. A JEOL
JNM-EX90A (84.21 MHz, FT) spectrometer and a JEOL JNM-AL400 NMR spectrometer were
used for determining the yield of the fluorine-containing products with hexafluorobenzene (C6F6) as
19
an internal reference. F NMR (376.05 MHz) spectra were measured with a JEOL JNM-AL400
spectrometer in a CDCl3 solution containing CFCl3 (F = 0) as an internal standard. High resolution
mass spectra (HRMS) were taken on a JEOL JMS-700 mass spectrometer by electron impact (EI),
chemical impact (CI) and fast atom bombardment (FAB) methods
4.2. Materials
All chemicals were of reagent grade, and if necessary, were purified in the usual manner prior to use.
Anhydrous tetrahydrofuran (THF) was purchased from Wako chemicals. Thin layer
chromatography (TLC) was done on aluminium sheets coated with Merck silica gel 60F254 plates,
and column chromatography was carried out using Wako-gel C-200 as adsorbent. The
1,4-diaryl-2,2,3,3-tetrafluorobutan-1,4-dione, 13a-c could be prepared from the corresponding
trifluoromethyl aryl ketones 11a-c, according to the literature.10,11 The synthetic procedures for
1,4-disubstituted 5,5,6,6-tetrafluorocyclohexa-1,3-diene (20) from 9, as shown in Scheme 4, were
described in the previous report.8
4.3. General procedure for the synthesis of  -unsaturated ester 14
In a three-necked round-bottomed flask were placed sodium hydride (60% dispersion in oil) (0.26 g,
6.5 mmol) in THF (10 mL) under argon atmosphere, and triethyl phosphonoacetate (1.3 g, 6.0
mmol) was added dropwise to the solution at 0 °C. The resultant homogeneous solution was stirred
at that temperature for 0.5 h, followed by the addition of diketone (1.5 mmol). After completion of
the addition of diketone, the whole was warmed up to room temperature and continuously stirred
for 3 h. The reaction mixture was quenched with saturated aqueous NH4Cl solution, and extracted
with AcOEt three times. The combined organic layers were washed with brine, dried over
anhydrous Na2SO4. After filtration, the filtrate was concentrated using rotary evaporator under
reduced pressure. The resulting crude product was purified by silica-gel column chromatography
(Hexane:AcOEt = 5:1) to obtain the corresponding  -unsaturated diester 14.
4.3.1. Diethyl (2E,6E)-4,4,5,5-tetrafluoro-3,6-diphenylocta-2,6-diene-1,8-dioate (14a).
1
Mp. 87–89 °C; H NMR (CDCl):  1.02 (6H, t, J = 7.2 Hz, CH3), 4.00 (4H, q, J = 7.2 Hz, CH2),

6.50 (2H, s, vinyl-H), 7.19 (4H, d, J = 7.2 Hz, ortho-H in aromatic ring), 7.32–7.40 (6H, m, meta-
and para-H in aromatic ring); 13C NMR (CDCl3):  13.6, 60.8, 115.3 (tt, J = 36.3, 256.2 Hz), 127.1
(m), 127.7, 128.7, 129.1, 132.3, 143.6 (t, J = 22.3 Hz), 164.3; 19F NMR (CDCl3):  –108.77 (4F, s,
CF2CF2); IR (KBr):  2982, 1734, 1374, 1230, 1139, 1027, 706 cm–1; HRMS: calcd for [M+H]+
C24H23F4O4: 451.1532, found 451.1526.
4.3.2. Diethyl (2E,6E)-4,4,5,5-tetrafluoro-3,6-bis(4-methylphenyl)octa-2,6-diene-1,8-dioate (14b).
Mp. 75–77 °C; 1H NMR (CDCl3):  1.03 (6H, t, J = 6.8 Hz, CH3), 2.33 (6H, s, CH3), 3.99 (4H, q, J
= 6.8 Hz, CH2), 6.46 (2H, s, vinyl-H), 7.07 (4H, d, J = 8.0 Hz, Ar-H), 7.13 (4H, d, J = 8.0 Hz,
Ar-H); 13C NMR (CDCl3):  13.6, 21.1, 60.6, 115.6 (tt, J = 35.5, 254.5 Hz), 126.8 (m), 128.3, 128.9,
129.3, 138.5, 143.8 (t, J = 22.2 Hz), 164.2; 19F NMR (CDCl3):  –108.88 (4F, s, CF2CF2); IR (KBr):
 2987, 1711, 1369, 1206, 1146, 1041, 905 cm–1; HRMS: calcd for [M+H]+ C26H27F4O4: 479.1845,
found 479.1851.
4.3.3. Diethyl (2E,6E)-4,4,5,5-tetrafluoro-3,6-bis(4-n-propylphenyl)-octa-2,6-diene-1,8-dioate
(14c).
1
Mp. 61–63 °C; H NMR (CDCl3):  0.95 (6H, t, J = 7.2 Hz, CH3), 1.00 (6H, t, J = 7.0 Hz, CH3),
1.64 (4H, sext, J = 7.2 Hz, CH2CH2CH3), 2.59 (4H, t, J = 7.2 Hz, CH2), 3.98 (4H, q, J = 7.0 Hz,
13
CH2), 6.45 (2H, s, vinyl-H), 7.07 (4H, d, J = 7.6 Hz, Ar-H), 7.14 (4H, d, J = 7.6 Hz, Ar-H); C
NMR (CDCl3):  13.6, 13.8, 24.3, 37.8, 60.7, 115.3 (tt, J = 37.2, 255.4 Hz), 126.8 (m), 127.8, 129.0,
129.6, 143.3, 143.7 (t, J = 24.0 Hz), 164.5; 19F NMR (CDCl3):  –108.91 (4F, s, CF2CF2); IR (KBr):
 2982, 1734, 11374, 1230, 1139, 1027, 706 cm–1; HRMS: calcd for [M+H]+ C30H35F4O4: 535.2471,
found 535.2469.
4.4. General procedure for synthesis of allylic alcohol 15
To a solution of  -unsaturated diester (0.40 mmol) in CH2Cl2 (5.0 mL) was added slowly
diisobutylaluminium hydride (DIBAL-H, 1.0 M in hexane, 2.4 mL, 2.4 mmol) at 0 °C. After being
stirred for 3 h, the reaction was quenched with saturated aqueous NH4Cl solution (20 mL), and the
whole was extracted with CH2Cl2 three times. The combined organic layers were dried over
anhydrous Na2SO4, concentrated in vacuo. The residue was purified by silica-gel column
chromatography (Hexane:AcOEt = 1:1) to give the corresponding allylic alcohol 15.
4.4.1. (2E,6E)-4,4,5,5-Tetrafluoro-3,6-diphenylocta-2,6-diene-1,8-diol (15a).
1
Mp. 148–150 °C; H NMR (Acetone-d6):  3.904.05 (6H, m, CH2OH), 6.41 (2H, t, J = 6.0 Hz,
vinylic-H), 7.05–7.15 (4H, m, Ar-H), 7.307.38 (6H, m, Ar-H); 13C NMR (Acetone-d6):  59.4,
19
116.9 (tt, J = 36.5, 253.8 Hz), 128.7, 128.9, 130.8, 132.3 (t, J = 30 Hz), 134.0, 139.9; F NMR
(CDCl3):  –107.67 (4F, s, CF2CF2); IR (KBr):  3290, 2940, 1138, 1082, 1016, 709 cm–1; HRMS:
calcd for [M+H]+ C20H19F4O2: 367.1321, found 367.1325.

4.4.2. (2E,6E)-4,4,5,5-Tetrafluoro-3,6-bis(4-methylphenyl)octa-2,6-diene-1,8-diol (15b).
1
Mp. 127–129 °C; H NMR (CDCl3):  2.29 (6H, s, CH3), 4.01 (4H, br s, CH2OH), 4.204.40 (2H,
m, OH), 6.356.45 (2H, m, vinylic-H), 6.95–7.10 (4H, m, Ar-H), 7.15–7.20 (4H, m, Ar-H); 13C
NMR (CDCl3):  21.2, 59.6, 115.9 (tt, J = 35.5, 291.0 Hz), 128.7, 129.7, 129.9, 133.4 (t, J = 24.7
Hz), 136.6 (m), 138.1; 19F NMR (CDCl3):  –107.83 (4F, s, CF2CF2); IR (KBr):  3348, 2920, 1430,
1138, 1088, 1040, 968 cm–1; HRMS: calcd for [M+Na]+ C22H22F4NaO2: 417.1454, found 417.1462.
4.4.3. (2E,6E)-4,4,5,5-Tetrafluoro-3,6-bis(4-n-propylphenyl)-octa-2,6-diene-1,8-diol (15c).
1H NMR (CDCl3):  0.96 (6H, t, J = 7.6 Hz, CH3), 1.65 (4H, sext., J = 7.6 Hz, CH2), 2.34 (2H, s,
OH), 2.59 (4H, t, J = 7.6 Hz, CH2), 4.02 (4H, br d, J = 6.4 Hz, CH2OH), 6.37 (2H, t, J = 6.4 Hz,
13
vinylic-H), 7.01 (4H, d, J = 8.4 Hz, Ar-H), 7.13 (4H, d, J = 8.4 Hz, Ar-H); C NMR (CDCl3): 
13.9, 24.4, 37.8, 59.5, 116.3 (tt, J = 36.3, 255.4 Hz), 128.1, 129.8, 130.2, 133.4 (t, J = 23.1 Hz),
19
136.8 (m), 142.8; F NMR (CDCl3):  –108.67 (4F, s, CF2CF2); IR (neat):  3347, 2960, 2872,
1457, 1219, 1081, 1021, 977 cm–1; HRMS: calcd for [M+Na]+ C26H30F4NaO2: 473.2080, found
473.2084.
4.5. General procedure for synthesis of allylic dicarbonate 16
The allylic alcohol (0.23 mmol) in CH2Cl2 (5.0 mL) was placed in a three-necked round-bottomed
flask with stirrer bar under an argon atmosphere. To the solution was added ethyl chloroformate
(1.15 mmol) at 0 °C, followed by adding pyridine (0.08 mL, 0.99 mmol). The reaction mixture was
allowed to warm up to room temperature and stirred overnight. The resultant solution was quenched
with saturated aqueous NH4Cl solution, and separated the organic layer. The aqueous solution was
washed with AcOEt twice and the combined organic layers were washed with brine, dried over
anhydrous Na2SO4, concentrated using rotary evaporator. The resulting mixture was purified by
silica-gel column chromatography (Hexane:AcOEt = 1:1) to obtain the corresponding allylic
dicarbonate 16.
4.5.1. Diethyl (2E,6E)-4,4,5,5-tetrafluoro-3,6-diphenylocta-2,6-diene-1,8-diyl dicarbonate (16a).
1
Mp. 56–58 °C; H NMR (CDCl3):  1.29 (6H, t, J = 7.2 Hz, CH2CH3), 4.17 (4H, q, J = 7.2 Hz,
CH2CH3), 4.50 (4H, d, J = 6.4 Hz, CH2O), 6.36 (2H, t, J = 6.4 Hz, vinylic-H), 7.11–7.36 (10H, m,
13
Ar-H); C NMR (CDCl3):  14.0, 63.9, 64.0, 115.3 (tt, J = 37.3, 254.6 Hz), 128.0, 128.4, 129.6,
19
131.8 (m), 132.1, 135.2 (t, J = 23.2 Hz), 154.6; F NMR (CDCl3):  –108.72 (4F, s, CF2CF2); IR
(KBr):  2987, 1748, 1252, 1139, 1092, 988, 791 cm–1; HRMS: calcd for [M+H]+ C26H27F4O6:
511.1744, found 511.1735.
4.5.2.
Diethyl
(2E,6E)-4,4,5,5-tetrafluoro-3,6-bis(4-methylphenyl)octa-2,6-diene-1,8-diyl
dicarbonate (16b).

1H NMR (CDCl3):  1.29 (6H, t, J = 6.8 Hz, CH2CH3), 2.35 (6H, s, CH3), 4.17 (4H, q, J = 6.8 Hz,
CH2CH3), 4.51 (4H, d, J = 6.2 Hz, CH2O), 6.32 (2H, t, J = 6.2 Hz, vinylic-H), 7.00 (4H, d, J = 8.4
Hz, Ar-H), 7.14 (4H, d, J = 8.4 Hz, Ar-H); 13C NMR (CDCl3):  13.8, 20.8, 59.9, 63.8, 115.3 (tt, J =
37.2, 255.4 Hz), 128.6, 129.1, 129.4, 131.4 (m), 135.2 (t, J = 23.9 HZ), 138.1, 154.5; 19F NMR
(CDCl3):  –108.79 (4F, s, CF2CF2); IR (neat):  2984, 1613, 1446, 1345, 1140, 1094, 873 cm–1;
HRMS: calcd for [M+H]+ C28H31F4O6: 539.2057, found: 539.2058.
4.5.3.
Diethyl
(2E,6E)-4,4,5,5-tetrafluoro-3,6-bis(4-n-propylphenyl)-octa-2,6-diene-1,8-diyl
dicarbonate (16c).
1H NMR (CDCl3):  1.03 (6H, t, J = 7.6 Hz, CH2CH3), 1.35 (6H, t, J = 7.2 Hz, OCH2CH3), 1.73
(4H, sext., J = 7.6 Hz, CH2CH2CH3), 2.67 (4H, t, J = 7.6 Hz, CH2CH2CH3), 4.24 (4H, q, J = 7.2 Hz,
OCH2CH3), 4.61 (4H, d, J = 6.4 Hz, CH2O), 6.44 (2H, t, J = 6.4 Hz, vinylic-H), 7.10 (4H, d, J = 8.0
Hz, Ar-H), 7.23 (4H, d, J = 8.0 Hz, Ar-H); 13C NMR (CDCl3):  13.6, 14.0, 24.1, 37.6, 64.00, 64.04,
115.4 (tt, J = 36.3, 254.5 Hz), 128.1, 129.4, 129.5, 131.6 (m), 135.4 (t, J = 24.0 Hz), 143.0, 154.7;
19F NMR (CDCl3):  –108.91 (4F, s, CF2CF2); IR (neat):  2961, 1748, 1370, 1139, 1037, 1000, 791
cm–1; HRMS: calcd for [M+H]+ C32H39F4O6: 595.2683, found: 595.2692.
4.6. General procedure for Pd(0)-catalyzed formate reduction
To a DMF solution of Pd(0) catalyst, prepared in situ by mixing Pd2(dba)3·CHCl3 (12 mg, 0.012
mmol) and PPh3 (24 mg, 0.092 mmol), was added dicarbonate (0.23 mmol) at room temperature.
After stirring of reaction mixture for 10 min at that temperature, a DMF solution of
triethylammonium formate, prepared from formic acid (0.021 mL, 0.55 mmol) and triethylamine
(0.090 mL, 0.64 mmol), was added to the reaction mixture, and the resultant was stirred at 80 °C for
2 h. The resultant solution was quenched with saturated aqueous NH4Cl solution, and the whole was
extracted with Et2O three times. The combined organic layers were washed with brine, dried over
anhydrous Na2SO4, concentrated in vacuo. The residual crude product was purified by silica-gel
column chromatography (Hexane:AcOEt = 10:1) to give the 4,4,5,5-tetrafluoroocta-1,7-diene 17 as
a mixture of regioisomers.
4.6.1. 4,4,5,5-Tetrafluoro-3,6-diphenylocta-1,7-diene (17a).
Diastereomeric ratio 17a:other isomers = 61:39; HRMS: calcd for [M+] C20H18F4: 334.1345, found:
1
334.1353; [Terminal diene 17a] H NMR (CDCl3):  3.90–4.10 (2H, m, allylic-H), 5.08–5.30 (4H,
m, CH=CH2), 6.13–6.25 (2H, m, CH=CH2), 7.17–7.37 (10H, m, Ar-H); 19F NMR (CDCl3):  –
1
112.87 to –110.62 (4F, m, CF2CF2); [Internal diene 18a] H NMR (CDCl3):  1.25 (6H, s, CH3),
6.30–6.45 (2H, m, vinylic-H); 19F NMR (CDCl3):  –112.87 to –110.17 (4F, m, CF2CF2).
4.6.2. 4,4,5,5-Tetrafluoro-3,6-bis(4-methylphenyl)octa-1,7-diene (17b).
1
Diastereomeric ratio 17b:other isomers = 62:38; [Terminal diene 17b] H NMR (CDCl3):  2.30–

2.36 (6H, m, CH3), 3.90–4.05 (2H, m, allylic-H), 5.07–5.25 (4H, m, CH=CH2), 6.16 (2H, dt, J =
19
16.8, 8.4 Hz, CH=CH2), 7.06–7.25 (8H, m, Ar-H); F NMR (CDCl3):  –113.03 to –110.18 (4F,
m); [Internal diene 18b] 1H NMR (CDCl3):  1.26–1.59 (6H, m, CH3), 2.36 (6H, s, CH3), 6.28–6.40
(2H, m, vinylic-H); 19F NMR (CDCl3):  –113.03 to –110.18 (4F, m, CF2CF2).
4.6.3. 4,4,5,5-Tetrafluoro-3,6-bis(4-n-propylphenyl)octa-1,7-diene (17c).
Diastereomeric ratio 17c:other isomers = 64:36; HRMS: calcd for [M+] C26H30F4: 418.2284, found:
1
418.2283; [Terminal diene 17c] H NMR (CDCl3):  0.89–0.98 (6H, m, CH3), 1.53–1.69 (4H, m,
CH2), 2.54–2.61 (4H, m, CH2), 3.88–4.10 (2H, m, allylic-H), 5.06–5.24 (4H, m, CH=CH2), 6.13–
6.36 (2H, m, CH=CH2), 7.08–7.18 (8H, m, Ar-H); 19F NMR (CDCl3):  –113.24 to –110.03 (4F, m,
1
CF2CF2); [Internal diene 18c] H NMR (CDCl3):  6.30–6.40 (2H, m, vinylic-H), 19F NMR
(CDCl3):  –114.24 to –109.68 (4F, m, CF2CF2).
4.7. General procedure for ring-closing metathesis of diene 17
To a solution of Grubbs 2nd generation catalyst (10 mg, 5 mol%, 0.011 mmol) in CH2Cl2 (5.0 mL)
was added the diene 17 (0.23 mmol) at room temperature. The reaction mixture was stirred at room
temperature for 5 days, then the solution was pass through silica-gel to give the crude solution. The
solution was evaporated using rotary evaporator under high vacuum to afford the crude residue,
which was purified by silica-gel column chromatography (Hexane:Benzene = 20:1) to yield the
cyclic compound as a mixture of diastereoisomers.
4.7.1. 4,4,5,5-Tetrafluoro-3,6-diphenylcyclohex-1-ene (19a).
Diastereomeric ratio cis/trans = 56/44; HRMS: calcd for [M+] C18H14F4: 306.1032, found:
1
306.1026; [cis isomer] H NMR (CDCl3):  4.19–4.26 (2H, m, allylic-H), 5.99 (2H, brs, CH=CH),
19
7.28–7.43 (10H, m, Ar-H); F NMR (CDCl3):  –123.76 to –123.06 (2F, m, CF2), –115.59 to –
1
19
114.87 (2F, m, CF2); [trans isomer] H NMR (CDCl3):  5.89–5.91 (2H, m, CH=CH); F NMR
(CDCl3);  –128.19 to –127.45 (2F, m, CF2), –124.26 to –123.41 (2F, m, CF2).
4.7.2. 4,4,5,5-Tetrafluoro-3,6-bis(4-methylphenyl)cyclohex-1-ene (19b).
1
Diastereomeric ratio cis/trans = 51/49; [cis isomer] H NMR (CDCl3):  2.37 (6H, s, CH3), 4.10–
19
4.25 (2H, m, allylic-H), 5.95 (2H, brs, CH=CH), 7.10–7.30 (8H, m, Ar-H); F NMR (CDCl3):  –
123.70 to –123.03 (2F, m, CF2), –115.56 to –114.85 (2F, m, CF2); (The trans isomer could be
obtained in a pure form after recrystallization.) [trans isomer] Mp. 163–165 °C; 1H NMR (CDCl3):
 2.39 (6H, s, CH3), 4.10–4.25 (2H, m, allylic-H), 5.82–5.88 (2H, m, CH=CH), 7.23 (8H, s, Ar-H);
13C NMR (CDCl3):  21.1, 47.3–48.0 (m), 115.6 (dddd, J = 245.5, 244.7, 37.2, 21.5 Hz), 127.7 (m),
19
129.2, 129.9, 130.2, 138.1; F NMR (CDCl3):  –128.13 to –127.40 (2F, m, CF2), –124.29 to –
123.44 (2F, m, CF2); IR (KBr):  1298, 1206, 1122, 1075, 861 cm–1; HRMS: calcd for [M+]
C20H18F4: 334.1345, found: 334.1337.

4.7.3. 4,4,5,5-Tetrafluoro-3,6-bis(4-n-propylphenyl)cyclohex-1-ene (19c).
Diastereomeric ratio cis/trans = 52/48; IR (neat):  3027, 2960, 2931, 2871, 1513, 1465, 1421,
1297, 1191, 1118, 1099 cm–1; HRMS: calcd for [M–H]+ C24H25F4: 389.1892, found: 389.1902; [cis
1
isomer] H NMR (CDCl3):  0.99 (6H, t, J = 7.34 Hz, CH3), 1.60–1.75 (4H, m, CH2CH2CH3),
2.60–2.68 (4H, m, CH2CH2CH3), 4.15–4.30 (2H, m, allylic-H), 5.98 (2H, brs, CH=CH), 7.20–7.35
19
(8H, m, Ar-H); F NMR (CDCl3):  –123.71 to –123.04 (2F, m, CF2), –115.59 to –114.89 (2F, m,
1
CF2); [trans isomer] H NMR (CDCl3):  1.00 (6H, t, J = 7.42 Hz, CH3), 5.855.95 (2H, m,
CH=CH); 19F NMR (CDCl3):  –128.11 to –127.44 (2F, m, CF2), –124.30 to –123.54 (2F, m, CF2).
4.8. General procedure for preparation of cyclohexane 7
To a suspension of Pd/C (24 mg) in MeOH (6.0 mL) was added the cyclohexene (19, 0.14 mmol) in
AcOEt (1.0 mL) at room temperature. Then, the argon in the flask was replaced into gaseous
hydrogen, and the whole was stirred at that temperature during overnight. The mixture was filtered,
and thus obtained filtrate was concentrated in vacuo. The residue was purified by silica-gel column
chromatography (Hexane:Benzene = 1:1) to afford the cyclohexane as a mixture of diastereomers.
4.8.1. 2,2,3,3-Tetrafluoro-1,4-diphenylcyclohexane (7a).
Diastereomeric ratio cis/trans = 56/44; IR (neat):  3096, 3065, 3034, 2964, 2878, 1602, 1584,
1498, 1456, 1262, 1228, 1168, 1103, 1082 cm–1; HRMS: calcd for [M+] C18H16F4: 308.1188, found:
1
308.1198; H NMR (CDCl3):  2.05–2.08 (1H, m, axial/equatorial-CH), 2.11–2.22 (2H, m, CH2),
2.47–2.51 (1H, m, axial/equatorial-CH), 3.35–3.37 (1H, m, CHCF2), 3.59–3.63 (1H, m, CHCF2),
7.32–7.44 (10H, m, Ar-H); [cis isomer] 19F NMR (CDCl3):  –113.16 (2F, d, J = 258.7 Hz, CF2), –
19
122.38 (2F, ddd, J = 17.7, 17.1, 258.7 Hz, CF2); [trans isomer] F NMR (CDCl3):  –125.08 to –
124.92 (4F, m, CF2CF2).
4.8.2. 2,2,3,3-Tetrafluoro-1,4-bis(4-methylphenyl)cyclohexane (7b).
Diastereomeric ratio cis/trans = 51/49; The trans isomer could be obtained in a pure form after
recrystallization. [trans isomer] Mp. 85–87 °C; 1H NMR (CDCl3):  1.95–1.98 (2H, m, CH2), 2.03–
2.12 (2H, m, CH2), 2.34 (6H, brs, CH3), 3.20–3.35 (2H, m, CHCF2), 7.17 (4H, d, J = 8.39 Hz,
Ar-H), 7.24 (4H, d, J = 8.39 Hz, Ar-H); 13C NMR (CDCl3):  21.0, 27.6, 46.3–46.9 (m), 116.9 (tt, J
= 25.6，256.2 Hz), 129.1, 131.8, 137.7, One carbon in the aromatic ring could not be detected by
overlapping with other signals; 19F NMR (CDCl3):  –125.11 to –125.06 (4F, m, CF2CF2); IR
(KBr):  2920, 1516, 1284, 1214, 1104, 1072, 1014, 905, 811 cm–1; HRMS: calcd for [M+]
C20H20F4: 336.1501, found: 336.1508.
4.8.3. 2,2,3,3-Tetrafluoro-1,4-bis(4-n-propylphenyl)cyclohexane (7c).
Diastereomeric ratio cis/trans = 52/48; The trans isomer could be obtained in a pure form after

1
recrystallization. [trans isomer] Mp. 112–114 °C; H NMR (CDCl3):  0.96 (6H, t, J = 7.40 Hz,
CH3), 1.66 (4H, sext., J = 7.40 Hz, CH2CH2CH3), 2.00–2.10 (2H, brs, axial/equatorial-CH), 2.10–
2.20 (2H, m, axial/equatorial-CH), 2.55–2.65 (4H, m, CH2CH2CH3), 3.20–3.40 (2H, brs, CHCF2),
13
7.11 (4H, d, J = 6.8 Hz, Ar-H), 7.20 (4H, d, J = 6.8 Hz, Ar-H); C NMR (CDCl3):  14.0, 24.6,
27.8, 37.8, 46.647.3 (m), 117.2 (tt, J = 27.6, 256.0 Hz), 128.7, 129.3, 132.2, 142.6; 19F NMR
(CDCl3):  –125.03 to –125.09 (4F, m, CF2CF2); IR (KBr): 1655, 1542, 1076, 817 cm–1; HRMS:
calcd for [M+] C24H28F4: 392.2127, found: 392.2133.
4.9. Typical procedure for the synthesis of cyclohexane 8a in a catalytic hydrogenation protocol
To a suspension of Pd/C (28 mg) in MeOH (10 mL) was added a pale yellow solid of diene8 (21a,
0.10 g, 0.27 mmol) at room temperature. Then, the argon in the flask was replaced into gaseous
hydrogen, and the whole was stirred at that temperature during overnight. The mixture was filtered
through silica-gel, and thus obtained filtrate was concentrated in vacuo. The resultant colorless oil
was purified by silica-gel column chromatography (Hexane:Benzene = 3:1) to give the
corresponding cyclohexane 8a (88 mg, 0.23 mmol) in 85% isolated yield as a colorless oil.
4.9.1. 1-(4-Ethylphenyl)-2,2,3,3-tetrafluoro-4-(4-n-propylphenyl)cyclohexane (8a).
Diastereomeric ratio: cis/trans = 60/40; IR (neat):  2963, 2932, 1516, 1177, 1108, 1077, 1012, 907
cm–1; HRMS: calcd for [M+] C23H26F4: 378.1971, found: 378.1973; [cis isomer]: 1H NMR (CDCl3):
 0.88 (3H, t, J = 7.6 Hz, CH3), 1.17 (3H, t, J = 7.6 Hz, CH3), 1.54–1.58 (2H, m, CH2), 1.94–2.01
(3H, m, CH2 and CH), 2.30–2.42 (2H, m, CH2), 2.49–2.60 (4H, m, CH2 and CH2), 3.46–3.55 (1H,
19
m, CH), 7.07–7.29 (8H, m, Ar-H); F NMR (CDCl3):  –122.77 to –121.99 (2F, m, CF2), –113.17
(2F, d, 1J = 248.6 Hz, CF2); [trans isomer] 1H NMR (CDCl3):  0.89 (3H, t, J = 7.2 Hz, CH3), 1.18
(3H, t, J = 7.2 Hz, CH3), 3.22–3.24 (1H, m, CH), other signals cannot be assigned due to an
extremely complicated spectrum; 19F NMR (CDCl3):  –125.07 to –125.02 (4F, m, CF2 and CF2).
4.10. Typical procedure for the synthesis of trans-cyclohexane trans-8b using a Barton-McCombie
radical reduction
Cyclohexan-1,4-diol8 (0.16 g, 0.38 mmol) was added into a reaction flask placed sodium hydride
(60% dispersion in oil, 0.15 g, 3.8 mmol), and the mixture was stirred at room temperature for 0.5 h.
Then, CS2 (0.23 mL, 3.8 mmol) was added to the reaction mixture and stirred at room temperature
for 2 h. To the resultant solution was added a solution of MeI (0.23 mL, 3.8 mmol) in CH2Cl2 (5.0
mL) and the whole was stirred another 2 h. The reaction mixture was quenched with water and
extracted with Et2O three times. The combined organic layers were washed with brine, dried over
anhydrous Na2SO4 and concentrated in vacuo. The residue was dissolved in CH2Cl2 (2.4 mL) and
nBu3SnH (0.40 mL, 1.5 mmol) was added into a flask at room temperature. After stirring at that
temperature for 24 h, the reaction mixture was quenched with water and extracted with CH2Cl2
three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4

and concentrated in vacuo. The resultant was purified by silica gel column chromatography (eluent:
Hexane:AcOEt = 20:1) to obtain the corresponding cyclohexane 8b as a mixture of diastereomers.
The mixture was purified by recrystallization from MeOH/Et2O three times to afford the trans
cis/trans = 0/100).
4.10.1.
trans-1-Ethyl-2,2,3,3-tetrafluoro-4-[4-(trans-4-n-propylphenyl)phenyl]cyclohexane
(trans-8b).
Mp. 117–118 °C; 1H NMR (CDCl3):  1.01 (3H, t, J = 7.2 Hz, CH3), 1.07 (3H, t, J = 7.6 Hz, CH3),
1.38–1.48 (2H, m, CH2), 1.72 (2H, sext., J = 7.6 Hz, CH2), 1.77–1.90 (5H, m, CH and CH2), 2.67
(2H, t, J = 7.6 Hz, CH2), 3.20–3.31 (1H, m, CH), 7.29 (2H, d, J = 7.6 Hz, Ar-H), 7.41 (2H, d, J =
8.4 Hz, Ar-H), 7.54 (2H, d, J = 7.6 Hz, Ar-H), 7.60 (2H, d, J = 8.4 Hz, Ar-H); 13C NMR (CDCl3): 
11.6, 13.9, 19.5, 24.5, 25.9 (d, J = 6.6 Hz), 27.5–27.6 (m, 1C for CH or CH2 on cyclohexane), 37.7,
42.6 (t, J = 20.3 Hz), 46.7 (dt, J = 20.7, 1.9 Hz), 114.4–121.1 (m, 2C for CF2CF2), 126.88, 126.91,
19
128.9, 130.0, 133.7, 138.0, 140.8, 142.0; F NMR (CDCl3):  –128.85 to –128.14 (1F, m, CF), –
127.49 (1F, dd, J = 253.8, 24.3 Hz, CF), –125.68 to –125.60 (2F, m, CF2); IR (KBr):  2975, 2935,
2875, 1497, 1283, 1184, 1143, 1119, 1011, 996 cm–1; HRMS: calcd for [M+] C23H26F4: 378.1971,
found: 378.1968.
4.10.2. trans-1-Ethyl-2,2,3,3-tetrafluoro-4-[4-(trans-4-n-propylcyclohex-1-yl)phenyl]cyclohexane
1
(trans-8c). Mp. 95–96 °C; H NMR (CDCl3):  0.91 (3H, t, J = 7.4 Hz, CH3), 1.03 (3H, t, J = 7.6
Hz, CH3), 1.00–1.10 (2H, m, CH2), 1.15–1.50 (9H, m, CH and CH2 on cyclohexane), 1.80–2.10
(9H, m, CH and CH2 on cyclohexane), 2.47 (1H, tt, J = 11.6, 3.4 Hz, CH), 3.10–3.25 (1H, m, CH),
13
7.19 (2H, d, J = 8.0 Hz, Ar-H), 7.24 (2H, d, J = 8.0 Hz, Ar-H); C NMR (CDCl3):  12.0, 14.8,
19.8, 20.4, 26.3 (d, J = 7.4 Hz), 27.9, 33.9, 34.6, 37.4, 40.1, 43.0 (t, J = 20.3 Hz), 44.6, 47.0 (t, J =
19.8 Hz), 114.5–121.5 (m, 2C for CF2CF2), 127.2, 129.5, 132.7, 147.9; 19F NMR (CDCl3):  –
128.54 (1F, d, J = 251.6 Hz, CF), –127.55 (1F, dd, J = 251.6. 24.4 Hz, CF), –126.50 to –125.10 (2F,
m, CF2); IR (KBr):  2924, 2846, 1459, 1114, 826 cm–1; HRMS: calcd for [M+] C23H32F4: 384.2440,
found: 384.2445.
4.11. X-Ray crystallographic analysis
X-Ray analysis crystal data C20H20F4, M=336.37, a=15.847(20) Å, =31.72(5) Å, c=10.528(7) Å,
=90°, =97.14(8)°, =90°, V=5250(11) Å3, calcd=1.276 g/cm3, Z=12. Intensities of 12481
reflections (Rint=0.058) were measured at 298.1 K with a Rigaku AFC7R using graphite
monochromated Mo K radiation (=0.71069 Å, /2 scan, ≤30°). The structure was solved by
direct method and refined by full matrix least squares against F2 in the anisotropic (H-atoms
isotropic) approximation. All hydrogen atoms were located from the electron density difference
synthesis and were included in the refinement in isotropic approximation. The refinement
converged to wR2=0.2294 and GOF=1.002 for 12485 independent reflections (R1=0.0717, I>2(I)).

The number of refined parameters was 710. All calculations were performed using the
CrystalStructure 3.8. Crystallographic data for this compound has been deposited with the
Cambridge Crystallographic Data Centre, whose CCDC no. CCDC 1483305. Copy of the data can
be obtained free of charge by applying to CCDC, 12 Union Road, Cambridge CB2, 1EZ, UK
(https://summary.ccdc.cam.ac.uk/structure-summary-form; email: deposit@ccdc.cam.ac.uk.
4.12. Computational studies
All calculations were carried out using the Gaussian09 program19 package and density functional
theory (DFT) method. We used the standard basis set, 6-311+G(d,p) levels of theory for the
geometry optimizations.
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[23] The shear viscosity () for new liquid crystals reported in this article was found to be
higher values (96 mPa·s for trans-8b and 77 mPa·s for trans-8c) than the corresponding
tetrafluorinated cyclohexadiene analogues reported in ref. [8].

Fig. 1. Various semi-fluorinated cyclic materials
(a)
(b)
Fig. 2 (a) Crystal structure and (b) Packing structure of trans-7b. Color legend: C, gray; H, light
gray; F, light green. Light blue line: short contact below the sum of van der Waals radii.

Fig. 3. SOMOs of 3,6-diphenyl-1,1,2,2-tetrafluorocyclohexyl and 3-ethyl-6-phenyl-1,1,2,2-
tetrafluorocyclohexyl radicals
Path A for symmetrical derivatives
O
R1
R2
R1MgBr
+
EtO
CF3
F
F
F
F
9
7 (R1=R2) : symmetrical
8 (R1≠R2) : unsymmetrical
3,6-Disubstituted
1,1,2,2-tetrafluorocyclohexanes
F
F
Br
Path B for unsymmetrical derivatives
F
F
– Catalytic hydrogenation of cyclohexadienes
– Radicalic Barton-McCombee reduction of
– cyclohexane-1,4-diols
10
Four
steps
Three
steps
HO
R1
OH
R2
O
F
F
F
R1
R2
R2
R1
F
F
F
F
F
F
F
O
F
F
Scheme 1. Synthetic approaches to unprecedented
3,6-disubstituted 1,1,2,2-tetrafluorocyclohexane derivatives

Scheme 2. Synthetic route to symmetrical 3,6-disubstituted 1,1,2,2-tetrafluorocyclohexane
derivatives

Ar
Rf
OCO2Et
H
PPh3
Pd
CO2
16
Ar
OEt
Rf
Oxidative
Addition
H
HCO2 NEt3H
Ph3P
Ar
PPh3
HOCO
OCOH
Pd
slow
Ar
Pd
cis-trans
Isomerization
a
g
a
Rf
g
Rf
H
H
Int-A
Int-B
PPh3
HOCO
Pd
– CO2
– CO2
Pd(0)
Ar
a
g
Rf
Ph3P
Ar
PPh3
H
H
H
Ar
Int-C
Pd
Pd
a
g
a
Rf
g
Rf
– CO2
H
H
PPh3
H
Pd
Ar
a
g
Rf
H
Reductive Elimination
Ar
Ar
a
g
a
Rf
g
Rf
17 (g-product)
H
H
18 (a -product)
Scheme 3. Possible reaction mechanism for -selective
formate-reduction of fluorinated allylic dicarbonate 16

Scheme 4. Previous work: an easy access to
various tetrafluoroethylenated cyclohexadienes
Scheme 5. Catalytic hydrogenation of 21a to unsymmetrical
tetrafluorocyclohexane derivative 8a and the reasonable
explanation on the stereoselectivity.

Scheme 6. Alternative approach to unsymmetrical
tetrafluorocyclohexanes 8 through Barton-McCombie radical reduction.
Scheme 7. Possible reaction mechanism for a radical
reduction of bisxanthate.