Synthesis of a mesogenic compound with a defined conformation

Article abstract of DOI:10.1055/s-2001-14633

The synthesis of the bicyclohexyl derivative 2 has been attained in 4 steps by bi-directional elaboration of bicyclohexanone 3. Due to the specifically placed methyl substituents, 2 populates a single conformation at the inter-ring bond, resulting in improved material properties.

Full text of DOI:10.1055/s-2001-14633

960
LETTER
Synthesis of a Mesogenic Compound with a Defined Conformation
Reinhard W. Hoffmann,*,a Trixi Brandl,a Peer Kirsch,b Klaus Harmsa
aFachbereich Chemie, Philipps-University of Marburg, Hans-Meerwein-Strasse, 35032 Marburg, Germany
bMerck KGaA, Liquid Crystals Division, 64271 Darmstadt, Germany
Fax +49 6421 2828917; E-mail: rwho@chemie.uni-marburg.de
Received 22 January 2001
and the trans conformation 1a (42%, calculated
=
Abstract: The synthesis of the bicyclohexyl derivative 2 has been
attained in 4 steps by bi-directional elaboration of bicyclohexanone
3. Due to the specifically placed methyl substituents, 2 populates a
single conformation at the inter-ring bond, resulting in improved
material properties.
0.4). A Boltzmann distribution over the two conforma-
tions 1a and 1b predicts an averaged -value of 1.7,
which is slightly lower than the experimentally deter-
mined value of
=
2.5. Obviously, if the conformer
equilibrium can be shifted in the direction of 1b, the com-
pounds should posses larger negative -values. A shift in
the conformer population toward 1b could be attained by
rational placement of substituents, i.e. by rational confor-
mation design.6
Key words: carbocycles, conformation, fluorine, liquid crystals
Increased use of liquid crystal displays in electronic de-
vices led to a constantly growing demand of new liquid
crystalline materials with optimal properties, such as high
clearing temperature, low rotational viscosity or high di-
electric anisotropy ( ).1 Recent studies on liquid crystal-
line compounds of the type 1 demonstrated a remarkable
dependence of the dielectric anisotropy of these axially
fluorinated bicyclohexyl derivatives on the conformation
of the molecular backbone.2 AM1-calculations indicated
that the dielectric anisotropy vanishes when the dipole
moments of the C-F bonds point in opposite directions
and cancel each other, i.e. if the conformation at the bicy-
clohexyl bond is trans ( = dihedral angle H-C-C-
H = 180°), cf. Scheme 1. In conformations with smaller
dihedral angles the dipoles reinforce each other: the small-
er the more negative will be the dielectric anisotropy
We therefore targeted the C2-symmetric compound 2,
which has two additional methyl groups compared to
compound 1. While maintaining free rotation about the in-
ter-ring bond the two equatorial methyl groups should de-
stabilize both the trans conformation 2a as well as one of
the two possible gauche conformations (2c) by two syn-
pentane interactions to the point that these arrangements
are no longer minima on the rotational energy profile (a
comparison of the calculated rotational profiles for 1 and
2 is given in Figure 1).4,5 The calculations show for 2 only
two minima on the rotational energy profile: 2b (
=
60°) and, substantially (+4.9 kcal mol-1) higher, another
conformer which reduces syn-pentane interactions by
increasing7 the dihedral angle
to 80°. Compound 2
should therefore populate exclusively the strain-free
gauche conformation 2b (cf. Scheme 2) which, due to the
small dihedral angle at the inter-ring bond should lead to
a significantly larger negative -value.
. The actual value of
average over the conformer population.
is then the population weighted
Compound 1 populates two types of conformation: The
gauche conformation 1b (58%, calculated
= 2.7)3-5
F
H
H
Φ
C5H11
H
H11C5
F
C5H11
H11C5
H
1a
F
F
1b
Scheme 1
H
F
H
H
H
C5H11
H11C5
11C5
C5H11
F
H
H
H
F
F
H
2a
2c
H
H
H
H11C5
F
C5H11
F
H
2b
Scheme 2
Synlett 2001, SI, 960–963 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthesis of a Mesogenic Compound with a Defined Conformation
961
O
O
26
22
18
H
a
H
4.9 kcal mol-1
O
O
3
4
0 kcal mol-1
b
14
Hf/
kcal mol-1
H
H
H
10
O
CH3
H
O
CH3
H
6
2
H
H3C
O
H3C
O
H
H
5
6
-2
-140
-90
-40
10
60
110
160
210
c
Torsion Angle
/°
H
F
H
CH3
H11C5
CH3
Figure 1 Influence of the torsion angle on the conformational en-
ergy Hf (MMFF94) • 1; = 2
H9C4
H
H
d
H
H
C4H9
H3C
H3C
C5H11
The synthesis of compound 2 originated from 4,4’-dicy-
clohexanone 3.8 In a bi-directional approach, 3 was con-
verted to the bis-silylenolether, which was transformed
into the bis-enone 49 using the Saegusa protocol.10 This
led to a 1:1 mixture of the meso- and d/l-diastereomers.
Subsequent addition of Me2CuLi introduced the two me-
thyl groups selectively trans to the cyclohexyl substituent
furnishing a mixture of meso-5 and d/l-6.11 The diastere-
omers were both crystalline compounds. X-ray crystal
structure analysis12 of 5 showed that this is the diastere-
omer which has the proper relative configuration for the
synthesis of 2. Wittig reaction of 5 with pentylidene-phos-
phorane led to an E/Z-mixture of the bisalkene 7.13 Fol-
lowing earlier precedent,2 the bis-alkene was converted
with HF/pyridine (Olah’s reagent14) into the target com-
pound 2, which was recrystallized to diastereomeric puri-
ty.15
H
H
F
2
7
Scheme 3 a) (i) LDA, THF, -78 °C, then TMSCl; (ii) Pd(OAc)2, p-
benzoquinone, CH3CN, rt, 72%; b) Me2CuLi, THF, -78 °C, separati-
on of meso 36% and d/l 36%; c) C5H11PPh3Br, KOtBu, Et2O, 0 °C,
95%; d) 70% HF•pyridine, THF, 28%
H
H
H
H
O
H
O
O
H
H
H
5a
5c
H
H
H
O
O
H
Conformational analysis of the bicyclohexyl derivatives
5b
3
rests on a determination of the JH-H coupling constant
across the inter-ring bond. In the case of compound 2, this
was prevented by severe signal overlap. We therefore
turned to conformational analysis of the precursor ketone
5, which should display a similar conformational behavior
to that of 2. The SELINCOR technique16,17 without proton
3
decoupling permitted the determination of the JH-H cou-
pling constant across the inter-ring bond to J = 3.0 Hz.
This value documents the predominance of a gauche con-
formation but does by itself not differentiate between the
two possible gauche conformations to 5b and 5c. Since
the conformation 5b is the only one free of syn-pentane in-
teractions, the latter is likely the predominant conforma-
tion. This is indeed the conformation found in the solid
state, as the X-ray crystal structure of 5 shows (Scheme 4).
Scheme 4
The high conformational preference found for the ketone
5 should also prevail in the difluoro compound 2, a fact
that should be reflected in the dielectric anisotropy of
compound 2: With a -value of 4.2,18 compound 2 pos-
seses indeed a much improved dielectric anisotropy com-
pared to compound 1.
We showed in this study that conformation design, i.e. the
selective destabilization of undesired conformers by ratio-
nal placement of substituents, led the way from 1 to com-
pound 2 with an attendant improvement in the
conformation-dependent material properties.
Synlett 2001, SI, 960–963 ISSN 0936-5214 © Thieme Stuttgart · New York

962
R. W. Hoffmann et al.
LETTER
dried (Na2SO4) and concentrated. Purification by flash
Acknowledgement
chromatography (pentane/tert-butyl methyl ether 1.5:1)
afforded d,l-diketone 5 (246 mg, 36%) and meso-diketone 6
(261 mg, 36%) as colorless solids. 5: Rf 0.50 (petroleum ether/
tert-butyl methyl ether 1:9) mp: 92 °C; 1H NMR (500 MHz,
CDCl3): = 1.03 (d, 6H, J = 6.4 Hz), 1.40 (dq, 2H, Jd = 4.3
Hz, Jq = 13.5 Hz), 1.72-1.78 (m, 2H), 1.87-1.91 (m, 4H), 2.14
(t, 2H, J = 13.5 Hz), 2.30 (dd, 2H, J = 6.1, 13.5 Hz), 2.39-2.43
(m, 4H); 13C NMR (75 MHz, CDCl3): = 19.7 (2C), 24.6
(2C), 35.1 (2C), 41.1 (2C), 42.5 (2C), 49.9 (2C), 210.7 (2C);
Anal. Calcd for C14H22O2: C 75.63; H 9.97; Found: C 75.50;
H 9.88. 6: Rf 0.44 (petroleum ether/ tert-butyl methyl ether
1:9); mp: 90 °C; 1H NMR (500 MHz, CDCl3): = 0.75 (d, 6H,
J = 6.6 Hz), 1.20-1.24 (m, 2H), 1.27 (dd, 2H, J = 4.2, 12.6
Hz), 1.34-1.42 (m, 2H), 1.50-1.59 (m, 2H), 1.78 (ddd, 2H,
J = 1.0, 10.7, 11.7 Hz), 1.95-2.00 (m, 2H), 2.23 (ddd, 2H,
J = 2.1, 4.5, 14.1 Hz), 2.27-2.31 (m, 2H); 13C NMR (75 MHz,
CDCl3): = 21.2 (2C), 28.6 (2C), 34.9 (2C), 40.7 (2C), 44.6
(2C), 49.4 (2C), 211.1 (2C); Anal. Calcd for C14H22O2: C
75.63; H 9.97; Found: C 75.92; H 10.06.
This study has been supported by the Deutsche Forschungsgemein-
schaft and by the Fonds der Chemischen Industrie (fellowship to
T.B.).
References and Notes
(1) Kirsch, P.; Bremer, M. Angew. Chem., Int. Ed. 2000, 112,
4216.
(2) Kirsch, P.; Tarumi, K. Angew. Chem., Int. Ed. Engl. 1998,
110, 484.
(3) The energy profile for the rotation about the inter-ring bond
was calculated using the MMFF94 force field. The structures
corresponding to the minima were optimized by AM1-
calculations and used as input for the calculations of the
values.
-
(4) Bremer, M.; Tarumi, K. Adv. Mater. 1993, 5, 842.
(5) Klasen, M.; Bremer, M.; Götz, A.; Manabe, A.; Naemura, S.;
Tarumi, K. Jpn. J. Appl. Phys. 1998, 37, L945.
(12) Crystallographic data (excluding structure factors) for the
structure reported in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication no. CCDC-157219. Copies of the data can be
obtained free of charge on application to CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK.
(6) Hoffmann, R.W. Angew. Chem., Int. Ed. 2000, 112, 2054.
(7) Tsuzuki, S.; Schäfer, L.; Goto H.; Jemmis, E.D.; Hosoya, H.;
Siam, K.; Tanabe, K.; Osawa, E. J. Am. Chem. Soc. 1991, 113,
4665.
(8) Pedersen, L.D.; Weiler, L. Can. J. Chem. 1977, 55, 782.
(9) Bicyclohexyl-2,2´-diene-4,4´-dione (4). n-BuLi (1.53 M in
hexane, 67.0 mL, 103 mmol) was added at 78 °C into a
solution of diisopropylamine (15.1 mL, 108 mmol) in THF
(150 mL). The mixture was warmed to 0 °C for 10 min, then
cooled to 78 °C prior to addition of a solution of the diketone
3 (4.857 g, 25.00 mmol) in THF (20 mL). After stirring for 2.5
h chlorotrimethylsilane (15.8 mL, 125.0 mmol) was added
and the mixture was allowed to warm to 0 °C over a 1 h
period. Saturated aqueous NaHCO3 solution (100 mL) was
added, the phases were separated and the aqueous phase was
extracted with pentane (3 70 mL). The combined organic
phases were dried (Na2SO4) and concentrated. The resulting
crude bis-silylenolether was dissolved in acetonitrile
(120 mL) and successively treated with Pd(OAc)2 (5.980 g,
55.00 mmol) and p-benzoquinone (12.350 g, 55.00 mmol).
The resulting mixture was stirred for 12 h and filtered over a
short pad of celite. After removal of the solvent the residue
was purified by flash chromatography (pentane/tert-butyl
methyl ether 1:9) to give dienone 4 (4.384 g, 92%) as a pale
yellow solid as a mixture of d,l- and meso-isomers. Rf 0.16
(petroleum ether/tert-butyl methyl ether 1:9); mp 40-44 °C;
1H NMR (500 MHz, CDCl3): = 1.84-1.87 (m, 2H), 1.91-
1.94 (m, 2H), 2.07-2.13 (m, 4H), 2.41 (ddd, 2H, J = 1.3, 5.0,
13.8 Hz), 2.45 (ddd, 2H, J = 1.2, 5.0, 13.6 Hz), 2.56 (q, 2H,
J = 4.3 Hz), 2.60 (q, 2H, J = 4.3 Hz), 2.63-2.70 (m, 2H), 2.72-
2.78 (m, 2H), 6.09-6.16 (mc, 4H), 6.80-6.83 (mc, 2H), 6.85-
6.88 (mc, 2H); 13C NMR (125 MHz, CDCl3): = 25.8 (2C),
26.1 (2C), 37.1 (2C), 37.2 (2C), 40.0 (2C), 40.1 (2C), 130.8
(2C), 131.2 (2C), 151.2 (2C), 151.6 (2C), 198.7 (2C), 198.8
(2C); HRMS Calcd for C12H14O2: 190.0994; Found:
(13) (1R*,2R*,1´R*,2´R*)-2,2´-Dimethyl-4,4´-dipentylidene-
bicyclohexyl (7). Potassium tert-butoxide (168 mg,
1.50 mmol) was added at 0 °C to a suspension of n-
pentyltriphenylphosphonium bromide (620 mg, 1.50 mmol)
in Et2O (4 mL). The mixture was stirred for 1.5 h and then
diketone 5 (98 mg, 0.44 mmol) was added. After stirring for 8
h at room temperature, silica gel (1.5 g) was added and the
solvent was removed in vacuo. The residue was purified by
flash chromatography (pentane) to afford an E/Z-mixture of
the diolefin 7 (139 mg, 95%) as a colorless oil. Rf 0.81
(petroleum ether/ tert-butyl methyl ether 1:1); 1H NMR (500
MHz, CDCl3): = 0.88-0.95 (m, 26H), 1.29-1.36 (m, 28H),
1.48 (t, 2H, J = 12.6 Hz), 1.60-1.66 (m, 6H), 1.80 (t, 2H,
J = 11.6 Hz), 1.95-2.07 (m, 8H), 2.14-2.20 (m, 4H), 2.57 (d,
2H, J = 13.2 Hz), 2.62 (dt, 2H, Jd = 12.6 Hz, Jt = 1.8 Hz), 5.05-
5.08 (m, 4H); 13C NMR (125 MHz, CDCl3): = 14.0 (4C),
19.5 (2C), 19.9 (2C), 20.0 (2C), 22.2 (2C), 26.0 (2C), 26.6
(2C), 28.6 (2C), 32.4 (2C), 34.9 (2C), 35.0 (2C), 35.7 (2C),
35.8 (2C), 37.0 (2C), 38.0 (2C), 44.3 (2C), 44.4 (2C), 44.5
(2C), 46.3 (2C), 121.1 (2C), 121.3 (2C), 138.9 (2C), 139.1
(2C); Anal. Calcd for C24H42: C 87.19; H 12.81; Found: C
87.01; H 12.58.
(14) Olah, G.A.; Welch, J.T.; Vankar, Y.D.; Nojima, M.; Kerekes,
I.; Olah, J.A. J. Org. Chem. 1979, 44, 3872.
(15) (1R*,2R*,4S*,1´R*,2´R*,4´S*)-4,4´-Difluoro-2,2´-
dimethyl-4,4´dipentyl-bicyclohexyl (2). A solution of an
E/Z-mixture of the diolefin 7 (165 mg, 0.50 mmol) and HF-
pyridine complex (1 mL, 70% w/w) in THF (1 mL) was
stirred for 12 h. The mixture was poured on ice and neutralized
with solid NaHCO3. The phases were separated and the
aqueous phase was extracted with pentane (3 3 mL). The
combined organic phases were dried (Na2SO4) and
190.0991.
(10) Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43, 1011.
(11) 2,2´-Dimethyl-bicyclohexyl-4,4´-dione (5,6). Methyllithium
(1.3 M in Et2O, 15.5 mL, 20.1 mmol) was added at 0 °C to a
suspension of CuI (1.916 g, 10.06 mmol) in Et2O (50 mL).
The solution was cooled to 78 °C and a solution of the
dienone 4 (598 mg, 3.14 mmol) in Et2O (10 mL) was added
dropwise. After warming to 0 °C over 5 h saturated aqueous
NH4Cl solution (50 mL) and concd. aqueous NH3 (25 mL)
were added. The phases were separated and the aqueous phase
was extracted with tert-butyl methyl ether (3 40 mL). The
combined organic phases were washed with brine (10 mL),
concentrated. Purification by flash chromatography (pentane)
furnished 2 (59 mg, 32%) along with monofluorinated product
(42 mg, 24%) and residual diolefin 7 (46 mg, 28%). Further
purification of the obtained product by crystallisation (n-
heptane) afforded 2 (52 mg, 28%) as a single isomer. Rf 0.11
(pentane); mp: 70 °C; 1H NMR (400 MHz, CDCl3): = 0.83
(d, 6H, J = 6.6 Hz), 0.89 (t, 6H, J = 6.6 Hz), 1.01 (dd, 2H,
J = 12.5, 13.7 Hz), 1.11-1.19 (m, 2H), 1.29-1.58 (m, 22H),
1.74-1.93 (m, 6H); 13C NMR (100 MHz, CDCl3): = 14.0
Synlett 2001, SI, 960–963 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthesis of a Mesogenic Compound with a Defined Conformation
963
(2C), 19.2 (2C), 20.3 (2C), 22.6 (2C), 22.8 (d, 2C, J = 4.7 Hz),
(18) The -values were determined by linear extrapolation from
a 10% w/w solution in the commercially available Merck
28.8 (2C), 32.3 (2C), 35.2 (d, 2C, J = 22.9 Hz), 41.1 (d, 2C,
J = 22.8 Hz), 43.3 (2C), 44.6 (d, 2C, J = 22.6 Hz), 96.0 (d, 2C,
mixture ZLI-2857 (TNI = 82.3 °C,
= 1.42, n = 0.0776)
J = 167.2 Hz); 19F NMR (188 MHz, CDCl3):
=
157.5;
as a standard host.
Anal. Calcd for C24H44F2: C 77.78; H 11.97; Found: C 77.79;
H 12.26.
(16) Berger, S. J. Magn. Reson. 1989, 81, 561.
(17) Fäcke, T.; Berger, S. Magn. Res. Chem. 1995, 33, 144.
Article Identifier:
1437-2096,E;2001,0,SI,0960,0963,ftx,en;Y02401ST.pdf
Synlett 2001, SI, 960–963 ISSN 0936-5214 © Thieme Stuttgart · New York