Facile synthesis of a series of 2-(4-alkyloxyphenyl)-5-cyanopyridine liquid crystalline compounds

Article abstract of DOI:10.3987/COM-07-11224

This study describes the facile synthesis of a homologous series of pyridine-containing liquid crystalline 2-(4-alkyloxyphenyl)-5-cyanopyridines (nOPPyCN, n = 3-7). The subject liquid crystals were prepared in a short two-step reaction. First, 4-alkyloxyp

Full text of DOI:10.3987/COM-07-11224

HETEROCYCLES, Vol. 75, No. 2, 2008
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HETEROCYCLES, Vol. 75, No. 2, 2008, pp. 375 - 382. © The Japan Institute of Heterocyclic Chemistry
Received, 20th September, 2007, Accepted, 1st November, 2007, Published online, 2nd November, 2007. COM-07-11224
FACILE SYNTHESIS OF A SERIES OF 2-(4-ALKYLOXYPHENYL)-5-
CYANOPYRIDINE LIQUID CRYSTALLINE COMPOUNDS
Win-Long Chia* and Yu Wei Cheng
Department of Chemistry, Fu Jen Catholic University, Taipei, Taiwan, Republic
of China
*Corresponding author. Tel: 2-29053567; Fax: 2-29023209;
E-mail: 027087@mail.fju.edu.tw
Abstract – This study describes the facile synthesis of a homologous series of
pyridine-containing liquid crystalline 2-(4-alkyloxyphenyl)-5-cyanopyridines
(nOPPyCN, n = 3-7). The subject liquid crystals were prepared in a short two-step
reaction. First, 4-alkyloxyphenylmagnesium bromides were added to N-
phenyloxycarbonyl-3-cyanopyridinium chloride, affording a 1,2-dihydropyridine,
which was then oxidized by o-chloronil. The resulting products, 2-(4-
alkyloxyphenyl)-5-cyanopyridines, were obtained in good yields (72%-83%).
Thermotropic behaviors of these liquid crystals were investigated using
differential scanning calorimetry (dsc) and polarized optical microscopy (pom).
INTRODUCTION
At least ten different liquid crystal material parameters must be optimized to achieve optimal TN-LCD
and STN-LCD display performance. Because a single liquid crystal shows at best one or two
distinguished properties, mixtures consisting of up to twenty or more polar and weakly polar compounds
have to be developed for a given application. In view of the growing need for more advanced displays in
the future, therefore, there is a high demand for new nematic liquid crystals and molecular synthesizing
methodologies.1
Although a plethora of prefunctionalized aromatic compounds are jointed by metal catalyzed C-C
coupling reactions developed for the syntheses of biaryls and homologous, only a few of them are
applicable to the synthesis of heteroarenes.2 In many instances, the scope of these reactions suffers from
low yields, expensive catalyst requirement, separation from homo-coupled products, and the limitations
of the functional groups that are affected.3
In former years, some pyridine containing liquid crystalline compounds were synthesized.4-7 Certain
pyridine-containing liquid crystalline compounds have shown enhanced properties in display

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applications.8 Previously, we prepared various 2- or 4-substituted pyridines and alkaloids by
regioselective addition of organometallic reagents to 1-acylpyridinium salts.9 With the simple Grignard
reagent and pyridine reactivity enhancement strategy, we have successfully applied this methodology in
preparing liquid crystalline 2-(4-alkylphenyl)-5-substituted pyridines.10 In this paper, facile synthesis of a
homologous series of liquid crystalline 2-(4-alkyloxyphenyl)-5-cyanopyridines (nOPPyCN, n = 3-7) 4 is
reported (Scheme 1).
CN
H
THF/N2
N
CnH2n+1
O
CN
+
MgBr
CnH2n+1
O
Cl
O
<-20 oC
N
O
O
O
1
2
3
o-chloranil
CnH2n+1
O
CN
toluene
N
4
Scheme 1
RESULTS AND DISCUSSION
2.1 Synthesis of 2-(4-alkyloxyphenyl)-5-cyanopyridines(nOPPyCN, n = 3 to 7) :
Except for famous liquid crystalline compound p-pentyl-cyanobiphenylene(5CB),11 p-heptyloxy-
cyanobiphenylene(7OCB) is also one of the major components in commercially available liquid
crystalline compound E7.12 Therefore, the pyridine analogue of 7OCB would be a fascinating molecule to
investigate. However, a tedious process of four synthetic steps for the preparation of 2-(4’-
alkyloxyphenyl)-5-cyanopyridines (nOPPyCN) was previously developed by Pavelyuchenko et al.13 The
overall yields from the four synthetic steps were poor (12%-24%) and an expensive metal, palladium, was
necessary and there were side products produced in the last reduction step.
In this research, Grignard reagent 4-alkyloxyphenylmagnesium bromides (prepared from commercial
readily available 4-hydroxy-bromobezene) 1 were reacted with N-phenyloxycarbonyl-3-cyanopyridinium
chlorides 2 to afford a 1,2-dihydropyridine 3 that was then oxidized by o-chloronil, providimg a valuable
approach to the synthesis of liquid crystalline 2-(4-alkyloxyphenyl)-5-cyanopyridines (nOPPyCN) 4, in
which the alkyloxy varied from n-propyloxy to n-heptyloxy (Scheme 1). The overall synthetic process
was completed in two-steps with very good yields (72%-83%) of 2-(4-alkyloxyphenyl)-5-cyanopyridines
(nOPPyCN) obtained (Table 1). Highly pure products can be obtained by re-crystallization several times

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377
Table 1. Synthesis of 2-(4-alkyloxyphenyl)-5-cyanopyridines 4a-4e
Entry
Alkyl
Yielda(%)
4a
4b
4c
4d
4e
propyl
butyl
pentyl
hexyl
heptyl
80
83
78
72
76
aIsolated yields by column chromatography (methylene chloride/hexane) on silica gel
It is known that nucleophilic attack of a Grignard reagent and its regioselectivity on the pyridine ring can
be greatly enhanced by phenyl chloroformate, even in the presence of a cyano group on the ring.14
α
-Regioselectivity of the pyridine ring by Grignard reagent attack was found to be overwhelmingly
dominant by this synthetic method. Trace amounts of g-addition product (≦2-3%) can be easily
separated from the majorα-addition product using simple liquid chromatography (hexane : methylene
choloride = 1:2) due to high polarity difference of these two compounds. Preparation of other
homologous series pyridine-containing liquid crystalline compounds was undertaken.
2.2 Thermotropic behavior of 2-(4-alkyloxyphenyl)-5-cyanopyridines:
Thermotropic behaviors of 2-(4-alkyloxyphenyl)-5-cyanopyridines (nOPPyCN, n = 3-7) we synthesized
were investigated using differential scanning calorimetry (dsc) and polarized optical microscopy (pom).
The mesomorphic phase transition temperatures from the heating cycle were found to be identical to
those reported by Pavelyuchenko et al.13 In addition, the phase transition temperatures of
2-(4’-alkyloxyphenyl)-5-cyanopyridines (nOPPyCN, n = 3-7) from the cooling cycle and their transition
enthalpies are reported herein (Table 2). It is assumed that entropy changes at TN-I transition are
dominated by intermolecular degrees of freedom in the nematic phase. 15 A trend of increasing DSN-I (J K-1
mol-1), 0.4052, 0.4789, 0.4886, 0.6176, 0.7559 for nOPPyCN, n = 3 to 7 respectively, is found, which
indicates that the longer the rod-like molecules is, the more ordered structure exists in the mesophase,
therefore, more orientational entropy changes have to occur at TN-I transition as alkyl chain length
increases. From pom study, it shows that nematic phase is mainly the mesophase in this homologue
(Figure 1), except a smectic phase appearing in 2-(4’-heptyloxyphenyl)-5-cyanopyridines (nOPPyCN, n
= 7).

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Table 2. Transition temperatures (°C) and corresponding transition enthalpies (kJ mol-1), in parentheses,
for homologous series of nOPPyCN, n = 3-7 were determined by the second scans at a heating
and cooling rate of 5°C min-1 from DSC
a
Entry
TCr-N
[TC-S]
93.6
TS-N
TN-I
TI-N
TN-S
TN-Cr
[TS-C]
76.1
(11.55)
64.9
(18.28)
35.9
(23.39)
32.7
4a
(n=3)
4b
(n=4)
4c
-
-
-
-
97.2
(0.15)
102.9
(0.18)
95.4
95.6
(0.24)
101.3
(0.24)
93.8
-
-
-
-
(15.06)
91.6
(15.27)
59.2
(18.28)
62.4
(n=5)
4d
(0.18)
99.4
(0.21)
97.8
(n=6)
4e
(n=7)
(23.31)
[58.4]
(16.02)
(0.23)
97.4
(0.28)
(0.32)
95.6
(0.38)
(31.92)
[43.2]
(19.37)
88.6
(0.17)
87.0
(0.079)
a Cr = crystalline phase, S = smectic phase, N = nematic phase, I = isotropic phase
There is a ready explanation for the odd-even effect of the TN-I values.16 It has been found for many
homologous series of liquid crystals that the odd carbon atom alkyl chain has a terminal Me group which
extends the long molecular axis, whereas in an even number carbon chain the terminal Me group tends to
lie off axis. In our study, the corresponding alkyloxy substituted series, the oxygen is equivalent to a CH2
group and a reverse situation has been found, although the alternation of the TN-I values is not great.
Figure 1. Polarized optical micrograph of nematic Schlieren texture of
2-(4’-propyloxyphenyl)-5-cyanopyridines (4a) nOPPyCN, n = 3 arises
from crystalline phase on heating to 97°C with magnification of × 100
It would be very interesting to compare the mesomorphic transitions of 2-(4-alkyloxyphenyl)-5-
cyanopyridines (nOPPyCN, n = 3-7) with those of p-alkyloxy-cyanobiphenylene(nOCB, n = 3-7),17 since
such comparison could not be found elsewhere. The comparison data (Table 3) shows that replacement of
the relatively nonpolar biphenyl core by more polar phenylpyridine moiety enhances not only the early

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379
appearance of smectic phase (nOPPyCN, n = 7) but also that of nematic phase (nOPPyCN, n = 3, 4).
Although it is known that the pyridine ring system with lone pairs of electrons on the nitrogen atoms acts
to broaden the molecule and introduces attractive forces which aid smectic formation,18 contrary to the
conventional point of view, it also promotes the early appearance of the enantiotropic nematic phase and
provides wider nematic phase ranges and gives higher TN-I values. This indicates that a fine tuned polarity
of core structure could allow lowering the number of carbon atoms in the flexible chain and also
enhancing its nematic stability.
Table 3. Transition temperatures (°C) for 2-(4-alkyloxyphenyl)-5-cyanopyridines (nOPPyCN, n = 3-7)
and p-alkyloxy-cyanobiphenylene(nOCB, n = 3-7)
Compounds
nOPPyCN
nOCB
n=3
93.6/-/97.2 91.6/-/102.9 59.2/-/95.4 62.4/-/99.4 58.4/88.6/97.4
74.5/-/(64) b 78/-/(75.5) b 48/-/68
57/-/75.5 54/-/74
n=4
n=5
n=6
n=7
a All data are listed in a sequence of TCr-S, N or I / TS-N / TN-I
b Values in the bracket indicate monotropy
EXPERIMENTAL
All chemicals and solvents were reagent grades from Aldrich Chemical Co. Anhydrous solvents and
chemicals were freshly distilled before use. The 1H and 13C-NMR spectra were recorded on a Brucker AC
300. Infrared spectra were carried out on a Perkin-Elmer 1600 Series. Thermographs were carried out on
a Perkin-Elmer DSC 7 Series, calibrated with pure indium. Polarizing optical microscopy was carried out
on an Olympus BH-2 equipped with a Mettler FP90/FP82HT hot stage. All phase transitions were
measured with a scan rate of 5°C min-1.
General Procedure for the Synthesis of 2-(4-Alkyloxyphenyl)-5-Cyanopyridines.
For 3a: To a (Grignard) solution of 1-bromo-4-propyloxybenzene (10 mmol) in THF (20 mL) was added
freshly dried magnesium granules (11 mmol) under an inert atmosphere. The Grignard solution 1 was
then slowly added by syringe into a preformed solution of 3-cyanopyridinium chloride 2, which was
prepared from phenyl chloroformate (10 mmol), 3-cyanopyridine (10 mmol) in dry THF (20 mL) at
-20°C, for half an hour. The resulting solution was warmed slowly to rt and stirred for another 8 h. After
evaporating the THF, the residue was extracted with Et2O. The organic layer was further washed once
20% aqueous NH4Cl solution and twice with distilled water and brine and dried with magnesium sulfate.
Yields of the intermediates were found to be around 90%. For 4a: To a solution of dry toluene (20 mL)
and crude 3a was added about 1.5eq. of o-chloranil. The reaction mixture was heated to reflux for about
3 h under inert atmosphere and then quenched by adding 1N NaOH (25 mL) and Et2O (25 mL) and

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filtered through Celite. Normal aqueous work up and isolation with column chromatography (hexane :
CH2Cl2 = 1:2) affords very good yield of 2-(4-propyloxyphenyl)-5-cyanopyridines (4a) (79.7%). The
crude products 4a were further purified by recrystallization several times from Et2O and n-hexane. All
1
compounds gave satisfactory data from H-NMR, 13C-NMR, ir and elemental analysis as illustrated
below.
2-(4-Propyloxyphenyl)-5-cyanopyridines (4a)
1H-NMR (CDCl3): d 8.88 (d, 1H, J=2.1 Hz), 8.00 (d, 2H, J=9 Hz), 7.94 (dd, 1H, J1=8.4 Hz, J2=2.1Hz),
7.76 (d, 1H, J=8.4 Hz), 7.01 (d, 2H, J=9 Hz), 3.99 (t, 2H, J=6.6 Hz), 1.90-1.78 (m, 2H), 1.06 (t, 3H,
13
J=7.5Hz). C-NMR (CDCl3): ppm 161.5, 160.1, 152.4, 139.7, 129.5, 128.9, 119.0, 117.3, 115.0, 106.8,
69.7, 22.5, 10.5. IR (KBr): cm-1 3049, 2966, 2937, 2874, 2221, 1587, 1469, 1247, 1015, 832. Anal. Calcd
for C15H14N2O: C, 75.61; H 5.92; N 11.76. Found: C, 75.63; H, 5.93; N, 11.74.
2-(4-Butyloxyphenyl)-5-cyanopyridines (4b)
1H-NMR (CDCl3): d 8.89 (d, 1H, J=2.1 Hz), 8.01 (d, 2H, J=9 Hz), 7.95 (dd, 1H, J1=8.4 Hz, J2=2.1 Hz),
7.78 (d, 1H, J=8.4 Hz), 7.01 (d, 2H, J=9 Hz), 4.04 (t, 2H, J=6.6 Hz), 1.85-1.76 (m, 2H), 1.58-1.45 (m,
2H), 0.99 (t, 3H, J=7.5 Hz). 13C-NMR (CDCl3): ppm 161.6, 160.1, 152.4, 139.7, 129.5, 129.0, 119.1,
117.2, 115.1, 106.9, 68.0, 31.3, 19.3, 13.9. IR (KBr): cm-1 3055, 2956, 2936, 2871, 2224, 1587, 1471,
1246, 1006, 829. Anal. Calcd for C16H16N2O: C, 76.16; H, 6.39; N, 11.10. Found: C, 76.12; H, 6.44; N,
11.09.
2-(4-Pentyloxyphenyl)-5-cyanopyridines (4c)
1H-NMR (CDCl3): d 8.89 (dd, 1H, J1=2.1 Hz, J2=0.9 Hz), 8.01 (d, 2H, J=9 Hz), 7.95 (dd, 1H, J1=8.4 Hz,
J2=2.1 Hz), 7.78 (d, 1H, J=8.7 Hz), 7.01 (d, 2H, J=9 Hz), 4.03 (t, 2H, J=6.3 Hz), 1.87-1.77 (m, 2H),
1.52~1.32 (m, 4H), 0.94 (t, 3H, J=7.2 Hz). 13C-NMR (CDCl3): ppm 161.5, 160.1, 152.4, 139.7, 129.5,
128.9, 119.1, 117.2, 115.0, 106.8, 68.3, 28.9, 28.2, 22.5, 14.0. IR (KBr): cm-1 3057, 2965, 2938, 2858,
2229, 1588, 1470, 1249, 1017, 832. Anal. Calcd for C17H18N2O: C, 76.66; H, 6.81; N, 10.52. Found: C,
76.68; H, 6.83; N, 10.52.
2-(4-Hexyloxyphenyl)-5-cyanopyridines (4d)
1H-NMR (CDCl3): d 8.88 (dd, 1H, J1=2.1 Hz, J2=0.6 Hz), 8.01 (d, 2H, J=9 Hz), 7.93 (dd, 1H, J1=8.4 Hz,
J2=2.1 Hz), 7.76 (d, 1H, J1=8.4 Hz, J2=0.6 Hz), 7.01 (d, 2H, J=9 Hz), 4.03 (t, 2H, J=6.6 Hz), 1.86-1.77
(m, 2H, J=7.8 Hz), 1.53-1.43 (m, 2H), 1.40-1.32 (m, 4H), 0.93 (t, 3H, J=6.9 Hz). 13C-NMR (CDCl3): ppm
161.5, 160.2, 152.4, 139.6, 129.6, 128.9, 119.0, 117.3, 115.0, 106.8, 68.3, 31.6, 29.2, 25.7, 22.6, 14.0. IR

HETEROCYCLES, Vol. 75, No. 2, 2008
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(KBr): cm-1 3053, 2950, 2925, 2855, 2225, 1589, 1471, 1249, 1020, 824. Anal. Calcd for C18H20N2O: C,
77.11; H, 7.19; N, 9.99. Found: C, 77.07; H, 7.20; N, 9.97.
2-(4-Heptyloxyphenyl)-5-cyanopyridines (4e)
1H-NMR (CDCl3): d 8.89 (d, 1H, J=2.1 Hz), 8.01 (d, 2H, J=8.7 Hz), 7.95 (dd, 1H, J1=8.4 Hz, J2=2.1 Hz),
7.77 (d, 1H, J=8.4 Hz), 7.00 (d, 2H, J=8.7 Hz), 4.02 (t, 2H, J=6.6 Hz), 1.86-1.77 (m, 2H), 1.50-1.31 (m,
8H), 0.90 (t, 3H, J=6.6 Hz). 13C-NMR (CDCl3): ppm 161.5, 160.1, 152.3, 139.8, 129.4, 129.0, 119.1,
117.2, 115.0, 106.8, 68.3, 31.8, 29.2, 29.1, 26.0, 22.6, 14.1. IR (KBr): cm-1 3071, 2953, 2930, 2855, 2235,
1593, 1471, 1249, 1046, 820. Anal. Calcd for C19H22N2O: C, 77.52; H, 7.53; N, 9.52. Found: C, 77.40; H,
7.55; N, 9.48.
ACKNOWLEDGEMENT
Financial support of our work by the office of research and development of Fu Jen Catholic University is
gratefully acknowledged. We also thank Prof. C. K. Lai in Department of Chemistry, National Central
University in Taiwan for helping with the elemental analysis.
REFERENCES AND NOTES
1. (a) S. Singh, Liquid Crystals: Fundamentals, World Scientific, 2002, Chap. 4, p. 92-173. (b) A. I.
Pavluchenko, V. F. Petrov, and N. I. Smirnova, Liquid Crystals, 1995, 19, 811.
2. (a) T. Thiemann and V. Vill, General Synthetic Strategies, in, Handbook of liquid crystals, ed. by, D.
Demus, Wiley-VCH, 1998, Chap. 4, p. 87. (B) M. Hird G. W. Gray, and K. J. Toyne, Mol. Cryst. Liq.
Cryst., 1991, 206, 187.
3. (a) N. Zhang, L. Thomas, and B. Wu, J. Org. Chem., 2001, 66, 1500. (b) S. M. Kelly, J. Fungschilling,
and A. Villiager, Liquid Crystals, 1993, 14, 1169.
4. J. A. Nash and G. W. Gray, Mol. Cryst. Liq. Cryst., 1974, 25, 299.
5. M. P. Burrow, G. W. Gray, D. Lacey, and K. J. Toyne, Liquid Crystals, 1988, 3, 1643.
6. V. Reiffenrath and M. Bremer, Angew. Chem. Int. Ed. Engl., 1994, 33, 1386.
7. (a) T. Asano, M. Uenoyama, K. Moriya, S. Yano, S. Takatani, and S. Kagabu, Liquid Crystals, 1997,
23, 365. (b) T. Asano, M. Uenoyama, K. Moriya, S. Yano, S. Takatani, and S. Kagabu, Liquid
Crystals, 1998, 25, 263. (c) K. Moriya, F. Harada, S. Yano, and S. Kagabu, Liquid Crystals, 2000, 27,
1647.
8. (a) E. Poetsch, V. Meyer, R. Hittich, H. Plach, J. Kraus, H.-M. Kompter, D. Coates, and G. Smith,
European Patent Appl. EP 0519370 A2 19920615 (1992) (Chem. Abst., 1993, 118, 191554w). (b) K.

382
HETEROCYCLES, Vol. 75, No. 2, 2008
Nigorikawa and M. Ichihashi, Jpn. Kokai Tokkyo Koho JP 04,213,386 [92,213,386], 04 Aug 1992
(Chem. Abst., 1992, 118, 136379t). (c) Y. Kosaka, T. Takiguchi, T. Iwaki, T. Togano, and S.
Nakamura, US Patent 5,695,684 (1997).
9. (a) W.-L. Chia and M.-J. Shiao, Tetrahedron Lett., 1991, 32, 2033. (b) T.-L. Shing, W.-L. Chia, M.-J.
Shiao, and T.-Y. Chau, Synthesis, 1991, 849. (c) M.-J. Shiao, W.-L. Chia, C.-L. Peng, and C. -C. Shen,
J. Org. Chem., 1993, 58, 3162.
10. W.-L. Chia, S.-W. Shen, and H.-C. Lin, Tetrahedron Lett., 2001, 42, 2177.
11. G. W. Gray, K. J. Harrison, and J. A. Nash, Electronic letters, 1973, 9, 130.
12. C. A. McFarland, J. L. Koenig, and J. L. West, Appl. Spectrosc., 1993, 47, 321.
13. A. I. Pavelyuchenko, N. I. Smirnova, T. A. Mikhailova, E. I. Kovshev, and V. V. Titov, Zh. Org.
Khim., 1986, 22(5), 1061.
14. (a) D. L. Comins and A. H. Abdullah, J. Org. Chem., 1982, 47, 4315. (b) D. L. Comins, E. D. Stroud,
and J. J. Herrick, Heterocycles, 1984, 22, 151.
15. G. W. Gray, Liquid Crystals and Molecular Structure: Nematics and Cholesterics, in ‘molecular
Physics of Liquid Crystals’, ed., G. R. Luckhurst and G. W. Gray, Academic Press Inc., 1979, Chap. 1,
p. 15.
16. G. W. Gray and A. Mosley, J. Chem. Soc., Perkin Trans. 2, 1976, 97.
17. (a) G. W. Gray, J. Physique., 1975, 36, C1, No. 3, 337. (b) K. J. Toyne, Liquid Crystal Behaviour in
Relation to Molecular Structure, in ‘Critical Reports on Applied Chemistry: Thermotropic Liquid
Crystals’, vol. 22, ed., G. W. Gray, John Wiley, and Sons, 1987, p. 33.
18. D. Coates, Chemical Structure, Molecular Engineering and Mixture Formulation, in ‘Liquid Crystals:
Applications and uses’, vol. 1, ed., B. Bahadur, World Scientific, 1990, Chap. 3, p. 122.