Synthesis of new series of 4, 5-dihydroisoxazole-5-carboxylate derivatives for the study of their liquid crystalline properties

Article abstract of DOI:10.1007/s12039-016-1114-0

A new series of 4,5-dihydroisoxazole-5-carboxylate derivatives were synthesized via [3 + 2] cycloaddition reaction between ethyl acrylate and nitrile oxide generated in situ in presence of Chloramine-T. The synthesized derivatives were characterized by Mass, IR and NMR Spectroscopy and their mesomorphic behavior were studied using DSC and Polarising Optical Microscopy. [Figure not available: see fulltext.]

Full text of DOI:10.1007/s12039-016-1114-0

c
J. Chem. Sci. ꢀ Indian Academy of Sciences.
DOI 10.1007/s12039-016-1114-0
Synthesis of new series of 4, 5-dihydroisoxazole-5-carboxylate derivatives
for the study of their liquid crystalline properties
SUMANA Y KOTIANa,∗, NARAYANA U KUDVA Na, K M LOKANATHA RAIa,∗
and K BYRAPPAb
aDepartment of Chemistry, University of Mysore, Manasagangotri, Mysuru, Karnataka, India
bCenter for Materials Science and Technology, Vijnana Bhavan, University of Mysore, Manasagangotri,
Mysuru, Karnataka, India
e-mail: sumanakotian@gmail.com; kmlrai@yahoo.com
MS received 21 March 2015; revised 4 May 2016; accepted 16 May 2016
Abstract. A new series of 4,5-dihydroisoxazole-5-carboxylate derivatives were synthesized via [3+2]
cycloaddition reaction between ethyl acrylate and nitrile oxide generated in situ in presence of Chloramine-T.
The synthesized derivatives were characterized by Mass, IR and NMR Spectroscopy and their mesomorphic
behavior were studied using DSC and Polarising Optical Microscopy.
Keywords. Dihydroisoxazole; Liquid crystals; Heterocycles.
1. Introduction
2. Experimental
Since the discovery of liquid crystalline phase, by 2.1 Materials and Methods
Friedrich Reinitzer, many liquid crystals have been
The chemicals, viz., 4-hydroxy benzaldehyde, n-bromo
synthesized and they have made their way to techno-
logical applications, especially as LCD’s whose com-
mercialization started way back in 1960s.1 The driving
force for the formation of mesophases is intermolec-
ular interactions such as hydrogen bonding, dipole-
dipole interactions and π-π interaction between the
molecules.2 Molecular geometry and anisotropy are
important aspects for the formation of mesophases,
and many such materials are known involving small
molecules,3–5 polymers,6–8 biological materials such
DNA9,10 and membranes,11 heterocyclic compounds
like oxadiazole,12,13 thiadiazole,14 imidazole,15 and
isoxazole.16 Our interest in synthesizing isoxazoline
derivatives comes from the ease of synthesis and excel-
lent mesomorphic behavior exhibited by them.17–19 The
1,3-dipolar cycloaddition reaction of a nitrile oxide gen-
erated in situ to an alkene or alkyne has proven to be
very useful in the preparation of a variety of compounds
in organic chemistry.20 The construction of the isoxa-
zoline rings by this method forms an easy way to pre-
pare a molecular base for the synthesis of attractive,
non-polymer liquid-crystalline materials.
alkyl halides (for n = 5, 6, 7, 8, 10, 12 and 16) were
procured from LOBA chemie, India. Hydroxylamine
hydrochloride was procured from SRL, India. Sodium
acetate, potassium carbonate, diethyl ether were pro-
cured from RANKEM, India. Ethanol was procured
from CHANGSHU YANGYUAN CHEMICAL, China.
Ethylacrylate was procured from SDFCL, India. Sil-
ica gel (60–120 mesh size) for column chromatography
was procured from LOBA chemie, India. The proposed
structure for the intermediate compounds and that of the
final compound were confirmed by the 1H-NMR spec-
tra obtained using an AGILENT (400 MHz) NMR spec-
trometer (Dueterated chloroform as solvent procured
from SIGMA ALDRICH, USA and Tetramethyl Silane
as internal standard). The following notations denoted
the peak types in the spectra: singlet (s), doublet (d),
doublet of doublets (dd), triplet (t), quartet (q) and mul-
tiplet (m). Infrared spectra (IR) were obtained using
1
a Perkin Elmer spectrophotometer. The H, 13C NMR
and IR spectra were used for the confirmation of the
molecular structure, hydrogen bonding and the purity
of samples. Differential Scanning Calorimetry (DSC)
thermograms were obtained using a Perkin-Elmer DSC
7, with a TAC 7/PC interface and a controlled cooling
accessory. Heating rate was 1◦C min−1. The LC phases
were characterized by their textural studies carried out
∗For correspondence

Sumana Y Kotian et al.
using an Olympus BH-2 polarizing microscope, fitted washing were combined and the solvent was evapo-
with a Mettler FP52 hot stage and a Mettler FP5 con- rated in vacuum. The residue was extracted with ether
troller. Samples were prepared as thin films between a (25 mL × 3), the extract was washed successively with
glass slide and a glass cover slip. Column chromatog- water (15 mL × 2), 10% NaOH (15 mL × 2), and sat-
raphy was carried out using silica gel (60–120 mesh) as urated brine solution (10 mL). The organic layer was
the stationary phase. Thin layer chromatography (TLC) dried over anhydrous Na2SO4. The crude product was
was carried out on aluminum sheets coated in Merck filtered and purified by column chromatography on sil-
Kieselgel silica gel 60, eluting with petroleum ether and ica gel using a mixture of petroleum ether: ethyl acetate
ethyl acetate (20%).
to give the corresponding pure product (scheme 1).
2.2 General procedure for synthesis of alkylated
benzaldehyde21 (2a–g)
2.4a Ethyl 3-[4-(pentyloxy)phenyl]-4,5-dihydroisoxa-
zole-5-carboxylate (4a): FT-IR (cm−1): 2935, 1732,
1421, 1346, 1299. 1H NMR (CDCl3, 400MHz) δ: 7.58
(d, J = 8.8 Hz, ArH, 2H), 6.88 (d, J = 8.8 Hz, ArH,
2H) 5.10 (dd, J = 10.4, 8 Hz, OCH, 1H), 4.25 (q,
OCH2, 2H) 3.95 (t, OCH2, 2H) 3.57-3.54 (m, CH2, 2H)
1.79-1.28 (m, CH2, CH3, 9H), 0.915 (t, CH3, 3H).13C
NMR (CDCl3, 100MHz) δ: 13.95, 14.07, 22.39, 28.11,
28.90, 39.10, 61.91, 68.12, 76.69, 77.79, 77.83, 114.67,
120.44, 120.81, 155.56, 160.95, 170.38 LCMS: 306.25
[M+H]+. Elemental Analysis: C-66.78; H-7.29; N-
4.44%. Yield: 83%.
Mixture of p-hydroxy benzaldehyde (1, 1 mmol) and
n-alkyl bromide (1 mmol) and K2CO3 (3 mmol) in
dimethyl formamide (20 mL) were stirred for 8 h
at room temperature 25◦C. The solid product was
extracted into ether layer and it was dried over anhy-
drous Na2SO4.
2.3 General procedure for synthesis of aromatic
aldoximes22 (3a–g)
n-alkylated benzaldehyde (1.0 mmol) in 15 mL ethanol
was added to a solution of hydroxylamine hydrochlo-
ride (1.4 mmol) and sodium acetate (1.4 mmol) in water
and the mixture was heated at 80–90◦C for 1 h. After
completion of the reaction, it was allowed to cool to
room temperature, precipitated aldoxime was collected
and purified by crystallization from ethanol to give
compounds (3a–g).
2.4b Ethyl 3-[4-(hexyloxy)phenyl]-4,5-dihydroisoxazole-
5-carboxylate (4b): FT-IR (cm−1): 2931, 1738, 1421,
1350, 1303. H NMR (CDCl3, 400MHz) δ: 7.60 (d,
1
J = 8.8 Hz, ArH, 2H) 6.90 (d, J = 8.8 Hz, ArH, 2H),
5.13 (dd, J = 10.4, 8 Hz, OCH, 1H) 4.27 (q, OCH2,
2H) 3.94 (t, OCH2, 2H) 3.65-3.62 (m, CH2, 2H), 1.35-
1.27 (m, CH2, CH3, 11H), 0.9 (t, CH3, 3H). 13C NMR
(CDCl3, 100MHz) δ: 14.01, 14.10, 22.57, 25.65, 29.68,
31.53, 39.12, 61.95, 68.13, 77.01, 77.32, 77.83, 114.66,
120.78, 128.46, 155.57, 160.94, 170.42. LCMS: 319.97
[M+H]+. Elemental Analysis: C-67.65; H-7.80;
N- 4.22. Yield: 78%.
2.4 General procedure for synthesis of isoxazoline
derivative22 (4a-g)
Ethyl acrylate (1 mmol), aldoxime (1 mmol) and chlora-
mine–T (1.5 mmol) in ethanol (20 mL) were taken in
a reaction flask and it was stirred for 8 h at 25◦C. The 2.4c Ethyl 3-[4-(heptyloxy)phenyl]-4,5-dihydroisoxazole-
completion of the reaction was monitored by TLC. 5-carboxylate (4c): FT-IR (cm−1): 2925, 1735, 1414,
1
After completion, sodium chloride formed was fil- 1352, 1304. H NMR (CDCl3, 400MHz) δ: 7.58 (d,
tered off and washed with ethanol (15 mL). Filtrate and J = 8.8 Hz, ArH, 2H),6.87 (d, J = 8.8 Hz, ArH, 2H),
Scheme 1. General reaction schemes for products 2a-g, 3a-g and 4a-g.

Synthesis of 4,5-dihydroisoxazole-5-carboxylate derivatives
5.08 (dd, J = 10.4, 8 Hz, OCH, 1H), 4.26 (q, OCH2, 2H), 3.96 (t, OCH2, 2H), 3.60-3.57 (m, CH2, 2H),
2H), 3.97 (t, OCH2, 2H), 3.60-3.57 (m, CH2, 2H), 1.45-1.25 (m, 23H, CH2, CH3), 0.86 (t, CH3, 3H). 13C
1.65-1.27 (m, CH2, CH3, 13H), 0.86 (t, CH3, 3H). NMR (CDCl3, 100MHz) δ: 14.07, 14.11, 22.61, 25.97,
13C NMR (CDCl3, 100MHz) δ: 14.04, 14.09, 22.56, 29.12, 29.34, 29.35, 29.54, 29.57, 29.62, 29.64, 39.12,
25.92, 28.99, 31.73, 39.11, 61.93, 68.14, 76.67, 76.98, 61.97, 68.13, 76.67, 77.31, 77.80, 114.66, 120.76,
77.30, 77.85, 114.67, 120.80, 128.45, 155.56, 160.95, 128.46, 128.57, 155.71, 161.88, 170.44. LCMS: 404.05
170.39. LCMS: 334.24 [M+H]+. Elemental Analysis [M+H]+. Elemental Analysis(%): C-71.38; H-9.20;
(%): C-68.39; H-8.11; N- 4.15. Yield: 81%.
N- 3.42. Yield: 82%.
2.4d Ethyl 3-[4-(octyloxy)phenyl]-4,5-dihydroisoxazole-
5-carboxylate (4d): FT-IR (cm−1): 2920, 1733, 1418,
1354, 1309. H NMR (CDCl3, 400MHz) δ: 7.58 (d,
2.4g Ethyl 3-[4-(hexadecyloxy)phenyl]-4,5-dihydroi-
soxazole-5-carboxylate (4g): FT-IR (cm−1): 2931,
1738, 1421, 1350, 1303. H NMR (CDCl3, 400MHz)
1
1
J = 8.8 Hz, ArH, 2H), 6.88 (d, J = 8.8 Hz, ArH, 2H),
5.10 (dd, J = 10.4, 8 Hz, OCH, 1H), 4.24 (q, OCH2,
2H), 3.96 (t, OCH2, 2H), 3.60-3.57 (m, CH2, 2H),
1.41-1.25 (m, CH2, 15H), 0.86 (t, CH3, 3H). 13C NMR
(CDCl3, 100MHz) δ: 14.04, 14.08, 22.61, 25.96, 29.18,
29.29, 31.76, 39.11, 61.91, 68.15, 76.66, 77.30, 77.80,
77.85, 114.69, 120.82, 128.44, 155.54, 160.96, 170.38.
LCMS: 348.22[M+H]+. Elemental Analysis(%):
C-69.12; H-8.37; N- 4.01. Yield: 82%.
δ: 7.74 (d, J = 8.8 Hz, ArH, 2H), 6.96 (d, J = 8.8 Hz,
ArH, 2H), 5.14 (dd, J = 10.4, 8 Hz, OCH, 1H), 4.30
(q, OCH2, 2H), 4.00 (t, OCH2, 2H), 3.61-3.57 (m,
CH2, 2H), 1.53-1.20 (m, CH2, CH3, 31H), 0.87 (t,
CH3, 3H). 13C NMR (CDCl3, 100MHz) δ: 14.06, 14.07,
22.65, 25.70, 29.32, 29.40, 29.56, 29.62, 29.64, 29.69,
29.72, 29.76, 29.80, 31.39, 32.79, 61.45, 76.65, 77.17,
77.29, 80.01, 114.50, 114.39, 122.01, 128.29, 128.45,
156.48, 161.99, 170.76. LCMS: 459.15 M+. Elemental
Analysis(%): C-73.14; H-9.83; N- 3.02. Yield: 80%.
2.4e Ethyl 3-[4-(decyloxy)phenyl]-4,5-dihydroisoxa-
zole-5-carboxylate (4e): FT-IR (cm−1): 2917, 1732,
1401, 1353, 1264. 1H NMR (CDCl3, 400MHz) δ: 7.42
(d, J = 8.8 Hz, ArH, 2H), 6.88 (d, J = 8.8 Hz, ArH,
2H), 5.11(dd, J = 10.4, 8 Hz, OCH, 1H), 4.24 (q, OCH2,
2H), 3.96 (t, OCH2, 2H), 3.61-3.59 (m, CH2, 2H),
1.71-1.26 (m, CH2, CH3, 19H), 0.86 (t, CH3, 3H). 13C
NMR (CDCl3, 100MHz) δ: 14.03, 14.14, 22.64, 25.96,
29.27, 29.52, 31.85, 39.10, 61.91, 68.14, 68.30, 76.67,
77.31, 77.71 77.94, 114.66, 120.81, 128.35, 128.53,
155.54, 160.95, 170.39. LCMS: 376.24 M+. Elemental
Analysis(%): C-70.33; H-8.90; N- 3.71. Yield: 84%.
3. Results and Discussion
3.1 Mesomorphic Properties
The changes in phases were identified by Polarizing
Optical microscope (figure 1) and they were found to be
in agreement with DSC transition temperatures. All the
synthesized derivatives were found to exhibit Nematic
and Smectic phases. Smectic phase was typical in the
intermediate compounds 3a-g and Nematic phase was
found to be the typical phase in all the synthesized Isox-
azolines 4a-g. Smectic phase was found in compounds
2.4f Ethyl 3-[4-(dodecyloxy)phenyl]-4,5-dihydroisoxazole- with long chain homologues and Nematic phase was
5-carboxylate (4f): FT-IR (cm−1): 2917, 1740, 1419, exhibited by compounds with short alkyl chain. The
1
1357, 1307. H NMR (CDCl3, 400MHz) δ: 7.58 (d, change in the mesomorphic phases is due to changes in
J = 8.8 Hz, ArH, 2H), 6.89 (d, J = 8.8 Hz, ArH, 2H), the orientations and free rotation of the rings, and vari-
5.11 (dd, J = 10.8, 8 Hz, OCH, 1H), 4.25 (q, OCH2, ous orientations are stabilized at different temperatures
Figure 1. POM images of 3a at 22◦C, 3b at 24◦C, 5b at 9.8◦C, 5d at 24◦C and 5e at 25◦C.

Sumana Y Kotian et al.
leading to the changes in the phases and probably due to facilities. Authors would also like to acknowledge
the non planarity. The formation of mesophase is purely Institute of Excellence, University of Mysore for the
a geometrical aspect. The Isotropic temperatures of the instrumentation facilities.
compounds 3a-g were high compared to the Isotropic
temperature of the final cyclised product which proves
the lowering of melting point in the presence of hete-
References
rocycles. Compounds 4a and 4b were liquid in nature
and they exhibited Nematic phase and the other mem-
bers exhibited Smectic phases. It shows that as the alkyl
chain length increases better mesophases are exhibited.
1. Gray G W, Harrison K J and Nash J A 1973 Electron
Lett. 9 130
2. Kato T, Mizoshita N and Kishimoto K 2006 Angew.
Chem. Int. Ed. 45 38
3. Tavares A, Ritter O M S, Vasconcelos U B, Arruda B
C, Schrader A, Schneider P H and Merlo A A 2010 Liq.
Cryst. 37 159
4. Kauhanka U and Kauhanka M 2004 Liq. Cryst. 31 1547
5. Kovganko V N and Konganko N N 2006 Russ. J. Org.
Chem. 42 243
6. Stewart D, Mchattie G S and Imrie C T 1998 J. Mater.
Chem. 8 47
7. Ritter O M S, da Silveira N P and Merlo A A 2006 J.
Braz. Chem. Soc. 17 348
8. Rueff J M, Barbera J, Donnio B, Guillon D, Marcos M
and Serrano J L 2003 Macromolecules 36 8368
9. Lydon J E 2003 Liq. Cryst. 12 1
10. Kurapati R, Reddy U V, Raichur A M and Suryaprakash
N 2016 J. Chem. Sci. 128 325
11. Goodby J W 2006 Liq. Cryst. 33 1229
12. Kandre S, Bhagat P R, Sharma R and Gupte A 2013
Tetrahedron Lett. 54 3526
13. Selvarasu C and Kannan P 2015 J. Chem. Sci. 127
1831
14. Gallardo H, Santos D M P de O, Caramori G F, Molin F
and Bechtold I H 2013 Liq. Cryst. 40 570
15. Roddecha S and Anthamatten M 2010 Liq. Cryst. 37
389
16. Haino T, Tanaka M, Ideta K, Kubo K, Morib A and
Fukazawaa Y 2004 Tetrahedron Lett. 45 2277
17. Passo J A, Vilela G D, Schneider P H, Ritter O M S and
Merlo A A 2008 Liq. Cryst. 35 833
4. Conclusions
We found that the incorporation of the alkyl group
in a new series of 4,5-dihydroisoxazole-5-carboxylate
derivatives increased the liquid crystalline nature of the
molecule caused by the presence of the heterocycle, and
it dramatically decreased the melting point of the com-
pounds. The design of novel thermotropic liquid crys-
tals as advanced functional materials involves selection
of suitable core fragment, linking group, and terminal
functionality. Heterocycles are of great of importance
as core units in thermotropic liquid crystals owing to
their ability to impart lateral and/or longitudinal dipoles
combined with changes in the molecular shape. The
incorporation of heteroatoms can result in considerable
changes in the corresponding liquid crystalline phases
and/or in the physical properties of the observed phases,
because most of the common heteroatoms (S, O and N)
are more polarizable than carbon.
Supporting Information (SI)
1H and 13C NMR, Mass, XRD and POM images are
available in Supplementary Information at www.ias.ac.
in/chemsci.
18. Aline Tavares, Paulo H Schneider and Aloir A Merlo
2009 Eur. J. Org. Chem. 889
19. Rafaela R da Rosa, Irwing S Brose, Guilherme D Vilela
and Aloir A Merlo 2015 Mol. Cryst. Liq. Cryst. 612
158
Acknowledgements
20. Rai K M L and Hassner A 1997 Synth. Commun. 27
467
The authors would like to acknowledge University with
Potential for Excellence (UPE), UGC for the financial
support and University of Mysore for the laboratory
21. Shi Min and Shen Yu-Mei 2002 Molecules 7 386
22. Raad Kasim Yhya, Lokanatha Rai K M and Ebraheem
Abdu Musad 2013 J. Chem. Sci. 125 799