Isoxazoline- and isoxazole-liquid crystalline schiff bases: A puzzling game dictated by entropy and enthalpy effects

Article abstract of DOI:10.1016/j.molliq.2019.111750

Two series of Schiff base (SB) liquid crystals (LC) containing the 5-membered rings isoxazoline or isoxazole were synthesized and characterized; 27 isoxazoline and 20 isoxazole compounds were obtained. Nematic, smectic A, and smectic C mesophases were fou

Full text of DOI:10.1016/j.molliq.2019.111750

Journal Pre-proof
Isoxazoline- and isoxazole-liquid crystalline schiff bases: A puzzling game dictated by
entropy and enthalpy effects
Luma Fritsch, Luis A. Baptista, Ivan H. Bechtold, Guilherme Araújo, Richard J.
Mandle, Aloir A. Merlo
PII:
S0167-7322(19)33369-0
DOI:
https://doi.org/10.1016/j.molliq.2019.111750
MOLLIQ 111750
Reference:
To appear in: Journal of Molecular Liquids
Received Date: 14 June 2019
Revised Date: 12 September 2019
Accepted Date: 14 September 2019
Please cite this article as: L. Fritsch, L.A. Baptista, I.H. Bechtold, G. Araújo, R.J. Mandle, A.A. Merlo,
Isoxazoline- and isoxazole-liquid crystalline schiff bases: A puzzling game dictated by entropy and
enthalpy effects, Journal of Molecular Liquids (2019), doi: https://doi.org/10.1016/j.molliq.2019.111750.
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Isoxazoline- and Isoxazole-liquid crystalline Schiff bases: A puzzling game
dictated by entropy and enthalpy effects
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Luma Fritsch,1 Luis A. Baptista,1 Ivan H. Bechtold,2 Guilherme Araújo,1 Richard J. Mandle,3
and Aloir A. Merlo1*
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1Instituto de Química, Universidade Federal do Rio Grande do Sul, 91501-970, Porto
7
Alegre, RS, Brazil
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2Departamento de Física, Universidade Federal de Santa Catarina, 88040-900,
Florianópolis, SC, Brazil
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3Department of Chemistry, University of York, York, UK
Corresponding author email: aloir.merlo@ufrgs.br
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Abstract
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Two series of Schiff base (SB) liquid crystals (LC) containing the 5-membered rings
isoxazoline or isoxazole were synthesized and characterized; 27 isoxazoline and 20 isoxazole
compounds were obtained. Nematic, smectic A, and smectic C mesophases were found and
characterized by Polarized optical microscopy (POM), Differential scanning calorimetry
(DSC), and X-ray diffraction. The scientific problem addressed was how the isoxazoline and
isoxazole rings affect the mesophase structure and stability. Molecular packing and
anisotropic interactions based on enthalpy and entropy properties were used to explain the
thermal and structural behaviour observed for both series. The proposed mechanism was
assisted by Density functional theory (DFT) calculations, providing new insights into the
molecular organization of this kind of system.
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Keywords: Liquid crystals; isoxazolines; isoxazoles; entropy effects; enthalpy effects.
1. Introduction
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Isoxazolines and isoxazoles have proven to be privileged structures in pharmaceutical
and biological areas.[1–10] As an example of a privileged natural structure, acivicin, an
isoxazoline derivative, was the inspiration for the synthesis of a collection of new molecular
probes for bacterial proteome analysis.[11] Considering their similar molecular connectivities
with isoxazolines, isoxazoles are also found in many pharmaceutical applications, and they
have been classified as privileged structures. As an example, nonsteroidal anti-inflammatory
drugs (NSAIDs) are widely used for the treatment of pain and inflammation, especially

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arthritis. NSAID drugs act as aspirin, whose function is to block the formation of
prostaglandins (PGs) originating from arachidonic acid by the cyclooxygenase (COX)
enzyme. Valdecoxib is one isoxazole example that has been tested as a potent and selective
inhibitor of COX-2.[12] The combination of two or more pharmacophore groups in a single
molecule enhances biological activity. In this regard, isoxazolines linked tetrazoles and uracils
tethered to isoxazoles, isoxazolines and triazoles were prepared for biological
screening.[13,14]
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The concept of privileged structures can be transferred to functional materials, where
some structural, electronic, and morphological prerequisites are required. In liquid crystal
science, it is well-established that mesomorphic properties represent a delicate balance
between steric constrains and anisotropic attractive interaction.[15–23]
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According to the best expert in thermotropic liquid crystal behaviour, visual inspection
of the molecular framework drawn on a piece of paper is almost decisive to define if such a
virtual molecule could be a liquid crystal (LC). Visual inspection works very well in almost
all situations. The decision is guided by some general rules established a long time ago based
on structural and electronic prerequisites that molecules need to have.[24]
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Rod-shaped molecules tend to be ordinary liquid crystals (calamitic liquid crystals,
CLCs), and disc-shaped molecules may present columnar LC behaviour. On the other hand,
bent-shaped molecules favour the appearance of an unusual polar order, or, as chameleons,
some conformational issues can induce two distinct liquid crystal behaviours and make it
difficult to define the existence of mesomorphism and the kind of mesophase.[25] In this
context, isoxazolines and isoxazoles open new perspectives in organic synthesis to be
explored by the organic experimentalist. In fact, they have been explored by us and
others[26–34] in the synthesis and characterization of new liquid crystal compounds. As
expected, isoxazolines and isoxazoles usually act as CLCs[35] and, more recently, as banana
liquid crystals.[36] Our progress in the preparation of LCs based on isoxazolines, isoxazoles,
thiazoline, and thiazoles has shown that they can also produce a false impression as to their
identity as a LC. This is especially the case for molecules with a match and mismatch of
hydrogenated and perfluorated alkyl chains.[36–38] Five-membered aromatic heterocycles
represent an interesting class of organic compounds to be explored in LCs due to their ability
to perform very well as mesogenic inductors. Less usual in LCs is the use of non-aromatic 5-
membered heterocyclic compounds. Facing the issues related to the existence of a mesophase
in 5-membered 3,5-disubstituted isoxazolines, we present our findings regarding the LC
behaviour of two series of Schiff bases (SBs) containing isoxazoline (9) and isoxazole (10)
rings (Figure 1). The SB 9 series carries a non-planar 5-membered heterocyclic isoxazoline,
while the SB 10 series carries a planar and aromatic 5-membered heterocyclic isoxazole. The
carbon atom, indicated by the arrow, defines the mesophase window, thermal stability of the
crystal phase, and the mesophase. Relevant to this subject is the relationship between the
enthalpy and entropy of these two series of SBs. A puzzling game was established with those
energetic parameters. They were tentatively used to explain the mesomorphic behaviour of the
9 and 10 series in terms of steric demands and anisotropic interactions in the mesophase and
in the solid state.

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Figure 1. Molecular structure of Schiff bases (SBs) containing isoxazoline 9 and isoxazole 10
rings.
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2. Results and discussion
2.1. Synthetic procedures
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Our target molecules, SBs 9 and 10, were synthesized by two molecular partnerships:
anilines 6 and 7 and aldehydes 8. To perform as LCs, heterocyclic rings were installed on the
aniline component. In this way, isoxazolines and isoxazoles were chosen, considering our
previous results concerning the properties of LCs.[39,40] Isoxazoles can be derived in two
steps: by oxidation from isoxazolines,[41] which were in turn built up via [3+2] 1,3-dipolar
cycloaddition between oxime 2 and styrenes 3.[42]
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Scheme 1 and Scheme 2 describe our strategy to build the heterocyclic isoxazolines and
isoxazoles in a straightforward way. Aldehyde 1 and styrenes 3a–f are commercially available
chemicals. Oximation of 1 yielded p-nitrobenzaldehyde oxime 2, which precipitated at the
end of the reaction when the temperature dropped to room temperature. It was collected as a
crystalline solid, without the need for recrystallization. Next, oxime 2 was exposed to a 5%
aqueous solution of NaOCl/CH2Cl2 to give, in situ, the reactive nitrile oxide, which was
captured by styrenes 3a–f. The cycloadducts 4a–f were obtained in fair to good yields.
Oxidation of the isoxazoline ring was performed using γ-MnO2 under toluene refluxing,
producing isoxazoles 5a–d and 5f. Transformations of 4a–f to 5a–f convert less anisotropic
isoxazolines to more anisotropic isoxazoles or pre-mesogenic ones.[16] Compounds 4e,4f and
5f are useful intermediates to be used in more elongated and anisotropic molecules. Acetyl
and tert-butyl protecting groups can be removed, providing the respective phenols 4g and 5g.
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101
102
103
104

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107
In doing so, removal of the protecting groups followed by Williamson alkylation with linear
and branched alkyl bromides, such as n-butyl bromide and 2-ethylhexyl bromide, gave 4h–i
and 5h–i in good yields.
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Scheme 1. Synthesis of isoxazolines 5a–f precursors and 4h–i and 5h–i intermediates.
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117
The next step in our strategy was to prepare a collection of anilines 6a–f and anilines
7a–f. Reduction of the nitro group to the aniline group was done using SnCl2.2H2O as the
reducing agent. The reaction was conducted under a nitrogen atmosphere and with absolute
ethanol as a solvent, as outlined in Scheme 2. The yields of the amino isoxazoles containing
an alkyl group were fair to low in general. We adopted this methodology because the
traditional reaction using H2 and Pd/C had failed, especially with isoxazoline derivatives. The
heterocyclic reduction to 1,3-aminoalcoohol was the main collateral reaction observed.

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Scheme 2. Reduction reaction of nitro compounds to anilines 6a–f and 7a–d.
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128
Scheme 3 outlines the Schiff bases 9an–9fn and 10an–10fn. The condensation
reaction between anilines 6a–f and 7a–f and aldehydes 8a–d with acetic acid was done in
ethanol under reflux for 2 h. At the end, the solution was cooled and the products were
collected as a precipitated solid. SBs were isolated as a solid powder. Purification was done
by two or three recrystallizations in ethanol. Solids obtained were resolubilized in DCM, and
SB solutions were filtrated using Millipore filters. A collection of 27 isoxazolines and 20
isoxazoles was prepared. The descriptor n in the code indicates the number of carbon atoms
that belong to the linear alkyl chain bonded in aromatic aldehydes.
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134

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Scheme 3. Preparation of SBs 9an–9fn and 10an–10fn.
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139
140
All final LC compounds were characterized by 1H and C NMR spectral and thermal
analysis (DSC and POM). Experimental descriptions, as well DSC traces and H and 13C
NMR spectroscopic characterizations, are available in the supporting information (SI).
1
141
2.2. Liquid-Crystalline Properties
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146
147
148
149
All final compounds showed mesomorphic behaviour, considering that molecules in
these series have rod-shape topologies. The transitional properties for all molecules with
isoxazoline and isoxazoles nuclei are given in Table 1 and Table 2, respectively. For both
series, 6 sets of liquid crystals were prepared for each series, 9an–9fn and 10an–10fn, with n
representing the linear alkyl chain (n=1, 2, 4, 6, 8, 10, and 12 carbon atoms) in one terminus
of the rigid core, while the other terminus contains a substituent X that differs in shape and
polar nature (a = Me, methyl; b = Cl, chlorine; c = Br, bromine; d = H, hydrogen; e = But, n-
butyl; and f = 2-EtHex, 2-ethylhexyl).
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158
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161
Figures 2–4 display some pictures that were selected for series 9 and 10 and were
taken by POM. Figure 2a displays the SmA texture of compound 9b8 with a polar chlorine
group, which was identified by the focal conic domains (FCDs) for the sample covered by a
cover glass and the parabolic (polygonal) texture outside the cover glass. Figure 2b displays
the texture of the nematic mesophase for 9d6, with black and coloured areas being relative to
the homeotropic and planar texture, respectively. Upon cooling, the transition between the
isotropic liquid phase and the N mesophase is seen by nematic droplets that formed at the
bottom left corner of Figure 2b. Figure 2c shows two distinct areas of SmC texture obtained
upon cooling at 150°C of 9e8. Broken focal-conic fan-shaped defects combined with flash
and bright areas of the Schlieren texture of SmC are seen for 9e8. Figure 2d displays
Schlieren texture with typical gray disclination points and lines of 9e12. Compounds with
short alkyl chains, such as 9e1 (methyl), 9e2 (ethyl), and 9e4 (n-butyl), showed the N

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mesophase, while 9e6–9e12, containing medium and long alkyl chains, presented the SmC
mesophase. Two examples of Schlieren texture of the SmC mesophase can be seen in Figure
2c,d. The nematic mesophase was observed for compounds without substituent at the para-
position of the phenyl ring (9d6 and 9d8).
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Figure 2. (a) Focal conic defects and homeotropic texture in the SmA mesophase for 9b8
upon cooling at 184°C (2nd heating scan). Polygonal texture at left side without coverslip and
focal conic domains at right side. (b) Schlieren and homeotropic texture for monotropic N
mesophase for 9d6. (c) SmC mesophase for 9e8 upon cooling at 150°C. (d) Schlieren texture
of the SmC mesophase for 9e12.
181

182 Table 1. Phase transition temperatures for isoxazolines Schiff bases 9.
N
O
N
RO
H
X
Transition Temperatures (°C)a [Enthalpy (kJ.mol–1)] {Entropy (J.mol–1K–1)}
Entry
R
X
Cr
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
SmC
SmA
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
-
N
●
●
-
I
9a6
9a8
C6H13
C8H17
C10H21
C12H25
C6H13
C8H17
C10H21
C12H25
C6H13
C8H17
C10H21
C12H25
C6H13
C8H17
C10H21
C12H25
CH3
Me
Me
144[37.5]{89.9}b,c
140 [25.0]{61.3}b,d
138 [25.6]{63.4}b,d
135 [34.8]{85.5}b
159 [24.7]{57.1}
149 [49.5]{117}
141 [32.8]{79.2}c
134 [29.7]{73.1}
169 [44.0]{99.6}
161 [36.4]{83.8}b
152 [28.5]{67.1}
148 [28.1]{66.6}
139 [38.4]{93.1}
139 [46.8]{113}
137 [38.7]{94.3}
136 [36.3]{88.7}
153 [29.0]{68.0}
148 [22.5]{54.0}
156[31.2]{73.0}
148 [25.1]{59.6}f
138 [24.8]{60.5}b
134 [24.3]{59.8}
133 [30.9]{76.3}
86 [13.2]{36.8}f
93 [15.4]{42.1}c
93 [20.7]{56.7}
97 [21.4]{57.7}
-
-
-
(135)
159 [0.35]{0.80}
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
-
149 [0.92]{2.20}
155 [0.57]{1.32}
9a10
9a12
9b6
Me
-
-
155 [5.04]{11.6}
-
Me
-
-
154 [6.60]{15.4}
-
-
Cl
-
-
183 [4.70]{10.3}
-
-
9b8
Cl
-
-
183 [12.7]{27.8}
-
-
9b10
9b12
9c6
Cl
-
-
183 [8.50]{18.6}
-
-
Cl
-
-
179 [4.56]{10.1}
-
-
Br
-
-
184 [7.30]{15.9}
-
-
9c8
Br
-
-
186 [8.50]{18.5}
-
-
9c10
9c12
9d6
Br
-
-
184 [7.22]{15.8}
-
-
Br
-
-
182 [7.36]{16.2}
-
-
H
-
-
(128) [1.14]{2.83}
●
●
-
(140)e [0.71]{1.73}
9d8
H
-
-
(128) [0.98]{2.45}
(141)e [4.32]{10.5}
9d10
9d12
9e1
H
-
-
144 [5.31]{12.7}
-
H
-
-
147 [5.67]{13.5}
-
-
n-BuO
n-BuO
n-BuO
n-BuO
n-BuO
n-BuO
n-BuO
2-EtHexO
2-EtHexO
2-EtHexO
2-EtHexO
-
-
-
●
●
●
●
-
166 [0.36]{0.83}
9e2
C2H5
-
-
-
-
177 [0.42]{0.92}
9e4
C4H9
-
-
-
-
170 [0.63]{1.50}
9e6
C6H13
C8H17
C10H21
C12H25
C6H13
C8H17
C10H21
C12H25
●
●
●
●
●
●
●
●
149 [0.16]{0.39}
158 [3.60]{8.30}
161 [5.90]{13.6}
162 [7.31]{16.8}
116[0.12]{0.31}
115 [2.30]{5.87}
124 [6.31]{15.9}
122 [6.10]{15.4}
●
-
162 [0.19]{0.43}
169 [1.38]{3.11}
9e8
-
-
-
-
-
-
-
-
9e10
9e12
9f6
-
-
-
-
-
-
●
-
124 [3.20]{8.06}
-
9f8
-
-
-
-
9f10
9f12
-
-
-
-

183
184
185
186
187
188
Scan rate = 10°C min–1 for all samples. Cr denotes the crystal phase. SmC = Smectic C phase, SmA = Smectic A phase, and N = Nematic phase. Monotropic N, SmA, and SmC
mesophases observed by POM upon cooling are in parentheses. The transition temperatures and enthalpy values were collected from a second heating scan to the isoxazolines-
BS. Tonset was considered for crystal to mesophase only. Reference 39. Reference 40. Values for enthalpy and entropy for the transition between crystal phases were
summed. ePeak temperature. fScan rate = 2°C min–1 .
a
b
c
d
Table 2. Phase transition temperatures for isoxazoles Schiff bases 10.
N
O
N
RO
H
X
Transition Temperatures (°C) [Enthalpy (kJ.mol–1)] {Entropy (J.mol–1K–1)}
Entry
R
X
Cr
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
SmC
SmA
N
●
●
●
●
●
-
I
10a6
10a8
10a10
10a12
10b6
10b8
10b10
10b12
10c6
C6H13
C8H17
C10H21
C12H25
C6H13
C8H17
C10H21
C12H25
C6H13
C8H17
C10H21
C12H25
C6H13
C8H17
C10H21
C12H25
C6H13
C8H17
C6H13
C8H17
Me
143 [32.3]{77.6}b,c
141 [37.3]{90,0}b
125 [23.1]{58.1}b
126 [44.0]{110.1}b
130 [34.8]{86.4}
128 [39.8]{99.4}
126 [47.7]{119,5}c
127 [52.4]{131,1}
143 [30.9]{74.3}
137 [53.8]{131.4}
132 [50.7]{125.2}b
129 [54.2]{134.6}
135 [39.9]{97.7}
129 [38.7]{98.0}d
139 [33.7]{101.8}d
118 [52.6]{134.7}
118 [17.9]{45.8}
122 [17.0]{43.1}b
96 [17.2]{46.7}
-
-
-
-
-
-
287 [0.48]{0.85}
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Me
-
-
278 [0.68]{1.24}
Me
●
●
-
(140)
-
-
253 [0.44]{0.84}
Me
178 [0.32]{0.70}
-
-
255 [1.05]{1.99}
Cl
-
●
●
●
●
●
●
●
●
-
278 [0.70]{1.26}
304 [0.68]{1.17}
Cl
-
-
289 [3.07]{5.48}
-
Cl
-
-
293 [5.19]{9.18}
-
-
Cl
-
-
288 [5.75]{10.3}
-
-
Br
-
-
299 [0.60]{1.03}
●
-
316 [0.27]{0.46}
10c8
Br
-
-
301 [5.52]{9.63}
-
10c10
10c12
10d6
10d8
10d10
10d12
10e6
10e8
10f6
Br
-
-
295 [4.50]{7.93}
-
-
Br
-
-
280 [4.30]{7.71}
-
-
H
H
-
-
-
-
-
-
-
-
-
-
●
●
●
●
●
-
231 [0.54]{1.06}
224 [0.53]{1.07}
198 [0.41]{0.90}
205 [0.59]{1.23}
270 [3.01]{7.54}
-
-
-
-
H
-
-
-
H
-
-
-
n-BuO
n-BuO
2-EtHexO
2-EtHexO
-
-
-
●
●
●
248 [1.09]{2.10}
139 [0.71]{1.72}
146 [0.88]{2.10}
-
-
●
-
173 [0.71]{1.60}
-
10f8
100 [34.7]{93.2}c
-
189

190
191
192
Scan rate = 10°C min–1 for all samples. Cr denotes the crystal phase, SmC = Smectic C phase, SmA = Smectic A phase, and N = Nematic phase. Monotropic SmA and SmC
mesophases observed by POM upon cooling are in parentheses. The transition temperatures and enthalpy values were collected from the first cycle for the isoxazole-BS. aTonset
was for the crystal to mesophase only. bReference 39. cReference 40. dValues for enthalpy and entropy for the transition between crystal phases were summed.
193

194
195
196
197
Figure 3 displays the texture presenting the undulation phenomenon [43,44] observed
for isoxazoline 9e6. The mesophase sequence Cr 148 SmC 149 SmA 162 N 169 Iso was
assigned. Some comments will be addressed to the LC behaviour of 9e6 concerning its
nematic mesophase texture in SI section
198
199
200
201
202
203
204
205
206
207
208
Figure 3. Polarizing optical microscopy (POM) images of the fingerprint texture observed for
SB 9e6 as the temperature approaches the transition to the isotropic state.
209
210
211
212
213
214
215
216
217
218
219
220
Figure 4 displays the representative textures for SBs containing the isoxazole ring.
Three SBs were selected and the texture was briefly described.[45] A planar texture of the N
mesophase is shown in Figure 4a for compound 10d10 near to the transition temperature to
the isotropic state. From left to right in Figure 4a, a dark red wave is seen, which flows over
the dark yellow region, leaving behind bubbles of air and black areas. Figure 4b shows the
SmC mesophase in two distinct defects - a grainy schlieren texture at the left and a broken
fan-shaped texture at the right for compound 10e8 at 230°C. A classical Schlieren texture of
the nematic mesophase is shown in Figure 4c for compound 10f6. In Figure 4d, the transition
between SmC and N mesophases upon cooling for 10f6 is shown. At the left side, the texture
is brighter than the right side due to freedom of the phase director in the N mesophase and the
greater order in the smectic mesophase.
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Figure 4. (a) Planar texture for the nematic mesophase of 10d10 upon heating. (b) Grainy
Schlieren texture (at left) and broken fan focal conic texture (at right) for SmC upon cooling
for 10e8. (c) Schlieren texture upon heating for 10f6 at 230°C and (d) Schlieren texture for
the N ꢀ SmC transition upon cooling.
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Upon examination of the transitional properties of this series, some trends may be
drawn according to data in Table 1. The series containing small and polar terminal groups
connected to the phenyl ring at the 5-position of the heterocyclic ring (methyl, chlorine,
bromine, and hydrogen) displayed SmA and/or N mesophases. For medium and large alkyl
groups in the same phenyl ring (n-butyl and 2-ethylhexyl), the tilted SmC and nematic
mesophases are predominant. The mesophase range and type for all LC compounds listed in
Table 1 and Table 2 are dependent on the nature of the heterocyclic ring. The SmA
mesophase was found for compounds 9an, 9bn, 9cn, 9dn, and 9f6. However, for series 10
only 10bn and 10cn displayed the SmA mesophase. Inversely, the N mesophase was
mandatory for series 10. As a general outcome, the results confirm that isoxazole is by far the
best molecular moiety to induce mesomorphism. The isoxazoline ring, even being a non-
planar core due to tetrahedral carbon atoms inserted into its framework, is also a mesophase
molecular inductor. The ranges of mesophases for isoxazolines were about 20°C. On the other
hand, the isoxazole nucleus showed an expressive wide mesophase range, sometimes higher
than 150°C. That is a huge mesophase stability, like compound 10b6, where the range up to
174°C. Anisotropic interactions originating from the planarity and more extensive resonance
conjugation are the reasons for the high mesophase stability of the isoxazole ring in the
mesophase, allowing it to interact in a more effective manner in the condensed and fluid state
through a π-stacking interaction.[29,] The main drawback of SBs containing the isoxazoles in
this series is that their thermal decomposition upon heating becomes more intense when the
samples are exposed to high temperatures, especially when the temperature ranges of the
analyses cross the line of the mesomorphic state to isotropic state. This is the price to pay to
be more stable and to resist losing their orientational order when going to the isotropic state
due to the efficient intermolecular interaction across the 3,5-diarylisoxazole system. DSC

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thermograms in Figure 5 represent this behaviour. Whereas 9c10 displays stable behaviour
during the second cycle of heating and cooling in the range of 60–220°C, 10c10 decomposes
during the first cycle of heating when the sample is exposed to temperatures of 60–350°C. In
general, temperatures of melting for isoxazolines are higher than the isoxazole ring. In
contrast, isoxazoles display high values of clearing temperature. Thermal stability here is a
relative concept considering that the LC behaviour remains stable for the isoxazoline series
due to the low value of the isotropic transition temperature. This means that the thermal
stability depends on the mesophase range under observation.
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Enthalpy and entropy values are dependent on both the nature of the transition
temperature that has been considered and the heterocyclic nuclei present in these SBs. In
general, enthalpy and entropy values for isoxazoles were superior for the transition of the
crystal phase to the mesophase, and they displayed lower enthalpy and entropy values for the
transition from the mesophase to the isotropic state. Steric packing considerations are
important to mesophase formation for isoxazolines, and anisotropic attractive interactions
rather than electrostatics are decisive for the stability of the mesophase in isoxazole systems.
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Considering the transitional data exemplified for SBs 9c10 and 10c10, we can discuss
some interesting features of these two SB molecular architectures. The mesophase range for
9c10 is ∆T = 32°C, while for 10c10 it is ∆T = 163°C, being five times higher owing to the
fact that the molecular topology favours molecular packing of isoxazole against the
isoxazoline ring in the mesophase. Clearing transition temperatures are also very discrepant
between them. While 9c10 goes to the isotropic state at 184°C, 10c10 enters the liquid state
only at 295°C. Enthalpy and entropy data collected for these SBs are also interesting, which
reflect the nature of molecular packing in the solid and in the mesomorphic state.
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Figure 5. DSC thermogram for compounds 9c10 and 10c10.
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Figure 6 describes the molecular arrangement for SBs 9c10 and 10c10 in the all-trans
conformation. This helps us to understand more regarding the thermal behaviour and the
dependence of the mesophase nature and transition temperatures observed in Table 1 and
Table 2. Differences in their LC behaviour cannot be attribute specifically to the electrostatic
interactions, considering that both LCs have high and similar dipole values. Estimated values
of the dipole moment for 9c10 and 10c10 by DFT calculations are 6.6 D and 5.6 D,
respectively.[46] Dipolar moment directions deviate partially from the molecular axis, being
more accentuated for isoxazolines 9c10. Molecular folds for 9c10 and 10c10 are indicated as
132.09° and 155.34°, respectively (SI). The longitudinal and lateral direction given by the
dipole moment corroborate the predominance of the nematic mesophase for series 10 and the
smectic mesophase for series 9. Orientational order is gained in series 10, while positional
order is gained in series 9.
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Figure 6. Ball-stick model for compounds 9c10 (up) and 10c10 (down) obtained by
molecular modelling and dipolar moments, respectively.
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Isoxazolines and isoxazoles can be considered cousin compounds due to their
similarity in molecular connectivity. However, despite the same sequence of atoms in their
structures, they drastically differ when viewed in three-dimensional (3-D) space. The SBs
described in this study assume a hockey-stick shape considering that the length (L1 and L2) of
the aryl substituent at position 3 and 5 of the heterocyclic compound are not symmetrical in
their constitution and are different in length. Estimated DFT values are ca 27.3 Å and 6.2 Å
for the longest and the shortest aryl groups for 9c10, respectively. For the isoxazole ring,
these two aryl groups are located on the same molecular plane σ (left side of Figure 7) and
the angle β describes the molecular bend of the 3,5-disubstituted arylisoxazoles. By changing
from isoxazole to isoxazoline, the tetrahedral carbon atoms are inserted into positions 4 and 5,
which pull the shorter aryl group off the σ plane (basal plane). Now that aryl groups are no
longer positioned in the same plane, the coplanarity is not observed anymore. Molecules
change their in-plane hockey-stick shape, as seen in the isoxazole, to assume a new out-of-
plane hockey-stick shape in the isoxazolines. Two new angles should be assigned - α is the
angle related to how the aryl group is compelled to be off the σ−plane and γ is the new
molecular bending of the isoxazoline ring. While the 3,5-disubstituted isoxazole ring has just
one molecular plane where all atoms are confined, the 3,5-disubstituted isoxazoline has two
molecular planes—the main plane (σ) and a secondary plane (σ´) that contains the shorter
aryl group.
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For isoxazoles, an anticlinic arrangement of molecules is proposed, according to
Figure 7. Molecules alter their relative nitrogen and oxygen heteroatom positions in-layers
and out-layers. Inside the layers, molecules change the molecular orientation considering that
the heterocyclic ring is non symmetric. By passing from layer to layer, the relative orientation
of the molecules is also alternated from right to left and vice-versa in an attempt to adjust the
dipole moment. The lamellar structure that emerges displays a packing density superior to the
isoxazoline counterparts by π-stacking, and the clearing transition temperatures and the
mesophase thermal window for isoxazoles assume higher values than the isoxazolines, as seen
in Table 1. For comparative purposes, entropy values of 9c10 and 10c10 associated with the

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transition from the crystal phase to the SmA mesophase are 67.1 J mol–1 and 125.2 J mol–1,
respectively. The entropy value observed, which is almost twice as high for 10c10, is a direct
consequence of the intermolecular interactions in the crystal phase for isoxazoles. In general,
enthalpy and entropy values for compounds listed in Table 1 and Table 2 follow this
tendency.
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Figure 7. General hockey-stick shape structure and distinct views of the anticlinic
arrangements in the SmA mesophase of the hockey-stick shape LC from SBs. From the left
side, isoxazoles are represented by a red bar with a bending angle of β and isoxazolines are
described by a blue bar with a bending angle of α out of the σ plane – basal plane. The side
views describe the hockey-stick molecules in the lamellar structure of the SmA mesophase.
At the right, the isoxazole ring orientation is shown as a way to clarify the anticlinic
arrangement. The neutrality of the layer is preserved by inversion of the isoxazole ring in-
layer and out-layer. In the interlayer, a synclinic molecular disposition is assumed to
accommodate interface fluctuations.
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A plausible arrangement of isoxazoline compounds is depicted in Figure 8. This is an
oversimplified view of the packing manner of the molecules prepared in this work. Attempts
to obtain single-crystal resolution of one of the SBs discussed in Table 1 and Table 2 have
failed. However, our more recent results have showed that isoxazoles and isoxazolines in their
crystal phase are packed in a similar way.[47] The single crystal resolution reported by
Zanata[48] and Zerirov[49] also supports our choice, as shown in Figure 8. Figure 8a
describes the molecular packing of isoxazoline compounds, considering that it is a racemic
mixture and the heterocyclic ring is non symmetrical. Thus, moving laterally from pile to pile,
the molecular dipole inverts its direction, pointed in the opposite direction to maintain
neutrality of charges between the layers. In layers, molecules develop a lamellar structure on
the y-coordinate (in-plane horizontal direction). Considering a racemic mixture, we can
envisage four piles of the molecules composed of R and S enantiomers in a vertical direction

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(z-axes). The aromatic moieties in black and blue in Figure 8 are positioned in two distinct
molecular planes: the main plane (σ) and a secondary plane (σ´), respectively. This molecular
arrangement in the crystal state of the isoxazolines is responsible for lower transitional values
than the isoxazoles during the melting process. In Figure 8, the possible molecular
arrangements in the crystal phase for isoxazoline based on X-ray data from the literature are
shown.[47-49] The chiral centre on the isoxazoline define that the solid could be envisaged
being constitute by racemic or homoquiral domains. It does not matter what kind of domain
we assume; molecules under these circumstances should retain neutrality in terms of polarity
and handness. Figure 8a shows the top view of isoxazoline piles, with their right-handness
and left-handness being obey as well as for molecular dipole. Figure 8b is an oversimplified
model of the chiral domains in the crystal phase for the (R)-isoxazoline configuration. The
blue ball and stick drawn in the σ´ plane represent the shortest molecular alkylaryl group
connected at the C-5 carbon atom on the isoxazoline ring. The principal molecular plane (σ)
contains the longest aryl group connected at the C-3 carbon atom of isoxazoline, and the blue
ball up and down represents the chiral centre (R or S). In both Figure 7 and Figure 8,
anticlinic arrangements are proposed for molecules of the 9 and 10 series. However, in the
interface of the layers, if we are independently considering the σ or σ´ plane, the synclinic
arrangement is assumed.[50-51] Upon heating, the void volume between σ´ planes increases
more significantly than between σ planes (Figure 8d). The compactness in the crystal phase is
looser (void volume) for series 9 than series 10. Conversely, values of the transitional
properties (enthalpy and entropy) for the SmA mesophase to the isotropic state are, in general,
smaller for isoxazoles than for isoxazolines, as indicated by 9c10 and 10c10 selected for this
discussion.
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Figure 8. General description of (a) racemic isoxazolines (b) and the homochiral
configuration for (R)-isoxazolines. (c) Hypothetical molecular arrangement through front- and
side-views. Molecules stack up, forming layer structures, and each layer is next to others with
the opposite chirality. Each pile has its own handness and its dipole moment is inverted to
maintain neutrality. (d) Anticlinic arrangement is reached when a set of four isomers is side-
view. (e) Main and secondary plane σ and σ’.

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The deviation of linearity as assigned by angles β and γ (Figure 7) of the LCs analysed
in this study, as well as the mesomorphic behaviour of series 9 and 10, are dependent on the
type of heterocyclic connecting the two aryl groups at 3- and 5-positions. Data in Table 1 and
Table 2 reveals that there is a gain in orientational order for more anisotropic molecules of
series 10, and positional order acts in favour of less linear LCs that belong to series 9. The
molecular bend of non-linear molecules generates geometrical defects on the mesophase
structure, which inhibits longitudinal diffusion and imposes a rotational restriction along the
phase director. To compensate for the non-linear shape, molecules respond in such a way that
they can move laterally, thus favouring the formation of a layered structure by lateral
diffusion. Upon cooling, the geometrical constrain of the non-linear molecules becomes more
evident and decisive for both the mesophase window and mainly the mesophase nature. The
molecular order that increases upon cooling highlights the conflict between molecular packing
and steric constraints - the excluded volume manifests itself through the geometric defect. The
maximization of available space and, therefore, the minimization of free volume are critical
for the formation of nematic or smectic mesophases. Considering that the bending of series 9
is composed of two molecular planes (σ and σ´), while series 10 presenting the 3,5-
diarylisoxazole embedded in a single molecular plane (σ) the excluded volume for series 9
tends to increase upon heating and, consequently, the void volume between molecules
becomes progressively high against anisotropic interaction of the mesogens. These
intermolecular forces are not enough to sustain molecules close together in the mesophase for
a long period of time as the temperature increases. Molecules of series 9 in the isotropic state
rotate and translate freely in the available space than in the mesophase. In the LC state for
series 9, molecules are hindered to rotate or translate and, therefore, molecule motions are
greatly hindered and the LC state has low rotational and translational entropy. When going to
the isotropic state, molecules gain considerable rotational and translational entropy and the
transition from mesophase to liquid state to series 9 is driven mostly by entropic effect.
Before reach the isotropic state, molecules for series 9 undergo to thermal expansion in
direction of short aryl group represented by blue bowl in Figure 8. The expansion induced by
the heat is responsible in some extension for the predominance of SmA mesophase for series
9. For series 10, molecules are not greatly hindered due to planarization and conjugation of
the heterocyclic ring. The void volume is reduced with gains in anisotropic (attractive forces)
interactions, and the balance between the minimization of free volume and attractive forces
manifests itself through a large mesophase range and, consequently, low enthalpy and entropy
values at the transition from the mesophase to the isotropic state (Figure 8).
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In the mesophase, linearity, flatness, and conjugation contribute significantly to the
molecules slides one over the others easier for a large superficial area. The orientational order
in this circumstance is maintained through the anisotropic interactions (π-stacking) due to
higher molecular anisometry. However, those attributes vanish and molecular fold overlaps
and orientational or translational motion become more diffuse because of the loss of
anisotropic interactions. The entanglement of the alkylaryl chains (blue ball and stick in
Figure 8) of the non-linear molecules (9) distributed in two molecular planes also contributes

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decisively to the shortening of the observed mesophase range and, consequently, to the
reduction in the clearing temperature. The entanglements of the two distinct aryl groups at the
3- and 5-position of the isoxazoline ring located in the main plane (σ) and a secondary plane
(σ´) inhibit the rotational and translational diffusion in the mesophase. Figure 8c briefly
describes the molecular packing for series 9, where we are assuming that the sliding of the
layers is reached only when the free space for every molecule is available. Piles of molecules
in racemic or homoquiral domains will be able to flow freely in the liquid state only when
individual molecules overcome the volume defined by the alkylaryl groups of the σ´ plane,
with an increase in the corresponding entropy due to the thermal expansion (Table 1 and
Table 2). Also, the chiral carbon atom in 9c10 contributes to the enthalpy value since every
single chiral carbon atom on every single isoxazoline molecule presents residual polarization,
and neutrality comes from the other isomer with opposite handness (Figure 8d).[52]
Compounds of series 9, considering the void volume, behave similar to side-chain polymers
with bulky side groups presenting high glass transitions.[53]. The void volume for
isoxazolines is bigger than isoxazoles due to the interwoven continuos and alternates
networks (Figure 8). Due to the intertwining of the molecular planes, the liquid state is
reached only after all the intermolecular interactions between the planes have broken down.
To be able to flow freely, molecules of series 9 must initially expand laterally across the
secundary sigma plane with increasing void volume. Lateral diffusion come first and then the
molecules can slide one molecule over the other logitudinally.In this way, the mesophases and
thermal data of series 9 and 10 can be understood according to Figure 9. The enthalpic factor
is the main driving force for maintaining close together molecules for series 10, while entropy
is determinant factor for molecules of series 9. For any fluid phase transition, these two
molecular planes carrying aromatic groups are sterically hindered to flow freely in the
mesophase. X-ray data reveals that in a wide angle region the intermolecular distance for 9c10
is higher than for 10c10, which is consistent with the formation of racemic or homoquiral
domains.
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Figure 9. Schematic model of the clearing process. Black arrows give the lateral and
longitudinal diffusion for 9 and 10 series, respectively. Gray circles represent the free space
generated by translation of the non-linear molecules. For clarification (simplification), the
molecular fold for 9 is not seen by the blue ball, as shown in Figure 8.
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In the melting process, the solid crystal collapses due to the increase in molecular
fluctuation, vibration, and rotation of atoms through chemical bonds. The energy of the
crystal lattice that evolved at the transition is partially retained in the mesophase. Steric
considerations of the solid state are critical for non-linear molecules where the void volume
tends to increase as the molecular bend changes from the σ plane to σ´ plane. Molecular
packing and electrostatic interactions in the solid-state are adjusted in such a way that they
determine the melting temperature of the solid. Of course, if the heat used to melt the material
is too high, the dynamic process between anisotropic attractive forces and packing issues to
sustain the long-range orientational order is lost and no mesophase will be formed. Thus, the
geometry and packing considerations are closely related with the mesophase nature and
transition temperature. Data in Table 1 and Table 2 establish a puzzling game, where more
anisometric mesogens for series 10 present a larger mesophase range than series 9, with a
predominance of the nematic mesophase and higher enthalpy and entropy values for the
melting process and lower values for the transition between the mesophase and the isotropic
state. Conversely, the less anisometric series 9 displays in general lower values for the
transition from the crystal state to the mesophase and higher values for the mesophase to the
isotropic state. The precise adjustment of electrostatic and packing preferences favours the
propagation of a long-range orientational order in more anisometric molecules such as series
10, while positional order or lateral diffusion by thermal expansion favours the less linear
molecules of series 9, favoured due to residual polarization of the chiral centre by molecular
bending of SBs containing the isoxazoline ring. As pointed out by Pinal[54], melting
temperature is dependent on the molecular symmetry (Carnelley´s rule). Data in Table 1 and
Table 2 related to the melting point for SBs of series 9 and 10 display, in general, divergent
behaviour of the Carnelley´s rule. Most compounds that belong to series 9 present melting
temperatures higher than compounds of series 10, which is probably an exception to this rule.
As an example, consider 9bn/9cn and 10bn/10cn SBs, where this violation is clearly seen for
less symmetric compounds having higher melting points. In addition, an interesting effect is
seen for 9bn/9cn compounds containing an alkyl chain and halogen atoms as terminal groups.
The melting point decreases as the alkyl chain increases, and 9bn/9cn present almost the same
clearing transition temperature around 184°C, which highlights the entropic effect that the
alkyl chains have on the crystal phase for isoxazolines rather than isoxazoles.
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X-ray diffraction measurements, as shown in Figure 10, were carried out with the selected
9c10 and 10c10 compounds to confirm the lamellar structure and to obtain the interlayer
spacing of the SmA mesophase. For both compounds, the d001/d002 ratio is approximately
equal to 2, which is consistent with a molecular lamellar structure. The interlayer spacings of
34.0 Å and 36.3 Å for compounds 9c10 and 10c10, respectively, are a little longer than their
calculated molecular lengths (31.8 Å and 32.5 Å), considering the most extended
configuration. Bent-shaped molecules can present an out-of-layer fluctuation (OLF) at the
interfacial curvature, independent of whether molecules assume synclinic or anticlinic
configurations.[50] Therefore, increasing the interlayer spacing as a result of this kind of
fluctuation is common to smectic liquid crystals.
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Figure 10. X-ray diffractogram of compounds 9c10 and 10c10 captured at 160°C and 180°C,
respectively. The 9c10 spectrum was divided by a factor of 3 and 10c10 vertically translated
for better view.
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3. Conclusions
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In summary, liquid-crystalline SBs containing 5-membered isoxazoline 9 and
isoxazole 10 were evaluated using DSC, POM, X-ray, and DFT calculations. A puzzling
game was established related to the mesomorphic properties by comparison of the enthalpy
and entropy data. They were used to justify the intricate thermal behaviour for both series,
transition temperatures between the crystal phase to the mesophase and the mesophase to the
liquid phase. The mesophase range and the nature of the mesophase were analysed based on
packing issues and anisotropic interactions. The void volume was tentatively assigned as one
of the major causes of this complicated behaviour, especially for compounds of the SBs 9. In
general, enthalpy and entropy values were considerably high for more anisometric SBs
belonging to series 10 in the transition from the crystal phase to the mesophase, while those
energetic values were inverted, favouring the less anisometric SBs belonging to series 9 in the
transition from the mesophase to the isotropic phase. Melting points were higher for series 9
than series 10 and clearing temperatures displayed the opposite behaviour. From the thermal
data, we have concluded that the entropy effect acts in favour of series 9, while enthalpy is the
driving force for series 10. The relationship between structure and liquid crystals properties
was also supported by X-ray diffraction data by indexation of Miller peaks for two SBs (9c10
and 10c10) and through DFT calculations. Molecular folding (bending) of the main molecular
axis was determinant in the nature and stabilization of the mesophase. SBs 10 have an in-
plane bent-core shape and displayed a huge mesophase range with a predominance of the N
mesophase. On the other hand, SBs 9 are out-of-plane bent-core shape and showed a small
mesophase range with a predominance of the smectic mesophase.
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Conflicts of interest

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There are no conflicts to declare.
Acknowledgements
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This work was supported by the CNPq/Edital Universal [n° 011/2016/403075/2016-5 and
407773/2016-9], CAPES, and INCT-INEO. This study was financed in part by the
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Brasil (CAPES) [Finance
Code 001].
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Notes and references
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[1]. J. Kim, H. Kim, and S. B. Park, J. Am. Chem. Soc., 2014, 136, 14629.
https://doi.org/10.1021/ja508343a
[2]. G. N. Pairas, F. Perperopoulou, P. G. Tsoungas and G. Varvounis, ChemMedChem,
2017, 12, 408. https://doi: 10.1002/cmdc.201700023
[3]. A. P. Kozikowski, Acc. Chem. Res., 1984, 17, 410.
https://doi.org/10.1021/ar00108a001
[4]. K. Kaur, V. Kumar, A. K. Sharma, G. K. Gupta. European Journal of Medicinal
Chemistry, 2014, 77, 121. https://doi: 10.1016/j.ejmech.2014.02.063
[5]. N. Agrawal and P. Mishra. Medicinal Chemistry Research, 2018, 27, 1309.
https://doi.org/10.1007/s00044-018-2152-6
[6].T. Weber and P. M. Selzer, Edited by S. Müller, R. Cerdan and O. Radulescu, 2016
Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany.
[7].S. Tilvi and K. S. Singh. Current Organic Chemistry, 2016, 20, 898. https://doi:
10.2174/1385272819666150804000046
[8].A. Kulyashova and M. Krasavin, Tetrahedron Letters, 2016, 57, 4395.
https://doi.org/10.1016/j.tetlet.2016.08.059
[9].S. Stosic-Grujicic, I. Cvetkovic, K. Mangano, M. Fresta, D. Maksimovic-Ivanic, L.
Harhaji, D. Popadic, M. Momcilovic, D. Miljkovic, J. Kim, Y. Al-Abed and F.
Nicoletti, J. Pharm. Exp. Therapeutics, 2007, 320, 1038. https://doi:
10.1124/jpet.106.109272
[10].
G. Shakya, H. Rivera Jr, D. J. Lee, M. J. Jaremko, J. J. La Clair, D. T. Fox, R.
W. Haushalter, A. J. Schaub, J. Bruegger, J. F. Barajas, A. R. White, P. Kaur, E. R.
Gwozdziowski, F. Wong, S. Tsai, M. D. Burkart. J. Am. Chem. Soc., 2014, 136,
16792. https://doi.org/10.1021/ja5064857
[11].
R. Orth, T. Böttcher and S. A. Sieber, Chem. Commun., 2010, 46, 8475.
https://doi: 10.1039/C0CC02825H
[12].
J. J. Talley, D. L. Brown, J. S. Carter, M. J. Graneto, C. M. Koboldt, J. L.
Masferrer, W. E. Perkins, R. S. Rogers, A. F. Shaffer, Y. Y. Zhang, B. S. Zweifel and
K. Seibert, J. Med. Chem., 2000, 43, 775. https://doi.org/10.1021/jm990577v
[13].
A. Kamal, A. Viswanath, M. Janaki Ramaiah, J. N. S. R. C. Murty, F. Sultana,
G. Ramakrishna, J. R. Tamboli, S. N. C. V. L. Pushpavalli, D. Pal, C. Kishor, A.
Addlagatta and M. pal Bhadra, Med. Chem. Commun., 2012, 3, 1386. https://doi:
10.1039/C2MD20085F

595
596
597
598
599
600
601
602
603
604
605
606
607
608
609
610
611
612
613
614
615
616
617
618
619
620
621
622
623
624
625
626
627
628
629
630
631
632
633
634
635
636
637
638
[14].
J. Cao and X. Huang, J. Comb. Chem., 2008, 10, 526.
https://doi.org/10.1021/cc800034v
[15].
[16].
[17].
N. A. Zafiropoulos, E. Choi, T. Dingemans, W. Lin and E. T. Samulski, Chem.
Mater., 2008, 20, 3821. https://doi.org/10.1021/cm701862w
J. W. Goodby, R. J. Mandle, E. J. Davis, T. Zhong and S. J. Cowling, Liquid
Crystals, 2015, 42, 593. https://doi: 10.1080/02678292.2015.1030348
W. Weissflog, U. Baumeister, M. Tamba, G. Pelzl, H. Kresse, R. Friedemann,
G. Hempel, R. Kurz, M. Roos, K. Merzweiler, A. Jákli, C. Zhang, N. Diorio, R.
Stannarius and A. E. U. Kornek, Soft Matter, 2012, 8, 2671. https://doi
10.1039/C2SM07064B
[18].
M. Alaasar, S. Poppe, C. Tschierske, Journal of Molecular Liquids, 2019, 277,
233. https://doi.org/10.1016/j.molliq.2018.12.088
[19].
S. Maisch, A. Krause, D. Schmidt and M. Lehmann, Liquid Crystals, 2018, 45,
136. https://doi.org/10.1080/02678292.2017.1369595
[20].
[21].
[22].
E. J. Foster, R. B. Jones, C. Lavigueur and V. E. Williams, J. Am. Chem. Soc.,
2006, 128, 8569. https://doi.org/10.1021/ja0613198
T. Zhong, R. J. Mandle, I. Saez, S. Cowling and J. W. Goodby, Liquid
Crystals, 2018, 45, 2274. https://doi: 10.1080/02678292.2018.1515371
S. Laschat, A. Baro, N. Steinke, F. Giesselmann, C. Hägele, G. Scalia, R.
Judele, E. Kapatsina, S. Sauer, A. Schreivogel and M. Tosoni, Angew. Chem. Int. Ed.,
2007, 46, 4832. https://doi: 10.1002/anie.200604203.
[23].
S. Kang, Y. Saito, N. Watanabe, M. Tokita, Y. Takanishi, H. Takezoe and J.
Watanabe, J. Phys. Chem. B, 2006, 110, 5205. https://doi.org/10.1021/jp057307a
[24].
D. Demus, Liquid Crystals, 1989, 5, 75.
https://doi.org/10.1080/02678298908026353
[25]. J. P. F. Lagerwall, F. Giesselmann, M. D. Wand and D. M. Walba, Chem.
Mater., 2004, 16, 3606. https://doi.org/10.1021/cm035294c
[26].
O. M. S. Ritter, F. C. Giacomelli, J. A. Passo, N. P. da Silveira and A. A.
Merlo, Polymer Bulletin, 2006, 56, 549. https://doi: 10.1007/s00289-006-0526-2
[27].
A. Tavares, J. M. Toldo, G. D. Vilela, P. F. B. Gonçalves, I. H. Bechtold, S. P.
Kitney, S. M. Kelly and A. A. Merlo, New J. Chem., 2016, 40, 393. https://doi:
10.1039/C5NJ02199E
[28]. V. Bezborodov, N. Kauhanka and V. Lapanik, Mol. Cryst. Liq. Cryst., 2004,
411, 1145. https://doi.org/10.1080/15421400490434874
[29].
H. Gallardo, C. Zucco and L. da Silva, Mol. Cryst. and Liq. Cryst., 2002, 373,
181. https://doi.org/10.1080/10587250210533
[30].
https://doi.org/10.1080/02678290500429976
[31].
https://doi.org/10.1016/j.tet.2012.11.013
[32].
Tetrahedron Letters, 2004, 45, 2277. https://doi.org/10.1016/j.tetlet.2004.01.116
[33].
U. M. Kauhanka and M. M. Kauhanka, Liquid Crystals, 2006, 33, 121.
H. Kuo, S. Tsai, G. Lee, H. Sheu and C. K. Lai, Tetrahedron, 2013, 69, 618.
T. Haino, M. Tanaka, K. Ideta, K. Kubo, A. Mori and Y. Fukazawa,
V. N. Kovganko and N. N. Kovganko, Russian Journal of Organic Chemistry,
2006, 42, 430. https://doi 10.1134/S1070428006060169

639
640
641
642
643
644
645
646
647
648
649
650
651
652
653
654
655
656
657
658
659
660
661
662
663
664
665
666
667
668
669
670
671
672
673
674
675
676
677
678
679
680
681
682
[34].
J. Barbera, R. Gimenez, J. L. Serrano, R. Alcala, B. Villacampa, J. Villalba, I.
Ledoux and J. Zyss, Liquid Crystals, 1997, 22, 265.
https://doi.org/10.1080/026782997209315
[35]. A. Tavares, P. R. Livotto, P. F. B. Gonçalves and A. A. Merlo, J. Braz. Chem.
Soc., 2009, 20, 1742. http://dx.doi.org/10.1590/S0103-50532009000900025
[36].
R. R. da Rosa, Isoxazolinas e Isoxazóis como reais candidatos na preparação
de cristais líquidos polares. PhD Thesis, 2018, Instituto de Química, UFRGS, Brazil.
http://hdl.handle.net/10183/180639.
[37].
A. Tavares, M. Tariq, S. Hameed, I. H. Bechtold, P. R. Livotto, and A. A.
Merlo, 26th International Liquid Crystal Conference (ILCC2016-346). 2016, Kent,
Ohio, USA.
[38].
J. M. F. M. Schneider, E. S. Sales, P. R. Livotto, Paulo H. Schneider and A. A.
Merlo, J. Braz.Chem. Soc., 2014, 25, 1493. http://dx.doi.org/10.5935/0103-
5053.20140132
[39].
L. Fritsch and A. A. Merlo, ChemistrySelect, 2016, 1, 23.
https://doi.org/10.1002/slct.201500044
[40].
https://doi.org/10.1080/02678292.2018.1488280.
[41].
L. Fritsch, V. L. Lavayen and A. A. Merlo, Liquid Crystals, 2018, 45, 1802.
G. D. Vilela, R. R. da Rosa, P. H. Schneider, I. H. Bechtold, J. Eccher and A.
A. Merlo, Tetrahedron Lett., 2011, 52, 6569.
https://doi.org/10.1016/j.tetlet.2011.09.122
[42]. L. J. Kately, W. B. Martin, D. C. Wiser and C. A. Brummond, J. Chem. Educ.,
2002, 79, 225. https://doi.org/10.1021/ed079p225
[43].
N. A. Clark and R. B. Meyer, Appl. Phys. Lett., 1973, 22, 493.
https://doi.org/10.1063/1.1654481
[44].
74, 011712. https://doi.org/10.1103/PhysRevE.74.011712
[45].
[46].
B. I. Senyuk, I. I. Smalyukh and O. D. Lavrentovich, Physical Review E, 2006,
I. Dierking, Texture of liquids crystals, Wiley VHC, Revised edition, 2003.
M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R.
Cheeseman, G. Scalmani, V. Barone, B. Mennucci, G. A. Petersson, H. Nakatsuji, M.
Caricato, X. Li, H. P. Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng, J. L.
Sonnenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T.
Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven, J. A. Montgomery Jr., J. E.
Peralta, F. Ogliaro, M. J. Bearpark, J. Heyd, E. N. Brothers, K. N. Kudin, V. N.
Staroverov, R. Kobayashi, J. Normand, K. Raghavachari, A. P. Rendell, J. C. Burant,
S. S. Iyengar, J. Tomasi, M. Cossi, N. Rega, N. J. Millam, M. Klene, J. E. Knox, J. B.
Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev,
A.J. Austin, R. Cammi, C. Pomelli, J.W. Ochterski, R. L. Martin, K. Morokuma, V. G.
Zakrzewski, G. A. Voth, P. Salvador, J. J. Dannenberg, S. Dapprich, A. D. Daniels, Ö.
Farkas, J. B. Foresman, J. V. Ortiz, J. Cioslowski, D. J. Fox, Gaussian 09 Rev. D01,
Gaussian, Inc., Wallingford, CT, USA, 2009.
[47].
L. D. Lopes, A. J. Bortoluzzi, G. Prampolini, F. P. Santos, P. R. Livotto and A.
A. Merlo, J. Fluorine Chemistry, 2018, 211, 24.
https://doi.org/10.1016/j.jfluchem.2018.04.007

683
684
685
686
687
688
689
690
691
692
693
694
695
696
697
698
[48].
M. M. Lobo, C. M. Viau, J. M. dos Santos, H. G. Bonacorso, M. A. P. Martins,
S. S. Amaral, J. Saffi and N. Zanatta, European Journal of Medicinal Chemistry,
2015, 101, 836. https://doi.org/10.1016/j.ejmech.2015.06.040
[49].
O. B. Bondarenko, A. Y. Gavrilova, V. V. Polunina, Z. A. Starikova, N. V.
Zyk, N. S. Zefirov, Mendeleev Communications, 2009, 19, 12.
https://doi.org/10.1016/j.mencom.2009.01.005
[50].
M. A. Glasser and N. A. Clark, Physical Review E, 2002, 66, 021711.
https://doi.org/10.1103/PhysRevE.66.021711
[51].
N. Hu, R. Shao, C. Zhu, Y. Shen, C. Park, E. Korblova, C. Guerra, J. A. Rego,
A. Hexemer, N. A. Clark and D. M. Walba, Chemical Science, 2014, 5, 1869.
https://doi.org/10.1039/C3SC53353K
[52].
[53].
Alan Berthod, Anal. Chem., 2006, 78, 2093. https://doi.org/10.1021/ac0693823
M. Portugall, H. Ringsdorf, R. Zentel. Makromol. Chem,. 1982, 183,
2311https://doi.org: 10.1002/macp.1982.021831003
[54].
R. Pinal, Org. Biomol. Chem., 2004, 2, 2692.
https://doi.org/10.1039/B407105K

Highlights
•
•
•
•
Synthesis of Schiff bases (SBs) containing isoxazoline and isoxazole rings.
Entropy and enthalpy effects dictated the liquid crystals properties.
Molecular geometry of heterocyclic is critical on mesomorphic behaviour.
Isoxazoline SBs were predominantly smectics while isoxazoles SBs were
nematics.
•
Lateral and longitudinal diffusion were express in terms of molecular geometry.

Conflicts of interest
No potential conflict of interest was reported by the authors.