Structural and morphological aspects of small 3,5-disubstituted isoxazoles

Article abstract of DOI:10.1016/j.jfluchem.2018.04.007

The structural and morphological features of small 3,5-disubstituted isoxazoles/isoxazolines are presented and discussed in the light of thermal analysis by differential scanning calorimetry (DSC), polarized optical microscopy (POM) technique, combined with single crystal X-ray diffraction and molecular modeling. The title compounds obtained were also characterized by ¹H, ¹³C and ¹⁹F NMR. Two of the 3,5-diarylisoxazoles reported here contain totally hydrogenated or fluorinated benzene rings on both sides of the heterocycle. Partially hydrogenated and fluorinated molecules were prepared alternating the position of the benzene rings on 3- and 5-position of the isoxazoles. Other isoxazoles were synthesized to compare the influence of fluorine atoms on the transitional properties. They were synthesized in two steps, starting from [3 + 2] 1,3-dipolar cycloaddition reaction of nitrile oxides with alkenes to yield the isoxazolines and subsequent MnO₂-oxidation process to reach the final isoxazoles.

Full text of DOI:10.1016/j.jfluchem.2018.04.007

Accepted Manuscript
Title: Structural and Morphological Aspects of Small
3,5-Disubstituted Isoxazoles
Authors: Luana D. Lopes, Adailton J. Bortoluzzi, Giacomo
Prampolini, Francisco P. dos Santos, Paolo R. Livotto, Aloir
A. Merlo
PII:
S0022-1139(18)30060-5
DOI:
Reference:
https://doi.org/10.1016/j.jfluchem.2018.04.007
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Revised date:
Accepted date:
5-2-2018
6-3-2018
11-4-2018
Please cite this article as: Lopes LD, Bortoluzzi AJ, Prampolini G, dos
Santos FP, Livotto PR, Merlo AA, Structural and Morphological Aspects
of Small 3,5-Disubstituted Isoxazoles, Journal of Fluorine Chemistry (2010),
https://doi.org/10.1016/j.jfluchem.2018.04.007
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Structural and Morphological Aspects of Small 3,5-
Disubstituted Isoxazoles
Luana D. Lopesa, Adailton J. Bortoluzzib, Giacomo Prampolinic, Francisco P. dos Santosa,
Paolo R. Livottoa and Aloir A. Merloa*
aInstituto de Química, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS,
Brazil.
bDepartamento de Química, Universidade Federal de Santa Catarina (UFSC), Florianópolis,
SC, Brazil.
cIstituto di Chimica dei Composti Organometallici (ICCOM), Consiglio Nazionale delle
Ricerche (CNR), Area della Ricerca, via G. Moruzzi1, I-56124, Pisa, Italy.
Graphical abstract
Highlights
1

 Single crystal X-ray diffraction analyses for fluorinated isoxazoles/isoxazolines were
resolved
 The molecular modeling of the isoxazoles showed that it exists in different conformers
 The nature of the aryl group modifies the intermolecular interactions and consequently
modifies the texture observed by POM
 Position of the perfluorinated benzene ring has a great impact in the molecular
arrangement and in the thermal properties
ABSTRACT
The structural and morphological features of small 3,5-disubstituted isoxazoles/isoxazolines are
presented and discussed in the light of thermal analysis by differential scanning calorimetry
(DSC), polarized optical microscopy (POM) technique, combined with single crystal X-ray
diffraction and molecular modeling. The title compounds obtained were also characterized by
1H, 13C and 19F NMR. Two of the 3,5-diarylisoxazoles reported here contain totally
hydrogenated or fluorinated benzene rings on both sides of the heterocycle. Partially
hydrogenated and fluorinated molecules were prepared alternating the position of the benzene
rings on 3- and 5-position of the isoxazoles. Other isoxazoles were synthesized to compare the
influence of fluorine atoms on the transitional properties. They were synthesized in two steps,
starting from [3+2] 1,3-dipolar cycloaddition reaction of nitrile oxides with alkenes to yield the
isoxazolines and subsequent MnO2-oxidation process to reach the final isoxazoles.
Keywords: Isoxazoline; isoxazole; fluorinated; intermolecular interactions; cycloaddition;
MnO2 oxidation.
1. INTRODUCTION
2

Isoxazoles and isoxazolines are important molecules, found in many natural and
pharmaceutical products, that exhibit a wide range of biological activities [1]. Beyond the well-
known medicinal properties, isoxazolines and isoxazoles are interesting intermediates in
organic synthesis [2], and play an important role in the synthesis of novel liquid crystalline
materials [3].
In the latter case, the isoxazole ring incorporates a strong dipole moment and this polar
effect favors the increasing of molecular anisotropic polarizability. Consequently, formation of
stable mesophase with enantiotropic behavior [4] is strongly favored.
The incorporation of fluorine into organic molecules has received intensive attention due to
the unique characteristics that this substituent brings to the products, both in material science
and in pharmaceutical industry [5]. In particular, in 3,5-diarylisoxazolines and 3,5-
diarylisoxazoles, the special features concerning their chemical nature can be greatly improved
with the introduction of fluorine atoms at peripheral region of the phenyl ring.
More in general, the study of fluorine influence on the control of the liquid crystalline
properties is being stimulated because of the important attributes of fluorine substituent, which
ensure significant modifications with respect to melting point, mesophase morphology and
transition temperatures [6].
Herein we describe the synthesis and characterization of several fluorinated isoxazolines
and isoxazoles (see Scheme 1), comparing them to their non-fluorinated counterparts.
Isoxazoles were obtained in a two steps transformation: [3+2] 1,3-dipolar cycloaddition of
nitrile oxide with alkene to access the key intermediate isoxazoline, and MnO2-oxidation
reaction of isoxazoline to render the corresponding isoxazole. This synthetic strategy has been
largely used by us in the preparation of new LC materials [7] and its main attribute is the high
regioselectivity in favor of 3,5-disubstituted isoxazolines [8]. Structural characterization was
carried out by polarized optical microscopy analysis (POM), differential scanning calorimetry
3

(DSC) studies, single crystal X-ray diffraction data and molecular modeling for isoxazoles 5a-
d. Isoxazolines’ structures 4b, 4c and 4d were also investigated through POM, single crystal
XRD and NMR. Finally, facing the challenge of synthesizing small molecules with short and
efficient strategies, other isoxazoles 5e-h with chemical diversity were prepared and their
thermal properties were also studied.
The aim of this work is to explore the chemical attribute of the fluorine atoms in small
isoxazolines/isoxazoles in contrast to hydrogen atoms widely used in the liquid crystals area.
The dichotomous behavior of long perfluorinated and hydrogenated alkyl chains in elongated
rod-like molecules has been explored in previous work [9]. In the literature, however, there are
many reports about the LC properties in molecules without any flexible alkyl chains, being
formed by phenyl groups connected in para position of benzene ring or by bent-shaped
molecules [10,11,12]. In these cases, the effect of fluorination of the substituents attached to the
isoxazole/isoxazoline core has received, up to our knowledge, much less attention. For
instance, if the long perfluorinated and hydrogenated alkyl chains are substituted with more
rigid perfluorinated and/or hydrogenated benzene rings, consequently reducing the molecular
width to length ratio, do the mesomorphic properties still persist? Despite the negative answer
obtained for the here investigated compounds, this study opens the opportunity to gain a further
comprehension about the influence of fluorine atoms on the structural and morphological
features of these small isoxazolines/isoxazoles.
2. RESULTS AND DISCUSSION
In the strategy briefly depicted in Scheme 1, the oxime is the precursor to the active nitrile
oxide, which acts as 1,3-dipolar component, and the alkene is the dipolarophile for [3+2] 1,3-
dipolar cycloaddition. The key intermediate 3,5-disubstituted isoxazoline is subsequently
oxidized using MnO2 to reach the final 3,5-disubstituted isoxazole [7].
4

Scheme 1. Synthesis of isoxazolines by [3+2] 1,3-dipolar cycloaddition followed by MnO2-
oxidation reaction. (i) NH2OH.HCl, EtOH, NaOAc, H2O, reflux, 1h; (ii) NCS, Py, CH2Cl2, r.t.,
24h; (iii) MnO2, toluene, reflux, Dean-Stark.
Classical synthetic methodology was employed in the preparation of the oximes. The
aldehydes 1 were the precursors to the oximes 2 that were obtained by a well-established
literature procedure [7b]. With the appropriate oximes synthesized in good yields, the [3+2]
1,3-dipolar cycloadditions were carried out using N-chlorosuccinimide (NCS) as oxidizing
agent and the alkenes 3, to form the 3,5-disubstituted isoxazolines 4a-h with high
regioselectivity.
To accomplish the final synthesis of title compounds, the oxidation step using activated
MnO2, which presents low toxicity, low cost, ease of handling and the absence of hazardous
additives/byproducts [13], led to the isoxazoles 5a-h in a good to excellent yield. The products
4a and 5a have already been published by Yoshimura et al. [14a] in 1970 and by Olivier et al.
in 2010 [14b], while Wakefield and Wright synthesized the products 4b and 5b [15]. The
5

isoxazoles 5b have been reported again by Hansen et al. in 2005 using alkyne as dipolarophile
[16a] and by She through oxidation of -unsaturated oximes [16b]. The products data are
listed in Table 2. Melting point, enthalpy and entropy for isoxazoles were obtained by DSC.
For isoxazolines, melting points listed in the supporting information were determined by POM.
The isoxazolines NMR analysis exhibited interesting splitting of the resonance lines of the
signals for methylene and methynic hydrogen atoms on C8 and C7 carbon atoms of the
heterocycle, respectively. For the compound 4b, 1H NMR spectrum displayed two sets of lines
usually assigned as doublet of doublets (dd) related to the atoms H8a and H8b, in the range of
3.0 – 4.0 ppm. However, each resonance line of dd is further splitted in three new resonance
lines and it is now defined as tdd. These new sets of signals appear as small chapel-shaped lines
[17]. These triplets were associated to the new coupling with the fluorine atoms in ortho
position relative to the heterocycle in the aromatic ring. The 1H NMR spectrum for 4b is shown
in Figure 1.
H8a
3.92
3.88
3.84
δ (ppm)
3.80
3.76
H8b
3.45
3.40
δ (ppm)
3.35
3.30
H7
H8a
H8b
6.0
5.8
5.6
5.4
5.2
5.0
4.8
4.6
δ (ppm)
4.4
4.2
4.0
3.8
3.6
3.4
3.2
Figure 1. 1H NMR spectrum (CDCl3, 400 MHz) of compound ±4b.
6

At difference with isoxazoline 4b, in compound 4c the perfluoroaryl ring is located on the
oxygen side and the coupling phenomenon with fluorine atom at ortho position of fluorinated
benzene ring is not observed, since it is not possible due to the tetrahedron carbon atom C7 on
the heterocyclic.
However, when both sides of the isoxazoline ring contain perfluorinated benzene rings (4d),
the splitting of the double doublets in triplets is not observed. In other words, the coupling
between H8a and H8b with fluorine atoms does not occur (Figure 2).
H8a
H8b
H7
H8a
H8b
Figure 2. 1H NMR spectrum (CDCl3, 400 MHz) of compound ±4d.
1
By performing the two-dimensional heteronuclear H-19F NMR analysis (Figure 3), it was
possible to confirm that there is no coupling of the hydrogens H8a and H8b with fluorine atoms
5
for the isoxazolines 4d. But a correlation resulting from J coupling between H7 and fluorine
atoms named as 2 and 4 was found. It is clear that there is a coupling between H7 and F2 and F4
5
through bonds, and that it does not exist the (H-F) J coupling with the F11 and F15 atoms
neither the 4J coupling with the F1 and F5 atoms [18].
7

Figure 3. 2D HMBC 19F-1H spectrum of compound ±4d (CDCl3,19F: 376 MHz, 1H: 400 MHz)
and the expansion of the region containing the correlation between H7 and F2 and F4.
For compound 4b, the 2D HMBC 19F-1H result is depicted on Figure 4, which proves the 5J
coupling of the hydrogens H8a and H8b with the fluorine atoms at the ortho position of the
aromatic ring.
8

Figure 4. 2D HMBC 19F-1H spectrum of compound ±4b (CDCl3,19F: 376 MHz,1H: 400 MHz)
and the expansion of the region containing the correlation of the hydrogens H8a and H8b with
F11 and F15.
The single crystal XRD results for the isoxazoles 5a-d are described in the next section to
complement the analysis of structural and morphological aspects. However, during the
synthesis, the intermediate isoxazolines 4b, 4c and 4d were also submitted to X-ray diffraction
experiment. Full crystallographic tables have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication numbers CCDC (4b) 1581029, (4c)
1581030 and (4d) 1581031. Copies of the data can be obtained, free of charge, via the CCDC
homepage (see Supporting Information). The data acquired are presented in this section as a
9

way to provide useful information on structural parameters related to the spectroscopic data of
the chemical couplings between H and fluorine, seen in the above discussed 19F-1H-
experiments. More specifically, the XRD data should help to elucidate if the mechanism of the
transmission of the spin takes place by chemical bond or through-space. Table 1 contains the
crystallographic data and thermal ellipsoids (cartoon) for isoxazolines 4b-d. Before discussing
the long-range H-F coupling constant observed in 4b and 4d, it is worth to mention that Flack
parameter [19] for 4b and 4c indicates that they were resolved as single enantiomer by single
crystal structure analysis. The absolute configuration for 4b was assigned as S, while for 4c was
assigned as R. Structure refinement for 4d resulted in a mirrored structure, being composed by
R and S contribution in equal ratio. This result is surprising and intriguing, considering that the
experimental procedure did not contain any chiral element capable to distinguish pro-chiral
faces during the step of cycloaddition of dipolarophile to 1,3-dipolar component. This topic is
under investigation and further experiments will be set up, to find the origin of this
configurational discrimination detected in the synthesis of the isoxazolines 4b and 4c.
As far as compounds 4b and 4c are concerned, the geometrical and structural parameters
(see Table 1 and supporting information) obtained from single crystal XRD furnish information
about dihedral angles and distances that promotes coupling at long distances and can
complement the above reported NMR analysis, clarifying if the observed 5J coupling occurs by
a through-space or through-bond route. The long-range 5J coupling (Figure 1) is consistent with
a through-space route for the transmission of the nuclear spin information from fluorine (F11
and F15) to H8a and H8b (cartoon 4b). The non-bonded distance between F11 and H8b and H8a,
estimated by X-ray data (2.745 Å and 2.471 Å, respectively (S2)) along with dihedral angles
C8-C9-C10-C11 (-22.1(3)o) and C9-C10-C11-F11 o (-7.6(3)°), fulfill the geometric
requirements for the existence of an intramolecular hydrogen bond [20]. The intramolecular
distances of F11 and H8b/H8a are in the range of H-F intermolecular hydrogen bonds, which can
10

be estimated from the sum of the van der Waals radii of hydrogen and fluorine [21] to be 2.5 -
2.6 Å . Thus, the long-range coupling [22] observed for 4b could be attributed to proximity of
the active nuclei, which can interact themselves through the space to transmit the spin coupling.
The analysis based on the intramolecular interaction between H and F11 done for 4b apparently
does not apply to the isoxazoline 4d. For 4d, the through-space coupling is no longer seen
5
(Figure 2 and 3), but a correlation resulting from J coupling between H7 and fluorine atoms
named as 2 and 4 has appeared (Figure 3). The non-bonded distance between F11 and H8b and
H8a calculated for 4d are 2.854 Å and 2.354 Å, respectively. Despite the intramolecular
distance fulfills the requirement for the existence of an intramolecular hydrogen bond, it does
not explain the absence of 5J coupling between F11 and H8a and H8b.
Again, single crystal X-ray data bring along dihedral angles of two fluorinated benzene
rings in 4d. The dihedral angle C8-C9-C10-C11 of +16.2(3)° and C9-C10-C11-F11 of
+1.0(3)° from the benzene ring from nitrogen atom side. Comparing 4b with 4d, the difference
between benzene ring rotation around C9-C10 bond goes from -22.1 (3)° to +16.2 (3)°. As 4d
has the second fluorinated benzene ring on the oxygen atom side, while 4b has a hydrogenated
benzene ring, it would be interesting to analyze torsional angle values in 4d with this
perspective. Thus, for 4d the dihedral angle of C8-C7-C6-C5 is -49.9 (3)° and F5-C5-C6-C7 is
-0.9 (3)°. This set of dihedral angles constrains the H8a and H8b into the ambient flanked by two
fluorine atoms F5 and F11. As pointed by Landis et al. long time ago [23], during the analysis of
19F-1H couplings in steroids containing an angular methyl groups spatially near to the fluorine
atom, the couplings were observed only when a special geometric requirement was met. The
19
empirical rule proposed by them states that the F-1H coupling will be observed only when a
vector directed along the C – F bond and originating at the carbon atom can converge upon
and intersect a similar vector directed along a C – H bond of the methyl group [24]. Applying
this empirical rule to 4b and 4d based on their single crystal structures, it is seen that for 4b the
11

C–F11 vector converges upon and intersects the C–H8b vector satisfying the geometrical
condition proposed by Landis. However, for 4d the rotation around C9 – C10 atoms defines a
new angle value of +16.2 (3)°, and now C – F11 vector does not converge upon neither
intersects the C – H8b or C – H8a vector. Instead, the vectors associated to these bonds are
orientated in a divergent manner. Since they do not cross each other in the space where they are
confined, the geometrical requirements to transmit the magnetization through-space cannot be
met, and the coupling between 19F-1H in the spectrum of 4d is not observed.
Finally, it is possible to attribute the long-range correlation between H7 and F2/F4 observed
in Figure 3 for 4d to a though-bond mechanism. Indeed, data extracted from single crystal X-
ray diffraction suggest that the isoxazoline’s carbon-carbon skeleton and the perfluorinated
benzene ring attached to the oxygen atom side assume different forms. For instance, it is
possible to associate a sickle-form for C8-C7-C6-C1-F1, a U-form for C8-C7-C6-C5-F5, a mix
W-form + sickle-form for C8-C7-C6-C1-C2-C3-F3 and a zig-zag-form or all-trans-form for
C8-C7-C6-C1-C2-F2. These conformational issues support the view of all-trans form as a
possible factor for the through-bond transmission of spin coupling in 4d, as showed in Figure 3.
12

Table 1. Crystallographic data for isoxazolines 4b,4c and 4d.
Isoxazoline
formula
temp (K)
space group
crystal system
a (Å)
4b
C15 H8 F5 N O
200(2)
4c
C15 H8 F5 N O
200(2)
4d
C15 H3 F10 N O
200(2)
P21
P212121
P212121
Monoclinic
8.5012(4)
5.8031(3)
5.8031(3)
90°
Orthorhombic
5.42210(10)
9.3338(2)
25.1912(6)
90°
Orthorhombic
9.6647(2)
10.3250(3)
13.7085(3)
90°
b (Å)
c (Å)
α (deg)
β (deg)
103.618(3)°.
90°
90°
90°
γ (deg)
90°
90°
V (Å3)
631.32(5)
2
1274.90(5)
4
1367.94(6)
4
Z
Final R indices
[I>2sigma(I)]
R1 = 0.0306, wR2 = 0.0767
R1 = 0.0251, wR2 = 0.0669
R1 = 0.0250, wR2 = 0.0641
R indices (all
data)
R1 = 0.0338, wR2 = 0.0791
R1 = 0.0260, wR2 = 0.0676
R1 = 0.0263, wR2 = 0.0649
0.26(13)
Flack parameter -0.02(9)
0.01(4)
Thermal ellipsoid (Cartoon)
4b
4c
4d
2.1. Morphologies of the crystals and transitional properties related.
Transition properties of 3,5-disubstituted isoxazoles were collected and analyzed by
polarized light optical microscopy (POM) and differential scanning calorimetry (DSC). The
melting points, enthalpy, entropy (Table 2) were recorded from 2nd heating cycles of DSC
thermograms. Microphotographs were taken at room temperature after second heating and
cooling cycles at a rate of 10 °C min−1, except for Figure 5 (4b, 4c) and Figure 6 (5d-I), which
were collected as pristine solids from the cooled recrystallization solution. The discussion is
focused on isoxazoles 5a-d due to their similarities and contrasts. They are similar in chemical
structures, being formed by a basic 3,5-disubstituted isoxazole framework, and the contrast is
13

due to polarity generated by the incorporation of fluorine atom on the benzene ring in
alternating way. So, 5a is completely hydrogenated isoxazole, 5b and 5c are partially
hydrogenated and perfluorinated isoxazoles, and 5d presents both fluorinated benzene rings
connected to the heterocycle. For comparative purposes, POM pictures of the precursor
isoxazolines 4b, 4c and 4d are also displayed. Crystal phase textures for isoxazoles 5a-d are
shown in Figures 5 and 6. The crystal structures of 5a-d were determined by single crystal X-
ray crystallography (Figures 7-10). Molecular modeling of 5a-d was also performed to
complete the structural and morphological study.
In general, crystallization for all melted samples takes place well-below of melting point
with a large hysteresis effect as demonstrated by the DSC thermograms (SI). The variation of
melting point (mp) and the crystallization point (cp) (T) were 17.7 °C, 19.6 °C, 21.5 °C and
45.5 °C for 5a-5d, respectively. The smallest and the largest hysteresis were observed for 5a
and 5d, respectively. When samples in the isotropic state are cooled, a slow crystallization
process starts characterized by the appearance of a radial texture or like-spherulitic textures.
The spherulite size is dependent on the rate of cooling. The dynamic lag between mp and cp is
also rate-dependent, taking into account that the recrystallization of the samples inside the hot
stage takes different values of temperature if the cooling rate is varied in time. Considering our
previous works dealing with this subject, this is an ordinary behavior observed for all
isoxazolines and isoxazoles synthesized in our laboratory. This pattern of crystal formation for
isoxazolines and isoxazoles after heating and cooling cycles is probably associated with the
molecular bent of 3,5-disubstituted arylisoxazolines and 3,5-disubstituted arylisoxazoles.
From POM textures we can also address comments related to the birefringence of the
samples. The birefringence, being a double refraction of light, is dependent on how ordered is
the material in its crystal state or in condensed anisotropic medium. Thus, the double refraction
of light when travelling through the isoxazoles medium, composed by hydrogenated and
14

perfluorinated benzenes, experiences a dichotomy in relation to molecular environment, and the
differences in refractive index are dependent on the orientation and on the molecule type.
Already at a visual inspection of the birefringence observed for isoxazoles 5a-d, it is
apparent that it depends on the nature of the atoms bonded in the periphery of benzene ring.
Visually, it decreases as more fluorine atoms are introduced in the benzene ring. For example,
5a is brighter and more colorful than the others, while 5b and 5c are intermediates in
birefringence, due to the molecules being partially hydrogenated and perfluorinated. Thus, 5c,
which contains a perfluorobenzene ring on the oxygen atom side, is more colorful than 5b
which has a perfluorobenzene ring on the nitrogen atom side. On the other extreme is 5d with
the smallest birefringence. We assume that the thickness of the sandwiched samples between
two cover glasses is similar. For isoxazolines 4b and 4c, despite their non-planarity due to the
C5 tetrahedral carbon atom, it is possible to associate the same behavior. 4b and 4c crystals
obtained from crystallization in ethanol are seen in Figure 5. Again, crystals of 4c are more
birefringent than 4b as a consequence of the side of the fluorinated benzene ring.
Figure 6 presents six pictures of compound 5d. Picture I is the virgin crystal, whereas the
others (II to VI) represent different textures for 5d obtained at room temperature, after cycles of
heating/cooling. As shown in 5d-III e 5d-IV , small domains of the entire sample present color.
In general, texture is darker and grayish, which is a clear manifestation of the two
perfluorinated benzene rings connected to the isoxazole ring. As will be discussed in the X-ray
section, the way that molecules arrange themselves in the crystal phase is responsible for such
behavior. Polarizability and electron delocalization are the main factors that control the
birefringence for molecular anisotropy. Comparing 5a/5d and 5b/5c the influence of such
factors becomes clear. Fluorine is the most non-polarizable atom and its interaction with light is
smaller than the other atoms present in the isoxazole or isoxazoline ring. Also, fluorine is an
electron-withdrawing group which acts electronically contrary to the imine (C=N) double bond.
15

On the one hand, when the perfluorinated benzene ring is located at the Nitrogen side of the
isoxazole (5b), it diminishes the electron delocalization over benzene ring and imine group. On
the other hand, if the perfluorinated benzene ring is attached to the Oxygen side of the
isoxazole (5c), it has less electronic interaction with imine group, and consequently the
polarizability and electron delocalization become more intense between hydrogenated benzene
ring at left and C=N group. Finally, 5d is less intense in color and brightness, as a direct
consequence of double perfluorbenzene rings connected on both sides of the heterocycle. The
grizzly and color pale texture in Figure 6 (II and III) looks like branches of wheat. In this way,
it will be named as wheat-branch textures. The microtextures resemble to the wheat spikes as
demonstrated clearly in Figure 6 (II and III). The crystallization occurs slowly in radial form
and the spikelet auto-assemble in a spiral around the imaginary stem. Every spiral stem is
connected in a single point at the center of the spherulites. Figure 6 (IV to VI) displays a
different texture for 5d where the molecules self-assemble in bent and irregular steep ribbon.
Some of them are vertically-orientated while the others are horizontally-orientated steep ribbon.
Figure 5. Crystal phase textures for isoxazolines 4d and isoxazoles 5a-c. Pictures of
isoxazolines 4b and 4c, crystals obtained from crystallization in ethanol (magnification: 10×).
16

Figure 6. I. Picture of isoxazole crystal 5d obtained from crystallization in ethanol. II-VI.
Crystal phase textures for isoxazoles 5d after different heating/cooling cycles. (magnification:
10×).
The transition properties collected from DSC in Table 2 do not follow a regular tendency as
expected. The isoxazole 5b displays smaller values of mp, enthalpy and entropy than 5c,
probably related to the weak intermolecular interaction in the crystal state. Interestingly, 5c
displays the highest value of entropy in this series of isoxazoles 5a-d, which reflects more
ordered state in the crystal phase. In 5d, the complete perfluorination of both benzene rings
causes an assembly in spiral form [25], where a gain in packing energy is retrieved by a
minimization of the free volume. The crystal form of compound 5d in contrast with 5a has the
best and tightest packing of the molecules creating a wheat-branch texture as discussed above,
as a way to compensate their lack of -stacking interactions in the crystals phase. Thus, when
5d melts it leaves behind a more ordered crystal state and enters into the isotropic liquid state
and, consequently, the entropy for this transition has to be higher than that registered for the 5a
analogue. Comparison between 5b and 5c is complicated due to their dichotomous nature. The
intermolecular interaction is more difficult to be guided only by the dipolar contribution of the
17

strong dipole moment of isoxazoles and the quadrupole moment of the perfluorinated benzene
ring. A second view could be associated with the behavior that is found in twist-bend nematic
phase, where the molecules’ topology dictates the incidence of this mesophase and it does not
occur due to dipolar contribution [26].
Compounds 5e-h were also synthesized as a complement of 5a-d and considering that they
are promesogenic molecules and good candidates to be liquid crystals having small length to
breadth ratio [27]. However, analyses of POM have demonstrated that they are not liquid
crystals in any regime of temperature (enantiotropic or monotropic), even for 5h which is
composed of perfluorinated alkyl chain [28].
Table 2. Transitional properties of products 5a-h.
Temperature (°C)
Entalphy
(kJ.mol-1)
Entropy
Entry
(J.mol-1K-1)
Melting
137.7
129.9
150.7
135.5
174.7
140.1
69.8
Crystalization
116.5
110.4
143.2
90.0
5ai
5bii
5c
23.5
20.6
30.5
27.6
28.0
26.3
23.7
31.6
57.3
51.2
72.0
67.5
62.5
63.7
69.0
89.1
5d
5e
172.1
134.2
iii
5f
5g
5h
81.9
36.5
i. mp 137°C, ref 14b; ii. mp 133-134 °C ref 15 and 16a. iii. Not determined
18

2.2. X-ray Crystallography for 5a-d.
Isoxazoles 5b-d were submitted to X-ray diffraction analysis from their single crystals
obtained from cold ethanol solution. The structural parameters such as distance and angles
bond as well as torsion angles for isoxazoles 5b-d were acquired. All molecular structures of
the 5b-d are represented by ORTEP diagrams, with thermal ellipsoids drawn at the 40%
probability level (Figure 7-10). Full crystallographic tables for compounds 5b-d have been
deposited with the Cambridge Crystallographic Data Centre as supplementary publication
numbers CCDC 1814921, 1814922 and 1814923. Copies of the data can be obtained, free of
charge, via the CCDC homepage (see Supporting Information).
The single crystal XRD data for 5a is available elsewhere [29]. Data collection and
structure refinement for the structures of 5b-d are given in SI section. The molecules of 5a-c in
their unit cells are piled and they are arranged in antiparallel manner forming 2D layer in
compound 5a and piles in compounds 5b-c by π-stacking interactions. The layers for 5a are
composed by stacks of molecules with inversion of atomic position of the heteroatoms N and O
in the isoxazole ring. For 5b and 5c the pile-structured packing is also composed by
intercalating the hydrogenated and perfluorinated benzene ring connected to the isoxazole. The
relative position of the hydrogenated and perfluorinated benzene ring in the crystal structure is
mixing and the stacks are sustained by -stacking interactions along of c axis.
The individual stack is build up by assembly one molecule after the other and inside the
stack the relative atomic position of the oxygen and nitrogen atoms are inverted. Moving from
5a to 5b and 5c the inversion of atomic position of the heteroatoms is followed by the inversion
of hydrogenated and perfluorinated benzene rings. In compounds 5b-c the neighbor stacks
grow in the same way, constituting a 1-D blocks of the stacks, whereas 2D layer is observed in
5a. The tilt of the stacks is more intense in isoxazoles 5d causing torsion of the 3-D
arrangement to adjust better the available space and to optimize the free volume final structure.
19

Following the definition of crystallization theory, in the hierarchy of intermolecular interactions
[30,31], in the crystallization process the strongest interactions come first, and then the
formation of weaker interactions occurs later at the secondary sites. The nucleation and crystal
growth of 5a-d is governed by mainly polar interactions of isoxazole ring [32] which constitute
the first hierarchy followed by the second hierarchy related to - interactions of the benzene
rings. For 5b-c additional -interactions sum up in the growth of crystals in solution due to
the dichotomous benzene rings [33].
For isoxazole 5a, both aromatic rings make four π-stacking interactions with neighbor
molecules forming layers parallel to (100) crystallographic plane. Hydrogen atoms in ortho and
meta positions with respect to isoxazole ring are involved in these interactions (Figure 7). The
calculated distances centroid-hydrogenortho and centroid-hydrogenmeta are 2.839 Å and 2.922 Å,
respectively. The dihedral angle between mean plane and neighboring benzene rings is 50.14o.
It seems clear that π-stacking induces the non-coplanarity of the phenyl groups in compound
5a, as well as governs packing arrangement in the crystal lattice.
Figure 7. Molecular structure 5a (left) and partial packing showing π-stacking thorough short
contacts of centroids (dashed lines) of the neighboring molecules (right). CE are calculated
centroids. Pictures were drawn from crystallographic data deposited at the Cambridge
Structural Database and labeling atoms have been changed (ref. code DPISOX) [21].
20

The molecular packing of 5b in its monoclinic crystal structure is pile-structured. The piles
are composed by intercalating the hydrogenated and perfluorinated benzene ring connected by
π-π-stacking interactions along [001] direction (Figure 8). The perpendicular average distance
between benzene rings in the stack is 3.424 Å. For 5b the torsion angles N1-C9-C10-C15 of
22.3(1)o and C1-C6-C7-O1 of 16.4(1)° show that hydrogenated benzene is less twisted than
the perfluorinated benzene ring. Thus, isoxazoles 5b presents a twist-shaped with torsion of
perfluorinated benzene being higher than hydrogenated benzene ring on the oxygen side.
Figure 8. ORTEP plot (left) and partial packing showing π-stacking interactions (right) for 5b.
Ellipsoids were drawn at 50% probability level. CE are calculated centroids.
The molecular packing of 5c is very similar to that observed for compound 5b. The
molecules are disposed in piles along [001] direction. The π-π-stacking interactions build a
piled-structure with average distance between centroids of 3.427 Å (Figure 9). The torsion
angles N1-C9-C10-C15 and C1-C6-C7-O1 are -17.9(5)o and 22.6(5)o, respectively. Contrary to
the 5b, isoxazoles 5c presents a twist-shaped with torsion of perfluorinated benzene on the
oxygen side being higher than hydrogenated benzene ring on the nitrogen side.
21

Figure 9. ORTEP plot (left) and partial packing showing π-stacking interactions (right) for 5c.
Ellipsoids were drawn at 50% probability level. CE are calculated centroids.
The molecular structure of 5d presents twisted spatial conformation and its packing is
absent of appropriate short contacts between adjacent molecules which is an indication of the
lack of the π−π interactions. In compound 5d the torsion angles N1-C9-C10-C15 and C1-C6-
C7-O1 are 27.6(2)o and -16.57(19)o, respectively. The increase of the torsion angle on the
perfluorinated benzene on nitrogen side and the lack of π-stacking interactions for 5d are the
reasons why the nucleation and the crystals growth for this isoxazole developed a helicoidal
superstructure, observed in POM analysis discussed above.
Figure 10. ORTEP plot (left) and partial packing of compound 5d (right). Ellipsoids were
drawn at 50% probability level.
22

In the crystalline state, 5a-d present benzene rings tilted with respect to isoxazole ring.
They are no coplanar even for 5a with two completely hydrogenated benzene rings. Two
representative torsion angles for 5a-d are shown in Newman projection in Figure 11. They
demonstrate clearly that the coplanarity between isoxazole ring and the benzene rings on both
sides is not observed in the crystal state. The presence of a perfluorinate ring attached on one or
two sides of the isoxazole unit, seems to enhance this effect, as the largest distrotions from
planarity were observed for 5d compound. The role of perfluorination is even clearer by
comparing 5b and 5b compounds, where the value of the considered dihedral depends on the
relative position of the perfluorinated benzene ring. A possible rationale might consist in the
polar effect of fluorine atom, which acts against resonance effect of benzene ring and N=C
double bond of isoxazole ring. The frustration of resonance effect is compensated by large
torsion angle. For isoxazole 5d the large value of the N1-C9-C10-C15 dihedral between the
central core and the perfluorinated phenyl ring attached to the Nitrogen side, works against the
coplanarity of perfluorinated benzene ring. However, the other torsional angle, between the
central isoxazole moiety and the perfluorinated benzene ring attached to the Oxygen side, has a
similar value to the one found in 5b, but smaller than that observed for 5c. Thus, the resulting
twisted shape of the whole diarly-isoxazole is more probable for molecules where the extended
-conjugation is less favorable to occur. It is possible to speculate an explanation using the
stereoelectronic effects between antibonding (*) orbital of carbon-carbon double bond on the
perfluorinated phenyl and  molecular orbital on the nitrogen atom. For hydrogenated benzene
rings it is possible to establish the same interaction using bonding molecular orbital of the
carbon-carbon double bond and  molecular orbital on the oxygen atom [34]. As a general
feature extracted from single crystal data, in this work all isoxazoles have twisted-shaped
conformations and for 5d X-ray data showed that the molecules are in a spiral form.
23

Figure 11. Newman projections and selected torsion angles for 5a-d (left) and stereoelectronic
effects in the twisted-shaped conformation for 5b.
2.3.Theoretical Calculations
To get a deeper insight into the different flexibility of the 5a-5d isoxazoles evidenced by
X-ray crystallography results, the minimum energy geometries of each compound were
characterized by density functional theory (DFT) calculations [35]. Incidentally, since the
calculations were performed on the isolated species, the comparison of the computed results
with the conformations evidenced by crystal structure determination through Newman
projections may shed some light on the effect of the intermolecular interactions, which take
place within the crystal, on the overall molecular shape.
Table 3. Equilibrium value of selected dihedral angles computed at B3LYP/6-311+G(2d,p)
level. Atom labels identifying the dihedral refer to Figures 7-10 obtained by X-ray experiments.
5a
5b
5c
5d
Dihedral
DFT
0.00
0.00
0.00
0.00
X-ray
-25.74
-25.30
DFT
-2.80
-3.00
39.32
39.15
X-ray
DFT
18.68
18.23
-14.68
-14.99
X-ray
22.6(5)
23.2(5)
-17.9(5)
-17.5(5)
DFT
-23.63
-22.82
40.18
40.04
X-ray
-16.6(9)
-17.2(2)
27.6(2)
28.9(2)
C1-C6-C7-O1
C5-C6-C7-C8
-16.33(17)
-16.36(14)
22.30(15)
22.62(15)
N1-C9-C10-C15
C8-C9-C10-C11
-25.74
-25.30
Table 3 reports the DFT computed equilibrium values of the dihedral angles ruling the
rotation of the (perfluorinated) phenyl substituents with respect to the isoxazole central moiety,
24

obtained for each investigated compound. To ease the discussion, the same dihedral notation
employed in Figures 7-11 (X-ray diffraction) was adopted. Qualitatively, the computed
geometries agree with their experimental counterparts, confirming that the perfluorination of
the aryl rings causes the rotation of the lateral phenyls, and the overall molecular shape is
distorted from planarity, which instead characterized the parent compound 5a. In more detail,
some differences arise between the values computed in vacuo and those evidenced from the X-
ray patterns. For compound 5b, for instance, the computed rotation seems to take place only for
the perfluorinated aryl moiety (~40°), whereas the phenyl substituent almost preserves its co-
planarity with the isoxazole central moiety (~3°). Conversely, both dihedrals are found to be
rotated (+22° and -16°, respectively), even if the first (perfluorinated) one is still larger than the
second one. A slightly better agreement stands for compounds 5c and 5d, but in the former case
computed values underestimate the experimental ones, while in the latter larger dihedral angles
are expected by calculations.
These differences should not be surprising, since the model adopted both neglects thermal
energy and the intermolecular interactions that in the crystal may significantly alter the
molecular conformations. It is then interesting to evaluate how the internal energy changes
upon rotation, to verify to what extent the molecular geometry can be altered by the above
mentioned external factors. In Figure 12 the torsional energy profiles are displayed for each
investigated compound. The computed curves are rather flat in all cases, and distortions from
the minimum geometries could indeed be expected, both from thermal energy or external
perturbations (as the presence of closely packed neighbors). From the comparison of the
profiles obtained for compounds 5a and 5d, it appears that the presence of perfluorinated
moieties on the one hand increases molecular flexibility by decreasing the barrier at ±90°, on
the other hand disfavors planarity, as suggested from the barrier centered at 0° that arises in
both 5b and 5d compounds. An analysis around the minimum region also reveals that in
25

average the four compounds may exhibit different shapes and flexibilities. More specifically,
5a and 5c compounds are expected to be nearly planar, with small distortions of ~30° at most.
Conversely, 5b and 5d compounds are more likely to be found more distorted, but in all cases,
rather weak interactions (~ 1-2 kcal/mol) seem to be able to change the molecular
conformation.
Figure 12. Torsional energy profiles computed for compounds 5a-d at B3LYP/6-311+G(2d,p)
level. Full optimized geometries are displayed in the inset of each panel, evidencing the
investigated dihedrals with blue (C8-C9-C10-C11) and red (C5-C6-C7-C8) arrows. Thermal
energy at 25°C is indicated in all panels with a dashed black line.
Indeed, a detailed comparison between the computed equilibrium values and the effective
angles evinced from crystal structure determination suggests that the intermolecular
interactions taking place in the crystal tend to favor nearly planar conformers, limiting the
rotation of the aryl substituents to less than 30°, even in the 5d case. From this observation, it
26

could be speculated that stacking interactions play a significant role in crystal packing, as their
strength is greatly enhanced when two nearly planar structure face each other.
The last feature that could be investigated is the possible coupling between the rotations on
the two sides of the isoxazole central moiety. The rotation around the C9-C10 bond next to
isoxazole’s nitrogen atom is essentially driven by the nature of the aryl substituent on that side,
independently from the ring linked to the C7 atom on the opposite side. Conversely, the
rotation around the C6-C7 bond close to the oxygen atom is not driven only by the aromatic
moiety connected to C7, but is also influenced by the substituent linked to C9, on the opposite
side. In this case, the two torsions seem to be coupled, since the presence of a perfluorinated
ring on the other side of the molecule is decisive to shift the minimum from a coplanar
conformation, whereas the barrier at 90° is more influenced by the type of ring that is actually
rotating. The different coupling patterns taking place between the two dihedral angles can be
seen by looking at Figure 13, where two dimensional scans of the torsional energy are
displayed for the four compounds. The apparent similarities between the 5a-5c and 5b-5d pairs
reflect, at least at a qualitative level, some of the experimental data presented therein, as
melting points (larger than 137 °C and less than 136 °C for 5a-5c and 5b-5d pairs,
respectively), POM textures and X ray derived geometrical data (C5-C6-C7-C8 dihedral larger
than the C8-C9-C10-C11 one in 5d and vice-versa for 5b and 5d).
27

5c
5a
5b
5d
Figure 13. Two-dimensional potential energy curves along the torsion angles C(8)-C(9)-C(10)-
C(11) (δ1) and C(5)-C(6)-C(7)-C(8) (δ2).
3. CONCLUSIONS
We have synthesized 3,5-disubstituted isoxazolines/isoxazoles, 4a-h and 5a-h, respectively,
using an efficient and regioselective synthetic route. Studies of structural and morphological
properties of the 3,5-diarylisoxazoles 5a-d were performed using POM textures analysis, DSC
techniques, single crystal X-ray experiment and molecular modeling. Isoxazoles under
consideration were composed by two hydrogenated benzene rings 5a, perfluorinated benzene
and hydrogenated benzene rings on either sides of the isoxazole central unit 5b and 5c and two
perfluorinated benzene rings 5d, at 3- and 5-position of isoxazole ring, respectively. All
analyses performed on isoxazoles 5a-d including POM textures, DSC thermograms combined
with single crystal X-ray diffraction and molecular modeling revealed that the introduction of
fluorine atoms in the benzene ring induces a greater distortion of the isoxazoles molecular
shape. The distortion is higher for the 5d and the dihedral angle between the benzene and the
28

isoxazole ring on nitrogen side is always higher than the dihedral angle on the oxygen one.
Modeling calculations confirm that the distortion between benzene ring and isoxazole increases
according to 5a < 5c < 5b < 5d. Two dimensional scans of the torsional energy for the four
compounds revealed that 5a and 5c have a minimum energy centered at 0°, whose flatness
suggests that significant distortions from planarity can take place simply by thermal effects.
Conversely, compounds 5b and 5d present an energy barrier for planar angles which separates
two local minima, centered around 40°, but again characterized by a rather flat profile, which
should allow relevant distortions induced by both thermal and intermolecular effects. The
helicoidal-shaped texture named wheat-branch textures discussed in the text for isoxazole 5d is
directly related to the highest energy barrier observed during the molecular modeling analysis.
The molecular modeling of the isoxazoles 5d in gas phase showed that it exists, at room
temperature, as equilibrium between two conformers where the minimum energy is reached
when the dihedral angle between benzene and isoxazole ring is 30° not 0°.
ASSOCIATED CONTENT
Supporting Information
Supplementary Material (Experimental procedure, 1H, 13C and 19F NMR spectrum,
spectroscopic data for final compounds, modeling pictures of the rotamers, X-ray tables, DSC)
is available free of charge at http://....
AUTHOR INFORMATION
Corresponding Author
*E-mail: aloir.merlo@ufrgs.br Tel: +55 51 3308 6293.
29