Synthesis, crystal structure, and supramolecular understanding of 1,3,5-tris(1-phenyl-1H-pyrazol-5-yl)benzenes

Article abstract of DOI:10.3390/molecules23010022

Understanding the supramolecular environment of crystal structures is necessary to facilitate designing molecules with desirable properties. A series of 12 novel 1,3,5-tris(1-phenyl-1H-pyrazol-5-yl)benzenes was used to assess the existence of planar stacking columns in supramolecular structures of pyrazoles. This class of molecules with different substituents may assist in understanding how small structural changes affect the supramolecular environment. The obtained compounds did not present the formation of planar stacking interactions between benzenes in solid or liquid states. This supposition was indicated by single crystal diffraction, Density Functional Theory (DFT) and quantum theory of atoms in molecules (QTAIM) calculations, and concentration-dependent liquid-state¹H nuclear magnetic resonance (NMR). NMR showed that chemical shifts of benzene and pyrazole hydrogens confirm that planar stacking interactions are not formed in solution. The crystalline structures presented different molecular conformations. The molecular structures of 5 and 9b are in a twisted conformation, while compound 7 showed a conformation analogous to a calyx form.

Full text of DOI:10.3390/molecules23010022

molecules
Article
Synthesis, Crystal Structure, and Supramolecular
Understanding of 1,3,5-Tris(1-phenyl-1H-pyrazol-
5-yl)benzenes
Marcos A. P. Martins 1,
*
ID , Alexandre R. Meyer 1, Paulo R. S. Salbego 1 ID , Daniel M. dos Santos 1,
Guilherme A. de Moraes 2, Helio G. Bonacorso 1 ID , Nilo Zanatta 1 ID , Clarissa P. Frizzo 1 and
Manfredo Hörner 2
1
Núcleo de Química de Heterociclos (NUQUIMHE), Department of Chemistry, Federal University of Santa
Maria (UFSM), 97105-900 Santa Maria, Brazil; alexandrerobisonmeyer@gmail.com (A.R.M.);
paulosalbego@gmail.com (P.R.S.S.); santosmarquesdaniel@gmail.com (D.M.d.S.);
helio.bonacorso@ufsm.br (H.G.B.); nilo.zanatta@ufsm.br (N.Z.); clarissa.frizzo@gmail.com (C.P.F.)
Núcleo de Investigação de Triazenos e Complexos (NITRICO), Department of Chemistry,
2
Federal University of Santa Maria (UFSM), 97105-900 Santa Maria, Brazil;
guilhermemoraes18@yahoo.com.br (G.A.d.M.); hoerner.manfredo@gmail.com (M.H.)
*
Correspondence: marcos.nuquimhe@gmail.com; Tel.: +55-(55)-3220-8756
Received: 1 December 2017; Accepted: 19 December 2017; Published: 22 December 2017
Abstract: Understanding the supramolecular environment of crystal structures is necessary to
facilitate designing molecules with desirable properties. A series of 12 novel 1,3,5-tris(1-phenyl-1H-
pyrazol-5-yl)benzenes was used to assess the existence of planar stacking columns in supramolecular
structures of pyrazoles. This class of molecules with different substituents may assist in understanding
how small structural changes affect the supramolecular environment. The obtained compounds
did not present the formation of planar stacking interactions between benzenes in solid or liquid
states. This supposition was indicated by single crystal diffraction, Density Functional Theory (DFT)
and quantum theory of atoms in molecules (QTAIM) calculations, and concentration-dependent
liquid-state 1H nuclear magnetic resonance (NMR). NMR showed that chemical shifts of benzene
and pyrazole hydrogens confirm that planar stacking interactions are not formed in solution.
The crystalline structures presented different molecular conformations. The molecular structures
of
5 and 9b are in a twisted conformation, while compound 7 showed a conformation analogous to
a calyx form.
Keywords: pyrazoles; crystal structure; QTAIM; NMR; X-ray; supramolecular chemistry;
crystal engineering
1. Introduction
When designing new molecules with enhanced properties, analysis should go beyond merely
investigating the molecular structure [1,2]. It is necessary to understand the supramolecular
environment, especially in the self-assembly of the desired molecules [3,4].
Heterocycles, and especially pyrazoles, may present supramolecular structures with columnar
stacked systems, such as one-dimensional constructs. As a result, these molecules present
potentially enhanced luminescent and fluorescent properties [5,6]. However, different supramolecular
arrangements can be observed between structures with similar molecular structures, which explains
why small structural differences can drastically affect the self-assembly observed both in solution and
in solid states [2,7].
Molecules 2018, 23, 22; doi:10.3390/molecules23010022
www.mdpi.com/journal/molecules

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The 1,3,5-trispyrazolylbenzenes are flat, disk-shaped molecules that can potentially present as
column formations in their self-assembly. However, different applications of these molecules may be
observed depending on the formation of different supramolecular arrangements, including ligands
for metal
−
organic framework (MOFs) formation [
8
]. In recent years, a series of pyrazoles with
]. The synthesis of
different molecular structures have been synthesized by our research group [
9
1,3,5-tris(1-phenyl-1H-pyrazol-5-yl)benzenes (TPB) was developed presenting a complex molecular
structure with chemical functionalities that may form a wide variety of intermolecular interactions
(Figure 1).
Figure 1. Intermolecular interaction sites of 1,3,5-tris(1-phenyl-1H-pyrazol-5-yl)benzenes.
This class of compounds is an excellent model to study the influence of subtle substituent
modifications on supramolecular arrangement. Thus, the main goal of this study is to present novel
TPB compounds, understand their self-assembly, and assess whether their stacking formation is
possible. Therefore, single crystal X-ray diffraction, QTAIM calculations, and liquid state NMR
experiments were performed.
2. Results and Discussion
2.1. Synthesis and Characterization
Enaminones are versatile reagents easily obtained and widely applied in heterocyclic
synthesis [10]. They can be obtained by condensation reactions of carbonyl compounds with
N,N-dimethylformamide diethyl acetal in refluxing aromatic hydrocarbons, ethanol, ether, toluene,
DMF, or without solvents [10]. Microwave irradiation can also employed be in the synthesis
of enaminones [11]. The enaminone 1,3,5-tris(3-dimethylamino-1-oxoprop-2-en-yl)benzene
1 was
synthesized according to a synthetic methodology adapted from the literature [11–13].
The synthesis of pyrazoles, based on cyclocondensation between enaminones and hydrazines,
is already well established in the literature. Several synthetic methodologies have been applied in the
synthesis of alkyl and aryl-1H-pyrazoles, including reflux in ethanol, methanol, propanol, acetic acid,
microwave irradiation, and ionic liquid [14–21].
The 1,3,5-tris(1-phenyl-1H-pyrazol-5-yl)benzenes
5–7 were obtained by a cyclization reaction
of enaminone with phenylhydrazines catalyzed by 4-toluenesulfonic acid in ethanol reflux
1
2–4
(Scheme 1). The product structures were confirmed by spectroscopic data (See Supplementary
1
Materials, Figures S3–S8 and S27–S29). Its H-NMR spectra show that the signal of the benzene
hydrogens appears in singlet form with chemical shifts in the range of 6.92–6.99 ppm. This signal
indicates that the three substituents at positions 1, 3, and 5 of the benzene are equal. Formation of
the pyrazole ring is confirmed by the presence of two doublets with coupling constant 3J = 2 Hz and
chemical shifts in the ranges of 6.13–6.20 and 7.43–7.64 ppm. The formation of the 1,5-isomer for
compounds 5 and 7 was confirmed by X-ray diffraction (Figure 2 and Table S1).

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Scheme 1. Synthesis of 1,3,5-tris(1-phenyl-1H-pyrazol-5-yl)benzenes 5–7.
(a)
(b)
Figure 2. ORTEP diagrams of 1,3,5-tris(1-phenyl-1H-pyrazol-5-yl)benzenes 5 (a) and 7 (b) drawn as
50% ellipsoids.
Several synthetic methodologies have been employed in halogenation reactions of pyrazoles,
including: CCl4, ethanol, water, DMF, acetonitrile, dichloromethane, THF, and ethyl acetate [22 31].
The halogenation reactions of the 1,3,5-tris(1-phenyl-1H-pyrazol-5-yl)benzenes were performed
with N-halosuccinimides 8a in ethanol reflux (Scheme 2). The structures of products 11 were
–
5–7
–
c
9–
confirmed by spectroscopic data (See Supplementary Materials, Figures S9–S26 and S30–S38). In its
1H-NMR spectra, the signal referent to the hydrogen of position 4 of the pyrazole ring was not
observed, while the hydrogen present at position 3 was observed in singlet form in the chemical
shift range of 7.64–7.78 ppm. The chemical shift of the carbon signal at position 4 of the pyrazole
ring in the 13C-NMR spectra changes from the range of 106.9–108.0 ppm to 110.8–111.6 ppm,
95.8–96.6 ppm, and 62.0–63.4 ppm, respectively, for the chlorinated, brominated, and iodinated
pyrazoles. Halogenation at position 4 of the pyrazole was also confirmed by X-ray diffraction of
compound 9b (Figure 3 and Table S1). At this moment, suitable single crystals for X-ray diffraction
were obtained solely for three compounds (5, 7, and 9b).

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Scheme 2. Synthesis of 1,3,5-tris(1-phenyl-4-halo-1H-pyrazol-5-yl)benzenes 9–11.
Figure 3. ORTEP diagram of 1,3,5-tris(1-phenyl-4-halo-1H-pyrazol-5-yl)benzene 9b drawn as
50% ellipsoids.
2.2. Supramolecular Arrangement
The crystalline structures for compounds
conformations (Figure 4). Compounds and 9b presented molecular structures with a twisted
conformation, and compound showed a distinct conformation analogous to a calyx form.
In this primary analysis, the crystalline structures presented a deviation from the benzene plane.
In compounds and 9b, one of the phenyl-1H-pyrazole-5-yl groups is in one direction of the benzene
plane (e.g., under the traced plane) while the other two groups are in the opposite direction (e.g., above
5, 7, and 9b presented with different molecular
5
7
5
the plane) (Figure 4a,b). The calyx form of compound
portions in the same direction (Figure 4c).
7 showed all phenyl-1H-pyrazole-5-yl group

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(a)
(b)
(c)
Figure 4. Molecular conformation of compounds
(d)
5
(a
) and 9b
(
b
) in twisted form; compound 7 (c) in
calyx form; and compound LIJJIY (CSD refcode) [6] in planar conformation (d).
Only one example of a similar structure was found in the Cambridge Structure Database.
Zhao et al. ] reported a 1,3,5-tris(1H-pyrazol-3-yl)benzene (Figure 5) (refcode LIJJIY) presenting
[
6
with a planar conformation, showing all three phenyl-1H-pyrazole-3-yl groups in almost the same
plane of the benzene ring (Figure 4d).
Figure 5. Molecular structure of 1,3,5-tris(1H-pyrazol-3-yl)benzene (refcode LIJJIY).
This initial assessment indicates a difficulty in the columnar packing formation of these structures,
although further investigation of crystal packing of these molecules should be performed. Therefore,
the possible 1D motif formed in these structures was investigated in order to assess the kind of packing
present in each one. Then, the observed packing was compared with the model reported by Zhao et al.,
which shows planar 1D column formation (Figure 6c). Since compounds
molecular behavior and consequently the same 1D supramolecular arrangement, only
The 1D arrangement for 9b can be observed in the Supplementary Materials (Figure S1).
5
and 9b showed the same
5
was showed.

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(a)
(b)
(c)
Figure 6. 1D arrangement for compounds 5 (a), 7 (b), and LIJJIY [6] (c).
The 1D projection for the structures, and differences when compared with the structure reported
by Zhao et al. [ ], can be seen in Figure 6. In our case, planar stacking, which is a parallel interaction
between the benzene rings of structures, was not observed. The observed columns occur in a different
form because of the conformational characteristics of each molecule. In compound , QTAIM analysis
6
5
revealed one C-H···π and six H···H intermolecular interactions in each dimer of the 1D arrangement.
The C-H···π interaction occurs between a hydrogen atom of one of the phenyl rings and a carbon atom
from the benzene ring. This is the second highest value of
$ (electronic density in the critical point),
which indicates the magnitude of the interaction strength (See Supplementary Materials, Figure S2
and Table S4). Moreover, the dimers involved in the 1D arrangement of compound presented one
π···π and two C-H···Cl interactions. The π···π interaction occurs involving the carbon atom of one of
the phenyl rings and a carbon atom from the central benzene ring, showing the highest value of
7
$
with 55% of the total dimer value (See Supplementary Materials, Figure S2 and Table S4). The two
dimers observed in the arrangement of compound 9b showed different interactions: one with seven
interactions (four C-H···N, one π···π, and two C···H) and the other with four C-H···Br interactions.
The first dimer showed low
C···H and π···π interactions (See Supplementary Materials, Figure S2 and Table S4).
$
values for the C-H···N interactions, presenting the highest values for the
This kind of approach can provide information regarding the possibility of stacking interactions
and guide the design of new molecules with desired properties. The structures obtained do not
present planar 1D stacking motifs, which indicate they are not viable for fluorescent or luminescent
methods, although they are desirable models for use as ligands in the formation of metallic complexes.
One remaining question regarding the self-assembly of these molecules is if the solid state behavior
(crystal) is maintained in the liquid state. To answer this pertinent question, concentration-dependent
liquid-state 1H-NMR experiments were carried out for pyrazole
this compound.
7 to evaluate the self-assembly of

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The chemical shift changes of the hydrogens of the central benzene and pyrazoles were monitored.
These nuclei are in a central position in the molecule and are ideal for evaluating the formation of
stacking interactions. The data from the 1H-NMR experiments (Figure 7) shows that the signal of
the benzene hydrogens is deshielded according to increases in concentration. This behavior reveals
that these hydrogens are involved in hydrogen bonds. The chemical shift of hydrogen H4 (in blue;
Figure 7) of the pyrazole ring practically does not change. The most external hydrogen, H3 (in green;
Figure 7), shows an upfield change in chemical shift. Therefore, the chemical shift changes of the
benzene hydrogens and H4 hydrogen of the pyrazoles confirm that stacking interactions are not
formed in solution.
Figure 7. Concentration-dependent 1H-NMR spectra of 1,3,5-tris(1-(2,4-dichlorophenyl)-1H-pyrazol-
5-yl)benzene 7 performed in CDCl3 at 298 K.
2.3. QTAIM Analysis
Quantum Theory of Atoms in Molecules (QTAIM) [32,33] analysis was carried out to identify
and assess the strength of the intramolecular interactions involved in the stabilization of the reported
structures. Bond critical points (BCPs) were obtained to confirm existence of the interactions.
QTAIM data on intramolecular interactions, which show BCPs, type of interaction,
summarized in Table 1. Additional information on QTAIM data are available in the Supplementary
Materials (Table S2). and EINT provide the magnitude of the interaction strength, since they
$, and EINT are
$
represent the electronic density at the critical point and intramolecular interaction energy (obtained
by EINT = V/2) [34], respectively. V/2 can be used as an estimation of the intramolecular interaction
strength [34].

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Table 1. QTAIM data and stabilization energies from intramolecular interactions presented in
compounds 5, 7, and 9a.
a
−1
)
Compound
Molecular Structure
Intramolecular Interaction
$ (a.u.)
EINT (kcal mol
I-CHB···πph
0.0017
−0.22
−0.33
−1.49
−0.44
−0.89
−0.97
−1.08
−0.42
−0.61
−0.49
−0.35
5
II-CHB···πph
III-CHB···πbz
I-CHA···ClC
II-ClB···πphA
III-ClA···πphC
IV-ClC···πphB
I-BrC···πPhA
II-BrA···πPhB
III-CHB···πPhC
IV-CHB···πPhC
0.0023
0.0089
0.0029
0.0061
0.0067
0.0071
0.0032
0.0042
0.0036
0.0026
7
9b
a
EINT = V/2 [34]. CCPs and RCPs were omitted for clarity purposes.
The twisted structures
Compound
shows only C-H···π interactions, where two are between the two phenyl groups
0.22 and -system
0.33 kcal mol−1) and one is between the C-H from one phenyl group and the
from the central benzene ring with the highest contribution (
1.49 kcal mol−1). The 1,3,5-tris(1H-
5 and 9b present three and four intramolecular interactions, respectively.
5
(
−
−
π
−
pyrazol-3-yl)benzene group above the benzene plane showed no interaction with another portion
of the molecule, which may indicate the influence of intermolecular interactions on the molecular
conformation. Compound 9b presents two C-H···π and two Br··· π interactions with almost the same
magnitude, ranging from −0.35 to −0.61 kcal mol−1
.
Compound
7
with the calyx-type molecular structure is stabilized by three major Cl···π
interactions (between
the phenyl group and the
−
0.89 and
π
−
1.08 kcal mol−1) between the chlorine atom at position 2 from
-system from another phenyl ring. Additionally, a C-H···Cl interaction was
observed with a lower contribution to the stabilization energy, which only presented −0.44 kcal mol−1
.
Geometric data of the observed intramolecular interactions are presented in the Supplementary
Materials (Table S3).

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2.4. Molecular Elestrostatic Potential of Compounds 5, 7, and 9b
The molecular electrostatic potential (MEP) [35,36] is a powerful tool to predict and understand
noncovalent interactions [37–42]. The MEPs of 5, 7, and 9b (Figure 8) were generated with the aim of
analyzing the interaction sites of the molecules, leading to complementation of the QTAIM analysis.
The MEP of compound
while the nitrogen atoms and
These opposite and complementary electrostatic potentials allied to its proximity in space allow the
in the QTAIM analysis.
5
shows that the hydrogen atoms present positive electrostatic potentials,
π-system of the phenyl ring show negative electrostatic potentials.
formation of the C-H···π interactions observed in the molecular structure of
5
The same behavior is observed for compound 9b, although the presence of the Br···π interaction
can be also observed. This interaction occurs by the attraction of the negative electrostatic potential
of the phenyl
π-system by the positive electrostatic potential (σ-hole) localized on the outer side of
the bromine atom. Compound
7
presents a distinct behavior from the other two compounds. In 7,
the chlorine atoms, which are attached to positions 2 and 4 of the phenyl group, showed negative
electrostatic potentials in the equatorial region and small positive electrostatic potentials on the outer
side of the atom. The electron withdrawing effect of the chlorine atoms turns the electrostatic potential
of the phenyl ring slightly positive. Therefore, the region of negative electrostatic potential of the
chlorine atom (position 2 of the phenyl) interacts with the phenyl ring and therefore causes Cl···π
interactions, resulting in the calyx form of compound 7.
Figure 8. Molecular electrostatic potential of compounds
the B97X-D/cc-pVDZ level of theory with the aid of GaussView software. Red
−0.005 au; Green 0.00 and Blue 0.01 au.
5
,
7
, and 9b. Isodensity value of 0.001 at
ω
−
0.01 au; Yellow

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3. Experimental Section
3.1. General Information
All reagents were purchased from commercial suppliers and used without further purification.
The reactions under microwave irradiation were performed in a Discovery CEM MW using the mode
operation without simultaneous cooling. The power of the equipment was established at 200 W,
and a maximum level of internal pressure of 250 psi was used. 1H- and 13C-NMR spectra were
recorded in a Bruker DPX-400 (1H at 400 MHz and 13C at 100 MHz) in CDCl3/TMS solutions at
298 K. Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) was performed
in an Agilent Model 6460 system with an electrospray ionization (ESI) source coupled to a QQQ
detector. The voltage of the capillary was maintained at 3500 V. The source temperature was 300 ◦C
with a flow rate of 5 L min−1. The jetstream temperature was 250 ◦C with a flow rate of 11 L min−1
All samples were injected with an autosampler, 1 L by volume. Data were acquired in scan mode
.
µ
in the 50–500 m/z range and the product ion mode (product ion) MS/MS. The melting points were
measured using a Microquıímica MQAPF 301 apparatus.
3.2. Synthesis
3.2.1. General Procedure for Preparation of 1,3,5-tris(3-dimethylamino-1-oxoprop-2-en-yl)benzene (
1)
Compound was obtained according to methodology adapted from the literature [11 12].
1
,
A mixture of propanone (10 mmol), N,N-dimethylformamide diethyl acetal (5 mmol), and boron
trifluoride etherate (3 drops) was added into a 10 mL microwave vessel equipped with a standard
cap (vessel commercially furnished by Discover CEM). Afterwards, the vessel was sealed and the
◦
sample irradiated for 5 min at 150 C. The propanone excess was evaporated under vacuum (reduced
pressure) providing (E)-4-(dimethylamino)but-3-en-2-one. Acetic acid (20 mL) was added to the
(E)-4-(dimethylamino)but-3-◦en-2-one (20 mmol) in a round-bottom flask equipped with a stir bar.
The mixture was stirred at 118 C in a pre-heated oil bath for 3 h. After cooling, 1,3,5-triacethylbenzene was
separated from the reaction mixture by filtration and recrystallized in a 3:1 mixture of ethanol/dioxane.
Finally, the 1,3,5-triacethylbenzene (1 mmol), N,N-dimethylformamide diethyl acetal (6 mmol),
and boron trifluoride etherate (3 drops) were added to a microwave vessel equipped with a standard
◦
cap. The vessel was sealed and the sample irradiated in a microwave oven at 150 C for 20 min.
Compound
1 was obtained after the addition of 10 mL of N-hexane to the reaction mixture and
subsequent filtration.
3.2.2. General Procedure for Preparation of 1,3,5-tris(pirazolyl)benzenes 5–7
The 1,3,5-tris-β-enaminone 1 (1 mmol), hydrochloride hydrazines 2–4 (3.6 mmol), and p-toluene
sulfonic acid (0.6 mmol) were dissolved in dry ethanol (5 mL) in a round-bottom flask equipped with
◦
a stir bar. The reaction mixture was stirred at 78 C in a pre-heated oil bath for 5 h. Afterwards,
the ethanol was evaporated under reduced pressure and 1,3,5-tris(pirazolyl)benzenes were isolated
with chloroform (10 mL) and washed with distillated water (3
with anhydrous sodium sulfate, and the solvent evaporated under reduced pressure.
×
10 mL). The organic phase was dried
◦
5 δ;
. Yield 91%, m.p. 183–184 C. 1H-NMR (400 MHZ, CDCl3,
1,3,5-Tris(1-phenyl-1H-pyrazol-5-yl)benzene
ppm): 6.13 (d, 3J = 2, 3H, H4), 6.99 (s, 3H, HBz), 7.18–7.21 (m, 6H, HPh), 7.33–7.36 (m, 9H, HPh), 7.64 (d,
3J = 2, 3H, H3). 13C-NMR (100 MHZ, CDCl3,
; ppm): 108.0 (C4), 125.5 (CAr), 128.0 (CAr), 128.7 (CAr),
129.1 (CAr), 131.3 (CAr), 139.8 (CAr), 140.4 (C3), 141.5 (C5). Positive ESI-MS m/z 505.2 [M + H]+.
δ
◦
1,3,5-Tris(1-(2,4-difluorophenyl)-1H-pyrazol-5-yl)benzene 6
. Yield 91%, m.p. 65–66 C. 1H-NMR (400 MHZ,
CDCl3,
δ
; ppm): 6.20 (d, 3J = 2, 3H, H4), 6.79–6.84 (m, 3H, 2-4-F-Ph), 6.95–7.00 (m, 3H, 2-4-F-Ph), 6.99
(s, 3H, HBz), 7.37–7.43 (m, 3H, 2-4-F-Ph), 7.64 (d, J = 2, 3H, H3). 13C-NMR (100 MHZ, CDCl3,
δ;
3
ppm): 107.3 (C4), 105.1 (dd, 2JC–F = 26, 2JC–F = 23, CAr), 112.2 (dd, 2JC–F = 23, 4JC–F = 4, CAr), 124.4

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(dd, 2JC–F = 12, 4JC–F = 4, CAr) 127.4 (CAr), 129.9 (d, 3JC–F = 10, CAr), 130.9 (CAr), 141.4 (C3), 143.4
(C5), 156.7 (dd, 1JC–F = 256, 3JC–F = 13, CAr), 162.6 (dd, 1JC–F = 252, 3JC–F = 11, CAr). Positive ESI-MS
m/z 613.1 [M + H]+.
◦
1
1,3,5-Tris(1-(2,4-dichlorophenyl)-1H-pyrazol-5-yl)benzene
(400 MHZ, CDCl3,
; ppm): 6.19 (d, 3J = 2, 3H, H4), 6.92 (s, 3H, HBz), 7.27 (s, 1H, 2-4-Cl-Ph), 7.30 (s, 2H,
2-4-Cl-Ph), 7.33 (d, 3J = 2, 2H, 2-4-Cl-Ph), 7.35 (d, 3J = 2, 1H, 2-4-Cl-Ph), 7.43 (d, 3J = 2, 3H, 2-4-Cl-Ph),
7.72 (d, 3J = 2, 3H, H3). 13C-NMR (100 MHZ, CDCl3,
; ppm): 106.9 (C4), 127.4 (CAr), 128.0 (CAr), 130.3
7. Yield 90%, m.p. 169–170 C. H-NMR
δ
δ
(CAr), 130.6 (CAr), 130.8 (CAr), 133.0 (CAr), 135.9 (CAr), 136.4 (CAr), 141.3 (C3), 143.4 (C5). Positive
ESI-MS m/z 710.8 [M + H]+.
3.2.3. General Procedure for Preparation of 1,3,5-Tris(4-halo-pirazolyl)benzenes 9–11
1,3,5-Tris(pirazolyl)benzenes 5-7 (0.25 mmol) and N-halosuccinimides 8 (2.25 mmol) were
dissolved in ethanol (3 mL). The reactions of chlorination and bromination were performed in
a round-bottom flask equipped with a stir bar in pre-heated oil bath for 5 h at 78 ◦C. For iodination,
trifluoroacetic acid (0.25 mmol) was added and the reaction performed in a sealed tube, which was then
◦
heated in a pre-heated oil bath for 5 h at 78 C. After cooling, pyrazole
9 was isolated from the reaction
mixture by filtration and washed with dry ethanol (3 mL). For pyrazoles 10 and 11, the ethanol was
evaporated under reduced pressure, and the products isolated with chloroform (5 mL) and washed
with distillated water (5
solvent evaporated under reduced pressure.
×
5 mL). The organic phase was dried with anhydrous sodium sulfate, and the
◦
1,3,5-Tris(4-chloro-1-phenyl-1H-pyrazol-5-yl)benzene 9a. Yield 63%, m.p. 266–267 C. 1H-NMR (400 MHZ,
CDCl3, ; ppm): 7.18 (s, 3H, HBz), 7.13–7.15 (m, 6H, HPh), 7.29–7.35 (m, 9H, HPh), 7.64 (s, 3H, H3).
13C-NMR (100 MHZ, CDCl3,
; ppm): 111.6 (C4), 125.0 (CAr), 128.2 (CAr), 129.4 (CAr), 129.4 (CAr),
131.7 (CAr), 137.3 (C5), 139.7 (CAr), 139.1 (C3). Positive ESI-MS m/z 609.0 [M + H]+.
δ
δ
◦
1,3,5-Tris(4-bromo-1-phenyl-1H-pyrazol-5-yl)benzene 9b. Yield 65%, m.p. 272–273 C. 1H-NMR (400 MHZ,
CDCl3, ; ppm): 7.20 (s, 3H, HBz), 7.13–7.15 (m, 6H, HPh), 7.26–7.34 (m, 9H, HPh), 7.67 (s, 3H, H3).
δ
13C-NMR (100 MHZ, CDCl3,
δ; ppm): 96.6 (C4), 124.9 (CAr), 128.0 (CAr), 129.3 (CAr), 130.0 (CAr),
132.1 (CAr), 138.9 (C5), 139.6 (CAr), 141.0 (C3). Positive ESI-MS m/z 740.8 [M + H]+.
1,3,5-Tris(4-iodo-1-phenyl-1H-pyrazol-5-yl)benzene 9c. Yield 66%, m.p. 299–300 ◦C. 1H-NMR (400 MHZ,
CDCl3, δ; ppm): 7.16 (s, 3H, HBz), 7.13–7.15 (m, 6H, HPh), 7.24–7.31 (m, 9H, HPh), 7.72 (s, 3H, H3).
13C-NMR (100 MHZ, CDCl3,
δ; ppm): 63.4 (C4), 124.8 (CAr), 128.0 (CAr), 129.3 (CAr), 131.4 (CAr),
132.9 (CAr), 139.5 (C5), 142.3 (CAr), 145.3 (C3). Positive ESI-MS m/z 662.8 [M + H]+.
1,3,5-Tris(4-chloro-1-(2,4-difluorophenyl)-1H-pyrazol-5-yl)benzene 10a. Yield 85%, m.p. 195–196 ◦C.
1H-NMR (400 MHZ, CDCl3,
δ; ppm): 6.76–6.81 (m, 3H, 2-4-F-Ph), 6.94–6.99 (m, 3H, 2-4-F-Ph), 7.18 (s,
3H, HBz), 7.39–7.45 (m, 3H, 2-4-F-Ph), 7.70 (s, 3H, H3). 13C-NMR (100 MHZ, CDCl3,
δ; ppm): 105.3
(dd, 2JC–F = 27, 2JC–F = 24, CAr), 110.9 (C4), 112.5 (dd, 2JC–F = 23, 4JC–F = 4, CAr), 124.1 (dd, 2JC–F = 12,
3
4JC–F = 4, CAr) 128.5 (CAr), 129.7 (d, JC–F = 10, CAr), 130.4 (CAr), 139.0 (C5), 140.1 (C3), 156.5 (dd,
1JC–F = 256, 3JC–F = 13, CAr), 162.9 (dd, 1JC–F = 253, 3JC–F = 11, CAr). Positive ESI-MS m/z 714.9 [M + H]+.
◦
1,3,5-Tris(4-bromo-1-(2,4-difluorophenyl)-1H-pyrazol-5-yl)benzene 10b. Yield 89%, m.p. 174–175 C.
1H-NMR (400 MHZ, CDCl3,
δ
; ppm): 6.73–6.78 (m, 3H, 2-4-F-Ph), 6.90–6.95 (m, 3H, 2-4-F-Ph), 7.17 (s,
3H, HBz), 7.34–7.40 (m, 3H, 2-4-F-Ph), 7.72 (s, 3H, H3). 13C-NMR (100 MHZ, CDCl3,
δ
; ppm): 95.9
(C4), 105.2 (dd, 2JC–F = 26, 2JC–F = 24, CAr), 112.3 (dd, 2JC–F = 23, 4JC–F = 4, CAr), 124.2 (dd, 2JC–F = 12,
4JC–F = 4, CAr) 129.1 (CAr), 129.8 (d, 3JC–F = 10, CAr), 131.3 (CAr), 140.9 (C5), 142.1 (C3), 156.6 (dd,
1JC–F = 256, 3JC–F = 13, CAr), 162.9 (dd, 1JC–F = 253, 3JC–F = 11, CAr). Positive ESI-MS m/z 850.7 [M + H]+.
◦
1,3,5-Tris(4-iodo-1-(2,4-difluorophenyl)-1H-pyrazol-5-yl)benzene 10c. Yield 90%, m.p. 188–189 C. 1H-NMR
(400 MHZ, CDCl3, ; ppm): 6.71–6.76 (m, 3H, 2-4-F-Ph), 6.88-6.93 (m, 3H, 2-4-F-Ph), 7.10 (s, 3H, HBz),
7.30–7.36 (m, 3H, 2-4-F-Ph), 7.76 (s, 3H, H3). 13C-NMR (100 MHZ, CDCl3,
; ppm): 62.2 (C4), 105.0
δ
δ

Molecules 2018, 23, 22
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(dd, 2JC–F = 26, 2JC–F = 24, CAr), 112.1 (dd, 2JC–F = 23, 4JC–F = 4, CAr), 124.0 (dd, 2JC–F = 12, 4JC–F = 4,
CAr) 129.7 (d, 3JC–F = 10, CAr), 130.0 (CAr), 131.2 (CAr), 144.2 (C5), 146.1 (C3), 156.5 (dd, 1JC–F = 256,
3JC–F = 13, CAr), 162.8 (dd, 1JC–F = 253, 3JC–F = 11, CAr). Positive ESI-MS m/z 990.7 [M + H]+.
◦
1,3,5-Tris(4-chloro-1-(2,4-dichlorophenyl)-1H-pyrazol-5-yl)benzene 11a. Yield 81%, m.p. 206–207 C.
1H-NMR (400 MHZ, CDCl3,
δ
; ppm): 7.15 (s, 3H, HBz), 7.25 (s, 1H, 2-4-Cl-Ph), 7.27 (s, 2H, 2-4-Cl-Ph),
7.31 (d, J = 2, 2H, 2-4-Cl-Ph), 7.33 (d, J = 2, 1H, 2-4-Cl-Ph), 7.41 (d, J = 2, 3H, 2-4-Cl-Ph), 7.70 (s,
3H, H3). 13C-NMR (100 MHZ, CDCl3,
δ; ppm): 110.8 (C4), 128.4 (CAr), 128.5 (CAr), 130.5 (CAr),
3
3
3
130.6 (CAr), 130.6 (CAr), 132.9 (CAr), 136.0 (CAr), 136.3 (CAr), 138.9 (C5), 140.0 (C3). Positive ESI-MS
m/z 814.7 [M + H]+.
◦
1,3,5-Tris(4-Bromo-1-(2,4-dichlorophenyl)-1H-pyrazol-5-yl)benzene 11b. Yield 82%, m.p. 208–209 C.
1H-NMR (400 MHZ, CDCl3,
δ
; ppm): 7.15 (s, 3H, HBz), 7.20 (s, 1H, 2-4-Cl-Ph), 7.23 (s, 2H, 2-4-Cl-Ph),
7.28 (d, 3J = 2, 2H, 2-4-Cl-Ph), 7.30 (d, 3J = 2, 1H, 2-4-Cl-Ph), 7.40 (d, 3J = 2, 3H, 2-4-Cl-Ph), 7.73 (s, 3H,
H3). 13C-NMR (100 MHZ, CDCl3,
; ppm): 95.8 (C4), 128.3 (CAr), 128.9 (CAr), 130.6 (CAr), 130.6 (CAr),
δ
131.3 (CAr), 132.9 (CAr), 136.0 (CAr), 136.3 (CAr), 140.6 (C5), 142.0 (C3). Positive ESI-MS m/z 948.5
[M + H]+.
◦
1,3,5-Tris(4-iodo-1-(2,4-dichlorophenyl)-1H-pyrazol-5-yl)benzene 11c. Yield 85%, m.p. 209–210 C. 1H-NMR
(400 MHZ, CDCl3, ; ppm): 7.08 (s, 3H, HBz), 7.15 (s, 1H, 2-4-Cl-Ph), 7.17 (s, 2H, 2-4-Cl-Ph), 7.25 (d,
3J = 2, 2H, 2-4-Cl-Ph), 7.28 (d, 3J = 2, 1H, 2-4-Cl-Ph), 7.39 (d, 3J = 2, 3H, 2-4-Cl-Ph), 7.78 (s, 3H, H3).
δ
13C-NMR (100 MHZ, CDCl3,
δ; ppm): 62.0 (C4), 128.0 (CAr), 129.9 (CAr), 130.5 (CAr), 132.3 (CAr),
132.9 (CAr), 135.9 (CAr), 136.3 (CAr), 144.0 (C5), 146.2 (C3). Positive ESI-MS m/z 1088.6 [M + H]+.
3.3. X-ray Crystallography
Single crystals suitable for X-ray diffraction were obtained in CHCl3/EtOH (1:1), EtOH, and
CHCl3 for compounds
were performed using graphite monochromatized MoK
X8 APEX II diffractometer with charge-coupled device (CCD) detector. Diffraction measurements
of compound were carried out using a Bruker D8 Venture with a Photon 100 CMOS detector with
graphite-monochromated Mo-K radiation ( = 0.71073 Å). Anisotropic displacement parameters
5,
7
, and 9b, respectively. Diffraction measurements of compounds
7 and 9b
α
radiation with = 0.71073 Å in a Bruker
λ
5
α
λ
for non-hydrogen atoms were applied. All hydrogen atoms of the aromatic rings and alkyl groups
were positioned geometrically (aromatic C-H = 0.93 Å for Csp2 atoms; methyl C-H = 0.96 Å for Csp3
atoms) and treated as riding on their respective C atoms with Uiso(H) values set at 1.2 UeqCsp2 and
1.5 UeqCsp3, respectively. Integration, scaling correction, and data reduction were performed using
BRUKER APEX-II. Absorption corrections were performed using Gaussian and multiscan methods.
The structures were solved and refined using the WinGX package [43]. The structures were solved
using SHELXS software [44] and refined based on the full-matrix least-squares method using SHELXL
software 2016/6 [45]. ORTEP projections of the molecular structures were generated using ORTEP-3
software [43].
3.4. Quantum Chemical Calculation
Quantum chemical calculations were performed with the Gaussian 09 software package [46].
Wavefunctions were generated at the
ωB97X-D/cc-pVDZ level of theory by single point calculations
with geometries obtained from X-ray data. The wavefunctions were subsequently analyzed from
the perspective of the quantum theory of atoms in molecules by AIMALL software [47]. Molecular
electrostatic potentials were generated with a isosurface value of 0.001 in GaussView software [48].
4. Conclusions
Understanding the supramolecular environment of molecular structures is vital to designing new
compounds with desired properties. A series of novel 1,3,5-tris(1-phenyl-1H-pyrazol-5-yl)benzenes
with different substituents was presented. A combination of molecular and supramolecular approaches

Molecules 2018, 23, 22
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was shown to evaluate the possibility of 1D stacked formation, which may lead to different applications.
The single crystal diffraction technique, DFT, and QTAIM analysis were reliable tools to detect
1
differences in molecular and supramolecular conformation. Additionally, liquid-state H-NMR
experiments confirmed that the same behavior observed in the solid-state occurs in solution without
the formation of planar stacking interactions.
Supplementary Materials: Supplementary materials are available online. CCDC numbers 1501480 (5), 1484377 (7),
and 1484578 (9b) contain the supplementary crystallographic data for the presented compounds. These data can
be obtained free of charge from the Cambridge Crystallographic Data Centre via http://www.ccdc.cam.ac.uk/
data_request/cif. Electronic Supplementary Materials (ESM) available: Tables S1–S4, Figures S1–S38.
Acknowledgments: The authors are grateful to the Conselho Nacional de Desenvolvimento Científico e
Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), and Fundação de
Amparo a Pesquisa (FAPERGS) for supporting this study. The authors acknowledge the research fellowships from
CNPq (M.A.P.M., P.R.S.S., M.H., H.G.B., N.Z., C.P.F., D.M.S.) and CAPES (A.R.M.).
Author Contributions: M.A.P.M., H.G.B., and N.Z. conceived and designed the experiments; A.R.M. and D.M.d.S.
performed the syntheses; C.P.F. contributed with the spectroscopy data; G.A.d.M. and M.H. contributed with the
crystallographic approach; M.A.P.M., A.R.M., and P.R.S.S. analyzed the data; P.R.S.S. and A.R.M. wrote the paper.
Conflicts of Interest: The authors declare no conflict of interest.
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©
2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).