Synthesis, structural characterization, and theoretical studies of new pyrazole (E)-2-{[(5-(tert-butyl)-1H-pyrazol-3-yl)imino]methyl}phenol and (E)-2-{[(1-(4-bromophenyl)-3-(tert-butyl)-1H-pyrazol-5-yl]imino]methyl}phenol

Article abstract of DOI:10.1016/j.molstruc.2019.02.004

In this paper, theoretical and experimental studies of two new Schiff bases were performed. The (E)-2-{[(5-(tert-butyl)-1H-pyrazol-3-yl)imino]methyl}phenol (3) and (E)-2-{[(1-(4-bromophenyl)-3-(tert-butyl)-1H-pyrazol-5-yl]imino]methyl}phenol (5)compounds were characterized by spectroscopic techniques, (i.e. MS, NMR, FT–IR, UV–vis, and single-crystal X–ray diffraction). The molecular geometry of both compounds in the ground state, vibrational frequencies, and chemical shift were calculated by using the functional density theory method, with B3LYP as functional and 6-31G** as basis set, using the GAUSSIAN 09 program package. With the VEDA 4 program, the vibrational frequencies were allocated in terms of potential energy distribution (PED). In this paper, theoretical and experimental studies of two new Schiff bases were performed. The (E)-2-{[(5-(tert-butyl)-1H-pyrazol-3-yl)imino]methyl}phenol (3) and (E)-2-{[(1-(4-bromophenyl)-3-(tert-butyl)-1H-pyrazol-5-yl]imino]methyl}phenol (5) compounds were characterized by spectroscopic techniques, (i.e. MS, NMR, FT-IR, UV–vis, and single-crystal X-ray diffraction). The molecular geometry of both compounds in the ground state, vibrational frequencies, and chemical shift were calculated by using the functional density theory method, with B3LYP as functional and 6-31G** as basis set, using the GAUSSIAN 09 program package. With the VEDA 4 program, the vibrational frequencies were allocated in terms of potential energy distribution (PED). Molecular stabilities were determined in terms of softness and hardness, and the values were determined from the energies of HOMO and LUMO orbitals. Remarkably, good agreements between the calculated IR, NMR and UV–vis spectra in comparison to those experimental ones, were found.

Full text of DOI:10.1016/j.molstruc.2019.02.004

Accepted Manuscript
Synthesis, structural characterization, and theoretical studies of new pyrazole (E)-2-
{
(
[(5-(tert-butyl)-1H-pyrazol-3-yl)imino]methyl}phenol and (E)-2-{[(1-(4-bromophenyl)-3-
tert-butyl)-1H-pyrazol-5-yl]imino]methyl}phenol
Fernando Cuenú, Andrés Restrepo-Acevedo, María Isabel-Murillo, John Eduard
Torres, Rodolfo Moreno-Fuquen, Rodrigo Abonia, Alan R. Kennedy, Juan Carlos
Tenorio, Christian W. Lehmann
PII:
S0022-2860(19)30128-0
DOI:
https://doi.org/10.1016/j.molstruc.2019.02.004
MOLSTR 26161
Reference:
To appear in: Journal of Molecular Structure
Received Date: 30 December 2018
Revised Date: 2 February 2019
Accepted Date: 3 February 2019
Please cite this article as: F. Cuenú, André. Restrepo-Acevedo, Marí. Isabel-Murillo, J. Eduard
Torres, R. Moreno-Fuquen, R. Abonia, A.R. Kennedy, J.C. Tenorio, C.W. Lehmann, Synthesis,
structural characterization, and theoretical studies of new pyrazole (E)-2-{[(5-(tert-butyl)-1H-
pyrazol-3-yl)imino]methyl}phenol and (E)-2-{[(1-(4-bromophenyl)-3-(tert-butyl)-1H-pyrazol-5-
yl]imino]methyl}phenol, Journal of Molecular Structure (2019), doi: https://doi.org/10.1016/
j.molstruc.2019.02.004.
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GRAPHICAL ABSTRACT

ACCEPTED MANUSCRIPT
Synthesis, structural characterization, and theoretical studies of
new pyrazole (E)-2-{[(5-(tert-butyl)-1H-pyrazol-3-
yl)imino]methyl}phenol and (E)-2-{[(1-(4-bromophenyl)-3-(tert-
butyl)-1H-pyrazol-5-yl]imino]methyl}phenol
a,*
a
a
Fernando Cuenú , Andrés Restrepo-Acevedo , María Isabel-Murillo , John Eduard
a
b
b
c
Torres , Rodolfo Moreno-Fuquen , Rodrigo Abonia , Alan R. Kennedy , Juan Carlos
Tenorio , Christian W. Lehmann
d
d
a
Laboratory of Inorganic Chemistry and Catalysis, Chemistry Program, Universidad del Quindío,
Carrera 15, Calle 12 Norte, Armenia-Colombia
b
Department of Chemistry, Universidad del Valle, Calle 13 No. 100-00, A.A. 25360, Cali-Colombia
c
Department of Pure & Applied Chemistry. University of Strathclyde, 295 Cathedral Street, Glasgow
G1 1XL Scotland
d
Max-Planck-Institut für Kohlenforshung, Kaiser-Wilhelm-Platz 145470 Mülheim an der Ruhr,
Germany
*
Corresponding Author: Laboratory of Inorganic Chemistry and Catalysis, Chemistry
Program, Universidad del Quindío, Carrera 15, Calle 12 Norte, Armenia-Colombia. Mail:
fercuenu@uniquindio.edu.co
ABSTRACT
In this paper, theoretical and experimental studies of two new Schiff bases were performed.
The (E)-2-{[(5-(tert-butyl)-1H-pyrazol-3-yl)imino]methyl}phenol (3) and (E)-2-{[(1-(4-
bromophenyl)-3-(tert-butyl)-1H-pyrazol-5-yl]imino]methyl}phenol (5) compounds were
characterized by spectroscopic techniques, (i.e. MS, NMR, FT-IR, UV-vis, and single-crystal
X-ray diffraction). The molecular geometry of both compounds in the ground state,
vibrational frequencies, and chemical shift were calculated by using the functional density
theory method, with B3LYP as functional and 6-31G** as basis set, using the GAUSSIAN 09
program package. With the VEDA 4 program, the vibrational frequencies were allocated in
terms of potential energy distribution (PED). In this paper, theoretical and experimental
studies of two new Schiff bases were performed. The (E)-2-{[(5-(tert-butyl)-1H-pyrazol-3-
yl)imino]methyl}phenol (3) and (E)-2-{[(1-(4-bromophenyl)-3-(tert-butyl)-1H-pyrazol-5-
yl]imino]methyl}phenol (5) compounds were characterized by spectroscopic techniques, (i.e.
MS, NMR, FT-IR, UV-vis, and single-crystal X-ray diffraction). The molecular geometry of
both compounds in the ground state, vibrational frequencies, and chemical shift were
calculated by using the functional density theory method, with B3LYP as functional and 6-

ACCEPTED MANUSCRIPT
3
1G** as basis set, using the GAUSSIAN 09 program package. With the VEDA 4 program,
the vibrational frequencies were allocated in terms of potential energy distribution (PED).
Molecular stabilities were determined in terms of softness and hardness, and the values were
determined from the energies of HOMO and LUMO orbitals. Remarkably, good agreements
between the calculated IR, NMR and UV-vis spectra in comparison to those experimental
ones, were found.
KEYWORDS: Pyrazoles, Schiff bases, FT-IR, NMR, Electronic absorption spectra, DFT.
1
. INTRODUCTION
Nitrogen containing heterocyclic rings, are the main frameworks of various biologically
active compounds showing a vast variety of applications in pharmacological and
agrochemical industries. Because of their widespread potential of pharmacological activities,
such as anti-inflammatory [1], antitumor [2], anticonvulsant [3], and antimicrobial [4], the
pyrazole ring and its derivatives are recognized in the literature as important biologically
active heterocyclic compounds. Additionally, many pyrazole derivatives have also been used
in catalysis, functional coordination ligands, and organic light emitting diodes [5-8].
Schiff bases containing azomethine bonds (-N=C-) are usually formed via the condensation
reaction of a primary amine with an aldehyde or ketone mediated by straightforward
protocols without stringent reaction conditions and water as only by-product [9]. Substituted
Schiff bases with π-conjugation play a vital role in the development of new generation of
electronic and photonic devices due to delocalization of electrons [10].
This study describes the synthesis, characterization, and computational calculations of two
new Schiff bases, (E)-2-{[(5-(tert-butyl)-1H-pyrazol-3-yl)imino]methyl}phenol (3) and (E)-
2
-{[(1-(4-bromophenyl)-3-(tert-butyl)-1H-pyrazol-5-yl]imino]methyl}phenol (5), with the
purpose of studying structural properties by using the functional density theory (DFT)
together with B3LYP and the standard set of bases 6-31G**. In addition, calculations of the
vibrational frequencies of the optimized geometries were performed to explain the differences

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between the solid and gaseous phases of the studied compounds. The chemical shifts in their
1
13
H and C NMR spectra were calculated, as well as, the energy of the molecules to determine
the highest occupied molecular orbitals and lowest unoccupied molecular orbitals (HOMO-
LUMO, respectively) in order to calculate their UV-vis spectra. Our research group has been
interested in synthesizing aminopyrazoles [11], to be used in the formation of imino-
pyrazoles (i.e. Schiff bases) of biological and physicochemical interest. In our previous
investigations, computational studies of the Schiff base {(E)-[(3-tert-butyl-1-phenyl-1H-
pyrazol-5-yl)imino]methyl}phenol [12] were performed. Now, in this work, we wish to
compare and discuss some physicochemical properties, like hardness, softness, and
electronegativity between two new synthesized Schiff bases.
2
. Experimental
2
.1. Analytical and physicochemical measurements
All chemicals and solvents used (analytical grade), were purchased from Sigma-Aldrich and
Across, and used without further purification. The reactions were monitored by thin layer
chromatography (TLC) using silica gel 60 F254 (Merck) alumina plates. The melting points
were determined on a Büchi melting point apparatus. Infrared spectra were taken on a Perkin
Elmer FT 2000 series spectrophotometer using KBr disks. The NMR spectra were recorded
1
on a Bruker Advance 400 spectrophotometer operating at 400 MHz for H and at 100 MHz
1
3
for C, using DMSO-d as solvent and tetramethylsilane as internal standard. Chemical shifts
6
(δ) are in ppm and the coupling constants (J) are in Hertz (Hz). The mass spectra were
obtained on a SHIMADZU-GCMS 2010-DI-2010 spectrometer equipped with a direct input
probe operating at 70 eV. The UV-Vis absorption spectra were obtained in a range of 200-
6
00 nm using a Shimadzu UV-Vis 160 spectrophotometer. Microanalyses were performed on
an Agilent CHNS elemental analyzer.
2
2
.2. Synthesis
.2.1. Synthesis of aminopyrazole

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2
.2.1.1. The 5-(tert-butyl)-1H-pyrazole-3-amine (1) was obtained following a previously
reported procedure [13]. Thus, in a test tube, a mixture of 4,4-dimethyl-oxopentanenitrile (1.0
g, 7.9 mmol) and hydrazine monohydrate (0.443 g, 8.66 mmol) was placed. The solvent-free
mixture was heated at 130 °C until complete consumption of the starting materials, affording
a white solid in 98% yield. No further purification was required.
2
.2.1.2 The 1-(4-bromophenyl)-3-(tert-butyl)-1H-pyrazol-5-amine (4), was prepared, as
described in the literature [14]. To a concentrated hydrochloric acid solution (3.8 mL) in
water (33 mL) was added (4-bromophenyl)hydrazine (2.12 g, 11.41 mmol) and 4,4-dimethyl-
3
-oxopentanenitrile (1.85 g, 14.79 mmol). The mixture was heated at 70 °C for 1 h, then,
additional concentrated hydrochloric acid (3.8 mL) was added and the mixture was heated for
one additional hour. After cooling, crushed ice was added and the mixture was neutralized
with concentrated ammonium hydroxide. The resulting solid was filtered under reduced
pressure, washed with cold water (3×5 mL). The starting precursor 2 was obtained in 86%
yield as a light brown solid. No further purification was required.
2
.2.2. Synthesis of the compounds 3 and 5
A mixture of the aminopyrazole (1 or 4) (1.44 mmol), 2-hydroxybenzaldehyde (2) (1.44
mmol) and glacial acetic acid (5 drops) was stirred for 10 min at room temperature. After the
reaction was complete (monitored by TLC), the crude solid formed was washed with cold
water (5 × 20 mL) and filtered under vacuum to dryness, affording the compounds 3 as a
yellow solid in 96% yield and 5 as a beige solid in 97% yield. Single-crystals of compounds 3
and 5, suitable for X-ray diffraction (XRD), were grown by slow evaporation of a CH Cl2
2
solution at room temperature. The synthetic procedures for compounds 3 and 5 are shown in
Scheme 1 and Scheme 2, respectively.
Insert Scheme 1.
Insert Scheme 2.
(E)-2-{[(5-(tert-Butyl)-1H-pyrazol-3-yl)imino]methy}phenol (3)
Anal. Cal. for C H N O: %C 69.11, %H 7.04, %N 17.25. Found: %C 69.22, %H 7.08, %N
1
4
17
3
+
+
+
1
7.31. M.p. 197-199 °C. MS (70 eV) m/z (%) 243 [M ] (100), 226 [M -17] (92.33), 228 [M -
+
-1
1
5] (14.75), 186 [M -57] (1.40) (see Supp. Inf. S1, S2). IR (KBr, cm ) νN-H 3140

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1
(
pyrazole), ν C-H 3085 (pyrazole), ν –CH 2957, ν –CH 2857, ν –C=N 1607. H NMR
as 3 s 3
(
400 MHz, DMSO-d , δ in ppm) 1.31 (s, 9H, tBu-H); 6.33 (s, 1H, H-9); 6.97 (m, 2H, H-3 and
6
3
3
H-5); 7.40 (t, 1H, J = 7.49 Hz, H-4); 7.62 (d, 1H, J =7.61 Hz, H-6); 9.07 (s, 1H, H-7); 12.61
1
3
(
bs, 1H, OH); 13.23 (bs, 1H, NH). C NMR (100 MHz, DMSO-d , δ in ppm) 30.3 (tBuC);
6
3
1
1.3 (C-11); 92.2 (C-9); 117.0 (C-3); 119.6 (C-5); 119.8 (C-8); 132.7 (C-6); 133.3 (C-4);
54.7 (C-10); 156.0 (C-1); 160.7 (C-2); 162.4 (C-7). The atoms were numbered according to
Figure 1 (compound 3). UV-Vis in MeCN, λ max nm, (log ε): λ 194 (4.42), λ 217 (4.36),
1
2
λ 231 (4.19), λ 281 (4.22), λ 307 (4.23), λ 338 (4.26).
3
4
5
6
(E)-2-{[(1-(4-Bromophenyl)-3-(tert-butyl)-1H-pyrazol-5-yl]imino]methyl}phenol (5)
Anal. Cal. for C H N OBr: %C 60.31, %H 5.06, %N 10.55. Found: %C 60.18, %H 5.11,
2
0
20
3
+
%
N 10.68%. M.p: 140-142 °C. MS: (70 eV) m/z (%) 399 (M+2, 98), 397 (M , 100), 384
+
+
-1
(
M -15, 60), 382 (M -15, 81), 359 (24), 357 (26) (see Supp. Inf. S3, S4). IR (KBr, cm ) ν C-
H 3119 (pyrazole), ν C-H 3054 (aromatic), ν –CH 2955, ν –CH 2861, ν-C=N 1604, ν-C-
as
3
s
3
1
Br 749. H NMR (400 MHz, DMSO-d , δ in ppm) 1.34 (s, 9H tBu-H ); 6.70 (s, 1H, H-9);
6
3
3
3
6
7
9
.95 (d, 1H, J = 8.3 Hz, H-3); 7.00 (t, 1H, J = 7.5 Hz, H-5); 7.45 (t, 1H, J = 8.0 Hz, H-4);
.63 (d, 2H, J = 8.8 Hz, H-16); 7.69 (d, 1H, J = 1.6 Hz, H-6); 7.74 (d, 2H, J = 8.81 Hz, H-17);
1
3
.13 (s, 1H, H-7); 11.60 (bs, 1H, OH); C NMR (100 MHz, DMSO-d , δ in ppm) 30.6
6
(tBuC); 32.7 (C-11); 92.0 (C-9); 117.2 (C-3); 120.1 (C-5); 120.2 (C-15); 120.3 (C-1); 126.5
(C-16); 132.0 (C-6); 132.4 (C-17); 134.5 (C-4); 138.6 (C-18); 149.0 (C-8); 160.1 (C-2); 162.5
(C-10); 163.0 (C-7). The atoms were numbered according to Figure 1 (compound 5). UV-
Vis in MeCN, λ max nm, (log ε): λ 195 (4.79), λ 205 (4.92), λ 236 (4.62), λ 280 (4.21), λ
1
2
3
4
5
3
11 (4.23), λ 325 (4.34), λ 360 (4.3).
6
7
2
.3. X-ray crystal structure determination
Crystal data for compounds 3 and 5 were deposited at CCDC with the reference number CCD
1
884085 and 1883927 respectively.
Insert Table 1.
3
. Computational study

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Theoretical calculations were determined in the gas phase and in the approximation of the
isolated molecule. Molecular optimization, harmonic vibration frequencies, and energy values
were calculated by using the DFT computational method, incorporating the Beck's three-
parameter exchange coupled with B3LYP correlation functional density hybrid with the base
set 6-31G** and the Gaussian packet 09 [15] without any obstacle to geometry. Nuclear
magnetic resonance calculations were carried out to quantify the chemical shifts of protons
with the gauge-independent atomic orbital (GIAO) method.
The molecular visualization software was used for the vibration frequencies where they were
analyzed in terms of potential energy distribution (PED), using the VEDA 4 program [16],
and the contribution percentage of the border orbitals in each transition of the electron
absorption spectra was performed by using The GaussSum program [17]. The frequencies and
bond lengths found in DFT methods provided good results compared to the experimental
values.
4
. Results and Discussion
4
.1. Structural analysis
Table 2 shows that the parameters of the optimized structures of compounds 3 and 5
calculated by the DFT/B3LYP method agree well with experimental data obtained through
XRD. The numbering of the atoms is given in Figure 2. The relation between calculation and
experimental data was obtained by linear function formula (see supplementary data, Figure
S5).
Insert Table 2.
For most bond distances and bond angles, the calculated values were very close to the
experimental ones and did not present significant deviations, as observed in Table 2.
Significant differences were observed in O-H and N-H bonds, which are associated with fact
that, in the solid state the experimental results are related to molecular packing, where
hydrogen bonds are relevant, while isolated molecules in gas phase are considered for
theoretical calculations (i.e. no hydrogen bonds are present). Moreover, in the solid state, it is

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observed that the presence of a crystal field together with the intermolecular interactions
connects the molecules together, giving rise to the variance in the binding parameters
between the calculated and experimental values [18].
Insert Figure 1.
Insert Figure 2.
4
.2 Supramolecular features
The projection of the molecular structure, generally related to atoms and covalent bonds,
towards a level dominated by non-covalent interactions should lead to the use of new rules
governing these structures, their dynamics, transformations and properties of molecular
assemblies. It is therefore interesting to undertake a supramolecular study of compounds 3
and 5 to find the non-covalent relationships governing each molecular structure[19].
4
.2.1 Compound 3
The relatively high directionality and strength of hydrogen bonds can predict, in certain
organic compounds, their orientation and behavior during the crystalline growth process. This
system has intra-intermolecular hydrogen bonds in its crystalline growth. An intramolecular,
relatively strong, O1-H1...N1 hydrogen bond [20] is observed and this allows to
approximately maintaining the planarity of the phenol ring with the central segment as shown
in Figure 3.
A relatively strong intermolecular hydrogen bond N3-H1H...N2 is observed. The N3 atom in
the molecule at (x,y,z) acts as hydrogen bond donor to the N2 atom of the pyrazole ring in the
molecule at (y+1/4,-x+3/4,-z+7/4). At the same time, two relatively weak intermolecular
hydrogen bonds are observed. The C7-H7 and C9-H9 groups in the molecule at (x,y,z) act as
hydrogen bond donors to the O1 atom in the molecule at (-y+1/4,+x-1/4,+z-1/4) (Table 3).
These interactions permitted to observe an arrangement with a fascinating architecture,
1
5
1
involving the formation of R
(81) synthons, facilitating crystalline system growth in the b
4
direction (see Figure 3).

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Insert Figure 3.
o
The central segment C1-C7-N1-C8 forms a dihedral angle with the phenol ring of 2.83 (10)
o
and with the pyrazole ring of 5.78 (12) .
4
.2.2 Compound 5
This system has a relatively strong intramolecular O1-H1H ... N1 hydrogen bond, similar to
the intramolecular bond presented in the compound 3 system, which enables observing a
planarity between the phenol ring and the central C1-C7-N1-C8 segment. Additionally, a
relatively weak C7-H7...N3 bond is observed. The C7-H7 group in the molecule at (x,y,z)
acts as hydrogen bond donor to the N3 atom of the pyrazole ring in the molecule at (x,-
y+3/2,z+1/2) as shown in Figure 4 (Table 3). The central segment forms dihedral angles with
o
o
the phenol and pyrazole ring of 4.36 (15) and 12.75 (16) , respectively. This segment,
o
additionally, forms a dihedral angle of 58.44 (6) with the bromophenol ring (see Figure 4
and Table 3).
Insert Figure 4.
4
.3 Vibrational assignments
Table 4 lists the wave numbers of the bands observed in the FT-IR spectra of the compounds
and 5. The theoretical frequencies and infrared intensities were calculated by the
DFT/B3LYP method.
3
Insert Table 4.
The experimental vibrational FT-IR spectra for 3 and 5 (Figure 5) shows the vibration
-1
frequencies due to asymmetric -CH stretching at 2964 cm and symmetrical -CH stretching
3
3
-1
at 2861 cm , corresponding to tert-butyl group for compound 3. For compound 5 it is
-1
-1
observed the -CH stretching at 2958 cm and symmetrical -CH stretching at 2861 cm .
3
3
-1
Stretching of the imine group -C=N is observed at 1614 and 1604 cm for compounds 3 and
-1
5
, respectively. The N-H absorption band of compound 3 is observed at 3143 cm . The

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characteristic band of the hydroxyl group does not appear in the IR of both compounds; this
finding could be attributed to the formation of intramolecular hydrogen bonding between the
nitrogen atom of the imine (N1) and the hydrogen of the hydroxyl (O1-H) group.
Comparison of the calculated frequencies, B3LYP with the experimental values, reveals
overestimation of the vibration modes calculated due to the neglect of the harmonicity in the
real system. Correction of the methods was performed according to Cruz et al. [21], Scale
factor for the described method (DFT-B3LYP/6-31G**) was 0.960461 . For the assignment
of frequencies, the VEDA 4 program was used.
Figure 5 shows the calculated (with DFT) and experimental spectra for compounds 3.and 5.
Figure S6 (see supplementary data), shows correlation curves between the calculated and
2
2
experimental data, where correlation coefficients (R ) = 0.9993 for 3, and (R ) = 0.9988 for 5
indicates that the results of the theoretical method provide an excellent fit to the experimental
values.
Insert Figure 5.
4
.3.1. N-H Stretching
-1
The N-H stretching band usually appears in the 3220-3100 cm region [22]. In the
-1
experimental IR spectrum of compound 3 this absorption band was observed at 3143 cm .
-1
This vibration was also calculated by B3LYP obtaining a value of 3530 cm . These results
are consistent with those reported in the literature by Tanis et al., [23].
4
.3.2. O-H and C-OH vibrations
It has been shown that the frequency of the absorption vibration of the O-H group in the gas
-1
phase is approximately 3657 cm [24-25]. The vibration of the OH functionality was not
observed in the experimental spectra of compounds 3 and 5 due to a widening of the band
[
24], attributed to aforementioned intramolecular hydrogen bond. The calculated values for 3
-1
and 5 are shown at 3029 and 3161 cm , respectively. The difference appears as a result of the
theoretically calculated values that do not consider the Coulombian attraction generated by

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the imino-nitrogen atom over the phenolic hydrogen that avoids vibration of the bond, which
is consistent with a strong intramolecular hydrogen bond reported by Harold et al., [26]. Binil
et al., [27] reported the vibration of the C-OH bond for [4-butyl-1-(4-hydroxyphenyl)-2-
-1
phenyl-3,5-pyrazolydinedione] at 1211 cm ; in this study this vibration is observed in the
-1
experimental IR spectra of 3 and 5 at 1213 and 1283 cm , respectively, agreeing with that
reported by us recently [28].
4
.3.3. Aromatic stretching
An aromatic moiety usually is recognized in IR by the presence of C-H vibration-stretching in
-1
the 3100-3000 cm [29] region and these vibrations are not generally affected by the ring
substitution [29]. In our study, the experimental frequency of C-H stretching appears at 3091
-1
-1
cm for compound 3 and at 3058 cm for compound 5. These frequencies matches with the
-1
-1
calculated values at 3089 cm for 3 and 3081 cm for 5.
4
.3.4. tert-Butyl C-H stretching
-1
The stretching vibration of aliphatic C-H bonds appear below 3000 cm [30]. The theoretical
-1
spectra show these vibrations at 3003 and 2926 cm for compound 3 and at 2983 and 2963
-1
3
cm for compound 5. These signals are related to the asymmetric and symmetrical sp (CH)
vibrations. The C-H stretching frequencies of the tert-butyl group in the experimental spectra
-1
-1
were observed at 2964 and 2861 cm for compound 3 and at 2958 and 2861 cm for
compound 5.
4
.3.5. C-C Stretching
The C=C vibrations of the aromatic ring are generally found in the region of 1650 and 1400
-1
-1
cm [31]. These absorptions bands are observed at 1571 and 1567 cm in the experimental
-1
spectra of both compounds while the calculated values appear at 1550 and 1540 cm for
compound 3 and 5 respectively.
4
.3.6. C=N and C-N Vibrations

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-1
The strong bands appearing in the region of 1614 and 1604 cm in the experimental spectra
of compounds 3 and 5, respectively, are attributed to their C=N bonds, which are
characteristic absorption bands of Schiff-base derivatives [32]. These bands appear in the
-1
-1
theoretical spectra at 1611 cm for compound 3 and at 1598 cm for compound 5.
In general, identification of the C-N vibration is a difficult task, given that in this region (i.e.
-1
1
600-1000 cm ) [33], it can be mixed with other bands (fingerprints region); however, C-N
stretching assignments are identified by the application of the GaussView graphical interface
-1
[
34]. The C-N stretching absorbs in the range of 1382-1266 cm [35]; in the experimental
-1
-1
spectra, this band appeared at 1279 cm for compound 3 and at 1381 cm for compound 5. In
-1
-1
the theoretical spectra the same bands appear at 1405 cm and 1433 cm , respectively.
4
.4. NMR studies
The nuclear magnetic resonance (NMR) spectrum is frequently used to analyze each H and C
atom in different chemical environments of the target compound [36]. DFT Theory level
optimization with the base 6-31G** and GIAO method were used to calculate the chemical
1
13
shifts of H and C NMR [37], of compounds 3 and 5.
1
13
The experimental and theoretical chemical shifts of H and C in DMSO-d as solvent are
6
1
shown in Table 5, (the atoms were numbered according to Figure 2). The experimental H
1
3
and C spectra of the studied molecules 3 and 5 are shown in Supp. Inf. S7, S8 for compound
3
and Supp. Inf. S9, S10 for 5, respectively.
Insert Table 5.
1
4
.4.1. H NMR
1
1
The experimental H NMR spectra have good correlation with the theoretical H NMR. The
2
1
correlation coefficient (R ) found for H NMR chemical shifts was 0.9983 for compound 3
1
and 0.9966 for compound 5 (Supp. Inf. S11). In the experimental H NMR spectra of
compounds 3 and 5 appears 8 and 9 signals that integrate for seventeen and twenty protons,
respectively.

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Usually the chemical shifts of aromatic protons in organic molecules are observed in the
1
range of 7.00-8.00 ppm. In the experimental H NMR spectra, chemical shifts of aromatic
protons appears in the range 6.95-7.61 ppm for compound 3 and 6.95-7.73 ppm for 5 while,
1
the calculated H NMR afforded chemical shifts in the range of 7.07-7.64 ppm for compound
3
and 7.08-8.06 ppm for 5. Thus, both experimental and calculated values agree with the
expected common chemical shifts range (i.e. 7.00-8.00 ppm).
The azomethyne protons appear at 9.07 and 9.12 ppm in the experimental spectra of
compounds 3 and 5, respectively, which is consistent with this type of protons in Schiff bases
(HC=N) [40-41]. These signals are observed in the theoretical spectra at 8.94 and 8.90 ppm
for compounds 3 and 5 respectively, in a very good agreement between both studies. At 13.23
and 11.61 ppm appears broad singlets in the experimental spectra of compounds 3 and 5,
respectively, assigned to protons of the -OH functionality. In the theoretical spectra these
signals appears at 13.45 and 12.45 ppm, respectively. Particularly, in compound 5 there is a
good correlation between the experimental and theoretical values. However, an appreciable
discrepancy is observed in compound 3, the N-H proton appear at 12.61 ppm in the
experimental and 9.42 ppm in theoretical NMR. This finding could be associated with a
major solvent effect (i.e. the polar DMSO) in compound 3 compared with compound 5 due
the presence of two protic N-H and O-H hydrogen atoms.
1
3
4
.4.2. C NMR
13
Taking into account that the C NMR chemical shifts interval for analogous aromatic organic
molecules is usually >100 ppm [38-39], the accuracy between calculated and experimental
spectra ensures reliable interpretation of spectroscopic parameters [38]. In consequence, our
2
13
(
R ) of calculated C NMR chemical shifts was 0.9991 for compound 3 and 0.9907 for
compound 5 (Supp. Inf. S12). Twelve signals for fourteen carbon atoms and sixteen signals
1
3
for twenty carbon atoms are observed in the experimental C NMR spectra for compounds 3
and 5 respectively. The aromatic carbons give signals in the overlapped areas of the spectrum
with chemical shift values from 100 to 150 ppm [42]; Similarly, chemical shifts were
observed in the values calculated between 102 to 147 ppm for compound 3 and 102 to 148 for
compound 5, while the chemical shifts in the experimental values were observed between 117

ACCEPTED MANUSCRIPT
to 160 ppm for compound 3 and 117 to 162 ppm for compound 5. The carbon atom signal of
the azomethine functionality is observed at 162.43 and 162.49 ppm in the experimental
spectra of compounds 3 and 5, respectively, consistent with that reported in the literature [37],
whereas the theoretical calculations showed these signals at 145.80 and 147.73 ppm.
1
13
In general, the experimental results of H and C NMR with the level DFT/6-31G**
represent a good approximation to the data observed experimentally.
4
.5. Electronic properties
The electronic absorption spectra of compounds 3 and 5 were measured in acetonitrile
solution and were compared with the calculated spectra at time dependent DFT (TD-DFT)
calculations based on the optimized molecular structure, as shown in Figure 6.
The theoretical calculations for compound 3 predicts an electronic transition of 3.699 eV with
an oscillator strength of
ƒ = 0.480 at 335 nm, showing good agreement with the measured
experimental data (338 nm) is assigned to the π→π* transition within the -C=N azomethine
group [43-46]. The calculations also predicted electronic transitions at 291 nm (4.260 eV),
which is equivalent to experimental absorption band at 293 nm. In compound 5 the theoretical
calculations predicted an electronic transition of 3.399 eV with an oscillator strength of
ƒ =
0
.496 at 364 nm, showing good agreement with the measured experimental data (360 nm) is
assigned to the π→π* transition within the -C=N azomethine group [43-46].
Insert Figure 6.
In the UV–Vis spectra of compounds 3 and 5, The remaining three absorption bands at
93/195, 216/205, and 231/236 nm for compounds 3/5, respectively, are assigned to π→π *
1
transitions associated to the aromatic rings (pyrazole and OH-phenyl) [28].
Insert Table 5.
4
.6. Molecular electrostatic potential (MEP)
The molecular electrostatic potential (MEP) was investigated through DFT-B3LYP
theoretical calculations at the 6-31G** level. The MEP mapping is very useful in the

ACCEPTED MANUSCRIPT
investigation of the molecular structures with their physicochemical property relationships
[
47–50]. The color scheme for the MEP surface is: red (partially negative charge or electron
rich); blue (partially positive charge or electron deficient); yellow (slightly electron rich
region); and light blue (slightly electron deficient region), respectively. The potential
increases in the order of red < orange < yellow < green < blue [50]. As shown in the MEP of
the title molecule 5 (Figure 7), regions with negative potential are on the electronegative
atoms (nitrogen atom of the pyrazole moiety and oxygen atom of the hydroxyl group that
offer on its surface a potential of -30.073 and -27.842 Kcal/mol respectivelly). Positive region
was found on the hydrogen atom of the imine group, offering a potential of 24.538 Kcal/mol
on its surface, indicating that this site may most likely be involved in nucleophilic processes.
From the MEP, it can be inferred that these compounds can be used as ligands in palladium or
platinum complexes, which can be coordinated through the N-3 in compound 3 and N-18 in
compound 5 and not by the azomethyne C=N moieties.
Insert Figure 7.
4
.8. Global reactivity descriptor
Increased LUMO energy level and decreased HOMO energy level results in higher HOMO-
LUMO gap. Higher HOMO-LUMO gap corresponds to higher kinetic stability, thus, lower
chemical reactivity [45-47]. That is, a small interval between HOMO-LUMO implies low
kinetic stability and high chemical reactivity, as it is energetically favorable to add electrons
to a LUMO and to extract electrons from a HOMO. The HOMO-LUMO energy of the
compound 3 is 4.15 eV and the HOMO-LUMO energy of the compound 5 is 3.92 eV, as
shown in Figure 8, whereby it can be inferred that compound 3 has higher stability while
compound 5 has higher reactivity. Among many others, the energy difference between
HOMO and LUMO has been used to predict the activity and intramolecular charge transfer in
organic molecules with conjugated π bonds [51-52].
Insert Figure 8.
The quantum chemical properties led us to know how to find the energy states of the
molecules. Chemical bonds are a source of energy and the movement of molecules in the
space is kinetic energy. The vibrations and rotations of molecules is another source of
chemical energy along with the chemical reaction, which is a rearrangement of atoms.

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Density functional theory has been successful in providing insights into the chemical
reactivity and selectivity in terms of global parameters, like electronegativity, hardness, and
softness [53].
The concept of hardness/softness is related to the reactivity of the molecules and it is a
property that measures the extent of chemical reactivity to which the addition of a charge
stabilizes the system. The chemical potential provides a global reactivity index and is related
to charge transfer from a system of higher chemical potential to one of lower chemical
potential. Electronegativity is the power to attract electrons and it is related directly to all
above properties mentioned. All these properties are defined as follows [54-55]. The
electrophilicity index is a measure of decrease in total energy during electron sharing [56].
The ionization potential (IP) and electron affinity (EA) can be calculated from the HOMO
and the LUMO energies using Koopmans' approximation, where IP = - HOMO and EA = -
LUMO: the chemical potential ꢀ and χ are defined as [54]:
ꢁ
ꢂ + ꢃꢄ
2
−
µꢀ ≈ χꢀ =
The larger the HOMO-LUMO energy gap, the harder the molecule will be [57]. Chemical
hardness can be calculated as follows:
ꢁ
ꢂ − ꢃꢄ
2
ꢅ =
Global softness is the inverse of global hardness [58]:
1
ꢆ =
η
Parr et al., [55] introduced the global electrophilicity index (ω), which measures the
propensity of a species to accept electrons. It can be calculated by using the electronic
chemical potential (µ) and chemical hardness (η):
ꢀ
ꢀꢈ
η
ꢇ =
2

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Molecules with a large HOMO-LUMO energy gap are called “hard” and those with a small
HOMO-LUMO energy gap are called “soft”. Frontier orbitals (HOMO – LUMO) of the
compounds 3 and 5 were calculated by using B3LYP/6-31G**. The hardness vs softness of
the title compounds are compared in order to obtain a better knowledge of the effect of the
substituents on their pyrazole rings. The HOMO-LUMO energy gap, electronegativity,
electrophilicity index, and chemical hardness and softness values of compounds 3 and 5 are
listed in Table 7.
Insert Table 7.
Compound 3 has 2.08 hardness, being harder than compound 5 (1.96), so it has a lower
electronegativity, indicating that the molecule is relatively hard so it tends to undergo changes
or reactions easily [54]. A molecule with a small frontier orbital gap is more polarizable and
is generally associated with a high chemical reactivity, low kinetic stability and is also termed
as a soft molecule [59]. Compound 5 with a smaller energy gap, with respect to compound 3,
is considered a soft molecule. The electrophilicity index (ω) is a measure of the energy
stabilization that occurs when the system acquires an additional charge from the environment.
Compound 3, have a great chemical hardness, so its electrophilicity index will be low. As
expected, 4-bromo phenyl moiety in 5 increases the electronegativity of this compound,
contributing to lower hardness and higher electrophilicity index.
5
. Conclusion
Two new pyrazolic Schiff-bases 3 and 5, were synthesized and characterized by different
1
13
spectroscopic and analytical techniques, such as FT-IR, H NMR, C NMR, DEPT 135, 2D
NMR (HSQC, HMBC), UV-Vis, MS and single-crystal X-ray diffraction. The compound 3
crystallized in the space group I41/a, while, its analogous 5 crystallized in the space group
P2 /c. The obtained data via X-ray diffraction and computational calculations indicated a
1
good correlation between experimental and theoretical data.
In order to predict the reactive sites for electrophilic and nucleophilic attacks in both
molecules, MEP´s were calculated in the optimized geometries.
The reactivity descriptors showed that compound 5 is softer than compound 3, showing that
compound 5 tends to make changes or react more easily.

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Acknowledgement
Total financial support from the Vice-Rectory of Research (Projects 789 y 920) from
Universidad del Quindío (Armenia, Colombia) is gratefully acknowledged.
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[
[
, J. Am. Chem. Soc, 121 (1999)
1
[
,
[
[
[
Pederson, A first-principles density-functional calculation of the electronic and vibrational
structure of the key melanin monomers, J. Chem. Phys. 120 (2004) 8608–8615.

ACCEPTED MANUSCRIPT
TABLES
Table 1. Crystallographic data and refinement parameters for compounds 3 and 5
Compound
Emp. Formula
FW (g/mol)
Temp. (K)
λ (Å)
Crystal system
Space group
Unit cell
ɑ (Å)
3
5
C
H
17
N
3
O
C
H
21BrN O
398.30
298
14
20
3
243.30
123
0.71073
Tetragonal
I41/a
0.71073
Monoclinic
P21/c
-
-
18.0282(5)
18.0282(5)
18.0795(9)
90
11.1456(11)
14.0544(8)
11.9729(11)
90
b (Å)
c (Å)
α (°)
β (°)
γ (°)
Volume (Å )
90
90
876.0(4)
100.321(8)
90
1845.1(3)
ꢀ
5
Z
16
1.100
0.07
4
3
ρ calcd (mg/m )
Abs.Coeff (mm )
F(000)
1.387
2.236
792
-
1
2080
ϴ range (°)
3.6 to 27
38985/3203[0.041]
3203/0/174
0.886
3.716 to 33.134
49874/7020[0.0576]
7020/0/233
1.076
Reflections collected/ Unique [R(int)]
Data/restraints/parameters
2
Gof on F
R1 [I>2σ(I)]
wR2[I>2σ(I)]
0.0517
0.1468
0.0387
0.0916

ACCEPTED MANUSCRIPT
Table 2. Optimized and experimental geometries of compounds 3 and 5 in the ground state
Compound 3
Compound 5
a
Experimental
X-ray)
DFT/B3LYP 6-
31G**(ꢀ )
a
Experimental
(X-ray)
DFT/B3LYP 6-
31G**(ꢀ )
Parameters
b
Parameters
b
(
Bond Lengths (Å)
N(5)-N(4)
C(13)-O(18)
C(13)-C(12)
C(12)-C(11)
1.352
1.349
1.391
1.377
1.375
1.379
1.283
1.335
1.404
1.349
1.512
1.507
1.550
1.514
0.876
0.894
1.347(6)
1.338(11)
1.404(13)
1.388(11)
1.404(29)
1.386(7)
1.293(10)
1.337(2)
1.426(22)
1.367(18)
1.516(4)
1.547(40)
1.547(3)
1.539(25)
0.999
C(34)-O(44)
C(34)-C(22)
C(22)-C(35)
C(35)-C(36)
C(36)-C(39)
C(39)-C(38)
C(22)-C(21)
N(21)-C(20)
N(5)-N(6)
1.343
1.396
1.394
1.379
1.373
1.342
1.444
1.275
1.374
1.322
1.414
1.345
1.430
1.356
1.388
1.368
1.352
1.510
1.540
1.546
1.515
1.341(2)
1.425(29)
1.411(17)
1.385(6)
1.404(31)
1.388(46)
1.444(0)
1.298(23)
1.359(15)
1.336(14)
1.411(3)
1.379(34)
1.420(10)
1.399(43)
1.394(6)
()C(11)-C(10)
C(10)-C(9)
C(7)-N(6)
C(3)-N(4)
C(3)-C(2)
C(1)-N(5)
C(1)-C(19)
C1(9)-C(25)
C(19)-C(26)
C(19)-C(24)
H(23)-O(18)
H(21)-N(5)
C(2)-N(6)
C(2)-C(1)
C(3)-N(5)
C(5)-N(24)
C(31)-C(24)
C(31)-C(30)
C(30)-C(28)
C(28)-C(26)
C(2)-C(7)
C(7)-C(10)
C(7)-C(8)
C(7)-C(9)
1.007
1.392(24)
1.394(42)
1.522(12)
1.545(5)
1.539(7)
1.545(30)
y=0.9081x+0.1441
0.9382
Linear function formula
y=0.8333x+0.2482 Linear function formula
0.9824
2
2
R
R
Bond angles (°)
O(18)-C(13)- C(8)
120.90
122.11
C(22)-C(34)-O(44) 122.42
122.15

ACCEPTED MANUSCRIPT
C(12)-C(13)-O(18) 119.11
C(11)-C(12)-C(13) 120.09
C(10)-C(11)-C(12) 120.61
118.66
120.34
121.03
119.05
111.37
114.22
122.41
109.69
109.70
109.60
107.41
118.35
C(35)-C(22)-C(34) 117.50
118.81
121.37
119.10
121.05
121.60
122.43
105.93
110.96
121.51
119.97
119.53
120.94
119.78
109.06
110.37
C(36)-C(35)-C(22) 121.68
C(35)-C(36)-C(39) 118.68
C(36)-C(39)-C(38) 122.23
C(21)-C(22)-C(34) 122.11
N(20)-C(21)-C(22) 121.54
C(11)-C(10)-C(9)
C(2)-C(3)-N(4)
C(1)-N(5)-N(4)
C(19)-C(1)-N(5)
C(25)-C(19)-C(1)
C(26)-C(19)-C(1)
C(24)-C(19)-C(1)
119.85
111.43
112.70
122.21
108.75
109.63
109.30
C(2)-N(6)-N(5)
C(1)-C(2)-N(6)
C(31)-C(24)-N(5)
105.49
110.81
120.45
C(24)-C(31)-C(30) 120.21
C(31)-C(30)-C(28) 118.83
C(30)-C(28)-C(26) 120.89
H(23)-O(18 )-C(13) 107.45
H(21)-N(5)-N(4)
118.99
C(7)-C(2)-N(6)
C(10)-C(7)-C(2)
C(8)-C(7)-C(2)
120.63
110.16
109.11
a
The atom numbering scheme of the molecular structure is given in Figure 2.
Deviation from experimental and calculated data.
b

ACCEPTED MANUSCRIPT
Compound D-H…A
D-H
H…A
1.78(3)
1.98(2)
2.38(2)
2.39
D…A
D…H…A
Compound 3 O1-H1HꢀꢀꢀN1 0.87(3)
2.5734(18) 150.0(3)
2.8671(18) 171.3(18)
i
N3-H31ꢀꢀꢀN2
0.89(2)
1.01(2)
0.95
ii
C7-H7ꢀꢀꢀO1
3.3710(2)
3.3020(2)
167.2(16)
161.0
ii
C9-H9ꢀꢀꢀO1
Compound 5 O1-H1HꢀꢀꢀN1 0.85(3)
1.90(3)
2.73(2)
2.6455(19) 145.0(3)
3.5020(2) 133.4(15)
iii
C7-H7ꢀꢀꢀN3
1.01(2)
o
Table 3. Hydrogen-bond geometry (Å. ).
Code symmetry: (i) y+1/4.-x+3/4.-z+7/4; (ii) -y+1/4.+x-1/4.+z-1/4; (iii) x.-y+3/2.z+1/2.
-1
Table 4. Assignments of vibrational wavelengths by VEDA 4 (cm ) for compounds 3 and
5
.
Compound 3
Compound 5
DFT/B3LYP
DFT/B3LYP
Assignments Experimental
Assignments Experimental
Freq
3530
3029
3089
3081
3003
2925
1611
1550
1360
1291
1222
%PED
100
98
99
99
98
98
73
44
Freq
%PED
ν
ν
ν
ν
ν
NH
OH
C-Haromatic
C-Hpyrazole
asCH
3143
-
-
-
-
-
ν
ν
ν
ν
OH
-
3161
3081
3150
2983
2963
1598
1540
1458
1392
1283
98
84
99
99
97
17
57
69
34
30
3091
3085
2964
2861
1614
1571
1363
1288
1213
C-Haromatic
C-Hpyrazole
asCH
3
3058
3118
2958
2861
1604
1567
1498
1398
1282
3
νsCH3
νsCH3
ν
ν
δ
ν
δ
C=N
ν
ν
δ
δ
ν
C=N
C-Caromatic
CH3
H-O-C
C-OH
C-Caromatic
CH3
C-OH
63
32
27
H-O-C
ν. stretching; δ. bending; s. symmetric; as. asymmetric. Potential Energy Distribution (PED).

ACCEPTED MANUSCRIPT
Table 5. NMR theoretical shifts (δTheo.) and experimental (δExp.) for compound 3,
tautomer of compound 3 and compound 5.
Compound 3
Compound 5
Exp.
1.34
a
a
Atom
H-26
H-27
H-28
H-29
H-30
H-31
H-32
H-33
H-34
H-20
H-17
H-15
H-16
H-14
H-22
H-21
H-23
-
Exp.
1.31
1.31
1.31
1.31
1.31
1.31
1.31
1.31
1.31
6.33
6.95
6.97
7.40
7.61
9.07
12.61
13.23
-
DFT
1.30
1.36
1.36
1.45
1.45
1.62
1.62
1.75
1.75
6.66
7.07
7.18
7.63
7.64
8.94
9.42
13.45
-
Atom
DFT
1.37
1.30
1.32
1.33
1.37
1.68
1.68
1.89
1.96
6.69
7.08
7.24
7.64
7.68
7.72
7.73
7.83
8.06
8.90
12.45
H-11
H-12
H-13
H-14
H-15
H-16
H-17
H-18
H-19
H-4
H-40
H-41
H-42
H-32
H-29
H-37
H-33
H-27
H-23
H-45
Linear
function
formula
C-8
1.34
1.34
1.34
1.34
1.34
1.34
1.34
1.34
6.70
6.95
7.00
7.44
7.62
7.62
7.70
7.73
7.73
9.12
11.61
-
-
-
-
-
-
Linear
function
formula
C-24
C-25
C-26
C-19
C-2
y=0.9014x+0.4573
R²=0.9983
y=1.0042x+0.1617
R²=0.9946
30.34
30.34
30.34
31.30
92.21
117.03
119.63
119.77
132.73
133.34
154.69
156.02
160.60
162.43
-
18.81
21.21
21.21
24.65
77.60
102.50
104.06
106.29
119.34
118.66
139.54
141.72
147.01
145.80
-
30.61
30.61
30.61
32.74
92.01
18.91
22.19
22.37
26.66
80.59
C-10
C-9
C-7
C-1
C-12
C-10
C-8
C-9
C-11
C-1
C-3
C-13
C-7
-
-
C-38
C-36
C-22
C-28
C-25
C-31
C-35
C-26
C-30
C-39
C-24
C-3
117.15
120.13
120.18
120.32
126.46
126.46
132.00
132.38
132.38
134.46
138.56
148.96
160.07
162.49
102.68
104.91
106.18
124.88
110.15
111.05
120.58
117.28
118.34
120.26
125.82
134.17
147.00
148.45
-
-
-
-
-
-
-
-
-
-
-
C-34
C-2

ACCEPTED MANUSCRIPT
-
-
-
C-21
162.95
147.73
Linear
function
formula
y=0.9535x–8.1405
R²=0.9991
y=0.9554x-7.0467
R²=0.9900
a
The atom numbering scheme of the molecular structure is given in Figure 2.