Structural characterization of benzoyl-1H-pyrazole derivatives obtained in lemon juice medium: Experimental and theoretical approach

Article abstract of DOI:10.1016/j.molstruc.2019.05.095

Simple, one-pot, and low-cost reactions of acetylacetone with a variety of substituted benzoyl hydrazides in lemon juice, as eco-friendly medium, were performed. In reactions of benzoyl hydrazides with electron-donating groups on phenyl ring, the 1-benzoy

Full text of DOI:10.1016/j.molstruc.2019.05.095

Accepted Manuscript
Structural characterization of benzoyl-1H-pyrazole derivatives obtained in lemon juice
medium: Experimental and theoretical approach
Vesna Milovanović, Zorica D. Petrović, Slađana Novaković, Goran A. Bogdanović,
Dušica Simijonović, Vladimir P. Petrović
PII:
S0022-2860(19)30665-9
DOI:
https://doi.org/10.1016/j.molstruc.2019.05.095
MOLSTR 26602
Reference:
To appear in: Journal of Molecular Structure
Received Date: 6 March 2019
Revised Date: 10 May 2019
Accepted Date: 22 May 2019
Please cite this article as: V. Milovanović, Z.D. Petrović, Slađ. Novaković, G.A. Bogdanović, Duš.
Simijonović, V.P. Petrović, Structural characterization of benzoyl-1H-pyrazole derivatives obtained in
lemon juice medium: Experimental and theoretical approach, Journal of Molecular Structure (2019), doi:
https://doi.org/10.1016/j.molstruc.2019.05.095.
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Graphical abstract
Structural characterization of benzoyl-1H-pyrazole derivatives obtained in
lemon juice medium: experimental and theoretical approach
Vesna Milovanović,a Zorica D. Petrović,*a Slađana Novaković,b Goran A. Bogdanović,b Dušica
Simijonovića, and Vladimir P. Petrovića
aUniversity of Kragujevac, Faculty of Science, Department of Chemistry, R. Domanovića 12, 34000
Kragujevac, Serbia.
bVinča Institute of Nuclear Sciences, University of Belgrade, P.O. Box 522, 11001 Belgrade, Serbia.
Corresponding author: *Z. Petrović: tel.: +381-34-336-223; +381-34-335-039; e-mail:
zorica.petrovic@pmf.kg.ac.rs

ACCEPTED MANUSCRIPT
Structural characterization of benzoyl-1H-pyrazole derivatives obtained in
lemon juice medium: experimental and theoretical approach
Vesna Milovanović,a Zorica D. Petrović,*a Slađana Novaković,b Goran A. Bogdanović,b Dušica
Simijonovića, and Vladimir P. Petrovića
aUniversity of Kragujevac, Faculty of Science, Department of Chemistry, R. Domanovića 12, 34000
Kragujevac, Serbia.
bVinča Institute of Nuclear Sciences, University of Belgrade, P.O. Box 522, 11001 Belgrade, Serbia.
Abstract
Simple, one-pot, and low-cost reactions of acetylacetone with a variety of substituted benzoyl
hydrazides in lemon juice, as eco-friendly medium, were performed. In reactions of benzoyl
hydrazides with electron-donating groups on phenyl ring, the 1-benzoyl-1H-pyrazole derivatives
were obtained in short reaction time, and in good to high yields. On the other hand, benzoyl
hydrazides with electron-withdrawing groups reacted slower, yielding the mixture of 1-benzoyl-
5-hydroxy-4,5-dihydro-1H-pyrazole and benzoyl-1H-pyrazole derivatives. It is worth pointing
out that two products, (2-chlorophenyl)(4,5-dihydro-5-hydroxy-3,5-dimethylpyrazol-1-
yl)methanone and (4-iodophenyl)(3,5-dimethyl-1H-pyrazol-1-yl)methanone are reported here for
the first time. All obtained compounds were characterized using IR, UV-Vis and NMR,
experimentally and theoretically, as well as with melting points. Good agreement between
1
13
experimental and simulated IR, UV-Vis, H and C NMR spectra was achieved. In addition,
crystal structures and Hirshfeld surfaces analysis of (4,5-dihydro-5-hydroxy-3,5-
dimethylpyrazol-1-yl)(4-iodophenyl)methanone were reported.
Keywords: Spectral characterisation, Crystal structure, Density functional theory, Green
synthetic procedure
Corresponding author:
*Z. Petrović: tel.: +381-34-336-223; +381-34-335-039; e-mail: zorica.petrovic@pmf.kg.ac.rs
1. Introduction
Nitrogen-containing heterocycles attract the attention of the researchers during
decades. These compounds present very interesting pharmacophores and building blocks
for compounds with biological or clinical interest. Heterocycles with pyrazolo moiety are
often an integral part of medically interesting compounds. Pyrazolo-containing
heterocycles have been applied as commercially available drugs such as Celecoxib (anti-
inflamatory
drug),[1]
Zoniporide
(cardioprotective
drug),[2]
Fezolamine
(antidepressant).[3] In addition, these compounds express antimicrobial,[4,5]
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antiproliferative,[6,7]
antitubercular,[8]
antiangiogenic,[9]
analgesic,[7,10]
anticonvulsant,[11] hypoglycemic,[12] anxyolitic,[13] and antiviral activity.[14,15]
According to their multifaceted activities, compounds with pyrazolo moiety are
constituents of agro-chemicals, such as herbicides (pyrazolynate, topramezone,
azimsulfuron), fungicides (furametpyr, bixafen, pyraclostrobin), insecticides (fenpiclonil,
tricyclazole, fipronil).[16] The pyrazoles are important intermediates in organic
chemistry[17] and useful ligands in coordination chemistry.[18,19] As one of the most
flexible nitrogen donor heterocycles, pyrazoles can be easily incorporated into
polydentate ligand structures.[18,20] There are several methods for the synthesis of
pyrazoles, such as: reaction of chalcones and hydrazines,[21,22] coupling of hydrazine,
aldehyde and ethyl acetoacetate,[23] the Knorr hydrazine condensation with 1,3-
dicarbonyles or their derivatives,[24–29]. In addition, Suzuki–Miyaura cross-coupling
reactions are powerful tool for the synthesis of pyrazole derivatives.[30] These reactions
are often performed at elevated temperature in organic solvents, and in the presence of
different harmful catalysts.[28–31]
Many analytical techniques, such as NMR, IR, UV-ViS, X-ray, ESI-MS, etc., as well as
quantum chemical calculations, have been developed to elucidate physico-chemical
properties of these compounds. Further, Hirshfeld surface analysis (HSA) is a powerful
tool for the analysis of intermolecular interactions within their crystal packing. [21,32,33]
Herein, we report a simple and low-cost protocol, where freshly squeezed lemon juice
was used as catalyst and solvent in one-pot synthesis of benzoyl-1H-pyrazole derivatives.
1
All synthetized compounds were experimental characterized using IR, UV-Vis, H and
13C NMR spectroscopy. Density functional theory (DFT) was used to perform the
geometry optimization and calculations of the NMR, IR, and UV-Vis electronic spectra of
the investigated compounds. X-ray determination and analysis of Hirshfeld surfaces in the
solved crystal structure were presented, also. To the best of our knowledge, the literature
fails with data related to the usage of lemon juice, as natural, recyclable and eco-friendly
medium for their synthesis,[34,35] as well as data for synergistic experimental and
theoretical approach to the elucidation of their structure.
2. Experimental
All the chemicals were procured from either Sigma-Aldrich Co. or Merck & Co. The IR
spectra were recorded on a Perkin-Elmer Spectrum One FT-IR spectrometer using the
KBr plates. The UV/Vis spectra were measured at room temperature within the 200-500
nm range on the Agilent Technologies, Cary 300 Series UV-Vis Spectrophotometer. A
solution of 2.5×10-5 M of each compound was prepared in methanol and then 2 mL of the
corresponding solution was injected into the 10 mm quartz cell and recorded spectrum.
The 1H NMR and 13C NMR spectra were run on a Varian Gemini spectrometer (200 MHz
1
13
and 50 MHz for H and C respectively) using CDCl3 as solvent. Melting points were
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determined on a Mel-Temp capillary melting points apparatus, model 1001. Elemental
microanalysis for carbon, hydrogen, and nitrogen were performed at the Faculty of
Chemistry, University of Belgrade. Lemon was purchased from local market.
2.1. Preparation of lemon juice
Lemon was squeezed, and obtained juice was filtered through Büchner funnel with a
sintered glass disc in order to remove pulp. The pH value of the filtrate was about 2. The
obtained juice was then used in the reaction.
2.2. General procedure for the synthesis of benzoyl-1H-pyrazole derivatives 2 and 3
A mixture of acetylacetone (1 mmol) and corresponding hydrazide (1 mmol) in lemon
juice (3 ml) was stirred at room temperature. Reaction progress was monitored using thin
layer chromatography (TLC). In case where reaction product precipitated during reaction,
the mixture was filtered and washed with water, without further purification. In cases
where mixture of two products were obtained, as well as when substances were liquid,
reaction mixture was dissolved in ethyl acetate and washed with water, and products were
separated by column chromatography. All products (2f-j and 3a-j) were characterized
with melting points, 1HNMR, 13CNMR and IR spectra. For the new compounds 2f and 3i
purity was confirmed by elemental analysis, and corresponding spectral data are
presented here, while for other compounds corresponding data are presented in
Supplementary material).
2.3. Spectral characterization of benzoyl-1H-pyrazole derivatives
(2-chlorophenyl)(4,5-dihydro-5-hydroxy-3,5-dimethylpyrazol-1-yl)methanone
(2f): White powder (10%); Eluent: dichloromethane/ethyl acetate (3:1); mp 95-97 ; H
1
NMR (200 MHz, CDCl3) δ: 1.95 (s, 3H), 1.99 (s, 3H), 2.98 (AB-q, ꢀνAB = 51.7 Hz,
J =
13
18.4 Hz, 2H), 4.85 (s, 1H), 7.44 – 7.29 (m, 4H), C NMR (50 MHz, CDCl3) δ: 16.11,
26.67, 51.56, 92.00, 126.40, 128.35, 129.30, 130.30, 131.02, 135.70, 155.80, 166.49; IR
(KBr): νmax = 3445, 3067, 2985, 2856, 1643, 1623, 1441, 1378, 1221, 1125, 1050, 975,
874, 746, cm-1; C12H13ClN2O2 (FW = 252.7): C, 57.04; N, 11.09; H, 5.19%; found: C,
57.20; N, 11.12; H, 5.20%
(4-iodophenyl)(3,5-dimethyl-1H-pyrazol-1-yl)methanone (3i): Yellow solid (36%);
Eluent: dichloromethane/ethyl acetate (2:1); mp 65-67 ; 1H NMR (200 MHz, CDCl3) δ:
2.25 (s, 3H), 2.63 (s, 3H), 6.07 (s, 1H), 7.72 (d, J = 8.5 Hz, 2H), 7.83 (d, J = 8.4 Hz, 2H);
13C NMR (50 MHz, CDCl3) δ: 13.88, 14.35, 100.07, 111.24, 128.72, 132.70, 137.03,
145.10, 152.33, 167.52; IR (KBr): νmax = 2924, 1694, 1583, 1376, 1352, 1008, 918, 833,
769, 742, 623 cm-1; C12H11IN2O (FW = 326.14): C, 44.19; N, 8.59; H, 3.40%; found: C,
44.03; N, 8.56; H, 3.41%.
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2.4. X-ray crystal structure determination
Single-crystal X-ray diffraction data for compound 2i were collected at an Oxford Gemini S
diffractometer, using monochromatized MoKα radiation (λ = 0.71073 Å). Data reduction and
empirical absorption correction were performed with CrysAlisPRO [36]. The structure was
solved by direct methods using SHELXS and refined on F2 by full-matrix least-squares using
SHELXL [37]. All non-hydrogen atoms were refined anisotropically. H atoms bonded to C
atoms were placed in geometrically calculated positions and refined using the riding model with
Uiso values constrained to 1.2Ueq or 1.5Ueq of the parent C atoms. H atom bonded to O atom was
constrained in position found from a difference Fourier synthesis. The PLATON [38] software
was used to perform geometrical calculation and the Mercury [39] was employed for molecular
graphics. In order to identify the relative importance of the intermolecular interactions within the
crystal packing of 2i the Hirshfeld surface analysis was performed by using CrystalExplorer[40].
The molecular Hirshfeld surface dnorm was mapped over a fixed colour scale: −0.53 (red) to 1.41 Å
(blue). Crystallographic details are summarized in Table S1. Crystallogrphic data have been
deposited with the Cambridge Structural Database, CCDC deposition numbers 1887548.
2.5. Density functional theory calculations
The Gaussian 09 program package was used to perform all calculations.[41] The
equilibrium geometries of all compounds were calculated using the B3LYP-D3 functional
in conjunction with the 6-311+G(d,p) basis set,[42,43] in the gas-phase and chloroform (ε
= 24.3) since it was used as solvent for experimental NMR spectra, using the conductor-
like solvation model (CPCM) as implemented in Gaussian09.[44–46] To confirm that all
structures are local minima, frequency calculations were done. The optimized geometries
in the gas-phase were used for simulation of IR spectra, while the NMR shifts for all
hydrogen and carbon atoms relative to TMS were calculated using the Gauge-
Independent Atomic Orbital (GIAO) method. UV–Vis spectra were simulated using TD-
DFT and structures optimized in methanol, because experimental spectra were acquired
using this solvent. It is worth pointing out that simulated IR bands were not scaled, since
obtained bands are in good agreement with experimental ones. On the other hand,
simulated NMR chemical shifts, both hydrogen and carbon, were scaled using scaling
factors obtained using the least squares method and amount 0.9639 and 0.9422.
3. Results and discussion
In continuation of our interest on synthesis of nitrogen heterocyclic compounds,[47,48] new
green synthesis of benzoyl-1H-pyrazole derivatives under mild reaction conditions was
achieved. The synthesis was performed in the presence of freshly squeezed lemon juice as
solvent and natural source of citric acid, i.e. Bronsted acid catalyst (pH ~ 2), Scheme 1.
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Scheme 1. General reaction for the synthesis of of benzoyl-1H-pyrazole derivatives in lemon juice.
3.1. Synthesis of 1-benzoyl-1H-pyrazole derivatives
To optimize reaction conditions, model reaction between benzohydrazide (1 mmol) and
acetylacetone (1 mmol) in different amounts of lemon juice was performed at room temperature,
Table 1. Initially, in the presence of 1 and 1.5 mL of juice and after 3 h, corresponding product
was formed in moderate yield. Higher amount of juice (2 and 2.5 mL) increased the yield and
reduced reaction time. In 3 mL of lemon juice, the yield of the product was very good and
reaction time shorter. Further increase of the lemon juice to 4 mL didn’t affect the yield and
reaction time. The formation of the pyrazole product 3 was tested in pure water, also. The
product was obtained in low yield and after prolongation of the reaction time to 24 h (Table 1,
entry 8). However, this reaction mixture contained final pyrazole product 3, as well as its
precursor 1-benzoyl-5-hydroxy-4,5-dihydro-1H-pyrazole 2 in 5:4 ratio. Moreover, to test the
influence of temperature on the dehydration of 2, the reaction mixture was heated to reflux,
Table 1 entry 9. After 5 hours of heating, the yield of 3 was improved to 70%, while amount of 2
was only 2%.
Table 1. Optimisation of the reaction conditionsa.
Lemon juice/water
Time
(h)
3
Yield
(%)
65
70
75
Entry
(mL)
1
1.5
2
2.5
3
1
2
3
4
5
3
1.5
1.5
1
85
90
6
4
1
90
7
5
3
3
1
24
5
90
47
70
8b
9c
aReaction conditions: benzohydrazide (1 mmol) and acetylacetone (1 mmol), room temperature; b,creactions
performed in water, broom temperature; creflux.
Considering obtained results, 3 mL of lemon juice was used as optimal for the
synthesis of 1-benzoyl-1H-pyrazoles derivatives starting from aromatic hydrazides 1a-j
and acetylacetone in molar ratio 1:1, Scheme 1. It is important to emphasize that, some of
the reactions with substituted benzoyl hydrazides (1b and 1d) finished much faster than
the control reaction with benzohydrazide 1a. Namely, these reactions finished after 15
minutes, with only final pyrazole products
3 present in the reaction mixtures, Table 2.
Therefore, we performed all reactions for the synthesis of pyrazole derivates for 15
minutes in 3 mL of lemon juice, starting from hydrazides 1a-j and acetylacetone in molar
ratio 1:1.
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Table 2. Product distribution (2:3) of the reactions of different benzoyl hydrazides (1a-j) with acetylacetone after 15
minutes.
Yield (%)
Compound
2
18
/
/
/
18
36
42
46
77
88
3
72
89
42
91
74
46
19
15
2
a
b
c
d
e
f
g
h
i
4
j
In the cases where benzoyl hydrazides with electron-donating groups on phenyl ring 1b and
1d reacted with acetylacetone, only the 1-benzoyl-1H-pyrazoles derivatives 3b and 3d were
obtained in high yields. On the other hand, benzohydrazides 1a and 1e, as well as benzoyl
hydrazides with electron-withdrawing groups 1f-j reacted slower, yielding the mixture of the
corresponding 1-benzoyl-5-hydroxy-4,5-dihydro-1H-pyrazoles 2 and final products 1-benzoyl-
1H-pyrazoles 3.
To improve yields, reaction time was prolongated, Scheme 2. Products 3b and 3d were
obtained in high yields after 15 minutes and increase of reaction time didn’t influence any
increase in yields of these products. Reactions where hydrazides 1a and 1e were used, finished
after 1 hour, and products were obtained in very good yield. On the other hand, reactions with
hydrazides 1c and 1f-j required prolongation of the reaction time, Scheme 2.
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Scheme 2. Products obtained in reactions of aromatic hydrazides with acetylacetone at room temperature in
lemon juice.
To get further insight in the reaction, and to find reasonable explanation for the
distribution of the products
Scheme 3. The reaction starts with concerted protonation of diketone with HB (in our
case citric acid), followed with nucleophilic attack of nitrogen N2 from
to the carbonyl
group of acetylacetone, and deprotonation of the same N2. This way formed intermediate
2 and 3, mechanism of this reaction is proposed and analysed,
1
I
undergoes dehydration in similar fashion. Here, HB from lemon juice protonates OH
group forming water molecule, with simultaneous deprotonation of N2. Hydrazido-imine
intermediate II is formed. Next, remaining carbonyl group of intermediate II is subjected
to protonation, while the N1 is being deprotonated. In the same time, 1-benzoyl-5-
hydroxy-4,5-dihydro-1
Dehydration of would be facilitated with the presence of citric acid. This agrees with
the fact that uncatalyzed test reaction in water produced high amount of , while the
presence of acid from lemon juice significantly favoured dehydration of to form final
H-pyrazoles 2 is formed, as product of cyclocondensation reaction.
2
2
2
product
3. In addition, dehydration process is dependent on the electron density on
N1.[49,50] This process would be favoured with increased electron density on N1, since
this would make aromatisation of the ring easier. Our results show that electron-donating
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groups positioned on the aromatic ring of the benzoyl hydrazide enable quick formation
of the final pyrazole adduct 3, while electron accepting groups decrease electron density
on N1 and therefore make this process slower.
Scheme 3. The suggested mechanism for the formation of 1-benzoyl-1H-pyrazole derivatives.
3.2. Structural characterization of 1-benzoyl-1H-pyrazole derivatives
All synthetized compounds were characterized using spectroscopic techniques such as IR, UV-
1
13
Vis, H and C NMR spectroscopy, as well as with melting points. Two of fifteen obtained
derivatives are newly synthetized compounds (2f and 3i). The purity of newly synthetized
compounds was confirmed and by elemental analysis. In addition, the structure of compound 2i
was confirmed by single-crystal X-ray diffraction analysis. To our best knowledge, the crystal
structure of that compound has not been reported so far.
Experimental and simulated IR spectra of 1-benzoyl-5-hydroxy-4,5-dihydro-1H-pyrazole
derivatives 2f and 2i, as well as of 1-benzoyl-1H-pyrazole 3i are presented in Fig. 1, while all
other spectra are given in Figs. S3 and S4. To assign experimental bands, IR spectra were
simulated using DFT. One can note that all simulated spectra are very similar to those
experimentally obtained. Here, IR spectral characterization of compounds 2f, 2i, and 3i will be
discussed. Deeper insight in experimental and simulated spectra of 2i and 3i revealed difference
in their structure. Particularly, the band at 3429 cm-1 present in the spectrum of 2i is absent from
the spectrum of 3i, suggesting that the OH group in compound 3i is not present. Vibration around
1630 cm-1 in the spectrum of 2i is redshifted to 1690 cm-1 in the spectrum of 3i and corresponds
to C=O vibration, while C-N vibrations from the spectrum of 2i are blueshifted from 1433 and
1376 cm-1 to 1376 and 1273 cm-1 in the spectrum of 3i. Bands around 1323, 1221, 1125, 964,
824, and 605 cm-1 are present only in the spectrum of 2i and correspond to CH2 deformational
vibration, C–O, N–C(OH), C–OH, C–CH2, and O–H out of plane deformational vibrations,
8

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respectively. In the spectra of 3i, bands around 917 and 833 cm-1 correspond to Ar–C–C=O and
=C–H deformational out of plane vibrations. Although Ar–C–C=O system is present in 2i, the
band of this vibration is most probably absent from spectra due to stabilization through
C=O…H–O hydrogen bonding. In both spectra, bands around 1580, 1480, 1010, and 745 cm-1
are present, and correspond to aromatic C–C, CH3 deformational, aromatic C–I vibration, and
aromatic deformational out of plane C–H vibrations, respectively. IR spectra of 2f and 2i are
mutually very similar. The only difference between these spectra is that vibration corresponding
to aromatic carbon halogen vibration is redshifted to 1125 cm-1 in the spectra of 2f.
Fig. 1. Optimised structures, dipole moment values of compounds 2f, 2i, and 3i, as well as their
experimental and simulated IR spectra.
All compounds were characterised using experimental and theoretical 1H and 13C NMR
spectra. Chemical shifts of 1-benzoyl-5-hydroxy-4,5-dihydro-1 -pyrazole derivatives 2f
and 2i, as well as of 1-benzoyl-1 -pyrazole 3i are presented in Tables 3 and 4, while the
H
H
corresponding data for other compounds are given in Tables S2 and S3.
1
The H NMR spectra of compounds 2f and 2i reveal that there is no pronounced
difference in chemical shifts, except in the aromatic region, Table 3. In both experimental
spectra two diastereotopic protons of methylene group (Ha and Hb) of pyrazole ring
resonate as AB quartets at 2.98 ppm (JAB = 18.4 Hz and ꢀνAB = 51.7 Hz) and 2.96 ppm
with (JAB = 18.4 Hz and ꢀνAB = 47.4 Hz). These diastereotopic protons undergo spin–spin
coupling to each other, Fig. 2. In simulated spectra these signals appear at 2.96 and 2.91
ppm. Singlets of methyl groups attached to C3 and C5 of the pyrazole ring appear at 1.95
and 1.99 ppm (1.78 and 1.94 ppm simulated) in the spectrum of 2f, and at 1.96 and 2.04
9

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ppm (1.84 and 1.99 ppm simulated) in the spectrum of 2i. Singlets for hydroxy group
bonded to stereocenter C5 appear at 4.85 and 5.00 ppm in corresponding spectrum of
each compound, while in predicted spectra at 4.51 and 4.88 ppm. The aromatic protons of
2f are observed as multiplet at 7.37 ppm (simulated 7.33 ppm), while in the spectra of 2i
they are observed as doublets at 7.85 and 8.07 ppm (simulated 7.57 and 7.78 ppm). In the
1H NMR spectrum of dehydrated product 3i singlet originating from proton bonded to C4
carbon of pyrazole ring appear at 6.07 ppm (simulated 6.10 ppm). Methyl groups attached
to C3 and C5 carbons of pyrazole ring are presented with two sharp singlets resonating at
2.25 and 2.63 ppm (simulated 2.26 and 2.62 ppm), and protons of phenyl group as
doublets at 7.72 and 7.83 ppm (simulated 7.62 and 7.86 ppm).
Fig. 2. Skeleton of compounds
2.
Table 3. Experimental and simulated 1H NMR chemical shifts (ppm).
2f
2i
3i
exp sim exp
sim
exp
sim
2.04 1.99
1.99 1.94
1.95 1.78
/
2.25 2.26
CH3
1.96 1.84
2.63 2.62
6.07 6.10
/
C4–H
/
2.96 2.91
C4–Ha, Hb 2.98 2.96
7.85 7.57 7.72 7.62
8.07 7.78 7.83 7.86
7.37 7.33
Ar
5.00 4.88
C5–OH
4.85 4.51
/
13
In C NMR spectra of compounds 2f and 2i carbon atoms of methyl groups appear
around 16 and 27 ppm in both experimental and simulated spectra, Table 4, Fig. S5.
Peaks around 156, 51, and 93 ppm originate from C3, C4, and C5 carbons (in simulated
spectra 159, 53, and 95 ppm), respectively. Carbons of C=O group appeared around 167
1
13
ppm. Similarly, to the case of H NMR spectra, the only difference between C NMR
spectra of compounds 2f and 2i is in the aromatic region. Namely, there are six peaks in
the spectrum of 2f in region of 126-136 ppm, while in the spectrum of 2i, owing to p-
substitution of I atom, there are four signals in the range of 98–137 ppm. In the spectrum
of compound 3i, both methyl groups appeared around 14 ppm (simulated 15 and 17 ppm),
and carbon atoms C3, C4, and C5 around 152, 100, and 145 ppm (simulated 153, 111,
and 147 ppm), respectively. Aromatic carbons were observed in the region 111-137 ppm
(simulated 132-138 ppm), and carbon of carbonyl group around 167 ppm (simulated 166).
It is worth pointing out that simulated 1H and 13C spectra reproduced chemical shifts with
high accuracy. Namely, average absolute errors (AAE) amount 0.13 and 1.69 ppm, while
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the correlation coefficients (R) for the dependencies of the calculated chemical shifts on
the experimental values are larger than 0.99, Tables S2 and S3, Fig. S5.
Table 4. Experimental and simulated 13C NMR chemical shifts (ppm).
2f
2i
3i
exp
sim
exp
sim
exp
sim
16.11
26.67
18.17
26.71
16.20
26.87
18.06
26.42
13.85
14.34
15.61
16.15
CH3
C4–H
/
/
111.20 110.82
C4–Ha, Hb 51.56
52.87
94.75
51.02
92.79
52.72
94.73
/
145.10 147.15
C5
C3
92.00
155.59 157.76 152.33 153.39
167.52 165.95 167.52 165.69
133.64 133.32 128.72 132.36
131.39 131.11 132.70 132.44
136.86 134.50 137.03 134.48
155.80 159.46
166.49 164.49
131.02 136.72
135.70 138.27
129.30 128.05
130.30 129.09
C=O
Ar
98.30
109.26 111.24 118.68
126.40 126.01
128.35 127.26
In addition to the IR and NMR spectral characterization, UV–Vis spectra of the
compounds 2f, 2i, and 3i were acquired and simulated, Fig. 3. In both, experimental and
simulated spectra of compounds 2f, 2i, and 3i, one major absorption band appeared. In
experimental spectra of 2f, 2i, and 3i absorption bands appear at 230, 251, and 263 nm,
respectively. In the simulated spectra of 2f, major band is somewhat blueshifted to 227 nm, while
in the case of 2i and 3i, bands are redshifted and appear at 277.5 and 288 nm. To distinguish the
parts of molecules responsible for electronic transitions, Kohn–Sham orbitals were constructed,
Figs. S6, S7, and S8. Experimental band at 230 nm (simulated 227 nm) in the spectrum of 2f is
consequence of HOMO to LUMO+2 electron transition. On molecular level, electron transition
from pyrazole moiety of the molecule to the benzoyl group is responsible for the appearance of
this band. In the spectrum of 2i, band at 251 nm is a consequence of electron transition from
HOMO to LUMO (from almost entire molecule to the benzoyl part of the molecule), with some
participation of HOMO-1 (benzoyl part of the molecule) and HOMO-4 (pyrazole part) to the
LUMO (benzoyl part) electron transitions. In the case of 3i, besides HOMO to LUMO transition
(from benzoyl to benzoyl part of the molecule), there is some contribution from HOMO-2 to
LUMO electron transition (from pyrazole part to the benzoyl part of the molecule). Considering
regions responsible for the appearance of the bands in the spectra of 2f, 2i, and 3i at 230, 251,
and 263 nm, respectively, it is clear that the highest energy band at 230 nm is consequence of
electron transition between different parts of the molecule (large spatial gap), while in the cases
of 251 and 263 nm, these bands are caused with smaller spatial gap electron transitions within
the same region of 2i and 3i molecules.
11

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Fig. 3. Experimental and simulated UV-Vis spectra of 2f, 2i, and 3i.
Solid-state structure of 2i was determined by single crystal X-ray diffraction. The molecular
structure is shown in Fig. 4, while the selected geometry parameters are given in Table 5. It is
worth pointing out, that there is very good agreement between X-ray diffraction geometrical
parameters and those obtained from the gas phase optimized structure of 2i. The pyrazoline ring
in 2i displays expected deviation from planarity, caused by the presence of two sp3 hybridized C
atoms (r.m.s 0.0757 Å). The ring adopts an envelope conformation, where the C5 atom, carrier
of the methyl and hydroxyl substituents, deviates for −0.28 (1) Å from the least-squares plane of
the remaining N1/N2/C3/C4 atoms (r.m.s 0.004 Å). Similar to previously reported 4,5-dihydro-
1H-pyrazole derivatives,[51–54] the N2–C3 bond [1.2786(17) Å] has the shortest length,
indicating a localization of electron density in this part of the ring.
Fig. 4. Molecular structure and atom-labeling scheme of 2i with displacement ellipsoids drawn at the 30%
probability level.
Table 5. Selected X-ray and calculated bond lengths (Å) and angles (°) of 2i.
calculated
AAE=0.013
calculated
AAE=0.5
X-ray
X-ray
N1–N2
N1–C5
N2–C3
C3–C4
C4–C5
N1–C1
C1–O1
C1–C7
1.406(8)
1.471(9)
1.283(10)
1.492(12)
1.518(11)
1.364(9)
1.239(9)
1.484(11)
1.392
1.501
1.280
1.506
1.538
1.369
1.234
1.493
N1–N2–C3 106.7(6)
N2–N1–C5 112.5(5)
N1–C5–C4 100.5(6)
N2–C3–C4 114.2(7)
N1–C1–C7 119.4(5)
N1–C1–O1 119.3(6)
C3–C4–C5 103.0(6)
108.6
112.8
100.8
114.1
120.0
119.3
103.4
12

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The molecule displays E configuration with regard to N1–C1 bond [1.364(9) Å], as evidenced
by the torsion angle N2–N1–C1–O1 of 161.4(7)°. The mean plane defined by atoms
N1/C1/O1/C7/ makes a smaller dihedral angle with the mean plane of pyrazoline ring [12.5(5)°]
in comparison to the dihedral angle toward the phenyl ring [48.1(3)°]. These values suggest that
the interrupted delocalization within the pyrazoline favorizes a delocalization of N2 free electron
pair towards the carbonyl group adjacent to the ring. This is also reflected in N1–C1 bond which
is notably shorter than analogue bond in 1-benzoyl-5-hydroxy-4,5-dihydro-1H-pyrazole derivatives.
The dihedral angle between the mean planes of pyrazoline ring and phenyl ring is 58.1(3)°.
The molecular structure is stabilized by intramolecular hydrogen bond formed between
hydroxyl group and carbonyl O acceptor [O2–H2…O1: H…O 2.50 Å O–H...O 123°]. In the
crystal packing the same donor and acceptor are involved in the formation of specific O2–
H…O1 centrosymmetric dimer [O2–H2…O1i: H…O 2.04 Å O–H...O 150°, (i) = -x, -y, -z+1].
The similar motif has been observed in previously literature data[53,54]. The dimers interconnect
by weak C–H…O interaction [C4–H4b…O2ii: H…O 2.57 Å C–H...O 145°, (ii) = x, -y+1, -z+1]
into a chain extending along the b axis, Fig. 3. The N2 acceptor of 2i has no role in hydrogen
bonding. The crystal structure of 2i is further stabilized only by weakly attractive interactions
arising from the van der Waals contacts.
Hirshfeld surface analysis (Figure 6) has been used to quantify the intermolecular interactions
stabilizing the crystal packing of 2i. [40] The deep red spots on Hirshfeld surface indicate the
shortest contacts in the 2i system result from dominant O2–H2…O1 hydrogen bond (Figure 6a).
In the corresponding 2D fingerprint plot (Figure 6b) this centrosymmetric interaction is indicated
by a pair of distinct spikes. The percentage contribution of the O...H interactions to the crystal
packing is only 14.0%, while the main contribution results from the H…H contacts (44.1%). The
majority of Hirshfeld surface area of 2i is characterized by light colors indicating the prevalence
of weak van der Waals and electrostatic contacts (Figure 6a and Figure S1). Short lateral spikes
in 2D fingerprint plot reflect the weak H...I contacts which contribute to the Hirshfeld surface
with 15.4%. In the crystal packing each iodine atom fits into the fold of a neighboring molecule
(Figure S2) resulting in weak van der Waals interactions. The distance between the iodine and
the centroid of phenyl ring is 3.799(3) Å.
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Fig. 5. The chain of centrosymmetric O–H...O bonded dimers of 2i.
Fig. 6. (a) Hirshfeld surface of 2i; (b) two-dimensional fingerprint plot.
4. Conclusion
A new green method for the synthesis of benzoyl-1H-pyrazole derivatives was performed in
lemon juice as eco-friendly medium and biocatalyst. Reaction of benzoyl hydrazides with
acetylacetone produced 1-benzoyl-5-hydroxy-4,5-dihydro-1H-pyrazoles 2 and 1-benzoyl-1H-
pyrazoles 3, depending on the hydrazide substitution. Benzoyl hydrazides with electron-
withdrawing groups reacted slower, yielding the mixture of 2 and 3. Electron-donating
substituted benzoyl hydrazides reacted faster, yielding only pyrazole products 3 in high yields.
Two compounds, 2f and 3i, and their structures are reported here for the first time. IR, NMR, and
UV-Vis spectral characterization was done experimentally, as well as theoretically. All simulated
spectra agree with the experimental ones. Solid-state structures of 2i was determined using single
crystal X-ray diffraction analysis. The molecule 2i displays E configuration described by the
14

ACCEPTED MANUSCRIPT
torsion angle N2–N1–C1–O1 of 161.4(7)°. The N1–C1 bond length of 1.364(9) Å as well as the
dihedral angle between N1/C1/O1/C7/ fragment and pyrazoline ring of 12.5(5)° suggest the
delocalization of the electron density from the pyrazoline N2 toward the carbonyl group. In the
crystal packing the molecules of 2i form O2–H…O1 hydrogen bonded centrosymmetric motif
characteristic for 1-benzoyl-5-hydroxy-4,5-dihydro-1H-pyrazole derivatives. Hirshfeld surface
analysis indicates the prevalence of weak van der Waals and electrostatic contacts in stabilization
of crystal packing, with small participation of hydrogen bonds.
Acknowledgements
This investigation was supported by the Ministry of Education, Science and
Technological Development of the Republic of Serbia project No. 172016 and 172014.
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Highlights
Green synthesis of benzoyl-1H-pyrazole derivatives
Experimental and theoretical spectral characterization of pyrazole derivatives
Crystal structure determination