Synthesis of chitosan-la2o3 nanocomposite and its utility as a powerful catalyst in the synthesis of pyridines and pyrazoles

Article abstract of DOI:10.3390/molecules26123689

Recently, the development of nanocatalysts based on naturally occurring polysaccharides has received a lot of attention. Chitosan (CS), as a biodegradable and biocompatible polysaccharide, is considered to be an excellent template for the design of a hybr

Full text of DOI:10.3390/molecules26123689

molecules
Article
Synthesis of Chitosan-La2O3 Nanocomposite and Its Utility as a
Powerful Catalyst in the Synthesis of Pyridines and Pyrazoles
Khaled D. Khalil 1,2,
Mohamed Hagar 2,6
*
, Sayed M. Riyadh 1,3, Mariusz Jaremko 4, Thoraya A. Farghaly 1,5 and
1
Department of Chemistry, Faculty of Science, Cairo University, Giza 12613, Egypt;
riyadh1993@hotmail.com (S.M.R.); thoraya-f@hotmail.com (T.A.F.)
Department of Chemistry, Faculty of Science, Taibah University, Al-Madinah Almunawarah,
2
Yanbu 46423, Saudi Arabia; mhagar@taibahu.edu.sa
Department of Chemistry, College of Science, Taibah University,
3
Al-Madinah Almunawrah 30002, Saudi Arabia
Biological and Environmental Sciences & Engineering Division (BESE), King Abdullah University of Science
4
and Technology (KAUST), Thuwal 23955-6900, Saudi Arabia; Mariusz.jaremko@kaust.edu.sa
Department of Chemistry, Faculty of Applied Science, Umm Al-Qura University,
5
Makkah Almukaramah 21514, Saudi Arabia
Chemistry Department, Faculty of Science, Alexandria University, Alexandria 21321, Egypt
6
*
Correspondence: kkhalil@taibahu.edu.sa or khd.khalil@yahoo.com
Abstract: Recently, the development of nanocatalysts based on naturally occurring polysaccharides
has received a lot of attention. Chitosan (CS), as a biodegradable and biocompatible polysaccharide,
is considered to be an excellent template for the design of a hybrid biopolymer-based metal oxide
nanocomposite. In this case, lanthanum oxide nanoparticles doped with chitosan at different weight
percentages (5, 10, 15, and 20 wt% CS/La2O3) were prepared via a simple solution casting method.
The prepared CS/La2O3 nanocomposite solutions were cast in a Petri dish in order to produce
the developed catalyst, which was shaped as a thin film. The structural features of the hybrid
nanocomposite film were studied by FTIR, SEM, and XRD analytical tools. FTIR spectra confirmed
the presence of the major characteristic peaks of chitosan, which were modified by interaction
with La2O3 nanoparticles. Additionally, SEM graphs showed dramatic morphological changes
on the surface of chitosan, which is attributed to surface adsorption with La2O3 molecules. The
prepared CS/La2O3 nanocomposite film (15% by weight) was investigated as an effective, recyclable,
and heterogeneous base catalyst in the synthesis of pyridines and pyrazoles. The nanocomposite
used was sufficiently stable and was collected and reused more than three times without loss of
catalytic activity.
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Citation: Khalil, K.D.; Riyadh, S.M.;
Jaremko, M.; Farghaly, T.A.; Hagar, M.
Synthesis of Chitosan-La2O3
Nanocomposite and Its Utility as a
Powerful Catalyst in the Synthesis of
Pyridines and Pyrazoles. Molecules
2021, 26, 3689. https://doi.org/
10.3390/molecules26123689
Academic Editor: Alessandra Puglisi
Received: 21 May 2021
Accepted: 8 June 2021
Published: 17 June 2021
Keywords: chitosan; La2O3; nanocomposite film; heterogeneous catalysis; pyridines; pyrazoles
Publisher’s Note: MDPI stays neutral
with regard to jurisdictional claims in
published maps and institutional affil-
iations.
1. Introduction
With the growing concern of nanocatalysis in organic transformations, naturally
occurring biopolymers have been used extensively as powerful substrates to be utilized
as an excellent stabilizer for the immobilizing of a variety of metal oxides nanoparticles
due to their biodegradable, nontoxic, low cost, and excellent structural properties [
Nanocomposite hybrid materials are where various materials combine to develop unique
properties guaranteeing that one of the materials has a size in the range of 1–100 nm [ ].
Therefore, much effort has been devoted to the design and synthesis of these hybrid
nanocomposites through flexible and efficient routes; there has also been careful study
of their new properties to adapt them to numerous applications in the areas of materials
science, especially their catalytic potency in the organic reactions [3–7].
1].
Copyright:
© 2021 by the authors.
2
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 (https://
creativecommons.org/licenses/by/
4.0/).
Chitosan (CS), the partially deacetylated form of chitin, is prepared via alkaline hy-
drolysis under certain conditions. Chitosan and its derivatives, rather than any other
Molecules 2021, 26, 3689. https://doi.org/10.3390/molecules26123689
https://www.mdpi.com/journal/molecules

Molecules 2021, 26, 3689
2 of 11
polysaccharide, are considered an excellent template to immobilize metal oxide nanoparti-
cles owing to its unique structural features, in particular the presence of the hydroxyl and
amino groups [8,9].
On the other hand, lanthanum oxide (La2O3) nanoparticles have shown considerable
basic properties that adapt to many base catalyzed reactions [10,11]. Unfortunately, some
difficulties limit its use, such as its difficult separation and reusability since the used
catalyst could not be quantitatively recovered and the purification of the products being
the biggest challenge.
Extending our earlier efforts in the area of nanocatalysis [5–7], in this article La2O3
nanoparticles immobilized onto the chitosan matrix were prepared (Figure 1) and then
employed as a promising heterogeneous basic catalyst to synthesis pyridines and pyrazoles.
These azines and azoles have privileged antitumor [12–15], antidiabetes [16], antimicro-
bial [17,18], anti-HCV [14,19,20], and antidepressant [21,22] activities.
Figure 1. A simplified view of chitosan-La2O3 nanocomposite.
2. Results and Discussion
2.1. Preparation and Characterization of CS/La2O3 Nanocomposite Film
Chitosan-La2O3 (CS/La2O3) nanocomposite films were prepared using a coprecipi-
tation method using chitosan as a biostabiliser [5,6]. The chitosan solution in acetic acid
was treated with the appropriate amount of La2O3 nanopowder, and then the solvent was
evaporated at ambient temperature. The prepared nanocomposite films were studied by
FTIR, SEM, and XRD as follows:
2.1.1. FTIR Characterization
The FTIR spectra of the chitosan (A), La2O3 nanoparticles (B), and chitosan-La2O3
nanocomposite (C) were measured and depicted in Figure 2. Figure 2A exhibited the
presence of m−ai1n characteristic bands of chitosan, −na1 mely, at
υ
= 3368 cm−1 (OH- group),
−1
2912, 2874 cm (C-H bond; CH3 groups), 1602 cm (amide carbonyl groups), 1381 cm
(CH2 groups), and 1057 cm−1 (C-O) [
5,
6
]. In addition, Figure 2B shows the main charac-
teristic bands of the La2O3 at 1523, 1362, and 829 cm−1
[
23]. For comparison, Figure 2C
shows mixed bands as result of the combination of the chitosan structure with the La2O3
nanoparticles, which is attributed to the presence of a chemical interaction between La2O3
molecules and the binding sites of OH and NH2 groups of chitosan.

Molecules 2021, 26, 3689
3 of 11
Figure 2. FTIR of chitosan (A), La2O3 nanoparticles (B), and the chitosan-La2O3 nanocomposite (15 wt%) (C).
2.1.2. SEM and Morphological Changes
A scanning electron microscope (SEM) was used to confirm the presence of mor-
phological changes in the surface caused by the incorporation of La2O3 into the chitosan
matrix. The micrographs of the pure chitosan (A), La2O3 nanoparticles (B), and the hybrid
nanocomposite films (C) with 15 wt% are shown in Figure 3. As can be seen, there is a
marked morphological change in the fibrous surface of chitosan, as opposed to the chitosan-
La2O3 hybrid nanocomposite films. According to the SEM images, La2O3 nanoparticles
were homogenously distributed over the whole surface of the chitosan matrix, and the
average size of La2O3 particles was found to be approximately 30 nm for 15 wt%. More-
over, an energy dispersive X-ray (EDX) of the CS/La2O3 nanocomposite film showed the
presence of La2O3 inside the polymer matrix (Figure 4). Thus, from the following EDX,
elemental analysis of the nanocomposite determined the La2O3 content to be ~15 wt%.
A
B
C
Figure 3. SEM images of chitosan (A), La2O3 nanoparticles (B), chitosan-La2O3 nanocomposite 15 wt% (C).

Molecules 2021, 26, 3689
4 of 11
Figure 4. Energy dispersive X-ray spectrum of chitosan-La2O3 (15 wt%).
2.1.3. X-ray Diffraction
The X-ray diffraction (XRD) measurement was performed to study the crystallinity
and nanostructure features of the native chitosan and the chitosan-La2O3 (15 wt%) thin film
nanocomposites. In F◦igure 5, the XRD of blank chitosan (A) shows the main characteristic
broad peak at 2θ = 20 , which indicates the presence of crystalline and amorphous regions
in chitosan as reported in the literature [12]. Moreover, the purity of chitosan was confirmed
by the absence of any additional peaks of impurities in the pattern. On the other hand,
the XRD of La2O3 nanoparticles (B) exhibits normal peaks at 26◦, 28.5◦, 30.2◦, and 39.4◦,
which is in agreement with the results reported in [24]. For the doped nanocomposite film
(15 wt% CS/La2O3) (C), a combination of the same peaks of the individual components
appeared, but in different intensities, indicating there was an interaction between La2O3
molecules and the OH and NH2 groups of the chitosan chain. The average grain size was
calculated from the XRD patterns using the Debye–Scherrer formula [25].
−0.9 × λ
D(nm) =
β × cos θ
is the wavelength of Cu-k
◦
where D(nm) is the crystalline size in nm,
λ
α
1 = 1.54060 A , and
β
can be calculated for the most intense peak for the CS/La2O3 nanocomposite pattern.
The average particle size was found to be 32.2 nm.
Figure 5. XRD of chitosan (A), La2O3 nanoparticles (B), and 15 wt% chitosan-La2O3 (C).

Molecules 2021, 26, 3689
5 of 11
2.2. CS/La2O3 Nanocomposite Film as Basic Catalyst in Synthesis of Pyridine Derivatives
The reaction between malononitrile dimer with enaminone 2a in absolute ethanol
1
was conducted in presence of the CS/La2O3 nanocomposite in order to estimate the
optimized conditions and the proper catalyst loading (Scheme 1).
Ph
O
H N
2
CN
CN
Ph
EtOH
NH
+
Catalyst
CN
Me N
2
2a
CN
3a
CN
1
CN
Scheme 1. Reaction of malononitrile dimer with enaminone 2a.
Optimizing the Catalyst Loading and the Reaction Conditions
In order to estimate the proper catalyst loading, a model reaction of malononitrile
dimer with enaminone 2a was carried out using 5, 15, 20, and 25 wt% of nanocomposite
1
film under the same conditions. From the obtained results, the catalyst loading 15 wt%
was found to be the optimal quantity for the maximum progress of the reaction (90% yield)
after refluxing for 2 h (Figure 6). Moreover, the recovered catalyst was successfully used
three times without significant change in its catalytic potency (Table 1).
Figure 6. Optimization of the chitosan graft copolymer as basic catalyst.
Table 1. Recyclability of the chitosan graft copolymer as basic catalyst.
State of Catalyst
Fresh Catalyst
Recycled (1)
Recycled (2)
Recycled (3)
Product 3a (%Yield)
90
89
88
88
Pyridine derivatives 3a–h with different aromatic moieties were prepared successfully
via mixing of malononitrile dimer 1 with enaminones 2a–h in absolute ethanol and in the
presence of basic catalyst (piperidine or chitosan, La2O3 or CS/La2O3 nanocomposite),
in a comparable yield (Scheme 2, Table 2). The results show that the use of CS/La2O3
nanocomposite afforded good yields of the products when utilized as a basic promoter
over piperidine, chitosan, or La2O3 under similar employed conditions. The use of La2O3
nanoparticles has obvious technical problems, such as the difficulty of its recovery from
the reaction medium; the contamination of the product is also a significant problem
that may affect the accuracy of the % yield calculation. Moreover, the chitosan-based
nanocatalyst was found to be superior in comparison to the others, not only due to its

Molecules 2021, 26, 3689
6 of 11
synergistic action but also owing to the cross-linking nature of the hybrid nanocomposite
that facilitated its removal from the reaction medium by simple filtration and, consequently,
its accessibility to reuse after washing with water and ethanol several times without loss of
its catalytic activity.
Scheme 2. Reaction of malononitrile dimer 1 with enaminones 2a–h.
Table 2. Yield percent of products 3a–h.
Yield (%)
Compd. No.
Ar
Ref.
Piperidine
CS
La2O3
CS/La2O3
3a
3b
3c
3d
3e
3f
C6H5-
4-Me-C6H4-
4-MeO-C6H4-
4-Cl-C6H4-
4-NO2-C6H4-
2-furyl
80
55
78
75
73
60
75
55
64
38
70
60
62
55
56
50
78
63
81
72
68
63
69
62
90
82
88
85
85
82
85
75
[12]
[13]
[14]
[14]
-
-
3g
3h
2-thienyl
2-pyrrolyl
[12]
-
In the following reasonable mechanism for the above-mentioned reaction (Scheme 3),
La2O3 nanoparticles acted as a Bronsted base [10 11] which deprotonated the active methy-
lene group of malononitrile dimer ( ) and gave the respective anion intermediate . The
latter carbanion attacked the -carbon of enaminone (2a ) with displacement of dimethy-
,
1
A
β
–h
lamine, as a good leaving group, to give the non-isolable intermediate B. Intramolecular
condensation of intermediate B afforded the pyridine derivatives 3a–h.
Scheme 3. Reasonable mechanism of the formation of compounds 3a–h.
The green protocol for the efficient synthesis of functionalized azoles was extended.
Thus, the reaction of 2-arylhydrazone-malono-1,3-dial (4a ) with chloroacetone ( ) un-
–
c
5

Molecules 2021, 26, 3689
7 of 11
der refluxing conditions using different base catalysts (piperidine, chitosan, La2O3, or
CS/La2O3 nanocomposite) proceeded smoothly to provide the corresponding pyrazoles
6a–c in a comparable yield (Scheme 4, Table 3). Again, the results show that CS/La2O3 is
superior in acting efficiently as a basic promoter for the reaction due to its synergistic effect
as well as its ease of recovery and recycling from the reaction medium.
Scheme 4. Synthesis of 5-acetyl-1-aryl-1H-pyrazole-3-carbaldehyde 6a–c.
Table 3. Yield percent of products 6a–c.
Yield (%)
Compd. No.
Ar
Ref.
Et3N
CS
La2O3
CS/La2O3
6a
6b
6c
C6H5-
4-Cl-C6H4-
4-MeO-C6H4-
68
66
72
57
54
60
68
70
75
75
78
84
-
[15]
-
From the results, the toxic triethyl amine can be replaced successfully by the greener
nanocomposite that gave the product in a relatively similar yield.
The latter reaction was promoted by the presence of the basic catalyst CS/La2O3,
which abstracted proton from arylazohydrazonals (4a–c) to initiate the nucleophilic dis-
placement of chlorine atoms and provided intermediate A. Further dehydrogenation
followed by base catalyzed cyclization gave intermediates B and C. Dehydration of inter-
mediate C provided the isolable pyrazoles 6a–c (Scheme 5).
Scheme 5. Mechanism of base catalyzed synthesis of 5-acetyl-1-aryl-1H-pyrazole-3-carbaldehyde 6a–c.

Molecules 2021, 26, 3689
8 of 11
3. Experimental
3.1. Materials and Methods
Sigma-Aldrich provided the chitosan (powder, shrimp shells, product no. C3646,
density = 0.15–0.3 g/cm3) and La2O3 (nano powder, TEM particle size 100 nm, product no.
634271). The FTIR (Fourier-Transform Infrared) spectra of nanocomposite were captured
using potassium bromide discs by a Pye-Unicam SP300 Instrument (Cambridge, UK). On
a high-resolution scanning electron microscope (model HRSEM, JSM 6510A, Jeol, Tokyo,
Japan), SEM analyses were recorded. A Philips Diffractometer (Model: X’Pert-Pro MPD;
Philips, Eindhoven, The Netherlands) was used to calculate XRD. On an electrothermal
Gallenkamp capillary apparatus (Leicester, UK), the melting points of samples were deter-
mined. On a Varian Mercury VXR-300 spectrometer (300 MHz for 1H NMR and 75 MHz
for 13C NMR), the chemical shifts of the newly synthesized compounds in DMSO-d6 were
recorded. The mass spectra were recorded on a GCMSQ1000-EX Shimadzu and GCMS
5988-A HP spectrometers; the ionizing voltage was 70 eV.
3.2. Preparation of CS/La2O3 Nanocomposite Film
A 2 wt% solution of medium molecular weight chitosan was prepared by dissolving
it in a 2% (w/v) aqueous acetic acid solution and stirring for 48 h at room temperature. The
resulting viscous solution was filtered to obtain the homogeneous clear chitosan solution.
A quantity of this solution was taken in a 50 mL bottle and 5, 10 and 15, 20 (w/v%) of La2O3
was added portion-wise with vigorous stirring, and then the stirring was continued for an
additional 24 h. To remove the solvent, the solution was poured into a Teflon Petri dish
(8 cm) and dried in a vacuum oven set to 50 ◦C for 3 days. After neutralization with 5 mL
of 1 M NaOH, the chitosan-La2O3 nanocomposite film was peeled off the Petri dish and
rinsed with distilled water. Finally, the film was held for two days at room temperature in
a vacuum desiccator.
3.3. Reaction of Malononitrile Dimer with Enaminone
Method A: Both 2-aminoprop-1-ene-1,3,3-tricarbonitrile (
1) (1.32 g, 0.01 mol) and
enaminones 2a (0.01 mol) were mixed in 10 mL of absolute ethanol and subsequently
–
h
treated with an appropriate amount (5 drops) of the piperidine as a base catalyst. The
reaction mixture was refluxed until all the starting materials were completely consumed
(within 2 h as monitored by TLC). When the reaction was finished, the mixture was cooled
and poured over the water–ice mixture while stirring. The precipitate was filtered, washed
with water and crystallized from ethanol as yellow crystals.
Method B: The same procedure as that of method A was applied under the same
conditions, but using CS, La2O3, or CS/La2O3 nanocomposite film (15 wt%) instead of the
piperidine. Once the reaction was complete, the film was carefully removed and washed
with water and ethanol for multiple uses in other reactions.
◦
2-(3-Cyano-6-phenyl-1H-pyridin-2-ylidene)malononitrile (3a) [26]. m.p. 257
−
259 C; Anal.
Calcd. C15H8N4 (244.26): C, 73.76; H, 3.30; N, 22.94. Found: C, 73.68, H, 3.24; N, 22.87%.
Accurate mass: 244.146.
2-(3-Cyano-6-(4-methylphenyl)-1H-pyridin-2-ylidene)malononitrile (3b) [27]. m.p. 297–298 ◦C;
Anal. Calcd. C16H10N4: C, 74.40; H, 3.90; N, 21.69. Found: C, 74.31; H, 3.76; N, 21.62%.
Accurate mass: 258.172.
◦
2-(3-Cyano-6-(4-methoxyphenyl)-1H-pyridin-2-ylidene)malononitrile (3c) [28]. m.p. 275
−
277 C;
Anal. Calcd. C16H10N4O: C, 70.06; H, 3.68; N, 20.43. Found: C, 69.93; H, 3.61; N, 20.37%.
Accurate mass: 274.015.
2-(3-Cyano-6-(4-chlorophenyl)-1H-pyridin-2-ylidene)malononitrile (3d) [28]. m.p. 255–256 ◦C;
Anal. Calcd. C15H7ClN4: C, 64.65; H, 2.53; Cl, 12.72; N, 20.10. Found: C, 64.48; H, 2.49; Cl,
12.67; N, 20.03%. Accurate mass: 278.719.

Molecules 2021, 26, 3689
9 of 11
2-(3-Cyano-6-(4-nitrophenyl)-1H-pyridin-2-ylidene)malononitrile (3e). m.p. 194
(KBr, cm−1): 3250 (NH), 2163 (3 CN); 1H-NMR (DMSO-d6):
Ar-H), 9.47 (br, 1H, NH, D2O exchangeable); 13C-NMR (DMSO-d6):
−
196 ◦C; IR
, ppm = 7.11–7.82 (m, 6H,
, ppm = 184.3, 164.2,
δ
δ
161.7, 155.9, 130.1 (2C), 128.9, 128.5, 117.3, 114.9, 110.2, 83.3, 62.7. Anal. Calcd. C15H7N5O2:
C, 62.29; H, 2.44; N, 24.21. Found: C, 62.17; H, 2.35; N, 23.89%. Accurate mass: 289.104.
◦
2-(3-Cyano-6-furan-2-yl-1H-pyridin-2-ylidene)malononitrile (3f). m.p. 182–183 C; IR (KBr, cm−1):
3263 (NH), 2157 (3 CN); 1H-NMR (DMSO-d6):
, ppm = 7.02–7.69 (m, 5H, Ar-H), 9.68 (br,
1H, NH, D2O exchangeable); 13C-NMR (DMSO-d6):
, ppm = 174.1, 160.6, 156.1, 151.0,
δ
δ
141.4, 129.2 (2C), 126.7, 117.4, 116.9 (2C), 106.8, 58.0. Anal. Calcd. C13H6N4O: C, 66.67; H,
2.58; N, 23.92. Found: C, 66.37; H, 2.48; N, 23.74%. Accurate mass: 234.067.
◦
2-(3-Cyano-6-thiophen-2-yl-1H-pyridin-2-ylidene)malononitrile (3g) [26]. m.p. 200
−
202 C;
Anal. Calcd. C13H6N4S: C, 62.39; H, 2.42; N, 22.39; S, 12.81. Found: C, 62.32; H, 2.37; N,
22.26; S, 12.72%. Accurate mass: 250.043.
◦
2-[3-Cyano-6-(1H-pyrrol-2-yl)-1H-pyridin-2-ylidene]-malononitrile (3h). m.p. 167
IR (KBr, cm−1): 3255 (2 NH), 2168 (3 CN); 1H-NMR (DMSO-d6):
−
168 C;
δ
, ppm = 5.84 (br, 1H,
pyrrole-NH, D2O exchangeable); 6.96–7.52 (m, 5H, Ar-H), 9.10 (br, 1H, pyridine-NH, D2O
exchangeable); 13C-NMR (DMSO-d6):
, ppm = 168.2, 156.9, 152.6, 148.2, 139.0, 127.8 (2C),
δ
127.4, 117.8, 117.3(2C), 104.1, 51.5. Anal. Calcd. C13H7N5: C, 66.95; H, 3.03; N, 30.03. Found:
C, 66.84; H, 2.96; N, 29.91%. Accurate mass: 233.163.
3.4. Reaction of 2-arylazomalonaldehyde 6 with Chloroacetone
Method A: A mixture of arylazomalonaldehyde 4a
–c (10.0 mmol) and α-chloroacetone
(5) (0.92 g, 10.0 mmol) was dissolved in 20 mL ethanol, containing a few drops of triethy-
lamine. The reaction mixture was stirred for 2 h at room temperature, and the solid material
was filtered and washed using a small quantity of ethanol. The crude products 6a–c were
purified by recrystallization from ethanol.
Method B: The same procedure as that of method A was applied under the same
conditions, but with the aid of CS, La2O3, or CS/La2O3 nanocomposite film instead of the
triethylamine. After completion of the reaction, the film was carefully removed and was
then washed with water and ethanol for several uses in other reactions.
5-Acetyl-1-phenyl-1H-pyrazole-3-carbaldehyde (6a). m.p. 164–166 ◦C. IR (KBr): v = 1703, 1683
(2 C=O) cm−1 1H NMR (DMSO-d6):
. δ, ppm = 2.72 (s, 3H, COCH3); 7.34–7.59 (m, 5H,
Ar-H); 7.89 (s, 1H, pyrazole-H); 9.84 (s, 1H, CHO). MS: m/z (%) = 214.1 (100) [M]+. Anal.
Calcd. C12H10N2O2: C, 67.28; H, 4.71; N, 13.08. Found C, 67.12; H, 4.61; N, 12.93.
5-Acetyl-1-(4-chlorophenyl)-1H-pyrazole-3-carbaldehyde (6b) [29]. m.p. 180–181 ◦C; MS: m/z
(%) = 248 (80) [M]+; Anal. Calcd. C12H9ClN2O2: C, 57.96; H, 3.65; Cl, 14.26; N, 11.27. Found
C, 57.84; H, 3.56; Cl, 14.18; N, 11.13.
o
5-Acetyl-1-(4-methoxyphenyl)-1H-pyrazole-3-carbaldehyde (6c). m.p. 152–153 C. IR (KBr):
1
v = 1705, 1690 (2 C=O) cm−1. H NMR (DMSO-d6):
δ
, ppm = 2.58 (s, 3H, COCH3); 3.75
(s, 3H, OCH3); 7.17–7.25 (d, 2H, J = 8.0 Hz, Ar-H), 7.44–7.56 (d, 2H, J = 8.0 Hz, Ar-H);
7.88 (s, 1H, pyrazole-H); 10.32 (s, 1H, CHO). MS: m/z (%) = 244.1 (80) [M]+. Anal. Calcd.
C13H12N2O3: C, 63.93; H, 4.95; N, 11.47. Found C, 63.84; H, 4.86; N, 11.32.
4. Conclusions
In this study, FTIR, FESEM, and EDX spectra were used to characterize the preparation
of a chitosan-La2O3 nanocomposite (as a green recyclable biocatalyst). For 15 wt%, the
average size of the La2O3 particles was found to be about 30–32 nm. In a comparison
study with respect to triethylamine as a conventional catalyst with chitosan, this hybrid
nanocomposite film worked well as a heterogeneous catalyst for the synthesis of pyridines
and pyrazoles. In addition to having a better environmental impact, the chitosan-La2O3
nanocomposite was found to be a more effective catalyst in these reactions than triethy-
lamine. From the catalytic studies, the synergistic effect produced by the combination of

Molecules 2021, 26, 3689
10 of 11
the basic nature of both La2O3 nanoparticles and chitosan itself was the main reason for the
superior catalytic potency of the chitosan-La2O3 nanocomposite as compared to the use
of its individual components. In addition to its green impact, the nanocatalyst film could
also be easily removed, restored, and reused without losing its catalytic activity. Finally,
the chitosan–metal oxide hybrid nanocomposite is a promising hybrid nanocomposite that
needs to be investigated further in a variety of organic transformations.
Author Contributions: Conceptualization, K.D.K., S.M.R. and M.H.; Data curation, K.D.K., S.M.R.,
T.A.F. and M.H.; Formal analysis, K.D.K., M.J. and M.H.; Investigation, K.D.K., S.M.R., M.J., T.A.F. and
M.H.; Methodology, K.D.K. and M.H.; Resources, K.D.K., S.M.R., M.J., T.A.F. and M.H.; Supervision,
K.D.K.; Writing—original draft, K.D.K., T.A.F. and M.H.; Writing—review and editing, K.D.K., S.M.R.,
M.J., T.A.F. and M.H. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Conflicts of Interest: The authors declare no conflict of interest.
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
Xu, G.; Blum, F.D. Surfactant-enhanced free radical polymerization of styrene in emulsion gels. Polymer 2008, 49, 3233–3238.
[CrossRef]
Ventra, M.; Evoy, S.; Heflin, J.R. Introduction to Nanoscale Science and Technology. Nanostructure Science and Technology; Springer:
Boston, MA, USA, 2004.
Ray, C.; Pal, T. Retracted Article: Recent advances of metal–metal oxide nanocomposites and their tailored nanostructures in
numerous catalytic applications. J. Mater. Chem. A 2017, 5, 9465–9487. [CrossRef]
Schauermann, S.; Nilius, N.; Shaikhutdinov, S.; Freund, H.-J. Nanoparticles for heterogeneous catalysis: New mechanistic insights.
Acc. Chem. Res. 2013, 46, 1673–1681. [CrossRef] [PubMed]
Riyadh, S.M.; Khalil, K.D.; Aljuhani, A. Chitosan-MgO nanocomposite: One pot preparation and its utility as an ecofriendly
biocatalyst in the synthesis of thiazoles and [1,3,4] thiadiazoles. Nanomaterials 2018, 8, 928. [CrossRef] [PubMed]
Khalil, K.D.; Riyadh, S.M.; Gomha, S.M.; Ali, I. Synthesis, characterization and application of copper oxide chitosan nanocomposite
for green regioselective synthesis of [1,2,3] triazoles. Int. J. Biol. Macromol. 2019, 130, 928–937. [CrossRef] [PubMed]
Khalil, K.D.; Ibrahim, E.I.; Al-Sagheer, F.A. A novel, efficient, and recyclable biocatalyst for Michael addition reactions and its
iron (iii) complex as promoter for alkyl oxidation reactions. Catal. Sci. Technol. 2016, 6, 1410–1416. [CrossRef]
Yilmaz, E. Chitosan: A Versatile Biomaterial. In Advances in Experimental Medicine and Biology; Hasirci, N., Hasirci, V., Eds.;
Springer: Boston, MA, USA, 2004; Volume 553.
Naskar, S.; Kuotsu, K.; Sharma, S. Chitosan-based nanoparticles as drug delivery systems: A review on two decades of research. J.
Drug Target 2019, 27, 379–393. [CrossRef] [PubMed]
10. Gill, R.; Singh, D.; Malik, H.K. Multifocal terahertz radiation by intense lasers in rippled plasma. J. Theor. Appl. Phys. 2017, 11,
103–108. [CrossRef]
11. Singh, A.; Palakollu, V.; Pandey, A.; Kanvah, S.; Sharma, S. Green synthesis of 1, 4-benzodiazepines over La2O3 and La (OH)3
catalysts: Possibility of Langmuir–Hinshelwood adsorption. RSC Adv. 2016, 6, 103455–103462. [CrossRef]
12. Li, X.-y.; Li, S.; Lu, G.-q.; Wang, D.-p.; Liu, K.-l.; Qian, X.-h.; Xue, W.-h.; Meng, F.-h. Design, synthesis and biological evaluation
of novel (E)-N-phenyl-4-(pyridine-acylhydrazone) benzamide derivatives as potential antitumor agents for the treatment of
multiple myeloma (MM). Bioorg. Chem. 2020, 103, 104189. [CrossRef] [PubMed]
13. Zhu, H.; Ying, S.; Zhou, B.; Liang, X.; He, Q.; Song, P.; Hu, X.; Shi, K.; Xiong, M.; Jin, H. Discovery of novel 2-aryl-3-sulfonamido-
pyridines (HoAns) as microtubule polymerization inhibitors with potent antitumor activities. Eur. J. Med. Chem. 2021, 211, 113117.
[CrossRef] [PubMed]
14. Abdel Hafez, N.A.; Hassaneen, H.M.; Farghaly, T.A.; Riyadh, S.M.; Elzahabi, H.S. Synthesis of new bis-spiropyrazoles as
antitumor agents under ultrasound irradiation. Mini-Rev. Med. Chem. 2018, 18, 631–637. [CrossRef]
15. Gouda, A.M.; El-Ghamry, H.A.; Bawazeer, T.M.; Farghaly, T.A.; Abdalla, A.N.; Aslam, A. Antitumor activity of pyrrolizines and
their Cu (II) complexes: Design, synthesis and cytotoxic screening with potential apoptosis-inducing activity. Eur. J. Med. Chem.
2018, 145, 350–359. [CrossRef] [PubMed]
16. Zhang, Y.; Ban, H.; Yu, R.; Wang, Z.; Zhang, D. Recent progress of sodium-glucose transporter 2 inhibitors as potential antidiabetic
agents. Future Med. Chem. 2018, 10, 1261–1276. [CrossRef] [PubMed]
˙
˙
17. Eryılmaz, S.; Çelikog˘lu, E.T.; Idil, Ö.; Inkaya, E.; Kozak, Z.; Mısır, E.; Gül, M. Derivatives of pyridine and thiazole hybrid:
Synthesis, DFT, biological evaluation via antimicrobial and DNA cleavage activity. Bioorg. Chem. 2020, 95, 103476. [CrossRef]
[PubMed]
18. Muhammad, Z.A.; Alshehrei, F.; Zayed, M.E.; Farghaly, T.A.; Abdallah, M.A. Synthesis of novel bis-pyrazole derivatives as
antimicrobial agents. Mini-Rev. Med. Chem. 2019, 19, 1276–1290. [CrossRef]

Molecules 2021, 26, 3689
11 of 11
19. Cheng, C.C.; Huang, X.; Shipps, G.W., Jr.; Wang, Y.-S.; Wyss, D.F.; Soucy, K.A.; Jiang, C.-k.; Agrawal, S.; Ferrari, E.; He, Z. Pyridine
carboxamides: Potent palm site inhibitors of HCV NS5B polymerase. ACS Med. Chem. Lett. 2010, 1, 466–471. [CrossRef] [PubMed]
20. Aydın, S.; Kaushik-Basu, N.; Özbas¸-Turan, S.; Akbug˘a, J.; Mega Tiber, P.; Orun, O.; Gurukumar, K.R.; Basu, A.; Güniz Küçükgüzel,
S¸. Synthesis of 1-aroyl-3, 5-dimethyl-1H-pyrazoles as Anti-HCV and anticancer agents. Lett. Drug Des. 2014, 11, 121–131.
[CrossRef]
21. Vacher, B.; Bonnaud, B.; Funes, P.; Jubault, N.; Koek, W.; Assié, M.-B.; Cosi, C.; Kleven, M. Novel derivatives of 2-
pyridinemethylamine as selective, potent, and orally active agonists at 5-HT1A receptors. J. Med. Chem. 1999, 42, 1648–1660.
[CrossRef] [PubMed]
22. Secci, D.; Bolasco, A.; Chimenti, P.; Carradori, S. The state of the art of pyrazole derivatives as monoamine oxidase inhibitors and
antidepressant/anticonvulsant agents. Curr. Med. Chem. 2011, 18, 5114–5144. [CrossRef]
23. Kabir, H.; Nandyala, S.H.; Rahman, M.M.; Kabir, M.A.; Stamboulis, A. Influence of calcination on the sol–gel synthesis of
lanthanum oxide nanoparticles. Appl. Phys. A 2018, 124, 1–11. [CrossRef]
24. CHERAGHALI, R.; Aghazadeh, M. A simple and facile electrochemical route to synthesis of metal hydroxides and oxides
ultrafine nanoparticles (M = La, Gd, Ni and Co). Anal. Bioanal. Electrochem. 2016, 8, 64−77.
25. Klug, H.P.; Alexander, L.E. X-ray Diffraction Procedures; John Wiley and Sons Inc.: New York, NY, USA, 1954; p. 633.
26. Helmy, N.M.; El-Baih, F.E.; Al-Alshaikh, M.A.; Moustafa, M.S. A route to dicyanomethylene pyridines and substituted benzoni-
triles utilizing malononitrile dimer as a precursor. Molecules 2011, 16, 298–306. [CrossRef] [PubMed]
27. Hassanien, A.Z.A.; Ghozlan, S.A.; Elnagdi, M.H. Enaminones as building blocks in organic synthesis: A novel route to poly-
functionally substituted benzonitriles, pyridines, eneylbenzotriazoles and diazepines. J. Heterocycl. Chem. 2003, 40, 225–228.
[CrossRef]
28. Al-Mousawi, S.M.; Moustafa, M.S.; Elnagdi, M.H. Green synthetic approaches: Solventless synthesis of polyfunctionally
substituted aromatics as potential versatile building blocks in organic synthesis utilizing enaminones and enaminonitriles as
precursors. Green Chem. Lett. Rev. 2011, 4, 185–193. [CrossRef]
29. Makhseed, S.; Hassaneen, H.M.; Elnagdi, M.H. Studies with 2-(arylhydrazono) aldehydes: Synthesis and chemical reactivity of
mesoxalaldehyde 2-arylhydrazones and of ethyl 2-arylhydrazono-3-oxopropionates. Z. Nat. B 2007, 62, 529–536. [CrossRef]