ZnO Nanoparticles Embedded on a Reduced Graphene Oxide Nanosheet (ZnO?NPs@r-GO) as a Proficient Heterogeneous Catalyst for a One-Pot A3-Coupling Reaction

Article abstract of DOI:10.1002/ejic.202100368

This study reports a simple and facile route for the synthesis of ZnO nanoparticles (ZnO?NPs) decorated on reduced graphene oxide nanosheet (ZnO?NPs@r-GO) as a heterogeneous catalyst and tested over multicomponent one-pot A³-coupling reaction.

Full text of DOI:10.1002/ejic.202100368

European Journal of Inorganic Chemistry
Accepted Article
Title: ZnO nanoparticles embedded on reduced graphene oxide
nanosheet (ZnO-NPs@r-GO) as a proficient heterogeneous
catalyst for one-pot A3-coupling reaction
Authors: Dikin Patel, Chetan K. Modi, Prafulla K. Jha, Himanshu
Srivastava, and Sanjeev R. Kane
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Inorg. Chem. 10.1002/ejic.202100368
Link to VoR: https://doi.org/10.1002/ejic.202100368
01/2020

10.1002/ejic.202100368
European Journal of Inorganic Chemistry
ZnO nanoparticles embedded on reduced graphene oxide nanosheet
(ZnO-NPs@r-GO) as a proficient heterogeneous catalyst for one-pot
A3-coupling reaction
Dikin Patel[a], Chetan K. Modi[a]*, Prafulla K. Jha[b], Himanshu Srivastava[c],
Mr. Sanjeev R. Kane[c]
[a]
Dr. Dikin Patel, Dr. Chetan K. Modi
Applied Chemistry Department, Faculty of Technology & Engineering, The Maharaja
Sayajirao University of Baroda, Vadodara-390 001, Gujarat, India
chetanmodi-appchem@msubaroda.ac.in
https://www.msubaroda.ac.in/Academics/Departments/teaching/
Prof. Prafulla K. Jha
Department of Physics, Faculty of Science, The Maharaja Sayajirao University of
Baroda, Vadodara, Gujarat 390 002, India
[b]
[c]
Dr. Himanshu Srivastava, Mr. Sanjeev R. Kane
Synchrotrons Utilisation Section, Raja Ramanna Centre for Advanced Technology,
Indore 452013, India
Abstract:
This study reports a simple and facile route for the synthesis of ZnO nanoparticles (ZnO-NPs)
decorated on reduced graphene oxide nanosheet (ZnO-NPs@r-GO) as a heterogeneous catalyst
and tested over multicomponent one-pot A3-coupling reaction. The reduction of graphene oxide
with the anchoring of ZnO-NPs on the r-GO nanosheet was observed through the X-ray
diffraction patterns, Raman, FTIR, and XPS results of the ZnO-NPs@r-GO sample. ZnO-NPs
(average particle size of 3.4±1.5 nm) with uniform size distribution over r-GO nanosheet were
substantiated through HRTEM analysis. Impressively, ZnO-NPs@r-GO significantly used for
A3-coupling reaction with different aromatic aldehydes, active methylene compounds, and urea
and under the optimized reaction conditions gave exceptional activity to produce synthetically
valuable 3,4-dihydropyrimidinones products (possessing diverse therapeutic and
pharmacological properties) i.e. 97% isolated yield of the product. In addition, excellent
reusability up to 4 repeated cycles are the key advantages of the present catalyst used for this
multicomponent A3-coupling reaction.
This article is protected by copyright. All rights reserved.

10.1002/ejic.202100368
European Journal of Inorganic Chemistry
Introduction
The nitrogen-based heterocyclic compounds have huge potential to be employed in wide range
of applications such as their pharmaceutical,1,2 biological activities,3,4 magnetism,5,6
luminescence,7,8 catalysis9,10 and so on. The formation of nitrogen-based heterocyclic
compounds via A3-coupling reaction involves the reaction between an aldehyde, β-keto ester,
and urea or thio-urea is nowadays one of the most fascinated coupling reactions that used to
produce dihydropyrimidinones (DHPMs). Additionally, these reactions are mild, low-cost and
one-pot (in situ) synthesis. The product dihydropyrimidinones (DHPMs) has received a much
attention owing to the discovery of the calcium channel modulating drug, Nifedipine, containing
the DHPM backbone, was used for cardiovascular disease. The discovery of monastrol
containing DHPMs compound was found effectual as an anticancer agent for inhibiting mitotic
kinesin Eg5. Furthermore, DHPMs compounds viz. SQ 32547 and SWO2 are found pertinent as a
useful orally active antihypertensive agent. On the other hand, several esters and cyanide
containing DHPMs are found suitable as antibacterial agents.11-16
In recent decades, the A3- coupling reaction has been performed over strong acidic catalysts such
as TiCl3, BF3.OEt2, ZrCl4, InBr3, BiCl3, Me3SiCl, LiBr, Mn(OAc)3.2H2O, La(OTf)3, Yb(OTf)3,
and Sc(OTf)3. All of the aforesaid systems have been proposed to demonstrate more or less
highly active and -selective products due to the presence of easily accessible active sites.17-30
However, these systems are often regarded as imprecise with many impediments, including
agglomeration of active sites; the contamination of toxic metal is also found along with the
product which is comparatively detrimental one when dealing with the synthesis of biological
products. In this regard, the non-recoverable catalyst from the product is the key challenging task
in the research field. Therefore, to get rid out of these problems and minimize hazards in
biological products, the solid supported catalysts have been widely preferred. In addition to this,
the need for the solid supported catalysts is caused by the presence of large surface area, defects
sites and excellent mechanical strength in relation to the total catalyst loading, which leads to
easily adsorb of the more active site i.e. active metal precursor. At the present time, the effective
and multifaceted solid supports such as silica, activated carbon, zeolites, SBA-15 and several
others have been reported for one-pot coupling reaction including Homo coupling, cross-
coupling and A3-coupling reactions.30-36 Previously, Fe3O4 nanoparticles embedded on the
This article is protected by copyright. All rights reserved.

10.1002/ejic.202100368
European Journal of Inorganic Chemistry
mesoporous SBA-15 support using an “in situ” approach have been reported by D. Bhuyan and
co-workers37 and catalytically tested over A3-coupling reaction. Bao-Dui Wang et al.38 have been
synthesized graphene-Fe3O4 catalyst with unwavering Fe3O4 NPs by the decomposition of
Fe(CO)5 on the surface of graphene oxide. The uniqueness of this work is that the decomposition
products of Fe(CO)5 retaliated with GO leading to the formation of graphene-Fe3O4. The
resulting catalyst was tested over A3-coupling reaction. Another work based on manganese-
containing periodic mesoporous organo silica with ionic-liquid framework (Mn@PMO/IL) in the
A3-coupling reaction was investigated by D. Elhamifar and co-workers.39
Transition metal oxide shows enormous prospective in many important organic transformations
due to their controlled shape, size, stability, a non toxic, crystallinity and functionality, corrosion
resistance, easily scalable, relatively cost effective and non-hygroscopic property, making it as a
proficient catalyst. In past few decades, rGO/ZnO nanocomposites have been explored in various
fields such as electrochemical capacitors,40 adsorbents for pollutants and removal of RhB dye
from water,41 photocatalysts and manufacture of organic photovoltaics.31 Though for organic
transformations,43-44 ZnO nanoparticles (NPs) have been established as solitary heterogeneous
catalysts however, to the best of our knowledge, only few reports on rGO/ZnO nanocomposites
as catalysts have been reported in the literature.45-47 In continuation of our earlier work48-50, here
in we report highly efficient ZnO-NPs@r-GO as a proficient heterogeneous catalyst and
substantiated through various characterization tools. The accountability of rGO in ZnO-NPs@r-
GO nanocatalyst is mainly providing tangible support which enhances the mechanical strength of
the catalyst and also uniform dispersibility of ZnO-NPs. In addition to this, the active sites are
easily accessible to the substrate molecule to be adsorbed effortlessly, which aids in easy
recoverability and recyclability of the catalyst.51,52 The catalytic aptitude in terms of superiority,
consistency and vitality was inspected over one-pot A3-coupling reaction with different aromatic
aldehydes, active methylene compounds and urea. The impact of discrete parameters influencing
catalytic activity such as catalyst dosage, solvent, varying amount of urea and time has also been
monitored.
This article is protected by copyright. All rights reserved.

10.1002/ejic.202100368
European Journal of Inorganic Chemistry
Results and discussion
The aforesaid synthesized ZnO-NPs@r-GO nanocatalyst was thoroughly corroborated by various
physico-chemical techniques such as FT-IR, Raman, XRD, XPS, HR-TEM, and
thermogravimetric analysis. The results of as-prepared nanocatalysts have been discussed as
follows:
In view of the fact that the Raman spectroscopy is an imperative tool to construe the structure in
predominantly defects and disorder nature of graphene-based materials. The Raman spectrum of
ZnO-NPs@r-GO nanocatalyst is shown in Fig. 1, which exhibits two notable peaks at around
~1383 and ~1563 cm-1 subsequent to the precise D- and G- band, respectively.
Figure 1. The Raman spectrum of ZnO-NPs@r-GO.
The graphitic peak (G band) at ~1563 cm-1 is owing to the E2g vibrational mode of the C-C bond
stretching, arises due to the sp2 carbon network of the graphene plane, whereas, the disorder peak
(D band) at ~1383 cm-1 is due to symmetry forbidden band of the longitudinal plane phonon
vibration or k-point phonons of the A1g vibrational mode.53 The intensity ratio of the D and G
This article is protected by copyright. All rights reserved.

10.1002/ejic.202100368
European Journal of Inorganic Chemistry
bands i.e. (ID/IG ratio) facilitates to estimate the defects of graphene based compounds where a
higher ratio makes sure of more defects on graphene. The calculated ID/IG ratio of ZnO-NPs@r-
GO nanocatalyst is 1.10, which is comparable to the spectrum of GO (fig. S1).The increment in
the intensity ratio was might be due to the attachment of the metal ion on the surface of GO.
Furthermore, we have also calculated the crystalline size of ZnO-NPs@r-GO nanocatalyst (i. e.
La = 17.48 nm) using Tuinstra–Koenig relation.54
The XRD patterns are the prominent technique used to determine the crystallinity of as-prepared
nanocatalysts. The XRD patterns of ZnO-NPs and ZnO-NPs@r-GO nanocatalysts are shown in
Fig. 2 whereas, XRD patterns of GO is given in supplementary file (see Fig. S2). The peak
observed at 11.8o in the XRD pattern of GO, which has been disappeared and a new diffraction
peak is observed at 24.3º (Fig. 2) with inter-layered distance of 3.6 Å after the in situ anchoring
of ZnO nanoparticles and reduction of GO nanosheets. This result clearly indicates that some of
the oxygen containing debris have been abolished and the formation of new in-plane sp2 domains
during the reduction process. The aforesaid results are in well accordance with Raman and XPS
results.
Figure 2. XRD patterns of (A) ZnO-NPs and (B) ZnO-NPs@r-GO.
This article is protected by copyright. All rights reserved.

10.1002/ejic.202100368
European Journal of Inorganic Chemistry
In the XRD patterns of ZnO-NPs@r-GO nanocatalyst [Fig. 2(B)], the diffraction peaks at 31.7º,
34.4º, 36.1º, 47.6º, 56.7º, 62.9º, 68.0º and 70.9º were reconcilable with those of (1 0 0), (0 0 2),
(1 0 1), (1 0 2), (1 1 0), (1 0 3), and (1 1 2), respectively,55 pointing towards the hexagonal
wurtzite structure of ZnO (JPCDS 36-1451). These results are more uniform to that observed in
neat ZnO-NPs XRD patterns [Fig. 2(A)].56 The diffraction peak observed at 24.3º, due to the
distinctive absorption peak for graphene. Whereas no such peak was observed together with no
strong absorption observed at the diffraction peak of 11.8º, suggesting that the GO is changed
into reduced graphene oxide during the reduction process.
The surface chemical composition and bonding environment of as-prepared nanocatalyst was
analyzed by the X-ray photoelectron spectroscopy (XPS). As shown in Fig. 3(A), the survey
spectra of ZnO-NPs@r-GO are displayed three prominent elements C 1S, O 1S and Zn 2p at
about 282.9, 534.8, and 1031.8, respectively. In the Zn 2p core level spectra [Fig. 3(B)], two
prominent peaks observed at 1022.6 eV and 1045.6 eV corresponds to Zn 2p3/2 and Zn 2p1/2,
respectively, indicating that Zn was present in the form of zinc oxide.
This article is protected by copyright. All rights reserved.

10.1002/ejic.202100368
European Journal of Inorganic Chemistry
Figure 3. XPS spectra (A) survey spectra of ZnO-NPs@r-GO, (B) Zn sp core level spectrum,
(C) C 1s spectra of ZnO-NPs@r-GO and (D) O 1s spectra of ZnO-NPs@r-GO.
While comparing C 1s spectra of GO (Fig. S3) with the high-resolution C 1s spectra of ZnO-
NPs@r-GO nanocatalyst [Fig. 3(C)] four prominent peaks observed at 286.4, 288.2, 289.3 and
291.3 eV, assigned to sp2-C, -CO, -C=O, and -COOH, respectively. These results showed that
the intensity of peaks -CO, -C=O and-COOH was considerably low and while the magnitude of
sp2-C peak was dramatically increased owing to the restoration of the sp2 domains in the new
plane. These results are in well agreement with the Raman spectra. The high resolution O 1s
spectrum of ZnO-NPs@r-GO nanocatalyst [Fig. 3(D)] has shown three peaks at ~533.2, ~538.2
This article is protected by copyright. All rights reserved.

10.1002/ejic.202100368
European Journal of Inorganic Chemistry
and ~539.3 eV. Among them, the first two peaks are attributed to the lattice oxygen (OL) and
chemisorbed oxygen (OC) species, respectively, whereas the later peak observed at ~539.3 eV,
indicating the C=O bond in the wurtzite structure of hexagonal ZnO. In addition, we have
calculated loading amount of ZnO using quantitative XPS and observed of about 0.6% loading in
ZnONPs@rGO catalyst.
Figure 4. (a, b) Low magnification TEM image of ZnO-NPs@r-GO, (c, d) HR-TEM image of
ZnO-NPs@r-GO with fringe spacing, (e) SAED pattern of ZnO-NPs@r-GO, (f) Histogram
graph of ZnO-NPs@r-GO.
The HR-TEM images of ZnO-NPs@r-GO nanocatalyst are shown in Fig. 4. The TEM images of
ZnO-NPs@r-GO demonstrated the fine narrow sized ZnO nanoparticles were dispersed on rGO
nanosheet [Fig. 4 (a, b)].The ZnO nanoparticles have observed an average particle size of
3.4±1.5 nm [Fig. 4(f)]and have clearly shown the size distribution of ZnO nanoparticles on the
rGO nanosheet, which was investigated by ImageJ software. As depicted in Fig. 4(d), the
nanocatalyst has given the information pertaining to the crystal lattice fringes of ZnO-NPs with a
d-spacing of 0.22 nm, indicating with the plane of cubic ZnO-NPs. In the SAED image of ZnO-
NPs@r-GO [Fig. 4(e)], the diffraction pattern was perceived, which substantiates the
polycrystalline nature of ZnO-NPs on the surface of r-GO nanosheets. The intense spherical dots
This article is protected by copyright. All rights reserved.

10.1002/ejic.202100368
European Journal of Inorganic Chemistry
of ZnO-NPs were also observed in the SAED pattern. These results are in well agreement with
the XRD data as discussed above.
The FTIR spectra of ZnO-NPs and ZnO-NPs@r-GO are shown in Fig. 5. In the FTIR spectrum
of ZnO-NPs, the band observed at 496 cm-1, which indicates the vibrational mode of Zn-O
bonds. However, in the spectrum of ZnO-NPs@r-GO, this band was slightly moved towards the
lower wavelength (480 cm-1), which might be due to ZnO nanoparticle supported on rGO
nanosheet.57
Figure 5. FTIR spectra of ZnO-NPs and ZnO-NPs@r-GO.
Moreover, the peak observed in the FTIR spectrum of ZnO-NPs at ~950 cm-1 is assigned to Zn-
OH bonds. The same band was also seen in the FTIR spectrum of ZnO-NPs@r-GO. In the FTIR
spectrum of ZnO-NPs@r-GO, two additional stretching vibrations are observed at ~3440 and in
the region, 2860-2880 cm-1, are corresponding to the -OH and aromatic C-H stretching
vibrations, respectively. In the FTIR spectra of GO (Fig. S5), the intense peak observed at
This article is protected by copyright. All rights reserved.

10.1002/ejic.202100368
European Journal of Inorganic Chemistry
around 1700 cm-1 is due to υ(C=O) stretching vibration of the –COOH group, was disappeared in
the spectra of ZnO-NPs@r-GO. In addition to this, one prominent peak observed at 1220 cm-1 in
the spectra of ZnO-NPs@r-GO, is due to the epoxy group and was remained intact after the
chemical reduction process.58
In the subsequent section, the thermal behavior of the as-synthesized catalyst, characterized on
the basis of thermogravimetric method is discussed. The quantitative purpose of the organic
content and the thermal stability of the compound have been achieved through the
thermogravimetric analysis. The thermogram of ZnO-NPs@r-GO nanocatalyst is fairly matched
with GO. As shown in Fig. 6, the first weight loss (~6.2%) observed in the temperature range
110-280 ºC is assigned to the removal of the most of the oxygen containing functional groups.
This was followed by a gradual plunge in the weight loss of 49.6% in the temperature range of
o
400- 650 C, assumed to be due to the pyrolysis of carbonaceous stuff of the graphene
nanosheets.
Figure 6. TG analysis of ZnO-NPs@r-GO.
This article is protected by copyright. All rights reserved.

10.1002/ejic.202100368
European Journal of Inorganic Chemistry
Catalytic study
In the previous section, as-prepared nanocatalysts have been successfully synthesized and
characterized. However, herein this segment, we have discussed the catalytic activity of as-
synthesized nanocatalysts executed over the One-pot A3-coupling reaction using aldehyde, ethyl
acetoacetate and urea as starting materials and ethanol as a greener solvent to form 3,4-
dihydropyrimidin-2 (1H)-ones as the main product (Scheme 1).
Scheme 1. A schematic representation of Biginelli reaction.
Under the typical reaction conditions, A3-components i.e. Benzaldehyde (1 mmol), ethyl acetate
(1 mmol) and urea (0.8 mmol) were dissolved into 5 mL ethanol and then 10 mg catalyst was
taken in RBF. To acquire the optimum results, first, all the catalysts like GO, ZnO, CuO,
Zn(CH3COO)2, Cu(NO3)2, ZnO-NPs@r-GO, and Cu-NPs@r-GO were employed to get best-
suited catalyst for this Biginelli reaction and the results are shown in Fig. 7. The results clearly
indicate lower yields are observed with species like GO, ZnO, CuO, Zn(CH3COO)2, Cu(NO3)2
and without catalyst. However, the conspicuous results are observed with supported systems like
ZnO-NPs@r-GO and Cu-NPs@r-GO. Amongst them, ZnO-NPs@r-GO has found most suitable
catalyst giving optimal yield (84%) under the optimized conditions and therefore, it has been
chosen for further experiments.
This article is protected by copyright. All rights reserved.

10.1002/ejic.202100368
European Journal of Inorganic Chemistry
Figure 7. The catalytic activity of various catalysts for one-pot A3-coupling reaction.
Reaction conditions: benzaldehyde (1 mmol), Ethyl acetoacetate (1 mmol), Urea (1.2 mmol)
varying catalysts (10 mg), Ethanol (5 mL), temp. (Reflux i.e. 75 ºC), Time (3.5 h).
Factor affecting the one-pot A3-coupling reactions
Effect of catalyst dosage
The catalyst concentration is a one of the significant aspects in the A3-coupling reaction. As
shown in Fig. 8, five different dosages viz. 5 mg, 10 mg, 15 mg, 20 mg, and 30 mg of the
representative catalyst, i.e. ZnO-NPs@r-GO were taken with keeping all other reaction
parameters fixed: temperature (65°C), benzaldehyde (1 mmol), ethyl acetoacetate (1 mmol), urea
(1.2 mmol), ethanol (5 mL), and reaction time (3.5 h).The results are shown in Fig. 8. The
maximum yield (93%) of the product was achieved with 15 mg of catalyst. While further
increasing the catalyst amount showed a downward trend of the product yield (see Fig. 8). The
reduction trend in the product yield was might be due to certain concentration of the product
This article is protected by copyright. All rights reserved.

10.1002/ejic.202100368
European Journal of Inorganic Chemistry
adsorbed on the catalytic active sites. As a result, the optimal catalyst amount has taken to be 15
mg for the further investigation.
Figure 8. The effect of catalyst dosage for One-pot A3-coupling reaction.
Reaction conditions: benzaldehyde (1 mmol), Ethyl acetoacetate (1 mmol), Urea (1.2 mmol)
ZnO-NPs@r-GO (X mg), Ethanol (5 mL), temp. (Reflux), Time (3.5 h).
Effect of various solvents
The effect of varying solvents such as polar protic i.e. ethanol, polar aprotic i.e. acetonitrile
(ACN) and non-polar i.e. toluene was examined (Fig. S7) over A3-coupling reaction with other
parameters kept fixed to increase the yield of the product. As shown in Fig. S7, the product yield
achieved with different solvent systems in the decreasing order as Ethanol (93%) > ACN (75%)
> toluene (51%). Initially, we have also performed the aforesaid catalytic reaction without
solvent, however; as prophecy, we could not observe the as-expected elevated yield (21%).
Among the various solvent systems, when ethanol was utilized, an optimum yield of the product
(93%) was obtained. Consequently, ethanol is preferred to be used as a solvent for the aforesaid
reaction.
This article is protected by copyright. All rights reserved.

10.1002/ejic.202100368
European Journal of Inorganic Chemistry
Effect of amount of urea
Varying amounts of urea such as 1:1:0.8, 1:1:1, 1:1:1.2, and 1:1:1.4 with benzaldehyde, ethyl
acetoacetate are employed to examine their effect on the A3- coupling reaction with keeping all
other parameters fixed. A key role of urea is clearly perceptible from Fig. S8. Highest product
yield of 3,4-dihydropyrimidin-2 (1H)-ones (97%) is obtained with 1:1:1 mole ratio, while on
further increasing the concentration of urea with increasing mole ratios i.e. 1:1:1.2 and 1:1:1.4,a
downtrend is observed with product yield of 93% and 89%, respectively. This reduction was
believed to be due to the probability of the extra urea and water to form ammonium. Hence,
1:1:1 mole ratio is preferred for the further experiments keeping other parameters fixed.
Effect of Time
To obtain the precise isolated yield of the product, it is of rather imperative to end up the reaction
at accurate time. This study is aiming to find out the accurate time for this multicomponent A3-
coupling reaction using ZnO-NPs@r-GO as a representative catalyst. As shown in Fig. S9, we
have conducted this experiment at five different time viz. 1, 2, 3, 3.5 and 5 h by keeping other
parameters fixed. It can be seen from the figure that to begin with at 1 h, 42% isolated product
yield was attained. However, on enduring the reaction with time, the product yield also upholds
in the increasing trend and achieved maximum (97%) at 3.5 h. If the reaction still continued to 5
h, no further increment in the yield of the product was achieved. As a result, we have chosen 3.5
h as the ideal time for further examination of other experimental variables.
After getting the optimized conditions, we have further been exploring the scope of A3-coupling
reaction etiquette by altering substrates like aldehydes, ethyl and/or methyl acetoacetate and urea
producing a wide range of dihydropyrimidinones (DHPMs) and its derivatives (Table 1). While
the reactions using various aldehydes including 4-methyl benzaldehyde and/or 4-methoxy
benzaldehyde, furfuraldehyde and ethyl acetoacetate and urea gave comparatively exceptional
yield than the product yields acquired using various aldehydes, methyl acetoacetate and urea
(Table 1). Consequently, ethyl acetoacetate is quite better substrate than methyl acetoacetate.59
This article is protected by copyright. All rights reserved.

10.1002/ejic.202100368
European Journal of Inorganic Chemistry
Table 1. The scope of ZnO-NPs@r-GO nanocatalyst over Biginelli condensation reaction using
various aldehydes, β-keto esters and urea
aTON (turnover number) = Moles of desired product formed/moles of catalyst.
A plausible mechanism for the Biginelli condensation reaction using ZnO-NPs@r-GO as a
representative catalyst is demonstrated in Scheme 2. The reaction begins with the activation of a
carbonyl group via the attachment of the substrate (aromatic aldehyde) onto the active site of
ZnO-NPs@r-GO, followed by the nucleophilic attack of urea to an activated aldehyde, so as to
generate the intermediate species (i.e. imine adduct). This imine intermediate is attacked by an
ethyl acetoacetate molecule forming another intermediate (Scheme 2). It was then followed by
the addition-elimination reactions, leading to the formation of the desired product.59
This article is protected by copyright. All rights reserved.

10.1002/ejic.202100368
European Journal of Inorganic Chemistry
Scheme 2. A plausible reaction mechanism for the Biginelli condensation reaction over ZnO-
NPs@r-GO nanocatalyst.
Recyclability
The reusability of the catalyst is of enormous consequence applicable to any heterogeneous
catalytic system. The reusability of ZnO-NPs@r-GO as a representative catalyst was tested over
A3-coupling reaction and the results are shown in Fig. S10. Prior to examine this, the catalyst is
recovered from the reaction mixture by filtration and washed several times with acetonitrile
This article is protected by copyright. All rights reserved.

10.1002/ejic.202100368
European Journal of Inorganic Chemistry
followed by drying in an oven before utilizing for the further catalytic test. As seen in Fig. S10 it
was recycled up to 5 times without any significant loss in activity, despite the fact that in the 4th
and 5th run, the product yield decreasing up to 93% and 90%, respectively.59
Table 2. Comparative study
In the past couple of years, catalytic studies over A3-coupling reaction by various research
groups using diverse homogeneous and/or heterogeneous catalysts have been discussed and are
tabulated in Table 2. J. Mondal et al.60 have executed the Biginelli reaction over Fe3O4@SBA-15
as an efficient heterogeneous catalyst using ethanol as a solvent at 90 oC, achieving 85% product
yield after 6 h (Table 2, entry 1). J. Ma et al.61 have accomplished Biginelli reaction over D-
o
Xylonic acid as a catalyst, getting 89% product yield after 5 h at 100 C (Table 2 entry 2). T. K.
Pal et al.62 developed a partially fluorinated, water-stable Cu(II)−MOF catalytic system,
o
achieving a maximum of 89% product yield at 60 C after 2 h (Table 2, entry 3). Shi and co-
workers63 have reported the Biginelli reaction catalyzed by PPF-SO3H (sulfonic acid
functionalized polypropylene fiber) using ethanol as a solvent under reflux for 8 h, achieving
74% product yield (Table 2, entry 4). Heravi and co-workers64 have used 12-Tungstophosphoric
acid as a catalyst for Biginelli reaction under reflux for 6-7 h, achieving 70% of the product yield
This article is protected by copyright. All rights reserved.

10.1002/ejic.202100368
European Journal of Inorganic Chemistry
.
(Table 2, entry 5). Furthermore, FeCl3 6H2O used as a catalyst by ZT Wang and co-workers65
over Biginelli reaction using acetonitrile as a solvent (under 12 h reflux time), obtaining 88% of
the product yield (Table 2, entry 6). Sujahta et al66 have used green CuO nanoparticles as catalyst
for Biginelli reaction under 90 oC for 50 min, obtaining 98% of the product yield (Table 2, entry
7). Here in this work, our own results (Table 2, entry 8) show that, when ZnO-NPs@r-GO was
used for ‘one-pot’ A3-coupling reaction under optimized reaction condition bestowed exceptional
product yield of 97% in 3.5 h under refluxing temperature i.e. 75 ºC.
Conclusion
In concluding remarks, we have synthesized highly efficient ZnO-NPs@r-GO as a proficient
heterogeneous catalyst for one-pot A3-coupling reaction. Graphene oxide was synthesized using
modified Hummer's method and during the anchoring of ZnO-NPs on rGO nanosheet; graphene
oxide was subjected to partial reduction as observed from the X-ray diffraction patterns, Raman,
FTIR and XPS results of ZnO-NPs@r-GO sample. ZnO-NPs were found to be successfully
diffused over the surface of rGO nanosheet as substantiated from HRTEM analysis with average
particle size of 3.4±1.5 nm was investigated by ImageJ software. The intense spherical dots of
ZnO-NPs were also examined in the SAED pattern. The as-synthesized ZnO-NPs@r-GO catalyst
demonstrated exceptional catalytic activity for one-pot A3-coupling (Biginelli condensation)
reaction under the optimized reaction conditions to give preferred DHPM products in good to
admirable yields. Besides, the plausible catalytic mechanism for the aforesaid condensation
reaction has also been proposed and discussed. The nanocatalyst ZnO-NPs@r-GO also exhibited
remarkable stability, recyclability and leaching-resistant performance with recycled up to four
times without significant loss of activity.
Experimental Section
Materials
Natural flake graphite (325 mesh, 99.95%) was purchased from Sigma Aldrich. potassium
permanganate, zinc acetate was acquired from MERCK India Pvt Ltd. Urea, ethyl acetoacetate,
methyl acetoacetate, sulphuric acid, sodium nitrate, l-ascorbic acid, hydrochloric acid, 30%
hydrogen peroxide, benzaldehyde, 4-methyl benzaldehyde, 4-methoxy benzaldehyde,
This article is protected by copyright. All rights reserved.

10.1002/ejic.202100368
European Journal of Inorganic Chemistry
furfuraldehyde, 4-nitro benzaldehyde were procured from S D Fine Chem Ltd. All the materials
are of analytical grade and used as received without further purification.
Synthesis of graphene oxide (GO)
Graphene oxide was synthesized from graphite flakes using a modified Hummer’s method.49, 67
Synthesis of ZnO nanoparticles (ZnO-NPs)
The ZnO-NPs were prepared as follows: Zinc acetate dehydrate (2 g) was dissolved in 20 mL of
deionized water. This aqueous solution of zinc acetate was then heated at 70 ºC with continuous
stirring in a magnetic stirrer. Then, a freshly prepared (4 g) NaOH solution was added drop wise
into an aqueous solution of zinc acetate with constant stirring and refluxed for 4 h at 70 ºC. The
obtained white suspension was filtered, carefully washed with deionized water (until the pH
maintained up to 6), dried in air oven at 70 °C and finally calcined at 550 °C for 6 h to get white
powder of ZnO-NPs.
Synthesis of ZnO-NPs@r-GO nanocatalyst
A 50 mg of GO was dispersed into deionized water (15 mL) in a 250 mL beaker followed by a
dropwise addition of 10 mmol Zn(CH3COO)2 solution and then ultrasonicated for 20 min to
produce uniformly dispersed suspension. A freshly prepared solution of l-ascorbic acid (25 mL)
was then added drop wise into the above suspension with constant stirring and heated at 90 ºC
for 4 h. The obtained black precipitates signify the successful reduction of both metal salts and
GO. The excess of ascorbic acid can be eradicated from the product using H2O2 solution. The
solid product was separated by centrifugation followed by washed with ethanol and deionized
water and finally dried in an oven at 65 oC.
Catalytic test
In a typical Biginelli reaction experiment, a mixture of 1 mmol of benzaldehyde, 1 mmol of ethyl
acetoacetate, 0.8 mmol of urea, 5 mL solvent and 10 mg catalyst were added into a 50 mL round
bottom flask and the reaction mixture was kept under vigorous stirring. The reaction progress
was screened by TLC. The reaction mixture was filtered; the solvent was evaporated from the
This article is protected by copyright. All rights reserved.

10.1002/ejic.202100368
European Journal of Inorganic Chemistry
filtrate under reduced pressure to achieve a solid product. However, separation was carried out
by column chromatography over silica gel using petroleum ether and ethyl acetate as an eluent.
The pure products were characterized by (1H & 13C NMR, FTIR) spectral analysis and compared
with reported data as given in Supplementary section, however, melting point (ºC) of products
are given in Table 1.
Conflicts of interest
The authors declare no conflict of interest.
Acknowledgements
We express our gratitude to the Head, Applied Chemistry Department, Faculty of Technology &
Engineering, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, India, for
providing the necessary laboratory facilities. The authors would like to present his deep thanks
and gratitude to Dr. R. J. Choudhary, Synchrotrons Utilisation Section, Raja Ramanna Centre for
Advanced Technology, Indore, India for the help in carrying out work on the Indus-1
synchrotron source.
Keywords: C-C coupling, reduced graphene oxide nanosheet, supported catalysts, ZnO
nanoparticles
This article is protected by copyright. All rights reserved.

10.1002/ejic.202100368
European Journal of Inorganic Chemistry
References
1. C.X. Su, J.F. Mouscadet, C.C. Chiang, H.J. Tsai, L.Y. Hsu, Chem. Pharm. Bull., 2006, 54,
682.
2. R. Chikhale, S. Menghani, R. Babu, R. Bansode, G. Bhargavi, N. Karodia, M. V.
Rajasekharan, A. Paradkar, P. Khedekar, Eur. J. Med. Chem. 2015, 96, 30−46.
3. K. L. Dhumaskar, S. N. Meena, S. C. Ghadi, S. G. Tilve, Bioorg. Med. Chem. Lett. 2014, 24,
2897–2899
4. M. Kidwai, S. Saxena, M. K. R. Khan, S. S. Thukral, Eur. J. Med. Chem. 2005, 40, 816–819.
5. J. X. Li, Z. X. Du, L. Y. Xiong, L. L. Fu, W. B. Bo, J. Solid. State Chem. 2021, 293, 121799.
6. J. X. Li, Z. X. Du, Q.Y. Pan, L. L. Zhang, D. L. Liu, Inorg. Chim. Acta 2020, 509, 119677.
7. Y.-J. Liang, G. Feng, X. Zhang, J. X. Li, Y. Jiang, J. Struct. Chem., 2021, 62, 300.
8. Z. Zheng, P. Xu, Y. Jiang, Y. J. Liang, J.-X. Li, J. Struct. Chem. 2021, 62, 292.
9. M. Barbero, S. Cadamuro, S. Dughera, Green Chem. 2017, 19, 1529–1535
10. G. Kour, M. Gupta, S. Paul, V.K. Gupta Rajnikant, J. Mol. Catal. A: Chem. 2014, 392,
260–269.
11. (a) T. Boer; A. Amore; R.V.A. Orru, Microwaves in Organic Synthesis, 2nd Edn, Wiley-
VCH, Weinheim, 2006, pp. 788-819; (b) M. Malacria, Chem. Rev. 1996, 96, 289-306.
12. (a) C. D. Graaff; E. Ruijter; R. V. A. Orru, Chem. Soc. Rev. 2012, 41, 3969-4009; (b) M. M.
Heravi; S. Asadi; B. M. Lashkariani, Mol. Divers. 2013, 17, 389-407.
13. K. S. Atwal; G. C. Rovnyak; S. D. Kimball; D. M. Floyd; S. Moreland; B. N. Swanson; J. Z.
Gougoutas; J. Schwartz; K. M. Smillie; M.F. Malley, J. Med. Chem. 1990, 33, 2629-2635.
14. (a) T. M. Mayer; T. M. Kapoor; S. J. Haggarty; R. W. King; S. L. Schreiber; T. J. Mitchison,
Science 1999, 286, 971-974; (b) C. O. Kappe; O. V. Shishkin; G. Uray; P. Verdino,
Tetrahedron 2000, 56, 1859-1862.
15. C. O. Kappe, Acc. Chem. Res. 2000, 33, 879-888.
16. L. Heys; C. G. Moore; P. J. Murphy, Chem. Soc. Rev. 2000, 29, 57-67.
17. D. Astruc; F. Chardac, Chem. Rev. 2001, 101, 2991-3024.
18. B. Helms; J. M. J. Fréchet, Adv. Synth. Catal. 2006, 348, 1125-1148.
19. M. Shema-Mizrachi; G. M. Pavan; E. Levin; A. Danani; N. G. Lemcoff, J. Am. Chem. Soc.
2011, 133, 14359-14367.
20. E. L. Margelefsky; R. K. Zeidan; M. E. Davis, Chem. Soc. Rev. 2008, 37, 1118-1126.
This article is protected by copyright. All rights reserved.

10.1002/ejic.202100368
European Journal of Inorganic Chemistry
21. A. Mondoli; M. Lessi; D. Pini; C. Evangelisti; P. Salvadori, Adv. Synth. Catal. 2008, 350,
375-379.
22. K. Ding; Z. Wang; L. Shi, Pure Appl. Chem. 2007, 79, 1531-1540.
23. Z. Wang; G. Chen; K. Ding, Chem. Rev. 2009, 109, 322-359.
24. L. Marchetti; M. Levine, ACS Catal. 2011, 1, 1090-1118.
25. Z. Zhang; Z. Wang, J. Org. Chem. 2006, 71, 7485-7487.
26. S. B. Kim; P. D. Pike; D. A. Sweigart, Acc. Chem. Res. 2013, 46, 2485-2497.
27. B. M. Choudhary; R. M. Sharma; K. K. Rao, Tetrahedron 1992, 48, 719-726.
28. L. Djakovitch; M. Wagner; C. G. Hartung; M. Beller; K. Kohler, J. Mol. Catal. A 2004, 219,
121-130.
29. L. Yin; J. Liebscher, Chem. Rev. 2007, 107, 133-173.
30. N. Pal; A. Bhaumik, RSC Adv. 2015, 5, 24363-24391.
31. Y. -B. Huang; J. Liang; X. -S. Wang; R. Cao, Chem. Soc. Rev. 2017, 46, 126-157.
32. H. Li; Q. Pan; Y. Ma; X. Guan; M. Xue; Q. Fang; Y. Yan; V. Valtchev; S. Qiu, J. Am.
Chem. Soc. 2016, 138, 14783-14788 .
33. H. Wang; C. Wang; Y. Yang; M. Zhao; Y. Wang, Catal. Sci. Technol. 2017, 7, 405-417.
34. H. Li; J. He; A. Riisager; S. Saravanamurugan; B. Song; S. Yang, ACS Catal. 2016, 6, 7722-
7727.
35. J. Du; M. Tao; W. Zhang, ACS Sustain. Chem. Eng. 2016, 4, 4296-4304.
36. L. V. Chopda, P. N. Dave, ChemistrySelect 2020, 5, 5552-5572.
37. D. Bhuyan; M. Saikia; L. Saikia, Catal. Commun. 2015, 58, 158-163.
38. X. Huo; J. Liu; B. Wang; H. Zhang; Z. Yang; X. She; P. Xi, J. Mater. Chem. A 2013, 1, 651-
656.
39. D. Elhamifar; D. Elhamifar; F. Shojaeipoor, J. Mol. Catal. A 2017, 426, 198-204.
40. Y. Chen; Z. Hu; Y. Chang; H. Wang; Z. Zhang; Y. Yang; H. Wu, J. Phys. Chem. C 2011,
115, 2563-2571.
41. B. Li; H. Cao, J. Mater. Chem. 2011, 21, 3346-3349.
42. K. S. Shin; H. Jo; H. -J. Shin; W. M. Choi; J. -Y. Choi; S. -W. Kim, J. Mater. Chem. 2012,
22, 13032-13038.
43. A. Kumar; D. Saxena; M. Gupta, Green Chem. 2013, 15, 2699-2703.
44. P. Ghosh; A. Das, J. Org. Chem. 2013, 78, 6170-6181.
This article is protected by copyright. All rights reserved.

10.1002/ejic.202100368
European Journal of Inorganic Chemistry
45. U. Rajesh; J. Wang; S. Prescott; T. Tsuzuki; D. Rawat, ACS Sustain. Chem. Eng. 2015, 3,
2397-2404.
46. Z. Li; H. Zhao; H. Han; Y. Liu; J. Song; W. Huo; W. Chu; Z Sun, Tetrahedron Lett. 2017,
58, 3984-3988.
47. Q. Zhang; C. G. Tian; A. P. Wu; T. Tan; L. Sun; L. Wang; H. Fu, J. Mater. Chem. 2012, 22,
11778-11784.
48. D. Patel; R. Vithalani; C. K. Modi, New J. Chem., 2020, 44, 2868-2881.
49. R. Vithalani; D. Patel; C. K. Modi; V. Sharma; P. K. Jha, Appl. Organomet. Chem. 2020, 34,
e5500.
50. R. Vithalani; D. Patel; C. K. Modi; N. N. Som; P. K. Jha; S. R. Kane, Diam. Relat. Mater.
2018, 90, 154-165.
51. A. Bahuguna; A. Kumar; T. Chhabra; A. Kumar; V. Krishnan, ACS Appl. Nano Mater.
2018, 1, 6711–6723.
52. Y. Zhu; S. Murali; W. Cai; X. Li; J. W. Suk; J. R. Potts; R. S. Ruoff, Adv. Mater. 2010, 22,
3906–3924.
53. S. Mondal; S. Sudhu; S. Bhattacharya; S. K. Saha, J. Phys. Chem. C 2015, 119, 27749-
27758.
54. F. Tuinstra; J. L. Koenig, J. Chem. Phys. 1970, 53, 1126-1130.
55. B. Helms; J. M. J. Fréchet, Adv. Synth. Catal. 2006, 348, 1125-1148.
56. S. Yang; X. Feng; S. Ivanovici; K. Muellen, Angew. Chem. Int. Ed. 2010, 49, 8408-8411.
57. K. B. Babitha; J. Jani Matilda; A. P. Mohamed; S. Ananthakumar, RSC Adv. 2015, 5, 50223-
50233.
58. D. Bhuyan; M. Saikia; L. Saikia, Micropor. Mesopor. Mater. 2018, 256, 39-48.
59. Z. Ghadamyari; A. Shiri; A. Khojastehnezhad; S. M. Seyedi, Appl. Organometal Chem.
2019, 33, e5091.
60. J. Mondal; T. Sen; A. Bhaumik, Dalton Trans. 2012, 41, 6173-6181.
61. J. Ma; L. Zhong; X. Peng; R. Sun, Green Chem. 2016, 18, 1738-1750.
62. T. K. Pal; D. De; S. Senthilkumar; S. Neogi; P. K. Bharadwaj, Inorg. Chem. 2016, 55, 7835-
7842.
63. X. L. Shi; H. Yang; M. Tao; W. Zhang, RSC Adv. 2013, 3, 3939-3945.
64. M. M. Heravi; F. Derikvand; F. F. Bamoharram, J. Mol. Catal. A 2005, 242, 173-175.
This article is protected by copyright. All rights reserved.

10.1002/ejic.202100368
European Journal of Inorganic Chemistry
65. Z. T. Wang; L. W. Xu; C. G. Xia; H. Q. Wang, Tetrahedron Lett. 2004, 45, 7951-7953.
66. S. Prakash, N. Elavarasan, A. Venkatesan, K. Subashini, M. Sowndharya, V. Sujatha, J.
Adv. Powder Technol. 2018, 29, 3315-3326.
67. R. Vithalani; D. Patel; C. K. Modi; P. K. Jha; H. Srivastava; S. R. Kane, Graphene Technol.
2020, 5, 83-101.
This article is protected by copyright. All rights reserved.

10.1002/ejic.202100368
European Journal of Inorganic Chemistry
Table of Contents
ZnO nanoparticles adorned on reduced graphene oxide nanosheet (ZnO-NPs@r-GO) have shown
admirable catalytic activity for multicomponent one-pot A3-coupling reaction under mild
reaction conditions to give preferred 3,4-dihydropyrimidinones products in good to venerable
yields.
This article is protected by copyright. All rights reserved.