A green, efficient and recoverable CeO2/MWCNT nanocomposite catalyzed click synthesis of pyridine-3-carboxamides

Article abstract of DOI:10.1002/aoc.5796

A facile, green and environmentally-friendly protocol for the preparation of ceria doped multi-walled carbon nanotubes (2.5percentCeO₂/MWCNTs) composite catalysts are developed. The synthesized catalyst materials have been characterized by usin

Full text of DOI:10.1002/aoc.5796

Received: 2 March 2020
DOI: 10.1002/aoc.5796
Revised: 18 April 2020
Accepted: 23 April 2020
F U L L P A P E R
A green, efficient and recoverable CeO2/MWCNT
nanocomposite catalyzed click synthesis of pyridine-
3-carboxamides
Singamsetty Harikrishna1 | Alice R. Robert1 | Himavathi Ganja1
|
Suresh Maddila1,2
| Sreekantha B. Jonnalagadda2
1Department of Chemistry, GITAM
Institute of Sciences, GITAM University,
Visakhapatnam, Andhra Pradesh, India
2School of Chemistry & Physics,
University of KwaZulu-Natal, Westville
Campus, Durban, Chiltern Hills, 4000,
South Africa
A facile, green and environmentally-friendly protocol for the preparation of
ceria doped multi-walled carbon nanotubes (2.5%CeO2/MWCNTs) composite
catalysts are developed. The synthesized catalyst materials have been charac-
terized by using P-XRD, SEM, TEM and BET analysis. Further, the composite
was utilized as a highly efficient and reusable heterogeneous nano-catalyst for
the synthesis of pyridine-3-carboxamide derivatives by multicomponent con-
densation of acetoacetanilide, ammonium acetate, substituted aromatic alde-
hyde and ethyl cyanoacetate via one-pot reaction under ethanol solvent
conditions at R.T. The remarkable advantages of this green protocol exhibits
operational simplicity, easy workup procedure, inexpensive, evading of toxic
solvents, shorter reaction times (≤ 15 mins), excellent yields and also avoid-
ance of column chromatography. Furthermore, the catalyst was recyclable and
reusability endured for a minimum of six consecutive cycles without signifi-
cant loss in the catalytic activity.
Correspondence
Suresh Maddila, Department of
Chemistry, GITAM Institute of Sciences,
GITAM University. Visakhapatnam,
Andhra Pradesh, India.
Email: sureshmskt@gmail.com
K E Y W O R D S
green synthesis, multicomponent reactions, one-pot reaction, Pyridine-3-carboxamides,
synthesized catalyst
1 | INTRODUCTION
inexpensive reagents and catalysts, synthetic efficiency,
diminished by-products, and higher yields.4–6 Conse-
Multi-component reactions (MCRs) are a synthetic meth-
odology involving the preparation of a large moiety in
superior yields through the combination of two or more
reactants at a time in a single-step reaction.1–3 Primarily,
MCRs are an ultimate conversion method to rapidly-
produce functionally varied frameworks for agricultural,
chemical, combinatorial and pharmaceutical chemistry
fields owing to high atom efficiency, saves time and
energy as well, thus serving as a diversified approach for
the synthesis of new organic complex molecules.3,4 Fur-
ther, MCRs show many benefits like operational simplic-
ity, short reaction times, mild reaction conditions, using
quently, the scheming of innovative MCRs is a vital and
gorgeous task.
Nowadays, heterogeneous solid catalysts are exten-
sively used for chemical reactions and industrial pro-
cesses.7 They offer various advantages over the
homogeneous catalysts like simple handling, extended
stability, simple recyclability and reusability without loss
in activity, and low-cost of the catalyst which can make
synthetic procedures very safer, cleaner, non-toxic, and
greener.8–11 Particularly, nano-catalysts owing to their
vast surface area and more catalytic active sites, are
mostly accountable for their admirable catalytic activity.
Appl Organomet Chem. 2020;e5796.
wileyonlinelibrary.com/journal/aoc
© 2020 John Wiley & Sons, Ltd.
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https://doi.org/10.1002/aoc.5796

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HARIKRISHNA ET AL.
Multi-walled carbon nanotubes (MWCNTs) are nested
forms of single-walled carbon nanotubes.12 The doping of
multi-walled carbon nanotubes with some competent mate-
rials has prominent applications in various fields due to
their unique properties which include large surface area,
porous structure, morphologies, and improved mechanical,
thermal and electrical properties.13 Mainly MWCNTs as
supports provide a large surface area for high dispersal of
catalysts, excellent crystallinity, distinctive porosity,
assisting electron conveyance for the length of reactions
and worthy interaction between the carbon support and
nanoparticles.13,14 On the other hand, metal oxides are sig-
nificant nanomaterials used in various fields of chemistry
particularly in heterogeneous catalysis areas. In recent
times, more attention has been focused on an eco-friendly
transition metal oxide ceria (CeO2) due to its non-hazard-
ous, inexpensive, easy accessibility, non-volatility, high
chemical and thermal stability. Mostly, the usage of hetero-
genized version of ceria is a desirable choice for green
organic transformations.15–17 Therefore, CNTs with metal
oxides have been broadly examined to obtain loaded cata-
lysts, which effectively cartels the benefits of metal oxide
with CNTs and offers an extensive potential application.
Heterocyclic frameworks are utilized as a significant
class of bioactive drug targets in the potent biological and
medicinal agents.18,19 Particularly, pyridines and their
derivatives are a vital class of heterocyclic molecules due
to their application in several fields like drug discovery,
natural products, and functional materials. Pyridines
exhibit a broad range of various biological properties, like
developed various heterocyclic molecules using efficient
green protocols.8,43–46 Herein the synthesis of new ceria
doped MWCNT catalysts and its efficacy in the C–C bond
evolving reactions is portrayed. We report 2.5% CeO2/
MWCNTs to catalyze the multicomponent reaction of
acetoacetanilide, ammonium acetate, aromatic aldehyde
and ethyl cyanoacetate under mild reaction conditions. This
protocol is found to be an efficient and excellent catalyst for
the synthesis of pyridine-3-carboxamides in aqueous etha-
nol medium for the first time.
2 | EXPERIMENTAL SECTION
2.1 | Synthesis of ceria doped multi-
walled carbon nanotubes (CeO2/MWCNTs)
nano-catalysts
Initially, MWCNTs were preserved with a mixture of con-
centrated sulfuric acid and concentrated nitric acid
(0.5 M H2SO4: 2.5 M HNO3) and sonicated for 5 hr at
60 ꢀC. Next, the MWCNTs material was afforded by
washing with deionized water. Then, it was vacuum
ꢀ
dried at 120 C. Further, the supported catalyst was pre-
pared by adding synthesized MWCNTs to a solution com-
prising weight percentage (1, 2.5 & 5 wt%) of cerium
nitrate (Ce (NO3)3, Aldrich). The mixture was sonicated
for 1 hr and stirred at R.T. for 12 hr after which the resul-
tant slurry was filtered under ꢀair vacuum. Furthermore,
it was dried in an oven at 110 C for 4 hr and calcined at
400 ꢀC for 6 hr to afford (1, 2.5 & 5 wt%) of CeO2/
MWCNTs catalysts.
anti-psychotic,20
anti-inflammatory,21
antitumor,22
antimicrobial,23 antioxidant,24 anti-tubercular,25 anti-
proliferative,26 anti-leishmanial,27 anticonvulsant,28 anti-
diabetic29 and anti-malarial30 activities. Moreover, these
are useful as pesticides, herbicides, insecticidal and dye-
stuff agents.31–33 Literature study shows that several syn-
thetic procedures have been published for the synthesis
of different pyridine scaffolds using catalysts such as p-
toluenesulfonic acid,34 Indium triflate,35 TEA36 and
NaOH.37 Even though several reported techniques are
effective, nevertheless suffer from weaknesses like pro-
long reaction times, low product yields, harsh reaction
conditions, expensive catalysts, toxic solvents, and
reagents, difficult handling and hard work-up process.
Additionally, the main drawback is that the catalysts are
not recyclable. For that reason, the instigation of a sim-
ple, efficient and enhanced environmentally-benign pro-
tocol to the synthesis of novel pyridine-3-carboxamide
derivatives is still indispensable.
2.2 | General procedure for the synthesis
of pyridine-3-carboxamides (5a–j)
In a round bottom flask, a mixture of acetoacetanilide
(1 mmol), ammonium acetate (1.1 mmol), substituted
aromatic aldehyde (1 mmol), ethyl cyanoacetate (1 mmol)
and 2.5%CeO2/MWCNTs (30 mg) was stirred in the pres-
ence of EtOH solvent (99.9%, 10 ml) at room temperature
(R.T) for 15 min (Scheme 1). The completion of the
Reinforced with the encouraging biological activities
displayed by the diverse heterocycle privileged scaffolds and
our sustained research focus on the synthesis of medicinally
fascinating heterocyclic molecules,38–42 recently we have
SCHEME 1 Synthesis of novel pyridine-3-carboxamide
derivatives

HARIKRISHNA ET AL.
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reaction was monitored by TLC (7:3 ratio n-Hexane:
EtOAc). Then the catalyst was separated by simple filtra-
tion. Further, the EtOH solvent of the filtrate was con-
centrated and dried under reduced pressure to obtain
pure products with excellent yields (5a-j). Instrumental
details and target molecules characterization data (1H-
NMR, 15N NMR and 13C-NMR) are included in the
supporting information (S1).
concord with the P-XRD analysis. The TEM micrograph
endorses that ceria particles are equally settled on
MWCNT. Further, the selected area electron diffraction
(SAED) image displays the fastening of the crystalline
structure of ceria particles on the MWCNTs.
3.1.3 | BET surface analysis
Figure 3 displays N2 adsorption–desorption isotherm of
2.5% CeO2/MWCNT catalyst sample. The isotherm of
CeO2/MWCNT is a type-IV with an H2 hysteresis loop,
which concurs with the presence of mesoporous struc-
tured material and the P/Po range is 0.69–0.98. The iso-
therm of CeO2/MWCNT nanocomposite revealed a BET
specific surface area of 111.67 m2g−1, a pore volume of
0.65 cm3/g and pore size of 23.8 nm owing to the meso-
porous and high surface area of the material.
3 | RESULTS AND DISCUSSIONS
3.1 | Catalyst characterization
3.1.1 | SEM analysis
The surface morphology of the synthesized CeO2/MWCNT
nanoparticles was examined by using SEM analysis. The
SEM micrograph exhibits a comparatively uniform and
equivalent particle dispersal. Ceria nanoparticles nurtured
homogeneously on MWCNTs. Figure 1a displays that the
aggregated fluffy particles of ceria along with tube-like
MWCNTs perceived in the surface morphology. Addition-
ally, the SEM-EDS investigation was used to study the CeO2
doped MWCNTs nano-catalyst. The EDS analysis reveals
that the nano-catalyst mostly consisted of Ce, C and O ele-
ments, which evidences that the CeO2/MWCNTs were effi-
ciently prepared (Figure 1b).
3.1.4 | P-XRD analysis
The diffraction peaks of CeO2 are observed at 2θ of 28.7ꢀ,
33.2ꢀ, 47.5ꢀ, 56.3ꢀ, 59.3ꢀ, 69.8ꢀ, 76.6ꢀ and 79.4ꢀ, which
correspond to the (111), (200), (220), (311), (222), (400),
(331) and (420), respectively, which conform with the
JCPDS data file No. 43–100254-0964 (Fig. The representa-
tive peaks at 2θ of 26.1ꢀand 43.1ꢀ are ascribed to the (002)
and (010) planes of the MWCNTs, which are approved
with the JCPDS data file No. 75–1621. Further, the peaks
observed in the diagram match the polycrystalline nature
of the catalyst (Figure 4). The average crystallite size of
the material was 7.8 nm based on the maximum intensity
diffraction peaks of ceria doped MWCNT using the
Scherrer formula.
3.1.2 | TEM analysis
The TEM image of the CeO2/MWCNT is shown in
Figure 2. The micrograph reveals that the average crystal-
lite size of the catalyst is 15–25 nm and also in good
FIGURE 1 SEM micrograph of (a) 2.5% CeO2-MWCNT and (b) SEM–EDX catalyst

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HARIKRISHNA ET AL.
FIGURE 2 A TEM micrograph of 2.5%
CeO2/MWCNT catalyst
FIGURE 3 N2 absorption and desorption isotherms of 2.5%
CeO2MWCNT catalyst
FIGURE 4 P-XRD spectra of 2.5% CeO2/MWCNT catalyst
3.1.5 | Optimization of reaction conditions
1 & 2). Then the reaction was ventured with several vari-
eties of inorganic and organic acidic catalysts like
CH3COOH, FeCl3, H3PO4, and BF3 in EtOH as a solvent,
no product was formed at R. T after 6 hr (Table 1, entries
3–6). Next, the same reaction was carried out with vari-
ous basic catalysts such as TEA, pyridine, Na2S, and urea
in ethanol systems, which generated low product yields
(Table 1, entries 7–10). The same reaction was then tested
by pure metal oxide/non-metal oxide catalysts like ceria,
titania, silica, and MWCNT in EtOH at R.T. The desired
product was obtained in moderate yields only after 2 hr.
Further to enhance the efficacy of the model reaction, a
The pilot reaction containing equal molar of
acetoacetanilide,
ammonium
acetate,
4-methoxybenzaldehyde, and ethyl cyanoacetate as reac-
tants were experimented under different reaction condi-
tions like presence/absence of several catalysts, using
various solvents and temperature conditions to improve
the reaction conditions. Initially, the reaction was con-
ducted under the absence of catalyst in EtOH solvent, but
the reaction did not progress and no product yielded even
after 12 hr at R. T and reflux conditions (Table 1, entry

HARIKRISHNA ET AL.
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TABLE 1
Optimum conditions for the preparation of trial reaction by 2.5%CeO2/MWCNT catalysta
Entry
1
Catalyst
Solvent
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
Temperature
Time (hr)
Yield (%)b
--
RT
Reflux
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
12
--
2
--
12
--
3
CH3COOH
FeCl3
6
--
4
6
--
5
H3PO4
6
--
6
BF3
6
--
7
TEA
6.0
5.0
6.0
5.5
2.1
3.5
4.5
2.5
0.25
0.50
0.25
13
19
10
21
78
51
48
69
97
89
96
8
Pyridine
Na2S
9
10
11
12
13
14
15
16
17
Urea
CeO2
SiO2
TiO2
MWCNT
2.5% CeO2/MWCNT
1% CeO2/MWCNT
5% CeO2/MWCNT
a4-Methoxybenzaldehyde (1 mmol), acetoacetanilide (1 mmol), ammonium acetate (1.1 mmol), ethyl cyanoacetate (1 mmol) and 2.5%CeO2/
MWCNTs (30 mg).
bIsolated yields. -- No reaction.
combination of the two solid materials, 2.5% CeO2 loaded
on MWCNTs was utilized as a catalyst, an MCR reaction
progressed with a remarkable product yield (97%) of tar-
get pyridine-3-carboxamide at R. T in 15 min.
TABLE 2
Optimum solvent conditions for the synthesis of
model reaction by 2.5% CeO2/MWCNT catalysta
Entry
Solvent
--
Time (hr)
4.0
Yield (%)
1
2
3
4
5
6
7
8
9
10
--
Solvents play a crucial role in the selectivity and
yields of the MCRs. Therefore, we examined the influ-
ence of different solvents (non-polar, aprotic and protic)
on the trial reaction. No anticipated product obtained,
when solvent-free and non-polar solvents like toluene, n-
hexane, and 1,4-dioxane were used. Next, low yields were
observed with polar aprotic solvents like acetonitrile, and
THF. Fascinatingly, when the reaction was studied with
polar solvents like EtOH, MeOH, (Me)2CHOH, H2O and
miscible mixture of aqueous EtOH (1:1) respectively, the
target molecule yields were moderate to excellent
(Table 2). Interestingly, the highly polar solvent (EtOH),
which can generate some heat, hence quickly supplies
optimal surroundings for the production of intermediates
on the solid surface and its subsequent conversion to
final molecules. In the perception of the green principle,
eco-friendliness, remarkable yields and short reaction
time, EtOH proved to be the best solvent for the current
protocol.
Toluene
n-hexane
Dioxane
MeCN
4.0
--
4.0
--
4.0
--
3.0
45
51
97
89
93
15
THF
2.5
EtOH
0.25
1.0
isopropyl alcohol
MeOH
H2O
0.50
2.0
a4-Methoxybenzaldehyde (1 mmol), acetoacetanilide (1 mmol),
ammonium acetate (1.1 mmol), ethyl cyanoacetate (1 mmol) and
2.5%CeO2/MWCNTs (30 mg).
-- No solvent/No reaction
reaction evidenced that when the quantity of catalyst
material was reduced from 30 mg to 10 mg, the product
yield decreased from 97% to 83% and reaction time also
increased. Next, when the amount of catalyst material
was augmented from 30 mg to 60 mg, the product yield
slightly reduced from 97% to 94%. Therefore, 30 mg of
After obtaining the above results, we studied the
effect of a catalytic amount of ceria doped MWCNTs on
the synthesis of pyridine-3-carboxamide (Table 3). The

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HARIKRISHNA ET AL.
TABLE 3
MWCNT catalyst in the reaction
Optimization of the quantity of by 2.5% CeO2/
excellent yields. However, it reveals that electronic effects
do not play much role in the desired product yields. Tar-
get molecules characterization data (1H-NMR, 15N NMR,
13C-NMR and HR-MS) are included in the supporting
information (S2).
Entry
Catalyst (mg)
Time (min)
Yield (%)
1
2
3
4
5
6
10
20
30
40
50
60
90
45
15
15
15
20
83
89
97
97
95
94
The plausible reaction mechanism for the synthesis of
pyridine-3-carboxamide, based the investigational conse-
quences is showed in Scheme 2. First reaction includes
the Knoevenagel condensation between an aryl aldehyde
(1) and acetoacetanilide (2) to obtain intermediate I. Sub-
sequently, up on dehydration, Michael addition follows
with active ethylcyanacetate (3), ensuing in the genera-
tion of intermediate II. Further, its reactive ketone func-
tional group being reacted with NH4OAc (4), amino
substitution occurs, via nucleophilic addition. The ami-
dation reaction takes place between the amino group and
ester, prior to the cyclization to afford target molecule
(5). The reaction intermediates were confirmed by the
HRMS analysis and included in the supporting
information (S3).
CeO2/MWCNTs catalyst, which afforded product yield
(97%), was adequate to endorse the reaction.
To ensure the reproducibility of this protocol and to
simplify the optimal circumstances, various substituted
aldehydes bearing both electron-withdrawing and/or
electron-donating groups were selected for the generation
of different types of pyridine-3-carboxamide derivatives
(Table 4). Both electron-withdrawing/electron-donating
groups on the aromatic ring (o/p/m) of the aldehydes
reacted well to afford the resulting target molecules in
3.1.6 | CeO2/MWCNT catalyst recyclability
TABLE 4
2.5% CeO2/MWCNT catalyst
Synthesis of pyridine-3-carboxamide catalyzed by
In view of environmental friendliness and cost-effectivity,
the test of recyclability and reusability of the solid cata-
lyst was carried out for the reaction between
Entry
R
Product
5a
Yield (%)
m.p ꢀC
228–230
236–235
211–212
251–252
209–210
259–261
242–243
271–272
205–206
218–219
acetoacetanilide,
ammonium
acetate,
1
2
4-OMe-C6H4
3-OMe-C6H4
4-Cl-C6H4
2-F-C6H4
2-NO2-C6H4
2-OMe-C6H4
H
97
95
93
94
90
97
93
90
92
93
4-methoxybenzaldehyde and ethyl cyanoacetate under
optimum reaction conditions. After completion of the
first run, the catalyst was separated, systematically
5b
3
5c
4
5d
ꢀ
washed with EtOH solvent, and dried at 120 C under
5
5e
vacuum oven. Then it was reused in the next run. It was
found that, the catalyst exhibited superb catalytic activity
up to six consecutive cycles without any significant
reduction in desired target yields (Figure 5). Based on the
above result, it displays that the catalyst leaching is very
small. Moreover, the catalyst after the reaction was inves-
tigated by SEM-EDS incorporated (Figure 6). This
6
5f
7
5 g
5 h
5i
8
Pyridyl
9
2-Cl-C6H4
2,6-OH-C6H4
10
5j
SCHEME 2 Proposed mechanism of
pyridine-3-carboxamide derivatives

HARIKRISHNA ET AL.
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the presence of ceria loaded MWCNTs nanocomposite as
heterogeneous catalyst. The present method suggests var-
ious benefits including low catalyst support, effortless
operation, clean reaction profiles, mild reaction condi-
tions, environmentally friendly, cost-effectiveness, short
reaction times, excellent yields, demanding no chromato-
graphic purification and catalyst recyclability for several
times without loss of activity.
ACKNOWLEDGMENTS
The authors are thankful to the GITAM University, India
and University of KwaZulu-Natal, Durban, for financial
support and research facilities.
ORCID
Suresh Maddila https://orcid.org/0000-0001-5183-2104
FIGURE 5 Recyclability of the CeO2/MWCNT nano-
composite catalyst
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with opportune heterocyclic scaffolds, through the mul-
ticomponent reaction of acetoacetanilide, ammonium
acetate, substituted aldehydes and ethyl cyanoacetate in

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How to cite this article: Harikrishna S,
Robert AR, Ganja H, Maddila S, Jonnalagadda SB.
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nanocomposite catalyzed click synthesis of
pyridine-3-carboxamides. Appl Organomet Chem.
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