Nanoalkalinecellulose immobilized on magnetic nanoparticles as a green catalyst for the synthesis of tetrahydrodipyrazolopyridines and mechanistic insights under base catalysis

Article abstract of DOI:10.1002/aoc.6386

The cotton-derived nanoalkalinecellulose (NAC) flocculated on the Fe₃O₄-nanoparticles was analytically characterized as Fe₃O₄@NAC. With the 1:5.7 weight ratio for organic:inorganic and the base-capacity equal to 7.5?mmol HO^?/g, the Fe₃O₄@NAC represented a catalytic advantage in the room-temperature one-pot pseudo-multicomponent synthesis of tetra-hydrodipyrazolopyridines (THDPPs) in water. Mechanistic monitoring supported no requisite to acid/base catalyst in the first phase for rapid formation of intermediate 3-methylpyrazolone (A) by Knorr reaction of the ethylacetoacetate with hydrazine hydrate in water at room temperature. Alternatively, Fe₃O₄@NAC showed catalytic roles in the further reaction phases in synthesis of THDPPs from the A. Excellent base capacity, hydrogen-bonding performance, and stability due to no significant activity loss and leaching after five reaction cycles are advantages of this organometallic catalyst.

Full text of DOI:10.1002/aoc.6386

Received: 19 April 2021
DOI: 10.1002/aoc.6386
Revised: 5 July 2021
Accepted: 12 July 2021
R E S E A R C H A R T I C L E
Nanoalkalinecellulose immobilized on magnetic
nanoparticles as a green catalyst for the synthesis of
tetrahydrodipyrazolopyridines and mechanistic insights
under base catalysis
1
1
2
Fatemeh Tamaddon
| Ehsan Ahmadi-AhmadAbadi
| Hossein Kargar
1
Department of Chemistry, Yazd
Abstract
University, Yazd, Iran
2
The cotton-derived nanoalkalinecellulose (NAC) flocculated on the Fe O -
3 4
Department of Biomedical Engineering,
Meybod University, Meybod, Iran
nanoparticles was analytically characterized as Fe O @NAC. With the 1:5.7
3 4
weight ratio for organic:inorganic and the base-capacity equal to 7.5 mmol
Correspondence
Fatemeh Tamaddon, Department of
Chemistry, Yazd University, Yazd
ꢀ
HO /g, the Fe O @NAC represented a catalytic advantage in the room-
3 4
temperature
one-pot
pseudo-multicomponent
synthesis
of
tetra-
89195-741, Iran.
hydrodipyrazolopyridines (THDPPs) in water. Mechanistic monitoring
supported no requisite to acid/base catalyst in the first phase for rapid forma-
tion of intermediate 3-methylpyrazolone (A) by Knorr reaction of the
ethylacetoacetate with hydrazine hydrate in water at room temperature. Alter-
natively, Fe O @NAC showed catalytic roles in the further reaction phases in
Email: ftamaddon@yazd.ac.ir
Funding information
Yazd University Research Council
3
4
synthesis of THDPPs from the A. Excellent base capacity, hydrogen-bonding
performance, and stability due to no significant activity loss and leaching after
five reaction cycles are advantages of this organometallic catalyst.
K E Y W O R D S
3-methylpyrazolone, Fe
3 4
O @nanoalkalinecellulose, magnetic base catalyst, tetra-
hydrodipyrazolopyridines
[
15–18]
1
| INTRODUCTION
MC/NC,
linking of them in FMNs needs higher
energy than hydrogen bonding and thermal stability than
cellulose at 70 C.
ꢁ
[2,19]
Functionalized magnetic nanoparticles (FMNs) by bio-
polymers are advanced nano-biomaterials
erative synergistic effects to resolve either agglomeration
issues of MNs or separation problems of biopolymers.
Microcellulose (MC) and nanocellulose (NC) are among
the best biopolymers applied for improving the dispersion
of magnetite (Fe O ) and maghemite-based FMNs.
Consequently, higher stable and
[
1–5]
with coop-
negatively charged micro-/nano-alkaline celluloses
(MAC/NAC) are superior to native MC/NC due to their
strong electrostatic interactions with FMNs. Recently, we
have developed anionic carbohydrate polymers including
MAC/NAC,
and anionic NC
issues for recycling. To solve these disputes,
[
6–8]
[
20]
[21]
[22]
anionic cellulose,
alkaline starch,
[
9–11]
[23]
with some filtration/centrifugation
3
4
[12–14]
Despite the performances of Fe O4
and
3
This work is fully related to the PhD dissertation of Ehsan Ahmadi-AhmadAbadi. The authors are also not employed by a nonacademic government
agency that has a primary function other than research and/or education and thus are not submitting this manuscript as an official representative or
on behalf of the government. The authors and reviewers do not have any conflict of interest as per the COPE Guidelines.
Appl Organomet Chem. 2021;e6386.
wileyonlinelibrary.com/journal/aoc
© 2021 John Wiley & Sons, Ltd.
1 of 14
https://doi.org/10.1002/aoc.6386

2
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TAMADDON ET AL.
immobilization of anionic-NAC on the nanoFe O4 by
leaching test for iron ions was evaluated by inductively
coupled plasma mass spectrometry (ICP-MS) analysis
(PerkinElmer, 9000). The nuclear magnetic resonance
(NMR) spectra were recorded in CDCl or DMSO-d on
3
flocculation is anticipated to give a new magnetically
recoverable base and organic–inorganic hybrid catalyst.
Tetra-hydrodipyrazolopyridines (THDPPs) are attrac-
tive fused heterocyclic compounds because of their elec-
3
6
Bruker Avance NMR 400 MHz.
[24]
troluminescence properties in polymer systems
and
the pharmaceutical role of the pyrazolopyridine in
[
25]
zaleplon, indiplon, etazolate, and cartazolate drugs.
Although the first synthesis of THDPPs is a Hantzsch
2.2 | Preparation of nanoFe O4
3
[
26]
-
type pseudo-multicomponent reaction (p-MCR) directed
To the FeCl .6H O (6.75 g) and FeCl .4H O (2.5 g) dis-
3
2
2
2
[27]
by Zhao et al.,
a recently modified acid-catalyzed p-
solved in distilled water (100 mL), NH OH was added
4
MCR of hydrazine, ethyl acetoacetate, ammonium ace-
tate, and aldehyde (2:2:1:1) has been developed for the
drop-wise within 1 h until pH 12, and the mixture was
ꢁ
stirred for 1 h at 40 C. After completion, the nanoFe O
3
4
[28–31]
synthesis of THDPPs.
We have also settled synthesis
was washed with water, separated by an external magnet,
ꢁ
of THDPPs in water using new DESs or nonhygroscopic
and dried at 50 C in an oven.
[31–33]
nitrogen sources,
although all acid-catalyzed proto-
cols emphasized the 3-methylpyrazolone (A) as the reac-
tion intermediate. However, no detail is available for the
less hazardous heterogeneous base-catalyzed synthesis of
THDPPs. Herein, for the first time, the magnetic base cat-
alyst Fe O @NAC was prepared by the immobilization of
2.3 | Preparation of NAC solution from
cotton
Prewashed cotton (1.75 g) was added to a mixture of urea
(4.0 g), sodium hydroxide (4.0 g), and thiourea (2.3 g) in
distilled water (40 mL); the resulting suspension
3
4
cotton-derived NAC on Fe O -MNPs, and the catalytic
3
4
activity of this novel core-shell catalyst investigated in
the very rapid p-MC synthesis of THDPPs in water at
room temperature. After some mechanistic insights for
this base-catalysis synthesis, the intermediate A was rap-
idly prepared and balanced in a very fast Fe O @NAC-
ꢁ
[21]
maintained at cold thermal shock (ꢀ12 C) for 6 h
;
and the final mixture stirred vigorously at room tempera-
ture to obtain NAC solution.
3
4
catalyzed p-MCR for the THDPPs synthesis. The excel-
lent stability of this heterogeneous, organic–inorganic
hybrid, reusable, and magnetic base catalyst was con-
firmed by different techniques to support its catalytic
performance.
2.4 | Immobilization of NAC on Fe O as
3
4
Fe O @NAC core-shell
3
4
To the dispersed mixture of nanoFe O (1.75 g) in the
3
4
above NAC solution, ammonium sulfate (2.86 g) was
added as a flocculating agent, and the suspension
ꢁ
2
2
| MATERIALS AND METHODS
.1 | General
was stirred vigorously for 6 h at 50 C. Then water and
acetone were added and decanted until removing free
NaOH and urea from the magnetically separated
ꢁ
Fe O @NAC that dried at 50 C.
3
4
All chemicals were purchased from Merck and Sigma
without further purification. All yields refer to isolated
products, which were characterized by spectral data. The
Fourier transform infrared (FT-IR) spectra were recorded
on a Bruker spectrophotometer as KBr disks. Melting
points were determined by a Buchi B-540 apparatus.
Melting points were determined by a Buchi B-540 appara-
tus. The vibrating sample magnetometry (VSM) of mag-
netic materials was monitored by the Lake Shore
Cryotronics 7404 at 298 K. Field-emission scanning elec-
tron microscopy (FESEM) and transmission electron
2.5 | Base capacity of Fe O @NAC
3
4
The dispersed Fe O @NAC (0.1 g) in distilled water
3
4
(20 mL) was titrated with standard HCl (0.22 M) using
the indicator bromtimol-blue to reach the end point.
2.6 | Synthesis and characterization of
3-methylpyrazolone (A)
microscopy
(TEM)
images
performed
with
MIRA3TESCAN-XMU. The X-ray diffraction (XRD) and
thermal gravimetric analysis (TGA) were recorded with
PHILIPS PW1730 and TGA-TA Q600, respectively. The
A mixture of hydrazine hydrate (2.0 mmol) and ethyl
acetoacetate (2.0 mmol) in water (1.0 mL) was stirred
at room temperature for 5 min without or with the

TAMADDON ET AL.
3 of 14
catalyst Fe O @NAC (12 mg). In the latter case, the
2.8.2 | 3,5-Dimethyl-4-(4-N,N-methyl-
3
4
catalyst was collected by a magnet, and the precipitated
product in water was rapidly filtered, washed, with
water/hexane, and dried to yield 97% A as a white solid
phenyl)-1,4,7,8-tetrahydrodipyrazolo[3,4-b,
4 ,3 -e] pyridine (THDPP2)
0
0
ꢁ
[34]
ꢁ
with mp = 222–224 C,
which then identified by its
Yield: 97%; yellow-orange solid, mp = 250–252 C. FT-IR
FT-IR spectrum.
(KBr): 3514, 3168 (NH stretching), 2942 (CH stretching),
1
608 (C═N stretching), 1520 (C═C aromatic), 1139 (C–N
ꢀ
1 1
stretching) cm
.
H NMR (400 MHz, DMSO-d6):
2
.7 | General method for the
δ = 2.26 (s, 6H, 2 CH ), 2.91 (s, 6H, 2 CH [para]), 4.9 (s,
1 H, CH), 6.75 (d, J = 8 Hz, 2H, Harom), 7.3 (d, J = 8 Hz,
2H, Harom), 4.07 (s, 1H, NH) 11.54 (s, 2H, 2 NH) ppm
3
3
Fe O @NAC-catalyzed synthesis of
THDPPs
3
4
(
Figures S4–S6).
For the p-MC synthesis of THDPPs from hydrazine
hydrate, Fe O @NAC (12 mg) was added to the mix-
3
4
ture of aldehyde (1.0 mmol), hydrazine hydrate
2.0 mmol), ethyl acetoacetate (2.0 mmol), and anhy-
2.8.3 | 3,5-Dimethyl-4-(4-methyl-phenyl)-
1,4,7,8-tetrahydrodipyrazolo[3,4-b, 4 ,3 -e]
pyridine (THDPP3)
0
0
(
drous NH OAc (1.0 mmol) in water (0.5 mL) and
4
stirred at room temperature for ꢂ5–15 min until the
product precipitation. Then, water was added, the cata-
lyst was collected by a magnet, and the pure THDPP
product was filtered.
ꢁ
Yield: 94%; white solid, mp = 244–246 C. FT-IR (KBr):
3170 (NH stretching), 2920 (CH stretching), 1610 (C═N
stretching), 1520 (C═C aromatic), 1139 (C–N stretching)
cm . H NMR (400 MHz, DMSO-d ): δ = 2.1 (s, 6H,
2 CH ), 2.20 (s, 3 H, CH [para]), 4.78 (s, 1 H, CH), 6.99–
7.00 (m, 4H, Harom), 11.25 (s, 3 H, 3 NH) ppm. C NMR
ꢀ
1
1
For the p-MC synthesis of THDPPs from the interme-
diate A, the mixture of Fe O @NAC (12 mg), aldehyde
6
3
4
3
3
1
3
(1.0 mmol), the as-prepared A (2.0 mmol), and anhy-
drous NH OAc (1.0 mmol) in water (0.5 mL) was stirred
(100 MHz, DMSO-d ): δ = 10.85, 20.98, 32.85, 104.85,
4
6
at room temperature for ꢂ5–15 min. Then, hot ethanol
127.82, 128.83, 134.70, 140.20, 140.75, 161.50 ppm
(Figures S7–S9).
(
4 mL) was added, the catalyst was collected by a magnet,
and the pure THDPP was isolated after the addition of
cold water and filtration.
2
1
.8.4 | 3,5-Dimethyl-4-(4-hydroxy-phenyl)-
,4,7,8-tetra-hydrodipyrazolo[3,4-b, 4 ,3 -e]
0
0
2.8 | Representative characterization
pyridine (THDPP7)
data for the selected products
ꢁ
Yield: 93%; white solid, mp = 267–269 C. FT-IR (KBr):
1
13
Although spectroscopic spectra (FT-IR, H NMR, and
C
3234 (overlapped NH and OH stretching), 2,935
(CH stretching), 1600 (C═N stretching), cm . H NMR
(400 MHz, DMSO-d ): δ = 2.05 (s, 6H, 2 CH ), 4.68 (s,
ꢀ
1 1
NMR) for all final products (THDPP1–9) are presented in
Figures S1–S24), the characteristic data for the selected
products are designated below.
6
3
1 H, CH), 6.57 (d, J = 8 Hz, 2 H, Harom), 6.89 (d,
J = 8 Hz, 2 H, Harom), 9.15 (s, OH), 11.52 (s, 3 H, 3 NH)
13
ppm. C NMR (100 MHz, DMSO-d ): δ = 10.35, 31.76,
6
2
1
.8.1 | 3,5-Dimethyl-4-(phenyl)-
,4,7,8-tetrahydrodipyrazolo[3,4-b, 4 ,3 -e]
104.51, 114.45, 128.25, 133.36, 139.75, 155.05, 161.05 ppm
(Figures S17–S19).
0
0
pyridine (THDPP1)
ꢁ
Yield: 97%; white solid, mp = 240–242 C. FT-IR (KBr):
410 (NH stretching), 2983, 2922 (CH stretching), 1605
C═N stretching), 1497, 1448 (CH bending), 1368
2.8.5 | 3,5-Dimethyl-4-(4-nitro-phenyl)-
1,4,7,8-tetra-hydrodipyrazolo[3,4-b, 4 ,3 -e]
pyridine (THDPP8)
0
0
3
(
(
ꢀ
1 1
Methyl-CH bending) cm . H NMR (400 MHz, DMSO-
ꢁ
d ): δ = 2.04 (s, 6H, 2 CH ), 4.79 (s, 1 H, CH), 7.10–7.20
Yield: 96%; cream solid, mp = 333–335 C. FT-IR (KBr):
6
3
(
(
3 H, ortho and para H ), 7.20–7.25 (2 H, meta H ), 11.34
3250 (NH stretching), 2985 (CH stretching), 1605 (C═N
s
1
s
3
s, 3 H, 3 NH) ppm. C NMR (100 MHz, DMSO-d6):
stretching), 1489 (asymmetrical stretching NO2 over-
δ = 12.1, 38.2, 104.8, 127.1, 128.7, 128.9, 141.0, 143.7,
45.5 ppm (Figures S1–S3).
lapped with the C═C aromatic), 1352 (NO symmetrical
stretching), 753 (out of plane bending C–H, para-
2
1

4
of 14
TAMADDON ET AL.
ꢀ
1
1
substituted) cm
.
H NMR (400 MHz, DMSO-d6):
δ = 2.1 (s, 6 H, 2 CH ), 4.95 (s, 1H, CH), 7.35 (d,
3
J = 8 Hz, 2 H, Harom), 8.1 (d, J = 8 Hz, 2 H, Harom), 11.20
13
(
s, 3H, 3 NH) ppm. C NMR (100 MHz, DMSO-d6):
δ = 10.70, 33.40, 103.60, 123.40, 129.20, 140.20, 146.1,
52.25, 161.35 ppm (Figures S20–S22).
1
2
.9 | Metal leaching, recycling, and
reusing of the catalyst
Owing to the insolubility of catalyst in water, it was sepa-
rated by a magnet after the model reaction completion
for synthesis of THDDP1, washed with acetone, dried at
ꢁ
5
0 C, and reused in further reaction runs. The leaching
+
2
+3
test for entering the Fe /Fe to reaction mixture was
evaluated for the fresh and reused filtrate solutions of
Fe O @NAC after fourth cycle by ICP-mass analysis.
3
4
3
3
| RESULTS AND DISCUSSION
.1 | Preparation of Fe O @NAC
3
4
Initially, NAC suspension was prepared by urea/thio-
urea/NaOH treatment of the cotton-derived MC and
SCHEME 1 Preparation of magnetic base catalyst
Fe O @NAC
ꢁ
[21–23]
additional freezing shock at ꢀ12 C.
Further coagu-
lation of NAC on the prepared Fe O nanoparticles led to
3
4
3
4
ꢀ
1
the Fe O @NAC, although salting-out effect by ammo-
ꢂ2800–3600 and 585 cm related to the surface OHs
3
4
nium sulfate and alkali washing provided maximum uni-
formity of flocculated NAC-shell and basicity
preservation of core–shell (Scheme 1).
and Fe/O vibration modes in the spectrum of nanoFe O .
3
4
The weak and broad absorption bands for O–H stretching
ꢀ
1
at 2500–3600 cm besides to C–H stretching, CH bend-
2
ing, and C–O stretching modes at 2890, 1424, and
ꢀ
1
1
018 cm in the spectrum of NAC confirmed its struc-
3
.2 | Characterization results of
ture. In the FT-IR spectrum of Fe O @NAC, shifted
3 4
Fe O @NAC
broad absorption bands to 3400–3600, 2922, 1455, and
3
4
ꢀ
1
1
021 cm attribute to the coating of Fe O nanoparticles
3 4
The structure of the Fe O @NAC was identified by base
by NAC (Figure 1).
3
4
capacity, FT-IR, XRD, FESEM, TEM, VSM, TGA, and
Brunauer–Emmett–Teller (BET) analyses. According to
the consumed standard HCl in the acid–base titration,
the base capacity of the Fe O @NAC was determined as
3.2.2 | X-ray diffraction
3
4
ꢀ
7
.5 mmol HO /g, which is significantly higher than
In the overlaid XRD patterns for the Fe O and
3 4
either neutral Fe O or NC. This high basicity matches
Fe O @NAC, the six sharp characteristic peaks at
3
4
3 4
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
with the created alkoxide groups by alkalizing of some
aggregate hydrogen-bonded NAC-OHs in the outer shell
of Fe O @NAC.
2θ = 30.81 , 36.04 , 43.78 , 54.00 , 54.10 , and 63.28 ,
correspond to (220), (311), (400), (511), (422), and (440)
planes, are compatible with the standard Fe O -phase
3
4
3 4
(
JCPDS card no. 39-1346). Repeating these planes as
slightly broader peaks in the Fe O @NAC phase reveals
3
4
3
.2.1 | Fourier transform infrared spectra
conserving the Fe O -crystalline phase in this core–shell
3
4
(
Figure 2). Such low phase transformation with the
ꢁ
The overlaid FT-IR spectra of the nanoFe O , NAC, and
Fe O @NAC show the broad absorption bands at
appearance of new broad peaks at 2θ = 20–25 in XRD
3
4
pattern of Fe O @NAC due to crystalline cellulose
3 4
3
4

TAMADDON ET AL.
5 of 14
FIGURE 1 The Fourier transform infrared (FT-IR) spectra of nanoFe
FIGURE 2 X-ray diffraction (XRD)
3 4 3 4
O , nanoalkalinecellulose (NAC), and Fe O @NAC
3 4 3 4
patterns of nanoFe O and Fe O @NAC
showed tiny immobilization of NAC on the Fe O , which
is further confirmed by TEM and TGA analyses.
diameter. This slight enlargement is due to a thin layer
immobilization of NAC on nanoFe O -particles in
3
4
3
4
Fe O @NAC that improved the nanoparticles agglomera-
3
4
tion and surface roughness (Figure 3, right).
3.2.3 | Field scanning electron microcopy
The comparative FESEM images of Fe O4 and
3.2.4 | TEM and histogram of Fe O @NAC
3
3 4
Fe O @NAC (Figure 3) show different surface morphol-
nanoparticles
3
4
ogies and size distribution for the spherical agglomerated
Fe O nanoparticles from 22–36 nm to slightly larger dis-
While the TEM of Fe O @NAC (Figure 4, left) shows the
3 4
well-defined coating of the Fe O nanospheres by NAC,
3 4
3
4
persed Fe O @NAC nanospheres with 25- to 38-nm
3
4

6
of 14
TAMADDON ET AL.
FIGURE 3 Field-emission scanning electron microscopy (FESEM) images of nanoFe
3
O
4
and nanoFe
3
O
4
@NAC
FIGURE 4 Transmission electron microscopy (TEM) image (left) and histogram of Fe
3
O
4
@NAC nanoparticles (right)
the histogram of the size distribution versus the particle
size, detected by MIRA3TESCAN software in FESEM
and TEM analyses, showed an average size of 20–35 nm
for these core–shell nanoparticles (Figure 4, right).
layer of NAC in the super-paramagnetic core–shell of
Fe O @NAC. Besides, the three times higher M , rema-
3
4
s
nence (M ), and coercivity (H ) of the Fe O @NAC
R
C
3 4
ꢀ
1
ꢀ1
(35.2 emu g , 1.86 emu g , and 66.23 Oe) than a previ-
ously prepared MC composite
[
14]
approve the profi-
ciencies of the nanosizing and surface charge of NAC in
these improved FMNs. Fe O @NAC is an anionic core-
3.2.5 | VSM, TGA, and BET analyses of
3
4
Fe O @NAC
shell with the excellent magnetic response to an external
magnet.
3
4
VSM curves of bare and NAC-coated nanoFe O show a
Comparing the thermal behaviors of the Fe O @NAC
3
4
3 4
decrease in magnetization saturation (M ) from 69.2 to
and Fe O by TGA in air shows respective 2% and 19%
3 4
weight losses at <500 C and defines 17% NAC sorption
s
ꢀ
1
ꢁ
3
5.2 emu g (Figure 5, left). Such decrease in M is
s
another evidence for Fe O coating by a nonmagnetic
on Fe O4 equal to 1:5.7 weight ratio for the anionic
3
4
3

TAMADDON ET AL.
7 of 14
3 4
FIGURE 5 Comparative vibrating sample magnetometries (VSMs) (left) and thermal gravimetric analyses (TGAs) of Fe O and
3 4
Fe O @NAC (right)
organic shell versus the inorganic magnetic core. The
ꢁ
break-in weight loss at ꢂ300 C for Fe O @NAC is attrib-
3
4
uted to the NAC-glucose-unit decomposition (Figure 5,
right).
Based on the BET analysis, the specific surface area,
total pore volume, and mean pore diameter for
SCHEME 2 The typical pseudo-multicomponent reaction (p-
2
ꢀ1
ꢀ1
nanoFe O dramatically decreased from 90.90 m
g
,
,
3
4
MCR) for THDPP1 synthesis
3
ꢀ1
2
ꢀ1
3
0
.3 cm g , and 13.37 nm to 14.1 m g , 0.030 cm g
and 9.96 nm in nanoFe O @NAC. The 14 times higher
3
4
FIGURE 6 Optimization of catalyst and catalyst-loading for THDPP1 synthesis

8
of 14
TAMADDON ET AL.
and 6.5 times lower surface area of this core–shell than
using very low loading of Fe O @NAC (12 mg) (Figure 6,
right).
3
4
2
ꢀ1
cotton (1.01 m
g
) and nanoFe O4 describes Fe O4
3
3
pores filling by a uniform thin layer of NAC shell in
Fe O @NAC and surface improving than cotton.
Comparing the reaction yield and time for NAC and
Fe O @NAC reveals that basicity is not the only factor
3
4
3 4
for catalytic activity. Thus, the proficiency of this magnet-
ically separable base catalyst is attributed to its multi-
3
.3 | Catalytic valuation of Fe O @NAC
functionality
and
hybrid
organic–inorganic
3
4
in the MC synthesis of THDPPs
nanostructure that forms a nanoporous magnetic gel in
water by a hydrogen-bonded network in swelling. These
properties provide multiactive sites, high diffusion power,
uniformity, and well dispersion of catalyst in the aqueous
medium of reaction to activate the reactants in nanopores
of catalyst and directing the reaction energy path to the
rapid yielding of product. The 33% decrease in
the THDPP1 yield for a similar reaction in EtOH supports
this interpretation (Figure 7, left). Evaluation of the
Firstly, the catalytic efficiencies of the Fe O @NAC, free
Fe O , and NAC (each 0.15 g) were compared in the typi-
cal synthesis THDPP1 by p-MCR of benzaldehyde,
NH OAc, hydrazine hydrate, and ethyl acetoacetate
3
4
3
4
4
(
(
1:1:2:2 molar ratio) in water at room temperature
Scheme 2, Figure 6, left). With a higher superiority in
yield at 10 min, THDPP1 was precipitated in 97% yield
FIGURE 7 Solvent effect (left) and reaction time for the Fe
benzaldehyde, NH
3
O
4
@NAC-catalyzed THDPP1 synthesis by the room temperature reaction of
4
OAc, hydrazine hydrate, and ethyl acetoacetate (1:1:2:2) in water
3 4
TABLE 1 Comparative performances of the Fe O @NAC with the previous methods for the synthesis of THDPP1 by p-MCR in
Scheme 2
Time
(min.)
Yield
(%)
Entry
Reaction conditions
Ref.
ꢁ
[35]
1
2
3
4
5
6
7
Choline chloride/urea, 110 C
30
92
95
90
72
92
94
97
Vanegas et al.
ꢁ
[36]
Ultrasonic, H
2
O, 50 C
120
30
Shabalala et al.
[37]
Pseudopolymeric nanoparticles, EtOH, r.t.
Reflux, EtOH
Dashteh et al.
[
28]
300
30
Dabiri et al.
[14]
Fe
3
O
4
@KCC-1-nPr-NH
2
, ethanol, reflux
Azizi et al.
ꢁ
[31]
Co4ChDES, H
2
O, 60 C
15
Tamaddon and Khorram
This work
Fe @NAC, H
3
O
4
2
O, r.t.
10
Abbreviation: p-MCR, pseudo-multicomponent reaction.

TAMADDON ET AL.
9 of 14
reaction's time impact on the THDPP1 yield using the
optimized catalyst loading (12-mg Fe O @NAC) revealed
that the optimum reaction time is 10 min (Figure 7,
right).
To weigh the performance of this magnetically sepa-
rable base catalyst in MC synthesis of THDPP1, our
results were compared with the previously reported
corresponding works (Table 1) and base catalysts in
water (Figure 8).
catalytic role in this one-pot p-MCR. However, the previ-
ous acid-catalyzed mechanisms for the THDPPs synthe-
3
4
[
29,30]
sis
proposed
formation
of
intermediate
3-methylpyrazolone (A) by Knorr pyrazole formation in
[
39]
the first reaction step.
To clear the catalytic role of
Fe O @NAC in the reaction of ethyl acetoacetate and
3
4
hydrazine hydrate, the product, yield, and time were
[
34]
compared in this phase by a classical method,
a deep-
ꢁ
[35]
[29]
eutectic catalyst at 110 C,
p-TsOH,
Fe O @NAC,
3
4
As performance results show, the organic–inorganic
hybrid catalyst Fe O @NAC with advantages of simple
and catalyst-free conditions in water. While the isolated
product in each case was identified by FT-IR and melting
point, none of the probable intermediates B–F were
detected (Scheme 3).
3
4
handling and easy separation at mild conditions
enhances the reaction yield and rate more efficiently than
the cited previous protocols in Table 1. Besides, superior-
ity of this magnetic base catalyst and procedure are
higher than the reported homogeneous base catalysts for
[
28,33,38]
the same MC synthesis of THDPP1 in water
Figure 8).
(
3.4 | Proposed reaction mechanism
To probe the mechanism and detailing the base-catalyzed
rapid synthesis of THDPP1 using Fe O @NAC, several
3
4
control experiments were performed. The comparative
typical p-MC synthesis of THDPP1 at room temperature
in the absence and presence of Fe O @NAC in water
3
4
yielded only 10% and 60% THDPP1 after 10 and 60 min
using no catalyst. Due to the isolation of THDPP1 in 97%
yield after 10 min using only 12-mg Fe O @NAC, it has a
SCHEME 3 Possible intermediates in the reaction of
hydrazine with ethyl acetoacetate
3
4
FIGURE 8 Performance of the
Fe @NAC for the synthesis of
THDPP1
3 4
O

10 of 14
TAMADDON ET AL.
FIGURE 9 The Fourier transform infrared (FT-IR) (KBr) spectrum of 3-methylpyrazolone A
SCHEME 4 Proposed mechanism for
Fe @NAC-catalyzed synthesis of THDPP1
3 4
O
from A
Besides, the analytical evidence confirmed the superi-
orities of both the catalyst-free and Fe O @NAC-
catalyzed reaction in water by isolation of 97% yield of
intermediate A after 5 min. These results surprised us for
no significant role of any catalyst in the formation of A in
the first period of one-pot synthesis of THDPP1. With
3
4

TAMADDON ET AL.
11 of 14
ꢁ
melting point 222–224 C, FT-IR spectrum of
-methylpyrazolone represented vibrational absorption
modes at 3416 (NH stretching), 2889 (CH stretching),
615 (overlapped-hydrogen-bonded amide-C═O
stretching and C═N stretching), 1553 (NH bending),
3
1
ꢀ
1
1
(
162 (C–N stretching), and 1015 (C–O stretching) cm
Figure 9).
To evaluate the catalytic role of Fe O @NAC in the
3
4
further steps, a different p-MCR was performed with the
A, NH OAc, and benzaldehyde (2:1:1) in water without
4
or with the optimal catalyst Fe O @NAC (12 mg) at
3
4
room temperature. The 46% lower yield of THDPP1 after
0 min for a reaction run without catalyst versus 97%
yield after 5 min for the Fe O @NAC-catalyzed experi-
6
3
4
ment describes the requirement of catalyst in further
reaction steps. Although we could not separate the highly
active transients and unstable intermediates formed in
further reaction steps, the following roles are proposed
for the catalyst Fe O @NAC in the reaction mechanism
3
4
(Scheme 4).
3
.5 | Metal leaching, hot filtration, and
FIGURE 10 Reusability of the Fe
of THDPP1 from A
3 4
O @NAC for the synthesis
recycling experiments
The ICP analysis conducted to test for leaching and
entering the iron ions to the reaction mixture for the fil-
trate solution of fresh Fe O @NAC detected no trace of
Fe /Fe in filtrate and confirmed no passing of them
through the NAC-shell membrane during the
filtration step.
proceeding, while repeating a comparable hot filtration
test for the reused catalyst after the fourth reaction run
gave identical results for the fresh catalyst. Based on
the BET analysis for the recovered Fe O @NAC after
3
4
+
2
+3
3
4
For reusability test, after completion of the
Fe O @NAC-catalyzed synthesis of THDPP1 from A in
the fourth run, the specific surface, total pore volume,
2
ꢀ1
and mean pore diameter were 14.08 m
g ,
3
4
3
ꢀ1
1
0-mmol scale, hot ethanol was added, and
0.029 cm g , and 9.97 nm and in agreements with the
2
ꢀ1
3
ꢀ1
nanocatalyst was collected by a magnet, washed with
fresh catalyst amounts (14.10 m g , 0.030 cm g ,
ꢁ
acetone, dried at 80 C, and reused in further four con-
and 9.96 nm, respectively). To find the more reliable
results for stability of Fe O @NAC, the FT-IR, XRD,
secutive cycles. The only 4% decrease in yield at the
constant time (5 min) after the fifth reaction run
reveals a little catalytic activity loss (Figure 10). An
analogous ICP analysis was performed for the filtrate
solution of the reused Fe O @NAC after the fourth run
3
4
FESEM, and TEM techniques were employed to analyze
the recovered catalyst Fe O @NAC after the fourth run
3
4
(Figure 11).
As results from the ICP, hot filtration test, BET, TEM,
FT-IR, FESEM, and XRD analyses for the recovered
immobilized NAC on Fe O display, Fe O @NAC is a
3
4
to check the possible leaching of iron ions from the
recycled catalyst. Once again no detection of iron
3
4
3 4
+
2
+3
showed no passing of Fe /Fe
shell during reusing processes.
from the cellulosic-
highly stable organometallic base catalyst.
The versatility of the heterogeneous and magnetic
base catalyst Fe O @NAC was then demonstrated in the
To check the heterogeneity of catalyst and leaching
3
4
[40]
of NAC, a hot filtration test
was done for the
base-catalysis synthesis of the THDPPs from the interme-
Fe O @NAC-catalyzed typical p-MC synthesis of
diate A, an aldehyde, and NH OAc in water at room tem-
3
4
4
THDPP1 from the A by its separation with a magnet
after 50% reaction progress (2 min) and keeping the
mixture without the catalyst under similar conditions.
No progress of the reaction showed heterogeneously
perature (Table 2).
As results demonstrate, in general, a range of alde-
hydes could undergo rapid reactions with A and NH OAc
4
to give the THDPPs in high yields.

12 of 14
TAMADDON ET AL.
FIGURE 11 The transmission electron microscopy (TEM) (a), Fourier transform infrared (FT-IR) (b), field-emission scanning electron
microscopy (FESEM) (c), and X-ray diffraction (XRD) (d) analyses for the recovered Fe
3
O
4
@NAC after the fourth run
3 4
TABLE 2 The Fe O @NAC-
catalyzed p-MCR for synthesis of
THDPPs from A
ꢁ
Melting point ( C)
found (reported)
Time
(min)
Yield
(%)
[31,36]
Entry
R
Product
THDDP1
THDDP2
THDDP3
THDDP4
THDDP5
THDDP6
THDDP7
THDDP8
THDDP9
1
2
3
4
5
6
7
8
9
C
6
H
5
5
97
97
94
88
96
91
93
96
95
240–242 (239–241)
241–243 (242–244)
245–247 (244–246)
163–165 (165–167)
252–254 (254–256)
221–223 (220–220)
265–267 (265–267)
235–237 (333–335)
285–287 (285–286)
4-Me
4-MeC
4-BrC
2
NC
6
H
4
7
6
H
4
8
6
H
4
15
10
10
12
7
4-ClC
2-ClC
6
6
H
H
4
4
6 4
4-HOC H
4-O
3-O
2
2
NC
6
6
H
H
4
NC
4
10

TAMADDON ET AL.
13 of 14
4
| CONCLUSIONS
ORCID
Fatemeh Tamaddon https://orcid.org/0000-0002-6686-
8094
Ehsan Ahmadi-AhmadAbadi https://orcid.org/0000-
0001-7057-8201
The eco-biocompatible core–shell Fe O @nanoalka
3
4
linecellulose (NAC) was prepared by coagulation of
cotton-derived NAC on the co-precipitated nanoFe O4
3
at
alkaline
medium.
The
nanoFe O @NAC
Hossein Kargar https://orcid.org/0000-0003-2319-0663
3
4
nanoparticles in the range of 25–38 nm are slightly
larger than Fe O , whereas the XRD pattern of
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