Ferric Sulfasalazine Sulfa Drug Complex Supported on Cobalt Ferrite Cellulose; Evaluation of Its Activity in MCRs

Article abstract of DOI:10.1007/s10562-020-03101-6

Abstract: The green and nano catalyst was simply prepared through the reaction of ferric sulfasalazine with nanomaterial CoFe₂O₄-cellulose as a magnetic biopolymer surface. This novel heterogeneous organometallic catalyst was charact

Full text of DOI:10.1007/s10562-020-03101-6

Catalysis Letters
https://doi.org/10.1007/s10562-020-03101-6
Ferric Sulfasalazine Sulfa Drug Complex Supported on Cobalt Ferrite
Cellulose; Evaluation of Its Activity in MCRs
Shahnaz Rostamizadeh1 · Zahra Daneshfar1 · Ali Khazaei1
Received: 3 September 2019 / Accepted: 9 January 2020
© Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract
The green and nano catalyst was simply prepared through the reaction of ferric sulfasalazine with nanomaterial
CoFe2O4-cellulose as a magnetic biopolymer surface. This novel heterogeneous organometallic catalyst was characterized
by X-ray difraction, feld emission scanning electron microscopy, FT-IR spectroscopy, thermal gravimetric analysis, and
energy dispersive analysis of X-rays, and inductively coupled plasma-mass spectrometry. This green sulfasalazine drug
complex supported on CoFe2O4 cellulose was applied as an efcient and recyclable catalyst for organic reactions such as
synthesis of functionalized 4H- pyrans and 1,4-dihydropyridines derivatives. All of the reactions were carried out success-
fully under mild conditions in a short reaction time. The used catalyst was easily separated and reused for 6 runs without
noticeable loss of its catalytic activity.
Electronic supplementary material The online version of
this article (doi:https://doi.org/10.1007/s10562-020-03101-6)
contains supplementary material, which is available to authorized
users.
* Shahnaz Rostamizadeh
rostamizadeh@kntu.ac.ir
1
Department of Chemistry, Faculty of Science, K. N. Toosi
University of Technology, P.O. Box 15875-4416, Tehran,
Iran
Vol.:(0123456789)
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S. Rostamizadeh et al.
Graphic Abstract
Keywords Sulfasalazine · Organometallic complex · Green chemistry · Magnetic catalyst · Heterogenic catalyst · Cellulose
as a bidentate chelator [25]. Copper (II) complex of salicylic
acid catalyzed cross-coupling reactions [7]. There is cur-
rently much interest in iron (III) salicylate complex, for its
applications in biomedicine and environmental monitoring
[23, 24, 26]. One important derivative of salicylic acid is
sulfasalazine drug. Sulfasalazine as an important sulfa drug
under the trade name Azulfdine is used to treat rheumatoid
arthritis, ulcerative colitis, and Crohn’s diseases [18]. Also
due to its ability to form stable complexes, a series of sul-
fasalazine complexes with diferent metals such as: Fe (III),
Co (II), Ni (II), Cu (II), Zn (II) and Cd (II) were reported
recently [34]. Based on the principle of green chemistry,
heterogeneous catalysts have some advantageous over homo-
geneous catalysts. They can be recovered from the reaction
mixture through fltration or centrifugation and reused after
activation. Thus it makes the process economically possible
[43, 44] Also heterogenization of organometallic compounds
through attaching them to inorganic or organic supports is
the most general method. Therefore a lot of approaches
have been established to attach complexes to diferent sol-
ids such as covalent anchoring, electrostatic adsorption,
ship-in-a bottle and supported liquid phase [36]. Magnetic
1 Introduction
Green chemistry as a critical and important major subject
in science and environment has increased the application of
recyclable heterogeneous acids which can be used instead
of harsh and non-reusable liquid acid catalysts like: hydro-
chloric acid, sulfuric acid and etc. Therefore, these days
application of novel solid acid catalysts has been increased
[2]. Also it is notable that organometallic complexes have
been recognized to perform as efective catalysts in organic
reactions [8, 22] and also with important bioactive proper-
ties [29]. In recent reports, metal carboxylates have been
extensively studied not only due to their interesting electro-
conductive, optical and magnetic properties [10], but also
because the carboxylic group can bind to metal ions in vari-
ous modes, such as monodentate, bidentate, and bridging
[28]. One important example of these ligands with ability
to form the metal complexes is salicylic acid. From the
coordination chemistry view point, salicylic acid is a useful
ligand for chelating with metal ions. It can ofer two hard
and strong basic O-donor centers either from both of car-
boxyl and hydroxyl groups or only from the carboxyl group
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Ferric Sulfasalazine Sulfa Drug Complex Supported on Cobalt Ferrite Cellulose; Evaluation…
nanoparticles (MNPs) are probably the most generally con-
sidered compared to other supports like silica, alumina,
activated carbon, metal oxides, zeolites and polymers. It is
as an excellent and ideal support with signifcant industrial
potential due to its extraordinary properties such as hav-
ing large specifc surface area, being readily dispersed in
reaction solution, and easy functionalization with various
groups [13]. Their super-paramagnetic character makes them
efective and easily recovered from the reaction mixture via
an external permanent magnet. Therefore, a wide range of
the magnetically recyclable, nano catalysts with excellent
catalytic activities have been developed [4, 6, 39–41, 43,
44]. Among the various MNPs as the core magnetic sup-
ports, cobalt ferrite is one of the most versatile magnetic
materials. It has moderated saturation magnetization, high
chemical stability and mechanical strength [27]. Also, cel-
lulose is an important natural material in the world. This
biodegradable polymer has an important role as a biocom-
patible and renewable resource containing hydroxyl groups
[33]. The presence of a great number of hydroxyl groups
makes it possible to attach to MNPs ions through chelation
mechanism without using any linkers [38]. Hence, through
the combination of the properties of cobalt ferrite with cel-
lulose, the development of novel, highly active and reus-
able immobilized catalyst is improved [43, 44]. Based on
the literature reports, magnetic cellulose has been linked to
diferent metals such as copper (II) and titanium (I) via its
hydroxyl groups [3, 30]. Also, ferric ion as a safe and ecof-
riendly cation is a good Lewis acid which is able to activate
carbonyl groups for nucleophilic addition reactions. Thus,
the main purpose of the present work is to prepare a new,
bio-based magnetic, nano heterogeneous and organometallic
catalyst which is “CoFe2O4@nano-cellulose/Fe (III)-SSZ”.
It is worth mentioning that multicomponent reactions
(MCRs) containing domino processes have developed as
potent tools to extent this important issue. Such transforma-
tions reduce the use of catalyst, solvent, time, and energy
[17, 42]. One of these MCRs is to synthesis 1,4-dihydro-
pyridine (DHP) derivatives contain a large family of medici-
nally important compounds with diverse pharmacological
and therapeutic properties [12]. Although the synthesis of
DHPs has been carried out by a variety of homogeneous and
heterogeneous catalysts, some of these methods sufer from
limited scope like low yields, long reaction time, expen-
sive catalysts and difcult work-up procedures [9, 15, 20,
31, 32, 35]. Another multicomponent reaction is preparing
4H-pyrans derivatives. 4H-pyrans and their derivatives are
considerable due to their pharmacological activities [14], for
instance spasmolytic, diuretic, anticoagulant, anticancer, and
anti-anaphylactic [1, 5, 37]. Many methods for the synthesis
of 4H-pyrans have been reported in the literature. Although,
these methods have their own advantages, but they still have
signifcant limitations like harsh reaction conditions, long
reaction time and use of expensive, unavailable catalysts [11,
16, 19, 21]. Also for synthesis of 4H-pyrans derivatives usu-
ally basic homogeneous catalysts were applied. So apply-
ing an inexpensive, heterogeneous and acidic catalyst could
be worthwhile. These fndings led us to do an efcient and
green process for synthesis of these ring systems. In this arti-
cle efcient methodologies were described for the synthesis
of 4H-pyran and DHP derivatives using “CoFe2O4@nano-
cellulose/Fe (III) SSZ” as a green heterogeneous catalyst.
2 Experimental
2.1 Materials
All materials were purchased from Sigma-Aldrich Company.
2.2 Preparation and Characterization
of CoFe2O4‑Cell‑Fe (III)/SSZ
The magnetic CoFe2O4 cellulose/ferric (III) sulfasala-
zine nanoparticles were prepared in three steps as pre-
sented in Scheme 1. The frst step was preparing magnetic
CoFe2O4-cellulose nanoparticles by a one-pot synthesis
method. Cellulose was dissolved in a 3% acetic acid solution,
then an aqueous solution of FeCl3 6H2O and CoCl2 6H2O
was added. The mixture was stirred vigorously for 2 h, and
then a sodium hydroxide solution was added [43, 44]. The
second step was to prepare ferric (III) sulfasalazine. It was
carried out by reaction of ferric chloride to a hot mixture of
ammonia and ethanol solution of sulfasalazine for the mono
complexation [34]. Then, CoFe2O4Cell presented a support
for the immobilization of ferric sulfasalazine by the reaction
of hydroxyl groups of cellulose with ferric chloride com-
plexed with sulfasalazine acid. Ferric sulfasalazine at refux
conditions in ethyl acetate was attached to CoFe2O4Cell nan-
oparticles. The content of ferric ion complexed to sulfasala-
zine supported on CoFe2O4-Cell was 0.16 mmol.g−1 deter-
mined by ICP-MS. Also, the EDAX analysis of this catalyst
showed elimination of the chloride ion. The preparation of
CoFe2O4Cell/ Fe (III) SSZ was described in Scheme 1 (For
more information see ESI).
2.3 General Procedure for the 4H‑ Pyrans
Derivatives Synthesis
A suspension of malonitrile (1 mmol), ethyl acetoacetate
(methyl acetoacetate, acetoacetate) (1 mmol), aldehyde
(1 mmol) and the catalyst (0.01 g, 0.0016 mmol) in ethanol
(10 ml) was stirred at 60 °C. After completion of the reaction
which was monitored by TLC, the catalyst was separated
by using an external magnet. The mixture was poured into
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S. Rostamizadeh et al.
Scheme 1 The preparation of CoFe2O4Cell-Fe (III) SSZ
cold water and the precipitate was fltered. The solid was
Mass spectra were recorded on a Finnigan-MAT 8430 mass
spectrometer operating at an ionization potential of 70 eV.
IR Spectra were recorded on a Shimadzu IR-470 spectrom-
eter. Proton nuclear magnetic resonance spectra (1H NMR)
were recorded on a Bruker DRX-300 Advance spectrometer
300.13 MHz; chemical shifts (δ scale) are reported in parts
per million (ppm). 1H NMR Spectra are reported in order:
number of protons, multiplicity and approximate coupling
constant (J value) in hertz (Hz); signals were characterized
as s (singlet), d (doublet), t (triplet), m (multiplet), and br
s (broad signal). The 13C NMR spectra were recorded at
75.47 MHz and 100 MHz; chemical shifts (δ scale) are
reported in parts per million (ppm). The elemental analyses
were performed with an Elementar Analysensysteme GmbH
Vario EL. Difraction data were collected on a STOE STADI
P with scintillation detector, secondary monochromator and
Cu-Ka1 radiation (λ = 1. 5406 Å). TG/DTA experiments
were carried out by a BÄHR Thermo analysis with a tem-
perature program from 10 to 800 °C at a constant rate of
recrystallized with ethanol and dried in an oven at 60 °C.
2.4 General Procedure for the 1, 4‑DHP Derivatives
Synthesis
In a 25 mL round-bottomed fask, aldehyde (1 mmol), ethyl
acetoacetate (methyl acetoacetate, acetoacetate) (2 mmol),
ammonium acetate (1 mmol), and the catalyst (0.01 g,
0.0016 mmol) in 10 ml ethanol were added. The reaction
mixture was stirred at 60 °C. After completion of the reac-
tion which was traced by TLC, the catalyst was separated by
using an external magnet. The pure product was obtained by
crystallization of the crude material from ethanol.
2.5 Physical Measurements
Reactions were carried out under air condition. Melting
points were measured on an Electro thermal 9200 apparatus.
1 3

Ferric Sulfasalazine Sulfa Drug Complex Supported on Cobalt Ferrite Cellulose; Evaluation…
20 °C per min. Scanning electron microscopy was carried
out by Philips XL-30 ESEM. Inductively coupled plasma-
mass spectrometry was obtained using a Perkin–ElmerElan
600 quadrupole ICP-MS with a CetaxLSX-200 UV laser
module.
the catalytic activity of CoFe2O4-Cell/Fe (III) SSZ, a one-
pot synthesis of two diferent multi component reactions
was chosen. First one was the reaction of malonitrile, alde-
hyde (or isatin) and ethyl acetoacetate (methyl acetoac-
etate or acetoacetone) to obtain 4H-pyrans. The second
one was the reaction of ammonium acetate, aldehyde and
ethyl acetoacetate (methyl acetoacetate or acetoacetone) to
gain 1,4-dihydropyridines. Benzaldehyde was chosen as
the model compound for the optimization of 4H-pyrans and
1,4-dihydropyridines synthesis.
3 Results and Discussion
The green and nano catalyst based on sulfasalazine drug
was characterized by X-ray difraction (XRD), feld emission
scanning electron microscopy (FE-SEM), FT-IR spectros-
copy, thermal gravimetric analysis (TGA), energy disper-
sive analysis of X-rays (EDAX), and inductively coupled
plasma-mass spectrometry (ICP-MS). In order to evaluate
3.1 XRD analysis
The XRD patterns of CoFe2O4@nano-cellulose/Fe (III) SSZ
and CoFe2O4Cell were shown in Figs. 1 and 2. The XRD
Fig. 1 XRD pattern of
CoFe2O4@ Cell/Fe (III)-SSZ
Fig. 2 XRD pattern of
CoFe2O4@ Cell
1 3

S. Rostamizadeh et al.
pattern of CoFe2O4@nano-cellulose/Fe (III)SSZ has shown
difraction peaks at 2θ=18.2°, 29.10°, 32.698°, 35.7935°,
43.42°, 57.51° and 61.78° with FWHM equal to 0.55, 0.56,
0.28, 0.42, 0.48, 0.23 and 0.53 respectively. They were quite
matched with the cubic spinel structure of pure CoFe2O4.
Also these data were similar with the XRD of CoFe2O4Cell.
The difraction peaks at 2θ=16.97° and 26.25° with FWHM
equal to 0.36 and 0.29 respectively, have shown the exist-
ence of cellulose. The observed signals at 2θ=23.81° and
presence of cobalt and ferric ions was obvious in CoFe2O4@
Cell (Table 2, entry 1). Based on EDAX, the presence of
Cl and Fe in Fe (III) SSZ confrmed chelation of ferric
ion to sulfasalazine (Table 2, entry 2). EDAX analysis of
CoFe2O4Cell/Fe (III)-SSZ demonstrated the presence of Co,
Fe, N and S which means contribution of the sulfa drug
organometal complex with the magnetic support (Table 2,
entry 3). Notably, elimination of chloride in CoFe2O4-Cell/
Fe (III)-SSZ was confrmed (Table 2, entry 3) indicating
the fnal structure of the catalyst. The EDAX analysis of
CoFe2O4Cell/Fe (III)-SSZ and CoFe2O4Cell were demon-
strated in Figs. 4 and 5. Also CHN analysis of cellulose,
CoFe2O4Cell, Fe (III)-SSZ and CoFe2O4Cell/Fe (III)-SSZ
were presented in Table 3. Based on the data, nitrogen in
Fe (III)-SSZ and CoFe2O4-Cell/Fe (III)-SSZ was obtainable
(Table 3, entries 4 and 5). The percentages of C, H and N
elements in cellulose, CoFe2O4Cell and Fe (III)-SSZ were
demonstrated in Fig. 5. Finally, a comparison of the ele-
ments for the reported substrates was obvious in Figs. 6 and
7.
38.0607°̊ with FWHM equal to 0.52 and 0.21 were related
to Fe (III)-SSZ. Other signals in 2θ= 13.68°, 34.25° and
45.71°, 53.94° and 70.16° with FWHM equal to 0.40, 0.57,
0.20, 0.22 and 0.51 exposed the existence of cellulose and
connection of ferric ion to cellulosic shell (Table 1).
3.2 TEM and SEM Measurement
The morphology and size details of the nano catalyst were
investigated by SEM measurement illustrated in Fig. 3. The
SEM image of pure CoFe2O4-Cell/Fe (III)-SSZ indicated
that the diameter of its particles were around 45 nm. Both
CoFe2O4-Cell/Fe (III)-SSZ and CoFe2O4Cell nanoparticles
have a core–shell mode and spherical morphology. Also the
TEM image shown in Fig. 3e and f indicate that magnet-
ite composites served as supports for the catalyst. Further-
more it has appropriate spherical morphologies and regular
core–shell structures.
3.4 FT‑IR Analysis
The FTIR of cellulose (a), CoFe2O4-Cell (b), SSZ (c),
Fe (III)-SSZ (d) and CoFe2O4-Cell/Fe (III)-SSZ (e) were
shown in Fig. 8. The FT-IR spectrum of nano-cellulose
(Fig. 8a) showed a broad band at 3338 cm−1 which was
related to the stretching vibrations of hydroxyl groups.
For CoFe2O4-Cell (Fig. 8b) the absorption signals at 1058
and 1108 cm−1 displayed the stretching vibrations of the
C–O bonds. In addition to the cellulose absorption bands,
stretching vibrations of Fe–O and Co–O groups at 582 and
681 cm−1 were appeared. These signals indicated that the
magnetic CoFe2O4 nano particles were coated by cellulose
[43, 44]. The IR spectrum of sulfasalazine drug (Fig. 8c)
showed a medium signal at 3438 cm−1 attributed to the phe-
nolic OH and carboxylic OH groups. A strong peak in fer-
ric sulfasalazine (M:L = 1:1), (Fig. 8d) at 1259 cm−1 was
related to the shift of the ν(C–O) of the phenolic group.
The phenolic hydroxyl group was found deprotonated in the
mono complexes, which was apparent from the absence of
the σ (OH) in plane bending in 1394 cm−1 strongly [34].
The presence of water molecules in the complex was deter-
mined by the appearance of ν (OH) as a broad peak in the
range of 3500–3000 cm−1, and Ɣ (OH) in the range of
965–914 cm−1. The other bending vibration of the water
molecule σ (OH) was appeared around 1600 cm−1, which
always interferes with the skeleton vibration of the benzene
ring (C=vibration). The spectrum of Fe (III)-SSZ showed
sharp peaks at 1616 and 1425 cm−1 assigned to asymmet-
ric and symmetric stretching vibration of the carboxylate
moiety, respectively. These two signals were either slightly
shifted to lower frequencies indicating the participation of
3.3 EDAX and CHN Measurement
EDAX analysis of ferric sulfasalazine, CoFe2O4Cell and
CoFe2O4Cell/ Fe (III)-SSZ were described in Table 2. The
Table 1 XRD analysis of CoFe2O4@Cell/ Fe (III) SSZ
Entry
Position (2θ°)
FWHM (2θ°)
1
2
3
4
5
6
7
8
13.6815
16.9791
18.2
23.8199
26.2532
29.1068
32.698
34.2572
35.7935
38.0607
43.4246
45.7114
53.9425
57.5101
61.7800
70.1670
0.4040
0.3650
0.5512
0.5210
0.2914
0.5600
0.2815
0.5710
0.4245
0.2106
0.4823
0.2011
0.2210
0.2300
0.5310
0.5120
9
10
11
12
13
14
15
16
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Ferric Sulfasalazine Sulfa Drug Complex Supported on Cobalt Ferrite Cellulose; Evaluation…
Fig. 3 FESEM images of CoFe2O4@nano-Cell/ Fe (III) SSZ (a, b); CoFe2O4Cell (c, d); TEM image of CoFe2O4@nano-Cell/ Fe (III) SSZ and
CoFe2O4Cell (e, f)
Table 2 EDAX analysis of the
Entry
Substrate
C
N
O
S
Cl
Co
Fe
catalysts
1
2
3
CoFe2O4-Cell
Fe (III)-SSZ
CoFe2O4Cell-Fe (III)/SSZ
19.3
38.5
39.9
0
9.4
15.5
15.0
21.2
16.2
0
9.1
2.0
4.6
11.6
0
2.7
0
4.1
37.4
10.2
22.3
1 3

S. Rostamizadeh et al.
Fig. 4 EDAX spectra of CoFe2O4-Cell/Fe (III)-SSZ
Fig. 6 CHN analysis of Cell, CoFe2O4Cell, SSZ, Fe (III) SSZ and
CoFe2O4Cell-Fe (III) SSZ
Fig. 5 EDAX spectra of CoFe2O4Cell
Table 3 CHN analysis
Entry
Substrate
C
H
N
Fig. 7 EDAX analysis of CoFe2O4, Fe (III) SSZ, CoFe2O4Cell-Fe
(III) SSZ
1
2
3
4
5
Cellulose
CoFe2O4-Cell
SSZ
41.8
20.8
53.27
37.80
26.3
6.26
4.67
3.5
3.48
4.64
0
0
13.06
9.47
2.87
of the carboxylate group in the structure of the fnal cata-
lyst. The sulfonyl group vibrations didn’t show any changes
obviously. Also a characteristic absorption band in 406 cm−1
could be due to Fe–O band for the ferric ion attached to cel-
lulose [43, 44].
Fe (III)-SSZ
CoFe2O4-Cell/Fe
(III)-SSZ
the carboxylate group in the complex formation. The other
ligand vibrations (O=S O,–N=N–) remained unchanged or
slightly shifted, which might be attributed to the electronic
density changes on these groups after the complex forma-
tion. The participation of the phenolic and carboxylic groups
was also confrmed by the appearance of a new signal in
the complex in 440 cm−1 region assigned to the ν (M–O)
stretching vibrations [34]. The spectrum of CoFe2O4-Cell/
Fe (III) SSZ (Fig. 8e) showed sharp signals at 1604 and
1410 cm−1 related to asymmetric and symmetric stretch-
ing vibrations of the carboxylate group, respectively. This
remarkable increase of frequency of the catalyst in com-
parison with ferric sulfasalazine indicated the participation
3.5 The Magnetic Properties
Magnetic properties of the magnetic properties of
CoFe2O4-cellulose and CoFe2O4-cellulose/Fe (III)-SSZ were
characterized at RT (300 K) by a vibrating sample mag-
netometer (VSM) and their hysteresis curves were presented
in Fig. 9. The amount of specifc saturation magnetization
(Ms) for CoFe2O4-cellulose nanoparticles was about 52.42
emu g−1, which decreased to 37.40 emu g−1 after connect-
ing ferric sulfasalazine to CoFe2O4-cellulose. Although
this noteworthy decrease, the saturated magnetization of
the MNPs was sufcient for magnetic separation. Therefore
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Ferric Sulfasalazine Sulfa Drug Complex Supported on Cobalt Ferrite Cellulose; Evaluation…
Fig. 10 TGA of (a) CoFe2O4Cell (b) CoFe2O4@Cell-Fe (III) SSZ
the prepared catalyst could be separated efciently via an
external permanent magnet.
3.6 Thermogravimetric Studies
The TGA curve of CoFe2O4Cell illustrated fourth mass-loss
steps in Fig. 10a. The frst one was a weight loss (18.2%)
from 50 to 100 °C because of removal of catalyst mois-
ture. The second step was the decomposition step with an
estimated mass loss of 25.1% in the temperature range of
100–310 °C, due to the liberation of two coordinated water
molecules. Consequently, the third weight loss in the series
of 310–610 °C (10.1%) was related to the decomposition
of cellulose units through the formation of levoglucosan
and other volatile compounds. The fourth step with a fnal
oxide residue of Fe2O3 and CoO (12.05%) was from 610 to
800 °C. Also the TGA curve of CoFe2O4Cell/ Fe (III)-SSZ
illustrated fve mass-loss steps in Fig. 10b. The frst one,
a very small weight loss (2.53%) from 50 to 100 °C was
related to removal of catalyst moisture. The second step, the
decomposition step with an estimated mass loss of 14.16%
within the temperature range of 100 °C to 300 °C might be
attributed to the liberation of two coordinated water mol-
ecules. Consequently, the third main weight loss observed
in the in the ranges of 300–465 °C (24.10%) was due to the
decomposition of cellulose units through the formation of
levoglucosan and other volatile compounds. The fourth step
from 465 to 645 °C with an estimated mass loss of 8.08%
was considered to the decomposition of the ligand molecule.
It ended at the ffth step with a fnal oxide residue of Fe2O3
and CoO (12.05%) with the range of 465–800 °C. Finally,
based on the TGA curve, the stability of CoFe2O4Cell/Fe
(III)-SSZ was increased compared to CoFe2O4Cell.
Fig. 8 FTIR of (a) cellulose (b) CoFe2O4Cell (c) SSZ (d) Fe (III) SSZ
(e) CoFe2O4@Cell-Fe (III) SSZ
Fig. 9 Magnetization curves of (a) CoFe2O4Cell (b) CoFe2O4@Cell-
Fe (III) SSZ
1 3

S. Rostamizadeh et al.
a short time, but Fe (III)-SSA exhibited a poor yield in a
long reaction time. Finally by attaching ferric sulfasalazine
on super magnetic cellulose, the yield of the reaction was
increased to 98% during 10 min. Furthermore the other fea-
tures of CoFe2O4@Cell/ Fe (III) SSZ were: decreasing of
the temperature to 60 °C and reusability (Table 4, entry 13).
3.7 Catalytic Activity of CoFe2O4‑Cell‑Fe (III)/ SSZ
for 4H‑Pyrans Synthesis
In order to evaluate the catalytic activity of ferric sulfa drug
complex supported on CoFe2O4Cell, one-pot synthesis
of malonitrile, aldehyde (or isatin) and ethyl acetoacetate
(methyl acetoacetate and acetoacetone) was chosen. Benza-
ldehyde and ethyl acetoacetate were selected as the model
compounds for the optimization of 4H-pyrans synthesis. The
time and yield of the reaction catalyzed by CoFe2O4Cell/
Fe (III) SSZ were compared to other catalysts in Table 4.
The reaction mostly was carried out successfully by strong
basic catalysts. So the present catalyst as a heterogeneous
acidic catalyst improved the yield under mild conditions.
The reported catalysts such as decaniobate salt [16] was a
homogeneous catalyst, which means it has no ability to be
recovered. Also the reaction was carried out at high tempera-
ture during 120 min. Chitosan-grafted-poly (4-Vinylpyridne)
[21] as a heterogeneous basic catalyst ofered the product at
refux conditions after 180 min. Besides, the reaction was
catalyzed by piperazine hydrate [21] and L- prolin [12] as
homogeneous catalysts, sufered from high temperature and
long reaction time. Although, the reaction was catalyzed by
ammonium acetate [45] was carried at room temperature,
but high catalyst loading applied (Table 4, entries 1–5). In
the present research, α-Fe2O3, FeCl3.6H2O, CoCl2.6H2O,
cellulose and CoFe2O4Cell were also applied as acidic base
catalysts (Table 4, entries 6–10). Noticeably, CoFe2O4Cell
improved the yield and decreased the reaction time com-
pared to them. Furthermore, ferric sulfasalazine and ferric
complex of salicylic acid (Table 4, entries 11 and 12) as
organometallic catalysts displayed diferent results. Some-
how, ferric sulfasalazine enhanced the yield to 78% in
3.8 Optimization of the Reaction Conditions
for the Synthesis of 4H‑ Pyrans
The temperature of the reaction from room temperature to
70 °C was studied (Table 5, entries 1–8). By applying the
catalyst at room temperature, 70% of product was obtained
during 100 min (Table 5, entry 1). Increasing the tempera-
ture from 40 to 55 °C improved production up to 90% obvi-
ously (Table 5, entries 2–5). The best result was obtained
at 60 °C, in which the yield was enhanced to 98% (Table 5,
entry 6). When the reaction was carried out at 65 °C, the
corresponding yield didn’t change (Table 5, entry 7). Con-
version of the starting materials to the product at 70 °C
decreased the yield to 95% (Table 5, entry 8).
Loading of the catalyst from 0 to 0.25 mol % was sum-
marized in Table 5 (entries 9–15). The reaction was carried
out without catalyst, somehow, after 720 min no product
was obtained (Table 5, entry 9). Loading of the catalyst
from 0.02 to 0.12 mol% increased production from 40 to
80% (Table 5, entries 10–12). Also the reaction time was
decreased from 40 to 15 min by adding amount of the cata-
lyst (Table 5, entries 10–12). When 0.16 mol% of the cata-
lyst was consumed, the related production was increased to
98% (Table 5, entry 13). It was noticeable that addition of
catalyst loading to 0.2 mol% and 0.25 mol% didn’t change
the yield (Table 5, entry 14–15).
Table 4 Optimization of catalyst for 4H- pyrans reaction
Entry Catalyst
Solvent
Catalyst amount Temperature (°C) Time (min) Yield (%) References
1
2
3
4
5
HPNb
Cs-PVP
Piperazine hydrate
L-proline
NH4OAC
Solvent free
Absolute ethanol 10 wt%
EtOH
EtOH
EtOH
100 mg
80
120
180
540
240
720
91
90
85
72
78
Sarnikar et al. [32]
Shukla et al. [33]
Soliman et al. [34]
Tamadon and Moradi [35]
Refux
Refux
Refux
rt
7 mol%
10 mol%
150 mol%
Valkenber and Hölderich
[36]
6
7
8
9
10
11
12
13
α-Fe2O3
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
0.01 g
0.01 g
0.01 g
0.01 g
0.01 g
0.01 g
0.01 g
0.01 g
60
60
60
60
60
60
60
60
30
69
20
23
80
85
78
35
98
Present
Present
Present
Present
Present
Present
Present
Present
FeCl3.6H2O
CoCl2.6H2O
Cellulose
CoFe2O4-Cell
Fe (III)-SSZ
Fe (III)-SSA
720
720
90
30
30
720
10
CoFe2O4-Cell/Fe (III)
SSZ
1 3

Ferric Sulfasalazine Sulfa Drug Complex Supported on Cobalt Ferrite Cellulose; Evaluation…
Table 5 Optimization of 4H- pyrans reaction
Entry
Catalyst
Solvent
X (mol%)
Temperature
(°C)
Time (min)
Yield (%)
Efect of temperature
1
2
3
4
5
6
7
8
CoFe2O4-Cell/Fe (III) SSZ
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
0.16
0.16
0.16
0.16
0.16
0.16
0.16
0.16
rt
100
100
80
40
20
10
10
10
70
76
79
85
90
98
98
95
CoFe2O4-Cell/Fe (III) SSZ
CoFe2O4-Cell/Fe (III) SSZ
CoFe2O4-Cell/Fe (III) SSZ
CoFe2O4-Cell/Fe (III) SSZ
CoFe2O4-Cell/Fe (III) SSZ
CoFe2O4-Cell/Fe (III) SSZ
CoFe2O4-Cell/Fe (III) SSZ
40
45
50
55
60
65
70
Efect of catalyst loading
9
CoFe2O4-Cell/Fe (III) SSZ
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
0
60
60
60
60
60
60
60
720
40
30
15
10
10
10
NR
40
60
80
98
98
98
10
11
12
13
14
15
CoFe2O4-Cell/Fe (III) SSZ
CoFe2O4-Cell/Fe (III) SSZ
CoFe2O4-Cell/Fe (III) SSZ
CoFe2O4-Cell/Fe (III) SSZ
CoFe2O4-Cell/Fe (III) SSZ
CoFe2O4-Cell/Fe (III) SSZ
0.02
0.07
0.12
0.16
0.2
0.25
Efect of solvent
16
17
18
19
20
21
22
23
CoFe2O4-Cell/Fe (III) SSZ
EtOH
EtOH/H2O, (1:1)
H2O
MeOH
THF
Toluene
Solvent free
DMF
0.16
0.16
0.16
0.16
0.16
0.16
0.16
0.16
60
60
60
60
60
60
60
60
10
15
20
10
60
120
15
14
98
75
35
90
27
23
53
71
CoFe2O4-Cell/Fe (III) SSZ
CoFe2O4-Cell/Fe (III) SSZ
CoFe2O4-Cell/Fe (III) SSZ
CoFe2O4-Cell/Fe (III) SSZ
CoFe2O4-Cell/Fe (III) SSZ
CoFe2O4-Cell/Fe (III) SSZ
CoFe2O4-Cell/Fe (III) SSZ
The efect of solvents on the reaction was studied in
3.9 Preparation of Functionalized 4H‑ Pyrans
in the Presence of CoFe2O4@Cell/Fe (III)‑SSZ
Table 5 (entries 16–23). Ethanol as a green solvent was
applied and increased the yield remarkably. Adding water
to ethanol decreased the yield from 98 to 75% (Table 5,
entry 17). Also applying water in the reaction resulted
poor yield (Table 5, entry 18). Methanol as another alco-
hol was consumed and the related yield was 90%. Tet-
rahydrofuran, toluene and dimethylformamide as aprotic
solvents didn’t increase the production as much as alcohols
(Table 5, entries 20, 21 and 23). It is worth mentioning
that the reaction was carried out in solvent free condi-
tions, but it didn’t enhanced the yield noticeably (Table 5,
entry 22).
After optimization of the reaction conditions, the gener-
ality and scope of the reaction were considered. A diver-
sity of aromatic aldehydes bearing electron donating and
electron withdrawing groups at either ortho-, meta- or
para-positions of the aromatic ring were transformed
to 2-amino-4H-pyran derivatives with excellent yields
(Table 6). An extensive range of useful functional groups
including halide, nitro and isatin stayed stable during
the reaction conditions (Table 6, entries 2, 6 and 13). In
addition, the presence of amide, methyl and methoxy as
1 3

S. Rostamizadeh et al.
Table 6 Derivatives of 4-H pyrans
electron donating groups on the aromatic aldehyde per-
formed well and ofered the desired products up to 90%
(Table 6, entries 4, 5 and 10). Furthermore, heterocycle
groups such as furan and thiophene were successfully con-
verted into the desired products with high yields (Table 6,
entries 14 and 15). 5-Chloroisatin with an electron with-
drawing group ofered the related 4H-pyran with 98%
yield after 10 min (Table 6, entry 13). Furthermore, methyl
acetoacetate (Table 6, entries 23–25) had similar results
as ethyl acetoacetate. It is noticeable, the reaction time
was decreased slightly by applying acetoacetone (Table 6,
entries 18–22). This could be due to more activity of
acetoacetone compared to ethyl acetoacetate (or methyl
acetoacetate).
3.10 Recycling of the Catalyst
The magnetic property of CoFe2O4@Cell/Fe (III)-SSZ
caused an efcient recovery of the catalyst from the reac-
tion mixture. After completion of the reaction, the catalyst
1 3

Ferric Sulfasalazine Sulfa Drug Complex Supported on Cobalt Ferrite Cellulose; Evaluation…
Table 6 (continued)
was separated by a strong external permanent magnet,
washed with ethanol, dried under vacuum, and reused
directly for another run. The catalyst was consumed with
sixth runs, and no signifcant loss of catalytic activity was
observed (Fig. 11). FT-IR and SEM images of fresh and
recovered catalysts indicated that no considerable change
didn’t occur (Figs. 12, 13). This showed that CoFe2O4@
Cell/Fe (III)-SSZ is a stable chemical compound.
1 3

S. Rostamizadeh et al.
Table 6 (continued)
catalysts (as indicated in Table 7). Silica gel/sulfonic acid
[15] as a heterogeneous catalyst needed high catalyst loading
and long reaction time. Also, p-toluene sulfuric acid [20]
catalyzed the reaction via ultrasonic irradiation. This homo-
geneous catalyst didn’t reduce the reaction time obviously.
3.11 Optimization of the Reaction Conditions
for the Synthesis of 1,4‑DHP
In order to compare the efciency of the nano catalyst, the
model reaction was carried out in the presence of various
1 3

Ferric Sulfasalazine Sulfa Drug Complex Supported on Cobalt Ferrite Cellulose; Evaluation…
Table 6 (continued)
Furthermore, samarium (III) chloride [32] as another homo-
geneous catalyst was not able to be reused. In addition, the
reaction needed long time and high catalyst loading. PdRuNi
supported on graphene oxide [9] catalyzed the reaction in
DMF, which is not a green solvent. However, the load-
ing of the catalyst was low, but the catalyst is expensive
1 3

S. Rostamizadeh et al.
Fig. 11 Recyclability of the catalyst for the 4-H pyran synthesis
Fig. 13 FT−IR spectra of (a) Fresh CoFe2O4@Cell/ Fe (III) SSZ and
(b) CoFe2O4@Cell/ Fe (III) SSZ after three runs
and it didn’t reduce the reaction time noticeably (Table 7,
entries 1–4). In this research, cellulose, FeCl3.6H2O and
CoCl2.6H2O (Table 7, entries 5–7) were applied as cata-
lysts. They all needed longer reaction time compared to
CoFe2O4Cell at 60 °C (Table 7, entry 8) which reduced the
reaction time to 30 min. Besides, ferric sulfasalazine and
ferric salicylic acid were used in which both required more
reaction time than CoFe2O4Cell (Table 7, entries 9 and 10).
Although Fe (III)-SSZ displayed more activity than Fe (III)
SSA. Finally CoFe2O4@Cell/Fe (III) SSZ catalyzed the
reaction successfully during 20 min with 97% yield (Table 7,
entry 11).
Fig. 12 SEM images of a Fresh CoFe2O4@Cell/ Fe (III) SSZ and b
Optimization of temperature, catalyst loading and sol-
vent of the reaction was summarized in Table 8. The efect
of the temperature was traced, and the reaction was car-
ried out from room temperature to 70 °C (Table 8, entries
1–5). The highest yield was obtained at 60 °C (Table 8,
CoFe2O4@Cell/ Fe (III) SSZ after three runss
1 3

Ferric Sulfasalazine Sulfa Drug Complex Supported on Cobalt Ferrite Cellulose; Evaluation…
Table 7 Optimization of catalyst for 1,4-DHP synthesis
Entry
Catalyst
Solvent
Catalyst amount
Temperature (°C)
Time (min)
Yield (%)
References
1
2
3
4
5
6
7
8
SiO2–SO3H
p-TSA
SmCl3
PdNiRu@GO
Cellulose
FeCl3.6H2O
CoCl2.6H2O
CoFe2O4Cell
Fe (III) SSZ
Fe (III) SSA
Solvent free
EtOH
CH3CN
DMF
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
0.2 g
60
330
60
180
45
300
120
120
30
90
78
85
93
41
30
32
79
56
40
97
Zhao et al. [43]
Zhao et al. [44]
Zonouz et al. [45]
Demirci et al. [9]
Present
Present
Present
Present
Present
Present
Present
10 mol %
20 mol %
0.006 g
0.01 g
0.01 g
0.01 g
0.01 g
0.01 g
0.01 g
0.01 g
Ultrasonic irradiation
70
70
60
60
60
60
60
60
60
9
10
11
35
45
20
CoFe2O4-Cell/Fe EtOH
(III) SSZ
Table 8 Optimization of 1,4-DHP synthesis
Entry
Catalyst
Solvent
X (mol%)
Temperature
(°C)
Time (min)
Yield (%)
Efect of temperature
1
2
3
4
5
CoFe2O4-Cell/Fe (III) SSZ
EtOH
EtOH
EtOH
EtOH
EtOH
0.16
0.16
0.16
0.16
0.16
rt
50
40
30
20
20
50
59
69
97
97
CoFeO4-Cell/Fe (III) SSZ2
CoFe2O4-Cell/Fe (III) SSZ
CoFe2O4-Cell/Fe (III) SSZ
CoFe2O4-Cell/Fe (III) SSZ
40
50
60
70
Efect of catalyst loading
6
7
8
9
10
11
CoFe2O4-Cell/Fe (III) SSZ
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
0
60
60
60
60
60
60
240
45
30
20
20
20
15
71
86
97
97
97
CoFe2O4-Cell/Fe (III) SSZ
CoFe2O4-Cell/Fe (III) SSZ
CoFe2O4-Cell/Fe (III) SSZ
CoFe2O4-Cell/Fe (III) SSZ
CoFe2O4-Cell/Fe (III) SSZ
0.02
0.125
0.16
0.2
0.25
Efect of solvent
12
13
14
15
16
17
18
19
CoFe2O4-Cell/Fe (III) SSZ
EtOH
EtOH/H2O, (1:1)
H2O
MeOH
THF
Toluene
Solvent free
DMF
0.16
0.16
0.16
0.16
0.16
0.16
0.16
0.16
60
60
60
60
60
60
60
60
20
30
30
20
60
120
20
25
97
70
36
89
29
33
63
74
CoFe2O4-Cell/Fe (III) SSZ
CoFe2O4-Cell/Fe (III) SSZ
CoFe2O4-Cell/Fe (III) SSZ
CoFe2O4-Cell/Fe (III) SSZ
CoFe2O4-Cell/Fe (III) SSZ
CoFe2O4-Cell/Fe (III) SSZ
CoFe2O4-Cell/Fe (III) SSZ
1 3

S. Rostamizadeh et al.
entry 4). Furthermore the reaction yield didn’t change
by increasing the temperature (Table 8, entry 5). It is
worth mentioning that loading of the catalyst from 0 to
0.25 mol% was summarized in Table 8 (entries 6–11),
somehow the best result occurred by loading 0.16 mol%
of the catalyst (Table 8, entry 9). It is notable that the yield
Table 9 Synthesis of 1,4-DHP derivatives
1 3

Ferric Sulfasalazine Sulfa Drug Complex Supported on Cobalt Ferrite Cellulose; Evaluation…
Table 9 (continued)
didn’t improve by increasing the amount of catalyst from
0.16 mol% to 0.2 and 0.25 mol% (Table 8, entries 10 and
11). Ethanol (Table 8, entry 12) was an appropriate and
green solvent between aprotic and protic solvents (Table 8,
entry 12–19). The production of 1, 4-DHP was decreased
by adding water as a solvent (Table 8, entries 13 and 14).
Also solvent free solvent conditions didn’t improve the
yield considerably (Table 8, entry 18).
1 3

S. Rostamizadeh et al.
Table 9 (continued)
1 3

Ferric Sulfasalazine Sulfa Drug Complex Supported on Cobalt Ferrite Cellulose; Evaluation…
might be because of its higher activity compared to ethyl
3.12 Preparation of Functionalized 1,4‑DHP
Derivatives in the Presence of CoFe2O4@Cell/
Fe (III)‑SSZ
acetoacetate (or methyl acetoacetate).
3.12.1 Proposed Mechanism of CoFe2O4@Cell/Fe (III)‑SSZ
Catalyzed 4H‑Pyran Synthesis
After optimization of the reaction conditions, the general-
ity and scope of the reaction were considered. As demon-
strated in Table 9, a diversity of aromatic aldehydes bear-
ing electron donating and electron withdrawing groups at
either ortho-, meta- or para-positions of the aromatic ring
were transformed to 1,4-dihydropyridines derivatives with
excellent yields under mild conditions. A wide variety of
synthetically useful functional groups including halide and
nitro stayed undamaged during the reaction conditions.
Furthermore, the presence of methoxy, methyl as electron
donating groups on the aromatic aldehyde performed well
and ofered the product up to 90% yield. Also, heterocy-
cle groups such as furan and thiophene were successfully
converted into the desired products in high yield (Table 9,
entries 11 and 12). Furthermore the related products
were obtained with high yields by applying acetoacetone
(Table 9, entries 15–19) and methyl acetoacetate (Table 9,
entries 20–22). Methyl acetoacetate ofered the desired
products almost same as ethyl acetoacetate. However, ace-
toacetone could reduce the time of reaction a little. This
The mechanism of 4H-pyran synthesis catalyzed by
CoFe2O4@Cell/Fe (III)-SSZ was illustrated in Scheme 2.
Ferric ion has ability to activate carbonyl and nitrogen
groups. So, 2-benzylidenemalononitrile was formed imme-
diately. Also 2-benzylidenemalononitrile and ethyl acetoac-
etate were catalyzed for Michael addition by connection to
ferric ion through nitrogen and oxygen elements. After this
step, cyclization occurred by enol addition to cyanide group
(catalyzed both groups via the catalyst). Finally, 4-H pyran
was produced after tautomerization. The catalyst was reused
for the next run.
3.12.2 Suggested Mechanism of CoFe2O4@Cell/Fe (III)‑SSZ
catalyzed 1,4‑DHP Synthesis
The mechanism of preparation of 1, 4-DHP catalyzed by
CoFe2O4@Cell/Fe (III)-SSZ was demonstrated in Scheme 3.
Firstly, intermediates of I and II were prepared by the
Scheme 2 The proposed mech-
anism of CoFe2O4Cell-Fe (III)
SSZ for 4-H pyran synthesis
1 3

S. Rostamizadeh et al.
Scheme 3 The suggested
mechanism of CoFe2O4Cell-Fe
(III) SSZ for 1, 4-DHP synthesis
heterogeneous catalyst. Ferric ion has ability to make carbonyl
and nitrogen groups active. So, they reacted with each other via
Michael addition. Consequently, intermediate of (III) was pro-
duced. After this step, cyclization was carried out by enamine
addition to the carbonyl group (activated both groups through
the catalyst). Tautomerization process ofered 1, 4-DHP (VI).
The catalyst was consumed again for the following run.
showed high activity for the one pot and atom-economical
synthesis of 4H- pyrans and 1,4-DHP derivatives. This envi-
ronmental heterogeneous organometallic catalyst proceeded
the reactions under green conditions which ofered products
in high to excellent yields. Also the use of sulfasalazine for
the frst time as a pharmaceutical ligand in this organometal-
lic catalyst was the novelty of research. Furthermore, ferric
ion as a green, available and inexpensive metal and cata-
lyst was consumed in the structure of sulfa drug complex.
Besides, cellulose as a bio-friendly and bio-polymer sup-
port was applied. Magnetization of the catalyst was carried
out by cobalt ferrite as one of the most versatile magnetic
materials. It is worth mentioning, the catalyst readily was
recovered by applying an external magnet. It was recycled
4 Conclusion
In summary, a nano sized magnetic CoFe2O4@Cell/Fe (III)-
SSZ was prepared and characterized by XRD, TEM, SEM,
TGA, EDX, ICP-MS and IR spectroscopy. The catalyst
1 3

Ferric Sulfasalazine Sulfa Drug Complex Supported on Cobalt Ferrite Cellulose; Evaluation…
13. Gawande MB, Luque R, Zboril R (2014) The rise of magnetically
for several times without considerable loss of its catalytic
activity. Finally the ability of the present catalyst with an
important potential use for other multi component reactions
is possible.
recyclable nanocatalysts. Chem Cat Chem 6(12):3312–3313. https
://doi.org/10.1002/cctc.201402663
14. Green GR, Evans JM, Vong AK (1995) Pyrans and their benzo
derivatives synthesis. In: Katritzky AR, Rees CW, Scriven EFV
(eds) Comprehensive heterocyclic chemistry II, vol 5. Pergamon
Press, Oxford, p 469
Acknowledgements The authors are thankful to Iran National Science
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sulfonic acid on silica gel as an efcient and reusable heteroge-
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