Chitosan decorated Fe3O4 nanoparticles as a magnetic catalyst in the synthesis of phenytoin derivatives

Article abstract of DOI:10.1039/c4ra06618a

In the present work, Fe₃O₄ nanoparticles were synthesized by the chemical coprecipitation process. Subsequently, the synthesized nanoparticles were modified with chitosan by a simple method and characterized by X-ray diffractometry (XRD), Fourier transform infrared spectrophotometry (FT-IR), vibrating sample magnetometry (VSM), scanning electron microscopy (SEM) and energy-dispersive X-ray spectroscopy (EDX). Then, phenytoin derivatives were catalyzed by magnetic Fe₃O₄-chitosan nanoparticles. Fe₃O₄-chitosan nanoparticles were found to be a recoverable organocatalyst for the efficient synthesis of 5,5-diphenylhydantoins and 5,5-diphenyl-2-thiohydantoins from substituted benzils and urea or thiourea derivatives. The nanocatalyst could be recovered easily under a magnetic field for reuse, and considerable loss of its catalytic activity was not observed after reuse in seven consecutive runs. This journal is

Full text of DOI:10.1039/c4ra06618a

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Chitosan decorated Fe3O4 nanoparticles as a
magnetic catalyst in the synthesis of phenytoin
Cite this: RSC Adv., 2014, 4, 48973
derivatives†
*
Javad Safari and Leila Javadian
In the present work, Fe3O4 nanoparticles were synthesized by the chemical coprecipitation process.
Subsequently, the synthesized nanoparticles were modified with chitosan by a simple method and
characterized by X-ray diffractometry (XRD), Fourier transform infrared spectrophotometry (FT-IR),
vibrating sample magnetometry (VSM), scanning electron microscopy (SEM) and energy-dispersive X-ray
spectroscopy (EDX). Then, phenytoin derivatives were catalyzed by magnetic Fe3O4–chitosan
nanoparticles. Fe3O4–chitosan nanoparticles were found to be a recoverable organocatalyst for the
efficient synthesis of 5,5-diphenylhydantoins and 5,5-diphenyl-2-thiohydantoins from substituted benzils
and urea or thiourea derivatives. The nanocatalyst could be recovered easily under a magnetic field for
reuse, and considerable loss of its catalytic activity was not observed after reuse in seven consecutive runs.
Received 3rd July 2014
Accepted 11th September 2014
DOI: 10.1039/c4ra06618a
www.rsc.org/advances
fuel cells. It should be noted that chitosan, as a polyamine, is
the second most abundant natural polysaccharide in the world
aer celloluse.12 Chitosan is synthesized by the deacetylation of
Introduction
Recently, iron oxide nanoparticles have received increasing
attention because of their fundamental properties and appli-
cation in different elds such as clinical use, sensors and high
density magnetic recording media.1 Fe3O4 nanoparticles (NPs)
are an important class of magnetic material that have been
extensively investigated for their applications in magnetic
resonance imaging (MRI), hyperthermia, drug targeting, cata-
lysts and catalyst supports.2,3 The growing demand for envi-
ronmental chemical processes has prompted many researchers
to extend heterogeneous catalysts that can be separated simply
and reused effectively. Magnetically green catalysts present
potential in combining the advantages of facile recovery and
high activities in catalytic systems.4–6 Fe3O4 magnetic nano-
particles (MNPs) are treated with various materials to improve
their biocompatibility and chemical stability. The modication
of Fe3O4 NPs has been carried out by carbon, precious metals,
silica and biopolymers.7–10 Biopolymers, such as chitosan and
cellulose, have been applied as support in many heterogeneous
catalytic systems.11 However, some of the biopolymers without
any postmodication can be utilized as heterogeneous orga-
nocatalysts. Chitosan is a natural, biocompatible and biode-
gradable polymer that has shown extensive applications in
several elds such as drug delivery, medicine, adhesives, and
chitin, which is a byproduct of the shing industry. The insol-
ubility of chitosan in most of the organic compounds explains
the potential of chitosan as a heterogeneous catalyst in organic
synthesis. In this regard, several catalytic systems using chito-
san have been developed.13–15 Chitosan contains both primary
and secondary hydroxyl groups and amino groups. Hence, it can
activate electrophilic and nucleophilic compounds by hydrogen
bonding and lone pairs.16 These requirements exist in the
reaction of benzil derivatives with urea or thiourea for the
synthesis of hydantoin derivatives.
Hydantoin derivatives are useful pharmacological
compounds and are widely applied as psychomotor epilepsy
ulcers, anticonvulsant, antidiabetic, antitumor, antimicrobial,
antiviral and antiarrhythmic agents.17–23 Phenytoin (5,5-diphe-
nylhydantoin) is widely prescribed as an epidermolysisbullosa,
treatment of grand mal and for the treatment of many diseases
including HIV.24,25 Because of the importance of the current
bioactive compounds, numerous methods have been reported
for the synthesis of hydantoin derivatives, such as the reactions
of aldehyde with gallium(III) triate salt,26 amino acid with
ammonium thiocyanate, carbodiimide with unsaturated
carboxylic acid, nitriles with organometallic,27–29 amino acid
with triphosgene,30 and various conditions such as microwave
and ultrasound irradiations.31–36 In addition, the synthesis of
phenytoin derivatives were reported by homogeneous systems
such as Almonds.37 However, using these systems limits their
applications because of the difficulties in product purication.
However, there are no reports on the use of Fe3O4–chitosan as a
heterogeneous catalyst for the synthesis of phentoin derivatives.
Laboratory of Organic Compound Research, Department of Organic Chemistry, College
of Chemistry, University of Kashan, P.O. Box: 87317-51167, Kashan, Islamic Republic
of Iran. E-mail: Safari@kashanu.ac.ir; Fax: +98-(0)31-55912397; Tel: +98-(0)31-
55912320
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c4ra06618a
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(Fig. 1b and c). The weaker diffraction lines of Fe3O4–CS MNPs
compared with Fe3O4 nanoparticles indicate that the Fe3O4
nanoparticles were covered by amorphous chitosan polymer.
Chitosan did not destroy the crystal structure of iron oxide NPs.
Moreover, a very weak broad band at 2q ¼ 12ꢀ–20ꢀ appeared in
the Fe3O4–chitosan MNPs, which could be related to the
amorphous chitosan formed around the Fe3O4 NPs (Fig. 1c).
The average crystal size of pure Fe3O4 and chitosan-coated
Fe3O4 nanoparticles are about 15 and 19 nm, respectively.
Magnetization curve for Fe3O4 and Fe3O4–CS NPs is shown in
Fig. 2. The superparamagnetic properties of Fe3O4 NPs can be
attributed to the small size of Fe3O4 NPs. The saturation
Scheme 1 Synthesis strategy of 5,5-diphenylhydantoins and 5,5-
diphenyl-2-thiohydantoins.
Herein, we explored the possibility of synthesizing 5,5-
diphenylhydantoins and 5,5-diphenyl-2-thiohydantoins from
substituted benzil and urea (or thiourea) derivatives in the
presence of Fe3O4–chitosan (Fe3O4–CS) as a green and magnetic
organocatalyst (Scheme 1).
magnetization value (Ms) of pure Fe3O4 NPs was 55.69 emu gꢁ1
,
demonstrating excellent crystal structure of iron oxide NPs. The
results of VSM show that the saturation magnetization value of
Fe3O4–CS NPs (50.27 emu gꢁ1) was lower than Fe3O4 NPs due to
the coated chitosan polymer.
Thus, such a magnetic property for Fe3O4–CS NPs is robust
enough to be quickly and easily separated from the reaction
mixture by a magnetic eld.
Results and discussion
Characterization of magnetic catalyst
Magnetic Fe3O4 nanoparticles were synthesized by the copreci-
pitation method. Then, the synthesized magnetic nanoparticles
were modied with chitosan as a natural polymer.
The FT-IR spectra of (a) Fe3O4 NPs, (b) chitosan and (c)
Fe3O4–CS are shown in Fig. 3. The characteristic peaks of Fe3O4
at 570 and 576 cmꢁ1 could be observed in Fig. 3a and c. In
addition, the O–H stretching vibration at 3423 and 3430 cmꢁ1
were detected in both Fig. 3a and c, which identies the pres-
ence of Fe3O4 NPs. The FT-IR spectra of chitosan were charac-
terized by the following absorption bands: the (NH) of backbone
polymer arising at 3435 and 1653 cmꢁ1, (C–O) of primary
alcoholic group at 1424 cmꢁ1, and the (C–H) at 2874 and 2940
cmꢁ1. Compared with the IR spectrum of samples (a–c), the
presence of chitosan shied the vibration of Fe3O4. The band
shis of Fe–O stretching from 570 to 576 cmꢁ1 and of N–H
bending vibration from 1653 to 1633 cmꢁ1 are signicant. This
phenomenon indicates that iron ions bind to the NH2 groups of
chitosan. Electrostatic interaction between the negatively
charged Fe3O4 NPs surface and the positively protonated chi-
tosan donates the IR spectra change. The band appearing at
1400 cmꢁ1 is related to the C–O of alcoholic groups of chitosan
in the FT-IR of Fe3O4–CS. From the FT-IR spectra of Fe3O4–CS, a
peak at around 2924 cmꢁ1 corresponds to the C–H stretching
The magnetically heterogeneous organocatalyst, Fe3O4–CS
MNPs, is characterized by X-ray diffraction (XRD), scanning
electron microscopy (SEM), energy-dispersive X-ray spectros-
copy (EDX), vibrating sample magnetometry (VSM) and Fourier
transform infrared (FT-IR) spectroscopy. The crystal structures
of Fe3O4, chitosan and Fe3O4–chitosan are shown in Fig. 1. The
XRD patterns of Fe3O4 and Fe3O4–chitosan MNPs indicate iron
oxide cubic structure and six peaks in 2q of 30.1, 35.5, 43.2, 53.5,
57.0 and 62.8, which were related to their corresponding indices
(2 2 0), (3 1 1), (4 0 0), (4 2 2), (5 1 1) and (4 4 0), respectively
Fig. 1 XRD pattern of (a) chitosan, (b) Fe3O4 and (c) Fe3O4–chitosan Fig. 2 Magnetization versus applied field (H) isotherms for Fe3O4 and
NPs.
Fe3O4–chitosan NPs.
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Fig. 3 FT-IR spectra of (a) pure Fe3O4 NPs, (b) chitosan and (c) Fe3O4–
chitosan.
band of chitosan. The peak at 3430 cmꢁ1 was attributed to the
amino groups of chitosan, which is overlapped by the O–H
groups stretching vibration of Fe3O4 NPs.
Fig. 4 exhibits the morphology and particle size of Fe3O4 and
Fe3O4–CS NPs. Fe3O4–CS NPs maintain the morphological
properties of Fe3O4 NPs except for the larger particle size. It
indicates that the chitosan polymeric matrix is uniformly
covered on the surface of Fe3O4 NPs (Fig. 4b). In addition, it
shows that the structure of Fe3O4–CS nanoparticles is looser
and its size is bigger. The SEM of Fe3O4–CS NPs clearly revealed
the structure of the CS-coated magnetite nanoparticle (Fig. 4b).
The TEM images presented in Fig. 4c and d indicate the struc-
ture of Fe3O4–CS NPs. The average particle size of Fe3O4–CS
nanoparticles was found to be 10 nm in diameter.
Elemental composition is calculated from the energy
dispersive X-ray. The elemental compositions of magnetic
Fe3O4–CS nanoparticles are 0.52%, 2.94%, 21.94%, and 74.6%
for N, C, O and Fe, respectively. This implied that chitosan
polymer was coated on the surface of the Fe3O4 NPs (Fig. 5).
Optimization of reaction
According to our previous survey, the reaction of benzil and
urea (mol ratio 1 : 1.8), as a model reaction, was investigated to
optimize the conditions in the presence of catalyst. Our studies
began with the investigation of Fe3O4–chitosan as a magnetic
catalyst in the model reaction. A comparative study of reported
catalysts in the literature to synthesize phenytoin is shown in
Table 1. In addition, other catalysts such as Fe3O4 nanoparticles
and chitosan were tested.
Interestingly, Fe3O4–chitosan MNPs were found to be an
efficient catalyst because the reaction in the presence of Fe3O4–
chitosan afforded the product in higher yield and shorter
reaction time. The effect of the amount of magnetic catalyst on
the preparation of phenytoin was considered by varying the
amount of nanocatalyst from 0 to 50 mg using the same molar
ratios of substrates (Table 2). The desired product was obtained
Fig. 4 SEM images of (a) pure Fe3O4, (b) Fe3O4–CS NPs and (c) and (d)
the TEM images of Fe3O4–CS NPs.
only in trace amounts in the absence of the magnetic catalyst
even aer 24 h. In the presence of the magnetic catalyst, the
yield of phenytoin improves with a quantity of nanocatalyst in a
shorter time. The best result was obtained with an amount of
45 mg Fe3O4–chitosan nanoparticles. Our studies showed that
all the mentioned catalysts conrmed good catalytic activity for
the synthesis of phenytoin, but Fe3O4–chitosan showed the best
catalytic activity compared with others. Fe3O4–chitosan has two
active components in catalytic activity including magnetite and
chitosan. Thus, it is clear that the Fe3O4–chitosan catalytic
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Table 3 Effect of temperature on the yield of reactiona
Entry
Temperature
Time (min)
Yieldb (%)
1
2
3
4
5
r. t.
40
50
60
70
15
10
6
3
3
88
90
95
99
99
a
Reaction conditions: 1 mmol of benzil, 1.8 mmol of urea, 10 mL of
H2O/EtOH (1 : 2) and 45 mg of catalyst. b Isolated yield.
Fig. 5 Energy dispersive X-ray (EDX) of Fe3O4–chitosan NPs.
various solvents. The maximum conversion in the procedure is
observed by H2O/EtOH (Table 4). Other solvents did not show
improvement in the yield of phenytoin, indicating the effect of
polarity and the nature (protic or aprotic) of the solvent.
According to the results, the optimized conditions were used
for 4,40-dimethoxybenzil and urea or thiourea derivatives to
synthesize phenytoin derivatives in the presence of Fe3O4–chi-
tosan. The results have been summarized in Table 5.
The scope of the reaction was further expanded when 4,40-
dimethoxybenzil instead of benzil was successfully applied to
afford 5,5-diphenylhydantoins and 5,5-diphenyl-2-thiohydantoins.
Furthermore, the present route was used for thiourea, N-methyl-
thiourea or N-methylurea instead of urea under the optimal
reaction conditions, and desired products were obtained.
However, the reaction time for the synthesis of 5,5-diphenylhy-
dantoins and 5,5-diphenyl-2-thiohydantoins catalyzed by Fe3O4–
chitosan is shorter compared to the previous methodologies. It
should be noted that all the results indicated the efficiency of
organocatalyst for the synthesis of phenytoin derivatives.
Table 1 Comparison of Fe3O4–chitosan nanoparticles catalyst with
other catalysts in the synthesis of phenytoin
Entry
Catalyst
Time
Yield (%)
1
2
3
4
5
6
Blank
Mg/Al-3calcined
KOH
Fe3O4 NPs
Chitosan
Fe3O4–chitosan NPs
24 h
24 h
25 min
12 min
13 min
8.0 min
— (ref. 38)
73 (ref. 38)
89 (ref. 33)
80
95
98
Table 2 Screening of Fe3O4–chitosan NPs loading for the synthesis of
phenytoina
Entry
Amount of nanocatalyst (mg)
Time (min)
Yield (%)
1
2
3
4
5
6
0
15
25
35
45
50
24 h
8.0
8.0
6.0
3.0
3.0
Trace
80
81
88
99
Reusability test of magnetic catalyst
We believe that one of the best advantages of this nontoxic and
efficient magnetic nanocatalyst is its ease of recovery. The
reusability of the Fe3O4–CS MNPs was tested in the reaction of
benzil with urea for the synthesis of 5,50-diphenylhydantoin
under the present reaction conditions. In a typical procedure,
aer completion of the reaction, the insoluble magnetic catalyst
was separated by attaching an external magnet. The nano-
catalyst was washed with diethylether several times, dried at
99
a
Reaction conditions: 1 mmol of benzil, 1.8 mmol of urea and 10 mL of
H2O/EtOH (1 : 2).
system accelerates the synthesis of phenytoin. Hence, Fe3O4–
chitosan MNPs was selected as the strongest catalyst for further
work.
ꢀ
120 C in an autoclave for 2 h and used for further reactions.
We next studied the model reaction at different tempera-
tures. As shown in Table 3, reaction temperature is an impor-
tant factor and the rate of the present reaction depends on
temperature. The yield and reaction time of the cyclo-
condensation was determined at various temperatures. It was
observed to regularly grow with increasing temperature to 60 ꢀC.
When the reaction was carried out at room temperature, the
rate of the reaction was slow. In addition, the yield of product 3a
was xed at temperatures higher than 60 ꢀC. Thus, an optimum
temperature of 60 ꢀC was chosen for this cyclocondensation
reaction.
Aer reusing the Fe3O4–chitosan MNPs for seven times, obvious
Table 4 Effect of solvent on the yield of reactiona
Entry
Solvent
Unreacted benzil (%)
Yieldb (%)
1
2
3
4
5
6
Ethanol
Methanol
H2O
Ethanol/H2O
DMSO
12
15
10
2
14
29
88
85
90
98
86
71
CH3CN
As shown in Table 4, to show the advantages of water/ethanol
in the reaction of urea or thiourea derivatives with benzil or 4,40-
dimethoxybenzil, a series of parallel reactions were tested in
a
Reaction conditions: 1 mmol of benzil, 1.8 mmol of urea and 45 mg of
catalyst at 60 ꢀC. b Isolated yield.
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Table 5 Synthesis of 5,5-diphenylhydantoins and 5,5-diphenyl-2-
thiohydantoins catalyzed by Fe3O4–CS NPs at 60 ꢀCa
the surface of chitosan activate the electrophilic property of the
nitrogen atom of urea that followed by ring closure. We believe
that the stability of the intermediate (6) controls the selectivity
of the major product (phenytoin) in the presence of chitosan.
Furthermore, chitosan prevents the reaction pathway (II) and
follows the reaction pathway (I). In the presence of KOH as
catalyst, the pathway (II) might be possible.38 Therefore, the
selectivity of the major product depends on the competitive
pathways (I) and (II).
Entry
R1
R2
X
Time (min)
Yieldb (%)
1
2
3
4
5
6
7
8
H
OCH3
H
OCH3
H
OCH3
H
H
H
CH3
CH3
H
H
CH3
CH3
O
O
O
O
S
S
S
S
8.0
10.0
7.5
8.0
7.0
7.5
5.0
6.0
98
94
98
97
98
97
99
95
OCH3
a
Experimental
General information
All the products are known, and spectral data of all the products
matched with the reported data. b Isolated yields.
Chemical reagents of high purity were purchased from the
Merck Chemical Company. All the materials were of commer-
cial reagent grade. Melting points were obtained with a micro
melting point apparatus (Electrothermal, MK3) and are uncor-
rected.1H NMR and 13C NMR spectra were recorded with a
Bruker DRX-400 spectrometer at 400 and 100 MHz, respectively.
NMR spectra were reported as parts per million (ppm) down-
eld from tetramethylsilane as an internal standard. FT-IR
spectra were obtained with potassium bromide pellets in the
range of 400–4000 cmꢁ1 with a Perkin-Elmer 550 spectrometer.
UV-vis measurements were obtained with a GBC cintra6 UV-vis
spectrophotometer. Nanostructures were characterized using a
Holland Philips Xpert X-ray powder diffraction (XRD) diffrac-
tometer (CuK, radiation, k ¼ 0.154056 nm), at a scanning speed
of 2ꢀ minꢁ1 from 10ꢀ to 100ꢀ (2q). Scanning electron microscope
characterization (SEM) was performed on a FEI Quanta 200 SEM
operated at a 20 kV accelerating voltage. The samples for SEM
were prepared by spreading a small drop containing nano-
particles onto a silicon wafer, drying it almost completely in air
at room temperature for 2 h, and then transferring it onto SEM
conductive tapes. Sonication was performed in a Shanghai
Branson-BUG40-06 ultrasonic cleaner (with a frequency of 40
kHz and a nominal power of 200 W). Magnetic properties were
characterized by a vibrating sample magnetometer (VSM,
MDKFD, University of kashan, Kashan, Iran)) at room temper-
ature. The TEM images were recorded using a Ziess EM10C
transmission electron microscope operated at a 80 kV acceler-
ating voltage.
loss of catalytic activity was not observed. Hence, it demon-
strates the practical recyclability of this nanocatalyst (Fig. 6).
Proposed mechanism
The model reaction was performed by KOH and Fe3O4–chitosan
to compare the catalytic activity and selectivity of the major
product. The results of chitosan catalyst showed that yield and
selectivity of the desired product increased with an increase in
the reaction time. However, we allowed the reaction to proceed
further to survey the formation of the undesired product.
Surprisingly, the selectivity and activity did not decrease.
Therefore, the product in the presence of chitosan is stable.
However, the selectivity of the desired product decreased and a
side product formed aer 5 h of reaction time using KOH. In
addition, Fe3O4–chitosan is a magnetic catalyst and is insoluble
in H2O/EtOH. Hence, it was separated easily from the reaction
mixture during work-up. According to the abovementioned
results, a plausible mechanism for the synthesis of phenytoin
derivatives catalyzed using chitosan-coated Fe3O4 is shown in
Scheme 2. Initially, Fe3O4 NPs was a Lewis acid, and the free
hydroxyl groups on the surface of chitosan through hydrogen
bonding activated the carbonyl group of the benzil for the
nucleophilic substitution of urea to form the corresponding
intermediate (5). In addition, lone pairs of an amino group on
Preparation of Fe3O4–chitosan nanoparticles
In the rst step, Fe3O4 NPs were prepared by chemical copre-
cipitation.39 In short, 5.2 g of FeCl3$6H2O and 2.0 g of
FeCl2$4H2O were dissolved in 20 mL deionized water. Next,
250 mL of 1.5 M NaOH solution was injected into the mixture
dropwise under vigorous stirring. The black magnetic nano-
particles were formed in the last step. Then, the reaction
mixture was cooled and Fe3O4 nanoparticles were isolated in the
magnetic eld and washed several times with distilled water. In
order to prepare Fe3O4–chitosan MNPs, the Fe3O4 nanoparticles
(0.5 g) were dispersed in 50 mL of distilled water under ultra-
sound irradiation, and 0.25 g of chitosan was slowly added in
70 mL of 2.0 wt% acetic acid solution with vigorous stirring at
Fig. 6 Reusability of Fe3O4–chitosan MNPs in the synthesis of 5,50-
diphenylhydantoin.
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Scheme 2 Plausible mechanism for synthesis of phenytoin by magnetic chitosan as a nanocatalyst.
50 ꢀC for 1 h. The modied Fe3O4–chitosan NPs were recovered water. The product was then recrystallized with ethanol and
through ltering, washing, and drying at 60 C (Scheme 3).40
dried. All the products are known and their structure was
conrmed by comparing their physical and spectroscopic data
with those reported in the literature.
ꢀ
General procedure for Fe3O4–chitosan-mediated preparation
of 5,5-diphenylhydantoins and 5,5-diphenyl-2-thiohydantoins
Typically, 1 mmol of benzil or 4,40-dimethoxybenzil, 1.8 mmol
of urea or thiourea derivatives, 10 mL H2O/EtOH (1 : 2) and 45
mg of Fe3O4–chitosan MNPs as a nanocatalyst were reuxed at
60 ꢀC. The course of the reaction was monitored by TLC
(petroleum ether: ethyl acetate, 2 : 2.2 v/v). Aer the completion
of the reaction, cold water was added to the mixture. Next,
magnetic catalyst was separated with an external magnet and
reused in the subsequent round. Then, the solvent was evapo-
rated under reduced pressure and the product was washed with
Conclusions
In this work, magnetic Fe3O4–chitosan nanoparticles were
prepared in a simple way. Subsequently, synthesized Fe3O4–
chitosan nanoparticles, as a robust magnetic organocatalyst,
have been successfully demonstrated for the synthesis of 5,5-
diphenylhydantoins and 5,5-diphenyl-2-thiohydantoins. Simple
and environmentally benign procedure, clean reaction proles,
reusability of the catalyst, low catalyst loading and operational
simplicity are the considerable features of this method for
preparation on a larger scale.
Acknowledgements
We gratefully acknowledge the nancial support from the
Research Council of the University of Kashan for supporting
this work by Grant no. 256722/XII.
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