Fe3O4@cellulose composite nanocatalyst: Preparation, characterization and application in the synthesis of benzodiazepines

Article abstract of DOI:10.1016/j.catcom.2014.05.004

A cellulose-based nanocomposite with highly loaded Fe₃O ₄ nanoparticles was prepared and characterized by Fourier transform infrared spectroscopy (FT-IR) spectra, scanning electron microscopy (SEM) images, energy-dispersive X-ray spe

Full text of DOI:10.1016/j.catcom.2014.05.004

Fe3O4@cellulose composite nanocatalyst: Preparation, characterization and
application in the synthesis of benzodiazepines
Ali Maleki, Maryam Kamalzare
PII:
DOI:
Reference:
S1566-7367(14)00176-9
doi: 10.1016/j.catcom.2014.05.004
CATCOM 3898
To appear in:
Catalysis Communications
Received date:
Revised date:
Accepted date:
12 April 2014
8 May 2014
10 May 2014
Please cite this article as: Ali Maleki, Maryam Kamalzare, Fe3O4@cellulose composite
nanocatalyst: Preparation, characterization and application in the synthesis of benzodi-
azepines, Catalysis Communications (2014), doi: 10.1016/j.catcom.2014.05.004
This is a PDF file of an unedited manuscript that has been accepted for publication.
As a service to our customers we are providing this early version of the manuscript.
The manuscript will undergo copyediting, typesetting, and review of the resulting proof
before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that
apply to the journal pertain.

ACCEPTED MANUSCRIPT
Fe3O4@cellulose composite nanocatalyst: Preparation, characterization and
application in the synthesis of benzodiazepines
Ali Maleki*, Maryam Kamalzare
Department of Chemistry, Iran University of Science and Technology, Tehran 16846-13114, Iran
* Corresponding author. Tel.: +98 21 77240540; fax: +98 21 73021584. E-mail address:
maleki@iust.ac.ir (A. Maleki).
Abstract
A cellulose-based nanocomposite with highly loaded Fe3O4 nanoparticles was prepared and
characterized by Fourier transforms infrared spectroscopy (FT-IR) spectra, scanning electron
microscopy (SEM) images, energy-dispersive X-ray spectroscopy (EDX) spectra and X-ray
diffraction (XRD) measurements. Its catalytic activity was investigated in the condensation
reaction between o-phenylenediamines and ketones that produced benzodiazepines in good to
excellent yields under mild reaction conditions. A good correlation between the amount of
surface acid sites and the morphology of the catalyst and its catalytic activity was observed. The
nanocatalyst could be recycled and reused without significant loss of its catalytic activity.
Keywords: Nanocatalyst; Nanocomposite; Cellulose; Fe3O4; Benzodiazepine.
1

ACCEPTED MANUSCRIPT
1. Introduction
Among natural polymers, cellulose is one of the most abundant and renewable polymer in
the world that has been widely studied in both academic and industrial researches [1]. As a
chemical crude material, it has been used in the form of fibers or other formatives for nearly 150
years for a large spectrum of products and materials in daily life [2]. Cellulose is a potentially
biodegradable material that can be used as an efficient support for bonding several functional
groups to produce clean and impressive biopolymer-based catalysts [3].
Benzodiazepines are an important class of nitrogen containing heterocyclic compounds that
own a wide range of therapeutic and pharmacological properties. They are widely used as
anticonvulsant, antianxiety, analgesic, sedative, anti-depressive, and hypnotic agents [4]. Due to
their wide applications, several methods for the synthesis of benzodiazepines have been reported.
A generally offered method for the synthesis of benzodiazepines is the condensation reaction
between o-phenylenediamines (OPDAs) and ketones [5], enones [6] or β-haloketones [7], using
ionic liquids [8], under microwave irradiation [9] and SbCl3-Al2O3 [10], HClO4 [11], acetic acid
[12], poly phosphoric acid or SiO2 [13], TiCl4/Sm [14], Yb(OTf)3 [15], H14[NaP5W30O110] [16].
The known methods of the synthesis of benzodiazepines suffer from restrictions such as hard
reaction conditions, expensive reagents, low yields, relatively long reaction time and the
formations of side products [17-25]. As a result, introducing of a new methodology for the
synthesis of benzodiazepines in terms of simplicity, eco-friendly and economic viability is still of
prime importance.
In recent decade, composite nanocatalysts, especially supported magnetic metal oxides have
attracted considerable interest of researchers, because of their potential applications in chemical,
2

ACCEPTED MANUSCRIPT
biomedical and materials science. They have several important advantages as heterogeneous
catalysts including readily available, high catalytic activity, simple separation using an external
magnet, high degree of chemical stability, reusability and environmentally benign properties [26-
29].
In continuation of our research on the introduction of recoverable catalysts in organic
synthesis [30-34], herein, cellulose-based nanocomposite containing high contents of Fe3O4
nanoparticles was used as a catalyst in the condensation reaction between various OPDAs 1 and
ketones 2 for synthesis of 1,5-benzodiazepines 3a-m in good to excellent yields under mild
reaction conditions (Scheme 1).
To the best of our knowledge, this is the first report of application of this nanocomposite as a
heterogeneous catalyst in the synthesis of organic heterocyclic compounds.
<Scheme 1>
2. Experimental
2.1. Preparation of Fe3O4@cellulose nanocomposite
First, 4 g of cellulose was dissolved straightly in 10 mL of NaOH/Urea/H2O solution and
immediately pre-cooled to -8 °C to give 4 wt% cellulose solution. Next, the solution was
centrifuged at 2000 rpm for 30 min. Then, it was placed onto a glass plate to give a thickness of
0.5 mm and was then immersed in a 2000 mL H2SO4 (5 wt%) bath for 5 min. After acid ejecting,
the resulting product was washed with distilled water several times. The obtained wet films were
immersed in a 500 mL mixture of aqueous FeCl3.6H2O (0.1 M) for 24 hours. Then, the iron ions
adsorbed on the surface of the composite were washed with distilled water. After that, the
3

ACCEPTED MANUSCRIPT
composite was immersed in 500 mL of aqueous NaOH (4 mol/L) for 20 min and was washed
with distilled water several times. Finally, the resulting product was dried at room temperature
for 3 days to give Fe3O4@cellulose nanocomposite.
2.2. General procedure for the synthesis of benzodiazepine derivatives (3a-m)
A mixture of an OPDA (1 mmol) and a ketone (2 mmol) and 0.02 g of Fe3O4@cellulose
catalyst in 5 mL of EtOH were stirred at room temperature for appropriate times according to
Table 2. After completion of the reaction, as indicated by TLC (ethyl acetate/n-hexane, 3/1), the
magnetic nanocomposite was easily removed with the help of a magnetic stirring bar when the
stirring was stopped. Then, the reaction solution was filtered and the residue was purified by
washing with water, and then crystallized from EtOH to give pure crystalline compounds 3a-m.
The Fe3O4@cellulose catalyst was then washed with EtOH, air-dried and used directly for
several times in other fresh reactions without a considerable loss of its catalytic activity.
2.3. Selected spectral data for 2-methyl-2,4-di-p-hydroxyphenyl-2,3-dihydro-7,8-dimethyl-1H-
1,5-benzodiazepine (3m)
Light cream crystals (0.338 g, 91%): mp 248 °C. IR (KBr) (υmax, cm-1): 3305, 3246, 3034,
1
2962, 2920, 2859, 1608, 1572, 1513, 1475. H NMR (300 MHz, DMSO-d6): δH (ppm) 1.54 (s,
3H, CH3), 2.14 (s, 6H, CH3), 2.73 (d, J = 12.1 Hz, 1H, CH2), 2.98 (d, J = 12.8 Hz, 1H, CH2),
5.07 (br s, 1H, NH), 6.60–6.70 (m, 4H, H-Ar), 6.75 (s, 1H, H-Ar), 6.85 (s, 1H, H-Ar), 7.35 (d, J
= 6.3 Hz, 2H, H-Ar), 7.55 (d, J = 6.6 Hz, 2H, H-Ar), 9.17 (br s, 1H, OH), 9.75 (br s, 1H, OH).
4

ACCEPTED MANUSCRIPT
13C NMR (75 MHz, DMSO-d6): δC (ppm) 18.9, 19.6, 30.8, 42.7, 72.1, 114.8, 115.1, 122.6,
127.0, 127.8, 129.0, 129.3, 131.1, 131.2, 133.5, 137.6, 137.9, 139.5, 156.1, 159.3, 166.4. MS,
m/z (%): 372 (M+), 277, 207, 168, 135, 120, 93, 77, 65, 55. Anal. Calcd for C24H24N2O2: C,
77.39; H, 6.49; N, 7.52. Found C, 77.42; H, 6.45; N, 7.61.
3. Results and discussion
3.1. Characterization of the Fe3O4@cellulose nanocatalyst
The nanocomposite containing Fe3O4 nanoparticles was prepared by in situ synthesis. As
shown in Figures 1 and 2, the SEM image of the Fe3O4@cellulose nanocomposite and its EDS
spectrum indicates that there were only C, O and Fe elements in the nanocomposite and the
amount of iron loading in Fe3O4@cellulose catalyst was 35%. The morphology of the
nanocomposite displayed homogeneous structure. As the cellulose was immersed into a mixture
of FeCl3.6H2O, the iron ions were effectively diffused and adsorbed into the hydroxyl groups of
cellulose by electrostatic interaction. When the composite with adsorbed iron ions were
immersed into the NaOH solution, the basic hydrolysis of the iron ions led to the formation of an
iron oxide nanoparticle colloidal solution, and the composite system turned darker because of the
formation of Fe3O4 nanoparticles. Since there was a strong interaction between the nanoparticles
and the cellulose matrix, the Fe3O4 nanoparticles dispersed in the composite were considerably
stable.
<Figure 1 >
<Figure 2>
5

ACCEPTED MANUSCRIPT
To clarify the structure of the inorganic nanoparticles in nanocomposite, its XRD pattern was
prepared and analyzed. As shown in Figure 3, the nanocomposite exhibited two main peaks at
2theta = 33-34, 44-46 which were corresponded to the characteristic peaks of Fe3O4 (Powder
Diffraction file, ASTM card no. 526-1136). Also, the average size of the prepared composite
nanoparticles determined from X-ray line broadening using the Debye-Scherrer formula was 25
nm.
<Figure 3>
Furthermore, we have obtained FT-IR spectra of the FeCl3.6H2O, cellulose and
Fe3O4@cellulose nanocomposite. Their comparison was also confirmed the efficient formation
of composite magnetic nanocatalyst (See the Supplementary data file).
3.2. Application of Fe3O4@cellulose in the synthesis of 1,5-benzodiazepine derivatives
In order to investigate the catalytic activity of the prepared Fe3O4@cellulose nanocomposite,
it was applied in an important organic reaction for the synthesis of 1,5-benzodiazepine
derivatives.
Initially, to optimize the reaction conditions, we studied the reaction of OPDA (1 mmol) and
cyclohexanone (2 mmol), as a simple model reaction in the presence of different catalytic
amount of Fe3O4@cellulose at room temperature in EtOH as a green solvent. It was found that
0.02 g of catalyst was efficiently catalyzed the reaction to give 3b in high yields and short
reaction times (Table 1). The reaction was not successful in the absence of the catalyst (entry 1).
The increasing of the amount of the catalyst neither improves the reaction times nor yields.
6

ACCEPTED MANUSCRIPT
To illustrate the importance of Fe3O4@cellulose for these reactions, three blank experiments
were conducted in the presence of Fe3O4 and cellulose alone, and a simple mixture of Fe3O4 and
cellulose under model reaction conditions at room temperature in EtOH. The yield in these cases
was trace or very low after 2 hours. As a result, Fe3O4@cellulose composite nanocatalyst was a
key component of the reaction.
The role of solvents in the reaction was also screened. As shown in Table 1 (entries 5-10), it
was found that EtOH is suitable solvent to give the target products in high to excellent yields and
relatively short reaction time in comparison with other polar, non-polar, protic and aprotic
solvents. Selecting EtOH is acknowledged as a green solvent as it is produced from agricultural
feed stocks. Under solvent-free conditions or using n-hexane as a solvent, only a trace amount of
the product was obtained (entries 5 and 10, respectively).
< Table 1>
After optimization of the reaction conditions, we studied the generality of this protocol.
Using this procedure, different kinds of ketones were reacted with OPDAs to produce the
corresponding benzodiazepines under mild reaction conditions in high to excellent yields. As
illustrated in Table 2, linear, cyclic and aromatic ketones react with 1,2-phenylendiamine and
4,5-dimethy-1,2-phenylendiamine to obtain various benzodiazepine derivatives.
< Table 2>
The suggested mechanism for the formation of 1,5-benzodiazepines 3a-m is shown in
Scheme 2. The first event is the formation of diimine 4 from condensation reaction between
OPDAs 1 and two moles of ketones 2 in the presence of the Fe3O4@cellulose nanocatalyst. The
oxygen atoms of 2 are adsorbed through their lone pair electrons on the surface acid sites of the
7

ACCEPTED MANUSCRIPT
catalyst, and the amino groups of 1 attack to the carbonyl groups of 2 to give compound 4. Then,
an intramolecular imine–enamine tautomerization-cyclization of intermediate 5 promoted by
nanocatalyst yields the products 3a-m.
< Scheme 2>
The reusability of the composite nanocatalyst was also investigated on the model reaction.
An important feature of Fe3O4@cellulose catalyst was its easy and reliable separation from the
reaction mixture. The heterogeneous nature of the catalyst allowed its facile recovery by simple
separation by an external magnet, washing with ethanol and drying at room temperature to
provide an opportunity for recycling experiments. The separated nanocatalyst was reused in the
mentioned reaction for the synthesis of 3b four times without considerable loss of its catalytic
activity (Figure 4). Furthermore, the removal was almost quantitative and the Fe3O4@cellulose
films were mechanically stable under the reaction conditions.
< Figure 4>
4. Conclusions
In summary, we have demonstrated the preparation and characterization of a cellulose-based
nanocomposite containing high contents of Fe3O4 nanoparticles. Fe3O4@cellulose as an eco-
friendly, inexpensive and efficient nanocatalyst was used for the synthesis of benzodiazepine
derivatives through a green and facile method. This protocol includes some important advantages
such as short reaction times, high yields, simple methodology, easy work-up procedure and green
reaction conditions. The nanocatalyst could be recycled and reused without significant loss of its
catalytic activity. Exceptionally, some reduction of the activity after the first reuses was
observed.
8

ACCEPTED MANUSCRIPT
Acknowledgement
The authors gratefully acknowledge the partial support from the Research Council of the Iran
University of Science and Technology.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in the online version, at
http://www.sciencedirect.com.
9

ACCEPTED MANUSCRIPT
References
[1] R.M. Brown, I.M. Saxena, Cellulose: Molecular and Structural Biology: Selected Articles
on The Synthesis, Structure and Application of Cellulose; Springer: Netherlands, 2007.
[2] Y. Habibi, L.A. Lucia, O.J. Rojas, Chem. Rev. 110 (2010) 3479–3500.
[3] K. Molvinger, F. Quignard, D. Brunel, M.J.M. Boissiere, Chem. Mater. 16 (2004) 3367–
3369.
[4] S. Chakraborty, N.H. Shah, J.C. Fishbein, R.S. Hosmane, Bioorg. Med. Chem. Lett. 21
(2011) 756–759.
[5] D. Antonow, D.E. Thurston, Chem. Rev. 111 (2011) 2815–2864.
[6] P. Stahlofen, W. Ried, Chem. Ber. 90 (1957) 815–824.
[7] W. Ried, E. Torinus, Chem. Ber. 92 (1959) 2902–2916.
[8] D.V. Jarikote, S.A. Siddiqui, R. Rajgopal, D. Thoma, R.J. Lahoti, K.V. Srinivasan,
Tetraheron Lett. 44 (2003) 1835–1838.
[9] K. Sucheta, B. Vital Rao, Indian J. Chem. Sect. B: Org Chem. Incl. Med. Chem. 44
(2005) 2152–2163.
[10] B.A. Ganai, S. Kumar, C.S. Andotra, K.K. Kapoor, Synth. Commun. 36 (2006) 803–807.
[11] M. Weissenfels, R. Kache, W. Krauter, J. Prakt. Chem. 35 (1967) 166–174.
[12] R.L. Amey, N.D. Heindel, Org. Prep. Proced. Int. 8 (1976) 306–307.
[13] D.I. Jung, T.W. Choi, Y.Y. Kim, I.S. Kim, Y.M. Park, Y.G. Lee, D.H. Jung, Synth.
Commun. 29 (1999) 1941–1951.
[14] W. Zhong, Y. Zhang, X. Chen, Tetrahedron Lett. 42 (2001) 73–75.
10

ACCEPTED MANUSCRIPT
[15] M. Curini, F. Epifano, M.C. Marcotullio, O. Rosati, Tetrahedron Lett. 42 (2001) 3193–
3195.
[16] M.M. Heravi, F. Derikvand, L. Ranjbar, F.F. Bamoharram, J. Mol. Catal. A: Chem. 261
(2007) 156–159.
[17] U.B. More, R.S. Kharat, P.P. Mahulikar, Asian J. Chem. 23 (2011) 4311–4313.
[18] A.V. Vijayasankar, S. Deepa, B.R. Venugopal, N. Nagaraju, Chin. J. Catal. 31 (2010)
1321–1327.
[19] A. Sandhar, R.K. Singh, Asian J. Chem. 24 (2012) 5643–5645.
[20] S.A. Suresh, J.S. Sandhu, Synth. Commun. 38 (2008) 3193–3198.
[21] J.S. Yadav, B.V.S. Reddy, S. Praveenkumar, K. Nagaiah, Synthesis (2005) 480–484.
[22] W. Zhong, Y. Zhang, X. Chen, J. Chem. Res. (S) 11 (2000) 532–534.
[23] G. Maiti, U. Kayal, R. Karmakar, R.N. Bhattacharya, Tetrahedron Lett. 53 (2012) 1460–
1463.
[24] J. Qian, Y. Liu, J. Cui, Z. Xu, J. Org. Chem. 77 (2012) 4484–4490.
[25] W.-Y. Chen, J. Lu, Synlett (2005) 1337–1339.
[26] M. Shokouhimehr, Y. Piao, J. Kim, Y. Jang, T. Hyeon, Angew. Chem. Int. Ed. 46 (2007)
7039–7043.
[27] S.G. Kwon, T. Hyeon, Acc. Chem. Res. 41 (2008) 1696–1709.
[28] F. Shirini, M. Abedini, J. Nanosci. Nanotechnol. 13 (2013) 4838–4860.
[29] X. Cai, H. Wang, Q. Zhang, J. Tong, Z. Lei, J. Mol. Catal. A: Chem. 383–384 (2014)
217–224.
[30] A. Shaabani, A. Maleki, M. R. Soudi, H. Mofakham, Catal. Commun. 10 (2009) 945.
[31] A. Maleki, Tetrahedron 68 (2012) 7827–7833.
11

ACCEPTED MANUSCRIPT
[32] A. Maleki, Tetrahedron Lett. 54 (2013) 2055–2059.
[33] A. Maleki, N. Ghamari, M. Kamalzare, RSC Adv. 4 (2014) 9416–9423.
[34] R. Rahimi, A. Maleki, S. Maleki, J. Magn. Magn. Mater. 355 (2014) 300–305.
12

ACCEPTED MANUSCRIPT
Scheme 1. Synthesis of 1,5-benzodiazepines in the presence of Fe3O4@cellulose nanocomposite.
13

ACCEPTED MANUSCRIPT
Fig. 1. SEM images of Fe3O4@cellulose nanocomposite.
14

ACCEPTED MANUSCRIPT
Fig. 2. EDS of Fe3O4@cellulose nanocomposite.
15

ACCEPTED MANUSCRIPT
Fig. 3. XRD of Fe3O4@cellulose nanocomposite.
16

ACCEPTED MANUSCRIPT
Table 1. Optimization of the reaction conditions on the model reaction.
Entry
1
Amount of catalyst (g)
-
Solvent
EtOH
Time (min) Yielda (%)
300
trace
EtOH
2
3
4
5
6
7
8
9
0.01
0.02
0.03
0.03
0.02
0.02
0.02
0.02
0.02
60
71
EtOH
EtOH
25
96
25
95
-
300
Trace
MeOH
EtOAc
CH2Cl2
CH3CN
n-hexane
25
40
77
80
25
86
25
90
340
Trace
10
a Isolated yield.
17

ACCEPTED MANUSCRIPT
Table 2. Synthesis of 1,5-benzodiazepine derivatives 3a-m in the presence of Fe3O4@cellulose.
Mp (°C)
Entry
1
Product
Time (min) Yielda (%)
Found
Reported
133-134
[17]
45
25
90
96
132-135
3a
135-137
[18]
2
3
136-139
133-135
3b
133-134
[19]
50
95
3c
122-124
[20]
4
5
6
70
65
75
89
97
92
120-122
115-117
99
3d
112-114
[21]
3e
3f
96-98 [22]
114-117
[22]
7
8
80
86
97
119-121
140-142
3g
139-141
[23]
105
3h
3i
9
120
90
141-143
141 [24]
18

ACCEPTED MANUSCRIPT
156-158
[18]
10
90
89
158-160
3j
219-220
[18]
11
12
150
135
115
83
80
91
218-220
142-144
248
3k
141-143
[25]
3l
13
New
3m
a Isolated yield.
19

ACCEPTED MANUSCRIPT
Scheme 2. The proposed mechanism for the formation of 1,5-benzodiazepines 3a─m.
20

ACCEPTED MANUSCRIPT
95
94
100
90
80
70
60
50
40
30
20
10
0
85
81
80
0
1
2
3
4
No. of Runs
Fig. 4. Recycling of Fe3O4@cellulose nanocatalyst for the synthesis of 3b.
21

ACCEPTED MANUSCRIPT
Graphical Abstract
Fe3O4@cellulose composite nanocatalyst: Preparation, characterization and
application in the synthesis of benzodiazepines
Ali Maleki*, Maryam Kamalzare
22

ACCEPTED MANUSCRIPT
Highlights
 A cellulose-based nanocomposite with highly loaded Fe3O4 was prepared.
 Its morphology was characterized by FT-IR, SEM, EDX and XRD analyses.
 Its catalytic activity was excellent in the synthesis of benzodiazepines.

Work-up procedure was easy.
23