Crosslinked chitosan nanoparticle-anchored magnetic multi-wall carbon nanotubes: A bio-nanoreactor with extremely high activity toward click-multi-component reactions

Article abstract of DOI:10.1039/c7nj01150d

In the present study, we have designed a procedure for the synthesis of a bio-nanoreactor catalyst, crosslinked chitosan nanoparticle-anchored magnetic multi-wall carbon nanotubes (CS NPs/MWCNT@Fe₃O₄), via an in situ ionotropic gelation method. The synthesized robust nanoreactor was fully characterized. Moreover, the catalytic activity was investigated towards the click-based multi-component reactions for the synthesis of 2,3-dihydroquinazolin-4(1H)-ones, trisubstituted imidazoles, and 1,2,3-triazoles in a green medium. Since the nanocatalyst can be recovered by applying an external magnetic field, which results in easy separation without filtration, and recycled several times without the loss of its significant activities, it shows admirable potential in reusable catalysis.

Full text of DOI:10.1039/c7nj01150d

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The crosslinked chitosan nanoparticles-anchored magnetic multi-wall carbon
nanotubes: A bio-nanoreactor with extremely high activity toward click-multi-
component reactions
Ahmad Shaabani,∗ Ronak Afshari and Seyyed Emad Hooshmand
Faculty of Chemistry, Shahid Beheshti University, G. C., P. O. Box 19396-4716, Tehran, Iran
∗
Corresponding author. Tel.: +982129902800; e-mail: a-shaabani@sbu.ac.ir
Abstract
In the present work, we have designed a procedure for synthesizing a bio-nanoreactor catalyst, crosslinked chitosan nanoparticles-anchored magnetic multi-
3 4
wall carbon nanotubes (CS NPs/MWCNT@Fe O ), by means of the in-situ ionotropic gelation method. The synthesized robust nanoreactor was fully
characterized. Also, the catalytic activity was investigated in the click-based multi-component reactions for the synthesis of 2,3-dihydroquinazolin-4(1H)-ones,
trisubstituted imidazoles and 1,2,3-triazoles in a green medium. Since the nanocatalyst can be recovered by applying an external magnetic field which results in
easy separation without filtration and recycled several runs without losing significant activities, it showed admirable potential in reusable catalysis.
Keywords: Chitosan nanoparticle, Multi-wall carbon nanotube, Nanoreactor, Bionanocomposite, Heterogeneous catalysis, Click
chemistry

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1
. Introduction
Nanocatalysis is one of the fascinating fields of chemistry. Along with a growing demand on homogeneous and
heterogeneous catalyst systems for wide ranges of organic transformations, nanocatalysis processes received increasing
attention because of their robust and reliable ability to combine the advantages of both systems, and can offer unique activity
1
with high selectivity. Among these fields, one of the important nanomaterials that have been widely used as a nanocatalyst is
carbon nanotubes (CNTs). Notwithstanding a quarter of century has elapsed since CNTs were discovered, these materials still
regarded as one of the multipurpose innovative nanostructures for the catalysis of various reactions, especially organic
2
-4
5, 6
reactions, owing to their large surface area and outstanding electronic conductivity. The poor solubility of CNTs in both
7
aqueous and organic solvents hampers its real applications, hence, functionalization with biopolymers can be caused effective
8
-11
solubilization, biocompatibility and biodegradability of CNTs.
1
2, 13
Chitosan (CS), as one of a few natural cationic polysaccharides,
is the attractive biostructure that can be robustly
With the development of nanoscience and nanotechnology
crosslinked CS nanoparticle (CS NP) systems have received a great deal of attention because of their nanosphere shape, large
1
4, 15
anchored to the sidewalls of CNT to provide catalytic centers.
1
6
surface area and great biocompatibility. One of the most important synthetic approaches for the preparation of CS NPs is
1
7
ionotropic gelation technique. In this method, a simple polyanion such as sodium tripolyphosphate (TPP) can interact with CS
1
8
to generate CS NP.
Recently, many researchers began to focus on the synthesis and application of nanoreactors as heterogeneous catalysts
because of their free space with high pressure, unique capability of encapsulating reagents, maximum metal-ligand interactions
1
9-21
and cavitation effects.
presence of the pore networks and pore size patterns, which are idealization of the real cavities in the catalyst supports.
Among these fields, hydrogel networks have been extensively used as binding sites with pore size distributions in nanoreactor
In this new generation of nanocatalysts, the driving force for the catalytic process is based on the
22
2
3
catalysts, but the CS NPs as a hydrogel-based nanoreactor have not been yet observed. Therefore we have decided to
synthesize the CS NPs, as a novel bio-nonreactor, on the wide surface of the magnetic MWCNTs and studying their abilities
through click chemical syntheses. Magnetic nanoparticles attached to a support have been showed the ability for the synthesis
2
4
of valuable organic scaffolds and their recovery and reuse are additional beneficial attributes.
"Click Chemistry" is a term that was introduced by Sharpless and coworkers in 2001 to describe reactions that are high
yielding, create only byproducts that can be removed without chromatography, highly diversity, simple to perform, and can be
2
5
conducted in easily removable or eco-friendly solvents. Several types of reaction have been identified that fulfill these
criteria, thermodynamically-favored reactions that lead specifically to a single product, but click chemistry ideals are admirably

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2
6
represented among cycloaddition reactions involving heteroatoms. These modular fusion reactions unite two or more
unsaturated reactants and provide direct access to an enormous variety of interesting five- and six-membered heterocycles.
Undoubtedly, nitrogen-containing heterocycles are an important class of organic compounds with a wide spectrum of
biological activities and pharmacological properties. Furthermore, click multi-component reactions open a gateway that gives
us the opportunity to access complex and diverse nitrogen-containing heterocycle scaffolds with potential bioactivity.
2
7, 28
29, 30
Among the nitrogen-containing heterocycles, 2,3-dihydroquinazolin-4(1H)-ones,
trisubstituted imidazoles
and 1,2,3-
3
1, 32
triazoles
are the most valuable organic structures. 2,3-Dihydroquinazolin-4(1H)-ones may show a wide range of medicinal
3
3
34
35
properties involving antibacterial, anticancer and anticonvulsant. Trisubstituted imidazoles, as well as synthetic derivatives
thereof, exhibit wide ranges of biochemical properties. These heterocyclic compounds are also the core structural skeleton in
many important biological molecules like histidine, histamine, and biotin, as well as several drug moieties such as trifenagrel
3
6, 37
and losartan.
Eventually, in the famous class of concerted click reactions, Huisgen dipolar cycloaddition of azides and
alkynes have gained a great attention. 1,2,3-Triazole derivatives are important heterocyclic compounds because of their wide
3
8
39
range of applications and biological activities such as anti-HIV and selective β3 adrenergic receptor agonist.
As part of our previous studies through the developing new chitosan and carbonaceous-based heterogeneous catalysts for
4
0-44
synthetic methodologies in organic transformations,
herein, we describe the synthesis and characterization of CS NP
) which could behave as a highly efficient nanoreactor for
hydrogels grafted to magnetic MWCNT (CS NPs/MWCNT@Fe
3
O
4
direct synthesis of 2,3-dihydroquinazolin-4(1H)-ones, trisubstituted imidazoles and 1,2,3-triazoles suggesting that the
nanocavities of CS NPs/MWCNT acted as an effective nanoreactors with pronounced effect on kinetics of the studied reaction.
Interestingly, 1,2,3-triazoles were synthesized via CS NPs/MWCNT@Fe O nanoreactor without need of any copper catalysts or
3
4
harsh reaction conditions. The incorporation of CS NPs into magnetic MWCNT produce the new type of biocomposite
nanoreactors with individual properties of each component as well their synergistic effect on the performance of the catalyst.
3 4 3 4
Also, the capability of CS NPs/MWCNT@Fe O to immobilization of Cu NPs has been investigated. Cu-CS NPs/MWCNT@Fe O
nanocatalyst was examined for quick access to 1,2,3-triazoles in the presence of water that is considered the greenest solvent,
yielding enhanced catalytic efficiency over several cycles.
2
. Results and discussion
3 4
The CS NPs/MWCNT@Fe O nanocatalyst was prepared through in situ synthesis by an ionotropic gelation technique. The
ionically cross-linked CS NPs have often been prepared by exploiting their cationic nature, in which the amino groups of the CS
backbone can interact with salts such as sodium sulfate, TPP or other multiple-charged anion molecules. The ionic cross-linking
4
5
of CS is advantageous since the process is simple and often carried out under mild conditions without using organic solvents.

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In the present method sodium tripolyphosphate (TPP) interacts with CS to generate CS NP and simultaneously couple to the
3 4 3 4
MWCNT surface. The schematic pathways for the preparation of CS NPs/MWCNT@Fe O and Cu-CS NPs/MWCNT@Fe O are
shown in Scheme 1.
3 4 3 4
Scheme 1 Preparation of the nanocatalysts: CS NPs/MWCNT@Fe O and Cu-CS NPs/MWCNT@Fe O
The CS NPs content in the CS NPs/MWCNT@Fe
content which was determined using CHN elemental analysis. Also, the Fe content of the nanocatalyst was determined by ICP-
OES analysis and the results demonstrate that the Fe NPs concentration is 385.88 ppm. FT-IR spectra of the MWCNT-COOH,
CS NPs/MWCNT, CS NPs/MWCNT@Fe O and Cu-CS NPs/MWCNT@Fe O are shown in Fig. 1. FT-IR peaks for MWCNT–COOH
3 4
O nanocatalyst was calculated to be 3.17 wt%, according to the nitrogen
3
O
4
3
4
3
4
-
1
show a broad peak at 3442 cm due to the stretching vibration of –OH bond, 1720 peak indicated C=O stretching of carbonyl
-1
groups. A peak at 1221 cm is assigned to C–O bond stretching (Fig. 1a). FTIR of CS NPs/MWCNT (Fig. 1b) confirmed the
-
1
presence of CS NPs and TPP crosslinked agent. The peak at 1722 cm is attributed to the presence of acetyl unit with –C=O
-
1
-1
stretching and 1531 cm attributed to NH bending vibrations. In the spectrum, the peak located at 3421 cm is broadened
2
-
1
due to the extensive hydrogen bonding. Moreover, the peak at 2354 cm is related to the presence of P–H and the peak at
-
1
46
−1
1
068 cm is due to the P=O stretching of TPP. FT-IR spectrum of CS NPs/MWCNT@Fe
3 4
O exhibits a broad-band at 570 cm
4
7
corresponding to the stretching vibration of the Fe–O bonds which is assigned to the spinel form of iron oxide (Fe
3
4
O ). Finally,

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in the FT-IR spectrum of Cu-CS NPs/MWCNT@Fe
3 4
O , in addition to the mentioned peaks, which confirmed the presence of CS
-
1
NPs and Fe–O bonds of iron oxide, the slight shift in the C=O stretching bonds to 1724 and 1635 cm is because of the
4
3
chelation of Cu NPs on the surface of CS NPs/MWCNT@Fe O .
3
4
Figure 1 FT-IR spectra of: MWCNT-COOH (a), CS NPs/MWCNT (b), CS NPs/MWCNT@Fe O (c) and Cu-CS
3
4
3 4
NPs/MWCNT@Fe O (d)
Selected images obtained using SEM were used to study the structure and morphology of the catalyst. SEM image of
MWCNT–COOH (Fig. 2a) shows distinct agglomeration and nanolength sizes of MWCNTs. SEM image of CS NPs/MWCNT (Fig.

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2
b) shows great bundles of MWCNT coated with CS NPs with great spherical structure established that the hydrogel provides a
controlled and uniform distribution of nanoparticles without addition of any further stabilizer. The average particle size was
found to be 50 nm.The presence of CS NPs on MWCNT surface causes nanotubes to change into distinguishable separated
3 4 3 4
bundles with accessible large surface area. The SEM image of CS NPs/MWCNT@Fe O shows that Fe O NPs are well
incorporated on the surface of CS NPs/MWCNT with semi-spherical morphology (Fig. 2c). The white dots represent anchored
Cu NPs, with a spherical-like shape, and a diameter of ~20 nm, that were dispersed on the surface of the CS NPs/MWCNT which
could be directly visualized from the SEM image (Fig. 2d). In order to further confirm the composition on the surface of
nanocomposites, the energy-dispersive spectra (EDS) from CS NPs/MWCNT and Cu-CS NPs/MWCNT@Fe O bionanocomposites
3
4
were performed. The EDS spectrum shows the elemental composition (C, N, O, P) of CS NPs/MWCNT which indicates the
presence of TPP in the nanocomposite for crosslinking the chitosan (Fig. 2e). The EDS spectrum in (Fig. 2f) shows the presence
3 4
of (C,N,P,O, Fe and Cu) in Cu-CS NPs/MWCNT@Fe O . The C, N and P signals are originated from the CS NPs/MWCNT, while the
Cu and Fe signals confirm the existence of Fe O and Cu NPs in the bionanocomposite.
3
4

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Figure 2 SEM images of: MWCNT-COOH (a), CS NPs/MWCNT (b), Cu-CS NPs/MWCNT@Fe O (c) and CS NPs/MWCNT@Fe O
4
3
4
3
(
3 4
d). EDX spectra of: CS NPs/MWCNT (e) and Cu-CS NPs/MWCNT@Fe O (f)
3 4
In a follow up investigation, particle size distribution of CS NPs/MWCNT@Fe O was measured with DLS analysis. The
nanoreactor possessed a narrow particle size distribution. The polydispersity index (PdI) and z-average for CS
NPs/MWCNT@Fe O nanoreactor were calculated 0.132 and 165 which were in agreement with SEM and TEM images. The
3
4
slight difference between SEM and DLS particle diameter was due to the nanocatalyst agglomeration occurred in DLS test
conditions.
The XRD patterns of MWCNT-COOH, CS NPs/MWCNT and Cu-CS NPs/MWCNT@Fe
peaks at 2θ=25.66 and 44.14 were associated with (002), (100) corresponding to the hexagonal graphite structure of MWCNT
that appeared in all the patterns. For CS NPs/MWCNT, XRD pattern shows the presence of peaks corresponding to both
chitosan and carbon nanotube. Three peaks at 2θ ~ 12.46 , 25.90 and 44.1 are observed of which the peak at 12.46
corresponds to CS and the peak at 44.1 corresponds to carbon nanotube. The broad peak at 25.90 belongs to CS and the
carbon nanotube so there is no obvious change in the structure of MWCNT after functionalization with chitosan nanoparticles
3 4
O are shown in Fig. 3. The diffraction
̊
̊
̊
̊
̊
̊
̊
̊
4
5
and the XRD pattern confirmed the formation of nano-chitosan on the surface of MWCNT. The cross-linking reaction via TPP
modifies the crystalline nature of CS and their grafted formulation and reduced crystallinity after cross-linking with TPP might
be expected. After formation of Cu and Fe
The peaks at 43.24, 53.74 and 74.86 were assigned to the (111), (200) and (220) demonstrating the formation of Cu NPs, also
the 30.34, 35.56, 43.24, 53.74, 57.34 and 62.98 peaks were obtained, which corresponded to the (220), (311), (400), (422),
511), and (440) because of the cubic spinel structure of the Fe O NPs.
3 4
O NPs on the surface of functionalized MWCNT, the pattern shows the new peaks.
̊
̊
4
8
(
3
4

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Figure 3 XRD patterns of MWCNT-COOH, CS NPs/MWCNT, Cu-CS NPs/MWCNT@Fe O .
3
4
Thermal stability is one of the most important factors in selecting a suitable catalyst for the reaction. In order to obtain
information on the thermal stability, TGA experiments are carried out by heating MWCNT-COOH, CS NPs/MWCNT, CS
3 4 3 4 2
NPs/MWCNT@Fe O and Cu-CS NPs/MWCNT@Fe O up to 600 °C under N at a heating rate of 10 °C/min (Fig. 4). In the case of
MWCNTs-COOH, the weight decreases linearly and quietly with increasing temperature. For CS NPs/MWCNT, obvious weight
loss can be observed in the temperature range of 200–350°C, resulting from the decomposition of coated CS NPs. TGA results
confirm that CS NPs have been tethered to MWCNT and the amount of CS NP were calculated about 15 wt% from the
difference in weight loss of the MWCNT-COOH and CS NPs/MWCNT. For CS NPs/MWCNT@Fe
CS NPs occurred in the temperature range of 200–350 °C and the residual weights prove that the amount of CS NPs in CS
NPs/MWCNT@Fe nanocatalyst is about 3.28% which is in agreement with CHN elemental analysis data. However, in the
case of Cu-CS NPs/MWCNT@Fe clearly observed three temperature ranges of weight diminution consisting of deformation
of organic functional groups and decomposition of CS and Cu NPs along with an MWCNT oxidation. The residual weights of
MWCNT-COOH, CS NPs/MWCNT, CS NPs/MWCNT@Fe and Cu-CS NPs/MWCNT@Fe were 93%, 75%, 87% and 62%,
respectively. Overall, results showed that the nanoreactors are remarkably thermally stable at the desired temperatures,
whereas, CS NPs/MWCNT@Fe nanocatalyst are more stable than Cu-CS NPs/MWCNT@Fe at high temperatures.
3 4
O , the thermal degradation of
3
O
4
3
O
4
3
O
4
3 4
O
3
O
4
3 4
O

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-1
Figure 4 TGA curves recorded at a heating rate of 10 °C min
3 4
To demonstrate the validity, usefulness and the multi-task capability of the synthesized CS NPs/MWCNT@Fe O
nanoreactor, efficient types of click organic transformations have been carried out. For this purpose, at the beginning, catalytic
activity of CS NPs/MWCNT@Fe O nanoreactor for the click-multi-component synthesis of 2,3-dihydroquinazolin-4(1H)-ones
3
4
derivatives 4 was evaluated in water. Conventionally, 2,3-dihydroquinazolin-4(1H)-ones are synthesized through the reaction of
4
9
2
-aminobenzamide derivatives and aromatic aldehydes. Comparing with the traditional methods, by virtues of the multi-
component reactions such as higher diversity and obtain of most complex products this efficient compounds by a re-
engineering approach was synthesis through a one-pot three-component cascade reaction of isatoic anhydride 1, various
amines 2 and aromatic aldehydes 3. Also, several approaches have been reported for the synthesis of substituted 2,3-
5
0
dihydroquinazolin-4(1H)-ones in the presence of Lewis and Bronsted acids such as strontium (III) chloride hexahydrate,
5
1
52
53
iron(III) chloride adsorbed on silica gel, zinc (II) perfluorooctanoate along with dodecylbenzenesulfonic acid. Nowadays the
5
4
55
56
57
2
nanocatalysts such as CuO nanoparticles, indium(III) oxide NPs, core–shell CuO–Pd NPs and CeO NPs have been used
too frequently for the synthesis of these useful heterocyclic compounds. Although these protocols have some benefits most of
them have important downsides such as using expensive and environmentally damaging metal catalysts. Our designed protocol
not only has been carried out in green medium by conventional stirring in one-pot step without using alternative energy input
systems such as microwave and ultrasonic processing in the absence of Lewis or Bronsted basic sites but also is based on the
presence of magical holes on the structure of eco-compatible hydrogels which can take place chemical reactions due to their
free space with high pressure, unique capability of encapsulating reagents and cavitation effects.
Initially, we started the reaction of isatoic anhydride (0.080 g, 0.500 mmol), benzaldehyde (0.053 g, 0.500 mmol), and aniline
(
0.046 g, 0.500 mmol) in water under reflux condition for 7 h in the absence of catalyst, which led to very poor yield (15%) of
,3-dihydroquinazolin-4(1H)-one (4a) . Then, for evaluating the catalytic efficiency of nanoreactor the model reaction using
2

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various amounts of catalysts (0.010, 0.020 and 0.030 g) and temperatures (room temperature, 60 °C and reflux) were
performed. The best conditions were found in water as a green solvent under reflux conditions and the best amount of catalyst
3 4
was 0.030 g for CS NP/MWCNT@Fe O .
3 4
Table 1. Synthesis of 2,3-dihydroquinazolin-4(1H)-ones catalyzed by CS NP/MWCNT@Fe O
O
O
O
R1
N
O
3 4
CS NP/MWCNT@Fe O
+
R1
NH
2
+
Water, 6-7 h
Reflux
2
N
H
N
O
R2
R2
H
3
4
1
1
2
R
a
Entry
R
product
Yields (%)
M.p./ °C
Found/Reported
5
8
1
2
3
4
5
6
Phenyl
Phenyl
H
4a
4b
4c
4d
4e
4f
86
85
92
90
84
80
219–221/217–218
201–203/203–204
210–213/212–214
165–166/164–166
125–128/126-127
118–120/120–122
5
5
5
0
3
4-CH O
0
8
4-CH
3
-Phenyl
4-NO
2
Benzyl
H
H
H
5
8
n-Propyl
n-Butyl
5
2
a
Isolated yields
In addition, for investigation the selectivity of magnetic bio-nanoreactor, this click-multi-component strategy performed by
2-formyl-phenoxy)-acetic acid ethyl ester. Although formation of some by-product is possible but we observed that only
(
aldehyde functional groups were reacted and ester groups were not involved (Scheme 2). Our literature survey revealed that
there is no report yet available on the utilization of (2-formyl-phenoxy)-acetic acid ethyl ester (4g) for preparation of 2,3-
dihydroquinazolin-4(1H)-ones scaffolds.
O
O
O
O
CS NP/MWCNT@Fe
Water, Reflux
3 4
O
O
N
O
O
N
H
O
N
H
O
NH
2
O
4
g
O
75%
Only product
Scheme 2 Direct selective synthesis of {2-[3-(4-methyl-benzyl)-4-oxo-1,2,3,4 tetrahydro-quinazolin-2-yl]-phenoxy}-
acetic acid ethyl ester

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Since one of the outstanding heterocyclic scaffolds is imidazole derivatives, recently, several catalytic performances for the
5
9, 60
61
synthesis of these heterocyclic compounds have been reported.
For example copper supported on the SiO
2
nanoparticle ,
2
-supported-β-
6
2
63
zirconium (IV) acetylacetonate using ultrasonic irradiation , ionic liquid under microwave irradiation , ZrO
6
4
65
cyclodextrin and magnetic silica nanoparticles with sulfonic acid groups been employed in preparation of imidazoles
derivatives. While many of them do suffer from tedious processes, detrimental metals, harsh reaction conditions and
alternative energy input systems such as microwave and ultrasonic processing. Considering the high importance of 2,4,5-
trisubstituted imidazoles and also in coincidence with the principles of click chemistry philosophy, we decided to investigate
the catalytic efficiency and applicability of CS NPs/MWCNT@Fe
trisubstituted imidazoles 8. These heterocyclic compounds synthesized via pseudo four component cascade reaction of benzil
, benzaldehyde 6 and ammonium acetate 7 in EtOH as a solvent.
3 4
O in the pseudo four-component cascade synthesis of 2,4,5-
5
3 4
Table 2. Synthesis of 2,4,5-trisubstituted imidazoles catalyzed by CS NP/MWCNT@Fe O
CHO
O
O
H
N
CS NP/MWCNT@Fe O
R
3
4
+
+
2 NH OAc
4
EtOH, Reflux
40-60 min
N
8
7
R
6
5
a
Entry
R
product
Yields (%)
M.p./ °C
Found/Reported
6
6
6
6
6
6
1
1
1
1
6
6
1
2
3
4
5
6
H
8a
8b
8c
8d
8e
8f
88
271-274/270-273
192-195/196-198
226-229/228-230
260-262/258-261
191-192/190-192
290-293/290-292
4-NO
2
95
4-Me
4-Cl
83
92
2-Cl
88
86
3- NO
2
a
Isolated yields
The results showed that this reaction could be efficiently catalyzed with CS NPs/MWCNT@Fe O nanoreactor in a pot, atom
3
4
and step economic synthesis based on the high pressure of the nanoreactors without need of any harsh reaction conditions.
For optimization of this reaction, three green approaches were examined including water, ethanol and solvent free condition.
Also, for obtaining the best reaction conditions various amounts of catalysts (0.010, 0.020 and 0.030 g) and temperatures

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(
room temperature, 60 °C and reflux) were investigated. The results showed that the best solvent is ethanol under reflux and
the optimized amount of the catalyst is 0.020 g. High yields are obtained using both electron-donating and electron-
withdrawing groups. As might be expected, this reaction in the absence of any catalyst in EtOH under reflux condition gave an
imidazole product in trace amount. Moreover, for assessing the selectivity of the bio-nanoreactor, this multi-component
reaction carried out by 2-(2-formylphenoxy) acetic acid, consequently have been showed that only aldehyde functional groups
were reacted and a carboxylic acid group was not implied (Scheme 3). Our literature scanning exhibit that there is no report yet
available on the utilization of 2-(2-(4,5-diphenyl-1H-imidazol-2-yl)phenoxy)acetic acid (8g) for the expeditious synthesis of
trisubstituted imidazole derivatives. Indeed these selective synthetic methods are versatile and effective manners in the field of
total synthesis or multistep processes.
O
O
OH
O
O
O
CS NP/MWCNT@Fe
EtOH, Reflux
3
O
4
O
OH
2
4
NH OAc
+
+
N
NH
O
8g
8
2%
Only product
Scheme 3 Direct selective synthesis of 2-(2-(4,5-diphenyl-1H-imidazol-2-yl)phenoxy) acetic acid
Continuing the work, we checked the catalytic performance of the CS NPs/MWCNT@Fe
cycloaddition as one of the remarkable and applicable click reactions. This investigation began with the evaluation of CS
NPs/MWCNT@Fe as a heterogeneous catalyst in the reaction of phenylacetylene (0.102 g, 1.000 mmol), benzyl bromide
0.171 g, 1.000 mmol) and sodium azide (0.065 g, 1.000 mmol) as a model reaction. The model reaction using various amounts
3 4
O on the Huisgen 1,3-dipolar
3
O
4
(
of catalyst (0.005, 0.010, 0.020 g) and temperatures (room temperature, 50 °C, 70 °C and reflux) were performed. Interestingly,
were observed that 0.020 g of this nanoreactor could accomplish the alkyne–azide coupling reaction with a good yield in water
at 70 °C in the absence of any Cu catalyst. While this reaction required a good deal of heat or sufficient amount of Cu to
overcome the activation barrier of deforming the alkyne’s bond angle to form the triazole and in the absence of any catalyst
6
7
the reaction is avoided .
This great results showed that the CS NPs bind to the substrates by means of hydrogen bonding and charge–dipole
interactions so enhance the pre-organization of the azide and alkyne groups with creating strain inside its cavity and so
3 4
promote the rate of the reaction without need of any Cu catalysts. Therefore, CS NPs/MWCNT@Fe O nanoreactor could be
introduced as strain-promoted nanoreactor.

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On the other hand, and due to our ongoing interest on active metals immobilized on the supports, Cu NPs were synthesized
6
8
on the surface of the CS NPs/MWCNT@Fe
which a transition metal catalyst is attached to substrate binding cavities of the nanoreactor. The schematic pathway for the
preparation of Cu-CS NPs/MWCNT@Fe is shown in Scheme 1. The FAAS method was used for determining Cu content of the
nanocatalyst and the weight percentage of Cu was 1.4%. The catalytic activity of Cu-CS NPs/MWCNT@Fe O was evaluated in
3 4
O using CS NPs as a ligand for complexation. Indeed, some examples are known in
6
9
3
O
4
3
4
the 1,3-dipolar cycloaddition reaction. Therefore, the same model reaction with Cu-CS NPs/MWCNT@Fe
conditions as mentioned above were performed. The results showed that comparing with the CS NPs/MWCNT@Fe
CS NPs/MWCNT@Fe (B) accelerates the 1,3-dipolar cycloaddition kinetics significantly. This can be proved that the
3
O
4
in the same
3
O
4
(A), Cu-
3
O
4
synergistic effect of Cu NPs and the cavity strain of nanoreactors have important roles in the mechanism of this reaction in
comparing with the copper free conditions. Then, the versatility of the catalysts for the 1,3-dipolar cycloaddition of structurally
diverse benzyl bromides and alkynes were explored for both of the catalysts and the results are summarized in Table 3.
Table 3. Synthesis of 1,4-disubstituted 1,2,3-triazoles catalyzed by CS NPs/MWCNT@Fe
3
O
4
3 4
(A) and Cu-CS NPs/MWCNT@Fe O
(
B)
2
R
a
Entry
Alkynes
product
Yields (%) A/B
M.p./ °C
Found/Reported
7
0
1
2
3
4
5
6
PhCH
2
12a
12b
12c
12d
12e
12f
84/99
79/92
80/95
82/98
77/89
78/97
128-130/128-131
7
1
3-BrC
6
6
H
4
CH
CH
2
2
93-96/93-94
7
7
1
1
0
4-BrC
H
4
154-155/150-152
152-154/155-158
2 6 4 2
4-NO C H CH
7
4-CH3-
C
6
H
4
CH
2
91-92/93-94
178-181
6 4 2
3-IC H CH
a
Isolated yields

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All the substrates produced the expected cycloaddition product in water with very good to excellent yields via Cu-CS
NPs/MWCNT@Fe and moderate to good yields via CS NPs/MWCNT@Fe
3
O
4
3 4
O .
The results indicated that CS NPs/MWCNT@Fe O as a novel magnetic nanoreactor shows great efficiency toward direct
3
4
access to three types of the click-multi-component reactions. We attribute this finding to the preparation procedure of TPP-CS
nanoparticles based on the ionic gelation process. Firstly, it seems that the reactions mainly catalyzed by –OH groups on the
3 4
surface of the CS NPs/MWCNT@Fe O nanocomposite. But the preparation procedure offers the other possibility that the
nanocomposite can act as a nanoreactor. In this procedure, the positively charged amino groups of chitosan react with the
negatively charged counter ion of tripolyphosphate to produce CS spherical nanoparticles with the empty inner space on the
surface of the MWCNT. Transmission electron microscopy (TEM) images of CS NPS, CS NPs/MWCNT and CS
3 4
NPs/MWCNT@Fe O confirm the spherical-like shapes of CS NPs with an inner space that appear darker than the outer space
(
Fig. 5) This result proves that the CS NPs were accessed by the solvents and reactants in the hydrogel forms, which are water-
.
insoluble crosslinked hydrophilic scaffolds capable of preserving a large amount of aqueous medium, so it can be rendition as a
nanoreactor. The images also reveal that CS nanospheres approximately have an average size of 20-60 nm and distributed
along the nanotube surface. In the case of CS NPs/MWCNT@Fe
semi-spherical morphology.
3 4 3 4
O , the nanotubes were coated with CS and Fe O NPs with
3 4
Figure 5 TEM images of CS NPs (a), CS NPs/MWCNT (b) and CS NPs/MWCNT@Fe O (c)
Although CNTs are already used as very effective nanoreactors for organic reactions where the chemo-, regio-, or
7
2
enantioselectivity can be tuned as a result of confinement in carbon nanotubes, the combination of cavitation effect of CS
NPs and MWCNT, in this case, have a great effect on the kinetics of the click reactions. In their swollen stage, chitosan
nanoparticles offer large free space within the crosslinked network on the surface of MWCNT by exploiting its multiple
channels and thus facilitate the synthesis of organic structures by providing sufficient space for reaction and the possibility of
confining reagents within them. Thus synthesized nanoreactors are well suited as accelerating catalysts for click-based MCRs in

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which the entropy of the reaction is decreased in the transition state therefore have pronounced effect on the kinetic and rate
of the reaction (Scheme 4). Proposed mechanism of three mentioned bio-nanoreactor catalyzed click reactions have been
presented in electronic supplementary information (ESI).
Scheme 4 Schematic plan of swelling effect in CS NPs/MWCNT as a nanoreactor for click multi-component reactions
To prove the nanoreactor performance of this nanoparticles three mentioned model click-multi-component reactions were
46
also catalyzed with the MWCNT support that functionalized with polymeric bulk chitosan in the exact similar conditions.
Table 4. Comparison of the isolated yield versus the structure of the chitosan in a nanosphere (CS NP/MWCNT) and bulk shape
CS/MWCNT)
(
a
Entry
Product
4a
Catalyst
Time (h)
Yield (%)
1
CS NP/MWCNT
CS/MWCNT
6
6
86
52

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2
3
8a
CS NP/MWCNT
CS/MWCNT
1
88
1
65
84
70
99
CS NP/MWCNT
CS/MWCNT
0.5
0.5
0.5
1
2a
3 4
Cu-CS NP/MWCNT@Fe O
a
Isolated yields
As the TEM images of CS/MWCNT show (Fig. 6a), CS matrices grafted to the MWCNTs without any obvious geometrical shape in
comparison with CS NPs/MWCNT (Fig. 5b) and the nanotubes enwrapped by the grafted CS polymer chains. There is no sign of any
spherical NPs that can act as a nanoreactor therefore, the reactions mainly catalyzed by –OH groups of bulk chitosan on the surface
of MWCNT.
3 4
Figure 6 TEM images of CS/MWCNT (a) and Cu-CS NPs/MWCNT@Fe O (b)
Although the conditions are similar, except the morphology of chitosan, and the same amount of catalyst was used, the yield of
the reaction has an enough improvement in the case of chitosan nanoparticles catalyzed. This finding again demonstrates the
importance of this nanoreactor catalyst in comparison to bulk supports. As a result, the nano-chitosan system served to create a
local high-pressure nanoreactor due to cavitation effect over the surface of the MWCNT. In the case of Cu-CS NPs/MWCNT@Fe
3 4
O
(
Fig. 6b), the outer structure of CS NPs hinder the aggregation of Cu NPs and acted as a ligand for Cu NPs. In addition, the interaction

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of Cu NPs and support is more effective than that of the bulk forms, has a dramatic impact on the catalytic performance of the
copper center.
7
3-79
The efficiency of the synthesized catalysts in comparison with other reported catalysts
that in the case of Cu-CS NPs/MWCNT@Fe , the reaction yield is rather increased at the relatively shorter reaction times. As
illustrated above the synergistic effect of Cu NPs and cavity strain of the nanoreactors could accelerate the kinetic of the reaction.
By contrast, CS NP/MWCNT@Fe shows a great catalytic efficiency toward this synthesis while having an outstanding advantage
of biocompatibility without incorporation of wasting metal under mild thermal conditions in H O.
is given in Table 5. The results depict
3
O
4
3
O
4
2
Table 5 Comparison of catalysts described in the literature for the synthesis of 1,4-disubstituted 1,2,3-triazoles
Entry
Catalyst
Reaction conditions Time (h) Yield (%) Ref.
o
1
2
3
4
5
6
7
8
Cellulose supported cuprous iodide NPs
H O, 70 C
2
7
96
88
95
92
90
92
94
99
84
73
2
o
Cu
2
O nanocrystals
EtOH, 55 C
74
o
Polyoxomolybdate-stabilized Cu
2
O NPs
H
2
O, 70 C
12
12
15
0.16
8
75
chitosan stabilised copper-iron oxide
Zn/C
DCM, r.t.
76
o
DMF, 50 C
77
Cu/SiO Composite
H O, MW
78
2
2
silver–graphene nanocomposite
H
2
O, r.t.
79
o
Cu-CS NPs/MWCNT@Fe
3
O
4
H
H
2
2
O, 70 C
0.5
0.5
This work
This work
o
9
CS NP/MWCNT@Fe
3
O
4
O, 70 C
a
Isolated yields
Another advantage of these designed nanocatalysts is their easy dispersion and separation in the reaction mixture. After
completion of the reaction, the catalyst was readily separated by an external magnet as shown in Figure 7.

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3 4
Figure 7 (a) Dispersion of CS NP/MWCNT@Fe O particles (b) Recycling of the catalyst through magnetic decantation
The reusability of CS NP/MWCNT@Fe
3 4
O was examined for the synthesis of 2,3-dihydroquinazolin-4(1H)-ones, trisubstituted
imidazoles and 1,2,3-triazoles. In addition, recyclability of Cu-CS NPs/MWCNT@Fe O for the synthesis of 1,2,3-triazoles was
3
4
investigated. The catalysts were reused in the reactions after washing with acetone and drying under vacuum at 60 °C. This
procedure was carried out for four repeat cycles. The results show that only minor decreases in the reaction yields are
observed and the recovered catalysts retained a significant fraction of the original activity (Fig. 8).
1
00
80
60
40
20
0
Run 1
Run 2
run 3
Run 4
2
1
,3-dihydroquinazolin-4(1H)-ones
,2,3-triazoles
Trisubstituted imidazole
1,2,3-triazoles (Cu)
Figure 8 Reusability of the nanoreactors in the click multi-component-reactions
3
. Conclusion
In conclusion, we introduced an ideal nanoreactor catalytic system comprising MWCNT and crosslinked chitosan
nanoparticles, through in situ synthesis by an ionotropic gelation technique, with empty inner space for the expeditious click-
multi-component synthesis of 2,3-dihydroquinazolin-4(1H)-ones, trisubstituted imidazoles and 1,2,3-triazoles. The CS
NPs/MWCNT@Fe O showed great efficiency toward the synthesis of 1,2,3-triazoles in water without need of any Cu catalyst
3
4
3 4
that can be introduced as a copper free strain-promoting nanoreactor. Also, the capability of CS NPs/MWCNT@Fe O to
immobilization of Cu NPs for 1,3-dipolar cycloaddition reaction has been investigated and showed that the interactions
between Cu NPs and nanoreactor precisely caused high yields in short reaction times due to their synergistic effect.
Characterizations results show that the catalyst provides highly disperse nanoparticles with a high thermal stability. Overall, the
present methodology offers several advantages such as simple procedure, magnetic nanoparticles as easily recoverable
catalysts, easy work-up process, excellent yields with short reaction times and biocompatibility. It is anticipated that this

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nanoreactor system will serve as a useful platform to study various heterogeneous catalytic reactions that need reactor
conditions and also could be a great candidate for large scale chemical productions. Therefore it seemed that this bio-
nanoreactor can shift from a laboratory to industrial production.
4
. Experimental
4
.1. Materials and methods
The materials were purchased from Merck and Aldrich and used without further purification. Carboxyl multi wall carbon
nanotubes (purity> 95 %, -COOH content: 2.00 wt%, outer diameter: 10-20 nm, inner diameter: 5-10 nm, length: 30μm, special
2
surface area: 220 m /g) was purchased from Atoor Sanat Abtin, Tehran, Iran. Products were analysed using a Varian 3900 GC.
The elemental analyses (CHN) were performed with an Elementar Analysensysteme GmbH VarioEL. X-ray diffraction (XRD)
pattern of catalyst was recorded on a STOE STADI P. Copper determination was carried out on a flame atomic absorption
spectrometer (FAAS, Shimadzu AA-680) with a Cu hollow cathode lamp at 324.7 nm, using an air–acetylene flame. The amount
3 4
of Fe O nanoparticles was estimated using an inductively coupled plasma optical emission spectrometer (ICP-OES; Varian Vista
PRO Radial). Scanning electron microscopy (SEM) observations were carried out on an electron microscopy Philips XL-30 ESEM.
Transmission electron microscopy (TEM) was performed using a transmission microscope (Philips CM30) with an accelerating
voltage of 150 kV. Nanoparticle size was measured by dynamic light scattering (DLS) (Zetasizer Nano ZS90, Malvern
Instruments). Thermogravimetric analysis (TGA) was carried out using NETZSCH TG 209 F1 Iris system at a heating rate of 10 °C
−
1
min under nitrogen atmosphere. Melting points were measured on an Electrothermal 9100 apparatus and are uncorrected. IR
1
13
spectra were recorded on a Shimadzu IR-470 spectrometer. H and C NMR spectra were recorded on a BRUKER DRX-300
AVANCE spectrometer at 300.13 and 75.47 MHz. NMR spectra were obtained in DMSO-d and CDCl
6
3
.
4
.2. Preparation of CS NPs/MWCNT@Fe
3 4
O nanobiocomposite
CS NPs/MWCNT were obtained based on an ionotropic gelation interaction between positively charged CS and negatively
8
0
charged TPP in the medium containing MWCNT at room temperature. MWCNT–COOH (0.050 g) was added to CS (0.250 g)
solution dissolved in acetic acid (2% v/v, 125 mL), then TPP solution (50 mL, 1.000 mg/mL) was added drop-wise to the mixture.
The gelation process was carried out under constant magnetic stirring for 5 h with CS to TPP ratio (in weight) of 5:2, and then
ultrasonication was performed at room temperature. The NPs were then separated by centrifugation (6000 rpm) at 8 °C. The
supernatant was removed and the CS NPs/MWCNT was rinsed with water followed by evaporation. The next step was the
8
1
synthesis of the magnetic Fe
3 4 3 4
O using co-precipitation technique. The Fe O NPs (1.000 g) was dispersed in water (15 mL) and
sonicated for 15 min then CS NPs/MWCNT (1.000 g) added and sonication continued for 2 h at room temperature. CS

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NPs/MWCNT@Fe
3 4
O were collected and washed three times with deionized water/ethanol and the magnetic precipitate was
dried under vacuum at 60 °C.
4
.3. Preparation of Cu-CS NPs/MWCNT@Fe
CS NPs/MWCNT@Fe (1.000 g) was dispersed in water and then ultrasonication was performed at room temperature.
Then, a solution of CuCl .2H O (0.043 g, 0.00025 mmol) in 5 mL of H O was added dropwise to the reaction mixture, followed
3 4
O
3
O
4
2
2
2
by the addition of ascorbic acid (50 mL, 0.025 M). The reaction mixture was stirred on a magnetic heater-stirrer at 80 °C for 24
h. Finally, by applying an external magnet, the Cu-CS NPs/MWCNT@Fe NPs were collected and then washed three times
with deionized H O/ethanol and the magnetic precipitate was dried under vacuum at 60 °C.
3
O
4
2
4
.4. General procedure for the synthesis of 2,3-dihydroquinazolin-4(1H)-ones
CS NPs/MWCNT@Fe O (0.030 g) was added to a mixture of isatoic anhydride (0.080 g, 0.500 mmol), amine (0.500 mmol)
3
4
and aromatic aldehyde (0.500 mmol) in water (5 mL) as a solvent. Then the mixture was stirred for the appropriate time under
reflux condition. After completion of the reaction (monitored by TLC hexane: ethyl acetate), the reaction mixture was cooled to
room temperature and the catalyst was separated by an external magnet and washed twice with ethyl acetate (5 mL) to
separate the adsorbed organic compounds. Then the organic phase was combined and extracted twice with water. Finally, the
solvent was removed under vacuum to give the crude product and recrystallization in EtOH for obtaining the pure product.
4
.5. General procedure for the synthesis of trisubstituted imidazoles
In a pilot experiment, a mixture of aldehyde (1.000 mmol), benzil (0.210 g, 1.000 mmol), ammonium acetate (0.190 g, 2.500 mmol)
3 4
and CS NPs/MWCNT@Fe O (0.020 g) in ethanol was heated under reflux conditions for 40-60 min. The progress of the reaction was
monitored by TLC (hexane: ethyl acetate). After the reaction was completed, the catalyst was separated by an external magnet. The
reaction mixture was concentrated on a rotary evaporator under reduced pressure and the solid product obtained was washed with
water and recrystallized from acetone–water 9 : 1 (v/v) to produce the desired trisubstituted imidazoles.
4
.6. General procedure for the synthesis of 1,2,3-triazoles
Alkynes (1.000 mmol), benzyl bromide derivatives (1.000 mmol) and sodium azide (0.065 g, 1.000 mmol) were added to a
3 4 3 4 2
suspension of CS NPs/MWCNT@Fe O (A, 0.020 g) or Cu-CS NPs/MWCNT@Fe O (B, 0.010 g) in H O (5 mL) then the mixture
was stirred at 70 °C. The progress of the reaction was monitored (TLC) (ethyl acetate/n-hexane). Upon completion, the mixture
was cooled to room temperature and the catalyst separated using an external magnet and the product was extracted with
chloroform (10 mL). The solvent was removed under vacuum to give the product. If necessary, the purification was performed
by recrystallization from ethyl acetate or ethanol.
Acknowledgments

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We gratefully acknowledge financial support from the Iran National Science Foundation (INSF), the Research Council of
Shahid Beheshti University and Catalyst Center of Excellence (CCE) at Shahid Beheshti University.
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