Copper(I) oxide nanoparticles supported on magnetic casein as a bio-supported and magnetically recoverable catalyst for aqueous click chemistry synthesis of 1,4-disubstituted 1,2,3-triazoles

Article abstract of DOI:10.1002/aoc.3559

Copper(I) oxide nanoparticles supported on magnetic casein (Cu₂O/Casein@Fe₃O₄NPs) has been synthesized as a bio-supported catalyst and was characterized using powder X-ray diffraction, transmission electron microscopy, ene

Full text of DOI:10.1002/aoc.3559

Received: 8 May 2016
DOI 10.1002/aoc.3559
Revised: 19 June 2016
Accepted: 25 June 2016
F U L L PA P E R
Copper(I) oxide nanoparticles supported on magnetic casein as a
bio‐supported and magnetically recoverable catalyst for aqueous
click chemistry synthesis of 1,4‐disubstituted 1,2,3‐triazoles
*
Shabnam Shaabani | Azadeh Tavousi Tabatabaei | Ahmad Shaabani
Faculty of Chemistry, Shahid Beheshti University,
Copper(I) oxide nanoparticles supported on magnetic casein (Cu2O/
Casein@Fe3O4NPs) has been synthesized as a bio‐supported catalyst and was char-
acterized using powder X‐ray diffraction, transmission electron microscopy, energy
dispersive X‐ray and Fourier transform infrared spectroscopies, thermogravimetric
analysis and inductively coupled plasma optical emission spectrometry. The
catalytic activity of the synthesized catalyst was investigated in one‐pot
three‐component reactions of alkyl halides, sodium azide and alkynes to prepare
1,4‐disubstituted 1,2,3‐triazoles with high yields in water. The reaction work‐up is
simple and the catalyst can be magnetically separated from the reaction medium
and reused in subsequent reactions.
GC, PO Box 19396‐4716, Tehran, Iran
Correspondence
Ahmad Shaabani, Faculty of Chemistry, Shahid
Beheshti University, GC, PO Box 19396‐4716,
Tehran, Iran.
Email: a‐shaabani@sbu.ac.ir
KEYWORDS
alkyne–azide cycloaddition, bio‐supported catalyst, casein, copper(I) oxide
nanoparticles, magnetically recoverable nanocatalyst
1
|
INTRODUCTION
unique click nature, namely no by‐products, high yields,
moderate reaction conditions and compatibility with water,
has emerged as a promising synthesis approach.[11]
Click chemistry based on green chemistry has emerged as a
fast and efficient approach for the design and implementation
of environmentally benign processes. One of the most power-
ful click reactions is Huisgen 1,3‐dipolar cycloaddition of an
alkyne and an azide to afford 1,2,3‐triazole derivatives.
Although the 1,2,3‐triazole structural moiety does not occur
in nature, several members of the 1,2,3‐triazole family have
revealed interesting biological properties, such as anti‐HIV
activity,[1] antimicrobial activity against Gram‐positive bacte-
ria,[2] anti‐allergic,[3] anti‐convulsant[4] and β‐lactamase
inhibitory activity,[5] selective β3 adrenergic receptor
agonism,[6] and so on.[7] Moreover, 1,2,3‐triazoles have been
used in industrial applications, such as in dyes, anticorrosive
agents, photographic materials and so on.[8]
In 2002, the discovery of copper(I)‐catalysed azide–
alkyne cycloaddition (CuAAC) by Sharpless and co‐
workers[9] and Meldal and co‐workers[10] improved the
regioselectivity of the Huisgen 1,3‐dipolar cycloaddition
reaction of azides and alkynes and provides a direct entry into
1,4‐disubstituted 1,2,3‐triazoles. CuAAC because of its
High regio‐, chemo‐ and enantio‐selectivity are some of
the advantages of homogeneous catalysis, but the difficulty
of catalyst separation from the final product creates economic
and environmental barriers to broadening its scope. Removal
of trace amounts of catalyst from the end product is essential
since metal contamination is highly regulated, especially by
the pharmaceutical industry. To overcome these problems,
chemists and engineers have investigated a wide range of
strategies; the use of heterogeneous catalyst systems appears
to be the best logical solution.[12]
As is well known, nanoparticles with small sizes tend to
aggregate in solution. To avoid uncontrolled growth or aggre-
gation in the preparation of nanoparticles, stabilizers such as
polymers, surfactants or small organic molecules are often
used. The conjugation of nanoparticles with biomolecules
such as proteins, DNA, enzymes, antibodies etc. has many
different applications including catalysis, biosensing, targeted
drug delivery and directed self‐assembly leading to high‐
order nanoscale materials.[13] This conjugation affords
Appl. Organometal. Chem. 2016; 1–6
wileyonlinelibrary.com/journal/aoc
Copyright © 2016 John Wiley & Sons, Ltd.
1

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SHAABANI ET AL.
long‐term stability of the system and also introduces biocom-
patible functionalities into the nanoparticles for further bio-
logical application.[14]
gas chromatograph (Varian Iberica, Madrid, Spain) equipped
with a split/splitless capillary injection port and flame ioniza-
tion detector. A CP‐Sil‐8 fused silica capillary column (25 m,
0.32 mm inner diameter and 0.52 mm film thickness) from
Chrompack was employed. Thermogravimetric analysis
(TGA) was carried out using an STA 1500 instrument at a
heating rate of 10°C min−1 in air. Powder X‐ray diffraction
(XRD) data were collected with an XD‐3 A diffractometer
using Cu Kα radiation. Energy dispersive X‐ray spectroscopy
(EDX) was performed with a Philips XL‐300 instrument.
Casein, a proline‐rich globular protein which is readily
available in milk, can be thought of as a block copolymer
consisting of blocks with high levels of hydrophobic or
hydrophilic amino acid residues. Thus, caseins are naturally
self‐assembled to form casein micelles with diameters rang-
ing from 50 to 200 nm (average 150 nm) via a balance of
attractive hydrophobic interactions and electrostatic repulsion
in aqueous solution.[15]
Functionalized magnetic nanocatalytic systems possess
several advantages over conventional catalyst systems such
as high surface area to volume ratio, reaction rates closer to
homogeneous counterparts and being magnetically separable.
As part of our ongoing research programme on the devel-
opment of new catalytic systems with emphasis on green and
natural supports,[16] herein, we present a successful prepara-
tion of copper(I) oxide nanoparticles supported on magnetic
casein (Cu2O/Casein@Fe3O4NPs) which has excellent cata-
lytic activity. One‐pot three‐component reactions of various
alkyl halides, sodium azide and various alkynes were carried
out under environmentally friendly conditions with excellent
yields in short reaction times at room temperature (Scheme 1).
To the best of our knowledge, the work presented is the first
example to demonstrate the usefulness of casein as a support
for copper(I) oxide nanoparticles and it is a novel catalyst
with unique properties for Huisgen 1,3‐dipolar cycloaddition
for the preparation of 1,4‐disubstituted 1,2,3‐triazoles.
2.2 | Synthesis of Cu2O/Casein@Fe3O4NPs
Casein (0.75 g) was mixed with 25 ml of deionized water and
was stirred for 5 min. Then FeCl2⋅4H2O (aq)/FeCl3⋅6H2O
(aq) (1:2) (0.65 g/1.75 g) which was dissolved in 2 ml of
deionized water was added while the temperature of the mix-
ture was increased to 80°C for 1 h. Ammonium hydroxide
(25%) was added dropwise to adjust the pH of the solution
to 8–9 (at this pH casein was dissolved) and then continually
stirred for 1 h at 80°C. Subsequently, the reaction mixture
was cooled to room temperature and CuCl2⋅2H2O (0.09 g,
0.50 mmol) which was dissolved in 5 ml of water was added
to it slowly. Then, the solution was neutralized with 0.5 M
hydrochloric acid solution, ascorbic acid (50 ml, 0.05 M)
was added, the temperature of the mixture was increased to
80°C and stirring was continued for another 24 h. Magnetic
casein‐supported copper(I) oxide was separated using an
external magnet, washed with deionized water several times
and once with ethanol, and then it was dried at 60°C to afford
Cu2O/Casein@Fe3O4NPs.
2
| EXPERIMENTAL
2.3 | Synthesis of magnetic casein (Casein@Fe3O4NPs)
Casein (0.75 g) was mixed with 25 ml of deionized water and
was stirred for 5 min. Then FeCl2⋅4H2O (aq)/FeCl3⋅6H2O (aq)
(1:2) (0.65 g/1.75 g) which was dissolved in 2 ml of deionized
water was added while the temperature of the mixture was
increased to 80°C for 1 h. Ammonium hydroxide (25%) was
added dropwise to adjust the pH of the solution to 8–9 (at this
pH casein was dissolved) and then continually stirred for 1 h at
80°C. Subsequently, the reaction mixture was cooled to room
temperature and the solution was neutralized with 0.5 M
hydrochloric acid solution. After 1 h, magnetic casein was
separated using an external magnet, washed with deionized
water several times and once with ethanol, and then it was
dried at 60°C to afford Casein@Fe3O4NPs.
2.1 | Materials and methods
Casein was purchased from Merck (CAS 9000‐71‐9). Copper
determination was carried out using inductively coupled
plasma optical emission spectrometry (ICP‐OES) with a
Varian Vista PRO Radial. Melting points were measured with
an Electrothermal 9100 apparatus and are uncorrected. Fou-
rier transform infrared (FT‐IR) spectra were recorded with a
Bomem MB series FT‐IR spectrophotometer. Scanning elec-
tron microscopy (SEM) observations were carried out with a
TESCAN Vega instrument. All samples were sputtered with
gold before observation. Transmission electron microscopy
(TEM) was performed using a Philips CM‐30 microscope
with an accelerating voltage of 150 kV. Identification and
quantification were carried out using a Varian model 3600
2.4 | General procedure for synthesis of 1,2,3‐triazoles
catalysed by Cu2O/Casein@Fe3O4NPs
Alkyne (1 mmol), benzyl bromide (1 mmol) and sodium
azide (1 mmol, 0.065 g) were added to a suspension of
Cu2O/Casein@Fe3O4NPs catalyst (0.43 mol%, 0.10 g) in
water (5 ml). The reaction mixture was stirred for 2–8 h at
55°C. The progress of the reaction was followed by TLC
SCHEME
1
Synthesis of 1,2,3‐triazoles catalysed by Cu2O/
Casein@Fe3O4NPs

SHAABANI ET AL.
3
(ethyl acetate–n‐hexane). After the completion of the reac-
tion, the mixture was cooled to room temperature and the cat-
alyst was removed using an external magnet and washed
twice with chloroform (6 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 pure product. If necessary the prod-
ucts were purified by recrystallization. Selected NMR spectra
may be found in the supporting information.
3
| RESULTS AND DISCUSSION
3.1 | Synthesis and characterization of Cu2O/
Casein@Fe3O4NPs
FIGURE 1 FT‐IR spectra of casein and Cu2O/Casein@Fe3O4NPs catalyst
The synthesis of Cu2O/Casein@Fe3O4NPs as a new catalyst
was accomplished using the synthetic route shown in
Scheme 2.
In order to evaluate the Cu content of the catalyst, it was
treated with concentrated HCl–HNO3 (3:1, v/v) to digest the
metal complex and then analysed using ICP‐OES. The results
reveal that the content of Cu is 0.28 wt%.
FT‐IR spectra of casein and Cu2O/Casein@Fe3O4NPs are
shown in Figure 1. The spectra of casein and Cu2O/
Casein@Fe3O4NPs show a band at 1557 cm−1, correspond-
ing to N─H bending vibrations of amide and a band at
1650 cm−1 assigned to the C═O stretch of peptide bond pres-
ent in the casein molecules.[17] The FT‐IR spectrum of Cu2O/
Casein@Fe3O4NPs exhibits a broad band at around 567–
621 cm−1 corresponding to the stretching vibrations of the
Fe─O and Cu─O bonds.[18]
SEM analysis (Figure 2(a)) was used to study the surface
morphology of the Cu2O/Casein@Fe3O4NPs catalyst. A
homogeneous surface is observed. Figures 2(b) and (c) show
TEM images of casein and the Cu2O/Casein@Fe3O4NPs cat-
alyst, respectively. TEM analysis of the catalyst shows the
presence of particles with spherical morphology dispersed
on the casein support with an average size range of
9–15 nm related to Cu2O and Fe3O4 nanoparticles.
The EDX spectrum, which allows for detection of the
chemical composition of the Cu2O/Casein@Fe3O4NPs cata-
lyst, is shown in Figure 3. The EDX spectrum shows peaks
for Fe, Cu, O, C and N, which are the major constituents of
Cu2O/Casein@Fe3O4NPs.
The powder XRD patterns of Casein@Fe3O4NPs and Cu2O/
Casein@Fe3O4NPs are shown in Figure 4. For
Casein@Fe3O4NPs, diffraction peaks at various angles (2θ) are
in good agreement with the reported XRD pattern of Fe3O4NPs
(JCPDF no. 03‐0863).[19] For Cu2O/Casein@Fe3O4NPs, all of
the diffraction peaks match well with the normal characteristic
diffractions of Fe3O4 and Cu2O nanoparticles. The diffraction
peaks at 30.34°, 35.40°, 43.42°, 57.19° and 62.86° correspond
to the Fe3O4 nanoparticles (JCPDF no. 03‐0863)[19] and those
at 29.74°, 35.74° and 43.12° correspond to the Cu2O
nanoparticles (JCPDF no. 78‐2076).[20]
Thermal stabilities of casein and Cu2O/Casein@Fe3O4NPs
were measured using TGA (Figure 5). The casein exhibits an
initial weight loss starting at about 70°C and a weight loss at
220°C. When the temperature is above 500°C, casein is
decomposed slowly and the total weight loss is about 96% at
900°C. In the TGA curve of the Cu2O/Casein@Fe3O4NPs cat-
alyst, at a temperature higher than 470°C a loss in weight of
about 45% is observable; the remaining weight is related to
the presence of Cu2O and Fe3O4.
3.2 | Catalytic activity
To evaluate the efficiency of the newly synthesized cata-
SCHEME 2 Synthesis of Cu2O/Casein@Fe3O4NPs catalyst
lyst, it was employed in 1,3‐dipolar cycloaddition reactions

4
SHAABANI ET AL.
FIGURE
4
XRD patterns of Casein@Fe3O4NPs and Cu2O/
Casein@Fe3O4NPs
FIGURE 5 TGA curves obtained under air atmosphere
exploration, the reaction between phenylacetylene and ben-
zyl bromide was chosen as a model reaction. The alkyne,
benzyl halide and sodium azide were added to a suspension
of Cu2O/Casein@Fe3O4NPs as a heterogeneous catalyst
(0.43 mol%, 0.1 g) in water. The reaction mixture was
stirred for 2 h at 55°C, and then the mixture was cooled
to room temperature and the catalyst was easily removed
using an external magnet and washed twice with chloro-
form to separate the adsorbed organic compounds. Then
the organic phase was combined and extracted. Finally
the solvent was removed under vacuum to afford the pure
1,4‐disubstituted 1,2,3‐triazole in 100% yield (Table 1,
entry 1).
FIGURE 2 (a) SEM image of Cu2O/Casein@Fe3O4NPs catalyst. (b) TEM
image of casein and (c) TEM image of Cu2O/Casein@Fe3O4NPs catalyst
For comparison, the model reaction was conducted in the
presence of casein and Casein@Fe3O4NPs as catalysts for 2 h
at 55°C in water, which gives both regioisomers, 1,4 and 1,5
cyclic adducts, in 1:1 ratio, and in 13 and 38% yield, respec-
tively (Scheme 3).
Solvents define a major factor of the environmental per-
formance of processes in the chemical industry and also have
an impact on safety, cost and health issues. The idea of
‘green’ solvents expresses the goal to minimize the environ-
mental impact resulting from the use of solvents in chemical
production.[22] Water as a potentially benign solvent was cho-
sen for carrying out the synthesis of 1,2,3‐triazoles and the
reactions proceed smoothly to completion, and the products
FIGURE 3 EDX spectrum of Cu2O/Casein@Fe3O4NPs
between terminal alkynes and organic azides in which the
azides are generated in situ from corresponding halides
and sodium azide.[21] As the starting point of our

SHAABANI ET AL.
5
TABLE 1 One‐pot synthesis of 1,4‐disubstituted 1,2,3‐triazoles from ben-
zyl bromides, NaN3 and alkynes catalysed by Cu2O/Casein@Fe3O4NPsa
Entry
R1
R2
Time (h)
Yield (%)b
98
1
Ph
Ph
Ph
Ph
Ph
PhCH2
2
3
4
4
4
2
8
2
7
5
5
2
4‐NO2C6H4CH2
3‐IC6H4CH2
4‐BrC6H4CH2
2‐CH3C6H4CH2
PhCH2
98
3
99
4
100
100
100
97
5
6
CH2N(Me)2
CH2N(Me)2
HOC(Me)2
HOC(Me)2
HOCHPh
7
4‐NO2C6H4CH2
PhCH2
8
100
72
9
4‐NO2C6H4CH2
3‐IC6H4CH2
4‐NO2C6H4CH2
SCHEME 4 Proposed reaction mechanism
10
11
70
HOCHPh
95
aReaction conditions: alkyne (1 mmol), benzyl bromide (1 mmol), sodium azide
(1 mmol), Cu2O/Casein@Fe3O4NPs (0.43 mol%, 0.10 g), H2O (5 ml), 55°C.
bIsolated yield.
SCHEME 3 Screening of casein and Casein@Fe3O4NPs catalysts
are isolated in excellent yields. As a result, there was no need
for solvent optimization.
FIGURE
6
Successive runs using recovered Cu2O/Casein@Fe3O4NPs
To investigate the applicability of the prepared catalyst
for 1,3‐dipolar cycloaddition reactions, alkynes containing
various functionalities and various benzyl halides were used.
As evident from Table 1, all products are obtained in high
yields. It is established that the triazole is formed in a
completely regioselective manner, with no contamination by
the 1,5‐regioisomer. The results indicate that the electronic
properties of benzyl halides affect the yields and longer reac-
tion times are required for 3‐iodobenzyl and 4‐nitrobenzyl
derivatives compared to other halides.
catalyst
carrying out the first cycloaddition reaction, the catalyst was
easily removed using an external magnet and washed twice
with chloroform to separate the adsorbed organic compounds,
dried at 60°C and reused for subsequent reactions. The Cu2O/
Casein@Fe3O4NPs catalyst could be reused at least three
times without any significant change in activity (Figure 6).
The proposed reaction mechanism is shown in
Scheme 4. Organic azide is formed through the nucleo-
philic substitution reaction of the azide ion and benzyl bro-
mide. The Cu(I) species reacts with an alkyne to give a
copper acetylide. The 1,3‐dipolar cyclization of the
resulting Cu acetylide and an organic azide followed by
the protonation provide the formation of a triazole and
the regeneration of Cu(I) catalyst.[23]
The recyclability of the catalyst is a very significant factor.
To determine recyclability of Cu2O/Casein@Fe3O4NPs, a set
of experiments was performed for the reaction of benzyl bro-
mide, sodium azide and phenylacetylene using recycled
Cu2O/Casein@Fe3O4NPs catalyst (Table 1, entry 1). After
4
| CONCLUSIONS
The approach of this research is to introduce a new magneti-
cally separable and easily recyclable heterogeneous copper(I)
oxide bio‐catalyst as a new and efficient catalyst with easy
preparation, high catalytic activity and low cost for the gener-
ation of 1,4‐disubstituted 1,2,3‐triazoles in a completely
regioselective manner in water. This work is the first example
to demonstrate the usefulness of casein as a support for cop-
per(I) oxide nanoparticles. Easy magnetic separation of the
catalyst eliminates the requirement of catalyst filtration after
completion of the reaction, which is an additional green attri-
bute of this system.

6
SHAABANI ET AL.
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We gratefully acknowledge financial support from the Iran
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SUPPORTING INFORMATION
Additional supporting information can be found in the online
version of this article at the publisher's website.
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How to cite this article: Shaabani, S., Tavousi
Tabatabaei, A., and Shaabani, A. (2016), Copper(I)
oxide nanoparticles supported on magnetic casein as
a bio‐supported and magnetically recoverable catalyst
for aqueous click chemistry synthesis of 1,4‐disubsti-
tuted 1,2,3‐triazoles, Appl. Organometal. Chem., doi:
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