Copper immobilized onto a triazole functionalized magnetic nanoparticle: A robust magnetically recoverable catalyst for "click" reactions

Article abstract of DOI:10.1039/c4ra13330g

A novel magnetic heterogeneous copper catalyst was synthesized by immobilization of copper ions onto triazole functionalized Fe₃O₄. The catalyst was fully characterized by FT-IR, TGA, CHN, SEM, TEM, EDX and atomic adsorption spectros

Full text of DOI:10.1039/c4ra13330g

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DOI: 10.1039/C4RA13330G
S o d ium as corb ate
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DOI: 10.1039/C4RA13330G
Copper Immobilized Onto the Triazole Functionalized Magnetic
Nanoparticle: A Robust Magnetically
Recoverable Catalyst for “Click” Reaction
Firouz Matloubi Moghaddam*, Seyed Ebrahim Ayati
Laboratory of Organic Synthesis and Natural Products, Department of Chemistry,
Sharif University of Technology, Azadi Street, PO Box 111559516
Tehran, Iran
E-mail Address: matloubi@sharif.edu
Abstract
A novel magnetic heterogeneous copper catalyst was synthesized by immobilization of
copper ion onto the triazole functionalized Fe3O4. The catalyst was fully characterized by FT-
IR, TGA, CHN, SEM, TEM, EDX and atomic adsorption spectroscopy. The resulting catalyst
was used in the synthesis of 1,2,3-triazoles via one-pot three component reaction of alkynes,
alkyl halides, sodium azides under green condition. The catalyst was reused for ten times and
no significant loss of activity was observed.
Keywords: Magnetic nanoparticle, copper catalyst, 1,2,3- triazoles,

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DOI: 10.1039/C4RA13330G
Introduction
Having a small glance to the recent literatures clearly reveals the huge number of
investigations related to "click chemistry"[1, 2]. Due to the growing demands of human
beings for pharmaceuticals, chemists have tended to the more challenging task of
biologically-oriented syntheses in recent years [3]. Conventional procedures used for total
synthesis of drugs and drug-like molecules have some main drawbacks such as being costly,
slow and complex, having laborious protection/deprotection and purification steps, etc. [4]
Considering all these facts, finding new, facile and uncomplicated techniques is still a
challenge in modern organic chemistry. Click chemistry is one of these techniques that its
objective is to establish an ideal set of straightforward and highly selective reactions,
simplifying compound synthesis and providing the faster lead discovery and optimization [1,
2, 4a, 5]. These reactions that are simple, modular, stereospecific and wide in scope result in
very high yields and have simple workup and purification steps [4a, 6].
One of the most investigated and also the prime example of click reactions is the Huisgen
reaction, the copper-catalyzed 1,3-dipolar cycloaddition of azides to alkynes that results to
the formation of a vast number of five-membered heterocycles [7]. This is a concerted [3+2]
cycloaddition of type [π4s+ 2s] thermally allowed reactions. Mild reaction conditions (low
π
reaction temperature, minimal workup and purification), very high functional group
tolerance, specificity and water tolerant nature of the reaction are main advantages of this
reaction [8].
Since alkynes are poor 1,3-dipole acceptors and also because of kinetic stability of alkynes
and azides, the rate of their reaction is quite slow in the absence of the catalyst and requires
elevated temperatures, if it is possible [9]. Furthermore, the uncatalyzed Huisgen reaction
suffers from a main drawback limiting its scope; that is, low regioselectivity in the
approaching mode of alkyne to azide [10]. Employing the copper-based catalysts in this

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reaction not only improves the regioelectivity in favor of 1,4- regioisomer but also causes an
DOI: 10.1039/C4RA13330G
increase in the rate of the reaction with a factor of 107 and rectifies the need for elevated
temperatures [11].
The copper(I) required for catalyzing this reaction can be originated from several different
sources including direct introduction of Cu(I) salts (usually copper iodide), or in situ
reduction of Cu(II) salts using appropriate reducing agents [12]. The later method, in which
sodium ascorbate is usually used as reducing agent, has been recognized as a very useful
method for this purpose. Copper salts such as copper iodide catalyze the Huisgen reaction in
short time and excellent yields under mild conditions. Due to hard recovery process of the
homogenous catalyst, the use of homogeneous catalyst could be costly and uneconomical in
large scale. Since trace amount of metal contamination could have undesired effects on
biological systems, the final products should be completely pure without any copper
contamination. To overcome this problem, designing heterogeneous catalyst is a useful and
applicable method. Several surfaces such as nanosilica[13-15], zeolite[16,17], mesoporous
silica[18,19], guar-gum [20], CuO Hollow Nanospheres [21] and charcoal[22] were used as a
supports for copper immobilization. However, copper immobilization on these surfaces has
some disadvantages such as difficult catalyst separation, high copper leaching, low catalyst
activity after immobilization and low thermal stability. Magnetic nanoparticles are one of the
best solid surfaces for immobilization of copper [23]. Fe3O4 magnetite nanoparticles are well
known as the most promising nanomaterials for biomedical and catalyst purposes. Easy
separation, high thermal stability, high surface area and low toxicity for biological systems
make these nanoparticles as an excellent catalyst in organic synthesis even in large scales
[24].
Taking into account the high appearance of click chemistry in academic and industrial drug
discovery programs and anticipating its growing impact, we intended to report for the first

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time the synthesis of a new efficient magnetite-base catalytic system, Fe3O4-
DOI: 10.1039/C4RA13330G
silicacoated@functionalized 3-Glycidoxypropyltrimethoxysilane [MNPs@FGly], along with
its application in a practical and highly efficient approach to 1,2,3-triazole derivatives. The
presented procedure uses phenyl acetylene and 1-heptyne as alkyne component and various
alkyl azides (from the in-situ reaction of alkyl halides (tosylates)) as the other component in
the presence of sodium ascorbate as reducing agent to form triazoles. The reaction was done
in mild and green condition. The reaction yields were excellent for most of alkyl halides as a
precursor.
Results and discussions
In this work, the silica-coated magnetite nanoparticles were synthesized according to the
procedure reported elsewhere in literature [25]. The magnetic Fe3O4 nanoparticles were first
prepared by coprecipitation method and then were used to synthesize [MNPs@FGly][Cl]
nanoparticles (Scheme1) through the procedure explained in the experimental section.
Scheme1: Immobilization and functionalization of 3-glycidoxypropyltrimethoxysilane on
Fe3O4@SiO2

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DOI: 10.1039/C4RA13330G
FT-IR spectra of Fe3O4, Fe3O4@SiO2, [MNPs@FGly] and [MNPs@FGly][Cl] are shown in
Fig. 1. The peak appeared at 650 cm-1 and 1100 cm-1 are attributed to Fe-O and Si-O
stretching vibrations of Fe3O4 and SiO2, respectively. The peaks appeared at 2950 and 2930
cm-1 (Fig. 1 c and d) are attributed to C-H stretching vibrations and confirms the presence of
alkyl silane groups on Fe3O4@SiO2.
Fig. 1. FTIR spectra of Fe3O4 (a), Fe3O4@SiO2 (b), [MNPs@FGly] (c) and
[MNPs@FGly][Cl] (d).
The SEM image of catalyst shows sphere magnetic nanoparticles (Fig. 2). The TEM image of
catalyst shows an average size of 5-15 nm. The EDX analysis also shows the presence of
copper ion in catalyst structure (Fig. 2).

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DOI: 10.1039/C4RA13330G
Fig. 2. SEM and TEM image and EDX analysis of [MNPs@FGly][Cl]
The CHN analysis of [MNPs@FGly] revealed that carbon, nitrogen and hydrogen contents of
the catalyst are 19.02, 2.922 and 2.398 wt%, respectively, indicating the alkyl silane groups
were successfully immobilized on magnetic nanoparticles. Loading calculation based on
carbon content showed that the amount of organic group is 1.13 mmol/g. The results show
that a high level of organosilane has been coated on magnetic nanoparticles.
TGA curve of catalyst (Fig.3) shows that the decomposition of organic groups starts at 265
°C and complete degradation occurs up to 720 °C. A 30 % content of organic groups proved
that a high value (1.14 mmol/g) of triazole groups have immobilized on magnetic
nanoparticles.

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DOI: 10.1039/C4RA13330G
Fig. 3. TGA of [MNPs@FGly]
Atomic absorption spectroscopy (AAS) of the catalyst showed that the amount of copper
loaded on magnetic nanoparticles is about 0.51 mmol/g. High yields and selectivity of
products is attributed to high loading of copper ions on the surface of magnetic nanoparticles.
The activity of the synthesized catalytic system was investigated in the 1,3-dipolar
cycloaddition reaction of phenyl acetylene to azides resulting to the formation of various
five-membered heterocyclic compounds (Scheme 2).
Scheme 2: Huisgen reaction catalyzed by [MNPs@FGly][Cl]
Initially, the optimized reaction conditions were determined in the reaction between sodium
azide, phenyl acetylene and benzylbromide as model substrates using various types of
solvents at different temperatures and in the presence of various concentrations of catalyst.
The results are listed in Table 1. Firstly, the reaction was done at room temperature in the
absence of catalyst. After 24 h the crude materials remained intact and no significant triazole
was detected even with increasing the temperature up to 70 ˚C (entries 1,2).

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The effect of type and the amount of the catalyst required for the reaction was then examined.
DOI: 10.1039/C4RA13330G
Reactions were carried out using different types of catalysts including CuSO4,
[MNPs@FGly][Cl], [MNPs@FGly][Br], [MNPs@FGly][NO3] and [MNPs@FGly][OAc]
(entries 3-9). The effect of different counter ions in the catalyst structure was investigated and
as can be seen, the best results were obtained using [MNPs@FGly][Cl] as catalyst (entry 6).
Both polar and non-polar solvents were applied in this reaction in the presence of 0.5 mol%
of catalyst (entries14-18). In the absence of sodium ascorbate, only a trace of corresponding
triazole was obtained after 5 hours. In order to meet the green chemistry principles, the
reaction was also conducted in water as a green solvent (entry 14). The results showed that
the reaction is completed in short time that is comparable with and in many cases is even
better than the other organic solvents. However, the yield of the reaction in the mixture of
H2O/t-BuOH (3:1) was higher in comparison with each of the solvents separately (entries 14
and 15). Therefore, this mixture was selected as the optimized reaction medium (entry 13).
Table 1. Control experiment for synthesis of 1,3,5-triazole catalyzed by copper
supported[MNPs@FGly][Cl] a

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DOI: 10.1039/C4RA13330G
Entry
Catalyst
Cat. Loading
Solvent
T
(°C)
r.t
Time
(h)
24
8
Yield
(%)b
<1d
<3d
<12d
28
(mol%)
1
2
3
4
5
6
7
8
-
-
-
-
H2O/t-BuOH c
H2O/t-BuOH
H2O/t-BuOH
H2O/t-BuOH
H2O/t-BuOH
H2O/t-BuOH
H2O/t-BuOH
H2O/t-BuOH
H2O/t-BuOH
H2O/t-BuOH
H2O/t-BuOH
H2O/t-BuOH
H2O/t-BuOH
H2O
70
100
55
110
55
55
55
55
r.t
[MNPs@FGly]f
CuSO4
10mg
5
8
10
10
2
2
2
2
2
9
2
2
2
4
4
4
4
5
CuSO4
5
1
1
1
1
1
1
0.8
0.5
0.5
0.5
0.5
0.5
0.5
0.5
87e
99
[MNPs@FGly][Cl]
[MNPs@FGly][Br]
[MNPs@FGly][NO3]
[MNPs@FGly] [OAc]
[MNPs@FGly][Cl]
[MNPs@FGly][Cl]
[MNPs@FGly][Cl]
[MNPs@FGly][Cl]
[MNPs@FGly][Cl]
[MNPs@FGly][Cl]
[MNPs@FGly][Cl]
[MNPs@FGly][Cl]
[MNPs@FGly][Cl]
[MNPs@FGly][Cl]g
83
72
88
80
99
99
99
91
81
83
69
37
9
10
11
12
13
14
15
16
17
18
19
r.t
55
55
55
55
55
55
55
55
t-BuOH
CH3CN
CH3OH
Toluene
H2O/t-BuOH
trace
a Reaction condition: phenyl acetylene (0.5 mmol), benzyl bromide (0.5 mmol), sodium azide (0.5
mmol), sodium ascorbate (10 mol%), solvent (3 mL).
b Isolated yield.
cThe ratio of H2O/t-BuOH is 3/1.
dMainly recovery of the starting materials.
eMixture of regioisomers.
fMagnetic catalyst without copper(II).
gWithout sodium ascorbate
To optimize the amount of the catalyst loading, the model reaction was repeated in the
presence of 1, 0.8 and 0.5 mol% of the catalyst under the optimized reaction conditions
(entries 6, 12 and 13)., It was demonstrated that useing 0.5 mol% of catalyst can effectively
catalyze the reaction in a short time with a reasonable yield (entry 13).
Having these optimized reaction conditions in hand, the scope of the reaction between
alkynes and alkyl halides was explored in the presence of sodium ascorbate and sodium
azide. According to the results shown in table 2, different alkyl halides (tosylates) can
participate effectively in this reaction under the defined conditions. In all cases, the rate of

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reactions for alkyl chlorides is lower than that of alkyl bromides/tosylates. However, alkyl
DOI: 10.1039/C4RA13330G
bromides and tosylates react with almost equal rates perhaps because of the fact that –Br and
–Ts are both good leaving groups and can be substituted by azide anion in the reaction
mechanism much better than –Cl.
Also, it can be concluded from table 2 that increasing the steric hindrance on alkyl halide
component causes lower reaction rates as can be realized by comparison of entries 2 and 15;
6 and 10; and 25 and 27. In the case of 1,2- dibromoethane as alkyl halide, the reaction was
proceeded from both sides of the chain and both Br atoms were participated in the reaction.
In general, the yields of the reactions in all cases were excellent and reactions were
completed in short reaction times. In the cases of alkynes with electron donor and acceptor
groups (entries 31- 33), the reactions were conducted with high yields and regioselectivity.
On the other hand, the reaction can be conducted using both linear (1-heptyne) and aromatic
(phenyl acetylene) alkynes; however, by using phenyl acetylene better results were obtained
in most cases.
Table 2. Huisgen 1,3-Dipolar Cycloaddition Catalyzed by [MNPs@FGly][Cl]a
Time
(h)
Yield
(%)b
Entry
1
Alkyne
Alkyl/Aryl halide
Product
2
3
99
97
98
2
3
2.5
2
3
97
96
4
5

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DOI: 10.1039/C4RA13330G
4.5
5
99
6
7
8
95
92
7
3.5
2.5
97
95
9
10
3
4
5
4
93
96
92
97
11
12
13
14
6
7
94
85
15
16
4.5
4
89
95
17
18

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3.5 DOI: 10.190349/C4RA13330G
19
20
Br
N
N
N
4
5
94
93
N
N
O
N
21
3
92
91
22
23
3.5
7
90
24
2
92
89
25
26
N
N
N
4.5
3
4
93
93
27
28
4
5
94
93
29
30
4
91
31

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DOI: 10.1039/C4RA13330G
5.5
4.5
90
32
33
N
N
N
O
95
NO2
a Reaction condition: alkyne (0.5 mmol), alkyl halide (0.5 mmol), NaN3 (0.5 mmol), sodium ascorbate
(10 mol%), Cu (0.5 mol%), solvent (H2O/ t-BuOH; 3/1), 55 °C.
bIsolated yield.
According to the results shown in table 2, all the reactions were proceeded with high
regioselectivity and in all cases, only the 1,4- regioisomers were obtained.
To check the reusability of the catalyst, the reaction of phenyl acetylene, benzyl bromide and
sodium azide was performed under the aforementioned optimized reaction conditions
(Scheme 1). After the first run, isolated yield of the reaction was measured exactly; then, the
catalysts were separated by using a magnet, washed twice with methanol and dried at room
temperature overnight. These recovered nanoparticles were reused in another run under the
same reaction condition. This process was repeated 10 times and each time the isolated yield
was calculated exactly. As is shown in Fig. 3 no significant decrease in reaction yield was
observed after repeated cycles of the reaction.
Fig. 3: Reuse of [MNPs@FGly][Cl] in the Huisgen reaction of phenyl acetylene and benzyl
bromide.

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AAS indicated taht there is no significant metal leaching even after 10 cycles of the reactVioiewnAsr.ticle Online
DOI: 10.1039/C4RA13330G
Having a reasonable comparison, reaction times were kept constant in all the experiments and
each reaction was stopped after 1h. The results shown in scheme 1 clearly indicate that the
catalytic efficiency of the catalyst remains almost constant during these cycles. Therefore,
according to these observations, the proposed catalytic system not only can catalyze the
cycloaddition of phenylacetylene to azides, but also can be easily separated and reused for
several times without any significant loss of activity.
Conclusion
Synthesis and application of [MNPs@FGly][Cl] in the 1,3-dipolar cycloaddition of phenyl
acetylene to azides was examined. This catalyst can catalyze the desired reactions with
excellent yields. Furthermore, due to its magnetic characteristic, separation of the catalyst is
easy using an external magnetic field; it can be totally removed from the reaction medium
and reused in another run. The stability of the nanoparticles to air, moisture and elevated
temperatures is very high and none of these parameters can cause its deactivation. In addition,
total removal of the copper-based catalyst from the reaction media makes it possible to use
the procedure in pharmaceuticals, drug discovery approaches and other sensitive synthetic
procedures. Some of the main advantages of the procedure include mild reaction conditions
(low reaction temperature, minimal workup and purification), very high functional group
tolerance, specificity and water tolerant nature of the reaction. The reaction under the defined
reaction conditions is caused to the desired triazoles with high regioelectivity in favor of 1,4-
regioisomer.

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DOI: 10.1039/C4RA13330G
Experimental
1. General data
All materials used are commercially available and were purchased from Merck and used
1
without any additional purification. H NMR and 13C NMR spectra were recorded on a
Bruker (Avance DRX-500) spectrometer using CDCl3 as solvent at room temperature.
Chemical shifts δ were reported in ppm relative to tetramethylsilane as an internal standard.
FTIR spectra of samples were taken using an ABB Bomem MB-100 FTIR
spectrophotometer. The morphology of the catalyst was observed using a Philips XL30
scanning electron microscope (SEM), transmission electron microscopy (TEM) images were
taken using a Philips CM30 electron microscope, thermogravimetric analysis (TGA) was
acquired under a nitrogen atmosphere with a TGA Q 50 thermogravimetric analyzer. CHN
analysis was done by LECO Truspec.
2. Synthesis of Fe3O4- silica coated nanoparticles
In a three necked flask, a solution of FeCl3 (66.58 mmol, 10.8 g) and FeCl2 (31.56 mmol, 4 g)
was prepared and diluted with deionized water (50 mL). In order for pH to reach 10, a
solution of ammonium hydroxide (28% v/v) was added drop wise to the solution under the
inert atmosphere of argon and the resulting solution was mechanically stirred at room
temperature for 20 min. The magnetic nanoparticles were collected employing an external
magnetic field using a magnet and washed with deionized water (30 mL) and ethanol (3×30
mL). The synthesized Fe3O4 nanoparticles were dispersed in ethanol (80 mL) with the aid of
ultrasonic waves for 20 min (ultrasonic power: 100 W). These magnetite nanoparticles were
used to synthesize the Fe3O4-Silica coated nanoparticles through the following procedure. In

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a round bottom flask 3 mL tetraethyl orthosilicate (TEOS) was slowly added to the solution.
DOI: 10.1039/C4RA13330G
Then, 3 mL ammonium hydroxide (28% v/v) was added to the mixture during a 15 min
interval while the solution was mechanically stirred. Stirring the mixture was continued for
further 12 h at 40°C. Finally, the magnetic nanoparticles coated with silica (Fe3O4@SiO2)
were collected using an external magnet and washed three times with ethanol (30 mL) and
dried under reduced pressure using a rotary evaporator.
3. Immobilization of 3-glycidoxypropyltrimethoxysilane on Fe3O4@SiO2
The synthesized magnetic nanoparticles of Fe3O4@SiO2 (2 g) were added to 10 mL of
toluene and sonicated for 30 min. Then, (11.32 mmol, 2.5 mL) of 3-
glycidoxypropyltrimethoxysilane was admixed to the above mixture while stirring and the
resulting mixture was refluxed for 48 h. The final product was washed with methanol (3×30
mL) and dried under reduced pressure using rotary evaporator.
4. Synthesis of (MNPs@FGly)[Cl]
In a round bottom flask equipped with a magnetic stirring bar, sodium azide (22.7 mmol, 1.5
g), copper (II) chloride (0.74 mmol, 0.1 g) and sodium ascorbate (0.76 mmol, 0.15 g) were
dissolved in a mixture of THF/water (80/20). Afterward, the modified magnetic nanoparticles
(1 g) and phenyl acetylene (18.2 mmol, 2 mL) were added, respectively. The mixture was
stirred and heated at 60 ˚C for 10 h. The final product was extracted by an external magnet,
washed with methanol three times (3×20 mL) and dried under reduced pressure.
5. General procedure for the synthesis of triazole
A glass tube was charged with sodium ascorbate (30 mg, 10 mol%), phenyl acetylene (0.5
mmol, 0.055 mmol), benzylbromide (0.5 mmol, 0.06 mL), sodium azide (0.5 mmol, 0.032 g),
catalyst (5 mg, 0.5mol%) and H2O/t-BuOH with 3/1 ratio (3 mL). The reaction mixture was
stirred at 55 ˚C for 4 h and the completion of the reaction was monitored by TLC (EtOAc/ n-
hexane, 25:75). In each case, after completion, the product was worked up and purified

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according to the following procedure: The mixture was diluted with ethyl acetate and water.
DOI: 10.1039/C4RA13330G
The organic layer was washed with brine, dried over MgSO4 and concentrated under reduced
pressure using a rotary evaporator. The residue was purified by recrystallization from ethyl
acetate/ n-hexane. In order to reuse the catalyst, the nanomagnetic Cu catalyst was collected
using an external magnet, washed with methanol and dried overnight to be ready for the next
run.
Acknowledgments
We gratefully acknowledge the funding support received for this project from the Sharif
University of Technology (SUT), Islamic Republic of Iran.
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DOI: 10.1039/C4RA13330G