A highly active magnetically recoverable nano ferrite-glutathione-copper (nano-FGT-Cu) catalyst for Huisgen 1,3-dipolar cycloadditions

Article abstract of DOI:10.1039/c2gc16301b

1,2,3-Triazoles were synthesized in water using magnetically recoverable heterogeneous Cu catalyst via one-pot multi component reaction using MW irradiation. Aqueous reaction medium, easy recovery of the catalyst using an external magnet, efficient recycl

Full text of DOI:10.1039/c2gc16301b

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PAPER
A highly active magnetically recoverable nano ferrite-glutathione-copper
nano-FGT-Cu) catalyst for Huisgen 1,3-dipolar cycloadditions†
(
R. B. Nasir Baig and Rajender S. Varma*
Received 18th October 2011, Accepted 25th November 2011
DOI: 10.1039/c2gc16301b
1
,2,3-Triazoles were synthesized in water using magnetically recoverable heterogeneous Cu catalyst via
one-pot multi component reaction using MW irradiation. Aqueous reaction medium, easy recovery of the
catalyst using an external magnet, efficient recycling, and the high stability of the catalyst renders the
protocol economic and sustainable.
Introduction
which an active component is dispersed or attached. Although
attempts have been made to make all active sites on solid sup-
ports accessible for reaction (allowing rates and selectivities
comparable to those obtained with homogeneous catalysts) only
sites on the surface are available for catalysis, which decreases
the overall reactivity of the catalyst system.
A homogeneous catalyst, where the catalyst is in the same phase
as the reactants, is generally accepted by chemists. One attrac-
1
tive property is that all catalytic sites are accessible because the
catalyst is generally a soluble metal complex where it is possible
to tune the chemo-, regio- and enantioselectivity of the catalyst.
Homogeneous catalysts have a number of other advantages such
as high selectivity, better yield, and easy optimization of catalytic
systems by modification of ligand and metals. They are used in a
number of commercial applications, but the difficulty of catalyst
separation from the final product creates economic and environ-
mental barriers to broadening their scope thus restricting their
wide use in a number of applications. Removal of trace amounts
of catalyst from the end product is essential since metal contami-
nation is highly regulated, especially by the pharmaceutical
industry. Even with the extensive and careful use of various
techniques such as distillation, chromatography, or extraction,
removal of trace amounts of catalyst remains a challenge.
Recently, functionalized magnetic nanoparticles have emerged
as viable alternatives to conventional materials, as robust, readily
4
available, high-surface-area heterogeneous catalyst supports.
They offer an added advantage of being magnetically separable,
thereby eliminating the requirement of catalyst filtration after
completion of the reaction. Engaged in the development of
5
greener and sustainable pathways for organic transformations,
6
7
nanomaterials, and nano-catalysis, herein, we report a simple
and efficient synthesis of a nano-ferrite-supported, magnetically
recyclable, and inexpensive Cu catalyst and its application in
Huisgen 1,3-dipolar cycloaddition reactions to synthesize 1,2,3-
triazoles via one of the most powerful click reactions. Several
members of the 1,2,3-triazole family have shown interesting bio-
8
9
To overcome these drawbacks, chemists and engineers have
investigated a wide range of strategies; the use of heterogeneous
logical properties, such as anti-allergic, anti-bacterial, and anti-
10
HIV activity. Additionally, 1,2,3-triazoles are found in fungi-
cides, herbicides, and dyes. The recently discovered copper(I)
2
11
catalyst systems appears to be the best logical solution. The
12
majority of the novel heterogenized catalysts are based on silica
supports, primarily because silica displays some advantageous
properties, such as excellent chemical and thermal stability, good
accessibility, porosity, and the fact that organic groups can be
catalysis of this transformation, which accelerates the reaction
up to 107 times, has placed it in a class of its own and has
enabled many novel applications. To further improve the utility
and user-friendliness of this process, a practical multi component
variant was developed. At the outset of this study, no example of
in situ azide generation-cycloaddition-magnetic nanoparticle-
supported Cu catalysts had been reported for cycloaddition reac-
tion, despite the potential inherent stability and activity of such
materials.
3
robustly anchored to the surface to provide catalytic centers.
The common structural feature of these materials is the anchor-
ing of the catalytic molecule (dopant) in the pores of silica, a
phenomenon that imparts unique chemical and physical proper-
ties to the resulting hybrid silica. A vast majority of the indus-
trial, heterogeneous catalysts are high-surface area solids onto
The first step in the accomplishment of this goal was the
synthesis and functionalization of magnetic nanoparticles
(Scheme 1). The catalyst was prepared by sonicating nano-fer-
Sustainable Technology Division, National Risk Management Research
Laboratory, U. S. Environmental Protection Agency, MS 443,
Cincinnati, Ohio 45268, USA. E-mail: varma.rajender@.epa.gov;
Fax: 513-569-7677; Tel: 513-487-2701
rites with glutathione in water for 2 h, followed by the addition
of CuCl chloride at a basic pH. Material with Cu nanoparticles
2
on the glutathione functionalized nano-ferrites was separated
using an external magnet, washed with water followed by
methanol and dried under vacuum at 60 °C for 8 h. Catalyst
†
Electronic supplementary information (ESI) available: See DOI:
0.1039/c2gc16301b
1
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Scheme 1 Nano ferrite supported glutathione-copper (nano-FGT-Cu) catalyst.
characterization by X-ray diffraction (XRD) (Fig. 1b and d) and
Table 1 Screening of magnetic nano-catalysts
transmission electron microscopy (TEM) (Fig. 1a and c) confirm
Entry
Catalyst
Fe
Time
Yield
Selectivity
the formation of single-phase Fe O nanoparticles, with spheri-
3
4
cal morphology of nano FGT-Cu catalysis and a size range of
0–25 nm. FT-IR confirms the anchoring of glutathione on
1
2
3
4
3
O
4
10 min
10 min
10 min
10 min
20%
20%
80%
99%
1 : 1
1 : 1
3 : 1
100 : 0
1
F O -Glut
3
4
7g
Fe
3
O
4
-Cu
ferrite surfaces. The signals pertaining to copper metal were
not detected in XRD, indicating that the Cu species is highly dis-
persed on ferrites. The weight percentage of copper was found to
be 1.57% by inductively coupled plasma-atomic emission spec-
troscopy (ICP-AES) analysis.
nano-FGT-Cu
Initially, experiments were performed to optimize the reaction
condition for cycloaddition of benzyl azide and phenylacetylene
in aqueous media. First, the reaction was conducted using nano-
Fe O and nano-Fe O -glutathione (nano-FGT) in water under
3
4
3 4
microwave irradiation (MW) at 120 °C, which furnished 1,4 and
,5 cyclic adducts in 20% of yield and in 1 : 1 ratio (Scheme 2,
Scheme 2 Screening of magnetic nano-catalysts for benzyl azide and
phenyl acetylene cycloaddition.
1
Table 1). In order to develop magnetically recoverable catalyst
for regio-selective cycloaddition of alkynes and azides, the reac-
1
3
tion of iron oxide with Cu(0) at it surface i.e. using nano-
Fe O -Cu bimetallic catalyst was performed. Though the rate of
immobilizing Cu(0) on nano-FGT surface (see Scheme 1) with
particle size, 10–25 nm, and tested for cycloaddition of benzyl
azide and phenyl acetylene. A very selective formation of 1,4
adduct in quantitative yield was observed (Scheme 2, Table 1).
After identifying the active nano magnetic catalyst, its role as
a catalyst was then explored for the Huisgen [3 + 2]-
3
4
reaction improved and 80% conversion was observed (10 min,
MW, 120 °C, H O), the selectivity of the reaction was poor
3 : 1). In order to develop a highly active magnetically recover-
able catalyst, nano-FGT-Cu catalyst was then prepared by
2
(
626 | Green Chem., 2012, 14, 625–632
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Fig. 1 (a) TEM of Fe
FGT-Cu.
3
O
4
-glutathione (nano-FGT), (b) XRD of Fe
3
O
4
-glutathione (nano-FGT), (c) TEM of nano-FGT-Cu, (d) XRD of nano-
cycloaddition. Initially, the reactions of benzyl azide with a
variety of alkynes under MW in water were examined (120 °C,
component reaction, the products formed from the reaction of
benzyl bromide and phenyl acetylene were compared (Table 3,
entry 1) with an authentic sample. It was established that the tria-
zole was formed in a completely regio-selective manner, with no
contamination by the 1,5-regioisomer. In almost all cases, the
reactions proceeded smoothly to completion within 10 min, and
the products were isolated in excellent yields and high purity
(Table 3). The 4-bromo butene (Table 3, entry 13) was found to
be less reactive among other halides. However, the reaction was
completed (as analyzed by TLC) within 15 min. In the case of
alkynes, the reactions were over in 10 min except for the reaction
of p-nitro phenylacetylene (Table 3, entry 6) which required
15 min. Presence of most of the functional groups (CHO, NO2,
halides, OMe etc.) and hetero ring in either of the substrate did
not affect the product formation in the one-pot treatment of alkyl
halides, alkynes and sodium azide with catalyst except for the
reaction of 2-amino phenylacetylene (Table 3, entry 12) which
gave the complex mixture of products. It is believed that the free
amine may react with benzyl bromide along with sodium azide,
which leads to the formation of multiple products. In order to
synthesize the corresponding triazole with a free amine group,
some changes were made in the sequence of addition of the reac-
MW, H O). MW-assisted chemistry was used due to the
2
efficiency of the interaction of microwaves with the polar nano-
catalyst as they allow rapid heating of the reaction mixture to
1
4,15
required temperatures with precise control.
The expeditious
reaction was completed within 8 min to give very high yields of
the corresponding 1,4 triazoles. In the case of a highly electron
withdrawing group present in the alkynes (entry 3, Table 2), the
rate of reaction was found to be relatively slow and required
1
1
2 min for completion whereas in all of the other cases (entry
–2, 4–6, Table 2) the reaction was completed within 8 min.
Inspired by the preliminary results, further studies were
embarked on to make the reaction greener and more sustainable.
It was decided to perform this reaction in one-pot via in situ
azide generation followed by cycloaddition using magnetically
separable nano-FGT-Cu catalyst. At the starting point of the
exploration, alkyl halides, aromatic alkynes, and sodium azide
were suspended in water, together with nano-FGT-Cu catalyst
(Scheme 3), in a 10 mL sealed glass tube. After 10–15 min of
irradiation and subsequent cooling to room temperature the cata-
lyst was separated magnetically. Very often the triazole product
solidified from the reaction mixture, was isolated by simple fil-
tration, and purified by crystallization or by using a short column
tants. First, benzyl bromide (1.2 mmol) with NaN (1.5 mmol)
3
were treated in water, irradiated in a MW oven for 4 min at
120 °C followed by the addition of 2-amino phenylacetylene
(Table 3). In order to check the regio-selectivity of multi-
(1.0 mmol) and further subjected to MW irradiation for another
8
min. The reaction proceeded very cleanly and furnished the
corresponding triazole in 87% of yield (Table 3, entry 12).
To further demonstrate the general applicability and versatility
of nano-FGT-Cu catalyst, the mixture of benzyl bromide,
sodium azide and aliphatic alkynes and catalyst (Table 4) were
Scheme 3 Synthesis of triazoles via one-pot multi-component
reaction.
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Table 2 Reaction of benzyl azide with alkynes catalyzed by magnetic nano-FGT-Cu catalyst
a
Entry
1
Alkyl halide
Alkyne
Time
Product
Yield
8 min
99%
97%
86%
98%
94%
95%
2
3
4
5
6
8 min
12 min
8 min
8 min
8 min
a
Reaction conditions: 1.2 mmol of benzyl azide, 1.0 mmol of alkyne, 100 mg of nano-FGT-Cu catalyst. MW, 120 °C, power 100 Watt.
irradiated in water. In all of the cases (Table 4, entries 1–3), the
reactions proceeded smoothly at 120 °C and required 12 min to
afford the desired triazoles. In the case of ethyl propionate
solvent after the completion reaction no Cu metal was detected.
This confirms the fact that glutathione provides enough binding
sites on the surface of Fe O nanoparticles to serve as a pseudo-
3
4
(Table 4, entry 4), the reaction gives a mixture of products. To
ligand for anchoring Cu. This minimizes deterioration and metal
minimize the formation of by-products the reaction temperature
was reduced to 80 °C which led to an increase in the reaction
time to 20 min (Table 4, entry 4) and furnished the correspond-
ing triazole in 85% yield.
leaching and facilitates efficient catalyst recycling.
Conclusion
For practical applications of such heterogeneous systems, the
lifetime of the catalyst and its level of reusability are very signifi-
cant factors. To clarify this issue, a set of experiments was estab-
lished for the cycloaddition of benzyl azide and phenyacetylene
using the recycled nano-FGT-Cu catalyst. After the completion
of the first reaction, the catalyst was recovered magnetically,
washed with methanol, and dried at 60 °C for 30 min. A new
reaction was then performed with fresh reactants, under the same
conditions. The nano-ferrite-supported Cu catalyst could be
reused at least three times without any change in activity
In conclusion, a very efficient, sustainable and green procedure
for azide-alkynes-cycloaddition (AAC) has been developed
using a magnetically separable and easily recyclable hetero-
geneous Cu catalyst in water under microwave irradiation con-
ditions. Easy magnetic separation of the catalyst eliminates the
requirement of catalyst filtration after completion of the reaction,
which is an additional green attribute of this reaction. To the best
of the author’s knowledge, this is an unprecedented example of
azide alkynes cycloaddition using magnetic recoverable hetero-
geneous copper catalyst in water.
(Table 5).
Metal leaching was studied by ICP-AES analysis of the cata-
lyst before and after the three reactions. The Cu content in the
nanoparticle was found to be 1.57% before the reaction and
Experimental
Synthesis of magnetic nano-ferrites
1
.55% after the reaction. The TEM image of the catalyst taken
after the third cycle of the reaction did not show significant
change in the morphology or in the size of the catalyst nanoparti-
cles (10–25 nm) (Fig. 2), which correlates with retention of cata-
lytic activity after recycling. The ICP-AES analysis of reaction
FeSO ·7H O (13.9 g) and Fe (SO ) (20 g) were dissolved in
4
2
2
4 3
500 mL water in a 1000 mL beaker. Ammonium hydroxide
(25%) was added slowly to adjust the pH of the solution to 10.
The reaction mixture was then continually stirred for 1 h at
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Table 3 Synthesis of triazoles via one-pot multi component reaction catalyzed by magnetic nano-FGT-Cu catalyst
a
Entry
1
Alkyl halide
Alkyne
Time
Product
Yield
10 min
94%
94%
92%
88%
86%
80%
90%
87%
2
3
4
5
6
7
8
10 min
10 min
10 min
10 min
15 min
10 min
10 min
9
10 min
10 min
89%
92%
1
0
1
1
10 min
10 min
89%
b
1
2
3
87%
1
15 min
91%
a
3
Reaction conditions: 1.2 mmol of alkyl halides, 1.5 mmol of NaN , 1.0 mmol of alkyne, 100 mg of Nano-FGT-Cu catalyst. MW, 120 °C, Power 100
b
Watt. i) Reaction conditions: 1.2 mmol of benzyl bromide, 1.5 mmol of NaN
of Nano-FGT-Cu catalyst. MW, 8 min, 120 °C, Power 100 Watt.
3
, MW, 4 min, 120 °C, Power 100 Watt. ii) 1.0 mmol of alkyne, 100 mg
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Table 4 Synthesis of triazoles using aliphatic alkynes catalyzed by nano-FGT-Cu
a
Entry
1
Alkyl halide
Alkyne
Time
Product
Yield
12 min
92%
84%
89%
2
3
4
12 min
12 min
20 min
b
85%
a
3
Reaction conditions: 1.2 mmol of benzyl bromide, 1.5 mmol of NaN , 1.0 mmol of alkyne, 100 mg of nano-FGT-Cu catalyst. MW, 120 °C, power
b
1
2
00 Watt. Reaction conditions: 1.2 mmol of benzyl bromide, 1.5 mmol of NaN
0 min, 80 °C, power 100 Watt.
3
, 1.0 mmol of alkyne, 100 mg of nano-FGT-Cu catalyst. MW,
Table 5 Recycling of catalyst
Number of cycles
Yield
1
2
3
99%
97%
98%
(
TEM). This magnetic nano-ferrite (Fe O ) was then used for
3 4
further chemical modification.
Surface modification of nano-ferrites
Nano-Fe O (0.5 g) was dispersed in water (15 mL) and metha-
3
4
nol (5 mL) and sonicated for 15 min. Glutathione (reduced form)
0.2 g) dissolved in water (5 mL) was added to this solution
(
and again sonicated for 2 h. The glutathione-functionalized
nanomaterial (nano-organocatalyst) was then isolated by cen-
trifugation, washed with water and methanol, and dried under
vacuum at 50–60 °C.
Synthesis of nano-FGT-Cu, catalyst
Fig. 2 TEM image after recycling of the catalyst.
Glutathione-functionalized nano-Fe O (1 gm) was dispersed in
3
4
water-methanol mixture (1 : 1). CuCl ·2H O (100 mg) solution
2
2
in water was added to the reaction mixture. Hydrazine monohy-
drate solution in water was added drop wise to bring the pH of
this mixture to 9, followed by the addition of 0.1 gm of NaBH4.
The reaction mixture was then stirred for 24 h at room tempera-
ture. The product was allowed to settle, washed several times
6
0 °C. The precipitated nanoparticles were separated magneti-
cally, washed with water until the pH reached 7, and then dried
under vacuum at 60 °C for 2 h. Ferrite was characterized by X-
ray diffraction (XRD) and transmission electron microscopy
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with water and acetone, and dried under vacuum at 60 °C for
h. Catalyst characterization by X-ray diffraction (XRD)
Fig. 1d) and transmission electron microscopy (TEM) (Fig. 1c)
thank Dr Douglas Young for reading the manuscript and for pro-
viding valuable comments.
2
(
confirm the anchoring of Cu nanoparticles on ferrite surfaces.
The weight percentage of Cu in the catalyst was found to be
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Benzyl azide (1.2 mmol), alkyne (1.0 mmol) and nano-FGT-Cu
catalyst (100 mg) were placed in a crimp-sealed thick-walled
glass tube equipped with a pressure sensor and a magnetic
stirrer. Water (4 mL) was added to the reaction mixture. The reac-
tion tube was placed inside the cavity of a CEM Discover
focused microwave synthesis system, operated at 120 °C (temp-
erature monitored by a built-in infrared sensor), 100 Watts and
3
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1
0–60 psi for 8–12 min (Table 2). After completion of the reac-
tion, the catalyst was easily removed from reaction mixture using
an external magnet. After separation of catalyst, the solid
product was filtered off or extracted with ethyl acetate and
recrystallized.
(
4
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(
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7
3, 7417; (e) V. Polshettiwar and R. S. Varma, J. Org. Chem., 2007, 72,
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3
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tion mixture. The reaction tube was placed inside the cavity of a
CEM Discover focused microwave synthesis system, operated at
6
7
(
(
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1
1
20 °C (temperature monitored by a built-in infrared sensor),
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2
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completion of the reaction, the catalyst was easily removed from
reaction mixture using an external magnet. After separation of
catalyst the solid product was filtered off or extracted with ethyl
acetate and recrystallized or purified by column chromatography.
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(
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(
except Table 3 entry 5) and were identified by comparison of
1
13
16
their FT-IR, H, and C NMR with literature data. The charac-
terization data for a representative compound, Table 3, entry 5 is
given below.
1540.
8
9
(a) D. R. Buckle and C. J. M. Rockell, J. Chem. Soc., Perkin Trans. 1,
1982, 627; (b) D. R. Buckle, D. J. Outred, C. J. M. Rockell, H. Smith
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4
-(1-Benzyl-1H-1, 2, 3-triazol-4-yl)benzaldehyde (Table 3
−1
entry 5). White solid, Yield 86%, FT-IR (cm ): 3130(w), 2839
2269.
(
(
m), 1690(s), 1608(s), 1572(m), 1305(m), 1213(s), 1171(s), 834
M. J. Genin, D. A. Allwine, D. J. Anderson, M. R. Barbachyn,
D. E. Emmert, S. A. Garmon, D. R. Graber, K. C. Grega, J. B. Hester, D.
K. Hutchinson, J. Morris, R. J. Reischer, C. W. Ford, G. E. Zurenko, J.
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2000, 43, 953.
1
s), 810(s), 720(s), 701(s), 680(s); H NMR (300 MHz; CDCl )
3
δ : 9.98(1H, s), 7.97–7.82(6H, m), 7.38–7.33(4H, m), 5.59 (2H,
H
1
3
s); C NMR (75 MHz; CDCl ) δ : 191.68, 146.86, 136.33,
3
C
1
5
1
35.76, 134.36, 130.34, 129.24, 128.95, 128.14, 126.01, 120.81,
4.37, Analysis calculated for C H N O: C 72.99, H 4.98, N
5.96; Found: C 72.97, H 4.96, N 15.98.
10 R. Alvarez, S. Velazquez, A. San-Felix, S. Aquaro, E. De Clercq,
C. F. Perno, A. Karlsson, J. Balzariniand and M. J. Camarasa, J. Med.
Chem., 1994, 37, 4185.
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