Copper on chitosan: A recyclable heterogeneous catalyst for azide-alkyne cycloaddition reactions in water

Article abstract of DOI:10.1039/c3gc40401c

Copper sulfate has been immobilized over chitosan by simply stirring an aqueous suspension of chitosan in water with copper sulfate; the ensuing catalyst has been utilized for the azide-alkyne cycloaddition in aqueous media and it can be recycled and reus

Full text of DOI:10.1039/c3gc40401c

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Copper on Chitosan: recyclable heterogeneous catalyst for azide-alkyne
cycloaddition reactions in water
R. B. Nasir Baig and Rajender S. Varma*
Abstract
Copper sulfate has been immobilized over chitosan by simply stirring an aqueous suspension of
chitosan in water with copper sulfate; the ensuing catalyst has been utilized for the azide-alkyne
cycloaddition in aqueous media and it can be recycled and reused many time without loosing its
activity.
Introduction
Enhanced environmental consciousness has promoted the efficiency of chemical reactions under
benign conditions with recycling and reuse of the catalysts, a trait that has become an integral
part of chemical research today.1-5 Immobilization of catalysts on solid supports is one of the best
methods to improve the efficiency and recycling catalysts;6-9 many solid supported catalysts have
been successfully utilized for catalytic applications.9, 10 Most commonly used solid supports
involve silica,11 zeolites,12-18 magnetic-materials,19-24 and soluble and insoluble polymers.8, 25, 26
In addition to these, some of the heterogeneous polymers are used for the removal of trace
metals.27-34 During the course of studies in our laboratories, the efficiency of chitosan as a
support and its ability to remove the copper from the aqueous medium is found to be very
impressive.
In modern drug research, a plethora of active organic molecules was required to be evaluated in a
short period of time. That is why simple methods that can easily generate large libraries of
compounds are emerging. Click chemistry is one of these methods based on reactions, which are
of wider scope, gives high yields, and forms irreversible carbon-heteroatom and carbon-carbon
bonds; the Huisgen 1,3-dipolar cycloaddition has become one of the most important reactions in
history.35-44 It involves the ligation of azides and terminal alkynes to generate triazoles and
usually entails the use of a copper salt in conjunction with a base. The catalyst could be Cu(I)
salt or Cu(I) generated in situ by the reduction of Cu(II) salts, usually in organo-aqueous media.
Engaged in the development of sustainable benign pathways for organic transformations,
nanomaterials, and nano-catalysis,45, 46 we decided to explore the use of copper deposited over
chitosan for such catalytic application. Chitosan is better known for metal extraction,47-52 their
applications as a catalytic support are rather sparse.53-55 Xia et al. have used chitosan-Schiff base
copper(II) complex as a catalyst for the cyclopropanation of styrene with ethyl diazoacetate.56
Taran and coworkers have synthesized a variety of chitosan schiff base-copper(I) triflate
complexes and demonstrated their application for Huisgen cycloaddition.57 Herein, we report a
simple and efficient synthesis of a chitosan-supported, recyclable, and inexpensive copper
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catalyst and its application in Huisgen 1, 3-dipolar cycloaddition reactions; 1,2,3-triazoles are
obtained in aqueous media at room temperature.
______________________________________________________________________________
Sustainable Technology Division, National Risk Management Research Laboratory, U. S.
Environmental Protection Agency, MS 443, Cincinnati, Ohio 45268, USA. Fax: 513- 569-7677;
Tel: 513-487-2701. E-mail: varma.rajender@.epa.gov
Results and Discussion
The first step in the accomplishment of this goal was the immobilization of copper over chitosan.
The catalyst was prepared by suspending chitosan in an aqueous solution of copper sulfate
(CuSO4) for 3 h under neutral conditions. Material with CuSO4 on chitosan was separated using
o
centrifuge and dried under vacuum at 50 C for 8 hours. Catalyst characterization was
accomplished by X-ray diffraction (XRD) (Fig. 1b) and SEM (Fig.1 a). The signals pertaining to
copper metal were not detected in XRD, presumably due to its complexation with chitosan or its
low percentage amount. The weight percentage of copper was found to be 5.1 wt % by
inductively coupled plasma-atomic emission spectroscopy (ICP-AES) analysis.
The experiments began with the intention of optimizing the reaction conditions for dipolar
cycloaddition of benzyl azide and phenylacetylene. Greener conditions were selected to study the
reaction; benign water was used as the solvent at room temperature (Scheme 1). The results
were very encouraging as the reaction was completed in 4 h and provided quantitative yield of
the desired product. Progress of the reaction could be monitored visually as the product
crystallized out from the aqueous reaction media (Figure 2). In order to optimize the reaction
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conditions, we have performed the reaction using varied quantities of the catalyst. There was no
difference in yield and reaction time when catalyst loading was reduced to 15 mg, 10 mg and 5
mg. However, it took longer time for completion of the reaction (12 h) when 2 mg of the catalyst
was used. Consequently, we decided to use 5 mg of the catalyst for further studies.
N3
N N
Chit-CuSO4
H2O, rt, 4 h
+
N
~100%
Scheme 1 Chit-CuSO4, catalysed dipolar cycloaddtion of benzyl azide and phenyl acetylene
Figure 2 Reaction mixture before and after completion of the reaction
After establishment of the optimum conditions for the cycloaddition of benzyl azide and phenyl
acetylene, its scope as a catalyst for the Huisgen [3 + 2]-cycloaddition reactions was explored. A
variety of benzyl azides were treated with acetylenes using Chit-CuSO4 catalyst in water at
ambient condition (Table 1); most of the reactions were completed within 4-6 hours to give high
yields of the corresponding 1,4 triazoles. The substituent’s (electron withdrawing, electron rich,
and heterocycle) do not have any peculiar effect, as most of the reactions were completed within
4-6 h. However, an aliphatic azide took 12 h for the formation of triazole (entry 17, Table 1).
The catalyst was not much effective for aliphatic alkynes (Table 1, entry 18); reaction was very
slow and we could isolate less than 12 % of product after overnight (12 h) stirring.
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Table 1. Click chemistry using Chit-CuSO4 catalyst
Yieldb
99%
Entry
Alkyl halide
N3
Alkyne
Times
Producta
N
N
Ph
1
N
4h
N
N
N
Ph
N3
N3
2
3
4h
4h
99%
99%
N
N
N
Ph
MeO
OMe
N
N
Ph
N3
N3
4
5
N
Cl
6h
6h
98%
97%
Cl
N
N
N
Ph
Ph
OHC
CHO
N
N
N
N
N3
6
O2N
6h
95%
NO2
N
Ph
O2N
N3
N3
N3
N
7
8
N
6h
6h
96%
94%
N
O2N
O2N
N
N
N
O2N
F
N
9
N
N
6h
6h
6h
96%
97%
94%
N
N3
N3
N
10
11
N
F
O2N
O2N
N
N
N
O2N
N3
N3
N
12
13
N
N
6h
6h
96%
98%
O2N
F
N
N
N
F
O2N
O2N
N3
N3
14
15
N
O
O
6h
6h
96%
96%
N
N
O
O2N
F
N
N
N
O
O2N
F
N
N3
N
16
O
6h
98%
O
N
N
N
17
18
12h
12h
93%
12%
N3
N3
N
N
N
N
Ph
a) Reaction conditions: 1.2 mmol of alkyl azide, 1.0 mmol of alkyne, 5 mg of Chit-Copper catalyst, H2O, rt;
b) Isolated yield; c) Product were charectorized using NMR and compared with the reported data.
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For the practical applications of such heterogeneous systems, the lifetime of the catalyst and its
level of reusability are very significant factors. To clarify this issue, a set of experiments were
performed for the cycloaddition of benzyl azide and phenylacetylene using the recycled Chit-
CuSO4 catalyst. After the completion of the first reaction, the product was extracted using ethyl
acetate and the catalyst was recovered by simple decantation and dried at 50 ◦C. A fresh reaction
was then performed with new reactants, under the same conditions. We have also performed
recycling experiments using 5 mmol of reagents (Table 2, entry 6-10). After 1h, the reaction was
stopped, the catalyst recovered and reused for the next cycle thus making it is clear that the Chit-
CuSO4 catalyst could be reused at least 5 times without any change in its activity.
Table 2 Recycling of Chit-CuSO4 catalyst
Chit-CuSO4, 5 mg
N
N
N3
+
N
H2O, rt, 4 h
No of cycles
Yield
1
2
3
>99%
>99%
>95%
4
5
6
7
>97%
>97%
>28%a
>29%a
>29%a
>28%a
8
9
>28%a
10
a) Recycling experiments were performed using 5 mmol of reagents for 1 h
Metal leaching was studied by ICP-AES analysis of the catalyst before and after the 5th reaction
cycle. The Cu concentration was found to be 5.1 % before reaction and 5.02 % after the reaction.
The SEM image of the catalyst taken after the 5th cycle of the reaction did not show significant
change in the morphology (Fig. 3), which indicates the retention of the catalytic activity after
recycling. No Cu metal was detected in the reaction solvent (water) after completion of the
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reaction. This confirms the fact that chitosan provides enough binding sites on the surface to
minimize deterioration and metal leaching and facilitates efficient catalyst recycling.
Figure 3 SEM image of the Chit-CuSO4 catalyst after the reaction.
Conclusions
Copper sulfate immobilized on chitosan, Chit-Cu catalyst, has been utilized for the azide-alkyne
cycloaddition reactions in aqueous media at ambient temperature. In general, the reaction can be
monitored visually as the desired product crystallizes out from the aqueous reaction media. Most
of the reactions proceed faster with the exception of the aliphatic azide and alkyne substrates.
The catalyst can be recycled and reused many times without losing its activity. Further
investigations using this catalyst system are under investigation.
Experimental procedure:
Experimental procedure for synthesis of Chitosan copper catalyst (Chit-CuSO4):
Chitosan (5 g, medium molecular weight, Aldrich, CSA # 9012-76-4) was suspended in 100 mL
of water. To this suspension, 1 g of CuSO4.5H2O was added and stirring was continued for 2h.
The catalyst was separated using centrifuge (5000 rpm 5 min), dried under vacuum at 50 oC. The
catalyst was characterized by X-ray diffraction (XRD) (Fig 1b, MS) and using SEM (Fig.1 a,
MS). The signals pertaining to copper metal were not detected in XRD; it may be due to
complexation with chitosan or low percentage. The weight percentage of copper was found to be
5.1 % by inductively coupled plasma-atomic emission spectroscopy (ICP-AES) analysis.
Synthesis of triazole from alkyl azide and alkyne
1.2 mmol of alkyl azide, 1.0 mmol of alkyne and 5 mg of Chit-CuSO4 catalyst were placed in a
reaction tube. To this 5 mL of water and a stirring bar was added. The reaction tube was placed
on a magnetic stirrer and stirs the reaction mixture for 4-12 h at room temperature. After the
completion of the reaction, product was separated using ethyl acetate extraction and catalyst by
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centrifuge (5000 rpm, 5 min). The products were purified by re-crystallization or column
chromatography. The recovered catalyst was dried and reused at least five times without losing
its activity.
Acknowledgements
Nasir Baig was supported by the Postgraduate Research Program at the National Risk
Management Research Laboratory administered by the Oak Ridge Institute for Science and
Education through an interagency agreement between the U.S. Department of Energy and the
U.S. Environmental Protection Agency. We thank Dr. Jiahui Kou for recording SEM image and .
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