Metallic copper wire: a simple, clear and reusable catalyst for the CuAAC reaction in supercritical carbon dioxide

Article abstract of DOI:10.1039/c5ra11797f

An efficient protocol for the CuAAC reaction catalyzed by metallic copper wire for the synthesis of 1,4-disubstituted triazoles has been developed in supercritical carbon dioxide (scCO₂) at 50 °C. The protocol could afford the corresponding pro

Full text of DOI:10.1039/c5ra11797f

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Metallic Copper Wire-A Simple, Clear and Reusable Catalyst for the CuAAC Reaction
in Supercritical Carbon Dioxide
Yuqin Jiang*, Xing He, Weiwei Zhang, Xingfeng Li, Niu Guo, Yaru Zhao, Guiqing Xu* and Wei
Li
Henan Engineering Laboratory of Chemical Pharmaceuticals & Biomedical Materials,
Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals,
Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, School of
Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, P. R. China.
Eꢀmail: jiangyuqin@htu.cn
An efficient protocol for the CuAAC reaction catalyzed by metallic copper wire for the
synthesis of 1,4ꢀdisubstituted triazoles has been developed in supercritical carbon dioxide (scCO2)
at 50 ºC. The protocol could afford the corresponding products in excellent yield with a very easy
workꢀup procedure. The metallic copper wire could be reused for more than 200 runs without
decreasing the catalytic efficiency.
Introduction
The 1,3ꢀdipolar cycloaddition reaction of azides and alkynes has been studied extensively by
Huisgen and coworkers in the 1960s.1 It again attracts much attentions due to the fact
independently discovered by the groups of Sharpless2 and Meldal3 that the copper catalysis could
increase its reaction rate by up to 107 and give in regioselective formation of 1,4ꢀdisubstituted
1,2,3ꢀtriazoles. The copper(I)ꢀcatalyzed azideꢀalkyne cycloaddition (CuAAC) reaction is generally
considered as the most striking example of click chemistry,4 which has emerged as a prominent
organic transformation.
The sources of the catalytic copper(I) ion for CuAAC reaction usually are Cu(I) salts or their
complexes,5 Cu(II) salts together with a reducing agent.2, 6 Since it is reported that the metallic
copper could be an alternative catalytic source for CuAAC reaction, the reaction exploiting
metallic copper as the catalyst is attractive because of much easier workꢀup and purification. The
early examples using metallic copper as the catalyst for CuAAC reaction in tertꢀbutyl
alcohol/water mixture were reported by Valey V. Fokin6 and Paul Knochel7 in 2005. Although it
was taken more than 24 h to complete the reaction, the CuAAC reaction could proceed
successfully. For shortening the reaction time, nanosized metallic copper particles were used as
the catalyst, which could greatly accelerate the CuAAC reaction rate due to their lager surface
areas.8ꢀ12 Owing to the aggregation behavior of metallic copper nanopartilcles,
poly(Nꢀvinylꢀ2ꢀpyrrolidone) (PVP) protected13 or supported copper nanoparticles14ꢀ16 were
prepared and used as the reusable catalyst. The nanosized metallic copper particles mentioned
above have limitation of applications due to their complicated and highꢀcost preparation.
Furthermore, copper nanoparticles in situ generated could also act as efficient nanocatalysts for
CuAAC reactions17ꢀ19 and physical technique such as ultrasound irradiation was also used to
accelerate the reaction when catalyzed by metallic copper.20, 21

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Traditional organic solvents could potentially cause various health and environmental concerns
due to their volatility and toxicity. In recently, considerable attentions have been focused on using
supercritical carbon dioxide (scCO2) as a reaction medium for organic reactions due to their
attractive physical and toxicological properties.22ꢀ24 Although the high reactor capital costs, the
scCO2 as a reaction medium for organic reactions has the unique benefits of easier workꢀup and
purification comparing with other easier to handle green solvents, such as water, ionic liquid,
PEGꢀ400 and so on. To the best of our knowledge, the CuAAC reactions performed in the green
scCO2 are rarely reported (Scheme 1, previous works).25ꢀ27 On the basis of our previous work,27
the main work described in this paper is showing a green protocol using copper wire as the
recyclable catalyst for CuAAC reaction in scCO2 with much easier workꢀup and purification
(Scheme 1, this work).
Previous works
R
O
N
O
O
O
10 mol %CuI
10 mol % perfluorinated amino ligand
O
5
4 O
O
4 O
5
n
m
x
N
n
m
x
scCO2 300 bar 40 °C
N3
N
R
O
O
N N
CuBr Macroligand
scCO2 300 bar 60 °C
Br
O
+
Br
+
N3
F
x
O
N
O
F
O
O
O
·
Cu(OAc)2 H2O
R2
0.01mol%
R1 N3
+
R2
N
N
R1
N
scCO2 80 bar 36 °C
This work
R2
copper wire
scCO2 50 °C
R1 N3
+
R2
N
N
R1
N
Scheme 1. The CuAAC reactions in scCO2
Results and Discussion
Scheme 2. Model reaction for optimizing the reaction conditions
The diameter of the used metallic copper wire is 0.16 mm. The powder Xꢀray diffraction
analysis (Fig. 1) showed that there was no surface oxidation on the used metallic copper wire

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before and after the reaction. XRD peaks at 43.4°, 50.3° and 73.9° respectively belong to Cu
(111), Cu (200) and Cu (220), which clearly demonstrate that the catalysts are metallic copper.
Figure 1. The powder Xꢀray diffraction analysis of metallic copper wire
The reaction between propargyl phenyl ether and phenyl azide was selected as the model
reaction for optimizing reaction conditions. Firstly, the reaction temperature was investigated. The
reaction conditions were settled as follows: propargyl phenyl ether (1.0 mmol), phenyl azide (1.0
mmol), copper wire (30 mol%, 10 cm, 19.2 mg), CO2 (100 bar). The model reaction was carried
out at 40 ºC, 50 ºC, 60 ºC, 70 ºC and 80 ºC in the presence or absence of 30 mol% metallic copper
wire in 10 h. As shown in Fig. 2, the obtained yields of the model reaction in the presence of
metallic copper wire were higher than those in the absence of metallic copper wire under the same
reaction temperature, which indicated that the metallic copper wire played an important role on
the CuAAC reaction. It also could be found that the higher the reaction temperature, the faster the
reaction rate. In the presence of copper wire, the obtained yields were almost the same (more than
98 %) when the temperature was above 50 ºC, which were much higher than that obtained at 40 ºC
(18 %). When at 40 ºC, the obtained yield could be imporved to 98 % by incresing the catalyst
lenthgh to 80 cm and the reaction time to 24 h. When at 80 ºC, it only took 1 h to complete the
model reaction. While in the absence of copper wire conditions, although the obtained yield could
reach to 92 % at 80 ºC, the regioselectivity was poor, which was consistent with our previous
reported results on the influence of temperature on the yield and regioselectivity of the CuAAC
reaction in the absence of copper catalysts.28 The ratio of the 1,4ꢀ to 1,5ꢀ disubstituted isomers
obtained at 80 ºC in the absence of metallic copper wire is 3:1 (see SI Fig. 1). Therefore, 50 ºC
was selected as the reaction temperature.

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Figure 2. The effects of temperature on the yields in the presence or absence of copper wire
As we all known that the surface areas are critical for the CuAAC reaction rate when catalyzed
by metallic copper. Therefore, the relationships between the length of the metallic copper wire and
the obtained yields of the model reaction were investigated. As it could be seen from Table 1 that
the yields increased along with the increasing length of the copper wire (Table 1, entry 1 ꢀ 6). The
obtained yield was only 15 % when catalyzed by 6 mol% (2 cm) copper wire (Table 1, entry 5).
When catalyzed by 30 mol% (10 cm) copper wire, the obtained yield was 98 % (Table 1, entry 1).
When catalyzed by the prepared copper nanoparticles17 (0.5 mol%) at 50 ºC, the reaction could
finish in 30 mins (Table 1, entry 7). It could be concluded that the longer the copper wire, the
larger the suface area, the faster the reaction rate, the higher the obtained yield. The suface areas
of the metallic copper wire could be increased by increasing their length or making surface
nanocrystallization. Under scCO2 conditions, it is preferable to increase the length of the metallic
copper wire to shorten the CuAAC reaction time for more attractive easier workꢀup and
purification (see SI Fig. 2). Finally, the optimized length of the metallic copper wire was 10 cm
for the model reaction.
Table 1. The model reaction was performed in scCO2 at 50 ºC a
Catalyst loading
(mol%)
Pressure
(bar)
100
Times
(h)
10
Temperature
Yield b
(%)
98
Entry
Copper
(ºC)
50
50
50
50
50
50
50
1
2
3
4
5
6
7
Cu wire
Cu wire
30 mol%, 10cm
24 mol%, 8cm
18 mol%, 6cm
12 mol%, 4cm
6 mol%, 2cm
180 mol%, 60cm
0.5 mol%
100
10
67
Cu wire
100
10
38
Cu wire
100
10
26
Cu wire
100
10
15
Cu wire
100
10
98
Cu nanoparticle
100
0.5
99
a Reaction conditions: propargyl phenyl ether (1.0 mmol), phenyl azide (1.0 mmol).
b Isolated yields.
For a heterogeneous catalytic system, its lifetime and level of reusability are very significant
factors. Some reported metallic copper nanoparticles could not be reused due to the homogeneous

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nature of the resulting mixture at the end of the reaction.11 The reusability of other supported
metallic copper nanoparticles10, 14ꢀ16 usually are carried out by adopting the following procedures.
After the completion of the reaction, the products are quantitatively recovered by simple
extraction with an organic solvent. One reusable way is that the catalysts are kept in the ramained
reaction mixture, then fresh quantities reactants are introudced for another cycle reaction. The
other way is that the catalyst is allowed to settle and the supernatant solution is pumped out from
the reaction flask. The catalysts are washed with organic solvents several times, and allowed to
settle and the supernatant organic solvents are pumped out. Quantities of fresh alkynes and azides
were introduced. Then the recovered catlysts are used for several cycles by repeating above
procedures. It could be seen that whatever way is used for the reusability of the metallic copper
nanoparticles, organic solvents are always needed. Such a drawback could be overcvome by using
scCO2 as the reaction medium due to their attractive physical and toxicological properties. As for
using metallic copper wire under scCO2 conditions, the heterogeneity of metallic copper wire is
very excellent. As could be seen from Table 2, the consistent activity of the metallic copper wire
had no influence on the activity after ten cycles. After picking up the metallic copper wire from
the reaction mixture, the metallic copper wire could be used for another cycle and the products
were obtained from the reactor without further purification. Comparing with the reported
heterogeneous metallic nanoparticles under the reported reaction system, the lifetime and level of
reusability of the metallic copper wire under scCO2 conditions are very exciting.
Table 2. The reusable of copper wire (10 cm)
Run
1
2
3
4
5
6
7
8
9
10
Yield (%) 99 100 99 99 100 100 100 100 99 99
The copper leaching was also studied. Initially, after ten cycles, the weight of the copper wire
decreased from 19.2 mg to 18.6 mg. The average of copper leaching in cycloaddition was 0.06 mg
per cycle. The copper wire was determined by SEM before and after ten cycles. The surface of
copper wire after the reaction became more rough (Fig. 3). Furthermore, the crude product
obtained directly from the model reaction was analyzed by energy dispersive Xꢀray spectrometer
(EDS) and no copper was detected (Fig. 4). Considering the relatively lower analytical sensitivity
of EDS than that of ICPꢀMS, the copper amout in the crude product was examined by ICPꢀMS
again. The ICPꢀMS analysis revealed that the copper leaching was about 0.08 mg per cycle.
According to the copper leaching obtained from ICPꢀMS, it is theoretically possible that the
metallic copper (30 mol%, 10 cm, 19.2 mg) used in the model reaction could be reused for more
than 200 cycles.

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Figure 3. TEM micrograph of copper wire. The surface of copper wire, (a) before the reaction and (b) after ten
cycles reaction.
Figure 4. EDS image of the product obtained from the model reaction
Proposed mechanism for the CuAAC reaction catalyzed by metallic copper would be the same
as established mechanism shown in earlier reports (Scheme 3).6, 13, 29 As mentioned above that no
surface oxidation on the used metallic copper wire was observed by XRD analysis, it could be
concluded that it was not the copper oxide participating the CuAAC reaction. Maybe the surface
of metallic copper, which is considered to be more reactive because of unfilled valencies of the
surface atom, attributes to the generation of the catalysis Cu(I).

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N
R1
N
N
N
R1
R
(5)
N
N
R
Cu(I)
R1-N3
(4)
- e
scCO2
R C C
Cu(I)
metallic copper
Cu(I)
(3)
Cu(I)
R C
C H
R C CH
(1)
(2)
Scheme 3. Proposed mechanism for the metallic copper catalyzedꢀAAC reaction in scCO2
Finally, to extend the general applicability of this protocol, reactions between wide range of
diversely substituted terminal alkynes and azides were carried out under the optimized conditions.
As shown in Table 3, the reactions work well not only with alkyl azides, but also with aryl azides.
It is worth to mention that the reaction could proceed smoothly even both the alkynes and the
azides in a solid state.
Table 3. Synthesis of triazoles catalyzed by copper wire (30 mol%, 10 cm) in scCO2 at 50 ºC a
Entry
azide
alkyne
Product
Time (hour)
Yield b（%
）
N3
N3
N3
N3
O
1
2
10
10
10
10
10
10
10
10
10
10
10
98
99
98
91
98
97
98
98
98
97
95
O
N
N
N
Cl
O
O
N
Cl
N
N
3
N
N
N
OH
4
OH
N
N
N
N
O
N3
5
O
N
N
NO
Cl
2
O
N3
N3
N3
N3
N3
N3
6
O
N
N
N
O2N
Cl
N
O
7
O
N
N
8
N
N
N
9
N
N
N
N
NH
2
H N
2
N
10
11
N
N
N
N

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OH
N3
N
N
12
13
14
15
16
17
18
19
20
10
10
10
10
10
10
10
10
10
91
98
97
90
94
99
98
96
98
OH
N
Cl
O
N
3
O
N
N
O N
N
2
Cl
O2N
N
3
N
N
N
O N
2
O N
2
N3
OH
OH
N
N
N
NO
2
O
O
O N
N
2
O N
N
3
2
O2N
N
N
N
O N
2
O N
N
3
2
N
N
O
O
O
O
N3
O
O
N
O
O
O
N
N
O
O
Cl
O
N3
O
O
N
Cl
N
N
O
N3
N
N
N
O
a Reaction conditions: terminal alkyne (1 mmol), azide (1 mmol).
b Isolated yields.
In conclusion, we presented a simple protocol for the CuAAC reaction using 30 mol% copper
wire as the catalyst in scCO2 (100 bar) at 50 ºC. Even in the absence of base or ligand, this green
protocol is suitable for efficient synthesis of small molecular triazoles.
Acknowledgments This work was supported financially by the Natural Science Foundation of
China (No. 21172058), Scientific Research Foundation for Doctors (No. 01036500508), Youth
Foundation (2012QK11) of Henan Normal University, Foundation of Henan Scientific and
Technological Committee (No. 132300410167) and Foundation of He’nan Educational Committee
(14A350005).
Supplementary data
Supplementary data associated with this article can be found, in the online version, at
http://dx.doi.org/
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Graphical Abstract