Highly Efficient and Stable Atomically Dispersed Cu Catalyst for Azide-Alkyne Cycloaddition Reaction

Article abstract of DOI:10.1002/cctc.202100831

In this study, we report a highly stable and efficient single-atom Cu dispersed on N-doped porous carbon as a superior catalyst for azide-alkyne cycloaddition reaction. A broad set of 1,4-disubstituted 1,2,3-triazoles was synthesized in high to excellent

Full text of DOI:10.1002/cctc.202100831

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Highly Efficient and Stable Atomically Dispersed Cu
Catalyst for Azide-Alkyne Cycloaddition Reaction
Peng Ren,[a, b] Qinglin Li,[a, b] Tao Song,[a, c, d] Zhaozhan Wang,[a, c, d] Ken Motokura,[e] and
Yong Yang*[a, c, d]
In this study, we report a highly stable and efficient single-atom
Cu dispersed on N-doped porous carbon as a superior catalyst
for azide-alkyne cycloaddition reaction. A broad set of 1,4-
disubstituted 1,2,3-triazoles was synthesized in high to excellent
yields with good tolerance of various functional groups in a
cost-effective, environment-friendly manner. Parallel studies
show that the single-atom Cu with unique coordination
structure exhibits superior catalytic activity to the metallic Cu
nanoparticles analogue. Remarkably, the single-atom Cu cata-
lyst demonstrates robust stability and can be reused several
times without variations in activity and regioselectivity.
Introduction
disproportionation.[4] Such treatments further complicate the
work-up procedure and also reduce the cost-efficiency. (ii) The
difficulty of separation of the catalyst from the final product for
homogeneous CuAAC. The contamination of copper within the
final products is a big problem in polymer science and
bioconjugation, because the residual Cu not only decreases the
quality of polymers with color change and easy degradation
but also is cytotoxic to live cell or organisms.[5] (iii) The low
catalytic efficiency for the heterogeneous Cu catalysts. The
catalytic activity for those currently developed heterogeneous
Cu catalysts is far from satisfactory due to the issues of diffusion
and steric hindrance.[1a,6] Therefore, it is urgently needed to
develop a highly stable and efficient heterogeneous Cu catalyst
for the AAC reaction.
Single-atom catalysts (SACs) have recently drawn consider-
able attention in the fields of heterogeneous catalysis and
energy conversion, and were regarded a potential to bridge
homogeneous and heterogeneous catalysis.[7] SACs have dis-
tinct advantages, such as atomic dispersion, maximized utiliza-
tion of metals, and easy of separation. In particular, the unique
structural and electronic features with special oxidation state
stemming from unsaturated coordination metal sites offer the
single-atom metal catalysts more fascinating catalytic
performance.[8] A number of single-atom Cu catalysts have been
developed for electrochemical nitrogen reduction reaction
(NRR),[9] photo/electrochemical CO2 reduction reaction (CRR),[10]
oxygen reduction reaction (ORR),[11] and other industrial cata-
lytic reactions (e.g., CO oxidation,[12] dehydrogenation of
propane,[13] acetylene semihydrogenation,[14] oxidation of
benzene[15]). They generally demonstrate remarkably increased
catalytic activity, selectivity and stability in comparison with
their Cu nanocrystalline catalysts or metal salts under compara-
ble conditions. Nonetheless, to our knowledge, single-atom Cu
catalyst for AAC reaction has not been explored yet.
Copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction
is undoubtedly one of the most powerful click reactions.[1] To
date, CuAAC has an incredible breadth of versatility and
application in the fields ranging from material science, polymer
chemistry, biochemistry, to drug discovery, owing to the high
catalytic efficiency and atomic economy as well as the excellent
orthogonality of the azide and alkyne functional groups.[2]
A number of homogeneous and heterogeneous Cu(I) catalysts
have been developed for AAC reaction.[3] However, both
homogeneous and heterogeneous Cu(I) catalyst possess their
respective inherent drawbacks, making their applications
challenging in practical scenario. For example, (i) The thermody-
namically unstable active Cu(I) species. Cu(I) is easily oxidized to
catalytically inactive Cu(II) species or disproportionated to a
mixture of Cu(II) and Cu(0), thereby reducing the reaction
efficiency or even terminating the reaction. To maintain the
high level of Cu(I) at all times during the reaction, addition of a
large excess of reducing agents or external ligands is necessary
to protect or stabilize Cu(I) from oxidation and/or
[a] Dr. P. Ren, Dr. Q. Li, Dr. T. Song, Z. Wang, Prof. Y. Yang
CAS Key Laboratory of Bio-Based Materials
Qingdao Institute of Bioenergy and Bioprocess Technology
Chinese Academy of Sciences
Qingdao 266101 (P. R. China)
E-mail: yangyong@qibebt.ac.cn
[b] Dr. P. Ren, Dr. Q. Li
University of Chinese Academy of Sciences
Beijing 100049 (P. R. China)
[c] Dr. T. Song, Z. Wang, Prof. Y. Yang
Shandong Energy Institute
Qingdao 266101 (P. R. China)
[d] Dr. T. Song, Z. Wang, Prof. Y. Yang
Qingdao New Energy Shandong Laboratory
Qingdao 266101 (P. R. China)
Very recently, we have reported an atomically dispersed Cu
on N-doped porous carbon with coordinately unsaturated Cu-
N2 sites (labelled as Cu1/NC-800) as a superior catalyst for the
oxidative Glaser-Hay coupling of terminal alkynes to deliver a
variety of (un)asymmetric 1,3-diynes.[16] We found that the
[e] Prof. K. Motokura
Department of Chemistry and Life Science
Yokohama National University
Yokohama 240-8501 (Japan)
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special coordination environment and oxidation state of Cu
active sites with N-doped carbon provided preferential adsorp-
tion and activation of terminal alkynes to form the key
intermediate Cuδ-acetylide species, which synergistically
boosted the catalytic activity and selectivity. Previous exper-
imental and computational studies reveal that the formation of
Cuδ-acetylide intermediate is a rate-determining step for CuAAC
reaction.[17] As such, we expect that the single-atom catalyst
Cu1/NC-800 can be a good candidate as a heterogeneous
catalyst for AAC reaction and might make a great advance for
expedient synthesis of 1,4-disubstituted 1,2,3-triazoles.
In this study, we investigated the catalytic performance for
the AAC reaction using Cu1/NC-800 as the catalyst. An out-
standing activity and excellent regioselectivity to the targeted
1,4-disubstituted 1,2,3-triazole products with a broad set of
alkynes and azides was achieved under mild conditions in a
cost-effective and sustainable manner. Meanwhile, the catalyst
Cu1/NC-800 remained highly stable in catalytic activity and
selectivity upon successive reuses without detection of Cu
leaching, thereby avoiding the contamination of copper within
the final products. Furthermore, a parallel study using the
supported Cu nanoparticles (NPs) dispersed on N-doped carbon
as the catalyst (labelled as Cu NPs/NC-900) demonstrates the
distinct advantage in catalytic performance and the potential
for practical application of the catalyst Cu1/NC-800 in AAC
reaction.
spectrum in the R space (Figure 1f) was observed, which verifies
the formation of metallic Cu NPs. The lower intensity of FT for
Cu NPs/NC-900 compared with Cu foil suggests the formation
of Cu NPs too. All these results demonstrate the formation of
metallic Cu NPs in the catalyst Cu NPs/NC-900. In addition,
comparison among N 1s XPS spectrum (Figure S1), BET analysis
(Figure S2 and S3), and elemental analysis (Table S1) reveals
that there are no big differences in the types and content of N,
surface area and pore size distribution between the catalyst
Cu1/NC-800 and Cu NPs/NC-900.
With both catalysts Cu1/NC-800 and Cu NPs/NC-900 in hand,
we next assessed their catalytic performance for AAC reaction.
We started to optimize the reaction conditions using cyclo-
addition of phenylacetylene with benzyl azide as the bench-
mark reaction in the presence of Cu1/NC-800 (Table 1). After
comprehensive screening, we found that complete conversion
with exclusive regioselectivity to 1-benzyl-4-phenyl-1,2,3-
triazole (3a) was achieved when the reaction was conducted
using 20 mg (2 mol% of Cu) of Cu1/NC-800 in acetonitrile as
solvent under air at room temperature for 12 h (entry 10). Poor
or no reactivity was detected when the reaction was performed
using other solvents including alcohols (MeOH, EtOH, iPrOH,
tBuOH), THF, dioxane, CHCl3, toluene, and H2O instead of CH3CN
under otherwise identical conditions (entries 1–9), indicating
the solvent has a critical role on the reactivity. The reaction
proceeded under argon atmosphere led to a rather reduced
reactivity (entry 12), suggesting that air can effectively boost
the reaction. No reaction took place at all in the absence of the
catalyst Cu1/NC-800 or using NC-800 as the catalyst (entries 13
and 14). As a contrast, when the reaction was performed using
Cu NPs/NC-900 as the catalyst under the equal conditions, a
Results and Discussion
As illustrated in our previous work,[16] the catalyst Cu1/NC-800
was prepared through
a facile and inexpensive one-pot
pyrolysis method using biochar and copper salt as starting
materials. The catalyst Cu NPs/NC-900 was synthesized accord-
ing to the same procedure to Cu1/NC-800 with exception of
Table 1. Optimization of reaction conditions.[a]
°
pyrolysis temperature at 900 C. The Cu loading contents in two
catalysts were determined to be 1.28 and 1.37 wt%, respec-
tively, by inductively coupled plasma atomic emission spectro-
scopy (ICP-AES). The formation of single-atom Cu with coordin-
ately unsaturated Cu-N2 sites in Cu1/NC-800 was unambiguously
confirmed by XRD, HR-TEM, AC HAADF-STEM, and XAFS in our
previous work.[16]
Entry
Catalyst
[2 mol% of Cu]
Solvent
GC Yield 3a
[%][b]
1
2
3
4
5
6
7
8
Cu1/NC-800
Cu1/NC-800
Cu1/NC-800
Cu1/NC-800
Cu1/NC-800
Cu1/NC-800
Cu1/NC-800
Cu1/NC-800
Cu1/NC-800
Cu1/NC-800
Cu NPs/NC-900
Cu1/NC-800
NC-800
MeOH
EtOH
Isopropanol
tBuOH
H2O
THF
Dioxane
CHCl3
Toluene
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
6
3
In contrast, upon increasing the pyrolysis temperature to
trace
trace
20
trace
0
°
900 C, metallic Cu nanoparticles were formed and well-
dispersed on N-doped carbon. HR-TEM images (Figure 1a and b)
show that Cu NPs with uniform size were homogeneously
dispersed on carbon material. XRD pattern (Figure 1c) of Cu
NPs/NC-900 shows an intensive and broad diffraction peak at
3
9
trace
>99
69
47
0
10
11
12[c]
13[d]
14[e]
°
around 26 , corresponding to the characteristic (002) plane of
graphitic carbon. Besides, three diffraction peaks situated at 43,
°
51, 63 were observed, which belong to the reflections of
Blank
0
metallic Cu (111), (200), and (220) planes (JCPDS # 04-0836). Cu
2p3/2 XPS spectrum (Figure 1d) shows a sharp peak at 932.4 eV,
suggesting the metallic Cu0 oxidation state.[18] The near-edge
feature of Cu NPs/NC-900 (Figure 1e) is very close to Cu foil,
further indicating the Cu0 oxidation state. An intensive peak at
2.20 Å, a typical value for CuÀ Cu bond, in the FT-EXAFS
[a] Reaction conditions: phenylacetylene (0.2 mmol), benzyl azide
(0.2 mmol), catalyst (2 mol% of Cu), solvent (2 mL), room temperature,
under atmospheric air. [b] Determined by GC using an internal standard
sample and confirmed with its corresponding authentic sample. [c] Under
argon atmosphere. [d] Using NC-800 as the catalyst instead of Cu1/NC-800.
[e] In the absence of catalyst.
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Figure 1. (a,b) HR-TEM images of Cu NPs/NC-900; (c) XRD pattern and (d) Cu2p3/2 XPS spectra of Cu1/NC-800 and Cu NPs/NC-900; (e) CuK-edge X-ray
absorption near-edge structure (XANES) and (f) FT-k3-weight extended X-ray absorption fine structure (EXAFS) spectra of Cu1/NC-800 and Cu NPs/NC-900 and
the reference samples.
considerably lower reactivity was observed (entry 11). This
result indicates that the single-atom Cu catalyst Cu1/NC-800 is
more active than its metallic Cu NPs/NC-900, highlighting the
advantage of SACs for AAC reaction.
To uncover the difference in catalytic activity between Cu1/
NC-800 and Cu NPs/NC-900, we performed the control experi-
ments. Kinetic studies (Figure S4) show that an induction period
is required for the AAC reaction catalyzed by Cu NPs/NC-900,
while this phenomenon is not observed for Cu1/NC-800. It is
quite reasonable because Cu species are in zero oxidation state
in Cu NPs/NC-900 as proved by XRD, HR-TEM, XPS, and XAS,
which need to be oxidized to catalytically active Cu+ to
facilitate the AAC reaction.[19] Furthermore, the initial reaction
rate for Cu NPs/NC-900 is rather slower than that of Cu1/NC-
800, indicating the nature of Cu NPs/NC-900 with lower
reactivity for AAC reaction compared with Cu1/NC-800. Our
previous studies have revealed that the catalyst Cu1/NC-800
with coordinately unsaturated Cu-N2 active sites has a stronger
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adsorption of terminal alkyne than metallic Cu NPs on the
support, which subsequently promotes the formation of the key
intermediate Cuδ-acetylide species with assistance from the
weak bonding interaction between the adjacent pyridinic-N site
and acetylenic proton of alkyne via the N···H bond.[16] This might
account for the higher reaction rate of the single-atom Cu
recycling. ICP-AES analysis (Table S2) reveals that nearly no loss
of Cu loading content was observed for the used Cu1/NC-800,
while around 20% of Cu leached out from the fresh Cu NPs/NC-
900. Furthermore, no obvious change in the oxidation state and
structure of single-atom Cu was observed for the used Cu1/NC-
800 (Figure S8 and S9). In addition, the catalyst Cu1/NC-800 also
allows for gram-scale synthesis of 1-benzyl-4-phenyl-1,2,3-
triazole 3a under the optimized conditions (Scheme S1), further
highlighting the practicability of this protocol.
1
catalyst. Indeed, H NMR spectroscopy (Figure S5) shows that
the chemical shift of acetylenic proton in phenylacetylene
gradually shifted to a high field with increasing the reaction
time for the reaction of phenylacetylene with Cu1/NC-800,
further verifying the interaction between acetylenic proton and
the catalyst. H3PO4-poison experiment (Figure S6) reveals that
the pyridinic-N as a basic site in the porous carbon plays a
critical role for the reactivity, where a significant reduced
activity or no reactivity was observed when H3PO4 was added
into the reaction mixture. Given nearly no difference in N type
and content as well BET surface area and pore volume for both
catalysts, we believe that the unique coordination and
oxidation structure of the single-atom Cu essentially boosts the
catalytic kinetics and overall activity for the AAC reaction.
We further investigated the stability of the catalysts Cu1/NC-
800 and Cu NPs/NC-900 under the optimized conditions. After
completion of the reaction, the catalyst was separated by
centrifugation and washing with acetonitrile for next use. The
catalyst Cu1/NC-800 could be recycled for at least 8 times
without variations in the catalytic activity and selectivity (Fig-
ure 2a), demonstrating the robust stability. The filtration experi-
ment was also conducted to disclose any possible Cu leaching
from the catalyst. No further consumption of phenylacetylene
and benzyl azide was observed after filtering off the catalyst at
around 40% conversion (Figure S7). In contrast, it was found
that the catalytic activity decreased gradually in each recycle for
the catalyst Cu NPs/NC-900, while the excellent regioselectivity
to the desired product was remained (Figure 2b). The stability
was further reflected by the Cu contents for both catalysts after
We subsequently explored the generality of this method for
the synthesis of various 1,4-disubstituted 1,2,3-triazoles. Overall,
a broad set of 1,4-disubstituted 1,2,3-triazoles was successfully
synthesized in an efficient and exclusively regioselective
manner, as shown in Table 2. Various aryl-, alkyl-, heteroaryl-
terminal alkynes could efficiently undergo cycloaddition with
benzyl azide to deliver their corresponding 1,4-disubstituted
1,2,3-triazoles in high to excellent yields. Aryl alkynes sub-
stituted by electro-rich (p-Me and p-OMe) (1b and 1c) groups
gave higher yields than those with electro-deficient substitu-
ents (p-Cl, p-NO2, p-CHO, and p-COOMe) (1d–g). Heteroaryl
alkynes, e.g., 3-ethynylpyridine (1h) and 2-ethynylthiophene
(1i), worked well to give rise to their respective 1,4-triazoles in
89 and 82% yields, respectively. Alkyl alkynes including 1-
hexylene (1k), ethynyltrimethylsilane (1l), 2-methylbut-3-yn-2-
ol (1n), (prop-2-yn-1-yloxy)benzene (1o) and 1-ethynylcyclo-
hex-1-ene (1j) also reacted with benzyl azide smoothly to
produce their corresponding 1,4-triazoles in good yields.
Remarkably, mestranol (1m), a biologically active compound,
could be cycloadded with benzyl azide to give its desired
product in decent yield. Likewise, a family of azides ranging
from substituted benzyl azides, ethyl 2-azidoacetate, 2-azidoe-
than-1-ol could efficiently cycloadd with various terminal
alkynes, exclusively affording their corresponding 1,4-triazoles
in good to high yields. Importantly, random combination of
both azides and terminal alkynes is successful for the
Figure 2. Stability of the catalysts Cu1/NC-800 (a) and Cu NPs/NC-900 (b) for the benchmark reaction under the optimized conditions.
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Table 2. Substrate Scope.[a]
[a] Reaction conditions: alkyne 1 (0.2 mmol), azide 2 (0.2 mmol), Cu1/NC-800 (2 mol% of Cu), CH3CN (2 mL), room temperature, 12 h, under air atmosphere.
°
[b] 24h instead of 12 h. [c] Alkyne1 (0.2 mmol), benzyl bromide (0.22 mmol), NaN3 (0.2 mmol), CH3CN (2 mL), 60 C, 18 h. Isolated yields are given.
construction of more functional 1,4-triazoles (3u–d’). It should
be pointed out that a facile one-pot cascade reaction of
terminal alkyne, benzyl bromide and NaN3 to efficiently and
regioselectively synthesize 1,4-triazoles (3p-s) under slight
variation of the optimized conditions could be accomplished.
Notably, the reactions proceeded in the present catalysis system
are very clean. After completion of the reaction, the pure
targeted products could be readily obtained via simple
separation of the catalyst and evaporation of the solvent
without requirement of chromatography column for purifica-
tion, making this protocol more time-saving, environment-
friendly, and cost-effective.
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the catalyst was carefully collected by centrifugation and washing
with CH3CN followed by drying under vacuum for next use.
Conclusion
In summary, we have demonstrated a highly active and stable
single-atom Cu catalyst with coordinately unsaturated Cu-N2
sites for the azide-alkyne cycloaddition reaction for the first
time. A broad spectrum of 1,4-disubstituted 1,2,3-triazoles was
efficiently and regioselectively synthesized, and various func-
tional groups are well tolerated. Importantly, the single-atom
Cu catalyst demonstrates strong stability in catalytic activity
and structure, without the detection of Cu leaching from the
Gram-scale CuAAC reaction. A 100 mL round-bottom flask was
charged with a magnetic stirring bar, phenylacetylene (5 mmol)
and benzyl azide (5 mmol), Cu1/NC-800 (2 mol% of Cu), CH3CN
(50 mL). The reaction was stirred at room temperature for 12 h
under atmospheric air. The pure product 3a was obtained via
simple separation of the catalyst and evaporation of the solvent.
catalyst after several successive recycles. This work provides a Acknowledgements
new stable heterogeneous Cu catalyst for expedient synthesis
of 1,4-disubstituted 1,2,3-triazoles in simple, cost-effective, and
sustainable manner and also expands the application of the
single-atom catalyst for organic transformations.
We gratefully acknowledge the financial support of the National
Natural Science Foundation of China (No. 22078350, 22002178),
the Natural Science Foundation of Shandong Province
(ZR2020KB016). Y.Y also thanks the Royal Society (UK) for a
Newton Advanced Fellowship (NAF\R2\180695).
Experimental Section
Materials. Unless otherwise noted, all reagents were purchased
commercially from Sigma-Aldrich, or Aladdin and used as received
without further purification. The fresh bamboo shoots were
obtained from Anhui Taiping Test Centre, International Centre for
Bamboo and Rattan, Anhui Province, China. All operations were
carried out in an argon atmosphere using glovebox and Schlenk
techniques unless otherwise specified.
Conflict of Interest
The authors declare no conflict of interest.
Keywords: Single-atom catalyst
· CuAAC reaction · 1,4-
disubstituted 1,2,3-triazoles · heterogeneous Cu catalysis ·
carbon material
Preparation of catalysts. The catalysts were prepared via a facile
tandem hydrothermal-pyrolysis process. Typically, fresh bamboo
shoots were first cut into small slices, dried and ground into
powder followed by the hydrothermal carbonization (HTC) process
in a Teflon-inner stainless-steel autoclave with deionized water at
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°
180 C. In this step, the bamboo shoots were converted into
biochar. The resulting brown biochar was filtered, washed thor-
oughly with deionized water, and then dried under vacuum at
room temperature. Next, the obtained solids were homogeneously
°
mixed with copper nitrate solution at 60 C for 2 h. Finally, the
resulting material was heated under N2 atmosphere to 800 and
900 C, respectively, with a heating rate of 5 C minÀ 1. The pyrolysis
was maintained under N2 for 2 h at the target temperature and
then cooled to room temperature. The obtained catalysts were
denoted as Cu1/NC-800 and Cu NPs/NC-900.
°
°
General procedures for CuAAC reaction. A 25 mL glass tube was
charged with a magnetic stirring bar, azide (0.2 mmol), alkyne
(0.2 mmol), Cu1/NC-800 (20 mg, 2 mol% of Cu), 2 mL CH3CN as
solvent. The reaction was stirred for 12 h at room temperature
under atmospheric air. After completion of the reaction, the organic
phase was analyzed by GC to measure the conversion and
selectivity. The products were purified by flash chromatography
column on silica gel using appropriate eluents to obtain the
isolated yields. For these reactions with up to 95% conversion of
starting material, chromatography column is not needed, the pure
products could be obtained by simple filtration of the catalyst and
evaporation of the solvent. The obtained products were structurally
confirmed by NMR.
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Recyclability of the catalysts for the benchmark reaction. The
benchmark reaction was chosen to investigate the recyclability of
the catalyst Cu1/NC-800 and Cu NPs/NC-900. A 25 mL reaction tube
was charged with
a magnetic stirring bar, phenylacetylene
(0.2 mmol) and benzyl azide (0.2 mmol), Cu1/NC-800 (2 mol% of
Cu), CH3CN (2 mL). The reaction was stirred at room temperature
under atmospheric air for 12 h. After completion of the reaction,
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Manuscript received: June 8, 2021
Revised manuscript received: June 30, 2021
Accepted manuscript online: July 4, 2021
Version of record online: ■■■, ■■■■
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FULL PAPERS
Dr. P. Ren, Dr. Q. Li, Dr. T. Song, Z.
Wang, Prof. K. Motokura, Prof. Y.
Yang*
1 – 8
Highly Efficient and Stable Atomi-
cally Dispersed Cu Catalyst for
Azide-Alkyne Cycloaddition
Reaction
Single-atom catalysis: A single-atom
Cu dispersed on N-doped carbon
exhibits superior catalytic activity for
efficient and selective AAC reaction to
access a broad set of 1,4-disubstituted
1,2,3-triazoles in a facile and environ-
mentally-benign manner. Single-atom
Cu catalyst demonstrates both higher
reactivity and stronger stability than
the supported Cu nanoparticles under
the same reaction conditions.