Cu2O spheres as an efficient source of catalytic Cu(I) species for performing azide-alkyne click reactions

Article abstract of DOI:10.1016/j.tetlet.2017.01.005

We report herein the high yield synthesis of Cu₂O spheres displaying well-defined shapes and monodisperse sizes that could be employed as the source of highly catalytic active Cu(I) species towards click reactions between several of alkynes and azides to produce a variety of 1,2,3-triazoles under ligand-free and ambient conditions (in an open reactor). The utilization of Cu₂O spheres enabled superior performance as compared to a conventional protocol in which CuSO₄is employed in combination with sodium ascorbate as the catalyst system. In addition, the compounds were obtained in synthetically useful yields, and seven of them have not been previously reported. We believe the results reported herein shed new insights into the optimization of activity and versatility of click reactions towards the synthesis of target molecules in environmentally friendly conditions.

Full text of DOI:10.1016/j.tetlet.2017.01.005

Accepted Manuscript
Cu2O Spheres as an Efficient Source of Catalytic Cu(I) Species for Performing
Azide-Alkyne Click Reactions
Thenner S. Rodrigues, Anderson G.M. da Silva, Lucas C. de Oliveira, Adalberto
M. da Silva, Róbson R. Teixeira, Pedro H.C. Camargo
PII:
S0040-4039(17)30004-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.01.005
TETL 48508
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
8 December 2016
22 December 2016
2 January 2017
Please cite this article as: Rodrigues, T.S., da Silva, A.G.M., de Oliveira, L.C., da Silva, A.M., Teixeira, R.R.,
Camargo, P.H.C., Cu2O Spheres as an Efficient Source of Catalytic Cu(I) Species for Performing Azide-Alkyne
Click Reactions, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.01.005
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Cu2O Spheres as an Efficient Source of Catalytic Cu(I) Species for Performing
Azide-Alkyne Click Reactions
Thenner S. Rodrigues,1 Anderson G. M. da Silva,1 Lucas C. de Oliveira,2 Adalberto M. da
Silva,3 Róbson R. Teixeira*,2 and Pedro H. C. Camargo1*
1Departamento de Química Fundamental, Instituto de Química, Universidade de São Paulo,
Av. Prof. Lineu Prestes, 748, 05508-000, São Paulo-SP, Brazil
2Departamento de Química – Universidade Federal de Viçosa, Av. P.H. Rolfs, S/N, 36570-
900, Viçosa-MG, Brazil.
3Instituto Federal de Educação, Ciência e Tecnologia Catarinense - Campus Araquari, 89245-
000, Araquari–SC, Brazil.
*Corresponding authors: E-mail: camargo@iq.usp.br; robsonr.teixeira@ufv.br
1

Abstract
We report herein the high yield synthesis of Cu2O spheres displaying well-defined shapes
and monodisperse sizes that could be employed as the source of highly catalytic active Cu(I)
species towards click reactions between several of alkynes and azides to produce a variety
of 1,2,3-triazoles under ligand-free and ambient conditions (in an open reactor). The
utilization of Cu2O spheres enabled superior performance as compared to a conventional
protocol in which CuSO4 is employed in combination with sodium ascorbate as the catalyst
system. In addition, the compounds were obtained in synthetically useful yields, and seven
of them have not been previously reported. We believe the results reported herein shed
new insights into the optimization of activity and versatility of click reactions towards the
synthesis of target molecules in environmentally friendly conditions.
2

Introduction
The copper(I)-catalyzed azide–alkyne cycloaddition (CuAAC) corresponds to one of the
best clic examples of click reactions. This transformation enables the connection of two
molecular fragments in a facile, selective, and high-yield approach under mild conditions,
being not sensitive to aqueous conditions, and with little or no by-product formation.[1–4]
Therefore, it represents a transformation of great interest in many fields such as organic
synthesis,[5,6] pharmaceuticals,[7,8] polymers,[9,10] and chemical biology[11] due to the
possibility of generate relatively complex products under mild conditions.
Conventionally, this click reaction is performed using a water soluble catalyst
comprised of Cu(I) salts, Cu(I) complexes, or Cu(II) salts combined with a reducing agent
such as sodium ascorbate or hydrazine.[6,12–17] However, the low efficiency of conversion
of Cu(II) into Cu(I) species associated with the high toxicity of the reducing agents as well as
the demand for improved and greener processes has driven the development of several
new catalytic systems towards click transformations.[6,18–21]
In this context, the employment of cuprous oxide (Cu2O) as the source of highly active
Cu(I) species for catalyzing CuAAC reactions represents a promising strategy. This can be
performed by two general approaches: by adding pre-synthetized Cu2O based structures as
catalysts in the reaction mixture or by synthetizing them in-situ before the substrate
addition by using Cu(II) salts combined with reducing agents.[13,22–24] The latter approach,
albeit is more widely employed, has several drawbacks that include: i) limited amounts of
produced Cu(I) based species; ii) poor control over their physicochemical properties (size
and shape) that usually lead to low substrate conversions and poor yields; and iii) formation
3

a more complex and toxic reaction mixture, which makes the product purification more
troublesome and also decrease environmentally friendliness of the process.[18]
In this paper, we report the high yield synthesis of Cu2O spheres displaying well-
defined shapes and monodisperse sizes by a facile and robust polyol approach. The Cu2O
spheres were then employed as source of highly catalytic active Cu(I) species towards click
reactions between a variety of alkynes and azides under ligand-free and mild conditions (in
an open reactor). More specifically, the utilization of Cu2O spheres enabled superior
performances as compared to a conventional protocol in which CuSO4 is employed in
combination with sodium ascorbate as the catalyst system. In addition, good yields for a
variety of click products was achieved, which enabled the synthesis of seven unpublished,
novel molecules.
Results and Discussion
Our studies started with the synthesis of Cu2O spheres by a polyol approach
employing Cu(NO3)2×3H2O as the precursor, ethylene glycol as the solvent and source of
reducing agents, PVP as the stabilizer/reducing agent, and 172 oC as the reaction
temperature (Scheme 1).[25]
Scheme 1. Synthesis of Cu2O spheres by a polyol approach employing Cu(NO3)2×3H2O as the
precursor, ethylene glycol as the solvent and source of reducing agents PVP as the
stabilizer/reducing agent at 172 oC.
4

As we were interested in the application of Cu2O spheres as a source of catalytic active Cu(I)
species towards click reactions, the development of a synthetic procedure that enabled
narrow size distribution in high yields was crucial to achieve reproducible and efficient click
protocols, which represents one of the bottlenecks in the field.[26] In fact, SEM images
(Figure 1A and B) for the product obtained after only 10 minutes following the addition of
Cu(NO3)2×3H2O to a solution containing ethylene glycol and PVP, revealed the formation of
Cu2O spheres displaying well-defined shapes and monodisperse sizes, having 346 ± 13 nm in
diameter (histogram of size distribution is shown in Figure 1C).
Figure 1. (A-B) SEM images for Cu2O spheres obtained after only 10 minutes following the
addition of Cu(NO3)2.3H2O to a solution containing EG and PVP (C) Histogram showing the
particle size distribution for the obtained Cu2O spheres.
5

The formation of Cu2O spheres was supported by XRD results (Figure 2), in which
only the presence of peaks assigned to Cu2O was detected (cuprite, with lattice constant of
4.26 Å, JCPDS card no. 77-0199) without any crystalline impurities or by-products.[27] The
UV-VIS spectrum also supports the formation of Cu2O (Figure 3). In this case, the UV-vis
spectrum for the obtained Cu2O spheres displayed a broad band centered at ~ 570 nm with
a shoulder centered at ~ 650 nm attributed to weak d10-d10 interactions in the cuprite
structure (bbc Cu2O array), which also explain the origin of the intense yellow color for this
material.[28] In addition, the bands centered at ~ 570 and at ~ 650 nm are in agreement
with the absorption of Cu2O structures with particle average size of 300 – 600 nm and their
calculated band gap energies corresponded to 2.18 and 1.91 eV, respectively.[29,30] The Cu
content from the synthesis, as determined by ICP-OES analyses, corresponded to 0.77
mmol, indicating a yield of 93% for the formation of the spheres under our employed
conditions.
Figure 2. (A) X-ray diffraction pattern recorded from the obtained Cu2O spheres.
6

Figure 3. (A) UV−VIS spectra recorded from aqueous suspensions containing the obtained
Cu2O spheres.
After the synthesis of Cu2O spheres in high yields, having monodisperse sizes, and
controlled shapes, we turned our attention to their application as source of highly catalytic
active Cu(I) species towards click transformations employing terminal alkynes and benzyl
azides as substrates under mild conditions, without additional ligands, and in an open
reactor (ambient atmosphere). The alkynes were prepared via standard alkylation
procedures of phenols, phtalimide, indan-1,3-dione and cinnamic acid. The synthesis of
azides were achieved according previous reports.[31] For the characterization of the
compounds, spectroscopic (IR and NMR) and spectrometric (mass spectrometry) techniques
were utilized.
Our catalytic investigation started with a control experiment without the utilization
of any catalyst (Table 1, entry 1), in which no significant substrate conversion was observed
after 10 h of reaction at room temperature, demonstrating the need of Cu(I) species to
achieve the target transformation, as demonstrated by previous reports.[1–4] This
hypothesis was probed when CuSO4 combined with sodium ascorbate (a traditional catalyst
7

system in click reactions) was added to the system under the same experimental conditions
(Table 1, entry 2), in which a yield of (46%) for click product (12) was observed after 10 h at
room temperature. However, when Cu2O spheres were employed as source of Cu(I) species
(Table 1, entry 3) a significant increase in yield for the click product was achieved (85%)
under the same Cu loading after 10 h, illustrating their superior catalytic activity which can
be associated with limited amount of Cu(I) species formed in situ using CuSO4 and sodium
ascorbate.
Table 1. Effect of the nature of the catalyst over the click reaction yield a
Entry
Source of Cu(I)
Yield (%)b
1
2
3
-
(-)c
46
85
CuSO4/Sodium ascorbate
Cu2O spheres
a
All the reactions were run using 1.0 equivalent of alkyne (1) and 1.2 equivalent of
azide (9), 20 mol% of catalyst (Cu basis), at room temperature for 10h.
b Isolated yields.
c Reaction performed without any catalyst; no product detected.
After demonstrating the superior activity of Cu2O spheres as catalysts (source of
Cu(I) species), we performed a series of experiments in order to optimize the efficiency of
8

our click process as a function of the temperature (Table 2) using the alkyne 1 and
benzylazide 9 as model substrates to afford the triazolic compound 12 as depicted in the
first row of Table 2. Herein, when the reaction was performed at room temperature (Table
2, entry 1), a yield of 85 % for compound 12 was obtained after 10 h of reaction. However,
o
when the reaction temperature was increased to 40 C (Table 2, entry 2), almost the same
o
yield (87 %) was achieved after only 2 h of reaction. Finally, at 60 C (Table 2, entry 3), the
total conversion of alkyne was observed but a lower yield for the compound 12 (63%) was
o
achieved, indicating a lower selectivity for the click product at this temperature. Thus, 40 C
corresponded to lowest temperature in which good yields and maximum selectivity were
achieved, and it was chosen as the temperature for our further studies.
Table 2. Optimization of the temperature parameter for the click reaction in the presence of
Cu2O spheres as catalystsa
Entry
Temperature
Reaction Time (h)
Yield (%)b
1
2
Room temperature
10
85
40 oC
60 oC
2
1
87
63
3
a
All the reactions were run using 1.0 equivalent of alkyne (1) and 1.2 equivalent of
azide (9), 20 mol% of catalyst (Cu basis, 310 µL of Cu2O suspension).
b Isolated yields.
9

Thus, by using the optimized conditions, several alkynes and azides were employed
as substrates in the click reactions to afford the corresponding 1,2,3-triazols as shown in
Table 3. Herein, we performed several experiments in order evaluate the influence of
substrate structures over the click reaction and probe the robustness of our system for the
synthesis of 1,2,3-triazols compounds with a large variety of chemical skeleton. Firstly, we
employed azides containing electron-donating 10 and electron-withdrawing 11 groups in
reactions with alkyne 1 (Table 3, entries 1 and 2, respectively). When the azide contained an
electron-donating group (Table 3, entry 1), the triazole product (13) was obtained in 41 %
yield after 5 h of reaction. However, when an azide containing an electron-withdrawing
group was employed (Table 3, entry 2) a yield of 75 % for the triazole product (14) was
observed after 3 h of reaction, indicating a higher reaction rate and selectivity for the click
compound in agreement with previous reports.[32,33] Then, we probed the influence of the
size of the chain linked to the triazole group over the yield for the respective click product.
To this end, we employed as substrates two alkynes derived from eugenol, a natural
product found in several aromatic plants and corresponding to the main component of
essential oil from cloves. More specifically, we employed alkynes with three (Table 3, entry
3) and five (Table 3, entry 4) carbon atoms in the aliphatic chain. In both cases, high yields
were observed after 3 h of reaction. When the eugenol derivative (2) (containing a three
carbon atom aliphatic chain) was employed as substrate, 90 % yield for the unpublished,
novel click product 15 was observed. On the other hand, the utilization of a substrate with a
five carbon aliphatic chain (3) lead to a drop in the yield to 71 % for 16, which is also
novel/unpublished. We also performed click reactions employing as substrates alkynes
derived from two other natural products, denoted compound 5, which was obtained from
10

cinnamic acid, and compound 6, which is derived from vaniline (Table 3, entries 6 and 7). In
both cases, the reaction of compounds 5 and 6 with benzyl azide 9 afforded the unpublished
click compounds 18 and 19 in synthetically useful yields (61 and 57 %, respectively). This
results indicate that the utilization of Cu2O spheres as source of Cu(I) species under our
reported conditions can represent a promising strategy for the synthesis of novel click
products derived from natural raw-materials, generating complex molecules with high
aggregated-value using natural products as starting material. In order to demonstrate the
versatility of our Cu2O spheres for this target application, satisfactory yields were obtained
for a variety of alkynes (4, 7 and 9) as substrates for the reaction with benzilazide 9 (Table 3,
entries 5, 8 and 9), which produced three novel, unpublished compounds (17, 20, and 21,
respectively).
11

Table 3 - Click reactions using different alkynes and azides in the presence of Cu2O spheres as catalysta
Reaction Yield
Time (h) (%)b
Entry
1
Alkyne
Azide
Product
5
3
41
75
2
3
4
3
3
90
71
12

Table 3 – continued
65
5
2
2
6
61
2
7
57
76
8
2
13

Table 3 – continued
17
9
11
(4)
a All the reactions were performed using 1.0 equivalent of alkyne (1) and 1.2 equivalent of azide (2), 20 mol% of catalyst (Cu basis, 310 µL of
Cu2O suspension).
b Isolated yields.
* novel/unpublished molecules
14

A general proposed mechanism for the cycloaddition reaction between terminal
alkynes and benzyl azides in the presence of Cu2O spheres as the source of Cu(I) catalytic
species is shown in Figure 4.[34] As we employed a suspension containing solid copper(I)
species (Cu2O), it is intuitive that the CuAAC reaction would occur at the particle
surface.[35,36] In this context, the proposed reaction mechanism would involve the
following steps: i) alkyne coordination onto the Cu2O surface; ii) its deprotonation to form
the alkynyl-copper(I) intermediate, iii) nucleophilic attack from alkynyl-copper(I)
intermediate to the azide followed by its coordination onto the Cu2O surface; (iv) the
cycloaddition reaction, (v) protonation of C–Cu bond followed by iv) desorption of 1,2,3-
triazole product to the reaction medium.
Figure 4. Proposed mechanism for the click reaction in the presence of Cu2O spheres as
catalysts (source of Cu(I) active species).
15

Conclusions
We described herein the utilization of monodisperse Cu2O spheres as an efficient
source of Cu(I) catalytic species for the synthesis of 1,2,3-triazoles via the Copper(I)-
catalyzed azide–alkyne cycloaddition (CuAAC) reaction (also known as click reaction)
between terminal alkynes and benzyl azides. The Cu2O spheres were successfully obtained
in high yields (93 %) in only 10 minutes by a simple and robust polyol approach using
o
ethyleneglycol as solvent and PVP as stabilizer at 172 C. The utilization of Cu2O spheres as
catalysts (source of Cu(I) species) led superior performance in the click reaction as
compared to conventional methods employing CuSO4 and sodium ascorbate as the catalyst
system under the same experimental conditions (time, temperature, and Cu loading).
Interestingly, using Cu2O spheres as source of Cu(I) species, satisfactory yields, for a wealth
of substrates with different chemical skeletons under mild conditions, ligand-free, and in an
open reactor (without inert atmosphere), were obtained demonstrating the promising
application of Cu2O spheres towards click reactions. Moreover, the reported approach
enabled the synthesis of seven unpublished/novel molecules including derivate compounds
from natural raw-material, showing the applicability of our reported approach for the
synthesis of new structures by click chemistry. We believe the results reported herein shed
new insights into the optimization of activity and versatility of click reactions towards the
synthesis of target molecules in environmentally friendly conditions.
Acknowledgements
This work was supported by the Fundação de Amparo à Pesquisa do Estado de São
Paulo (FAPESP, grant number 2015/21366-9). T.S.R. thanks CAPES, A.G.M.S. thanks CNPq,
16

and L.C.O. thanks FAPEMIG for the fellowships. R.R.T is grateful to FAPEMIG for financial
support.
References
[1]
[2]
[3]
[4]
H.C. Kolb, M.G. Finn, K.B. Sharpless, Angew. Chemie Int. Ed. 40 (2001) 2004–2021.
K. V Gothelf, K.A. Jørgensen, Chem. Rev. 98 (1998) 863–910.
A. Padwa, in:, I.B.T.-C.O.S. Fleming (Ed.), Pergamon, Oxford, 1991, pp. 1069–1109.
V. V Rostovtsev, L.G. Green, V. V Fokin, K.B. Sharpless, Angew. Chemie 114 (2002)
2708–2711.
[5]
[6]
[7]
[8]
[9]
J.E. Moses, A.D. Moorhouse, Chem. Soc. Rev. 36 (2007) 1249–1262.
M.-O. Simon, C.-J. Li, Chem. Soc. Rev. 41 (2012) 1415–1427.
H.C. Kolb, K.B. Sharpless, Drug Discov. Today 8 (2003) 1128–1137.
P. Thirumurugan, D. Matosiuk, K. Jozwiak, Chem. Rev. 113 (2013) 4905–4979.
P.L. Golas, K. Matyjaszewski, Chem. Soc. Rev. 39 (2010) 1338–1354.
[10] B. Yao, J.Z. Sun, A. Qin, B.Z. Tang, J. Inorg. Organomet. Polym. Mater. 25 (2015) 37–
46.
[11] D. Rosner, T. Schneider, D. Schneider, M. Scheffner, A. Marx, Nat. Protoc. 10 (2015)
1594–1611.
[12] A. Baron, Y. Bleriot, M. Sollogoub, B. Vauzeilles, Org. Biomol. Chem. 6 (2008) 1898–
1901.
[13] Y. Jiang, D. Kong, J. Zhao, Q. Qi, W. Li, G. Xu, RSC Adv. 4 (2014) 1010–1014.
[14] S. Díez-González, S.P. Nolan, Angew. Chemie Int. Ed. 47 (2008) 8881–8884.
[15] S. Özçubukçu, E. Ozkal, C. Jimeno, M.A. Pericàs, Org. Lett. 11 (2009) 4680–4683.
[16] J. Garcia-Alvarez, J. Diez, J. Gimeno, Green Chem. 12 (2010) 2127–2130.
17

[17] A. Pathigoolla, R.P. Pola, K.M. Sureshan, Appl. Catal. A Gen. 453 (2013) 151–158.
[18] F. Alonso, Y. Moglie, G. Radivoy, Acc. Chem. Res. 48 (2015) 2516–2528.
[19] T. Jin, M. Yan, Y. Yamamoto, ChemCatChem 4 (2012) 1217–1229.
[20] C. Deraedt, N. Pinaud, D. Astruc, J. Am. Chem. Soc. 136 (2014) 12092–12098.
[21] J. Totobenazara, A.J. Burke, Tetrahedron Lett. 56 (2015) 2853–2859.
[22] K. Chanda, S. Rej, M.H. Huang, Chem. – A Eur. J. 19 (2013) 16036–16043.
[23] K. Chanda, S. Rej, M.H. Huang, Nanoscale 5 (2013) 12494–12501.
[24] Y.-H. Tsai, K. Chanda, Y.-T. Chu, C.-Y. Chiu, M.H. Huang, Nanoscale 6 (2014) 8704–
8709.
[25] R.R. Teixeira, J.L. Pereira, S.F. Da Silva, S. Guilardi, D.A. Paixão, C.P.A. Anconi, W.B. De
Almeida, J. Ellena, G. Forlani, J. Mol. Struct. 1061 (2014) 61–68.
[26] T.F. Borgati, R.B. Alves, R.R. Teixeira, R.P. de Freitas, T.G. Perdigão, S.F. da Silva, A.A.
dos Santos, A. de J.O. Bastidas, J. Brazilian Chem. Soc. 24 (2013) 953–961.
[27] W. Chen, L. Li, Q. Peng, Y. Li, Nano Res. 5 (2012) 320–326.
[28] H. Nandivada, X. Jiang, J. Lahann, Adv. Mater. 19 (2007) 2197–2208.
[29] J.C. Park, J. Kim, H. Kwon, H. Song, Adv. Mater. 21 (2009) 803–807.
[30] A. Buljan, M. Llunell, E. Ruiz, P. Alemany, Chem. Mater. 13 (2001) 338–344.
[31] M. Yang, J.-J. Zhu, J. Cryst. Growth 256 (2003) 134–138.
[32] L. Xu, X. Chen, Y. Wu, C. Chen, W. Li, W. Pan, Y. Wang, Nanotechnology 17 (2006)
1501-1505.
[33] Z.P. Demko, K.B. Sharpless, Angew. Chemie Int. Ed. 41 (2002) 2113–2116.
[34] Z.P. Demko, K.B. Sharpless, J. Org. Chem. 66 (2001) 7945–7950.
[35] N. Balcioǧlu, I. Uraz(Ünalan), C. Bozkurt, F. Sevin, Polyhedron 16 (1997) 327–334.
[36] W.F. Paxton, J.M. Spruell, J.F. Stoddart, J. Am. Chem. Soc. 131 (2009) 6692–6694.
18

[37] P. Veerakumar, M. Velayudham, K.-L. Lu, S. Rajagopal, Catal. Sci. Technol. 1 (2011)
1512–1525.
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Graphical abstract
20

Highlights
·
·
·
·
·
Cu2O spheres with improved performance towards azide-alkyne click reactions
High yield synthesis of Cu2O well-defined spheres displaying monodisperse sizes
Click reactions under ligand-free and ambient conditions in an open reactor
Cu2O spheres enabled superior performance as compared to a conventional protocol
High yields for click products and seven of them have not been previously reported
21