Click chemistry from organic halides, diazonium salts and anilines in water catalysed by copper nanoparticles on activated carbon

Article abstract of DOI:10.1039/c1ob05735a

An easy-to-prepare, reusable and versatile catalyst consisting of oxidised copper nanoparticles on activated carbon has been fully characterised and found to effectively promote the multicomponent synthesis of 1,2,3-triazoles from organic halides, diazonium salts, and aromatic amines in water at a low copper loading.

Full text of DOI:10.1039/c1ob05735a

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PAPER
Click chemistry from organic halides, diazonium salts and anilines in water
catalysed by copper nanoparticles on activated carbon†‡
Francisco Alonso,*a Yanina Moglie,a Gabriel Radivoyb and Miguel Yus*a
Received 10th May 2011, Accepted 16th June 2011
DOI: 10.1039/c1ob05735a
An easy-to-prepare, reusable and versatile catalyst consisting of oxidised copper nanoparticles on
activated carbon has been fully characterised and found to effectively promote the multicomponent
synthesis of 1,2,3-triazoles from organic halides, diazonium salts, and aromatic amines in water at a low
copper loading.
achieve good yields. More advantageous are the methodologies
in which the organic azides are generated in situ from organic
Introduction
The concepts of click chemistry1 and green chemistry2 share a
halides (three-component alkyne–azide cycloaddition) since (a)
series of stringent criteria in order to design and implement more
hazards derived from their isolation and handling are minimised,
efficient and environmentally benign processes. In recent years,
(b) the time consuming and waste generating additional synthetic
nano-catalysis has emerged as a sustainable and competitive
step is avoided, and (c) the common organic solvents utilised
alternative to conventional catalysis since the metal nanoparticles
(e.g., dioxane, toluene, DMF, dichloromethane, hexane) can be
possess a high surface-to-volume ratio, which enhances their
replaced by neat water. In this vein, CuNPs on alumina catalysed
activity and selectivity, while at the same time maintaining the
the multicomponent synthesis of 1,2,3-triazoles, in modest to
intrinsic features of a heterogeneous catalyst.3 In particular,
good yields, starting from activated organic halides at room
temperature in water.9 The catalyst was reused for three cycles but
its preparation seems rather tedious, through an aerogel method
under supercritical conditions using copper(II) acetylacetonate,
aluminium isopropoxide, methanol, toluene, and deionised water.
CuI/Cu NPs of 80–300 nm were supported on pre-treated
activated carbon and the resulting catalyst applied to the three-
com◦ponent reaction of activated organic halides in water at
100 C.10
The above described methods based on supported CuNPs are
clearly convenient in the sense that the catalysts can be easily
recovered and reused. However, the long and tedious procedures
usually required for the heterogenisation of copper and the limited
substrate scope can curtail the widespread utilisation of this type of
catalyst. Therefore, there is still an upsurge of interest in developing
easy-to-prepare and versatile heterogeneous copper catalysts that
efficiently enable the synthesis of triazoles in water.
the immobilisation of metal nanoparticles on high-surface-area
inorganic supports allows a higher stability and dispersity of the
particles as well as a further exploitation of the special activity
and recycling properties of the catalyst.4 With these principles in
mind, new possibilities arise for the copper-catalysed Huisgen5 1,3-
dipolar cycloaddition of organic azides and alkynes,6 the paradigm
of a click reaction.
In fact, despite the fact that the aforementioned cycloaddition
has been intensively studied, the application of supported copper
nanoparticles (CuNPs) to this reaction is scant. For instance,
CuNPs immobilised in aluminium oxyhydroxide nanofiber were
shown to be highly active in the cycloaddition of azides and alkynes
at room temperature in hexane.7 Very recently, copper nitride
nanoparticles supported on a superparamagnetic mesoporous
microsphere, Cu3N/Fe3N@SiO2, were found to catalyse the click
cycloaddition at room temperature in acetonitrile.8 In this case,
the catalyst was reusable but the presence of triethylamine and
long reaction times (12 h to 14 d) were mandatory in order to
Owing to our dedication to study and understand the re-
activity of active metals,11 we found out that active copper
[obtained from CuCl2·2H2O, lithium metal, and a catalytic
amount of 4,4¢-di-tert-butylbiphenyl (DTBB) in THF at room
temperature] was able to reduce carbonyl compounds, imines and
sulfonates, and promoted the hydrodehalogenation of organic
halides under very mild conditions.12 We also discovered that
CuNPs are formed when the active copper is generated from
anhydrous CuCl2 under the above mentioned conditions. These
unsupported copper nanoparticles (10 mol%) effectively catalysed
the 1,3-dipolar cycloaddition of organic azides and terminal
aDepartamento de Qu´ımica Orga´nica, Facultad de Ciencias and Instituto
de S´ıntesis Orga´nica (ISO), Universidad de Alicante, Apdo. 99, 03080 Al-
icante, Spain. E-mail: falonso@ua.es, yus@ua.es; Fax: (+34) 965903549;
Tel: (+34) 965903548
bDepartamento de Qu´ımica, Instituto de Qu´ımica del Sur (INQUISUR-
CONICET), Universidad Nacional del Sur, Avenida Alem 1253, 8000 Bah´ıa
Blanca, Argentina
† Dedicated to the memory of Professor Rafael Suau.
‡ Electronic supplementary information (ESI) available: general remarks,
XRD spectrum of the catalyst, experimental procedures, and spectroscopic
characterisation of new compounds. See DOI: 10.1039/c1ob05735a
◦
alkynes in the presence of triethylamine at 65 C in THF.13
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Table 1 Screening of copper catalysts in the three-component azide–
Remarkably short reaction times (10–120 min), comparable to
those previously reported under microwave heating, were recorded
in the absence of any stabilising additive or ligand. Unfortunately,
the CuNPs underwent dissolution under the reaction conditions
which precluded their reuse. More recently, we introduced a
catalyst consisting of oxidized copper nanoparticles on activated
carbon, readily prepared under mild conditions, which manifested
a high versatility in the multicomponent Huisgen 1,3-dipolar
cycloaddition in water.14 Not only organic halides, but examples of
other azide precursors, such as an epoxide, diazonium salt, aniline,
and alkene, were successfully transformed into the corresponding
1,2,3-triazoles. We would like to present herein a more complete
study on the catalyst and its substrate scope, including diazonium
salts and anilines as aryl halide substitutes.
alkyne cycloaddition in watera
Entry
Support (mol% Cu)b
T/◦C
Time(h)
Yield(%)c
1
2
3
4
5
6
7
8
SiO2 (1)
Al2O3 (1)
TiO2 (1)
MgO (1)
ZnO2 (1)
Al silicate (1)
Al (1)
70
70
70
70
70
70
70
70
70
70
70
25
25
70
70
70
70
25
70
70
4
9
90 (16)
>99 (13)
74
16
57
>99 (19)
18
17
>99 (0)
80
0
33
31
90
>99 (20)
>99
24
24
24
6
24
24
9
14
24
24
24
7
MCM-10 (1)
magnetite (1)
graphite (5)
9
10
11
12
13
14
15
16
17
18
19
20
graphite (5)d
graphite (5)
Catalyst screening
graphite (1)
graphite (1)
In order to analyse the effect of the support, an array of
copper catalysts were prepared by simply adding the support to
a suspension of the recently prepared CuNPs. This suspension
was readily obtained by mixing anhydrous copper(II) chloride,
lithium metal, and a catalytic amount of DTBB (10 mol%) in
THF at room temperature. The catalysts were used as prepared
without any further pre-treatment. The activity of the different
catalysts was tested in the cycloaddition of benzyl bromide
(1a) and phenylacetylene (2a) (Table 1). The best results were
obtained with SiO2 (entry 1), Al2O3 (entry 2), Al silicate (entry 6),
magnetite (entry 9), graphite (entry 14), MWCNT (entry 15), and
activa◦ted carbon (entry 19), with the yields being ≥90% in £9 h
at 70 C. Among them, activated carbon15 exhibited the highest
activity (>99% yield, 3 h), giving triazole 3aa in quantitative yield
after reuse in a second cycle (entry 19). In a control experiment,
the model reaction was carried out with activated carbon, in the
absence of copper (entry 20); the reaction yield was much lower
(50%) and the process lacked regioselectivity.
MWCNTe (5)
activated carbon (5)
activated carbon (5)d
activated carbon (5)
activated carbon (1)
activated carbon (0)
6
7
24
24
3
0
30
>99 (>99)
24
50f
a Reaction conditions: 1a (1 mmol), NaN3 (1.1 mmol), and 2a (1 mmol)
in H2O. b Amount of copper added to the support. c GLC yield; the yield
after a second cycle is in parenthesis. d Solvent-free reaction. e Multi-walled
carbon nanotube. f 3aa was obtained as a 1 : 1.3 mixture of regioisomers;
alkyne 19%; azide 31%.
of which would be expected at 934.0 eV, a correction could be
applied accordingly. Therefore, the corrected values would be:
529.8 and 531.8 eV for O (1s), and 931.7, 934.0 and 943.3 eV
for Cu (2p3/2). From these results we can deduce that the surface
of the copper nanocatalyst is mainly oxidised. The O (1s) peak
at 529.8 can be ascribed to the CuO phase, whereas the peak at
531.8 eV is suggested to be associated with species chemisorbed
on the carbon.17 The Cu (2p3/2) region might be assigned to Cu2O
(931.7 eV) and CuO (934.0 eV), with the peak at 943.3 eV being a
satellite shake-up feature characteristic of Cu(II) species.18 These
data are in agreement with the presence of Cu2O and CuO detected
in the selected-area electron-diffraction pattern (SAED) of the
CuNPs (Fig. 5). The application of oxidised CuNPs to the click
reaction is a matter of recent discovery.19 Mixed Cu/Cu-oxide19a
(mostly composed of Cu2O and CuO nanoparticles), CuO hollow
nanostructures,19b and PVP-stabilised Cu2O nanoparticles19c have
been found to catalyse the 1,3-dipolar cycloaddition of pre-formed
azides and terminal alkynes. To the best of our knowledge,
however, this is the first time that oxidised CuNPs have been
utilised in the three-component version, i.e. the reaction of an
organic halide with sodium azide and a terminal alkyne in one
pot.
Catalyst characterisation
The copper-on-activated-carbon catalyst was fully characterised
in order to ascertain its nature and morphology. A copper content
in the catalyst of 1.6 wt% was determined by inductively coupled
plasma mass spectrometry (ICP-MS). Transmission electron mi-
croscopy (TEM) revealed the presence of spherical nanoparticles
dispersed on the active carbon support with an average size of
ca. 6 2 nm (Fig. 1). Energy-dispersive X-ray (EDX) analysis on
various regions confirmed the presence of copper on the support,
with energy bands of 8.04, 8.90 keV (K lines) and 0.92 keV (L line)
(Fig. 2). The XRD diffractogram did not show any significant peak
for copper due to the small crystal domains and/or low copper
loading weight.16 The XPS spectrum displays two O (1s) peaks at
532.2 and 534.2 eV (Fig. 3), and three Cu (2p3/2) peaks at 934.1,
936.4, and 945.7 eV (Fig. 4). Both the O (1s) and Cu (2p3/2) values
are abnormally high with respect to those found in the literature
for copper-on-carbon catalysts.17 Since the C (1s) peak (284.4 eV)
was used as an internal standard to calibrate the binding energies,
we believe that a differential charge phenomenon could occur
as a result of the difficulties in differentiating the adventitious
carbon from the carbon support by XPS. If we, however, assume
that the peak at 936.4 eV corresponds to Cu(II), the typical value
Synthesis of 1,2,3-triazoles from organic halides
With an optimised catalyst and reaction conditions in hand,
we first studied the multicomponent click reaction of activated
organic halides and phenylacetylene (2a) in water at 70 ◦C, using
0.5 mol% CuNPs/C (Table 2, entries 1–7). Both benzyl bromide
and chloride (1a) gave triazole 3aa in excellent yield, although the
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Fig. 3 XPS spectrum of the CuNPs/C at the O (1s) level.
Fig. 4 XPS spectrum of the CuNPs/C at the Cu 2p3/2 level.
Fig. 1 TEM micrograph and size distribution of CuNPs/C.
Fig. 2 EDX spectrum of CuNPs/C.
former reacted faster (entry 1). Benzyl bromides bearing either
electron-withdrawing (1b) or electron-donating groups (1c), as
well as the more electronically neutral 9-anthryl bromide (1d),
also reacted nicely (entries 2–4). Cinnamyl bromide (1f) yielded
a single triazole 3fa under the reaction conditions, in spite of the
fact that allylic azides are prone to undergo a [3,3]-sigmatropic
rearrangement leading to mixtures of triazoles (Table 2, entry 5).20
Some a-halocarbonyl compounds, such as a-chloroacetophenone
(1g) or ethyl a-bromoacetate (1h), were also studied, with the
chloride again reacting more sluggishly than the bromide (entries
6 and 7). It is worthy of note that deactivated alkyl halides
could be also used as the azide precursors in the reaction with
phenylacetylene (entries 8–10), with a solvent system composed of
H2O–EtOH 1 : 1 providing the best results in entries 8 and 9. As
expected, the reactivity followed the trend RI > RBr > RCl, with
both the iodide (1i, X = I) and bromides (1j, 1k) reacting at 70 ◦C
Fig.
CuNPs/C.
5 Selected area electron diffraction (SAED) pattern of the
◦
and the chloride (1i, X = Cl) at 100 C. Then, we tested alkynes
other than phenylacetylene in the reaction with benzyl bromide
(1a). Phenyl propargyl ether (2b), 4-methoxyphenylacetylene (2c),
2-ethynylpyridine (2d), and N-propargylphthalimide (2e) were
transformed into the corresponding triazoles in good yields under
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Table 2 Three-component 1,3-dipolar azide–alkyne cycloaddition catalysed by CuNPs/C using organic halides as the azide precursorsa
Entry
1
Organic halide
Alkyne
Time(h)
Triazole
Yield(%)b
3
6
98
99
2
3
2a
2a
5
4
99
98
4
2a
6
90
5
6
2a
2a
3
7
94
82
7
2a
4
98
8
9
2a
2a
5c
98
94
8c,d
8c
93
89
10
11
2a
8
7
76
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Table 2 (Contd.)
Entry
12
Organic halide
Alkyne
Time(h)
6
Triazole
Yield(%)b
90
13
14
1a
1a
6
8
92
84
15
16
1a
8
82
92
8c,d
17
18
8c,d
89
92
6e
19
20
1a
10e
8
87
89
a Reaction conditions: 1 (1 mmol), 2 (1 mmol), NaN3 (1.1 mmol), CuNPs/C (0.5 mol%) in H2O at 70 ◦C. b Isolated yield. c Reaction in H2O–EtOH 1 : 1.
d Reaction at 100 ◦C. e 2 mmol of 1a
the standard reaction conditions (entries 11–14). The successful
reaction with trimethylsilylacetylene (2f) provides an indirect entry
into the 1-monosubstituted triazoles, which could be obtained
after proper desilylation, thus making unnecessary the handling
of acetylene or acetylene precursors (entry 15).21 Interestingly,
the 1,3-dipolar cycloaddition was also accomplished for the more
reluctant to react alkyl-substituted halides and alkynes (1i and 1l
with 2g and 2h, respectively) (entries 16 and 17). The synthesis of
bistriazoles was also readily effected from diynes 2i and 2j with
two equivalents of benzyl bromide (entries 18 and 19). Moreover,
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Table 3 Three-component 1,3-dipolar azide–alkyne cycloaddition catalysed by CuNPs/C using diazonium salts as the azide precursorsa
Entry
1
Diazonium salt
Alkyne
Time(h)
2
Triazole
Yield(%)b
85
2
3
2a
2a
4
4
75
71
4
5
2a
2a
4
4
78
92
6
7
4a
4b
2
4
88
91
8
9
4e
4e
3
8
90
83
a Reaction conditions: 4 (1 mmol), 2 (1 mmol), NaN3 (1.1 mmol), CuNPs/C (0.5 mol%) in H2O at 70 ◦C. b Isolated yield.
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Table 4 Three-component 1,3-dipolar azide–alkyne cycloaddition catalysed by CuNPs/C using aromatic amines as the azide precursorsa
Entry
1
Aromatic amine
Alkyne
Time(h)
3
Triazole
Yield(%)b
90
2
3
2a
2a
3
7
95
64
4
2a
7
80
5
6
2a
2a
4
3
78
90
7
8
2a
2a
3
8
66
70
9
6a
6a
3
3
93
89
10
a Reaction conditions: 6 (1 mmol), 2 (1 mmol), NaN3 (1.1 mmol), t-BuONO (1.6 mmol), CuNPs/C (0.5 mol%) in H2O at 70 ◦C. b Isolated yield.
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the haloalkyne 1m was directly converted, for the first time, into
the bicyclic triazole 3m, while other reported procedures involve
multistep syntheses.22
6h) behaved better than the more sterically demanding ortho-
chloroaniline (6f) (entries 3–5). A lower yield was recorded for
4-(trifluoromethyl)aniline 6j, with an I(-) inductive effect group,
in comparison with 4-methylaniline (6i), with an I(+) inductive
effect group (entries 6 and 7). Naphthyl-1-amine (6k) reacted
somewhat more sluggishly giving rise to the expected triazole in
70% isolated yield (entry 8). The methodology was also applicable
to the alkyl- and cycloalkyl-substituted alkynes 2h and 2k, which
when combined with aniline produced 5ah and 5ak, respectively,
in high yields and relatively quickly (entries 9 and 10).
Synthesis of 1,2,3-triazoles from diazonium salts
Generally, the synthesis of 1,2,3-triazoles through click chemistry
involves pre-formed azides or, more desirably, in situ generated
azides from organic halides. In some cases, however, the sub-
strate availability and functionality hampers this synthesis and
a functional group transformation prior to the click reaction is
required. In this respect, we explored some alternative substrates
to the organic halides as azide precursors which, being compatible
with the standard reaction conditions, could expand the versatility
of the catalyst. We discovered that diazonium salts are potential
substitutes for the less reactive aromatic halides and could be used
in the three-component synthesis of 1,2,3-triazoles under the same
conditions applied to the organic halides (Table 3).
In a first example, commercially available phenyldiazonium
tetrafluoroborate (4a) and phenylacetylene (2a) gave 1,4-diphenyl-
1,2,3-triazole (5aa) in 85% yield and relatively short reaction
time (entry 1). Isolated yields of around 75% were achieved for
diazonium salts with either electron-donating (4b) or electron-
withdrawing (4c, 4d) substituents at the para position (entries
2–4). The reaction with commercial 4-nitrophenyldiazonium
tetrafluoroborate (4e) led to the expected triazole 5ea in high
yield and the same reaction time as for the substrates 4b–
4d (entry 5). The process proved to be less efficient for alkyl-
substituted alkynes, with 4a mainly leading to azobenzene. In
contrast, other alkynes with electronically different substituents,
such as 4-methoxyphenylacetylene (2c), 2-ethynylpyridine (2d),
4-trifluoromethylphenylacetylene (2k) or trimethylsilylacetylene
(2f), readily gave the products derived from the diazonium salts
4a, 4b, and 4e (entries 6–9).
Stability and recycling of the catalyst
The catalyst was handled in air and all the experiments were
carried out without air exclusion; these are advantages that
make the process operationally simple. The reaction of benzyl
bromide (1a) and phenylacetylene (2a), when conducted at 0.1 M
(1 mmol starting materials, 10 ml H2O) and 0.01 M (1 mmol
starting materials, 100 ml H2O), also afforded the expected
triazoles in high conversions (>99% and 80%, respectively), albeit
longer reaction times were required (8 and 24 h, respectively).
Furthermore, in most cases the progress of the reaction could be
followed visually. The original triphasic reaction was composed
of a bottom aqueous phase and a top oily layer, with the latter
containing both the catalyst and the starting materials. When the
reaction ended, one solid piece at the surface of a transparent
and colourless solution was observed, where the triazole was in
the core of the solid covered by the catalyst. The black solid was
nearly spherical or with a shape which resembled that of a virus or a
naval mine (Fig. 6). This shape was the result of the intermolecular
forces operating between two hydrophobic components in an
aqueous medium. It is worthwhile mentioning that, despite the
small amount of catalyst utilised, it could be easily recovered by
filtration (after treating with ethyl acetate) and reused, leading to
triazole 3aa in excellent yields along five consecutive cycles (Fig. 7).
No detectable leaching of copper was observed after the fifth cycle
by ICP-MS.
Synthesis of 1,2,3-triazoles from aromatic amines
Due to the successful use of diazonium salts in the three-
component dipolar cycloaddition, we went one step ahead and
implemented a protocol to use anilines as aromatic azide precur-
sors. Among the different methods of synthesis of aromatic azides
from anilines, that recently developed by Moses et al. is worthy
of note.23 In this article, anilines were reacted with t-BuONO
and TMSN3 in CH3CN, with the resulting azides being further
subjected to the click reaction in one pot.23a The rate of formation
of the triazoles was significantly enhanced by using microwave
radiation.23b The whole process was, however, sequential and,
therefore, the course of the azide formation needed monitoring
before the cycloaddition. We were delighted to find out that
the direct conversion of anilines into 1,2,3-triazoles could be
attained with t-BuONO and NaN3 in water under the catalysis
of CuNPs/C. This four-component reaction is favourable since
cheaper sodium azide is used, it is performed in water, and no
monitoring of intermediates is needed.
Fig. 6 Images of triazole products covered with the catalyst at the end of
the reaction. Approximate size: 8 mm (left), 10 mm (right).
Nature of the catalysis
A variety of electronically different anilines was studied in
the reaction with phenylacetylene (2a) (Table 4). The triazoles
derived from electronically neutral aniline (6a) and electronically
rich 4-methoxyaniline (6b) were obtained in high yields after 3 h
(entries 1 and 2). The meta- and para-chloroanilines (6g and
Copper is an essential nutrient needed to prevent anemia and
keep the skeletal, reproductive, and nervous systems healthy. The
U.S. National Research Council currently recommends that adults
receive 1.5–3.0 mg of copper daily to prevent deficiencies. A
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Fig. 7 Recycling of the CuNPs/C in the synthesis of the triazole 3aa.
study on the response of healthy adults to varying concentra-
tions of copper in drinking water supported the World Health
Organization’s (WHO) guideline of 2.0 mg L-1 as a safe limit.24
Accumulation of copper in different organs due to a metabolism
disorder (Wilson’s disease) leads to liver cirrhosis, neurological
disturbances and to a complexity of different symptoms.25 It is
also known that an increase in the levels of Cu(I)/Cu(II) in the
brain can increase the likelihood of reactive oxygen species being
generated inappropriately, leading to the oxidative stress that is
observed in neurodegenerative diseases.26
Scheme 1 Experiments on the nature of the catalysis.
According to the above antecedents, to reduce the amounts
of copper in solution for click chemistry should be a priority,
particularly for biological applications. In this sense, it is important
to unveil the nature of the catalysis, with heterogeneous catalysis
by supported metals being advantageous over the homogeneous
counterpart.27 For this purpose, benzyl bromide (1a) and pheny-
lacetylene (2a) were reacted up to a >99% conversion (<3 h)
(Scheme 1). Then, the resulting mixture containing the triazole
3aa was subjected to additional heating, until a total time of 24 h,
in order to force any possible copper leaching. The catalyst and
the triazole were removed by filtration, the aqueous phase was
extracted with ethyl acetate, followed by the addition of fresh
1a and 2a to the resulting aqueous phase. The new mixture was
allowed to react at 70 ◦C for 24 h, affording a ca. 1 : 1 mixture
of the corresponding regioisomeric triazoles in 17% conversion.
This result evidenced that the 1,3-dipolar cycloaddition proceeded
in a non-catalysed manner under thermal conditions. In fact,
this assertion could be corroborated by ICP-MS analyses of the
resulting aqueous phase which gave <50 ppb of copper. All these
experiments are in agreement with a process of heterogeneous
nature.28
and phenylacetylene (2a) at both 10 and 1 mol% catalyst loadings.
Copper metal gave the expected triazole 3aa in about 50% yield,
which remained steady after prolonged heating (Table 5, entry 1).
Notably, a maximum 90% yield was observed for 10 mol% Cu2O
catalyst with a similar trend seen for 10 mol% CuO (entries 2
and 3). Some side products (10%) were, however, detected and
its recycling furnished triazole 3aa, in only 20% conversion after
24 h, as a ca. 4 : 1 mixture of regioisomers. The conversions
dropped when reducing the catalyst loading for both Cu2O and
CuO (entries 4 and 5). Therefore, the nanosized character seems
to be decisive in the high performance of our catalyst (entry 6).
Very recently, it has been disclosed that defect sites on CuNPs
can induce intense dissociation of water to form atomic oxygen,
Table 5 Three-component 1,3-dipolar azide–alkyne cycloaddition catal-
ysed by different copper catalystsa
Entry
Catalyst
mol (%)
Yield(%)(3 h)b
Yield(%)(24 h)b
1
2
3
4
5
6
Cu
Cu2O
CuO
Cu2O
CuO
CuNPs/C
10
10
10
1
1
0.5
52
52
90c
69
90c,d
88
Comparison with other catalysts
In principle, any laboratory-made catalyst should be more efficient
than commercially available catalysts used for the same purpose.
Otherwise, it is difficult to economically justify the time, materials
and human resources employed during its preparation. Taking
into account this premise, we undertook a comparative study on
the reactivity of the CuNPs/C with the commercially available
Cu, Cu2O, and CuO heterogeneous catalysts. The standard
conditions were applied to the reaction of benzyl bromide (1a)
46
75
78
—
53
>99e
a Reaction conditions: 1a (1 mmol), 2a (1 mmol), NaN3 (1.1 mmol), catalyst
in H2O at 70 ◦C. b GLC yield. c 10% side products were obtained. d In a
second cycle, the product was obtained in 20% conversion after 24 h as
a ca. 4 : 1 mixture of regioisomers. e Reutilised in five cycles with near
quantitative yield of triazole 3aa.
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which might somehow participate in the redox mechanism of the
reaction.29 This fact, together with the large surface-to-volume
ratio of the nanocatalyst and its distribution on the support, could
account for the behaviour of the CuNPs/C when compared with
the commercial bulk catalysts.
General procedure for the CuNPs/C-catalysed click reaction in
water using organic halides or diazonium salts as the azide
precursors
NaN3 (72 mg, 1.1 mmol), the organic halide or diazonium salt
(1 mmol), and the alkyne (1 mmol) were added to a suspension
of CuNPs/C (20 mg, 0.5 mol% Cu) in H2O (2 mL). The reaction
mixture was warmed to 70 ◦C and monitored by TLC and/or GLC
until total conversion of the starting materials. Water (30 mL)
was added to the resulting mixture, followed by extraction with
EtOAc (3 ¥ 10 mL). The collected organic phases were dried with
anhydrous MgSO4 and the solvent was removed in vacuo to give the
corresponding triazoles 3 or 5, which did not require any further
purification.
Conclusions
We have developed a catalyst consisting of copper nanopar-
ticles supported on activated carbon for the synthesis of 1,4-
disubstituted-1,2,3-triazoles through a multicomponent alkyne–
azide 1,3-dipolar cycloaddition in water. The catalyst was fully
characterised and the copper nanoparticles were determined to
mostly be in the oxidised forms of Cu2O and CuO. A wide
range of triazoles has been synthesised from organic chlorides,
bromides and iodides, either activated or non-activated, and
different terminal alkynes. Two new protocols were devised for
the click reaction involving diazonium salts or anilines as aryl
azide precursors, with the latter being a tetra-component process.
The catalytic system and methodologies described herein follow
the majority of the principles of the Green Chemistry1 framework
and the rigorous criteria of click chemistry,2 namely: (a) waste
is minimised to the corresponding sodium salt by-products since
the azides are generated in situ; (b) the atom economy is high as
three or four materials are incorporated into the final product; (c)
the handling of potentially hazardous organic azides is prevented;
(d) all reactions are performed in neat water or ethanol–water;
(e) the catalyst preparation is conducted at ambient temperature
and, though heating is necessary in the triazole synthesis, most
of the reaction times are relatively short (£ 5 h); (f) derivatisation
is also minimised; (g) the catalyst is used at low copper loading
and can be reused; (h) the monitoring of the process can be done
visually; (i) all the experiments presented in this article are safe
and no explosion occurred by in situ generation of the azides;
(j) the methodology is modular (applicable to different types
of starting materials in the same medium), wide in scope, and
high yielding; (k) all starting materials, reagents, and the catalyst
are commercially or readily available; (l) the reaction conditions
are simple and the process is insensitive to oxygen and water;
(m) the process is regioselective, providing exclusively the 1,4-
disubstituted-1,2,3-triazoles; (n) the product is easily isolated and
does not require purification. In addition, the catalyst is superior
to other commercial heterogeneous copper catalysts and seemingly
operates under heterogeneous conditions.
General procedure for the CuNPs/C-catalysed click reaction in
water using aromatic amines as the azide precursors
NaN3 (72 mg, 1.1 mmol), aromatic amine (1.0 mmol.), t-BuONO
(190 mL, 1.6 mmol) and the alkyne (1.0 mmol) were added to a
suspension of CuNPs/C (20 mg, 0.5 mol% Cu) in H2O (2 mL).
The reaction mixture was warmed to 70 ◦C and monitored by
TLC until total conversion of the starting materials. Water (30 mL)
was added to the resulting mixture, followed by extraction with
EtOAc (3 ¥ 10 mL). The collected organic phases were dried with
anhydrous MgSO4, and the solvent was removed in vacuo to give
the corresponding triazoles 5, which did not require any further
purification.
Acknowledgements
This work was generously supported by the Spanish Ministe-
rio de Ciencia e Innovacio´n (MICINN; CTQ2007-65218 and
Consolider Ingenio 2010-CSD2007-00006), and the Generalitat
Valenciana (GV; PROMETEO/2009/039). Y. M. acknowledges
the Vicerrectorado de Investigacio´n, Desarrollo e Innovacio´n of
the Universidad de Alicante for a grant. We are also very grateful to
Juan Carlos De Jesu´s, Surface Analysis System, PDVSA Intevep,
Venezuela, for his valuable comments on the XPS analyses.
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The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 6385–6395 | 6395
©