Unsupported copper nanoparticles in the 1,3-dipolar cycloaddition of terminal alkynes and azides

Article abstract of DOI:10.1002/ejoc.200901446

Readily prepared copper nanoparticles were found to catalyse the 1,3-dipolar cycloaddition of azides and alkynes up to rates comparable to those of microwave chemistry. Both the preparation of the nanoparticles and the click reaction are carried out under mild conditions, in short reaction times and in the absence of any stabilising additive or ligand. A variety of 1,2,3-triazoles were prepared in excellent yields. A reaction mechanism was postulated on the basis of different reactivity studies and deuteration experiments. Copper(I) acetylides were demonstrated to be the real intermediate species.

Full text of DOI:10.1002/ejoc.200901446

FULL PAPER
DOI: 10.1002/ejoc.200901446
Unsupported Copper Nanoparticles in the 1,3-Dipolar Cycloaddition of
Terminal Alkynes and Azides
Francisco Alonso,*[a] Yanina Moglie,[a,b] Gabriel Radivoy,[b] and Miguel Yus*[a]
Dedicated to Professor Stephen G. Davies on occasion of his 60th birthday
Keywords: Click chemistry / Cycloaddition / Alkynes / Azides / Copper / Nanoparticles
Readily prepared copper nanoparticles were found to cata-
lyse the 1,3-dipolar cycloaddition of azides and alkynes up
to rates comparable to those of microwave chemistry. Both
the preparation of the nanoparticles and the click reaction
are carried out under mild conditions, in short reaction times
and in the absence of any stabilising additive or ligand. A
variety of 1,2,3-triazoles were prepared in excellent yields. A
reaction mechanism was postulated on the basis of different
reactivity studies and deuteration experiments. Copper(I)
acetylides were demonstrated to be the real intermediate
species.
copper(I)-catalysed process the preferred choice. Recently,
Feringa et al. synthesised various benzotriazoles by a cop-
per-free cycloaddition of azides and arynes, as an interest-
ing variation of the classical 1,3-dipolar cycloaddition.[11e]
The copper(I)-catalysed cycloaddition is normally ac-
complished with success independently of the copper source
utilised, namely, copper(I) salts, normally in the presence of
a base and/or a ligand; in situ reduction of copper(II) salts
(e.g., copper sulfate with sodium ascorbate); and compro-
portionation of copper(0) and copper(II) (generally restric-
ted to biological applications).[4]
Introduction
In recent years, much attention has been devoted to the
Huisgen 1,3-dipolar cycloaddition reaction of organic az-
ides and alkynes[1] taking advantage of the paramount dis-
covery by the groups of Meldal[2] and Sharpless,[3] who in-
dependently reported an unprecedented cycloaddition rate
under copper(I) catalysis. In addition, mild reaction condi-
tions could be applied, furnishing exclusively the 1,4-re-
gioisomer of the triazole product.[4] The fulfillment of a
series of rigorous requirements, as defined by Sharpless et
al.,[5] makes this reaction the click reaction par antonoma-
sia. Nowadays, many research fields[4b,6] benefit from the
high reliability of this reaction, including organic chemis-
try,[4] drug discovery and medicinal chemistry,[7] polymer[8]
and materials science[8a,9] and bioconjugation.[7a,9,10]
Despite the fact that the 1,3-dipolar cycloaddition of al-
kynes and azides has reached an advanced level of develop-
ment, the introduction of variants that can further improve
the efficiency of the reaction and fulfill the requirements of
a truly click reaction are welcome. For instance, different
ligands were found to promote this cycloaddition reaction
by stabilisation of the CuI oxidation state under aerobic
and/or aqueous conditions.[12] The in situ generation of the
organic azides (three-component reaction) also represents
an important advantage, simplifying the experimental pro-
cedure and minimising risks derived from handling hazard-
Catalyst-free Huisgen cycloadditions[11] have been re-
ported in water,[11a,11b] as well as for particularly substituted
or strained alkynes.[11b,11c] In most of the studies, however,
the kinetics and/or the regioselectivity is low, making the
[a] Departamento de Química Orgánica, Facultad de Ciencias and ous azides.[13] The application of microwave chemistry has
Instituto de Síntesis Orgánica (ISO), Universidad de Alicante,
contributed to dramatically reduce the reaction times from
Apdo. 99, 03080 Alicante, Spain
12–24 h (for most of the protocols) to less than 1 h.[14] Ul-
Fax: +34-965903549
E-mail: falonso@ua.es
trasound also proved to be an effective technique to shorten
the reaction times of the three-component version in
water.[15] Some other advances in the title reaction involve
heterogeneous catalysis.[16] Thus, catalysts based on cop-
per(I) immobilised on different supports, such as char-
coal,[16a] zeolites,[16b] silica[16c] or an ionic polymer,[16d] have
yus@ua.es
[b] Departamento de Química, Instituto de Química del Sur (IN-
QUISUR-CONICET), Universidad Nacional del Sur,
Avenida Alem 1253, 8000 Bahía Blanca, Argentina
Fax: +54-2914595187
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200901446.
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F. Alonso, Y. Moglie, G. Radivoy, M. Yus
FULL PAPER
an added value due to their easy recovery and reutilisation more complete study including a wider substrate scope and
capability. Ley et al. reported the successful cycloaddition some experiments that contribute to clarify the reaction
of alkynes and azides by using immobilised reagents and mechanism.
scavengers in prepacked glass tubes in a modular flow reac-
tor.[17]
Results and Discussion
In 2005, it was discovered that copper metal turnings or
powder, in stoichiometric quantity, could be a source of the
catalytic species involved in the title click reaction.[18] Since
then, the use of copper nanoparticles (CuNPs), instead of
bulk copper, has been increasingly explored to reduce both
the catalyst loading and the reaction times.[19] Despite the
interesting behaviour unveiled for CuNPs, there are some
issues that limit their application, competitiveness and gene-
ral acceptance that need to be addressed. For instance, most
of the methods of preparation of CuNPs are rather tedious
due to the multiple steps involved, long reaction time, high
temperatures or use of noncommercially available reagents.
The presence of stabilising agents or solid supports to pre-
vent nanoparticle agglomeration is mandatory in some
cases. The limited substrate scope, as well as the necessity
of an acidic medium or the chromatographic purification of
the reaction products, are additional disadvantages found in
some methodologies. The reaction times, though consider-
ably reduced in some cases, are still relatively long (2–24 h).
Recently, several heterogeneous catalysts based on copper
nanoparticles have disclosed an interesting reuse capability.
Thus, PVP-stabilised CuNPs in formamide were applied to
benzyl azide and some aryl azides and reutilised in up to
four subsequent runs with high product yields in very short
reaction times (15–50 min) at room temperature.[19e] Inmo-
bilised CuNPs in aluminium oxyhydroxide nanofibre were
shown to be also effective and reusable in n-hexane at room
temperature, albeit longer reaction times were required (1–
24 h).[19f] Furthermore, larger copper nanostructures (80–
300 nm) on charcoal catalysed the three-component click
reaction in water at 100 °C (0.5–24 h) and could be reused
in more than 10 successive reactions.[19g]
A suspension of CuNPs was instantaneously prepared
from anhydrous copper(II) chloride, powder lithium metal,
and a catalytic amount of DTBB (10 mol-%, as an electron
carrier) in THF at room temperature. This method was
proven to be more convenient than that originally devel-
oped by Rieke et al., involving the reduction of copper(I)
iodide with potassium metal, along with a catalytic amount
of naphthalene (10 mol-%) in 1,2-dimethoxyethane.[23] In
this case, the extended periods of stirring required (8–12 h
at room temperature) favoured sintering, leading to a grey-
black granular solid suspended in a clear colourless solu-
tion.
The aforementioned suspension of the CuNPs was ana-
lysed by transmission electron microscopy (TEM), X-ray
photoelectron spectroscopy (XPS) and powder X-ray dif-
fraction (XRD). Well-defined spherical nanoparticles were
observed by TEM, with a particle size distribution of ca.
3.0Ϯ1.5 nm (Figure 1). The size of the nanoparticles ob-
tained was smaller than that obtained by using some physi-
cal methods[24] or other reducing agents[25] and akin to that
attained by the clustering of acetone-solvated copper
atoms,[26a] laser electrodeposition[26b] or microwave-assisted
alcohol reduction.[26c]
As part of our dedication to study the reactivity of active
metals,[20] we discovered that a system composed of cop-
per(II) chloride dihydrate (CuCl2·2H2O), lithium metal and
a catalytic amount of 4,4Ј-di-tert-butylbiphenyl (DTBB) in
THF generates active copper with interesting reducing
properties. This copper found application in (1) the re-
duction of carbonyl compounds and imines to alcohols and
secondary amines, respectively;[21a] (2) the hydrodehaloge-
nation of alkyl and aryl fluorides, chlorides, bromides and
iodides (including polyhalogenated aromatic com-
pounds);[21b] and (3) the reduction of alkyl and vinyl sulfo-
nates (including dienol triflates) to alkanes and alkenes,
respectively.[21c] All these reactions were carried out at room
temperature, and deuterated products were easily prepared
by using the corresponding deuterated copper salt
(CuCl2·2D2O). More recently, we observed that CuNPs are
formed under the above-mentioned conditions when using
either copper(II) chloride dihydrate or anhydrous cop-
per(II) chloride. In the latter case, the CuNPs were found
to effectively catalyse the 1,3-dipolar cycloaddition of az-
Figure 1. TEM micrograph and size distribution of the CuNPs. The
ides and terminal alkynes.[22] We wish to present herein a sizes were determined for 230 nanoparticles selected at random.
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Cu Nanoparticles in the 1,3-Dipolar Cycloaddition of Alkynes and Azides
Energy-dispersive X-ray (EDX) analysis on various re-
gions confirmed the presence of copper, with energy bands
of 8.04, 8.90 keV (K lines) and 0.92 keV (L line) (Fig-
ure 2).[27] The XPS spectrum displays a single Cu 2p3/2 peak
at 933.0 eV, which in principle, could be ascribed to Cu0, as
no significant shoulder peak of CuO at 934 eV was ob-
served (Figure 3).[28] The oxidation state of copper is, how-
ever, difficult to assign on the basis of only XPS studies due
to the close proximity of the binding energies of the Cu0,
CuI and CuII states.[28] Further information was obtained
when a sample was exposed to air for a prolonged time. In
this case, two Cu 2p3/2 peaks at 932.8 and 934.1 eV were
observed, with the latter corresponding to CuII in the form
of CuO (Figure 4).
Figure 4. XPS spectrum of the CuNPs exposed to air.
Figure 5. XRD spectrum of the CuNPs (* denotes LiCl).
Figure 2. EDX spectra of the CuNPs obtained from two different
areas.
Figure 3. XPS spectrum of the CuNPs.
The XRD spectrum shows peak positions that are con-
sistent with the presence of face-centred-cubic copper (Fig-
ure 5).[24a,24b] The additional peaks correspond to lithium
chloride formed during the generation of the CuNPs,
though formation of small amounts of Cu2O in the reaction
Figure 6. Selected area electron diffraction (SAED) pattern of the
CuNPs.
The reaction conditions for the click reaction were op-
medium or during sample handling cannot be ruled out. At timised by using benzyl azide (1a) and cyclohexylacetylene
any rate, peaks corresponding to CuO were not detect- (2a) as model substrates (Table 1). Two control experiments
ed.[28c] The selected area electron diffraction (SAED) were carried out under the conditions of generation of the
pattern is in agreement with the presence, primarily, of met- CuNPs but in the absence of the copper salt (with or with-
allic copper (Figure 6).[25d,26c]
out Et3N), leading to starting 1a and 2a. The presence of
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Et3N was shown to be crucial for the reaction to occur azoles in 85–98% yield (Table 2, Entries 2–5). Hex-1-yne
(Table 1, Entry 1). The CuNPs, in a stoichiometric amount, (2b) and oct-1-yne (2c) reacted very fast (Table 2, Entries 2
were found to be superior to other sources of copper, fur- and 3), whereas a progressive increase in the reaction time
nishing 3aa in the highest yield and shortest reaction time was observed for the longer alkyl-chain alkynes dec-1-yne
(Table 1, Entries 2–8). Excellent yields of 3aa were obtained (2d) and dodec-1-yne (2e) (Table 2, Entries 4 and 5). Very
even by decreasing the amount of CuNPs up to 1 mol-%, short reaction times were also recorded for the phenyl-sub-
albeit longer reaction times were required (Table 1, En- stituted alkynes 4-phenylbut-1-yne (2f) and phenylacetylene
tries 9–13). Interestingly, a short reaction time of only (2g), with the expected products being obtained in high
30 min at 25 °C was recorded by the addition of Ͼ1 equiv. yields (Table 2, Entries 6 and 7). The conjugated alkyne 1-
of Et3N, with the yields being also excellent (Table 1, En- ethynylcyclohex-1-ene (2h) behaved similarly to the noncon-
tries 14 and 15). Unfortunately, this remarkable decrease in jugated cyclohexylacetylene (2a) as regards both the reac-
time was not so general for some other substrates tested at tion time and product yield (Table 2, Entry 8). Two propar-
25 °C. The same excellent result as aforementioned, how- gylic alcohols were also tested, with prop-2-yn-1-ol (2i)
ever, was obtained when the model reaction was conducted manifesting a better performance than the more sterically
at 65 °C (Table 1, Entry 16). Under the latter reaction con- demanding 1-ethynylcyclohexanol (2j) (Table 2, Entries 9
ditions, CuCl or CuNPs in the solvent mixture tBuOH/H2O and 10). Phenyl azide (1b) exhibited very close reactivity to
(1:2) or in air led to lower product yields in much longer that previously mentioned for benzyl azide (1a) with al-
reaction times (Table 1, Entries 17–20). In view of the above kynes 2a, 2b, 2g and 2j. Thus, the same reaction times and
results, we considered the reaction conditions in Entry 16 near yields were obtained in all cases except for hex-1-yne
the most appropriate, providing a method of more general (2b), the reaction of which was higher yielding for benzyl
application at the same time that the short reaction time is azide (1a) (Table 2, Entry 12).
maintained.
Table 1. Copper-catalysed 1,3-dipolar cycloaddition of benzyl azide
and cyclohexylacetylene.[a]
Scheme 1. General conditions for the CuNPs-catalysed 1,3-dipolar
cycloaddition of azides and terminal alkynes.
We next studied the reactivity of various structurally and
electronically different azides (Table 3). The linear alkyl and
Entry Catalyst (mmol)
Additive
(mmol)
T [°C] t [h] Yield [%][b]
cyclic azides n-dodecyl azide (1c) and cyclohexyl azide (1d),
respectively, required, in general, longer reaction times with
some of the previously assayed alkynes. Nonetheless, the
expected triazole products were obtained in good-to-excel-
lent yields (Table 3, Entries 1–5). A similar behaviour was
observed for the electron-deficient aryl azide 4-azidoace-
tophenone (1e), which was shown to be less reactive than
the electronically neutral phenyl azide (1b) (Table 2, En-
tries 12 and 14 vs. Table 3, Entries 6 and 8, respectively).
Ethyl 2-azidoacetate (1f) readily reacted with phenyl acetyl-
ene (2c) and 1-ethynylcyclohex-1-ene (2h), though in the lat-
ter case the triazole yield was below the average (Table 3,
Entries 9 and 10). Allylic cinnamyl azide (1g) provided ex-
cellent yields of five different triazoles, with the reaction
times ranging from 10 to 120 min (Table 3, Entries 11–15).
Under these reaction conditions, cinnamyl azide did not un-
dergo a [3,3]-sigmatropic rearrangement leading to the sec-
ondary allylic azide,[29] as compounds 3ga, 3gb, 3gc, 3gf and
3gh were the only detected products.
1
2
3
CuNPs (100)
CuNPs (100)
Cu (100)[c]
none
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
65
25
65
65
65
12
1
2
2
2
2
3
3
6
0
98
0
0
0
Et3N (1)
Et3N (1)
Et3N (1)
Et3N (1)
Et3N (1)
Et3N (1)
4
5
6
7
CuO (100)
Cu2O (100)
CuCl2 (100)
CuCl (100)
0
85[d]
58
98
98
98
100
100
99
99
100
70
80
75
71
8
CuNPs (100) PVP/Et3N (1)[e]
9
CuNPs (20)
CuNPs (10)
CuNPs (5)
CuNPs (2)
CuNPs (1)
CuNPs (10)
CuNPs (10)
CuNPs (10)
CuCl (10)
Et3N (1)
Et3N (1)
Et3N (1)
Et3N (1)
Et3N (1)
Et3N (3)
Et3N (2)
Et3N (1)
Et3N (1)
Et3N (1)
Et3N (1)[f]
Et3N (1)[g]
10
11
12
13
14
15
16
17
18
19
20
6
24
24
24
0.5
0.5
0.5
24
24
24
24
CuCl (10)
CuNPs (10)
CuNPs (10)
[a] Reaction conditions: 1a (1 mmol) and 2a (1 mmol) in THF.
[b] GLC yield. [c] Cu powder (1–5 µm). [d] Multiple side products
were detected. [e] 1 g PVP (MW ca. 29000). [f] Reaction in tBuOH/
H2O, 1:2. [g] Reaction in air.
It is worthy to mention that, under the standard condi-
tions, all reactions were highly regioselective towards the
1,4-disubstituted triazoles and completed in 10–120 min.
Simple workup operations involving filtration and crystalli-
The optimised reaction conditions (Scheme 1) were ex- sation or solvent evaporation were generally applied, fur-
tended to a variety of azides and terminal alkynes (Tables 2 nishing the corresponding 1,2,3-triazoles in excellent iso-
and 3). We first explored the reactivity of benzyl and phenyl lated yields. The short reaction times needed are compar-
azide. The reaction of benzyl azide (1a) with linear alkyl- able to those of the methodologies involving microwave
substituted terminal alkynes led to the corresponding tri- chemistry but under milder conditions (65 vs. 75–
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Cu Nanoparticles in the 1,3-Dipolar Cycloaddition of Alkynes and Azides
Table 2. 1,3-Dipolar cycloaddition of benzyl and phenyl azide with
terminal alkynes catalysed by CuNPs.[a]
Table 3. 1,3-Dipolar cycloaddition of various azides with terminal
alkynes catalysed by CuNPs.[a]
[a] Reaction conditions: 1 (1 mmol), 2 (1 mmol), CuNPs (10 mol-
%), Et3N (1 mmol) in THF at 65 °C. [b] Isolated yield after crystal-
lisation in Et2O unless otherwise stated. [c] Isolated yield after fil-
tration and solvent evaporation. [d] Isolated yield after column
chromatography.
[a] Reaction conditions: 1 (1 mmol), 2 (1 mmol), CuNPs (10 mol-
%), Et3N (1 mmol) in THF at 65 °C. [b] Isolated yield after crystal-
lisation in Et2O unless otherwise stated. [c] Isolated yield after fil-
tration and solvent evaporation.
140 °C).[14] In fact, some of the 10-min reactions were thor-
oughly monitored and found to proceed almost instantane-
ously (during the first minute), although a standard time of
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10 min was used. This methodology was proven to be of the original suspension of the CuNPs, however, when
equally effective for more complex alkynes, such as 17α- aged for 5 d, were successfully used in additional experi-
ethynyloestradiol (2k), which was subjected to the standard ments, with a decrease in activity being observed after the
procedure with benzyl azide to afford the corresponding tri- 10th day (Scheme 4).
azole-substituted steroid derivative in, practically, quantita-
tive yield after 30 min (Scheme 2). Moreover, a double 1,3-
dipolar cycloaddition reaction took place when starting
from hepta-1,6-diyne (2l), giving bistriazole product 3al in
good yield after 2 h (Scheme 3). The regioselectivity of the
process was unequivocally established by X-ray crystal-
lography of 3al (Figure 7).[30]
Scheme 4. 1,3-Dipolar cycloaddition of 1a and 2b after aging the
suspension of the CuNPs.
The reaction mechanism of the alkyne–azide cycload-
dition catalysed by copper nanoparticles is not well under-
stood.[19] The formation of copper(I) acetylide is generally
invoked (but not demonstrated) by dissolution of Cu0 to
CuI or by reaction with CuI on the nanoparticle surface. We
gained insight into the reaction mechanism from various
observations and a series of experiments: (1) A colourless
solution was obtained at the end of the reaction, which
changed to a blue colour after addition of an ammonia
solution; these assays point to a resulting colourless solu-
tion essentially containing CuI ions, the disproportionation
of which would be prevented in THF. (2) Dissolution of
CuNPs did not occur under the standard conditions in the
absence of Et3N. (3) Neither Et3N nor the triazole product
Scheme 2. 1,3-Dipolar cycloaddition of 17α-ethynyloestradiol and
1a.
exhibited any capability of dissolution over the CuNPs by
themselves. (4) The suspension of the CuNPs in the pres-
ence of Et3N and phenylacetylene, but in the absence of the
azide, led to a colourless supernatant and a yellow precipi-
tate (insoluble in water or diethyl ether) that could be attrib-
uted to copper(I) phenylacetylide[31] [Scheme 5, Equa-
tion (1)]. The amine was suggested to have a double role,
promoting the formation of the anion and stabilising the
CuI species.[16a] The easy formation of the phenylacetylide
anion by the action of Et3N, under the cycloaddition condi-
tions (THF, 65 °C), was demonstrated by deuteration ex-
periments [Scheme 5, Equation (2)]. A sequential process
was performed including the reaction of phenylacetylene
with Et3N, followed by the reaction with the CuNPs and
final addition of BnN3 [Scheme 5, Equation (3)]. Under
these conditions, the reaction was slower and afforded the
expected triazole in 47% after 1 h and reached completion
after 5 h. In order to find an explanation for the colourless
solution obtained at the end of the reaction, a black suspen-
sion of the CuNPs was subjected to the action of Et3NHCl
in THF [Scheme 5, Equation (4)]. Rapid dissolution of the
nanoparticles was observed, leading to a colourless solution
that should be mainly composed of CuCl. No change in the
appearance of this solution was observed after the addition
of phenylacetylene. The addition of an excess amount of
Et3N, however, instantaneously generated a yellow precipi-
tate of copper(I) phenylacetylide. According to all these ex-
Scheme 3. 1,3-Dipolar cycloaddition of diyne 2l and 1a.
Figure 7. Plot showing the X-ray structure and atomic numbering
of bistriazole 3al. The disorder of the phenyl groups in 3al (shown
with a different type of bond) was solved by splitting these groups
over two positions with 50% occupancy each.[30]
Unfortunately, the CuNPs could not be recovered at the periments, it could be inferred that copper(I) acetylides are
end of the reaction due to the homogeneous nature of the very likely the real intermediate species in the reactions re-
resulting mixture (colourless solution). Some other aliquots ported herein.
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Cu Nanoparticles in the 1,3-Dipolar Cycloaddition of Alkynes and Azides
acetylene (2g), which produced the following interesting re-
sults (Scheme 7). A standard reaction quenched with D2O
led to nondeuterated triazole 3ag [Scheme 7, Equation (1)].
As expected, deuterated triazole [D1]-3ag was obtained
when deuterated alkyne [D1]-2g was subjected to the cyclo-
addition reaction followed by deuteriolysis [Scheme 7,
Equation (2)]. In a third experiment, near-to-quantitative
deuterium incorporation was achieved when the reaction
with [D1]-2g was filtered through Celite at the end
[Scheme 7, Equation (3)]. From these experiments it could
be deduced that the protonolysis/deuteriolysis of the inter-
mediate copper(I) triazolide complex occurs in situ, with
the proton/deuterium transfer from the alkyne being very
efficient.
Scheme 5. Different experiments demonstrating the formation of
copper(I) phenylacetylide under the cycloaddition reaction condi-
tions.
Notwithstanding the aforementioned results, we per-
formed an additional experiment to bring out further evi-
dence on the in situ formation of the intermediate copper(I)
acetylides. Thus, the Sonogashira reaction, a cross-coupling
reaction that is well known to proceed through intermediate
copper(I) acetylides, was studied.[32] Hex-1-yne (2b) was
treated with phenyl iodide and a catalytic amount of
PdCl2(PPh3)2 under the standard cycloaddition reaction
conditions in the absence of the azide (Scheme 6). Coupled
product 4 was obtained in 33% yield, indicating that the
formation of the intermediate copper(I) acetylide also oc-
curs to some extent.
Scheme 7. Deuteration experiments in the CuNPs-catalysed 1,3-di-
polar cycloaddition of benzyl azide (1a) and hex-1-yne (2b).
A reaction mechanism for the CuNP-catalysed 1,3-di-
polar cycloaddition of terminal alkynes and azides is out-
lined on the basis of all the previously described experi-
ments (Scheme 8). Deprotonation of the acetylene could oc-
cur at a first stage, which in the presence of the lithium
Scheme 6. The CuNPs-catalysed Sonogashira reaction of hex-1-yne
and phenyl iodide under the cycloaddition reaction conditions.
The general mechanism for the copper(I)-catalysed 1,3- chloride derived from the preparation of the CuNPs would
dipolar cycloaddition of alkynes and azides is still a subject form triethylammonium chloride. The action of the latter
of intense debate.[18a,33] Although the formation a molecu- on the CuNPs could induce the in situ generation of cop-
lar copper(I) triazolide complex has been often postulated, per(I) chloride, which in turn would react with acetylide
only recently, Straub et al. isolated this type of complex species to furnish the corresponding copper(I) acetylide. It
as direct evidence for the existence of such structures as is known that copper(I) acetylides can be prepared from
intermediates in the click reaction.[33c] Final protonolysis of ammoniacal copper(I) iodide and acetylenes and that the
this type of intermediate would afford the triazole product. generation of fresh solutions of copper(I) salts results in
This step is supposed to occur either in situ, when the reac- acetylides with higher purities.[34] This fact could explain
tion is carried out in an aqueous medium (e.g., H2O/tBuOH the lower catalytic activity observed for the cycloaddition
mixtures), or after aqueous workup. A different reaction reaction when using commercial CuCl in comparison with
mechanism, parallel to that of the Meldal–Sharpless ver- that using CuNPs (Table 1, Entries 2 and 16 vs. 7 and 18,
sion, has been recently suggested for the click reaction per- respectively). It is also known that triethylamine can form a
formed with copper(I) zeolites.[16b] In this parallel mecha- 1:1 complex with anhydrous copper(I) chloride[35] and that,
nism, the formation of copper(I) acetylide intermediates therefore, it could play an additional role in the click reac-
was discarded on the basis of the fact that, if such species tion to stabilise the CuI species. From this point, the reac-
were formed inside the zeolites, then deuterioalkynes would tion mechanism would follow the original stepwise pathway
not give deuterated triazoles. We also performed several published by Noodleman, Sharpless, and Fokin et al.,[18a]
deuteration experiments with benzyl azide (1a) and phenyl- namely, (1) replacement of one ligand in the copper(I) acet-
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F. Alonso, Y. Moglie, G. Radivoy, M. Yus
FULL PAPER
Scheme 8. Reaction mechanism proposed for the CuNPs-catalysed 1,3-dipolar cycloaddition of terminal alkynes and azides.
tion was passed through a pad of Celite or alternatively subjected
to aqueous workup and extraction with EtOAc. The organic phase
was dried with MgSO4, and the solvent was removed in vacuo to
give the corresponding triazole, which was pure enough or was
purified by crystallisation (Et2O) or column chromatography (hex-
ane/EtOAc) (see footnotes in Tables 2 and 3).
ylide by the azide, (2) attack of the distal nitrogen of the
azide to the C-2 carbon of the acetylide to give a six-mem-
bered copper(III) metallacycle and (3) ring contraction to
afford a copper(I) triazolide complex. Final protonolysis of
the latter by triethylammonium chloride would render the
triazole product and regenerate copper(I) chloride.
1-Benzyl-4-cyclohexyl-1H-1,2,3-triazole (3aa): Yellow solid (95%),
m.p. 110.2–112.0 °C; tR = 13.62 min (GLC); Rf = 0.58 (hexane/
1
EtOAc, 8:2). H NMR (400 MHz, CDCl3): δ = 7.41–7.22 (m, 5 H,
Conclusions
Ar), 7.16 (s, 1 H, CH), 5.48 (s, 2 H, CH2), 2.80–2.67 (m, 1 H, CH),
Unsupported copper nanoparticles have been easily and 2.10–1.15 (m, 10 H, 5ϫCH2) ppm. 13C NMR (100 MHz, CDCl3):
δ = 154.1, 134.9, 128.9, 128.5, 127.8, 119.1, 53.8, 35.3, 32.9, 26.1,
rapidly generated from anhydrous copper(II) chloride, lith-
ium metal and a catalytic amount of DTBB as an electron
carrier, in the absence of any stabilising additive or ligand.
These nanoparticles have been found to catalyse the 1,3-
dipolar cycloaddition of azides and terminal alkynes in the
presence of triethylamine by using THF as solvent at 65 °C.
All reactions tested were accomplished in short reaction
times (10–120 min) and rendered the corresponding tri-
azoles in good-to-excellent isolated yields. The copper
nanoparticles in THF exhibited superior catalytic activity
when compared with other commercially available copper
sources. On the basis of different observations, reactions
and deuteration experiments, a reaction mechanism has
been postulated in which copper(I) acetylides appear as the
true intermediate species.
25.9 ppm. IR (KBr): ν = 3118, 2918, 2844, 1539, 1495, 1452, 1050,
˜
755, 703 cm–1. GC–MS (EI): m/z (%) = 241 (12) [M]+, 122 (13), 91
(100). HRMS (EI): calcd. for C15H19N3 241.1579; found 241.1577.
Selected X-ray Data for Compound 3al:[30] C21H22N6, M = 358.45;
monoclinic, a = 9.705(8) Å, b = 6 5.054(4) Å, c = 39.65(3) Å, β =
90.923(16)°; V = 1945(3) Å3; space group C 2; Z = 4; Dcalcd.
=
1.224 Mgm–3; λ = 0.71073 Å; µ = 0.077 mm–1; F(000) = 760; T =
22Ϯ1 °C.
Supporting Information (see also the footnote on the first page of
this article): General experimental details, methods and compound
characterisation data.
Acknowledgments
This work was generously supported by the Spanish Ministerio de
Educación y Ciencia (MEC) (grant no. CTQ2007-65218 and Con-
solider Ingenio 2010-CSD2007-00006), the Generalitat Valenciana
(grant no. PROMETEO/2009/039) and the Secretaría General de
Ciencia y Tecnología (SeCyT), Universidad Nacional del Sur (PGI
24/Q014). Y.M. thanks the SeCyT of the Universidad Nacional del
Sur and the Vicerrectorado de Investigación, Desarrollo e Innova-
ción, Universidad de Alicante for a grant. We are also grateful to
J. A. Sirvent (Universidad de Alicante) for carrying out some assays
related to the reaction mechanism.
Experimental Section
Typical Procedure for the Preparation of CuNPs: Anhydrous cop-
per(II) chloride (135 mg, 1 mmol) was added over a suspension of
lithium (14 mg, 2 mmol) and 4,4Ј-di-tert-butylbiphenyl (DTBB,
27 mg, 0.1 mmol) in THF (2 mL) at room temperature under an
atmosphere of argon. The reaction mixture, which was initially
dark blue, rapidly changed to black, indicating that the suspension
of the CuNPs was formed. This suspension was diluted by further
addition of THF (8 mL).
[1] a) R. Huisgen, G. Szeimies, L. Moebius, Chem. Ber. 1965, 98,
4014–4021; b) R. Huisgen, Pure Appl. Chem. 1989, 61, 613–
628.
General Procedure for the CuNP-Catalysed 1,3-Dipolar Cycload-
dition of Azides and Alkynes: Et3N (1 equiv.), the azide (1 equiv.)
and the alkyne (1 equiv.) were added over a suspension of the
CuNPs (10 mol-%) in THF under an atmosphere of argon. The
reaction mixture was warmed up to 65 °C and monitored by TLC
until total conversion of the starting materials. The resulting solu-
[2] C. W. Tornøe, C. Christensen, M. Meldal, J. Org. Chem. 2002,
67, 3057–3064.
[3] V. V. Rostovtsev, L. G. Green, V. V. Fokin, K. B. Sharpless, An-
gew. Chem. Int. Ed. 2002, 41, 2596–2599.
1882
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Eur. J. Org. Chem. 2010, 1875–1884

Cu Nanoparticles in the 1,3-Dipolar Cycloaddition of Alkynes and Azides
[4]
Fokin, E. Van der Eycken, Org. Lett. 2004, 6, 4223–4225; c)
H. S. G. Beckmann, V. Wittmann, Org. Lett. 2007, 9, 1–4; d)
F. Pisaneschi, F. M. Cordero, M. Lumini, A. Brandi, Synlett
2007, 2882–2884; e) for a recent microreview, see: P. Appukkut-
tan, E. Van der Eycken, Eur. J. Org. Chem. 2008, 1133–1155; f)
A. D. Moorhouse, J. E. Moses, Synlett 2008, 2089–2092.
B. Sreedhar, P. S. Reddy, Synth. Commun. 2007, 37, 805–812.
See, for instance: a) B. H. Lipshutz, B. R. Taft, Angew. Chem.
Int. Ed. 2006, 45, 8235–8238; b) S. Chassaing, A. S. S. Sido, A.
Alix, M. Kumarraja, P. Pale, J. Sommer, Chem. Eur. J. 2008,
14, 6713–6721; c) T. Miao, L. Wang, Synthesis 2008, 363–368;
d) U. Sirion, Y. J. Bae, B. S. Lee, D. Y. Chi, Synlett 2008, 2326–
2330.
C. D. Smith, I. R. Baxendale, S. Lanners, J. J. Hayward, S. C.
Smith, S. V. Ley, Org. Biomol. Chem. 2007, 5, 1559–1561.
a) F. Himo, T. Lovell, R. Hilgraf, V. V. Rostovtsev, L. Noo-
dleman, K. B. Sharpless, V. V. Fokin, J. Am. Chem. Soc. 2005,
127, 210–216; b) N. Gommermann, A. Gehrig, P. Knochel,
Synlett 2005, 2796–2798.
a) L. Durán Pachón, J. H. van Maarseveen, G. Rothenberg,
Adv. Synth. Catal. 2005, 347, 811–815; b) H. A. Orgueira, D.
Fokas, Y. Isome, P. C.-M. Chan, C. M. Baldino, Tetrahedron
Lett. 2005, 46, 2911–2914; c) M. Laksmi Kantam, V.
Swarna Jaya, B. Sreedhar, M. Mohan Rao, B. M. Choudary, J.
Mol. Catal. A 2006, 256, 273–277; d) G. Molteni, C. L. Bian-
chi, G. Marinoni, N. Santo, A. Ponti, New J. Chem. 2006, 30,
1137–1139; e) A. Sarkar, T. Mukherjee, S. Kapoor, J. Phys.
Chem. C 2008, 112, 3334–3340; f) I. S. Park, M. S. Kwon, Y.
Kim, J. S. Lee, J. Park, Org. Lett. 2008, 10, 497–500; g) H.
Sharghi, R. Khalifeh, M. M. Doroodmand, Adv. Synth. Catal.
2009, 351, 207–218.
For reviews, see: a) F. Alonso, G. Radivoy, M. Yus, Russ. Chem.
Bull. Int. Ed. 2003, 52, 2563–2576; b) F. Alonso, M. Yus, Chem.
Soc. Rev. 2004, 33, 284–293; c) F. Alonso, M. Yus, Pure Appl.
Chem. 2008, 80, 1005–1012.
a) F. Alonso, C. Vitale, G. Radivoy, M. Yus, Synthesis 2003,
443–447; b) F. Alonso, Y. Moglie, G. Radivoy, C. Vitale, M.
Yus, Appl. Catal. A: Gen. 2004, 271, 171–176; c) G. Radivoy,
F. Alonso, Y. Moglie, C. Vitale, M. Yus, Tetrahedron 2005, 61,
3859–3864.
F. Alonso, Y. Moglie, G. Radivoy, M. Yus, Tetrahedron Lett.
2009, 50, 2358–2362.
a) R. D. Rieke, L. D. Rhyne, J. Org. Chem. 1979, 44, 3445–
3446; b) R. D. Rieke, M. S. Sell, W. R. Klein, T. Chen, J. D.
Brown, M. V. Hanson in Active Metals (Ed.: A. Fürstner),
VCH, Weinheim, 1996, pp. 33–48.
For recent reviews, see: a) V. D. Bock, H. Hiemstra, J. H.
van Maarseveen, Eur. J. Org. Chem. 2006, 51–68; b) M. Meldal,
C. W. Tornøe, Chem. Rev. 2008, 108, 2952–3015.
For a review, see: H. C. Kolb, M. G. Finn, K. B. Sharpless,
Angew. Chem. Int. Ed. 2001, 40, 2004–2021.
[5]
[6]
For general reviews, see: a) M. V. Gil, M. J. Arévalo, O. López,
Synthesis 2007, 1589–1620; b) J. E. Moses, A. D. Moorhouse,
Chem. Soc. Rev. 2007, 36, 1249–1262; c) see also the special
issue on Click Chemistry: QSAR Comb. Sci. 2007, vol. 26, iss.
11 and 12, pp. 1115–1326.
For reviews, see: a) H. C. Kolb, K. B. Sharpless, Drug Discovery
Today 2003, 8, 1128–1137; b) G. C. Tron, T. Pirali, R. A. Bill-
ington, P. L. Canonico, G. Sorba, A. A. Genazzani, Med. Res.
Rev. 2008, 28, 278–308; c) A. D. Moorhouse, J. E. Moses,
ChemMedChem 2008, 3, 715–723; d) C. Mamat, T. Ramenda,
F. R. Wuest, Mini-Rev. Org. Chem. 2009, 6, 21–34; e) M. D.
Best, Biochemistry 2009, 48, 6571–6584; K. New, M. W. Brech-
biel, Cancer Biother. Radiopharm. 2009, 24, 289–302.
For reviews, see: a) J.-F. Lutz, Angew. Chem. Int. Ed. 2007, 46,
1018–1025; b) D. Fournier, R. Hoogenboom, U. S. Schubert,
Chem. Soc. Rev. 2007, 36, 1369–1380; c) J. A. Johnson, M. G.
Finn, J. T. Koberstein, N. J. Turro, Macromol. Rapid Commun.
2008, 29, 1052–1072; d) L. Billiet, D. Fournier, F. Du Prez,
Polymer 2009, 50, 3877–3886; e) C. Barner-Kowollik, A. J. In-
glis, Macromol. Chem. Phys. 2009, 210, 987–992.
[15]
[16]
[7]
[17]
[18]
[8]
[9]
[19]
For reviews, see: a) H. Nandivada, X. Jiang, J. Lahann, Adv.
ˇ
Mater. 2007, 19, 2197–2208; b) I. Aprahamian, O. S. Miljanic´,
W. R. Dichtel, K. Isoda, T. Yasuda, T. Kato, J. F. Stoddart,
Bull. Chem. Soc. Jpn. 2007, 80, 1856–1869; c) T. P. Lodge, Mac-
romolecules 2009, 42, 3827–3829; d) G. Franc, A. K. Kakkar,
Chem. Eur. J. 2009, 15, 5630–5639; e) J. Lahann (Ed.), Click
Chemistry for Biotechnology and Materials Science, Wiley,
Chichester, 2009.
[20]
[21]
[10]
[11]
[12]
For reviews, see: a) A. Dondoni, Chem. Asian J. 2007, 2, 700–
708; b) Y. L. Angell, K. Burgess, Chem. Soc. Rev. 2007, 36,
1674–1689; c) S. Dedola, S. A. Nepogodiev, R. A. Field, Org.
Biomol. Chem. 2007, 5, 1006–1017; d) J.-F. Lutz, Z. Zarafshani,
Adv. Drug Delivery Rev. 2008, 60, 958–970; e) S. Bräse, A.
Friedrich, M. Gartner, T. Schröder, Top. Heterocycl. Chem.
2008, 12, 45–115; f) F. Amblard, J. H. Cho, R. F. Schinazi,
Chem. Rev. 2009, 109, 4207–4220; g) T. Kodadek, Nat. Chem.
2009, 1, 183–185.
a) Z. Li, T. S. Seo, J. Ju, Tetrahedron Lett. 2004, 45, 3143–3146;
b) P. Li, L. Wang, Lett. Org. Chem. 2007, 4, 23–26; c) N. J.
Agard, J. A. Prescher, C. R. Bertozzi, J. Am. Chem. Soc. 2004,
126, 15046–15047; d) J.-F. Lutz, Angew. Chem. Int. Ed. 2008,
47, 2182–2184; e) L. Campbell-Verduyn, P. H. Elsinga, L. Mir-
feizi, R. A. Dierckx, B. L. Feringa, Org. Biomol. Chem. 2008,
6, 3461–3463; f) for a recent review, see: C. Remzi Becer, R.
Hoogenboom, U. S. Schubert, Angew. Chem. Int. Ed. 2009, 48,
4900–4908.
See, for instance: a) T. R. Chan, R. Hilgraf, K. B. Sharpless,
V. V. Fokin, Org. Lett. 2004, 6, 2853–2855; b) B. Gerard, J.
Ryan, A. B. Beeler, J. A. Porco Jr., Tetrahedron 2006, 62, 6405–
6411; c) S. Díez-González, S. P. Nolan, Synlett 2007, 2158–
2167; d) S. Díez-González, S. P. Nolan, Aldrichimica Acta 2008,
41, 47–51; e) N. Candelon, D. Lastécouères, A. Khadri Diallo,
J. Ruiz Aranzaes, D. Astruc, J.-M. Vincent, Chem. Commun.
2008, 741–743; f) F. Wang, H. Fu, Y. Jiang, Y. Zhao, Green
Chem. 2008, 10, 452–456.
See, for instance: a) K. Odlo, E. A. Høydahl, T. V. Hansen,
Tetrahedron Lett. 2007, 48, 2097–2099; b) K. Barral, A. D. Mo-
orhouse, J. E. Moses, Org. Lett. 2007, 9, 1809–1811; c) B. Saha,
S. Sharma, D. Sawant, B. Kundu, Synlett 2007, 1591–1594; d)
K. Yamaguchi, M. Kotani, K. Kamata, N. Mizuno, Chem.
Lett. 2008, 37, 1258–1259.
[22]
[23]
[24]
[25]
See, for instance: a) N. A. Dhas, C. P. Raj, A. Gedanken, Chem.
Mater. 1998, 10, 1446–1452; b) S. U. Son, I. K. Park, J. Park,
T. Hyeon, Chem. Commun. 2004, 778–779; c) A. A. Ponce, K. J.
Klabunde, J. Mol. Catal. A: Chem. 2005, 225, 1–6.
See, for instance: a) H. H. Huang, F. Q. Yan, Y. M. Kek, C. H.
Chew, G. Q. Xu, W. Ji, P. S. Oh, S. H. Tang, Langmuir 1997,
13, 172–175; b) A. C. Curtis, D. G. Duff, P. P. Edwards, D. A.
Jefferson, B. F. G. Johnson, A. I. Kirkland, A. S. Wallace, J.
Phys. Chem. 1988, 92, 2270–2275; c) S.-H. Wu, D.-H. Chen, J.
Colloid Interface Sci. 2004, 273, 165–169; d) H. Zhu, C. Zhang,
Y. Yi n , Nanotechnology 2005, 16, 3079–3080; e) M. Kidwai, V.
Bansal, N. K. Mishra, A. Kumar, S. Mozumdar, Synlett 2007,
1581–1584; f) M. Takahashi, J. Kamada, K. Iwata, K. Goto,
H. Watanabe, S. Tamai, Bull. Chem. Soc. Jpn. 2008, 81, 168–
170.
a) G. Vitulli, M. Bernini, S. Bertozzi, E. Pitzalis, P. Salvadori,
S. Coluccia, G. Martra, Chem. Mater. 2002, 14, 1183–1186; b)
T. N. Rostovshchikova, V. V. Smirnov, V. M. Kozhevin, D. A.
Yavsin, M. A. Zabelin, I. N. Yassievich, S. A. Gurevich, Appl.
Catal. A: Gen. 2005, 296, 70–79; c) T. Nakamura, Y. Tsukah-
ara, T. Sakata, H. Mori, Y. Kanbe, H. Bessho, Y. Wada, Bull.
Chem. Soc. Jpn. 2007, 80, 224–232.
[13]
[14]
[26]
[27]
See, for instance: a) F. Pérez-Balderas, M. Ortega-Muñoz, J.
Morales-Sanfrutos, F. Hernández-Mateo, F. G. Calvo-Flores,
J. A. Calvo-Asín, J. Isac-García, F. Santoyo-González, Org.
Lett. 2003, 5, 1951–1954; b) P. Appukkuttan, W. Dehaen, V. V.
a) F. L.-Y. Lam, Y. Zhang, X. Hu, P. Sheng, Z. Yan, Inter-
national Conference on Nanoscience and Nanotechnology,
Eur. J. Org. Chem. 2010, 1875–1884
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1883

F. Alonso, Y. Moglie, G. Radivoy, M. Yus
FULL PAPER
ICONN 2006, Brisbane, Australia, pp. 15–18; b) S. Bhadra, A.
Saha, B. C. Ranu, Green Chem. 2008, 10, 1224–1230.
[28] a) N. Toshima, Y. Wang, Langmuir 1994, 10, 4574–4580; b)
A. F. Carley, L. A. Dollard, P. R. Norman, C. Pottage, M. W.
Roberts, J. Electron Spectrosc. Relat. Phenom. 1999, 98–99,
223–233; c) M. Laksmi Kantam, S. Laha, J. Yadav, P. R. Li-
khar, B. Sreedhar, B. M. Choudary, Adv. Synth. Catal. 2007,
349, 1797–1802.
[29] A. K. Feldman, B. Colasson, K. B. Sharpless, V. V. Fokin, J.
Am. Chem. Soc. 2005, 127, 13444–13445.
[30] CCDC-752783 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[31] D. C. Owsley, C. E. Castro, Org. Synth. 1972, 52, 128–131.
[32] a) K. Sonogashira, J. Organomet. Chem. 2002, 653, 46–49; b)
R. Chinchilla, C. Nájera, Chem. Rev. 2007, 107, 874–922.
[33] a) M. Ahlquist, V. V. Fokin, Organometallics 2007, 26, 4389–
4391; b) B. F. Straub, Chem. Commun. 2007, 3868–3870; c) C.
Nolte, P. Mayer, B. F. Straub, Angew. Chem. Int. Ed. 2007, 46,
2101–2103.
[34] a) V. A. Sazonova, N. Y. Kronrod, J. Gen. Chem. U.S.S.R.
(Engl. Transl.) 1956, 26, 2093–2097; b) C. E. Castro, R. D. Ste-
phens, J. Org. Chem. 1963, 28, 3313–3315.
[35] J. T. Yoke III, J. F. Weiss, G. Tollin, Inorg. Chem. 1963, 2, 1210–
1216.
Received: December 11, 2009
Published Online: February 24, 2010
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