Click chemistry: Copper clusters catalyse the cycloaddition of azides with terminal alkynes

Article abstract of DOI:10.1002/adsc.200404383

Air-stable copper nanoclusters are good catalysts in the Cu(I)-catalysed "click" cycloaddition of azides with terminal alkynes to give 1,4-disubstituted 1,2,3-triazoles. No additional base or reducing agent is required. The reaction kinetics using various

Full text of DOI:10.1002/adsc.200404383

FULL PAPERS
Click Chemistry: Copper Clusters Catalyse the Cycloaddition of
Azides with Terminal Alkynes
Laura Dur a´ n Pach o´ n, Jan H. van Maarseveen, Gadi Rothenberg*
vanꢀt Hoff Institute of Molecular Sciences, University of Amsterdam, Nieuwe Achtergracht 166, 1018 WV Amsterdam, The
Netherlands
Fax: (þ31)-20-525-5604, e-mail: gadi@science.uva.nl
Received: December 16, 2004; Accepted: March 8, 2005
Abstract: Air-stable copper nanoclusters are good cat- catalyst types and the function of copper particles in
alysts in the Cu(I)-catalysed “click” cycloaddition of this system are studied and discussed.
azides with terminal alkynes to give 1,4-disubstituted
1,2,3-triazoles. No additional base or reducing agent is Keywords: azides; cycloaddition; kinetics; mechanism;
required. The reaction kinetics using various copper nanoclusters; triple bonds
[
2]
Introduction
ganic synthesis and drug discovery. Perhaps the most
remarkable example is the copper-catalysed version of
ꢁ
Click chemistryꢀ, a term recently coined by Sharpless the Huisgen 1,3-dipolar cycloaddition of azides to termi-
[1]
[3,4]
and co-workers, denotes a growing family of powerful nal alkynes (Scheme 1, top). This reaction tolerates a
chemical reactions that are based on ꢁspring–loadedꢀ variety of functional groups, is insensitive to water and
energy-intensive substrates that can, under the right oxygen, and gives easy access to regiospecific 1,4-disub-
conditions, unload their energy to form stable products stituted 1,2,3-triazoles. The 100% atom economy and
in high selectivity. Ever since their debut in 2001, click simple product isolation make this reaction useful in var-
reactions are finding more and more applications in or- ious applications ranging from bio-orthogonal bioconju-
Scheme 1. Huisgen-type 1,3-cycloaddition of azides to terminal alkynes catalyzed by Cu(I) ions (top) and by Cu nanoclusters
(
bottom).
Adv. Synth. Catal. 2005, 347, 811–815
DOI: 10.1002/adsc.200404383
ꢂ 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
811

FULL PAPERS
Laura Dur a´ n Pach o´ n et al.
[
5–8]
[9,10]
[11]
gation,
the construction of peptide bond surrogates and pow- both aromatic and aliphatic azides.
erful pharmacophores. The reaction is catalysed by Sharpless and co-workers recently reported that the
Cu(I) species that are either added directly as cuprous Cu(I)-catalysed synthesis of 1,2,3-triazoles from azides
polymer
and dendrimer syntheses to nal alkyne-Cu(I) species. This effect was observed for
[
12]
[2]
[
13]
salts (with or without ligands ), or generated by the re- and terminal alkynes could also be catalysed by Cu(0)
duction of Cu(II) salts, or by the in situ oxidation of cop- turnings, as well as by CuSO /sodium ascorbate. In
[
3]
[6,7]
4
per metal turnings to give Cu(I) species. The last option both cases it was suggested that the Cu(0) and Cu(II)
is particularly attractive, as copper metal is inexpensive, precursors are oxidised or reduced to give the active
and there is no need for a reducing agent as in the case of Cu(I) catalytic species. Such switching between the
Cu(II). However, reactions are relatively slow and re- Cu(0)/Cu(I)/Cu(II) oxidation states was also observed
quire a significant amount of catalyst. These drawbacks by one of us in the catalytic oxidation of allylic olefins
are increasingly important when large-scale production with t-butyl hydroperoxide (TBHP), which could also
[26]
is considered.
be catalysed by copper clusters as catalyst precursors.
The fact that both Cu(0) and Cu(II) can be used as cat- The interesting point about the azide-alkyne cycloaddi-
alyst precursors, plus the ubiquitous presence of Cu(I)- tions, however, is that copper clusters may play a special
[
14]
alkyne intermediates in similar chemical systems,
role here, rather than just serving as ꢁreservoirsꢀ for
such as the Glaser homocoupling and the Stephens–Cas- Cu(I) ions. This is analogous to our findings on Sonoga-
[15]
[16,17]
tro and Sonogashira
reactions, led us to think that shira cross-coupling, where copper clusters exhibited
copper nanoclusters could be efficient catalysts for very different catalytic properties compared to Cu(I)
[
20]
Huisgen-type cycloadditions. Our previous studies salts.
showed that Cu clusters are particularly suited to Suzu- To gain further insight into the role of the copper clus-
and Sonogashira cross-coupling reactions. In ters in azide-alkyne cycloadditions we monitored the ki-
[18,19]
[20]
ki,
this paper, we show the use of nanometric copper clus- netics of the model reaction between benzyl azide (1b)
ters as efficient ligand-free catalysts for 1,3-dipolar cy- and prop-2-yn-1-ol (2c). We compared profiles for four
cloaddition reactions between azides and terminal al- cases, catalysed by copper shavings, copper powder, cop-
[21–25]
kynes.
These clusters are active and stable, and per nanoclusters, and CuSO /ascorbate, respectively
4
comply with the requirements of ꢁclick chemistryꢀ. We (Figure 1). All other reaction conditions were kept con-
demonstrate the application of the system to a variety stant and blank experiments were performed to exclude
of substrates, compare the reaction rates using different systemic effects.
types of copper catalysts, and examine whether copper
atoms and/or ions are leaching into the solution or not.
Results and Discussion
The copper nanoclusters were prepared by reducing
cuprous chloride in solution with tetraoctylammonium
formate (TOAF). This method gives a stable suspension
that can be kept for months, with a narrow cluster size
[
18]
distribution and is very easy to handle.
In a typical cluster-catalysed cycloaddition reaction
(
Scheme 1, bottom), one equivalent of azide 1 was
mixed at 258C and pressure with two equivalents of al-
kyne 2 and 0.001 equivalents of copper clusters, in
50 mL of 2:1 water:t-butyl alcohol. Good conversions
and yields were observed for a variety of azide/alkyne
combinations (Table 1). The 1,4-disubstituted 1,2,3-tri-
azoles 3a–f were easily isolated by filtration, followed
by recrystallisation, and identified by their melting
1
points and H NMR spectra.
Aliphatic alkynes gave higher yields than aromatic
ones (typically 85–100% vs. ~80%, respectively). The
presence of an electron-withdrawing hydroxy group in-
creased the product yield. The phenyl group in the 1-
phenylprop-2-yn-1-ol (entries 2 and 5) was found to
Figure 1. Time-resolved reaction profiles observed for the
,3-cycloaddition of prop-2-yn-1-ol to benzyl azide using var-
ious copper catalytic systems. Reaction conditions are as in
1
slightly impede the reaction, probably because of steric Table 1. All reactions were performed in duplicate (with er-
effects, i.e., interfering with the formation of the termi- ror of ꢀ2.3%).
812
ꢂ 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Adv. Synth. Catal. 2005, 347, 811–815

Cycloaddition of Azides with Terminal Alkynes
FULL PAPERS
[a]
Table 1. Huisgen-type cycloadditions catalysed by copper nanoclusters.
[
b]
Entry
Azide
Alkyne
Product
Yield [%]
1
1a
1a
2a
2b
3a
3b
80
2
85
[c]
3
4
1a
1b
2c
2a
3c
>99
3d
82
5
6
1b
1b
2b
2c
3e
3f
97
[c]
>99
[a]
[b]
[c]
Reaction conditions: 10 mmol azide, 20 mmol alkyne, 0.1 mmol Cu nanoclusters, 50 mL H O/t-BuOH (2: 1), 258C; 18 h.
Yields of isolated products, reported in mol % based on azide starting material.
Yields calculated based on GC values, corrected for the presence of an internal standard.
2
Several interesting things can be observed in Figure 1. ution or not. Indeed, this question stands at the heart of
[
27]
Perhaps the most significant are the differences between many an argument in heterogeneous catalysis. To try
the reaction rates of the various catalyst types. This indi- to answer this question, we performed a separate set
cates that the role of Cu particles in the Huisgen 1,3-di- of reactions to give 3f catalysed by Cu(0) powder. As be-
polar cycloadditions is similar to that in the Sonogashira fore, reactions were monitored by GC. This time, how-
cross-coupling. If the Cu particles were mere ꢁreservoirsꢀ ever, we filtered the powder out of the reaction vessel af-
for Cu(I) and/or Cu(II) ions, one would expect similar ter 7 h, continued to stir, and added the powder back af-
reaction profiles regardless of the copper source {cf. ter 20 h. Figure 2 shows the resulting kinetic profile (ꢁꢁꢀ
the oxidative Cu/TBHP system where the kinetic pro- symbols), together with a control reaction with no filtra-
files for Cu(0) clusters, Cu(I) salts and Cu(II) salts are in- tion (broken curve).
[26]
distinguishable }.
The clear difference between the reaction curves in
Copper nanoclusters displayed the highest activity of Figure 2 supports our hypothesis that the reaction oc-
the four systems tested, affording 100% conversion after curs on the surface of the copper particles, rather than
18 h. The activity trend is Cu(0) clusters>Cu(0) via Cu(0) atoms or Cu(I)/Cu(II) ions that are leached
powder>Cu(0) shavings>Cu(II) /ascorbate. This is in into the reaction mixture. Furthermore, all four profiles
good agreement with the catalyst surface area [in the in Figure 1 exhibit an induction period, from 1 h in the
case of Cu(0)]. The specific surface area of the clusters case of Cu clusters, and up to 5 h in the case of Cu(II)/as-
2
2
and the powder was 168 m /g and 0.15 m /g, respectively. corbate. For the Cu(0) catalysts, the duration of the in-
One key scientific question is whether the Cu(0) clus- duction period corresponds to the catalystsꢀ surface
ters and powder are leaching copper atoms into the sol- area. This fact is also in agreement with a reaction that
Adv. Synth. Catal. 2005, 347, 811–815
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FULL PAPERS
Laura Dur a´ n Pach o´ n et al.
that a Cu(I)-alkyne intermediate is involved, similar to
the case with Sonogashira reactions. Further studies to
elucidate the mechanism of these cluster-catalysed click
reactions will be the subject of future research in our lab-
oratory.
Experimental Section
Materials and Instrumentation
1
H NMR was measured on a Varian Mercury vx300 NMR spec-
trometer at 258C. Chemical shifts of spectra are referenced to
Me Si and internal solvent resonances. GC analysis was per-
4
formed on a GC-8000 gas chromatograph with a 100% dime-
thylpolysiloxane capillary column (DB-1, 30 mꢂ0.325 mm).
All products were identified by their GC retention times and
1
their H NMR spectra. Samples for GC were diluted with
1
mL dimethylformamide (DMF) and filtered through an alu-
mina plug prior to injection. GC conditions: isotherm at 1108C
(
(
2 min); ramp at 308C/min to 2808C; isotherm at 2808C
15 min). A Coulter Multisizer Isoton II particle counter was
used to measure the particle size of copper powder. Unless not-
ed otherwise, chemicals were purchased from commercial
firms and were used as received. Tetra-n-octylammonium for-
Figure 2. Time-resolved reaction profile observed for the 1,3-
cycloaddition of prop-2-yn-1-ol and benzyl azide using Cop-
per powder as catalyst. Reaction conditions are as in Table 1.
[18]
mate (TOAF) was prepared as published previously. Azides
[30,31]
ꢁ
ꢁꢀ symbols represent the kinetic profile of the experiment fil-
were synthesised following literature procedures.
tering and adding back Cu powder. The broken line shows a
control experiment without filtering of the copper catalyst.
Procedure for 1,3-Dipolar Cycloaddition of Azides
with Terminal Alkynes
occurs at the catalyst surface. The reaction is probably
Example (1): 1,4-diphenyl-1H-1,2,3-triazole (3a): A solution
of phenyl azide (1a; 10 mmol, 1.33 g) and phenylacetylene
mediated via a Cu(I) ion on the surface, similar to the
[
20]
mechanism of the Sonogashira coupling.
(
2a; 20 mmol, 2.04 g) in 50 mL of 2:1 H O:t-BuOH was stirred
2
Notwithstanding this evidence, two more points
should be considered: First, it may be that after the cop-
per powder is filtered off, some Cu(I) and/or Cu(II) may
still remain in solution, but as there is no more reducing
in a round-bottomed flask equipped with a magnetic stirring
bar. A pre-prepared suspension of copper nanoclusters
(
0.1 mL, 10 mM, equivalent to 0.1 mol % of copper relative
to 1a) was then added in one portion and the reaction mixture
agent, it will rapidly convert all Cu(II) (in Figure 2 we was stirred at 258C for 18 h. Reaction progress was monitored
see that after 7 h, when the copper powder is filtered by GC. The product precipitated in the reaction mixture and
was collected by filtration, washed (2ꢂ20 mL H O), and dried
off, the reaction slows down considerably, but does not
stop). Second, recent studies on the mechanism of the
homogeneously-catalysed reaction show that Cu(I) ace-
tylide is almost certainly an intermediate in the catalytic
2
under vacuum to obtain colourless needles of the product;
yield: 1.77 g (80% yield based on 1a); mp 176–1798C (lit.,
1
1
7
81–1838C); H NMR (Me Si): d¼7.26–7.58 (m, 7H, Ph),
4
.79–7.95 (m, 3H, Ph), 8.27 (s, 1H, CH). Good agreement
[28]
cycle. If this is the case, it means that Cu(0) by itself
cannot catalyze the reaction – one way or another,
[32]
was found with literature values.
Example (2): (1-benzyl-1H-1,2,3-triazol-4-yl)(phenyl)me-
thanol (3e): Reaction and work-up were performed as above,
but using benzyl azide (1b; 10 mmol, 1.19 g) and 1-phenyl-2-
propyn-1-ol (2b; 20 mmol, 2.64 g), to give the product as a
white solid; yield: 2.21 g (97%); mp 120–1238C; H NMR
Me Si): d¼2.24 (1H, OH), 5.46 (s, 2H, CH ), 6.01 (s, 1H,
[
29]
Cu(I) has to form.
1
Conclusion
(
4
2
CH), 6.91–7.93 (m, 10H, Ph).
In conclusion, we show here that Cu nanoclusters are ef-
ficient catalysts for 1,3-cycloadditions of azides to termi-
nal alkynes. Reaction conditions are improved in com-
parison with previous catalytic systems. There is evi-
dence that the catalysis occurs on the particlesꢀ surface,
Reaction Profiles and Kinetic Analysis
The reaction profiles were obtained for the model reaction be-
but the mechanism is complex, and more work is needed tween benzyl azide (1b) and prop-2-yn-1-ol (2c) for four differ-
to ascertain the specific role of the clusters. It is possible ent catalytic systems: copper shavings, copper powder, copper
814
ꢂ 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Adv. Synth. Catal. 2005, 347, 811–815

Cycloaddition of Azides with Terminal Alkynes
FULL PAPERS
nanoclusters, and CuSO /ascorbate (see Figure 1 above). All
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4
other reaction conditions were kept constant and appropriate
blank experiments were performed to exclude systemic effects.
2
In this analysis, the correlation coefficient, R , gives a measure
[
[
[
12] W. S. Horne, M. K. Yadav, C. D. Stout, M. R. Ghadiri, J.
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2
a given model (in this case, a 2nd–order rate equation). The R
values and the second-order rate constants (k) were as follows:
2
ꢃ3
Cu colloids: R ¼0.886, k¼8.3ꢂ10 (four observations); Cu
2
ꢃ3
powder: R ¼0.912, k¼6.7ꢂ10
(four observations); Cu
2
ꢃ3
shavings: R ¼0.921, k¼3.1ꢂ10 (five observations); Cu sul-
2
ꢃ3
fate/sodium ascorbate: R ¼0.908, k¼0.9ꢂ10 (six observa-
[
[
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Surface Analysis and Calculation Procedures
The surface area of copper powder was calculated assuming
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2
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2
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[
[
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Acknowledgements
We thank Prof. V. V. Fokin (The Scripps Research Institute, La
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Adv. Synth. Catal. 2005, 347, 811–815
asc.wiley-vch.de
ꢂ 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
815