A versatile solvent-free azide-alkyne click reaction catalyzed by in situ generated copper nanoparticles

Article abstract of DOI:10.1016/j.apcata.2012.12.025

A general, high-yielding and efficient methodology for the copper catalyzed azide-alkyne cycloaddition (CuAAC) reaction catalyzed by in situ generated copper nanoparticles (CuNPs) or their clusters is reported. This simple reaction is facile in water, org

Full text of DOI:10.1016/j.apcata.2012.12.025

Applied Catalysis A: General 453 (2013) 151–158
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Applied Catalysis A: General
journal homepage: www.elsevier.com/locate/apcata
A versatile solvent-free azide–alkyne click reaction catalyzed by in
situ generated copper nanoparticles
Atchutarao Pathigoolla, Ramachandra P. Pola, Kana M. Sureshan∗
School of Chemistry, Indian Institute of Science Education and Research, Thiruvananthapuram, CET Campus, Thiruvananthapuram 695016, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A general, high-yielding and efficient methodology for the copper catalyzed azide–alkyne cycloaddition
(CuAAC) reaction catalyzed by in situ generated copper nanoparticles (CuNPs) or their clusters is reported.
This simple reaction is facile in water, organic solvents and solvent-free conditions under ambient, open-
air conditions and requires no special reaction conditions and chromatographic separation.
© 2012 Elsevier B.V. All rights reserved.
Received 2 August 2012
Received in revised form
11 December 2012
Accepted 14 December 2012
Available online xxx
Keywords:
Click reaction
Cycloaddition
Copper nanoparticles
Solvent-free
Green chemistry
1. Introduction
presumed to show superior catalytic profile due to their large
surface area. Sarkar et al. reported an elegant methodology for
Sharpless coined the term ‘click chemistry’ to high yielding
modular chemical reactions of wide scope, high regiospecificity
giving no or inoffensive by-products under simple reaction con-
ditions [1]. Independent discoveries by Sharpless et al. [2] and
Meldal et al. [3] that Cu(I) catalysts can facilitate the otherwise non-
selective Huisgen’s azide–alkyne 1,3-dipolar cycloaddition [4] in a
regiospecific manner to give only 1,4-substituted triazole deriva-
tives under mild conditions have attracted much attention due to
their applications in various branches of science such as materials,
pharmaceuticals, drug discovery, biochemistry, in vivo and in vitro
labeling of biomolecules [5], etc. Today CuAAC is considered as the
‘cream of the crop’ among all click reactions. Due to the impor-
tance of this reaction, several modifications to improve the yield,
efficiency or to reduce the cost have been reported. While Cu(I) salts
[3] and Cu(I) complexes [6–9] are used in organic solvents, water as
the solvent necessitates the in situ reduction of Cu(II) salts to Cu(I)
with reducing agents [2].
CuAAC in organic solvents using polymer coated CuNPs as reusable
catalyst [11]. Mixed Cu/Cu-oxide NP [12], Cu-Fe nanoparticles
[13,14], tetraalkylammonium stabilized copper nanoclusters [15],
unsupported copper nanoparticles [16,17] and CuNPs supported
on solid matrices [18–26] have been exploited as catalysts for
azide–alkyne click reaction. However, the major limitations of
these methods are (i) They involve two-step process; synthesis
(and isolation) of nanoparticles and the subsequent use of these
pre-formed nanoparticles as the catalyst, (ii) The preparation of
these CuNPs involve the use of expensive Cu salts, stabilizing agents
[11,14,15] or solid supports [18–26] to prevent agglomeration and
special conditions such as very high temperature, argon atmo-
sphere, ultrasound, etc. We herein report a cheap, simple and
versatile methodology for CuAAC at room temperature using in situ
generated naked CuNPs or their clusters as catalysts which do
not require stabilizers/solid support, special conditions (e.g. argon
atmosphere) and can be carried out not only in aqueous and organic
solvents but also under solvent-free conditions.
The discovery that copper turnings can catalyze azide–alkyne
click reaction [10] has aroused interests in exploring copper
nanoparticles (CuNPs) as the catalyst for CuAAC as they are
2. Experimental
2.1. Materials and methods
Abbreviations: CuAAC, copper catalyzed azide–alkyne cycloaddition; CuNPs,
copper nanoparticles; AAC, azide–alkyne cycloaddition.
Chemicals and solvents were purchased from Sigma–Aldrich
and used directly. TLC analyses were done using precoated TLC
silica gel 60 F254 (Merck) plates. Melting points were recorded
∗
Corresponding author. Tel.: +91 4712599412; fax: +91 4712597437.
E-mail address: kms@iisertvm.ac.in (K.M. Sureshan).
0926-860X/$ – see front matter © 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.apcata.2012.12.025

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A. Pathigoolla et al. / Applied Catalysis A: General 453 (2013) 151–158
Table 1
Reaction in aqueous and organic mediaa
N
R1
CuSO4.5H2O,
N2H4.H2O
N
N
R1
N3
R2
+
H2O or MeCN, rt
1
3
2
R2
2a. R2: Ph
1a. R1: Bn
3a. R1: Bn; R2: Ph
2b. R2: p-Tolyl
1b. R1: Ph
3b. R1: Bn; R2: p-Tolyl
3c. R1: Bn; R2: CH2OH
3d. R1: Ph; R2: Ph
2c. R2: CH2OH
1c. R1: Dodecyl
2d. R2: (CH2)7CH2OH
1d. R1: β-D-Galactosyl
3e. R1: Ph; R2: CH2OH
3f. R1: Ph; R2: (CH2)7CH2OH
3g. R1: Dodecyl; R2: Ph
3h. R1: Dodecyl; R2: CH2OH
3i. R1: -D-Galactosyl; R2: Ph
β
1
2
D
3j. R : β- -Galactosyl; R : CH2OH .
Entry
Azide
Alkyne
Reaction time and yield
A (in water)
B (in MeCN)
1
2
3
4
5
6
7
8
9
1a
1a
1a
1b
1b
1b
1c
1c
1d
1d
2a
2b
2c
2a
2c
2d
2a
2c
2a
2c
45 min, 95%
45 min, 99%
45 min, 85%
60 min, 91%
60 min, 82%
75 min, 96%
100 min, 98%
120 min, 91%
70 min, 80%
70 min, 95%
17 h, 98%
8 h, 87%
8 h, 85%
40 h, 92%
48 h, 89%
40 h, 88%
24 h, 99%
40 h, 92%
8 h, 87%
8 h, 94%
10
a
Azide (1.0 equiv.), Alkyne (1.5 equiv.), CuSO4.5H2O (0.1 equiv.), N2H4.H2O (1.0 equiv.), rt.
on a Stuart, SMP 30 melting point apparatus. NMR spectra were
recorded on an Avance III-500 (Bruker) NMR spectrometer. IR spec-
tra were recorded by preparing KBr pellets, using IR Prestige–21
(Shimadzu) spectrometer. Elemental analyses were done on Ele-
mentar, vario MICRO cube elemental analyzer. Sizes of the CuNPs
or clusters were analyzed using Zetasizer (Malvern). Transmission
2.4. General methods for AAC reaction in solution
2.4.1. General procedure A (aqueous medium)
Azide (1 equiv.), alkyne (1.5 equiv.) and CuSO4·5H2O (0.1 equiv.)
were dissolved (suspended) in water (12 mL) and then hydrazine
hydrate (1 equiv.) was added dropwise. The solution turned into
pale yellow in color. The product was precipitated within few min-
utes (see Table 1 for exact reaction time). Reaction mixture was
diluted further with water and filtered. The colorless precipitate
was washed with excess of water. This solid could be crystallized
or passed through a small pad of celite after dissolving in an appro-
priate solvent to get analytically pure product.
ˆ
Electron Microscopy images of CuNPs were taken using Tecnai G2
30 Twin with EDAX. Energy Dispersive X-ray spectroscopy (EDAX)
was used to characterize CuNPs or clusters. Benzyl azide (1a) [35],
Phenyl azide (1b) [36], Dodecyl azide (1c) [37] and Galactosyl azide
(1d) [38] were prepared as reported.
2.2. Determination of the size of the CuNPs or their clusters using
dynamic light scattering
2.4.2. General procedure B (organic medium)
To a solution of azide (1 equiv.) and alkyne (1.5 equiv.) in ace-
tonitrile (12 mL), powdered CuSO4·5H2O (0.1 equiv.) was added.
Hydrazine hydrate (1 equiv.) was added dropwise to the above mix-
ture. Most of the copper precipitated as red colored aggregates at
the bottom of the flask. Reaction was monitored by TLC. After com-
pletion of the reaction (see Table 1 for exact reaction time), the
mixture was passed through a celite pad and the filtrate was evap-
orated under reduced pressure to obtain pure product as colorless
solid (unless mentioned).
CuNPs or their clusters were prepared in appropriate solvent
(water or acetonitrile or water + acetonitrile 2:1 (v/v)) by the reduc-
tion of CuSO4·5H2O (10 mg/12 mL) using hydrazine monohydrate.
The resultant gray colored suspension was immediately taken in
a cuvette and measured the sizes of the particles using Dynamic
Light Scattering.
2.3. Transmission electron microscopy image of CuNPs or their
clusters
2.4.3. General procedure C (2:1, v/v H2O: MeCN)
Azide (1 equiv.), alkyne (1.5 equiv.) and CuSO4·5H2O (0.1 equiv.)
were dissolved in a mixture of water and acetonitrile (12 mL; 2:1,
v/v) at room temperature. Hydrazine hydrate (1 equiv.) was added
dropwise to the above solution under vigorous stirring. The reaction
mass turned to pale yellow or light green in color. After a few min-
utes (see Table 3 for exact reaction time) TLC showed completion
of the reaction. Usually the product got precipitated as colorless
solid (unless mentioned). The reaction mixture was diluted with
excess of water and filtered. The precipitated product was washed
Hydrazine monohydrate was added to a solution of CuSO4·5H2O
(10 mg) in a 2:1 (v/v) mixture of water and acetonitrile (12 mL)
under vigorous stirring. The solution turned into a gray colored
suspension instantaneously. This suspension was drop-casted on
a TEM copper grid and was dried for three days under high vac-
uum. This was imaged using Transmission Electron Microscope.
This showed spherical CuNPs/clusters of sizes 400–500 nm

A. Pathigoolla et al. / Applied Catalysis A: General 453 (2013) 151–158
153
Table 2
stirred at room temperature. As there was no reaction at rt (till
4 h), the temperature was increased to 100 ◦C and continued stir-
ring. The reaction was monitored by TLC. After completion of the
reaction (1 h at 100 ◦C), the reaction mixture was diluted with ethyl
acetate and the organic layer was separated, dried over anhydrous
sodium sulfate and evaporated under reduced pressure. The crude
solid product thus obtained was purified by column chromatogra-
phy to get pure 3a (110 mg, 81%) as a white solid.
Optimization of the AAC reaction conditions in solution
N
N
N3
N
+
2a
1a
3a
.
Entry
Aa (eq.)
Bb (eq.)
Solvent (v/v) H2O:MeCN
Time
Yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.05
0.02
0.1
1
0
1
0
1
1
1
1
100% H2O
100% H2O
100% MeCN
100% MeCN
3:1
2:1
3:2
1:1
1:2
2:1
2:1
2:1
2:1
45 min
24 h
17 h
95
0
98
0
2.6. General procedure for solvent-free AAC reaction
24 h
35 min
25 min
30 min
2 h
12 h
20 h
17 h
12 h
24 h
24 h
99
99
97
91
97
40
54
92
75
0
Two equivalents of hydrazine hydrate were added to a mixture
of alkyne (1 equiv.), azide (1 equiv.) and CuSO4·5H2O (0.05 equiv.) at
room temperature. The reaction was monitored by TLC (see Table 5
for exact reaction time). After completion of the reaction, ethyl
acetate was added to the crude mixture and filtered through a celite
pad. The filtrate was concentrated under reduced pressure to get
pure compound.
1
0.1
0.5
1
1
0
2:1
2.7. Compound characterization data
a
CuSO4·5H2O.
b
N2H4.H2O.
1-Benzyl-4-phenyl-1,2,3-triazole (3a) [17]: Yield: 97%. Melting
point: 130–131 ◦C (lit. M.P. 132.0–133.1 ◦C). 1H NMR (DMSO-d6,
500 MHz) ı: 8.66 (s, 1H, triazole-H), 7.87–7.85 (m, 2H), 7.47–7.33
(m, 8H), 5.66 (s, 2H, Ph-CH2).
1-Benzyl-4-(p-tolyl)-1,2,3-triazole (3b) [39]: Yield: 96%. Melt-
ing point: 178–180 ◦C (lit. M.P. 179–180 ◦C). 1H NMR (DMSO-d6,
500 MHz) ı: 8.59 (s, 1H, triazole-H), 7.75 (d, J = 7.9 Hz, 2 H, tolyl ring
protons), 7.42–7.34 (m, 5H, Phenyl-H), 7.26 (d, J = 7.9 Hz, 2H, tolyl
ring protons), 5.65 (s, 2H, Ph-CH2), 2.33 (s, 3H, –CH3).
(1-Benzyl-1,2,3-triazol-4-yl)methanol (3c) [17]: Yield: 85%. This
compound is partially soluble in water and 2:1 (v/v) of water and
acetonitrile. In this case, the reaction solvent was evaporated, dis-
solved in chloroform, filtered through a small pad of silica and
with water and dried. The solid thus obtained could be crystal-
lized or passed through a small pad of celite after dissolving in an
appropriate solvent to get analytically pure product.
2.5. Procedure for three-component reaction
Benzyl bromide (100 mg, 0.584 mmol, 1eq), phenyl acetylene
(90 ␮L, 0.876 mmol, 1.5 eq), sodium azide (42 mg, 0.642 mmol, 1.1
eq) and CuSO4.5H2O (15 mg, 0.06 mmol, 0.1 eq) were dissolved in
water (10 mL) at room temperature. To this mixture, hydrazine
hydrate (30 ␮L, 0.584 mmol, 1 eq) was added and the mixture was
Table 3
Click reaction of various azides and alkynes in mixture of water and acetonitrile (2:1, v/v)a
N
N
CuSO4.5H2O,
R1
N2H4.H2O
N
R2
R1
N3
+
H2O/MeCN (2:1), rt
Ph
R2
Ph
H
H
O
O
OH
O
O
OH
O
O
O
HO
HO
4,6-O-
BnO
OH
OH
OBn
4,6-O-Benzylidene-2,3-di-
O-benzyl-β-D-galactosyl
β-D-Galactosyl
Benzylidene-β-D-
galactosyl
.
Entry
R1
R2
Time (min.)
Yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Phenyl
Phenyl
Phenyl
Phenyl
Benzyl
Benzyl
Benzyl
Benzyl
Phenyl
p-Tolyl
CH2OH
(CH2)7CH2OH
Phenyl
p-Tolyl
CH2OH
CH2CH2OH
Phenyl
CH2OH
p-Tolyl
CH2CH2OH
p-Tolyl
Phenyl
CH2OH
15
15
40
40
30
30
30
30
30
97
96
95
99
97
96
85
98
91
89
90
97
90
87
94
n-Dodecyl
n-Dodecyl
30
4,6-O-Benzylidene-␤-d-galactosyl
4,6-O-Benzylidene-␤-d-galactosyl
4,6-O-Benzylidene-2,3-di-O-benzyl-␤-d-galactosyl
␤-d-Galactosyl
45
45
30
360
360
␤-d-Galactosyl
a
Azide (1.0 equiv.), Alkyne (1.5 equiv.), CuSO4·5H2O (0.1 equiv.), N2H4.H2O (1.0 equiv.), rt.

154
A. Pathigoolla et al. / Applied Catalysis A: General 453 (2013) 151–158
evaporated under reduced pressure. Melting point: 74–75 ◦C (lit.
M.P. 76.0–78.0 ◦C). 1H NMR (DMSO-d6, 500 MHz) ı: 8.05 (s, 1H,
triazole-H), 7.4–7.32 (m, 5H), 5.58 (s, 2H, Ph-CH2), 5.16 (br, 1H,
–OH), 4.51 (br, 2H, –CH2OH).
1,4-Diphenyl-1,2,3-triazole (3d) [11]: Yield: 97%. Melting point:
179–180 ◦C (lit. M.P. 166–171 ◦C). 1H NMR (DMSO-d6, 500 MHz)
ı: 9.32 (s, 1H, triazole-H), 7.99–7.97 (m, 4H), 7.67–7.64 (m, 2H),
7.55–7.50 (m, 3H), 7.42–7.39 (m, 1H).
(1-Phenyl-1,2,3-triazol-4-yl)methanol (3e) [39]: This compound
is partially soluble in water and 2:1 (v/v) of water and acetonitrile.
In this case, the reaction solvent was evaporated, dissolved in chlo-
roform, filtered through a small pad of silica and evaporated under
reduced pressure. Yield: 95%. Melting point: 120–121 ◦C (lit. M.P.
122–123 ◦C). 1H NMR (DMSO-d6, 500 MHz) ı: 8.69 (s, 1H, triazole-
H), 7.92 (d, J = 7.7 Hz, 2H, ArH), 7.61 (t, J = 7.7 Hz, 2H, ArH), 7.49 (t,
J = 7.3 Hz, 1H, ArH), 5.34 (t, J = 5.0 Hz, 1H, –OH), 4.63 (d, J = 4.7 Hz,
2H, –CH2OH).
500 MHz) ı: 7.97 (s, 1H, triazole-H), 5.36 (d, J = 9.2 Hz, 1H),
5.17–5.12 (br, 3H), 4.6 (br, 2H), 4.44 (s, 2H), 3.93 (t, J = 9.3 Hz, 1H),
3.46 (br, 1H), 3.60 (t, J = 5.9 Hz, 6.1 Hz, 1H), 3.46–3.26 (m, 3H). 13C
NMR (CD3OD-d4, 125 MHz) ı: 149.28, 123.02, 90.22, 79.93, 75.33,
71.47, 70.41, 62.44, 56.50.
1-Benzyl-4-(2ꢀ-hydroxyethyl)-1,2,3-triazole (3k) [11]: Yield: 98%.
Melting point: 90–92 ◦C (lit. M.P. 90–91 ◦C). 1H NMR (DMSO-d6,
500 MHz) ı: 7.91 (s, 1H, triazole-H), 7.39–7.30 (m, 5H), 5.55 (s, 2H,
–PhCH2), 4.69 (t, J = 5.3 Hz, 1H, –OH), 3.63 (q, J = 6.75 Hz, 12.2 Hz, 2H,
–CH2OH), 2.77 (t, J = 6.9 Hz, 2H, CH2CH2OH).
1-Phenyl-4-(p-tolyl)-1,2,3-triazole (3l) [39]: Yield: 96%. Melt-
ing point: 171–172 ◦C (lit. M.P. 173–174 ◦C). 1H NMR (DMSO-d6,
500 MHz) ı: 9.26 (s, 1H, triazole-H), 7.97–7.96 (m, 2H, Ph),
7.86–7.85 (d, J = 8.0 Hz, 2H, tolyl), 7.67–7.64 (m, 2H, Ph), 7.55–7.52
(m, 1H, Ph), 7.34–7.32 (d, J = 7.9 Hz, 2H, tolyl) 2.37 (s, 3H, –CH3).
1-(4ꢀ,6ꢀ-O-Benzylidene-ˇ-d-1ꢀ-galactosyl)-4-tolyl-1,2,3-triazole
(3m): Yield: 90%. Melting point: 125–126 ◦C. 1H NMR (DMSO-d6,
500 MHz) ı: 8.74 (s, 1H, triazole-H), 7.84 (d, J = 8.1 Hz, 2H, tolyl),
7.57–7.55 (m, 2H), 7.44–7.4 (m, 3H), 7.28 (d, J = 7.9 Hz, 2H, tolyl),
5.68 (d, J = 9.2 Hz, 1H, H-1), 5.64 (s, 1H, PhCH), 5.41 (d, J = 5.9 Hz,
1H, 2-OH), 5.28 (d, J = 5.9 Hz, 1H, 3-OH), 4.27–4.21 (m, 2H, H-4 &
H-2), 4.13–4.05 (m, 2H, H-6a & H-6b), 3.94 (br, 1H, H-5), 3.82–3.78
(m, 1H, H-3), 2.35 (s, 3H, ArCH3). 13C NMR (DMSO-d6, 125 MHz)
ı: 146.89, 139.02, 137.72, 129.89, 129.18, 128.43, 128.31, 126.99,
125.74, 120.47, 100.58 (PhCH), 88.31 (C-1), 76.42 (C-4), 72.74 (C-3),
69.12 (C-5), 69.04 (C-2), 68.71 (C-6), 21.33 (ArCH3). Elemental
analysis calcd. for C22H23N3O5: C 64.54, H 5.66, N 10.26; found: C
64.51, H 5.79, N 9.99.
1-Phenyl-4-(8ꢀ-hydroxyoctyl)-1,2,3-triazole (3f): After comple-
tion of the reaction, the solvent was evaporated under reduced
pressure and the crude material thus obtained was chro-
matographed using 22% ethyl acetate in petroleum ether as eluent.
Yield: 99%. Melting point: 63–64 ◦C. 1H NMR (DMSO-d6, 500 MHz)
ı: 8.58 (s, 1H, triazole-H), 7.89–7.88 (m, 2H), 7.61–7.58 (m, 2H),
7.49–7.46 (m, 1H), 4.32 (t, J = 5.2 Hz, 1H, OH), 3.4–3.37 (m, 2H,
8-CH2), 2.71 (t, J = 7.5 Hz, 2H, 1-CH2), 1.71–1.65 (m, 2H, 2-CH2),
1.43–1.34 (m, 10H). 13C NMR (DMSO-d6, 125 MHz) ı: 148.15,
136.81, 129.80, 128.26, 119.99, 119.73, 60.69 (C-8), 32.52, 28.82,
28.80, 28.78, 28.55, 25.47, 24.99. Elemental analysis calcd. for
C16H23N3O: C 70.30, H 8.48, N 15.37; found: C 70.12, H 8.73, N
15.10.
1-(4ꢀ,6ꢀ-O-Benzylidene-ˇ-d-1ꢀ-galactosyl)-4-(2ꢀꢀ-hydroxyethyl)-
1,2,3-triazole (3n): Yield: 97%. Melting point: 157–158 ◦C. 1H NMR
(DMSO-d6, 500 MHz) ı: 8.01 (s, 1H, triazole-H), 7.53 (br, 2H), 7.41
(br, 3H), 5.62–5.59 (m, 2H, PhCH & H-1), 5.31 (br, 2H, 2 x OH), 4.74
(br, 1H, –CH2OH), 4.24 (d, J = 3 Hz, 1H, H-4), 4.14 (t, J = 9.5 Hz, 1H,
H-2), 4.06 (AB system, J = 14 Hz, 26 Hz, 2H, H-6a & H-6b), 3.88 (br,
1H, H-5), 3.76 (m, 1H, H-3), 3.70–3.67 (m, 2H, –CH2CH2OH), 2.83 (t,
J = 7 Hz, 2H, –CH2CH2OH). 13C NMR (DMSO-d6, 125 MHz) ı: 144.45,
138.53, 128.7, 127.94, 126.41, 121.26, 99.99 (PhCH), 87.49 (C-1),
75.87 (C-4), 72.23 (C-3), 68.63, 68.41, 68.18, 60.28 (CH2CH2OH),
29.09 (–CH2CH2OH). Elemental analysis calcd. for C17H21N3O6: C
56.19, H 5.83, N 11.56; found: C 55.99, H 5.92, N 11.19.
1-Dodecyl-4-phenyl-1,2,3-triazole (3g) [17]: Yield: 91%. Melt-
ing Point: 92–93 ◦C. 1H NMR (DMSO-d6, 500 MHz) ı: 8.49 (s, 1H,
triazole-H), 7.75 (d, J = 7.5 Hz, 2H), 7.36 (t, J = 7.5 Hz, 2H), 7.24 (t,
J = 7.5 Hz, 1H), 4.3 (t, J = 7.0 Hz, 2H, N-CH2), 1.77 (br, 2H, N-CH2CH2),
1.19–1.14 (br, 18H), 0.76 (t, J = 7.0 Hz, 3H, –CH3).
1-Dodecyl-4-hydroxymethyl-1,2,3-triazole (3h): Yield: 89%. Melt-
ing point: 70–71 ◦C. 1H NMR (DMSO-d6, 500 MHz) ı: 7.86 (s, 1H,
triazole-H), 5.05 (t, J = 5.5 Hz, 1H, –OH), 4.41 (d, J = 5.5 Hz, 2H,
CH2OH), 4.22 (t, J = 7 Hz, 2H, N-CH2), 1.73–1.67 (m, 2H, N-CH2CH2),
1.15 (br, 18H), 0.77 (t, J = 7 Hz, 3H, –CH3). 13C NMR (125 MHz, DMSO-
d6) ı: 148.36, 122.75, 55.05, 49.27, 31.27, 29.72, 28.99, 28.93, 28.86,
28.69, 28.38, 25.84, 22.07. Elemental analysis calcd. for C15H29N3O:
C 67.37, H 10.93, N 15.71; found: C 67.11, H 11.03, N 15.46.
1-(1ꢀ-ˇ-d-Galactosyl)-4-phenyl-1,2,3-triazole (3i) [40]: This com-
pound was partially soluble in both water and 2:1 (v/v) mixture
of water & acetonitrile. Hence, after the completion of the reac-
tion, the solvent was evaporated under reduced pressure and the
crude material thus obtained was re-dissolved in methanol and fil-
tered through a short silica column. The filtrate was evaporated
under reduced pressure and dried under high vacuum. Yield: 87%.
Melting point: 239–240 ◦C. 1H NMR (DMSO-d6, 500 MHz) ı: 8.78
(s, 1H, triazole-H), 7.92 (d, J = 7.6 Hz, 2H), 7.47 (t, J = 7.6 Hz, 2H),
7.36 (t, J = 7.3 Hz, 1H), 5.5 (d, J = 9.2 Hz, H-1), 5.3 (d, J = 5.85 Hz, 1H,
2-OH), 5.09 (d, J = 5.35 Hz, 1H, 3-OH), 4.74–4.7 (m, 2H, H-5 & 4-
OH), 4.15–4.1 (m, 1H, H-2), 3.81 (br, 1H, H-4), 3.78 (t, J = 6 Hz, 1H,
6-OH), 3.61–3.59 (m, 3H, H-3, H-6a & H6b). 13C NMR (DMSO-d6,
125 MHz) ı: 146.33, 130.64, 128.89, 127.90, 125.19, 120.24, 88.30,
78.46, 73.62, 69.34, 68.44, 60.46.
1-(4ꢀ,6ꢀ-O-Benzylidene-2ꢀ,3ꢀ-di-O-benzyl-ˇ-d-1ꢀ-galactosyl)-4-
(p-tolyl)-1,2,3-triazole (3o): Yield: 90%. Melting point: 200–201 ◦C.
1H NMR (DMSO-d6, 500 MHz) ı: 8.92 (s, 1H, triazole-H), 7.82 (d,
J = 8 Hz, 2H, tolyl), 7.56 (d, J = 7 Hz, 2H, tolyl), 7.47–7.42 (m, 5H),
7.37–7.28 (m, 5H), 7.16–7.14 (m, 3H), 6.90–6.89 (m, 2H), 5.94 (d,
J = 9.5 Hz, 1H, H-1), 5.74 (s, 1H, PhCH), 4.84, 4.7 (AB, J = 12.1 Hz,
68 Hz, 2H, PhCH2), 4.73, 4.27 (AB, J = 11 Hz, 227.5 Hz, 2H, PhCH2),
4.72 (m, 1H, H-4), 4.48 (t, J = 9.5 Hz, 1H, H-2), 4.15 (s, 2H, H-6a
& H-6b), 4.06 (dd, J = 3.5 Hz, 13 Hz, 1H, H-3), 3.99 (br, 1H, H-5),
2.35 (s, 3H, CH3). 13C NMR (DMSO-d6, 125 MHz) ı: 146.78, 138.35,
138.34, 137.94, 137.41, 129.43, 128.79, 128.23, 128.05, 127.97,
127.63, 127.52, 127.49, 127.43, 127.28, 126.35, 125.32, 120.25,
100.03 (PhCH), 86.17 (C-1), 79.53 (C-3), 76.24 (C-2), 74.24 (PhCH2),
72.11 (C-4), 69.79 (PhCH2), 68.48 (C-5), 68.20 (C-6), 20.83 (CH3).
Elemental analysis calcd. for C36H35N3O5: C 73.33, H 5.98, N 7.13;
found: C 73.18, H 5.86, N 6.96.
1-Benzyl-4-(3,5-difluorophenyl)-1,2,3-triazole (3p) [41]: Yield:
94%. Melting point: 117–118 ◦C. 1H NMR (DMSO-d6, 500 MHz) ı:
8.78 (s, 1H, triazole-H), 7.58 (d, J = 7.2 Hz, 2H), 7.42–7.36 (m, 5H),
7.20 (t, J = 9.3 Hz, 1H), 5.68 (s, 2H, PhCH2). 13C NMR (DMSO-d6,
125 MHz) ı: 163.83, 161.87, 144.73, 135.67, 134.16, 128.83, 128.24,
127.96, 122.88, 108.16, 108, 103.07, 53.18.
1-Benzyl-4-(p-fluorophenyl)-1,2,3-triazole (3q) [42]: Yield: 85%.
Melting point: 105–106 ◦C (lit. M.P. 106–108 ◦C). 1H NMR (DMSO-
d6, 500 MHz) ı: 8.64 (s, 1H), 7.91–7.88 (m, 2H), 7.40 (m, 2H), 7.37
(d, J = 7.1 Hz, 3H), 7.29 (t, J = 8.8 Hz, 2H), 5.65 (s, 2H, PhCH2).
1-(1ꢀ-ˇ-d-Galactosyl)-4-hydroxymethyl-1,2,3-triazole (3j) [40]:
This compound was partially soluble in both water and 2:1 (v/v)
mixture of water & acetonitrile. Hence, after the completion of the
reaction, the solvent was evaporated under reduced pressure and
the crude material thus obtained was re-dissolved in methanol and
filtered through a short silica column. The filtrate was evaporated
under reduced pressure and dried under high vacuum to obtain 3j
as a gum. Yield: 94%. Melting point: 68–69 ◦C. 1H NMR (DMSO-d6,

A. Pathigoolla et al. / Applied Catalysis A: General 453 (2013) 151–158
155
Table 4
Optimization of the solvent-free AAC reaction conditions
N
N
N3
N
+
2a
1a
3a
.
Entry
Aa (eq.)
Bb (eq.)
Time (min.)
Yield (%)
1
2
3
4
5
6
7
8
9
0.2
0.1
2
2
2
2
2
2
2
2
2
0
5
5
10
14
17
20
25
28
240
300
92
91
91
91
91
84
83
82
82
0
0.08
0.05
0.03
0.02
0.01
0.005
0.0025
0.1
10
a
CuSO4·5H2O.
b
N2H4.H2O.
2-(1-Benzyl)-1,2,3-triazole-4-yl)-phenylamine (3r) [43]: Yield:
for C21H33N3O: C 73.43, H 9.68, N 12.23; found: C 73.25, H 9.61, N
12.31.
96%. Melting point: 113–115 ◦C. (lit. M.P. 97–98 ◦C). 1H NMR
(DMSO-d6, 500 MHz) ı: 8.59 (s, 1H), 7.46 (dd, J = 1.3, 7.75 Hz, 1H),
7.42–7.34 (m, 5H), 7.04–7.01 (m, 1H), 6.76 (dd, J = 0.75, 8.15 Hz, 1H),
6.60–6.56 (m, 1H), 6.17 (br, 2H, –NH2), 5.66 (s, 2H, PhCH2).
2-(1-Benzyl-1,2,3-triazole-4-yl)-pyridine (3s) [44]: Yield: 82%.
Melting point: 112–114 ◦C (lit. M.P. 112–113 ◦C). 1H NMR (DMSO-
d6, 500 MHz) ı: 8.68 (s, 1H), 8.59 (d, J = 4.8 Hz, 1H), 8.03 (d, J = 7.9 Hz,
1H), 7.89 (t, J = 7.8 Hz, 1H), 7.39–7.34 (m, 6H), 5.68 (s, 2H, PhCH2).
4-(1-Benzyl-1,2,3-triazole-4-yl)-phenylamine (3t) [42]: Yield:
94%. Melting point: 170–172 ◦C (lit. M.P. 160–161 ◦C). 1H NMR
(CDCl3, 500 MHz) ı: 7.52 (dd, J = 1.95, 4.7 Hz, 2H), 7.45 (s, 1H),
7.31–7.29 (m, 3H), 7.23–7.22 (m, 2H), 6.63 (d, J = 8.6 Hz, 2H), 5.48
(s, 2H), NH2 - peaks not seen.
1-Benzyl-4-hexyl-1,2,3-triazole (3z) [17]: Yield: 82%. Melting
point: 54–55 ◦ C. 1H NMR (DMSO-d6, 500 MHz) ı: 7.80 (s, 1H, triazol-
H), 7.31–7.26 (m, 3H), 7.24– 7.19 (m, 2H), 5.45 (s, 2H, PhCH2),
2.51 (t, J = 7.5 Hz, 2H), 1.51–1.46 (m, 2H), 1.23–1.19 (m, 6H), 0.77
(t, J = 6.4 Hz, 3H). 13C NMR (DMSO-d6, 125 MHz) ı: 147.23, 136.31,
128.66, 127.96, 127.73, 121.88, 52.61, 30.94, 28.87, 28.19, 24.96,
21.97, 13.86.
3. Results and discussion
We envisioned generating CuNPs in solvents containing alkyne
and azide partners to investigate whether the in situ formed CuNPs
or clusters will catalyze cycloaddition as soon as they are gener-
ated. Such a method will be interesting as it can avoid the use
of stabilizers, supports, special reaction conditions, etc. to prevent
the aggregation/clusters of CuNPs. Reduction of inexpensive copper
sulphate using hydrazine hydrate is known to generate CuNPs in
both aqueous [27] and organic media [11,28]. We have planned to
adopt this method for the in situ generation of the CuNPs/clusters
catalysts as such a method, if successful, will be facile in both
organic and aqueous solvents. In order to test this hypothesis, a sus-
pension of benzyl azide (1a), phenylacetylene (2a) and CuSO4·5H2O
(1:1.5:0.1 molar ratio) in water was treated with hydrazine hydrate
(1 equiv.) at ambient temperature in an open flask. This resulted in
the quantitative formation of 1,4-triazole 3a as a white precipitate,
which was purified by simple filtration. Though both the azide 1a
and alkyne 2a are insoluble in water, the surprisingly high yield of
this reaction suggests that the solubility of the reactants is not very
crucial for this reaction.
Similar reactivities of insoluble reactants in water have been
reported previously [18,29]. Use of acetonitrile as the solvent
also resulted in the formation of 1,4-triazole 3a in almost quan-
titative yield. As CuSO4·5H2O is insoluble in acetonitrile, it was
introduced as a very fine powder. Interestingly, this insolubility
also did not affect the yield of the reaction but it took relatively
longer time (Table 1: entry 1; condition B) for the completion of
the reaction. The product 3a being soluble in acetonitrile could
be isolated by simple filtration of the catalyst and evaporation.
In order to investigate the generality of this methodology, we
have screened the reactivity of different pairs of alkyne (aryl
acetylene, alkyl acetylene) and azides (aryl, benzyl, alkyl, glyco-
syl) in both aqueous and organic media (Table 1). In all these
cases, the reaction was very smooth in both aqueous and organic
1-Benzyl-4-(p-methoxyphenyl)-1,2,3-triazole (3u) [45]: Yield:
98%. Melting point: 138–139 ◦C (lit. M.P. 141–142 ◦C). 1H NMR
(DMSO-d6, 500 MHz) ı: 8.53 (s, 1H), 7.77 (d, J = 8.8 Hz, 2H),
7.40–7.35 (m, 5H), 7.01 (d, J = 8.85 Hz, 2H), 5.63 (s, 2H, PhCH2), 3.79
(s, 3H, OCH3).
4-(p-Methoxyphenyl)-1-phenyl-1,2,3-triazole (3v) [24]: Yield:
80%. Melting point: 146–148 ◦C (lit. M.P. 153–155 ◦C). 1H NMR
(DMSO-d6, 500 MHz) ı: 9.20 (s, 1H), 7.97–7.95 (m, 2H), 7.89–7.87
(m, 2H), 7.66–7.63 (m, 2H), 7.54–7.51 (m, 1H), 7.09 (d, J = 4.9 Hz,
2H), 3.83 (s, 3H).
4-(p-Fluorophenyl)-1-phenyl-1,2,3-triazole (3w): Yield: 95%.
Melting point: 197–199 ◦C. 1H NMR (DMSO-d6, 500 MHz) ı: 9.30
(s, 1H), 8.01–7.98 (m, 2H), 7.97–7.95 (m, 2H), 7.67–7.64 (m,
2H), 7.56–7.52 (m, 1H), 7.39–7.35 (m, 2H). 13C NMR (DMSO-d6,
125 MHz) ı: 162.97, 161.02, 146.44, 136.62, 129.92, 128.74, 127.42,
126.85, 126.83, 120.02, 119.55, 115.85. Elemental analysis calcd. for
C14H10FN3: C 70.28, H 4.21, N 17.56; found: C 70.35, H 4.15, N 17.61.
2-(1-Phenyl-1,2,3-triazol-4-yl)-ethanol (3x): Yield: 93%. Semi-
solid. 1H NMR (DMSO-d6, 500 MHz) ı: 8.57 (s, 1H), 7.88 (d, J = 8.1 Hz,
2 H), 7.59 (t, J = 7.65 Hz, 2H), 7.48 (t, J = 7.55 Hz, 1H), 4.77 (t, J = 5.35,
1H), 3.71 (q, J = 6.7, 12.3 Hz, 2H), 2.87 (t, J = 6.9 Hz, 2H). 13C NMR
(DMSO-d6, 125 MHz) ı: 145.62, 136.79, 129.83, 128.31, 120.68,
119.78, 60.21, 29.16. Elemental analysis calcd. for C10H11N3O: C
63.48, H 5.86, N 22.21; found: C 63.55, H 6.01, N 22.08.
1-Dodecyl-4-(p-methoxyphenyl)-1,2,3-triazole (3y): Yield: 93%.
Melting point: 104–106 ◦C. 1H NMR (CDCl3, 500 MHz) ı: 7.78
(d, J = 8.75 Hz, 2H), 7.68 (s, 1H), 6.99 (d, J = 8.75 Hz, 2H), 4.40 (t,
J = 7.25 Hz, 2H), 3.87 (s, 3H), 1.96 (m, 2H), 1.37–1.28 (m, 18H), 0.90
(t, J = 7.05 Hz, 3H). 13C NMR (CDCl3, 125 MHz,) ı: 159.10, 147.08,
126.52, 122.97, 118.06, 113.76, 54.83, 49.93, 31.40, 29.86, 29.09, 29,
28.88, 28.81, 28.52, 26.02, 22.17, 13.59. Elemental analysis calcd.

156
A. Pathigoolla et al. / Applied Catalysis A: General 453 (2013) 151–158
Fig. 1. (A) Spherical copper clusters of different sizes. (B) copper clusters aggregating to each other.
solvents giving the corresponding 1,4-triazole in excellent yields.
In general, the reaction in water was much faster than in ace-
tonitrile. In both the cases, the products could be isolated by
filtration.
screened the reactivity of different pairs of alkynes and azides under
the optimized condition. Interestingly, the reaction was very gen-
eral and the yields were consistently very high (Table 3). While both
aromatic and aliphatic azides show high reaction rates, the glycosyl
azides have shown different reactivity depending on the availabil-
ity of free hydroxyl groups. Fully protected glycosyl azides reacted
faster than partially protected glycosyl azides. ␤-azidogalactose
having four free hydroxyl groups showed the lowest reaction rate
(Table 3, entries 14 and 15). Almost all products could be iso-
lated without adopting rigorous chromatography (Experimental
section).
We were curious to investigate the reusability of the recov-
ered catalyst after the reaction. Hence the catalyst recovered from
a reaction between 1a and 2a in aqueous solution was used for
another round of reaction between 1a and 2a in water. It is inter-
esting to note that the reaction was facile even with the recovered
catalyst. However, the yield of the reaction was decreased to 75%
(Supporting Information). This may be due to the air oxidation of
the catalyst or the agglomeration of copper particles or both. Also,
the click reaction between in situ formed azide 1a (from benzyl bro-
mide and sodium azide) and the alkyne 2a in water was found to be
viable in presence of our catalyst. However, this multi-component
reaction was not feasible at room temperature but was facile only
at higher temperatures. Moreover, the product formed in this reac-
tion was not very homogeneous unlike other conditions and hence
necessitates chromatographic purification.
Having established the versatility and efficacy of this method-
ology in both aqueous and organic solvents, we set out to optimize
the reaction conditions further. In both the reaction solvents (water
and acetonitrile), the reaction mixture is heterogeneous; while in
water the hydrophobic alkynes and azides are insoluble, in acetoni-
trile CuSO4·5H2O is insoluble. We envisioned that in an optimal
mixture of these two solvents the reaction mixture will form a
homogeneous solution and thus show better reactivity profile. In
order to find the optimal solvent system, we have carried out the
reaction between benzyl azide 1a and phenyl acetylene 2a in dif-
ferent mixtures of water and acetonitrile (Table 2). In general, the
rate of the reaction in a mixture of water and acetonitrile was faster
than that in pure acetonitrile. The rate of the reaction was fastest in
2:1 (v/v) mixture of water and acetonitrile (Table 2, entry 4). When
the amount of acetonitrile was more than 50%, the CuSO4·5H2O
remained insoluble and hence in these solvent systems the rate was
relatively slow but faster than the rate in pure acetonitrile (Table 2,
entries 6 and 7). For further optimizing the amount of CuSO4·5H2O
and hydrazine hydrate, 2:1 water-acetonitrile (v/v) was chosen
as the solvent as the reaction was fastest in this solvent system.
Varying hydrazine hydrate from 10–100 mol% revealed that bet-
ter yields are obtained when 100 mol% (1 equiv. with respect to
azide) is used. It has been reported that the presence of a base facil-
itates CuNP mediated CuAAC reaction. This is proposed to be due
to the assistance of the base in deprotonation of alkyne. In a simi-
lar sense, hydrazine might have a dual role; as a reducing agent to
reduce Cu2+ to Cu(0) and also as a base to deprotonate the alkyne.
Though 5 mol% of CuSO4·5H2O was sufficient for the clean reaction
to give the product in very good yield, the reaction took more time
(Table 2, entry 10). But 2 mol% of CuSO4·5H2O was insufficient to
drive the reaction to completion (Table 2, entry 11).
Transmission Electron Microscopy revealed that spherical par-
ticles are formed under the reaction conditions. For instance, the
It is clear that this method is very modular and hence any of
the high-yielding conditions can be chosen from Table 2 depending
upon the specific convenience expected (e.g. easy product isolation,
less catalyst usage, less reaction time). For instance, for easy prod-
uct isolation, water is the preferred solvent if the expected product
is hydrophobic solid so that the precipitated product in the reac-
tion mixture can be separated by simple filtration. Similarly, if the
product is not expected to precipitate in the reaction mixture, ace-
tonitrile is the ideal solvent as the insoluble solid catalyst can be
filtered off and the filtrate can be evaporated to get the product.
In order to establish the generality of this methodology, we have
Fig. 2. Particle size at 5 min. (A) Size distribution spectrum of copper clusters
in water + acetonitrile (2:1, v/v). (B) Correlation diagram of copper clusters in
water + acetonitrile (2:1, v/v).

A. Pathigoolla et al. / Applied Catalysis A: General 453 (2013) 151–158
157
Table 5
at very low catalyst loading. Implementation of this solvent-free
condition in the reaction between different azides and alkynes
revealed that this green method is very general and gives good
yields of 1,4-substituted triazole derivatives. It is noteworthy that
this solvent-free reaction is much faster than the corresponding
solution state reaction.
CuNPs/clusters catalyzed azide–alkyne cycloaddition reaction under solvent-free
conditiona
Entry
R1
R2
Time (min.)
Yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Benzyl
Benzyl
Benzyl
Benzyl
Benzyl
Benzyl
Benzyl
Benzyl
Benzyl
Benzyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
n-Dodecyl
Phenyl
p-Tolyl
5
5
91
98
94
85
96
97
94
98
95
82
70
83
80
95
93
94
3,5-Difluorophenyl
4-Fluorophenyl
2-Aminophenyl
2-Pyridyl
4-Aminophenyl
4-Methoxyphenyl
CH2CH2OH
n-Octyl
Phenyl
p-Tolyl
10
10
10
10
10
15
20
60
15
20
20
20
25
180
4. Conclusion
We presented a novel and high yielding methodology for room
temperature azide–alkyne click cycloaddition using in situ gener-
ated CuNPs/clusters as the active catalyst. The fact that inexpensive
CuSO4 and hydrazine are used for the generation of CuNPs or their
clusters makes this an economically viable strategy. Also this reac-
tion can be carried out in open air condition and requires no special
reaction conditions. As the CuNPs/clusters are generated at the
reaction site itself, there is no requirement of stabilizer/support.
The versatility of this methodology has been illustrated by the facile
reaction of a variety of azides such as aliphatic, aromatic, benzylic
and glycosyl azides with diverse alkynes. This methodology is very
attractive as it can be adopted in aqueous, organic, mixed solvent
and solvent-free conditions. The simple reaction conditions, ease
of purification of the product, facility in environmentally benign
solvent/solvent-free conditions, economical viability and excellent
yields make this an attractive methodology.
4-Methoxyphenyl
4-Fluorophenyl
CH2CH2OH
4-Methoxyphenyl
a
Azide (1.0 equiv.), Alkyne (1.0 equiv.), CuSO4.5H2O (0.05 equiv.), N2H4.H2O (2.0
equiv.), rt.
particles formed in a mixture of 2:1 (v/v) mixture of water and
acetonitrile showed spherical particles of approximate diameter
500 nm (Fig. 1, Figs. S5 & S6). EDAX and PXRD analysis of the par-
ticles revealed that the particle/clusters mainly consisted of Cu
with minute amounts of sulphur and oxygen (might be the resid-
ual CuSO4; Supporting Information). Also, the air oxidation of the
sample, under open air reaction conditions, can’t be ruled out.
Dynamic Light Scattering experiments (Supporting Information)
revealed that CuNPs/clusters formed in different medium have dif-
ferent sizes and behavior. NPs formed in pure acetonitrile were
much smaller (average size 30 nm) than the particles formed in
water medium (average size 1.1 ␮m) and particles formed in a
2:1 H2O–MeCN mixture were of intermediate size (average size
523 nm, Fig. 2). Since most of the copper precipitated in pure ace-
tonitrile due to the insolubility of CuSO4, the actual amount of NPs
formed is very less. This explains why the reaction took more time
in acetonitrile despite the smaller size of the NPs. In both water and
mixed solvent (2:1 (v/v) H2O–MeCN), CuSO4 was completely solu-
ble and hence the CuNPs/clusters formed a colloidal solution with
uniform distribution. CuNPs formed in the mixed solvent was rel-
atively more stable and the rate of aggregation was much slower.
Relatively smaller size and better stability of CuNPs/clusters formed
in the mixed solvent make it a better solvent for the faster reaction.
Solvent-free chemistry has attracted much attention recently
due to their economic viability and environmental benignness
[31,32]. Though click reactions satisfies some of the criteria for
green reactions, an ideal green click reaction will be the one that is
facile under solvent-free conditions [29,30,33]. We have recently
reported a topochemically controlled click reaction that avoid both
solvent and catalyst [34]. We were curious to know the catalytic
activity of CuNPs/clusters under solvent-free conditions. Interest-
ingly, an equimolar mixture of azide 1a and alkyne 2a on treatment
with CuSO4·5H2O (0.05 equiv.) and hydrazine monohydrate (2.0
equiv.) gave the product 3a in excellent yield. Notably, this reac-
tion was facile even at a very low catalyst loading of 0.25 mol%
(Table 4). In order to optimize the amount of catalyst for AAC under
solvent-free conditions, we have carried out the reaction between
benzyl azide 1a and phenylacetylene 2a by varying the amount
of CuSO4·5H2O from 20 to 0.25 mol%. It was found that 5 mol% of
catalyst is sufficient to get excellent yields of 1,4-substituted tri-
azole (3a) (Table 4, entry 4) Even 0.25 mol% amount of catalyst is
enough though it takes longer time to produce good yield of triazole
(3a).
Acknowledgements
A.P. and R.P.P. thank Council of Scientific and Industrial Research
(CSIR) for Research Fellowships. KMS thanks DST for a Ramanujan
Fellowship and a fast-track grant and CSIR for an EMR project grant.
Appendix A. Supplementary data
Supplementary data associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/j.apcata.
2012.12.025.
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