Facile immobilization of copper(I) acetate on silica: A recyclable and reusable heterogeneous catalyst for azide–alkyne clickable cycloaddition reactions

Article abstract of DOI:10.1016/j.poly.2019.06.030

The structurally well-defined copper(I) acetate was immobilized on silica gel via electrostatic interactions. The catalytic activity of the immobilized catalyst Cu(I)–SiO₂ was examined in the click synthesis of 1,2,3-triazoles in water/ethanol

Full text of DOI:10.1016/j.poly.2019.06.030

Accepted Manuscript
Facile Immobilization of copper(I) acetate on silica: a recyclable and reusable
heterogeneous catalyst for azide-alkyne clickable cycloaddition reactions
Noura Aflak, Hicham Ben El Ayouchia, Lahoucine Bahsis, Hafid Anane, Rachid
Laamari, Alejandro Pascual-Alvarez, Donatella Armentano, Salah-Eddine
Stiriba
PII:
S0277-5387(19)30441-3
https://doi.org/10.1016/j.poly.2019.06.030
POLY 14021
DOI:
Reference:
Polyhedron
To appear in:
Received Date:
Accepted Date:
7 May 2019
11 June 2019
Please cite this article as: N. Aflak, H.B. El Ayouchia, L. Bahsis, H. Anane, R. Laamari, A. Pascual-Alvarez, D.
Armentano, S-E. Stiriba, Facile Immobilization of copper(I) acetate on silica: a recyclable and reusable
heterogeneous catalyst for azide-alkyne clickable cycloaddition reactions, Polyhedron (2019), doi: https://doi.org/
10.1016/j.poly.2019.06.030
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To be submitted to Polyhedron- Revised Version 2-
Facile Immobilization of copper(I) acetate on silica: a recyclable and reusable
heterogeneous catalyst for azide-alkyne clickable cycloaddition reactions
Noura Aflaka, Hicham Ben El Ayouchiaa,*, Lahoucine Bahsis,a Hafid Ananea, Rachid Laamaria,
Alejandro Pascual-Alvarezb, Donatella Armentanoc, and Salah-Eddine Stiribaa,b,*
a Laboratoire de Chimie Analytique et Moléculaire, LCAM, Faculté Polydisciplinaire de Safi, Université Cadi
Ayyad, Safi, Morocco
b
Instituto de Ciencia Molecular/ICMol, Universidad de Valencia, C/ Catedrático José Beltrán 2, 46980
Valencia, Spain
c Dipartimento di Chimica e Tecnologie Chimiche, Università della Calabria, 87036, Rende, Cosenza, Italy
Dedicated to Prof. Miguel Julve, a nice friend and outstanding inorganic chemist at the occasion of his
65th birthday.
*Corresponding author: Hicham Ben El Ayouchia/Salah-Eddine Stiriba
E-mail: belayou@gmail.com (H. B.) and stiriba@uv.es (S.-E. S.)
1

1. Introduction
The copper(I)-catalyzed azide-alkyne [3+2] cycloaddition reaction (CuAAC) is the most popular
and well-established click reaction that comply with click chemistry criteria. This method initially
performed under strict click chemistry conditions, yields 1,4-disubstituted-1,2,3-triazoles in a
regioselective manner at room temperature and up to ten million times faster than the thermal version
of Huisgen [3+2] cycloaddition reaction [1,2]. The molecules containing triazolic moieties are
predominant in the nitrogen-containing heterocyclic compounds widely used as powerful structural
motifs in several fields, including biological chemistry [3], pharmaceutical drugs [4], and materials
science [5]. The first example of CuAAC involved copper(II) sulfate as a precatalyst in the presence
of sodium ascorbate as a reducing agent [1,2]. Various copper salts have also been used to catalyze the
Huisgen [3+2] cycloaddition reaction, combined with organic or non-organic solvents. However, the
direct employment of copper(I) species in homogenous systems presents many complications under
aerobic experimental conditions due to its thermodynamic instability and oxidation into copper(II) [6].
The search for stabilizing ligands that would keep copper(I) catalytically active, led to the preparation
of stable copper(I) catalysts such as, N-heterocyclic copper carbene compounds [7], and
tris(triazolyl)methanol- [8] and dipicolinate-copper complexes [9]. Nevertheless, these catalysts are
homogeneous systems that face the problem of catalyst/product separation, in addition to its recovery
and reuse in further catalytic assays. In order to circumvent these problems, the heterogenization of
homogenous catalysts such as copper(I) species become a very relevant task to overcome the final
product/catalyst separation issue and to achieve the recovery/reuse purposes in ideal catalytic
protocols, which are criteria of greener chemical reactions [10,11]. Several supports such as carbon
[12] polymers [13-15], biopolymers like chitosan [16], alginate[17], cellulose [18] and inorganic solids
such as aluminum oxyhydroxide nanofibers [19] and zeolites [20] have been used for the
immobilization of copper(I) catalysts in the azide-alkyne [3+2] cycloaddition reaction.
2

We herein report, the immobilization of the well-established highly efficient dinuclear copper(I)
acetate catalyst in silica (SiO2) [21]. This silica supported immobilized catalyst was used in clicking
azides and alkynes in water/ethanol at room temperature (Scheme 1). The reactions of terminal alkynes
with organic azides in the presence of Cu(I)-SiO2 (1-2 mol %), take place under strict click chemistry
conditions to regioselectively produce the corresponding 1,4-disubstituted-1,2,3-triazoles in excellent
yields (80-90 %) at room temperature. The immobilized catalyst was recovered from the reaction
mixture by simple filtration and reused for up to five times.
copper(I) acetate
previous work
N
R´
R
N
N
+
N3
R´
Azide
CuAAC
Alkyne
R
1,4-disubstituted-1,2,3-triazole
copper(I) acetate-SiO2
this work
Scheme 1. Synthetic routes for the azide-alkyne [3+2] cycloaddition reaction.
2. Experimental
2.1. Materials and instruments
All chemicals were used as received without further purification. All reactions were performed
at the open air. NMR spectroscopy was carried out on a Brucker AC-400 MHz (400 MHz for proton,
100 MHz for carbon) spectrometer by using deuterated chloroform as solvent. The chemical shifts ()
are expressed in ppm. The high-resolution mass spectra (HRMS) were recorded in the EI (70 eV) or
FAB mode at the mass spectrometry service of the University of Valencia. FT-IR spectra (400-4000
cm-1 range) were performed with a Nicolet 5700 FT-IR spectrometer on samples prepared as KBr
pellets. X-ray powder measurements of the grounded samples filled into 0.5 mm borosilicate capillary
were taken on an Empyrean PANalytical powder diffractometer using Cu Kα radiation ( = 1.54056
Å). Melting points (Mp) were determined using a Stuart melting point apparatus SMP3, employing the
3

capillary tubes. Copper content was measured by ICP‐AES on a Varian Vista pro analyzer. The
Scanning Electron Microscopy (SEM) was carried out using a VEGA3 TESCAN microscope and a
high-resolution JEOL Field Emission Gun-Scanning Electron Microscope (FEG-SEM).
2.2. Procedure for the synthesis of benzyl azide
Benzyl bromide (10.0 g, 58.5 mmol) and NaN3 (11.4 g, 175 mmol) were dissolved in 200 mL
of DMF. The reaction mixture was stirred and protected from light for 20 hours at room temperature.
After filtration of the residual salts, water was added to the filtrate and the product was extracted with
dichloromethane. The organic phase was dried with MgSO4, and then filtered-off. The organic solvents
were evaporated under vacuum, yielding a colorless liquid.
2.2.1. Synthesis of 1-(azido methyl)benzene
Colorless liquid. Yield: 90%. Rf = 0.83 (hexane/ethyl acetate, 4/1 v/v).1H NMR (400 MHz,
CDCl3, δ ppm): 4.39 (s, 2H, CH2); 7.41-7.50 (m, 5H, CHar). FT-IR: 2097 cm-1 (N3).
2.3. Procedure for the synthesis of aryl azide derivatives
The aniline derivative (13 mmol) was suspended in 80 mL hydrochloric acid (17%) at room
temperature and then ethanol was added until a clear solution was obtained. The solution was cooled
to 0 °C and NaNO2 (19.5 mmol) was added in small portions. After stirring at 0 °C for 15-30 min,
NaN3 (19.5 mmol) was slowly added and the resulting mixture was stirred for 2 h at room temperature.
The reaction mixture was extracted with diethyl ether (3 x 80 mL) and the combined organic fractions
were washed with a saturated NaHCO3 solution (3 x 50 mL) and with brine (50 mL). After drying over
MgSO4 the ether was removed under reduced pressure and the wanted azides were obtained without
further purification.
2.3.1. Synthesis of 1-azidobenzene
4

Brown liquid. Yield: 90%. Rf = 0.86 in hexane. 1H NMR (400 MHz, CDCl3, δ ppm): 7.08-7.44
(m, 5H, CHar) .13C NMR (100 MHz, CDCl3, δ ppm): 119.46 (CHar); 125.31 (2 CHar); 130.19 (2CHar);
140.6 (Car). FT-IR: 2119 cm-1 (N3).
2.3.2. Synthesis of 1-azido-4-iodobenzene
Brown liquid. Yield: 90%. Rf = 0.81 (hexane/ethyl acetate, 9:1 v/v). 1H NMR (400 MHz,
CDCl3, δ ppm): 6.74-6.76 (d, J = 8.00 Hz, 2H, CHar); 7.6-7.62 (d, J = 8.00 Hz, 2H, CHar). FT-IR:
2126 cm-1 (N3).
2.3.3. Synthesis of 1-azido-4-methoxybenzene
Brown liquid. Yield: 93%. Rf = 0.56 (hexane/ethyl acetate, 9:1 v/v).1H NMR (400 MHz, CDCl3,
δ ppm): 3.79 (s, 3H, OMe), 6.89-6.91 (d, J = 8.0 Hz, 2H, CHar); 6.95-6.98 (d, J = 12.0 Hz, 2H, CHar);
FT-IR: 2106 cm-1 (N3).
2.4. Procedure for the immobilization of copper(I) acetate on silica (Cu(I)-SiO2)
Silica gel (2 g, 230-400 mesh) (MERK silica gel for chromatography) was previously dried at
70ºC under vacuum for 2 h and suspended in 20 mL of acetone. Powdered white to greenish copper(I)
acetate was added and the mixture was stirred overnight at room temperature, then filtered-off. The
greenish solid was washed with hexane and diethyl ether and dried under vacuum overnight. The
immobilized copper(I) acetate catalyst on silica was characterized by X-ray powder diffraction,
inductively coupled plasma (ICP-AES), Scanning Electron Microscopy (SEM), EDX and FT-infrared
spectroscopy.
2.5. General click synthesis of1,2,3-triazoles
5

Azide (0.75 mmol, 1.2 equivalent), alkyne derivative (0.62 mmol, 1 equivalent) and 0.02
equivalent of the Cu(I)-SiO2 catalyst were placed in a reaction tube and 5 mL of water/ethanol (1:1
v/v) was added. The mixture was stirred for 48 h at room temperature. After completion of the reaction
as evidenced by TLC, the product was extracted by using diethyl ether and the immobilized catalyst
separated by filtration. The combined diethyl ether washings were evaporated under pressure to yield
the corresponding final pure triazole. The recovered catalyst was dried and reused at least five times.
2.5.1. Synthesis of 1-benzyl-4-phenyl-1H-1,2,3-triazole (3a)
1
White solid. Yield: 94%. Rf = 0.29 (hexane/ethyl acetate (3:1 v/v)). Mp = 130-132°C. H NMR
(400MHz, CDCl3, δ ppm): 5.60 (s, 2H, CH2); 7.28-7.44 (m, 8H, CHar); 7.68 (s, 1H, CHTriazole); 7.81-
7.83 (d, J = 8.00 Hz, 2H, CHar). 13C NMR (100MHz, CDCl3, δ ppm): 54.4 (CH2); 119.5 (CHar); 125.9
(3CHar); 127.8 (2CHAr); 128.2 (2CHar); 129.2 (CHTriazole); 131.5 (Car); 135.0 (Car); 148.3 (CTriazole).
HRMS (FAB+) m/z: Calcd for C15H14N3: 236.1188; Found: 236.1177.
2.5.2. Synthesis of 1-benzyl-4-(4-fluorophenyl)-1H-1,2,3-triazole (3b)
1
White solid. Yield: 88%. Rf = 0.34 (hexane/ethyl acetate, 3:1 v/v). Mp =114-116 °C. H NMR (400
MHz, CDCl3, δ ppm) : 5.59 (s, 2H, CH2); 7.08-7.13 (d, J = 20.00 Hz, 2H, CHar); 7.28-7.42 (m, 5H,
13
CHar); 7.64 (s, 1H, CHtriazole); 7.78-7.80 (d, J = 8.00 Hz, 2H, CHar). C NMR (100 MHz, CDCl3, δ
ppm): 54.3 (CH2); 115.7 (2CHar); 115.9 (2CHar); 119.2 (CHar); 127.4 (Car); 127.5 (2CHar);
128.1 (CHtriazole); 128.7 (Car); 129.2 (Ctriazole); 134.6 (CFar). HRMS (FAB+) m/z: Calcd for C15H13N3F:
254.1094; Found: 254.1087.
2.5.3. Synthesis of 1-benzyl-4-p-tolyl-1H-1,2,3-triazole (3c)
6

1
White solid. Yield: 91%. Rf = 0.38 (hexane/ethyl acetate, 3:1 v/v). Mp =152-154 °C. H NMR (400
MHz, CDCl3, δ ppm) : 2.38 (s, 3H, CH3); 5.56 (s, 2H, CH2); 7.213-7.401(m, 7H, CHar); 7.52 (s, 1H,
CHtriazole); 7.58 (d, J = 8.00 Hz, 2H, CHar).13C NMR (100 MHz, CDCl3, δ ppm): 21.3 (CH3) 54.2
(CH2); 119.2 (CHar) ; 125.6 (2CHar); 127.7 (2CHar); 128.0 (2CHar); 128.7 (2CHar); 129.1 (Car); 129.5
(CHtriazole); 134.8 (Car); 138.0 (Car); 148.0 (Ctriazole). HRMS (FAB+) m/z: Calcd for C15H14N3:
250.1344; Found: 250.1327.
2.5.4. Synthesis of methyl 4-(1-benzyl-1H-1,2,3-triazol-4-yl)benzoate (3d)
Yellow solid. Yield: 79%. Rf = 0.22 (hexane/ethyl acetate, 3:1 v/v). Mp = 164-166 °C. 1H NMR (400
MHz, CDCl3, δ ppm): 3.94 (s, 3H, CH3); 5.61 (s, 2H, CH2); 7.28-7.40 (m, 5H, CHar); 7.76 (s, 1H,
CHtriazole); 7.88-7.90 (d, J = 8.00 Hz, 2H, CHAr); 8.07-8.10 (d, J = 12.00 Hz, 2H, CHar).13C NMR (100
MHz, CDCl3, δ ppm) : 52.1 (CH3); 54.3 (CH2); 120.3 (CHar); 125.4 (2CHar); 128.1 (2CHar); 128.9
(2CHar); 129.2 (2CHar); 129.5 (Car); 130.1 (CHtriazole); 134.3 (Car); 134.8 (Car); 147.1 (Ctriazole); 166.7
(Ccarbonyle). HRMS (FAB+) m/z: Calcd for C17H16N3O2: 294.1243; Found: 294.1243.
2.5.5. Synthesis of 4-(1-benzyl-1H-1,2,3-triazol-4-yl)benzaldehyde (3e)
White Solid. Yield: 90%. Rf = 0.14 (hexane/ethyl acetate, 3:1 v/v). Mp = 134-135 °C. 1H NMR (400
MHz, CDCl3, δ ppm) : 5.62 (s, 2H, CH2); 7.28-7.43(m, 5H, CHar); 7.8 (s, 1H, CHtriazole); 7.92-7.94 (d,
J = 8.00 Hz, 2H, CHar); 7.98-8.00 (d , J = 8.00 Hz, 2H, CHar); 10.02 (s, 1H, CHO). 13C NMR (100
MHz, CDCl3, δ ppm): 54.4 (CH2); 120.7 (CHar); 126.0 (2CHar); 128.2 (2CHar); 129.0 (2CHar); 129.3
(2CHar); 130.4 (CHTriazole); 134.3 (CHar); 135.8 (CHar); 136.3 (CHar); 146.9 (CTriazole); 191.7 (CHO).
HRMS (FAB+) m/z: Calcd for C16H14N3O: 264.1137; Found: 294.1134.
2.5.6. Synthesis of 1-benzyl-4-(4-phenoxyphenyl)-1H-1,2,3-triazole (3f)
7

Yellow solid. Yield: 90%. Rf = 0.3 (hexane/ethyl acetate, 3:1 v/v). Mp = 173-175 °C. 1H NMR (400
MHz, CDCl3, δ ppm): 5.59 (s, 2H, CH2); 7.05-7.15 (m, 5H, CHar); 7.28-7.42 (m, 7H, CHar); 7.64 (s,
1H, CHtriazole); 7.77-7.79 (d, J = 8.00 Hz, 2H, CHar). 13C NMR (100 MHz, CDCl3, δ ppm): 54.8 (CH2),
118.5 (2CHar); 118.9 (2CHar); 123.4 (CHar); 125.9 (CHar); 127.3 (Car); 128.0 (2CHar); 128.5 (2CHar);
129.0 (2CHar); 129.2 (2CHar); 130.1 (CHtriazole); 135.2 (Car); 147.6 (Ctriazole); 157.5 (2Car). HRMS
(FAB+) m/z: Calcd for C21H18N3O: 328.1449; Found: 328.1449.
2.5.7. Synthesis of 1-(4-methoxyphenyl)-4-phenyl-1H-1,2,3-triazole (3g)
1
White solid. Yield: 95%. Rf = 0.37 (hexane/ethyl acetate, 3:1 v/v). MP = 162-163°C. H NMR (400
MHz, CDCl3, δ ppm): 3.87 (s, 3H, OCH3); 7.02-7.05 (d, J = 12.00 Hz, 2H, CHar); 7.35-7.49 (m, 5H,
13
CHar); 7.69-7.71 (d, J = 8.00 Hz, 2H, CHar); 7.95 (s, 1H, CHtriazole). C NMR (100 MHz, CDCl3, δ
ppm): 56.1 (CH3); 114.9 (CHar); 115.3 (Car); 122.7 (2CHar); 126.3 (CHar); 126.5 (2CHar); 126.9
(2CHar); 129.2 (CHtriazole); 129.4 (Car); 146.3 (Ctriazole); 160.5 (Car). HRMS (FAB+) m/z: Calcd for
C15H14N3O: 252.1137; Found: 252.1133.
2.5.8. Synthesis of 1-(4-methoxyphenyl)-4-p-tolyl-1H-1,2,3-triazole (3h)
1
White solid. Yield: 87%. Rf = 0.36 (hexane/ethyl acetate, 3:1 v/v). Mp = 172-173°C. H NMR (400
MHz, CDCl3, δ ppm) : 2.8 (s, 3H, CH3); 4.29 (s, 3H, OCH3); 7.03-7.08 (d, J = 20.00 Hz, 2H, CHar);
7.27-7.31 (d, J = 16.00 Hz, 2H, CHar); 7.49-7.52 (d, J = 12.00 Hz, 1H, CHar); 7.68-7.71 (d, J = 12.00
Hz, 1H, CHar); 7.82-7.85 (d, J = 12.00 Hz, 1H, CHar); 7.90-7.93 (d, J = 12.00 Hz, 1H, CHar); 8.59 (s,
13
1H, CHtriazole). C NMR (100 MHz, CDCl3, δ ppm): 21.83 (CH3); 56.08 (OCH3); 114.97 (2CHar);
115.39 (Car); 122.81 (2CHar); 126.33 (2CHar); 127.05 (Car); 129.75 (2CHar); 130.22 (CHtriazole); 130.87
(Car); 139.12 (Ctriazole); 160.43 (Car). HRMS (FAB+) m/z: Calcd for C16H16N3O: 266.1288; Found:
266.1281.
2.5.9. Synthesis of 1,4-diphenyl-1H-1,2,3-triazole (3i)
8

White solid. Yield: 92%. Rf = 0.48 (hexane/ethyl acetate, 3:1 v/v). Mp = 183-184 °C. 1H NMR (400
MHz, CDCl3, δ ppm): 7.33-7.4 (m , 2H, CHar) ; 7.44-7.49 (t, J = 7.47 Hz, 2H, CHar); 7.53-7.58 (t, J =
7.56 Hz, 2H, CHar); 7.79-7.81 (d, J = 7.80 Hz, 2H, CHar); 7.92-7.94 (d, J = 7.93 Hz, 2H, CHar); 8.22
13
(s, 1H, CHtriazole). C NMR (100 MHz, CDCl3, δ ppm): 119.0 (2CHar); 120.98 (Car); 126.3 (2CHar);
129.0 (CHar); 129.3 (CHar); 129,37 (2CHar); 130.2 (2CHar); 130.34 (CHtriazole); 130.7 (Car); 137.47
(Ctriazole). HRMS (FAB+) m/z: Calcd for C14H12N3: 222.1031; Found: 222.1029.
2.5.10. Synthesis of 1-(4-iodophenyl)-4-phenyl-1H-1,2,3-triazole (3j)
1
White solid. Yield: 85%. Rf = 0.53 (hexane/ethyl acetate (3:1 v/v)). Mp = 170-172°C. H NMR
(400MHz, CDCl3, δ ppm): 7.33-7.46 (m , 7H, CHar); 7.67-7.74 (d, J= 12.00 Hz, 2H, CHar); 8.0 (s, 1H,
CHTriazole). 13C NMR (100MHz, CDCl3, δ ppm): 110.8 (Car); 121.02 (Car); 126.3 (2CHar); 129.05
(CHar); 129.0 (2CHar); 129.44 (2CHTriazole); 129.45 (2CHar); 130.82 (Car); 130.95 (2CHar); 139.73
(CTriazole).
2.5.11. Synthesis of (1-(4-methoxyphenyl)-1H-1,2,3-triazol-4-yl)methanol (3k)
1
White solid. Yield: 86%. Rf = 0.4 (hexane/ethyl acetate, 3:1 v/v). Mp = 128-129°C. H NMR (400
MHz, CDCl3, δ ppm): 3.87 (s, 3H, OCH3); 4.79-5.04 (t, J = 40.00, 1H, OH); 5.49 (s, 2H, CH2); 7.04-
13
7.06 (d, J = 12.00 Hz, 2H, CHAr); 7.67-7.7 (d, J = 12.00 Hz, 2H, CHar); 8.04 (s, 1H, CHtriazole). C
NMR (100 MHz, CDCl3, δ ppm): 56.1 (CH3); 56.1 (CH2); 115.4 (2CHAr); 122.8 (CHtriazole); 123.0
(2Car); 130.23 (2CHar); 141.04 (Ctriazole); 160.82 (Car). HRMS (FAB+) m/z: Calcd for C10H12N3O2:
206.0929; Found: 206.0937.
2.6. X-ray crystallography
Single crystal X-ray diffraction data for 3g were collected at 296 K on a Bruker-Nonius X8
APEXII CCD area detector diffractometer using graphite-monochromated Mo-Kα radiation (λ =
0.71073 Å) at room temperature, performing φ-and ω-scans. A suitable crystal of approximate
9

dimensions 0.30 x 0.28 x 0.20 mm was selected for data collection. Data reduction and multi-scan
absorption corrections were performed using SAINT [22] and SADABS [23]. The structures were
solved by direct methods using SHELXS and refined against F2 on all data by full-matrix least squares
with SHELXL-2013 software.[24] Graphical manipulations were performed with CrystalMaker
software.[25] Crystal data for 3g are summarized in Table S1. Cambridge Crystallographic Data
Centre reference number is CCDC 1586019.
2.7. Computational methods
The DFT method employing the B3LYP functional with the 6‐31G(d, p) basis set has been
used for all atoms except Cu, for which the effective core potentials, LANL2DZ, were used together
to carry out the full optimization of the compounds of interest in the gas phase with the G09 package.
[26] The global electrophilicity index (ω) [27] is given by the expression ω = (µ2/2η) where μ and η
are the electronic chemical potential and the chemical hardness, respectively. Both quantities may be
approached in terms of the one-electron energies of the frontier molecular orbitals HOMO and LUMO
(εH and εL) as µ ≈ (εH+εL)/2 and η = (εL−εH). [28,29] The empirical (relative) nucleophilicity index (N)
[30,31], based on the HOMO energies obtained within the Kohn–Sham scheme [32], is defined as N
= EHOMO(Nu) − EHOMO(TCE), where tetracyanoethylene (TCE) is the reference, because it presents the
lowest HOMO energy in a long series of already investigated molecules in the context of polar organic
reactions. Besides ω, it is possible to define its local (or regional) counterpart condensed to atoms. The
local electrophilicity (ωk) or local nucleophilicity (Nk) condensed to the k atom is easily obtained by
projecting the global quantity onto any atomic center k in the molecule by using the Parr function, ωk

k
= ω
and N = N  . The electrophilic (  ) and nucleophilic (  ) Parr functions were obtained
P P P
k
k k k
P
through the analysis of the Mulliken ASD of the radical anion and the radical cation by single-point
energy calculations over the optimized neutral geometries using the unrestricted UB3LYP formalism
for radical species [33].
10

3. Results and discussion
3.1. Preparation and characterization of the immobilized Cu(I)-SiO2 catalyst
The immobilization of copper(I) acetate on silica was achieved by the impregnation technique. In fact,
the structurally well-defined copper(I) acetate was dissolved in acetone and silica was added and the
mixture was stirred overnight at room temperature (Scheme 2).
1. Mix in acetone
2. Stirring at r.t.
"Cu(I)-SiO2"
Cu(O2CCH3)
+
SiO2
3. Filtration
4. Washing with hexane / Et2O
5. Drying
Scheme 2. Preparation of the Cu(I)-SiO2 catalyst.
The greenish solid was then filtered-off and then dried overnight in an oven at 60°C. The copper-silica
particles were fully characterized by several techniques such as FT-IR, X-ray powder diffraction
(XRPD), inductively coupled plasma-atomic emission spectroscopy (ICP-AES), Scanning Electron
Microscopy (SEM), Energy-dispersive X-ray (EDX) and cyclic voltammetry in order to determine
their nature and morphology.
FT–IR spectrum of Cu(I)-SiO2 was recorded and compared with those of Cu(O2CCH3) and SiO2 to
further understand the types of interaction occurring between the copper acetate and the silica (Figure
1). The wide peak located at 3614.0 cm-1 which corresponds to the elongation vibration of the OH
groups of silica, becomes sharp in the FT–IR spectrum of Cu(I)-SiO2 due to the interaction of the
hydroxyl groups with the copper acetate (O—H---O—Cu). The asymmetric carbonyl elongation band
of acetate [υ(CO)] which is found at 1680 cm-1 in the FT–IR spectrum of Cu(O2CCH3) is considerably
weakened Cu(I)-SiO2 and occurring as two peaks around 1450 and 1550 cm-1. These peaks are
associated with the frequency band υ(CO) of the bridging acetate group of the immobilized copper(I)
acetate [34].
11

SiO
2
Cu(O CCH )
2
3
40
30
20
10
Cu(I)-SiO2
3500
3000
2500
2000
1500
1000
500
-1
Wavenumbers (cm )
Figure 1. FT-IR spectra of Cu(O2CCH3), silica and Cu(I)-SiO2.
X-ray powder diffraction (XRPD) patterns recorded for silica and Cu(I)-SiO2 are shown in Figure 2;
they unambiguously support the presence of copper on silica. In fact, in comparison to the XRPD
spectrum of silica, the X-ray diffraction pattern recorded for Cu(I)-SiO2 shows the typical diffraction
peaks of copper located at 12.76, 14.38, 16.43, 18.05, 25.22 and 36.49°, confirming the immobilization
of copper(I) acetate on silica. The average crystallite size D of the copper-silica particles Cu(I)-SiO2
was calculated from the Scherrer equation. The peak of the highest intensity was chosen to measure
the diameter of such particles, which was found to be close to 23.54 nm.
12

10000
8000
6000
4000
2000
0
SiO
2
Cu(I)-SiO
2
0
0
5
5
10
10
15
15
20
20
25
25
30
30
35
35
40
40
45
45
2Theta (°)
Figure 2. XRPD patterns of silica and Cu(I)-SiO2.
The elemental composition of Cu(I)-SiO2 was determined based on energy dispersive X-ray (EDX)
measurements (Figure 3). The EDX analysis shows that the given immobilized solid catalyst is
composed of C, Si, O and Cu elements, which further supports that the copper acetate was successfully
immobilized on silica.
Figure 3. EDX spectrum of Cu(I)-SiO2.
13

Scanning electron microscopy (SEM) of Cu(I)-SiO2 is shown in Figure 4. The SEM image of the
immobilized copper(I) acetate on silica clearly reveals the formation of copper-silica solid particles.
Figure 4. SEM image of Cu(I)-SiO2.
3.2. Catalytic activity and reusability of Cu(I)-SiO2 catalyst
As starting point of the study of the catalytic activity of the immobilized catalyst Cu(I)-SiO2; the [3+2]
cycloaddition of benzyl azide and phenylacetylene was chosen as model reaction to test the activity of
Cu(I)-SiO2 under different reaction conditions such as loading copper catalyst and solvent (Table 1).
When the cycloaddition reaction between benzyl azide and phenylacetylene was carried out in the
absence of catalyst, no product was obtained under such conditions (entry 1, Table 1) indicating the
need of copper as catalytic species for the azide-alkyne cycloaddition reaction. The same result was
obtained when the silica was added to the reaction mixture (entry 2, Table 1). In the presence of
Cu(O2CCH3)(2 mol%), a lower yield was obtained most likely due to the oxidation of copper(I) during
the prolonged reaction time (48 h). However, when benzyl azide and phenylacetylene were treated
with immobilized copper(I) acetate on silica Cu(I)-SiO2, a good yield was obtained, likely because the
silica kept the copper catalytically active along the reaction. The effect of the catalyst loadings was
also investigated. By increasing the catalyst loading from 1 to 5 mol% an increasing in the conversion
14

yields from 81 to 98% (entries 5−7, Table 1) was observed. However, no further increasing conversion
yields were observed when the catalyst amount was more than 5 mol%. Consequently, a catalyst
loading of 2 mol% appears to be optimal with respect to yield and reaction time.
Table 1. Catalyst loading and screening of the click reaction of phenylacetylene and benzyl azidea
N
N
N
Ph
Catalyst
N3
Ph
+
Solvent
Ph
r.t. / 48h
Catalyst loading
(mol%)
Entry
Solvent
Catalyst
Yield b (%)
1
2
Water/Ethanol
Water/Ethanol
Water/Ethanol
Water/Ethanol
Water/Ethanol
Water/Ethanol
Water/Ethanol
Ethanol
none
SiO2
-
-
0
0
3
Cu(O2CCH3)
Cu(I)-SiO2
Cu(I)-SiO2
Cu(I)-SiO2
Cu(I)-SiO2
Cu(I)-SiO2
Cu(I)-SiO2
Cu(I)-SiO2
Cu(I)-SiO2
Cu(I)-SiO2
2
10
5
2
1
2
2
2
2
2
41
98
98
94
81
86
93
71
82
31
4
5
6
7
8
9
Water
10
11
12
Toluene
Acetonitrile
Hexane
a Reaction conditions: benzyl azide (0.75 mmol), phenylacetylene (0.62 mmol), solvent (5 mL) and catalyst.
b Yield of the isolated product.
Different solvents from polar to non-polar were also tested in this click reaction, as shown in Table 1.
The catalytic conversion yields in water and acetonitrile are higher than in toluene and ethanol and
lower in the non-polar hexane solvent. Using water as the catalytic reaction medium gave the best
result of 93% yield (entry 9, Table 1). However, by assuming the poor solubility of the organic
compound in water, we decided to carry out the reaction in a mixture of water: ethanol (1:1 v/v), which
indeed resulted in an excellent conversion of 94% (entry 6, Table 1).
15

Once the conditions were established and in order to enlarge the scope of the Cu(I)-SiO2-catalyzed
[3+2] cycloaddition reaction of azide and alkyne, a variety of organic azides and alkyne substrates
were used. As shown in Figure 5, a 1,2,3-triazole library has been obtained by clicking a series of
benzyl azide and para-substituted aryl azide derivatives with different terminal phenyl alkynes para-
substituted bearing electron withdrawing/releasing groups in a water/ethanol solvent mixture at room
temperature. Excellent yields ranging from 85 to 95% of one regioisomer, namely 1,4-disubstituted-
1,2,3-triazoles were obtained. All clicked 1,2,3-triazoles were characterized by NMR spectroscopy,
HRMS analysis (see Supp. Information) and single crystal X-ray diffraction in the case of the 1,4-
regioisomer of the 3g product.
16

Figure 5. 1,4-disubstituted-1,2,3-triazoles obtained by clicking azides and alkynes in the presence of
the Cu(I)-SiO2 catalyst [reaction conditions: azide (0.75 mmol), alkyne (0.62 mmol), water/ethanol (5 mL)
and Cu(I)-SiO2 (2 mol%) at room temperature (48 h); TON = Turnovers number (moles substrate/ moles of
catalyst)].
17

Figure 6. ORTEP drawing of 3g together with the atom numbering. The thermal ellipsoids are
drawn at the 30% probability level. Selected bond lengths (Å): C(9)―C(10) 1.466(3); N(1)―C(5)
1.430(3); C(9)―N(3) 1.365(3); C(8)―N(1) 1.349(3); N(2)―N(3) 1.308(3); N(2)―N(1) 1.359(3).
Compound 3g was characterized by single crystal X-ray diffraction (see Crystallographic section and
Table S1 in ESI). Its molecular structure which is shown in Figure 6 confirms the formation of the 1,4-
disubstituted triazolic regioisomer. The five-membered triazole rings are perfectly planar [with a
maximum deviation of 0.0010(9) Å on N(3) atom] and the carbon-carbon and carbon-nitrogen bond
lengths in the triazole ring are in agreement with their expected double bond character (see Table S2
in ESI). The values of the intramolecular dihedral angles between the triazole ring and the adjacent
external phenyl rings are 27.2 and 20° for C(2)-C(7) and C(10)-C(15) mean planes respectively,
whereas the two phenyl rings are tilted by 12° each other. The crystal packing is characterized by weak
and moderate intermolecular interactions of the O···H-C type [O(1)···C(1a) and O(1)···H(1a) of
3.463(3) and 2.657(3) Å; symmetry code: (a) = 0.5 + x, y, - z] and bifurcated N···H-C interactions
[3.706(3), 3.571(3), 2.847 and 2.669 Å for N(2)···C(8b) , N(3)···C(8b), N(2)···H(8b) and
N(3)···H(8b), respectively; (b) = 1 + x, y, z], which build sheets lying in the crystallographic ab plane
(see Figure S1 in ESI). - stacking between external phenyl rings of adjacent supramolecular planes
with triazole ring at centroids (of C2-C7 and C10-C15 phenyl rings) to mean plane (of triazole ring)
distances of 3.83 and 3.82 Å (with an overlapping of ca 20%) ensure the cohesion of the crystal lattice
(see Fig. S2 in Supp. Information).
18

In Heterogeneous catalysis, the catalyst recovery and reuse are very important issues from practical,
economic and environmental points of view. In order to check the recyclability of the catalyst, the
reaction between benzylazide and phenylacetylene was chosen as a model reaction to explore the
reusability of Cu(I)-SiO2. When the reaction was performed, the catalyst was easily filtered and
washed with a minimum amount of diethyl ether. Then it was reused for the next run. Figure 7 shows
that the immobilized catalyst could be recycled and reused for up to five times although the yields
decrease notably, a feature which is due to the copper leaching from the silica solid support. In fact,
copper leaching was confirmed by ICP-AES analysis of the catalyst before and after the fifth reaction
run. The copper contents were initially found to be 7.16% before the reaction and 4.86% after the fifth
reaction run.
N
N
N
Ph
Cu(I)-SiO
cat.
2 (2 mol%)
N3
Ph
+
H2O/EtOH
r.t. / 48 h
Ph
1,4-isomer
100
80
60
40
20
0
1
2
3
4
5
Number of cycles
Figure 7. Recycling of the Cu(I)-SiO2 catalyst in the cycloaddition of benzyl azide and
phenylacetylene.
19

3.3. Global and local electrophilicity/nucleophilicity index analysis in CuAAC
Numerous studies devoted to polar organic reactions have proven that the analysis of the reactivity
indices defined within the conceptual DFT (CDFT) [35, 36] is an effective tool to understand the
reactivity of the reagents involved in polar reactions. Consequently, the global CDFT indices, namely,
µ, η, ω and N of methyl acetylene, methyl azide, dinuclear copper-acetylide (1) are reported in Table
2.
Table 2. Electronic chemical potential (µ), chemical hardness (η), global electrophilicity (ω) and
global nucleophilicity (N) of azide, alkyne, dinuclear copper-acetylide
µa
ηa
ωa
Na
Methyl acetylene
Methyl azide
-2.68
-3.85
-3.77
8.74
6.18
4.74
0.41
1.19
1.5
2.06
2.17
2.97
Dinuclear copper-acetylide (1)
aValues in eV.
The methyl azide is a moderate electrophile (ω =1.19 eV) and a moderate nucleophile (N = 2.17 eV)
within the ω and N scale. Alkyne has an electrophilicity power of 0.41 eV, which is classified as a
marginal electrophile [37, 38]. The low electrophilic and nucleophilic character of methyl azide and
methyl acetylene indicates that the corresponding uncatalyzed 32CA reaction will have a low polar
character. However, the coordination of the copper(I) acetate to the carbon terminal of alkyne forming
complex 1 increases notably the electrophilicity of the corresponding complex dinuclear copper-
acetylide (ω = 1.50 eV, see Table 2) being classified as a strong electrophile. This large value indicates
that this complex (activated dipolarophiles) will participate in the [3+2] dipolar cycloaddition with a
large polar character.
In order, to predict the regioselectivity in the [3+2] dipolar cycloaddition reaction, recent studies
indicate that the most favorable reactive channel is that involving the initial two-center interaction
20

between the most electrophilic and nucleophilic centers of both reagents. Recently, Domingo proposed

k
the electrophilic  and nucleophilic
Parr functions [33] as powerful tools in the study of the local
P
P
k
reactivity in polar processes. Hence, in order to characterize the most nucleophilic and the most
electrophilic centers of the species which would participate in this [3+2] cycloaddition reaction, and
P
thus, to propose the most likely intermediates that will would be formed, the electrophilic
Parr
k

k
functions of the dinuclear copper-acetylide, and the nucleophilic
were analyzed (see Figure 7).
Parr functions of methyl azide
P
Figure 7. (a) Optimized geometry of the dinuclear copper-acetylide (1). (b) Local nucleophilicity (Nk)
of azide and local electrophilicity (ωk) of dinuclear copper-acetylide calculated with the Parr function.
The first step of the mechanism consists of the exchange of acetate ligand in the dinuclear copper(I) acetate
(A) by the alkyne substrate, forming complex (B) [21]. The analysis of the local electrophilicity at the
dinuclear copper-acetylide complex (B), indicates that the copper atom is the more electrophilically
activated center of this intermediate (ωCu6= 0.60 eV) whereas the one of the local nucleophilicity at
the organoazide indicates that the N1 nitrogen atom adjacent to the radical methyl is the most
nucleophilic center (NN1= 1.4 eV). Consequently, the most favorable bond formation would
correspond to the N–Cu interaction (C) (Scheme 3); then, the formation of the first C4–N3 single bond
will take place through the nucleophilic attack of the C4 carbon adjacent to methyl of the acetylide on
21

the N3 of the azide forming the intermediate six-membered cupracycle (D). Next, a triazolide ligand is
formed by reductive elimination (E). The last step corresponds to a fast protonation of the copper
triazolide, leading to the corresponding 1,4-disubstituted-1,2,3-triazole (Scheme 3), in complete
agreement with the regioselectivity experimentally observed, as mentioned in previous work [39].
N
N
N
R'
O
O
Cu O
R
Cu O
R
(A)
R'
N
N
Cu O
N
Cu O
Cu O
Cu O
(B)
R
R
(E)
R'
N
N3 R'
N
N
R'
N
Cu O
N3
N1
Cu O
Cu O
Cu O
R
C4 C5
R
(D)
(C)
Scheme 3. The proposed mechanism for the formation of 1,4-disubstituted-1,2,3-triazoles catalyzed
by Cu(I) acetate-SiO2.
4. Conclusion
In conclusion, highly efficient and strictly click chemistry between organic azides and terminal alkynes
can be heterogeneously catalyzed by a new immobilized catalyst Cu(I)-SiO2. This immobilized
catalyst showed high catalytic activity with reasonably recycling for the regioselective click of 1,4-
disubstituted 1,2,3‐triazoles in a benign solvent such as water/ethanol at room temperature. Conducting
the reaction under conventional conditions, appropriate work up procedure, easy recovery and efficient
reusability of catalyst are conspicuous features of this methodology. The most nucleophilic center N1
that belongs to the organic azide and most electrophilic center, which found to be the copper atom of
22

the dinuclear copper-acetylide intermediate species, were computationally characterized. The
regioselectivity outcome of the [3+2] cycloaddition reaction using copper(I) acetate was also explained
using CDFT.
Acknowledgments
The authors thank Dr. Samia Benmansour for XRPD measurements and the Center of Analysis and
Characterization (CAC) in University Cadi Ayyad in Marrakech for the SEM and EDX analyses. This
work was supported by the Spanisch Ministerio de Economia y Competividad (Project CTQ2016-
75068P] and the Ministero Italiano dell’Università e della Ricerca MIUR.
Appendix A. Supplementary data
Supplementary data of this article including NMR and HRMS spectra of 1,2,3-triazoles,
cyclovoltametry graphs and crystallographic tables of compounds 3g can be found online at
http://doi.org/xxxxx.
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28

Graphical Abstract (Revised)
Facile Immobilization of copper(I) acetate on silica: a recyclable and reusable heterogeneous
catalyst for azide-alkyne clickable cycloaddition reactions
Noura Aflak, Hicham Ben El Ayouchia*, Lahoucine Bahsis, Hafid Anane, Rachid Laamari, Alejandro
Pascual-Alvarez, Donatella Armentano, and Salah-Eddine Stiriba*
copper(I) acetate
homogenous
N
R´
R
N
N
+
CuAAC
N3
R´
Azide
Alkyne
R
copper(I) acetate-SiO2
only 1,4-disubstituted 1,2,3-triazole
11 exemples
heterogenous
up to 5 cycles
yield (%)= 85-95
Graphical Abstract_ Synopsis
Revised version
Copper(I) acetate was immobilized on silica gel via electrostatic interactions. The catalytic activity of
the immobilized catalyst Cu(I)-SiO2 was successfully examined in the click synthesis of 1,2,3-triazoles
in water/ethanol at room temperature. The heterogeneous catalyst showed high catalytic activity and
regioslectivity as well as recyclability/recovery.
29