Synthesis, Characterisation and Crystal structure of a New Cu(II)-carboxamide Complex and CuO nanoparticles as New Catalysts in the CuAAC reaction and Investigation of their Antibacterial activity

Article abstract of DOI:10.1016/j.ica.2020.119514

The bidentate carboxamide ligand N-(thiazole-2-yl) picolinamide (LH) was synthesized in the environmentally friendly ionic liquid TBAB, and the five-coordinated Cu^II-complex, [Cu(L)₂(H₂O)].CHCl₃ (1) was synthesized from LH and copper(II)acetate. Cupric oxide [CuO] nanoparticles (2) have been prepared by the thermal decomposition of (1) as a new precursor at 600 °C for 3 h under air atmosphere. (1) was characterised using FT-IR spectroscopy, elemental analyses and its solid state structure was confirmed by single crystal X-ray diffraction. (2) were identified by FT-IR spectroscopy, X-ray powder diffraction, scanning electron microscopy, energy dispersive X-ray analysis and thermo-gravimetric differential thermal analyses. The electrochemical behaviour of LH and (1) has been investigated by cyclic voltammetry: irreversible Cu^II/I reductions were observed. The catalytic activity of (1) and (2) were evaluated in the one-pot azide–alkyne cycloaddition click reaction in water without additional agents. LH, (1) and (2) were also screened for their in vitro antibacterial activity: they showed promising antibacterial activity comparable to that of the antibiotic penicillin.

Full text of DOI:10.1016/j.ica.2020.119514

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Research paper
Synthesis, Characterisation and Crystal Structure of a new Cu(II)-Carboxamide
Complex and CuO Nanoparticles as new Catalysts in the CuAAC Reaction and
Investigation of their Antibacterial Activity
Mahsa Kiani, Mojtaba Bagherzadeh, Soraya Meghdadi, Farzaneh Fadaei-Tirani,
Maryam Babaie, Kurt Schenk-Joß
PII:
S0020-1693(19)31843-2
https://doi.org/10.1016/j.ica.2020.119514
ICA 119514
DOI:
Reference:
Inorganica Chimica Acta
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Revised Date:
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27 November 2019
8 February 2020
9 February 2020
Please cite this article as: M. Kiani, M. Bagherzadeh, S. Meghdadi, F. Fadaei-Tirani, M. Babaie, K. Schenk-Joß,
Synthesis, Characterisation and Crystal Structure of a new Cu(II)-Carboxamide Complex and CuO Nanoparticles
as new Catalysts in the CuAAC Reaction and Investigation of their Antibacterial Activity, Inorganica Chimica
Acta (2020), doi: https://doi.org/10.1016/j.ica.2020.119514
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Synthesis, Characterisation and Crystal Structure of a new Cu(II)-
Carboxamide Complex and CuO Nanoparticles as new Catalysts in
the CuAAC Reaction and Investigation of their Antibacterial
Activity
Mahsa Kiani a, Mojtaba Bagherzadeh a*, Soraya Meghdadi b, Farzaneh Fadaei-Tirani c, Maryam
Babaie b and Kurt Schenk-Joß d
aDepartment of Chemistry, Sharif University of Technology, Tehran 11155-3516, Iran
bDepartment of Chemistry, Isfahan University of Technology, Isfahan 84156-83111, Iran
cInstitute of Chemical Sciences and Engineering, École Polytechnique Fédérale de Lausanne, CH-1015 Lausanne,
Switzerland.
dInstitute of Physics, École Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
Corresponding authors: M. Bagherzadeh,
*E-mail address: bagherzadeh@sharif.edu
1

Abstract
The bidentate carboxamide ligand N-(thiazole-2-yl) picolinamide (LH) was synthesized in the
environmentally friendly ionic liquid TBAB, and the five-coordinated CuII-complex,
[Cu(L)2(H2O)].CHCl3 (1) was synthesized from LH and copper(II)acetate. Cupric oxide [CuO]
nanoparticles (2) have been prepared by the thermal decomposition of (1) as a new precursor at
600°C for 3 h under air atmosphere. (1) was characterised using FT-IR spectroscopy, elemental
analyses and its solid state structure was confirmed by single crystal X-ray diffraction. (2) were
identified by FT-IR spectroscopy, X-ray powder diffraction, scanning electron microscopy,
energy dispersive X-ray analysis and thermo-gravimetric differential thermal analyses. The
electrochemical behaviour of LH and (1) has been investigated by cyclic voltammetry:
irreversible CuII/I reductions were observed. The catalytic activity of (1) and (2) were evaluated
in the one-pot azide–alkyne cycloaddition click reaction in water without additional agents. LH,
(1) and (2) were also screened for their in vitro antibacterial activity: they showed promising
antibacterial activity comparable to that of the antibiotic penicillin.
Keywords: N-(thiazole-2-yl) picolinamide; Cu(II)-carboxamide complex; Copper oxide; Azide–
alkyne cycloaddition and antibacterial activity.
2

Introduction
The concept of “click chemistry” has revolutionised molecular engineering including
applications to organic and medicinal chemistry [1, 2] and polymer and material science [3].
Numerous analyses have shown Cu2+ to be able to catalyse several mechanisms such as
cycloaddition reactions between azides and alkynes (a typical click reaction) as well as other
types of click reactions [4-7]. Applying Cu2+ nanoparticles [NP] to catalyse the specific click
reaction associated with a carboxamide-based ligand would appear to be a promising approach
for designing and implementing a highly efficient catalyst [8-10].
Cost-awareness is primordial in designing an experiment and scaling it up to the industrial phase,
but high purity and suitable isomerisation of the desired compound without losing sight of an
easy conversion to technology [11] are hardly less important. If the catalyst could be green,
efficient and affordable, we would have achieved something truly promising [12].
In the industrial and laboratory phases, catalytic reactions functionalising C-H bonds are being
considered important owing to their economic and ecologically benign nature. The scale-up of
this series of reactions requires that they be sustainable, cost-effective and one-pot reactions.
There seems to be a consensus that a one-pot reaction requires the use of expensive transition
metals such as ruthenium and palladium [13-18]. Logically, sustained efforts are currently
devoted to finding a greener catalyst working with cheaper metals. Numerous attempts at finding
green and highly reproducible ways of synthesising organic and inorganic compounds have been
undertaken in the last decade[19]. Ideally, these ought to be inexpensive, too. At present, one of
the largest barriers to the industrialization of organic and inorganic compounds is the use of
organic solvents. Perhaps the most important tenet of green chemistry is the use of harmless
green solvents capable of increasing the reaction rate and the efficiency. For a catalytic
3

application it is primordial to design a high-performance system and relentlessly apply the
optimised strategy [20-22].
In an intense search for suitable alternatives to hazardous solvents, ionic liquids (ILs) have
emerged as the top-choice for a sustainable chemistry[23, 24]. But even ILs come with their own
risks and perils, such as toxicity and flammability. In our study, we used molten tetrabutyl-
ammonium bromide [TBAB] which was shown to be safe and clean in numerous studies; it can
be considered a suitable catalyst for this type of reactions [25-29].
Carboxamide-based compounds play a role in several fields owing to their potential applications
in biomedical science[30, 31], catalytic processes[32, 33] and sensors[34-36]. The heart of these
compounds is the carboxamide linkage, –C(O)NH–, considered as one of the most vital and
essential functional groups in nature, and also an important concept in bio-inspired studies[37,
38]. The conventional method for the synthesis of carboxamide-based compounds consists in the
typical reaction between an appropriate carboxylic acid and the corresponding amines in an
organic solvent, for instance pyridine, and, possibly, in the presence of an activator. This
conventional method is not much fancied by green chemistry because of its low yield and the
toxicity of the organic solvent[39]. Several critical applications have, however, traditionally been
optimised in the conventional procedure. Nowadays, extensive investigations have been devoted
to engineering non-toxic carboxamides for catalytic and biomedical applications [40-43].
Catalytic application of this kind of ligand is judged a promising way of improving the bench-
scale and scale-up phases of some crucial mechanisms. The design and synthesis of
organometallic complexes from these ligands then becomes a primordial task [44, 45].
Advances in nm-sized metal and metal oxide particles in several shapes have sparked important
and vital developments in both science and technology. Preparation of these NPs lies in the
4

hands of chemists, who are able to skilfully design an experiment, optimise it and implement
several procedures for obtaining the NPs, but their application mostly profits process and
biomedical engineering and, in some cases, the catalysis of the fundamental chemical reactions
in chemistry [46-49].
Cupric oxide [CuO] (Tenorite) is a p-type metal-oxide semiconductor widely applied in gas
sensors, electrochemical and solar cells, photoconductive and thermoelectric materials owing to
its unique catalytic and electrical properties. Recently, it has also been used as an antimicrobial
agent against various bacterial species [50].
We have synthesised the bidentate carboxamide ligand N-(thiazole-2-yl) picolinamide [LH] in
TBAB serving as the reaction medium and catalyst. The complex (1) was prepared using LH and
copper(II) acetate; then (1) was thermally decomposed to give CuO NPs (2). (1) was
characterised using FT-IR, elemental analysis, CV and X-ray diffraction. (2) was identified by
FT-IR, XRD, FESEM, EDX and TGA-DTA. The catalytic properties of (1) and (2) were
assessed in the one-pot azide-alkyne cycloaddition [AAC] reaction in the presence of water as a
solvent without any additional reducing agents or bases. (1) and (2) were furthermore
investigated regarding their antibacterial activity.
2. Experimental
2.1. Materials and General Methods
All solvents and chemicals were of commercial reagent grade and used as received from Aldrich
and Merck. Elemental analyses were performed by using a Carlo ERBA Model EA 1108
elemental analyser. UV–Vis spectra were recorded on a JASCO V-570 spectrophotometer.
Infrared spectra (KBr pellets) were obtained using a Unicam Matson 1000 FT-IR
1
spectrophotometer. The H NMR spectra of the ligand was obtained on a Bruker FT-NMR 500
5

MHZ spectrometer; proton chemical shifts are reported in parts per million [ppm] relative to an
internal standard of Me4Si. Cyclic voltammograms were recorded by using a SAMA 500
Research Analyser. Three electrodes were utilized in this system, a glassy carbon working
electrode, a platinum disk auxiliary electrode and a silver wire as the reference electrode. The
glassy-carbon working-electrode (Metrohm 6.1204.110) of a 2.0 ± 0.1 mm diameter was
manually cleaned with 1-mm alumina and polished prior to each scan. Tetra butyl ammonium
hexafluorophosphate (TBAH) was used as the supporting electrolyte. The solutions were
deoxygenated by purging with Ar for 5 min. All electrochemical potentials were calibrated
versus the internal Fc+/o (E8 = 0.40 V vs. SCE) couple under the same conditions.
Thermogravimetric-differential thermal analysis (TG-DTA) was conducted on a Netzsch STA
449F3 thermal analyser at a constant heating rate of 10°C min–1 in air. An X-ray (=1.54060Å)
powder diagram was recorded in 25≤2θ≤100° at 25ºC with a step-size of 0.05° on an MPD PRO
from PANalytical. The morphology and composition of CuO NPs were observed by field
emission scanning electron microscopy (FESEM, MIRA3 TESCAN) and FE-SEM coupled
energy-dispersive X-ray spectroscopy (EDX).
2.2. Synthesis of N-(thiazole-2-yl) Picolinamide (LH )
A mixture of 3.22 g (10 mmol) of triphenylphosphite, 1.61 g (5 mmol) of TBAB, 1.23 g (10
mmol) of picolinic acid and 1 g (10 mmol) of 2-aminothiazole in a 25 mL round-bottomed flask
was placed in an oil bath. This reaction mixture was heated until it formed a homogeneous
solution which was then stirred for 1 h at 120°C. The viscous solution was then cooled to room
temperature and treated with 5 mL cold methanol. The resulting light yellow solid was filtered-
off and washed with cold methanol. Yield 79%. Anal. Calc. for C9H7N3OS (205.32 g mol-1): C,
52.67; H, 3.44; N, 20.47; S, 15.61. Found: C, 52.31; H, 3.46; N, 20.34; S, 15.21% .FT-IR (KBr,
6

cm-1) νmax: 3175 (NH), 1675 (C=Oamide), 1525 (C-N) cm-1. UV–visible (Acetonitrile) λmax (nm)
(ε, L mol-1 cm-1): 287 (32,800), 221 (32,440). 1H NMR (CDCl3, 500 MHz): 7.36 (d, Hc), 7.58 (d,
Hb), 7.73 (m, He), 8.12 (m, Hf), 8.19 (d, Hd), 8.77 (d, Hg), 11.94 (s, NH).
2.3. Synthesis of [Cu(L)2(H2O)].CH3Cl (1)
For the synthesis of this complex, 0.041 g (0.199 mmol) of the ligand LH were dissolved in 20
mL of chloroform and then 0.02 g (0.1 mmol) of copper(II) acetate were added to this solution.
This reaction solution was stirred for 2 h and then filtered. Then 20 mL of ethanol were added to
the filtrate and the green solution left to evaporate in a refrigerator. After some time green
crystals of (1) suitable for X-ray diffraction had grown and were isolated by filtration, washed
with cold ethanol and dried in vacuum. Yield 76%. Anal. Calc. for C19H15Cl3CuN6O3S2: C,
37.45; H, 2.48; N, 13.79; S, 10.59. Found: C, 38.2; H, 2.408; N, 14.03; S, 10.92%. FT–IR (KBr,
cm-1) νmax = 1627 (C=Oamide), 1583 (C-N) cm-1. UV–visible (Acetonitrile) λmax (nm) (ε, L mol-1
cm-1): 709 (240), 324 (26,400), 280 (35,200), 261 (47,200).
2.3. Preparation of Nanoparticles of Cupric Oxide (2)
CuO NPs of (2) were prepared by the thermal decomposition of (1). A very small amount of (1)
was loaded into a crucible and then placed in oven and heated at a rate of 10°C/min in air. NPs of
CuO were obtained after heating at 600°C for 3 hours. The resulting NPs were characterized by
FT-IR, FE-SEM and XRD analysis.
2.4. Biological Studies
The ligand LH, the Cu(II) complex (1) and the CuO NPs (2) were individually tested against a
panel (Gram negative and Gram positive) of microorganisms, namely Bacillus cereus and
Staphylococcus aureus as Gram +ve and Salmonella typhi, Klebsiellap neumoniae and
7

Escherichia coli as Gram –ve species. The organisms were grown by the well-known diffusion
method using Sabouraud-dextrose and Müller-Hinton agar. The minimum zone of inhibition
[MZI] was recorded upon the completion of the incubation and the mean diameter for each
complex at 300 μg mL-1 was recorded. Stock solutions of the compounds were prepared in
dimethylsulfoxide. The MZI produced by the compounds were compared with those of the
standard antibiotic penicillin at similar concentrations. Each test was carried out three times to
minimize the error. In order to clarify any effect of DMSO in the biological screening, blank
studies were carried out, and no activity was observed against any bacterial strains in pure
DMSO.
2.5. General Procedure for the CuAAC Reaction
To a reactor containing alkyne (0.5 mmol), the organic halide (0.55 mmol), NaN3 (0.55 mmol)
and H2O (2 mL), either (1) or (2) were added as the catalyst. The reaction mixture was stirred at
70 °C for 4-6 h and the completion of the reaction was judged by thin layer chromatography.
Water (5 mL) was then added to the resulting mixture and the product was extracted with ethyl
acetate (2 x 10 mL) from the aqueous phase. The organic layer was dried over anhydrous MgSO4
and the solvent was removed under reduced pressure to give the corresponding 1,2,3-triazoles.
Further purification was necessary in the case of complex 1, since it was not soluble enough in
ethyl acetate. To obtain the pure products, after extraction with ethylacetate, the reaction mixture
was filtered and the residue was subjected to column chromatography (eluent, 40% EtOAc in n-
hexane).
2.6. X-ray Crystallography
Green crystals of 1 suitable for X-ray diffraction were obtained from ethanol and
dichloromethane. Bragg intensities of 1 were collected, at room temperature, on a Stoe IPDS II
8

using graphite-monochromatized Mo Kα (λ = 0.71073 Å) with the help of X-Area WinXpose
[51]. The cell refinement was carried out by means of X-Area Recipe [52], data reduction and a
numerical absorption correction, based on the habitus, with X-Red32 [53] and X-Area Integrate
[54].
The solution and refinement of the structure were performed by the latest available versions of
ShelXT[55] and ShelXL[56]. All non-hydrogen atoms were refined anisotropically using full-
matrix least-squares based on |F|2. The hydrogen atoms were placed at calculated positions by
means of the “riding” model in which each H-atom was assigned a fixed isotropic displacement
parameter with a value equal to 1.2 Ueq of its parent C-atom (1.5 Ueq for the methyl groups), but
hydrogen atoms of coordinated water molecule were found in a difference map and refined
freely. Details of the data collection, structure solution and refinement of 1 are compiled in Table
1.
In the structure 1, the solvent molecule of chloroform is disordered over two positions which
could be located in a difference map and refined anisotropically, yielding site occupancy ratios
of 0.56(6)/0.44(6), but SADI restraints were used to optimise the bond lengths and SIMU
restraints were applied to refine the displacement-ellipsoids of the atoms.
3. Results and discussion
3.1. Synthesis of the Ligand and the Complex
The ligand LH was synthesised in the IL TBAB in order to decrease the reaction time, increase
the efficiency and reduce the risks of toxic solvents such as pyridine. The complex (1) was
synthesised by the reaction of LH with copper(II) acetate. Green crystals of (1) suitable for X-
ray diffraction were obtained by slow evaporation from ethanol and dichloromethane at
refrigerator temperature.
9

3.2. Description of the Structure of (1)
The complex (1) is shown in Fig. 1 and some of its geometrical details are given in Table 2. The
complex crystallizes in the monoclinic space group P21/n with four complexes in the unit cell.
The ligand LH is bidentate and coordinates to the Cu2+ ion via its carboxamide nitrogen and its
nitrogen of the pyridine ring. The oxygen atom of a water molecule completes the coordination-
pyramid; its ADDISON parameter of 0.26 for (1) confirms the Jahn-Teller “axially” elongated
square pyramidal coordination (the N6 pyridine atom occupying the long axial position of the
Cu(II) ion). The lengths of the bonds for Cu-Namid [Cu-N2= 2.006(2), Cu-N5= 1.990(2)] and Cu-
Npyridyl [Cu-N3= 2.027(3), Cu-N6= 2.227(3)] are comparable to the lengths of those bonds
observed in analogous copper complexes [18-20]. The length of the Cu-Namid bonds is slightly
shorter than that of Cu-Npyridyl. The trans angles around the central ion [N5-Cu-N6= 77.67(10)°,
N2-Cu-N6= 106.98(10)°, N3-Cu-N6= 99.68(11)°, N6-Cu-O3= 101.62(11)°] deviate from the
value 90° for the ideal square pyramid structure. It is also observed that the two equatorial angles
[N2-Cu-N3=81.45(11)°] and [N5-Cu-O3=89.17(10)°] are smaller than 90° and two equatorial
angles [O3-Cu-N2= 93.18(10)°] and [N5-Cu-N3= 94.47(11)°] are greater than 90°. This indicates
a pressure in coordination space owing to the strong ligand structure. Information about
.....
important hydrogen bonds in (1) is given in the Table 3; there is an intramolecular O3-H3B
N1 hydrogen bond involving the coordinated water O3 and the N1 nitrogen of the thiazole, an
.....
intermolecular O3-H3A O2 one again between the water O3 and the carboxamide oxygen O2
.....
.....
and, finally, quite a few weak C-H O and C-H Cl hydrogen bonds.
10

3.3. Spectroscopic properties
The FT-IR spectral data of LH, (1) and the nanoparticle (2) are shown in Fig S1 and Fig 2,
respectively. The FT–IR spectra of the free ligand exhibit a band at 3178 cm-1, which
corresponds to v(NHamidic); the absence of this stretching band in the spectra of the corresponding
Cu(II) complex confirms that the ligand is coordinated in its deprotonated form [57]. The
decrease of the carbonyl stretching frequency of the ligand upon complex-formation furnishes a
further indication of the coordination of the deprotonated amide. The sharp C=O stretching
vibration bands at 1676 cm-1 are red-shifted to 1627 cm-1 for (1), which is in accordance with the
data reported for the related complexes [58].
The observation of a significant increase in the frequency of C–N stretching vibration of medium
intensity for the coordinated L1- (1583 cm-1) relative to the free ligand (1525 cm-1) gives
additional support to the coordination of the amide in the deprotonated form. This blue-shift is
presumably due to the resonance enhancement in the deprotonated amide which in turn leads to
the strengthening of C–N bond[59, 60].
In the FT-IR spectra of the calcination products, presented in Fig. 2b, no relevant peaks
indicating the presence of organic ligands or fragments are observed. However, the appearance
of two strong bands (at 535 and 580 cm−1) in the FT-IR spectra of the thermal decomposition
products confirms the tenorite structure of CuO as the decomposition product [61]. The broad
band at about 3434 cm−1 and a weak band at 1628 cm-1 are assigned to adsorbed water.
The electronic absorption spectrum of LH in acetonitrile is shown in Fig S2. This spectrum
includes two bands at 221 and 287 nm, assigned to the intra-ligand transitions (π→π* of aromatic
rings and n→π*). The UV-Vis spectrum of the [Cu(L)2(H2O)].CH3Cl complex is shown in Fig. 3.
11

This complex has a distorted square pyramid structure. The copper centre has a d9 configuration,
so it presents d-d transitions. The green colour of the complex is due to the presence of an
absorbent band in the 500-800 nm region. The absorption bands at 324, 280 and 261 nm,
observed in the electron spectrum, are related to the displacements of charge and intra-ligand
transitions. Also, the absorption band at 703 nm is related to a d-d transition.
Fig. 4 shows the thermogram of the [Cu(L)2(H2O)].CH3Cl precursor indicating that the
decomposition of the complex (1) takes place in two steps. A significant mass change (Found
21.91%, Calc. 21%) starting at 128 °C corresponds to the expulsion of water and CH3Cl
molecules. An exothermic process (sharp exothermic peak at 670°C) with a weight loss of
69.37% is related to the decomposition of the ligand and the production of cupric oxide CuO.
The structure of CuO (tenorite) is confirmed by FT-IR and XRD.
The X-ray powder diagram of CuO, obtained from the thermal decomposition of (1) at 600 °C
for 3 h, is shown in Fig. 5. The diagram can be indexed in the monoclinic cell 4.6797(5),
3.4314(4), 5.1362(6); 99.262(5) and the space group C2/c (04-015-5876)[62, 63].
These results confirm that the (1) is completely decomposed into the cupric oxide phase at 600
°C, in good agreement with the TG-DTA and FT-IR results. The crystallite size of the as
synthesized product, Dc, was calculated from the average of the major diffraction peaks using
Scherrer’s equation (Eq(1)) [64]:
Dc = Kλ/ βcosθ ,
(1)
where K is a constant (ca. 0.9); λ is the X-ray wavelength used in XRD (1.5418 Å); θ the Bragg
angle; β is the pure diffraction broadening of a peak at half-height, i.e., the broadening due to the
dimensions of the crystallites. The size of the NPs calculated according to Scherrer’s equation
from Fig. 5, is 39 nm.
12

The size and morphology of the cupric oxide NPs were investigated by scanning electron
microscopy (FESEM) .The FESEM images and size distribution of the CuO NPs are shown in
Fig. 6. as can be seen, cupric oxide NPs are sphere-like and the average particle size is 39 nm.
The particles have a uniform size, a homogeneous sphere-like morphology and a narrow size
distribution. The image clearly shows the aggregation of grains of high surface area.
The chemical composition of the prepared CuO was investigated by using energy dispersive X-
ray analysis (EDX). As observed in Fig. 7, EDX analysis of the CuO NPs confirms the presence
of copper and oxygen in structure. Comparison of copper and oxygen peak intensities are
compatible with the XRD findings, namely that these particles mainly consist of cupric oxide.
The peak characteristic of carbon is probably due to the coating of the grid [65].
3.4. Electrochemical Studies
The electrochemical behaviour of LH and (1) have been studied by cyclic voltammetry in DMF
solution at a scan rate of 100 mVs-1, with 0.1 M TBAH as the supporting electrolyte at a glassy
carbon working electrode. As expected and previously reported, the carboxamide ligands are
electro-active in common organic solvents[66]. As shown in the voltammogram of LH (Fig. 8),
the two irreversible reduction waves of thiazole and pyridine rings are observed at -2.3 V and -
1.54 V and are shifted for the Cu(II) complex (1).
The electrochemistry of [Cu(L)2(H2O)2].CHCl3 in DMF (Fig. 9) shows an irreversible CuII/I
reduction peak at -0.45 V and an irreversible CuI/II peak at 0.36 V. Also, in this voltammogram,
an irreversible reduction peak of a solvation complex, due to the partial solvation of the central
metal, is observed at a potential of 0.01 V and the oxidation peak at a potential of 0.06 V. The
irreversible reductions observed at the potentials -2.01 and -2.38 V are related to pyridine and
thiazole rings, respectively.
13

3.5. Catalytic Activity
The catalytic activity of complex (1) and CuO (2) for the AAC reaction were investigated.
Following previously published work [67], we initially considered the reaction between phenyl
acetylene and benzyl chloride with sodium azide as the model reaction for complex (1). To
obtain the optimal reaction conditions, the critical parameters such as catalyst loading, solvent,
base, temperature and time of reaction were compared (Table 4). In our first set of experiments, a
blank reaction with no catalyst was studied (Table 4, entry 1); as expected no conversion to the
product was observed. In subsequent experiments, an aqueous solution of phenyl acetylene (0.5
mmol) and benzyl chloride (0.55 mmol) was allowed to react with sodium azide (0.55 mmol) in
the presence of different loadings of catalyst from 0.54 mol% to 2.59 mol%. Heating the reaction
mixture to 70 °C afforded the AAC reaction product with 79% (entry 2) to 99% (entry 6) after 6
h. A further increase in the amount of catalyst to 5.18 mol% afforded no improvement in the
yield (Table 4, entry 7).
The analogous procedure showed the optimal amount of catalyst (2) to be 1.35 mol% with a
95% yield (entry 12); unsurprisingly, the results depended on the amount of catalyst (entry 13)
used. It was also found that temperature has an essential effect on this catalytic system. As can
be seen in Table 4, for catalyst (1), at room temperature, the yield obtained was only 11% (entry
14). By increasing the temperature from 40 to 60 °C, the product yield increased to 66% and
84% (entries 15-17). The most suitable temperature for the AAC reaction in the presence of
catalyst (1) was 70 ˚C (Table 4, entry 6). The analogous values for the catalyst (2) were 70 °C
and a yield of 95% (entry 12). The reaction was considered completed after 6 h, but an effective
improvement in the yield of the triazole was observed when decreasing the reaction time from 6
to 4 h (entries 22 and 23, Table 4), but the yield of the reaction decreased. To establish the
14

optimal conditions for the catalyst, the effect of various solvents on the model reaction was
investigated in-depth (Fig. 10). The results of these experiments reveal that among the different
solvents screened such as (methanol, dichloromethane, water, ethanol, acetone, toluene, and
chloroform), water can be used as a green, inexpensive and efficient solvent for AAC reaction.
Under the optimised reaction conditions (Table 3, entry 6 for catalyst (1) and entry 12 for
catalyst (2)) a variety of diversely substituted phenyl acetylenes with a mixture of benzyl
bromides/chlorides and sodium azide to generate the desired 1,2,3-triazoles (Table 5) were
studied. Electron withdrawing and electron donating groups on the phenyl ring of the benzyl
halides and the phenyl acetylenes have little effect on the yield of the reaction (entries 2-6).
Furthermore, steric hindrance and coordination ability of substrates to the Cu centre were
observed for ortho substituents on the benzyl chloride as compared to the para derivatives
(entries 2 and 3), for instance, that o-methyl benzyl chloride was less reactive than p-methyl
benzyl chloride. Steric effects also seem to cause the fact that the ortho-substituted groups
needed longer reaction times to afford the corresponding products in an acceptable yield than
those obtained with para-substituted ones. We also observed that aliphatic alkynes require longer
reaction times to give high yields compared with aromatic alkynes, which seems to indicate that
the reactivity of the substrate is low. When propargyl alcohol or 2-methyl-3-butyn-2-ol was used
as a terminal alkyne, the reaction proceeded smoothly to give the corresponding products in
moderate yields (entries 7, 8, 12 and 13). The lower reaction yields are probably due to the
complexation of copper by alcoholic hydroxy groups[68]. Furthermore, 2-methyl-3-butyn-2-ol
gave lower yields compared to the propargyl alcohol owing to the high steric hindrance.
Replacing benzyl chloride with benzyl bromide for both catalysts seemed to indicate that benzyl
chloride is slightly more reactive than benzyl bromide (entries 9-13).
15

From the vantage point of green chemistry, reusability is one of the most important properties of
any metal catalysis. In this regard, the reusability of catalyst (1) and (2) were studied by
monitoring successive cycles of the AAC reaction of phenyl acetylene, benzyl chloride and
NaN3 under the optimised reaction conditions. After the first catalytic cycle, the catalyst was
easily separated by filtration from the reaction mixture, washed with ethanol and acetone (3 × 5
mL) and dried at 55 ˚C for 1 h. Then, a new AAC reaction of fresh reactants was started using
the recovered catalyst. The catalysts were seen to be stable and reusable for up to four runs
during the catalytic reaction as they afforded almost identical results in each cycle, but a slight
decrease in the yields was observed and the reaction yield reduced to 81% for catalyst (1) and
79% for catalyst (2) (Fig. 11). This decrease in the catalytic activity was judged to be due to the
decomposition of the complexes and structural changes.
We designed two reactions for investigating the active copper species performing the catalytic
reaction according to previous papers [69], with a 2:1 ratio of sodium ascorbate:catalyst (sodium
ascorbate is used as a mild reducing agent) in the catalytic system and the results are presented in
Table 4, (entries 24 and 25). No progress of efficiency could be detected by adding a reducing
agent.
The reduction of Cu(II) to Cu(I) during the catalytic reaction was extensively studied by means
of EPR and UV analysis [70]; it was found that the active species for the catalytic reaction is
copper(I). If copper(II) is used as catalyst for the AAC reaction, it must therefore be reduced to
copper(I) and only then the catalytic reaction cycle can start. In the absence of a reducing agent,
the real catalytic Cu(I) species was generated within a short induction period via reducing Cu(II)
salts by alcohol oxidation, homocoupling of terminal alkyne[71-74] or sodium azide [74, 75]; in
16

the present case, in which there were no alcoholic solvents, Cu(II) had to be reduced through
homocoupling of terminal alkyne or by sodium azide.
Let us finally compare the catalytic reactivity of catalysts (1) and (2) with recently reported
catalytic systems for the AAC reaction. Our catalysts work without the need of an inert
atmosphere or additional reducing agents. Furthermore, the previously reported systems often
require higher amounts of catalysts (entries 1-4 and 8), higher temperature (entries 4 and 8),
more solvent (entries 1, 2, 4, 7 and 9) or longer reaction times (entries 2, 4-7) for the reaction to
progress. Other advantages of our catalysts are: in situ generation of organic azides, simple
preparation of the catalysts, easy and quick isolation of products and the use of water as a green
solvent.
3.6. Antibacterial studies
The ligand LH and its corresponding Cu(II) complex (1) and CuO nanoparticles (2) were tested
for antibacterial activity against Bacillus cereus and Staphylococcus aureus as Gram +ve and
Salmonella, Klebsiella pneumoniae and Escherichia coli as Gram –ve species. The screening
results (MZI) are summarized in Fig. 12. While LH does not show significant activity, it is
evident that the compounds 1 and 2 exhibit antibacterial activity comparable to that observed for
the standard antibiotic penicillin. The inertness of the metal-ligand linkage presumably increases
its lipophilicity, cell permeability, and protection against enzymatic degradation [76]. However,
the exact mechanism is unclear yet and further biological studies are necessary to get a clear
picture of this behaviour [77].
In this study, the cupric oxide nanoparticles showed remarkable antibacterial activity against
both Gram-positive (S. aureus) and Gram-negative (E. coli and kelebseilla) bacteria (Fig. 12).
The observed extent of inhibition of bacterial growth suggests that the antibacterial activity of
17

CuO nanoparticles (2) is higher than that of the Cu (II) complex (1). This is in accord with
previously reported works [63].
Conclusions
The carboxamide ligand N-(thiazole-2-yl) picolinamide (LH), has been synthesised in the ionic
liquid TBAB and characterised; this benign way increased the product-yield and reduced the
reaction-time. The complex [CuII(L)2(H2O)].CHCl3 and cupric oxide NPs (tenorite) have been
synthesised, characterised and assessed as catalysts in the AAC reaction for two dozens of
typical compounds. Crystals of the CuII-complex were grown from ethanol/dichloromethane,
studied by X-ray diffraction and their structure discussed. The electrochemical study of the CuII-
complex revealed a CuII/I reduction process important for the catalytic activity. The CuII-complex
catalysed the AAC reaction under mild conditions and excellent yields in a short reaction time
under aerobic conditions in water and the Cu(II)-complex is more reactive than CuO NPs. The
ligand LH, the CuII-complex and the cupric oxide NPs were also screened for their in vitro
antibacterial activity: the complex and CuO present strong biological activity comparable to that
of the antibiotic penicillin, while the ligand is not active; the antibacterial activity of the cupric
oxide NPs is higher than that of the CuII-complex.
Acknowledgments
Support of this work by the Research Council of Sharif University of Technology is gratefully
acknowledged.
18

Appendix A. Supplementary Material
The CCDC number 1952723 contains the crystallographic data for the compound (1), namely
[Cu(L)2(H2O)].CH3Cl, in this paper. These data can be obtained, free of charge, from
www.ccdc.cam.ac.uk/data_request/cif.
19

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22

Table 1. Crystal data and structure refinement for [Cu(L)2(H2O)].CH3Cl
Formula
C19H15Cl3CuN6O3S2
1.687
1.454
Dcalc./ g cm-3
/mm-1
Formula Weight
Colour
609.38
green
Shape
prism
Size/mm3
0.35×0.10×0.04
292(1)
monoclinic
P21/n
T/K
Crystal System
Space Group
a/Å
b/Å
9.8921(6)
14.3386(6)
16.9234(11)
90
92.123(5)
90
c/Å
α/°
β/°
γ/°
V/Å3
2398.7(2)
4
Z
Z'
1
Wavelength/Å
Radiation type
0.71073
Mo K
1.862
29.223
22878
6476
3492
0.0559
341
49
°
min
max
/
°
/
Measured Refl's.
Ind't Refl's
Refl's with I > 2(I)
Rint
Parameters
Restraints
Largest Peak/e Å-3
Deepest Hole/e Å-3
GooF
0.304
-0.478
0.898
wR2 (all data)
wR2
R1 (all data)
R1
0.1026
0.0842
0.0968
0.0418
23

Table 2. Selected bond distances (°A) and angles (°) for [Cu(L)2(H2O)].CHCl3 (1)
Bond lengths
Cu-N5
Cu-N2
Cu-N6
Cu-N3
Bond angles
1.990(2)
2.006(2)
2.227(3)
2.027(3)
N5-Cu-O3
N5-Cu-N2
O3-Cu-N2
N5-Cu-N3
O3-Cu-N3
N2-Cu-N3
N5-Cu-N6
O3-Cu-N6
N2-Cu-N6
N3-Cu-N6
89.17(10)
174.21(11)
93.18(10)
94.47(11)
158.68(11)
81.45(11)
77.67(10)
101.62(11)
106.98(10)
99.68(11)
Table 3. Hydrogen Bond information for [Cu(L)2(H2O)].CHCL3 (1)
D
H
A
O21
N1
d(D-H)/Å
d(H-A)/Å
d(D-A)/Å
2.712(3)
2.625(4)
D-H-A/deg
O3
O3
H3A
H3B
0.80(3)
0.80(3)
1.91(3)
1.87(3)
173(5)
158(5)
––––
1-x,2-y,1
24

Table 4. The effect of time, temperature and the amount of catalyst on the cycloaddition of benzyl chloride with
phenyl acetylene in the presence of sodium azide.a
Entry
1
Cat (mol %)
-
Temp (°C)
70
Time (h)
Yeild (%)b
12
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
0
2
1(0.54)
1(1.03)
1(1.55)
1(2.08)
1(2.59)
1(5.18)
2(0.27)
2(0.54)
2(0.81)
2(1.08)
2(1.35)
2(1.62)
1(2.59)
1(2.59)
1(2.59)
1(2.59)
2(1.35)
2(1.35)
2 (1.35)
70
79
81
88
92
99
99
31
58
65
80
95
95
11
84
78
66
9
3
70
4
70
5
70
6
70
7
70
8
70
9
70
10
11
12
13
14
15
16
17
18
19
20
70
70
70
70
r.t.
60
50
40
r.t.
60
79
64
50
25

21
2(1.35)
1(2.59)
2(1.35)
1(2.59)
2(1.35)
40
70
70
70
70
6
4
4
6
6
44
81
57
99
93
22
23
24c
25c
aReaction conditions: 0.5 mmol of phenylacetylene, 0.55 mmol of benzyl chloride, 0.55 mmol of sodium azide, 2
mL of H2O.
b Isolated yields.
c The reactions were performed by adding sodium ascorbate as a reductant with a molar ratio of 2:1 of sodium
ascorbate to the catalyst.
26

Table 5. Cycloaddition of alkyl halides with terminal alkynes in the presence of 1 and 2 and NaN3 under the
optimized reaction conditions.a
N
R1
[Cu(tp)2(H2O)]. CHCl3 (1)
CuO(2)
N
N
+
X
+R2
NaN3
R1
R1
H2O, 70 °C
R2
Entry
R2
X
Yield (%)b
Yield (%)b
CuO(2)
Cu(II)
complex(1)
1
2
Ph
Ph
Ph
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Br
Br
Br
Br
Br
99
95
91
85
92
90
63
59
88
92
84
63
47
95
89
80
75
86
83
57
48
76
74
68
43
41
4-Me-Ph
3
2-Me-Ph
Ph
4
4-NO2-Ph
Ph
5
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-MeO-Ph
4-Me-Ph
CH2OH
(CH3)2COH
Ph
6
7
8
9
10
11
12
13
4-MeO-Ph
4-Me-Ph
CH2OH
(CH3)2COH
a Reaction conditions: 0.5 mmol of terminal alkyne, 0.55 mmol of alkyl halide, 0.55 mmol of sodium azide, 2 mL of
H2O, 70 °C and 6 h
b Isolated yields.
27

Table 6. Recently reported catalytic systems for AAC in the presence of CuO nanoparticle.
Entry
Catalyst
Conditions
Yield(%)
Ref
1
Cu NPs
Catalyst (10 mol %) / 5 ml EtOH /5 h 95
[78]
/ 25 °C
2
3
4
Cu(OAc)2·H2O
Catalyst (20 mol %) / 3 ml H2O /20 h / 77
r.t.
[73]
[79]
[80]
Cu NPs/silica coated Catalyst (4.3 mol %)/2 ml H2O/2 h/70 83
maghemite
CuSO4-sodium
Ascorbate
°C
CuSO4-sodium ascorbate (10 mol %
each)/15 ml acetone: water (1:1)/8.5
h/80 °C
89
5
6
7
8
[CuL2]
Catalyst (0.86 mol%)/2 ml H2O/14 76
h/70 °C
Catalyst (1.40 mol%)/2 ml H2O/12 95
h/70°C
Catalyst (50 µM)/0.15 mmol sodium 99
ascorbate/10 ml H2O/24 h/37°C
Catalyst (3 mol%)/NaN3 /1.5 ml 80.3
H2O/MeCN (1:1) /15 min/125°C/MW
irradiation (10 W)
[69]
[81]
[82]
[83]
[CuL2]
Cu-complex
Cu-complex
9
Cu-complex
Catalyst (2.5 mol%)/NaN3 /5 ml 98
MeOH/30 min/60°C/MW irradiation
(30 W)
[84]
10
11
Cu(II) complex(1)
CuO NPs(2)
Catalyst (2.59 mol%)/ NaN3 /2 ml 99
H2O /6h/70 °C
Catalyst (1.35 mol%)/ NaN3 /2 ml 95
H2O /6h/70 °C
Present
work
Present
work
28

Fig. 1. The structure of [Cu(L)2(H2O)].CH3Cl (1) Displacements ellipsoids are drawn at the 50% level
29