Copper(II)-faciliated synthesis of substituted thioethers and 5-substituted 1H-tetrazoles: Experimental and theoretical studies

Article abstract of DOI:10.1016/j.jorganchem.2019.06.008

Benzoylhydrazine based Schiff base-ligated two new copper(II) complexes, [Cu(L¹)₂] (1) and [Cu(L²)₂] (2) were synthesized by the reaction of Cu(CH₃COO)₂·H₂O with respective Schiff base ligand 1-[(4-nitrophenyl)ethylidene] benzohydrazide (HL¹) or 1-[(4-methoxyphenyl)ethylidene] benzohydrazide (HL²). Both complexes were isolated as greenish solid and fully characterized by elemental analysis, FT-IR, EPR, thermo-gravimetric (TG) analysis and Cyclic Voltammetry. The molecular structures of both complexes have also been determined by single crystal X-ray crystallography, which confirmed the coordination of Schiff base ligands through N, O donor atoms and distorted square planar geometry around the Cu(II) ion. Both complexes were found to be good homogeneous catalysts for the synthesis of a wide range of substituted thioethers and 5-substituted 1H-tetrazoles in 92% and 93% yield, respectively, at a low catalyst loading (0.5 mol%). The bond angles and distances, as discerned from the DFT calculations, commusurated with the experimental findings. The energy difference between the HOMO and the LUMO, calculated from DFT studies, was found to be 5.645 eV and 6.459 eV for complex 1 and complex 2, respectively. These results are in harmony with the observed higher catalytic activity of complex 1.

Full text of DOI:10.1016/j.jorganchem.2019.06.008

Accepted Manuscript
Copper(II)-faciliated synthesis of substituted thioethers and 5-substituted 1H-
tetrazoles: Experimental and theoretical studies
Samaresh Layek, Bhumika Agrahari, Shuvankar Dey, Rakesh Ganguly, Devendra D.
Pathak
PII:
S0022-328X(19)30245-1
DOI:
https://doi.org/10.1016/j.jorganchem.2019.06.008
JOM 20820
Reference:
To appear in: Journal of Organometallic Chemistry
Received Date: 10 May 2019
Revised Date: 5 June 2019
Accepted Date: 9 June 2019
Please cite this article as: S. Layek, B. Agrahari, S. Dey, R. Ganguly, D.D. Pathak, Copper(II)-faciliated
synthesis of substituted thioethers and 5-substituted 1H-tetrazoles: Experimental and theoretical studies,
Journal of Organometallic Chemistry (2019), doi: https://doi.org/10.1016/j.jorganchem.2019.06.008.
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Copper(II)-faciliated synthesis of substituted thioethers and 5-substituted 1H-tetrazoles:
Experimental and theoretical studies
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Samaresh Layeka, Bhumika Agraharia, Shuvankar Deyb, Rakesh Gangulyc, Devendra D. Pathaka*
a Department of Applied Chemistry, Indian Institute of Technology (ISM), Dhanbad-826004,
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India
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b Department of Chemistry, School of Sciences, Gujarat University, Ahmedabad-380009, India
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c Division of Chemistry & Biological Chemistry, Nanyang Technological University, Singapore-
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639798
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*Email: ddpathak@iitism.ac.in
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Abstract
Benzoylhydrazine based Schiff base-ligated two new copper(II) complexes, [Cu(L1)2] (1) and
[Cu(L2)2] (2) were synthesized by the reaction of Cu(CH3COO)2.H2O with respective Schiff base
ligand 1-[(4-nitrophenyl)ethylidene] benzohydrazide (HL1) or 1-[(4-methoxyphenyl)ethylidene]
benzohydrazide (HL2). Both complexes were isolated as greenish solid and fully characterized
by elemental analysis, FT-IR, EPR, thermo-gravimetric (TG) analysis and Cyclic Voltammetry.
The molecular structures of both complexes have also been determined by single crystal X-ray
crystallography, which confirmed the coordination of Schiff base ligands through N, O donor
atoms and distorted square planar geometry around the Cu(II) ion. Both complexes were found
to be good homogeneous catalysts for the synthesis of a wide range of substituted thioethers and
5-substituted 1H-tetrazoles in 92% and 93% yield, respectively, at a low catalyst loading (0.5
mol%). The bond angles and distances, as discerned from the DFT calculations, commusurated
with the experimental findings. The energy difference between the HOMO and the LUMO,
calculated from DFT studies, was found to be 5.645 eV and 6.459 eV for complex 1 and
complex 2, respectively. These results are in harmony with the observed higher catalytic activity
of complex 1.
Keywords
copper(II) complex, crystal structure, homogeneous catalysis, thioethers, tetrazoles
1. Introduction
The miscellaneous applications of copper-based complexes have accentuated a great deal of
interest in the field of catalysis,[1] biology[2] and active pharmaceutical ingredients (API’s).[3]
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These complexes have been reported to catalyze a broad range of organic reactions.[4] Owing to
the versatility of design and fine-tuning of these complexes, one can achieve an easy control over
the reaction mechanism, rate and selectivity of the respective catalytic processes.[5] Copper-
catalyzed coupling reactions are important tools for formation of carbon-heteroatom bonds.[6]
Among the various copper-catalyzed coupling reactions, C-S and C-N bond forming reactions
have gained much impetus due to their applications in the preparation of numerous important
products in the field of pharmaceutical, biological, and material science.[7]
Development of efficient methods for the C-S bond formation is a significant research
theme of organic synthesis.[8] In this perception, transition metal-catalysed C-S cross-coupled
thioethers have occupied a prominent role in organic synthesis.[9] Aryl and aryl alkyl thioethers
are used as essential building blocks for many biologically and pharmaceutically active
compounds such as, antibiotic (Gemmacin B) and HIV protease inhibitor agents (Nelfinavir).
Diaryl thioether scaffolds are an intergral structural motif of several biologically important
products, viz. Lissoclibadin 6, an antimicrobial agent, and AZD4407, a natural product-inspired
drug molecules which acts as 5-lipoxygenase inhibitor. (Figure 1).[10]
Figure 1. Typical examples of biologically significant thioether.
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A perusal of the literature indicated that these thioethers were synthesised by the reaction
of the corresponding Grignard reagent or arylboronic acid/aryl halide derivatives with a suitable
electrophilic aryl sulfur reagent (thiols) in presence of a variety of palladium, copper, nickel,
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cobalt and other metal complexes.[11-12] Although spectacular success in these reactions were
achieved using different catalysts, but all these methods suffer from one or other drawback such
as, use of precious palladium precursor and an additional ligand, inert atmosphere, use of
hazardous solvents, high catalyst loading, and prolong reaction time etc.[13]
The formation of C-N bond in aromatic compounds is another powerful tool in the
armoury of an organic chemist for the design of biological active molecules.[14] Tetrazoles are
some of the most stable nitrogen rich heterocyclic compounds that have received bewildering
range of applications in the field of coordination chemistry, organic synthesis, material science
and medicinal chemistry as antiprotozoal, antihypertensive and antibiotic.[15-16] For instance,
Valsartan and Losartan are the typical examples of anti- hypertive drugs and both contain
tetrazole moiety as an integral part of their structure (Figure 2).[17]
Figure 2. Typical examples of biologically significant 1 H-tetrazoles
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Owing to the versatile applications of numerous tetrazole derivatives, several methods for
their synthesis have been documented.[18] The most convenient method involves a [3+2]-
cycloaddition of organic nitriles to azides, which was first reported by Hantzsch et al. in 1901.[19]
As perusal of the literature reveals that many catalysts have been reported for the synthesis of
tetrazoles.[20-30] Although different nitriles served as successful substrates for the synthesis of
tetrazoles, majority of them are legitimately expensive, toxic and not readily available. Hence,
the use of easily available, less toxic and cheap starting materials for efficient synthesis of 5-
substituted 1H-tetrazoles is an attractive preposition. In view of the ease of availability, wide
diversity, lower toxicity, and ease of handling of aldehydes compared with nitriles, the direct
application of aldehydes for synthesis of 5-substituted 1H-tetrazole derivatives may be a highly
attractive and worth investigating.[31]
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In view of the easy synthesis and stability of Schiff base ligand derived copper(II)
complexes and of our ongoing research interest on the synthesis, structural characterization and
catalytic applications of transition metal complexes,[32] we herein describe the synthesis of
benzoylhydrazine based Schiff base ligated two new copper(II) complexes, namely [Cu(L1)2] (1)
and [Cu(L2)2] (2), and their catalytic activity towards the synthesis of diaryl sulphides via C-S
bond formation from the reaction of a number of aryl halides and various thiophenols and in
synthesis of 5-substituted 1H-tetrazoles from three component reaction of aldehyde,
hydroxylamine hydrochloride and sodium azide.
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2. Results and discussion
2.1. Synthesis and characterization of ligands and complexes
The preparation of benzoylhydrazone based Schiff base ligands (HL1 & HL2) and two new
copper complexes of the type [Cu(L1/L2)2] is outlined in Scheme 1. Condensation of 4-
nitroacetophenone and 4-methoxyacetophenone with benzoylhydrazine in 1:1 molar ratio in
ethanol under reflux lead to the formation of the N, O donor bidentate Schiff base ligands HL1
and HL2, respectively in 75-85% yield. These Schiff base ligands are stable, solids and can be
stored without precautions. In general, HL1 and HL2 ligands are fully soluble in common organic
solvent such as methanol, N, N-dimethyl formamide (DMF), dimethyl sulfoxide (DMSO) and
sparingly soluble in dichloromethane (DCM), chloroform (CHCl3), and ethanol etc. The reaction
of the Schiff base ligands with copper acetate in 2:1 molar ratio in methanol at room temperature
for 12 h afforded the corresponding complexes, [Cu(L1)2] (1) and [Cu(L2)2] (2) in good yields.
Both complexes were isolated as green block shaped crystals. Suitable single crystals for X-ray
crystallography were grown over a period of few days on standing a concentrated solution of the
complexes in DMF at room temperature.
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Scheme 1. Synthesis of Schiff base ligands and copper(II) complexes
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2.2. FT
‐
IR spectra of free ligands (HL1 and HL2) and complexes
FT‐IR spectra of free ligands (HL1 and HL2), complexes 1 and 2 were recorded by use of
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KBr disc and their characteristic bands are summarized in Table 1S and spectra are shown in
Fig. S1-S4. The FT-IR spectra of the synthesized Schiff base ligand HL1 and HL2 exhibited a
band at 3187 cm-1 and 3193 cm-1 respectively, due to νNH groups. Both ligands revealed a sharp
band at 1667 cm-1 and 1643 cm-1, respectively due to νC=O. The presence of νNH and νC=O
clearly indicated that both ligand existed predominantly in keto form in the solid state. The FT-
IR spectra of the ligand HL1 and HL2 also showed an intense band at around 1519 cm-1 and 1593
cm-1, respectively due to the presence of azomethine group of Schiff base ligands. The FT-IR
spectra of both copper(II) complexes 1 and 2 exhibited bands at 1511 cm-1 and 1591 cm-1
respectively, assignable to νC=N stretching frequency. A comparison of the FT-IR of the each
ligand and their complexes clearly indicated that the C=N stretching frequency were shifted to
lower wave number by 8 cm-1 and 16 cm-1 in complex 1 and complex 2, respectively. The
shifting of azomethine stretching frequency to lower wave number may be taken as evidence for
the coordination of the nitrogen atom to the metal.[33] The disappearance of νNH and νC=O
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peaks and appearance of a peak at 572 cm-1 and 564 cm-1 (νCu-O) and 508 cm-1 and 514 cm-1
(νCu-N) in the FT-IR spectra of complex 1 and complex 2, respectively supports the formation
of complexes.
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2.3. 1H and 13C NMR spectra of Ligands
The H and C NMR spectra of HL1 and HL2 were recorded in DMSO-d6 (Fig. S5-S8)
and their spectral data are summarized in Table 2S. The 1H NMR spectra of both ligands show a
singlet at δ 10.97 and δ 10.67, due to presence of -NH proton. A singlet at δ 2.43 and δ 2.33
corresponds to aliphatic CH3 protons of acetophenone moiety in HL1 and HL2, respectively. In
ligand HL2, an additional singlet at δ 3.80 is due to the presence of -OCH3 protons of 4-
methoxyacetophenone moiety. All aromatic protons appear in the range of δ 6.99-8.29. Both
ligands show an intense peak at δ 3.55 and δ 3.55 may be due to the impurity in the solvent.[34]
The 13C NMR spectra of both ligands exhibited a signal at δ 164.97 and δ 164.04 corresponding
to characteristic carbonyl (C=O) carbon of benzoylhydrazine moiety. The signal at δ 148.07 and
δ 156.52 appeared due to presence of imine carbon (C=N) of ligand HL1 and HL2 respectively.
The methyl carbon (-CH3) of acetophenone moiety in both ligands showed a signal at δ 14.90
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and δ 15.00. An additional signal in the C NMR spectrum of HL2 at δ 55.77 accounted to the
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aliphatic -OCH3 carbons.
2.4. EPR spectrum of the complexes
The EPR spectrum of both complexes were recorded at room temperature and the spectra
are shown in Figure 3. Complex 1 displayed well resolved an isotropic behaviour with a sharp
signal and without any hyperfine splitting having giso value of 2.0907, indicative of square planar
Cu(II) geometry.[35] The EPR spectrum of complex 2 exhibits four well-defined anisotropic
signals with hyperfine splitting which may be attributed to single electron interaction of
copper(II) with nuclear spin I = 3/2 [36]. Analysis of the EPR spectrum of the complex 2, g|| =
2.392, g⊥ = 2.066 and A|| = 13 mT. Since g|| and g⊥ values are closer to 2 and observed g|| > g⊥, it is
concluded that the unpaired electron is located at dx2-y2 orbital having distorted square planar
geometry for copper complex.[37]
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Figure 3. EPR spectra of complex 1 & complex 2
2.5. Thermogravimetric analysis (TGA) of the complexes
Thermogravimetric analysis (TGA) of the complexes was carried out in the temperature
range of 30-800 oC with a 10 oC/min interval in nitrogen atmosphere (Fig. S9), in order to assess
the stability and mode of decomposition of the complexes. The TGA thermograms indicated the
absence of water molecule in both complexes. The complex 1 and 2 were found to be stable up
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o
o
to 220 C and 202 C, respectively. Above these temperatures, both complexes undergo
decomposition in three well separated stages. In the first step, complex 1 shows a weight loss of
o
30.03% in the temperature range 220-320 C and complex 2 shows a weight loss of 11.60% in
the temperature range 202-315 oC. In the second stage, weight loss for complex 1 and complex 2
were observed by 16.92% and 45.07% within the temperature range 320-530 oC and 315-497 oC,
respectively. The corresponding weight loss at this stage may be attributed to removal of nitro
and methoxy groups of the corresponding complexes. In the third or final decomposition stage,
the remaining organic moiety i.e. chelate part was eliminated in the temperature of beyond 500
oC.
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2.6. Cyclic Voltammetry
To investigate the redox properties of Cu(II) complexes, the electrochemical behaviour of
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the Schiff base ligands (10–3 M) and their copper(II) complexes (10–3 M) were investigated by
Cyclic Voltammetry (CV) technique using 0.1M [nBu4N][ClO4] as a supporting electrolyte in
DMF solvent at scan rate of 100 mV S-1 (Figure 4). The Cyclic Voltammogram of the ligand 1
shows three reduction peaks at -1.49, -1.13 and -0.96 V vs. SCE. But in case of complex 1, the
metal based redox peak appeared at E1/2= -0.261 V vs. SCE due to CuII/CuI redox couple. Along
with the metal based redox process, two ligand centered reduction peaks also appeared at -1.74
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and -1.17 V vs. SCE. In case of ligand 2, the Cyclic Voltammogram shows two irreversible
peaks at -2.07 and -1.84 V vs. SCE. Complex 2 shows one quasi reversible peak at E1/2= -0.41 V
vs. SCE due to CuII/CuI redox couple.[38]
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Figure 4. Cyclic Voltammogram of the ligands and complexes at scan rates of 100 mV/s SCE
2.7.
Single crystal X-ray studies
Diffraction quality crystals of both complexes, namely [Cu(L1)2] (1) and [Cu(L2)2] (2)
were grown by slow evaporations of DMF solution of the complexes at room temperature and
structures of both complexes was unambiguously confirmed by single crystal X-ray studies. The
molecular structures (ORTEP Digrams) along with the non C, H atom numbering schemes are
depicted in Figure 5. The X-ray investigation exposes that both complexes crystallizes in
monoclinic system, having space group P 21/n for complex 1 and P 21/c for complex 2. Both
complexes show monomeric square planar geometry around the metal center where the metal ion
is four-coordinated by two imine N atoms and two benzoyl O atoms from two units of Schiff
base ligands in a trans- position through creating two five-membered metallocycle with metal
center. A summary of the crystallographic and refinement data of complexes is given in Table 1
and selected bond lengths and bond angles are also given in Table 3S. The complex 2 is slightly
distorted from square planar geometry when compared to that of complex 1 as the O1-Cu1-O2,
O1-Cu1-N4 and N(1)-Cu(1)-N(3) chelate bite angles of the complexes 1 and 2 are in the range of
83.7(2)o-95.2(2)o, 83.61(10)o-94.62(10)o and 174.6(2)o-174.88(11)o, respectively. The Cu-O
bond distances in the range of 1.9038(18)-1.9199(18) Å in complex 2 are slightly longer than
that of 1.8903(1)-1.8966(1) Å observed in complex 1, while the Cu-N bond distances in the
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range of 1.955(2)-1.981(2) Å in complex 2 are slightly shorter than that of 2.030(1)-2.032(1) Å
of complex 1. This may be due to the electron withdrawing effect of the nitro substituent of the
complex 1[39]. Packing structure of complexes 1 and 2 is shown in ESI Fig. S10 and Fig. S11
respectively.
Figure 5. ORTEP diagram of [Cu(L1)2] (1) and [Cu(L2)2] (2) complexes with the non C, H
atoms labelling scheme (Thermal ellipsoids are drawn at the 50% probability level).
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Table 1. Crystallographic and refinement data for [Cu(L1)2] (1) and [Cu(L2)2] (2) complexes
Crystal data
CCDC deposition
number
Complex 1
1585130
Complex 1
1585131
Chemical formula
Formula weight
Temperature
C30H24CuN6O6
628.09 g/mol
100(2) K
C32H30CuN4O4
598.14 g/mol
103(2) K
Wavelength
0.71073 Å
0.71073 Å
Crystal size
Crystal system
Space group
0.060 x 0.140 x 0.200 mm
monoclinic
P 21/n
0.160 x 0.240 x 0.300 mm
monoclinic
P 21/c
Unit cell dimensions
a = 9.6565(3) Å
b = 9.6293(3) Å
c = 29.1154(8) Å
α = 90°; β = 92.5730(10)°;
γ = 90°
a = 13.3310(12) Å;
b = 15.2582(12) Å
c = 14.1779(12) Å;
α = 90°; β = 97.088(2)°;
γ = 90°
Volume
Z
2704.58(14) Å3
4
2839.3(4) Å3
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Density (calculated)
Absorption coefficient
F(000)
1.543 g/cm3
0.866 mm-1
1292
1.399 g/cm3
0.814 mm-1
1244
Reflections collected
Independent reflections
Goodness-of-fit on F2
Final R indices
48810
8601 [Rint = 0.0406]
1.037
25402
5822 [Rint = 0.0635]
1.008
7058 data; I>2
σ(I);
4045 data; I>2σ(I);
R1 = 0.0392, wR2
= 0.0773
0.068 eÅ-3
R1 = 0.0392, wR2 = 0.0773
0.063 eÅ-3
R.M.S. deviation from
mean
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Catalytic Studies
In continuation of our previous studies and research interest on transition metal catalysed
organic reactions, we were interested in finding a simple and efficient method for the synthesis
of diaryl sulphides via C-S coupling of thiols with various bromo- or iodo-benzenes and 5-
substituted 1H-tetrazole via one-pot three component reaction of aldehyde, hydroxylamine
hydrochloride and sodium azide using fully characterized new copper(II) complexes 1 and 2 as
homogeneous catalysts (Scheme 2).
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Scheme 2. Application of complex 1 and 2 for synthesis of substituted thioethers and 5-
substituted 1H- tetrazoles
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To explore the catalytic potential of the complexes 1 and 2 for C-S bond formation
reaction, 4-methoxyiodobenzene and thiophenol were chosen as model substrates. To optimize
the reaction conditions, a series of experiments were performed with variation of reaction
parameters, such as solvent, base, temperature, time and catalyst loading (Table 2). Initially, the
reaction was carried out between 4-methoxyiodobenzene (0.234 g, 1.0 mmol) and thiophenol
(0.132 g, 1.2 mmol) in the presence of 0.2 mol % complex 1 as catalyst, K2CO3 (1.0 mmol) as
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base in ethylene glycol as solvent at 90°C for 6h under atmospheric conditions. In this case, the
desired product was obtained in only 65% yield (Table 2, entry 1). It was further observed that
increasing the catalyst loading up to 0.5 mol% increases the product yield from 65 to 92% under
the same reaction conditions (Table 2, entry 2). Further increase in the catalyst loading beyond
0.5 mol% did not increase the product yield appreciably (Table 2, entry 3). Control experiments
confirmed that no conversion occurred without catalyst (Table 2, entry 4). Having determined
the best solvent for this C-S coupling reaction, we studied the influence of other solvents such as
toluene, dimethylformamide (DMF), acetonitrile, water, ethanol and PEG-200 on the reaction
system (Table 2, entries 5-10). Among various solvents, environmentally benign ethylene glycol
was found to be most effective solvent at 90°C for the titled coupling reaction (Table 2, entry 2)
and no reaction was observed in water, because of catalyst insolubility (Table 2, entry 8). When
the reaction temperature was lowered to 60°C, the yield also decreased (Table 2, entry 11).
Further increase in the reaction temperature did not affect the reaction yield (Table 2, entry 12).
In addition, the effect of base on this coupling reaction was also studied by using various bases
such as, K2CO3, KOH, NaOH, Et3N etc. where K2CO3 was found to be the best base (Table 2,
Entries 2 & 13-15). A comparative catalytic study was carried out involving both catalysts
(complex 1 & 2) towards the chosen C-S coupling reaction (Table 2, entries 2 & 16). Complex 1
achieved better catalytic performance than the complex 2 which may be related to electronic
effects of the coordinated ligand in the complex. This result is consistent with the theortical
calaculations carried out on both complexes.
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Table 2. Optimization of the C-S coupling reaction to synthesized diaryl sulphidesa
Entry
Catalyst
Catalyst loading
Solvent
Base
Temp (oC) Yield (%)b
(mol %)
1
2
3
4
Complex 1
Complex 1
Complex 1
-
0.2
0.5
0.8
-
Ethylene glycol K2CO3
Ethylene glycol K2CO3
Ethylene glycol K2CO3
Ethylene glycol K2CO3
90
90
90
90
65
92
92
n.r.
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6
Complex 1
Complex 1
Complex 1
Complex 1
Complex 1
Complex 1
Complex 1
Complex 1
Complex 1
Complex 1
Complex 1
Complex 2
0.5
Toluene
DMF
K2CO3
90
90
80
90
80
90
60
120
90
90
90
90
47
45
55
n.r.
35
82
75
92
75
55
58
83
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
7
CH3CN
H2O
8
9
Ethanol
PEG-200
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11
12
13
14
15
16
Ethylene glycol K2CO3
Ethylene glycol K2CO3
Ethylene glycol
Ethylene glycol
Et3N
KOH
Ethylene glycol NaOH
Ethylene glycol K2CO3
aReaction condition: Aryl halide (1.0 mmol), Thiol (1.2 mmol), base (1.0 mmol) for 6 h;
bIsolated yields after column chromatography
n.r. = no reaction
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After optimization of the reaction conditions, this catalytic protocol was applied to the
synthesis of a wide range of diary sulfides from a variety of substituted aryl halides (iodo or
bromo) and substituted thiols. All products were obtained in good to excellent yields (Table 3).
It is evident from Table 3, that both electron-donating and electron‐withdrawing groups in the
aryl iodide moiety were effective in this process, providing the corresponding products in good
to excellent yields (Table 3, entries 2-6). Aryl bromides were also found to be suitable substrates
for this coupling reaction (Table 3, entries 9-10). The scope of the reaction was extended to a
number of thiols having electron-rich groups, i.e. p-toluenethiol, neutral thiophenol (thiophenol),
electron-deficient thiophenol i.e. 4-chloro benzenethiol and also to sterically hindered
thiophenol, i.e. 2-aminothiophenol under the optimized conditions (Table 3). The coupling
appears to be insensitive to the electronic properties of the substrates. All reactions of both
electron-rich and electron-defficient thiophenols with substituted iodobenzene or bromobenzene
proceeded smoothly (Table 3). The sterically hindered ortho-substituted thiophenol (2-
aminothiol) underwent arylthiolation with 4-methyliodobenzene without any difficulty (Table 3,
entry 6). It is noteworthy that, under optimized conditions, heteroaryl thiol, i.e. 2-
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mercaptobenzimidazole, also provided the expected product in good yield (Table 3, entry 8).
This clearly indicated that catalyst
poisioning did not occur with heteroaryl thiols.
Unfortunately, our efforts to use aryl chloride substrates instead of iodo or bromo analoues, did
not succeed (Table 3, entry 16) owing to the less reactivity of C-Cl bond due to higher bond
[12a-12f]
energy. In comparison with other reported catalytic systems
for synthesis of diaryl
sulphides, the present catalyst showed better catalytic performance in terms of yields, catalyst
loading, reactions time, TON, TOF etc. as shown in Table 4.
Table 3. Copper(II)-catalyzed synthesis of diaryl sulphidesa
Entry Aryl halide
1
Thiols
Product
Time (h) Yields (%)b
6
6
6
6
6
7
90
91
92
91
92
90
2
3
4
5
6
7
8
6
7
91
88
9
7
7
86
83
10
11
12
6
6
90
89
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6
7
6
91
90
91
16
12
trace
aReaction condition: Aryl halide (1.0 mmol), Thiol (1.2 mmol), K2CO3 (1.0 mmol)
bIsolated yields after column chromatography
268
269
Table 4. A comparison study with some of the reported catalysts for the synthesis of diaryl
sulphides
Entry
Catalyst
Reaction
conditions
Yields (%)
91
TON
9.1
TOF
(h-1)
0.38
Ref.
1
10 mol% FeCl3,
20 mol% DMEDA
Toluene/
[12a]
NatObu/135
oC/24h
2
3
4
10 mol% In(OTf)3,
20 mol% DMEDA
10 mol% Ni(OAc)2,
5 mol% Ipr
1 mol% Pd(OAc)2,
1.2 mol% N-amido
imidazolium salts
20 mg Cu-grafted
furfural funtionalised
mesoporous silica
10 mol% I Mess-Cu-
Cl
DMSO/
96
92
95
9.6
9.2
95
0.40
0.77
7.90
[12b]
[12c]
[12d]
KOH/135 oC/24h
DMF/
NatObu/70 oC/12h
DMSO/
NatObu/80 oC/12h
5
DMF/
K2CO3/110
85.2
-
-
[12e]
[12f]
oC/12h
6
7
Toluene/
82
90
8.2
1.40
30.0
LitObu/120 oC/6h
Ethylene glycol/
K2CO3/90 oC/6h
0.5 mol% Copper(II)
Schiff base
180
This
work
(Complex 1)
270
271
272
273
Complexes 1 and 2 were also screened for their catalytic potential in the syntheses of 5-
substituted 1H tetrazole. In order to find the optimum conditions, the reaction of benzaldehyde
‐
with hydroxylamine and sodium azide was studied as a model reaction. For this reaction, the
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effect of solvents, the amounts of the catalyst and the temperature were studied (Table 5). The
reaction was carried out in the presence of 0.2 mol % of complex 1 as catalyst, in DMF at 110°C
for 5 h. In this case, the desired product was obtained in only 60 % yield (Table 5, entry 1). It
was further observed that an increase in the catalyst loading from 0.2 mol % to 0.4 mol % and
0.5 mol %, the yield of product significantly increases to 85% and 91%, respectively under the
same reaction conditions (Table 5, entries 2-3). Further, no improvement in yield was noted
when the catalyst loading was increased to 0.8 mol % (Table 5, entry 4). After optimization of
the catalyst loading, the effect of solvents in the reaction was also investigated using different
solvents such as ethylene glycol, DMSO, ethanol, methanol, H2O etc. (Table 5, entries 5-10).
DMF was found to be the most suitable solvent affording the maximum yield (91%) of the
product. We noted the formation of oxime only, when the reaction was performed in methanol or
ethanol (Table 5, entries 8-9). It was found that temperature has a profound effect on synthesis of
5-substituted 1H-tetrazoles. In the model reaction, the synthesis of 1H-tetrazoles was also
conducted at different temperatures ranging from 80°C to 130°C (Table 5, entries 11-13). In
presence of complex 2 as catalyst, there was afforded only 78% in yield of the product (Table 5,
entry 14).
Table 5. Optimization of the reaction condition for the synthesis of 5-substituted 1H-tetrazolea
Entry Catalyst
Catalyst loading
Solvent
Temp. (o C) Time (h) Yields
(%)b
(mol %)
0.2
1
2
3
4
5
6
7
Complex 1
DMF
DMF
DMF
DMF
DMF
DMSO
Ethylene
glycol
110
110
110
110
110
110
110
5
7
7
7
9
7
7
60
85
91
92
92
86
45
Complex 1
Complex 1
Complex 1
Complex 1
Complex 1
Complex 1
0.4
0.5
0.8
0.5
0.5
0.5
8
9
Complex 1
Complex 1
0.5
0.5
Ethanol
Methanol
110
110
7
7
n.r.
n.r.
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12
13
14
15
Complex 1
Complex 1
Complex 1
Complex 1
Complex 2
-
0.5
0.5
0.5
0.5
0.5
-
H2O
DMF
DMF
DMF
DMF
DMF
110
80
100
130
110
110
7
7
7
7
7
n.r.
75
78
92
78
18
n.r.
a Reaction condition: Benzaldehyde (1 mmol), hydroxylamine hydrochloride (1.2 mmol),
sodium azide (1.5 mmol), Solvent, catalyst
b Isolated yields; n.r. = no reaction.
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298
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300
301
302
303
304
305
306
307
308
309
310
311
312
313
314
315
In order to extend the scope of the reaction, various aldehydes were examined under the
optimized conditions and the results are summarized in Table 6. As demonstrated in Table 6, this
protocol is rather general for a wide range of electron-withdrawing as well as electron-donating
aromatic aldehydes and afforded good to excellent yields (Table 6, entries 2-11). However
aldehydes containing electron-withdrawing groups (Cl, Br, NO2, COCH3) gave products in better
yields than those containing electron-donating groups (CH3, OCH3, OH) (Table 6). Steric
hindrance on substrates is also an important parameter affecting the yield of the products. The
para- and meta- substituted aldehydes resulted in good yield as compared to substituent at ortho-
position may be due to steric effect. For instance, time and yield of the reaction for 3-nitro-
benzaldehyde, 4-nitrobenzaldehyde, 3-bromobenzaldehyde, 4-bromobenzaldehyde, 2-
hydroxybenzaldehyde, 4-hydroxy- benzaldehyde show this fact (Table 6, entries 4,8; 6,7; 10,11).
The reaction of terepthaldehyde with one equivalent of other reactants afforded the
corresponding tetrazole product, 4-(1H-tetrazol-5-yl)benzaldehyde in good yield (Table 6, entry
12). Heterocyclic aldehydes such as 2-thiophene-carboxaldehyde and 2-furancarboxaldehyde
also underwent this three component reaction smoothly to afford corresponding tetrazoles
products in good yields (Table 6, entries 13-14). Isolated products were fully characterized by
standard spectroscopic methods. A comparison of the activities of complex 1 with some of the
reported catalysts[31a-d] for the synthesis of 5-substituted 1H
‐tetrazoles showed that complex 1
has better catalytic activity compared to the other in terms of yields, catalyst loading, reactions
time, TON, TOF etc. as shown in Table 7. The enhanced catalytic activity using copper(II)
complexes may be due to the N, O-donor Schiff base ligands which increases the Lewis acidity
and stability of the copper(II) catalysts and facilitate the reactions smoothly. Among the two,
complex 1 exhibited better catalytic activity than the complex 2, which may be related to
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electronic effects of the coordinated ligand in the complex. The complex 1 contains an electron
withdrawing -NO2 group which presumably renders the metal center more electron deficient
(better Lewis acid) and showed higher catalytic activity. This result is also consistent with the
theortical calaculations carried out on both complexes.
Table 6. Cu(II)-catalyzed synthesis of 5-substituted 1H-tetrazoles form various aldehydes a
Entry
1
Aldehyde
Product
Time (h) Yield
(%) b
M.P (Exp./ Lit.)
(oC)
214-216/ 213-214
7
7
8
8
7
8
9
91
89
90
92
93
91
89
2
3
4
5
6
7
250-251/ 251-252
232-233/ 231-233
217-218/ 219-221
251-253/ 252-253
262-263/ 263-265
155-156/ 154-155
8
9
9
8
87
91
152-154/ 154-156
173-175/ 174-176
10
11
7
9
89
86
233-234/ 234-235
223-224/ 224-225
12
7
83
187-188/ 184-185
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14
8
8
90
91
203-205/ 205-206
197-198/ 199-201
aReaction condition: Aldehyde (1 mmol), hydroxylamine hydrochloride (1.2 mmol),
sodium azide (1.5 mmol); bIsolated yields
321
322
Table 7. A comparison study with some of the reported catalysts for the synthesis of 5-phenyl-
1H-tetrazole from benzaldehyde.
Entry
Catalyst
Reaction conditions
Yields
(%)
78
96
90
TON TOF
(h-1)
Ref.
1
2
3
4
5
10 mol% CuNO3. 3H2O DMSO/ 120 oC/24h
20 mol% Cu(OAc)2
30 mg Cu-MCM-41
30 mg Nano-Cu2O-MFR
0.5 mol% Copper(II)
Schiff base (Complex 1)
7.8
4.8
-
0.33
0.4
-
[31a]
[31b]
[31c]
[31d]
This
DMF/ 120 oC/12h
DMF/ 140 oC/12h
DMF/ 100 oC/8h
DMF/ 110 oC/7h
92
91
-
-
182
26
work
323
324
Based on the previous reports[30a, 40] and our observations, a plausible reaction mechanism
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328
329
330
331
332
for the synthesis of 5-substituted 1H-tetrazole is represented in Scheme 3. It is proposed that at
first, Cu(II) coordinates with with oxygen of aldehyde to increases the electrophilicity of
aldehyde [I]. After that the hydroxylamine attacks the carbonyl carbon of aldehydes to form
oxime [III]. The oxime undergoes rearrangement followed by exclusion of water to afford the
corresponding intermediate nitrile [IV]. The [3+2]-cycloaddition between the pre-coordinated
nitrogen atom of the C≡N bond (intermediate [IV]) with azide ion takes place readily to form the
intermediate [VI]. Protonolysis of the intermediate [VI] by 2 (N) HCl produce more stable
desired product, 5-substituted 1H-tetrazole as white solid.
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Scheme 3. Plausible mechanism for the synthesis of 5-substituted 1H-tetrazoles
335
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343
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345
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347
348
349
350
351
352
DFT Study:
To gain insight into the reactivity, vibrational attributions and absorption behaviour of the
ligands as well as the corresponding complexes, the Density Functional Theory (DFT) and Time
Dependent Density Functional Theory (TD-DFT) have been performed. After carefully
observing the optimized structure of both the complexes, we compare them with the
experimentally obtained data from single crystal XRD. A detailed comparison of the theoretical
and experimental bond length and bond angle data are given in Table 4S. One can easily observe
close resemblances between the two data. It is concluded from comparison of the optimized
structures of both the complexes, that in the case of Complex 1, unsubstituted phenyl ring was
coplanar with Cu+2 forming a perfect square planer complex although the nitro substituted
phenyl rings was tilted by about 120o. But, Complex 2 was devoid of such planarity and owing to
the distorted structure.
An analysis of lowest energy configurations and frontier orbitals leads to qualitative
insight towards the reactivity and optical responses of the complexes. The HOMO-LUMO
energy gap of a complex influences in its chemical reactivity.[41] Larger the gap implies high
kinetic stability and low chemical reactivity as it is energetically unfavorable to add electron to
high lying LUMO or to extract an electron from low lying HOMO[42]. The d-orbital of Cu(II)
interacting with the p-orbitals of oxygen and nitrogen atoms constitute these FMOs.
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Figure 6. Frontier molecular orbital diagrams of complex 1 and 2.
The HOMO energies of both the complexes were found nearer to each other and
positioned primarily over Cu as well as unsubstituted benzene rings. The substituted (nitro or
methoxy) benzene rings have only small share of these HOMOs (Figure 6). On the other hand,
Complex 1 LUMO which is primarily localized over the (-NO2) substituted aromatic ring,
acquires lower energy as compared to Complex 2, reduces the band gap between HOMO and
LUMO. Consequently, Complex 1 obtained significantly lower energy gap compared to
Complex 2, Which eventually ascertains the reactivity of Complex 1 is higher than Complex 2.
There is also a good match between experimentally observed and calculated distances for Cu-O
and Cu-N bonds. The calculated and experimentally found bond angles are also very close
(Table 4S).
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369
370
371
372
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374
Molecular ESP Calculation:
The Electrostatic potential (ESP) has a unique role in the prediction and analysis of molecular
recognition and is often helpful in demonstrating non-covalent molecular interaction
properties.[43] The electrostatic potential surface of any molecule or complex is influenced by the
charge density distribution. By employing the ESP surface, we can determine the spatial regions
in the molecular structures at which point the molecular electrostatic potential is negative or
positive [44]. The ESP surface visualize charged regions of a molecule and is qualitatively useful
in the analysis of catalytic activity of a compound. Three-dimensional plots of the molecular
electrostatic potentials of the ligands are illustrated in Fig. S12. The negative ESP regions are
indicated in red, and the positive regions in blue. Potential is coded in the following order: red <
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orange < yellow < green < blue. Both the ligands have positive potential over aliphatic region
and hydrogen atoms due to low electron density and lower electronegativity respectively. The
most negative ESP region (shown in dark red), is located around carbonyl oxygen and its
surrounding atoms. This large negative value is due to the lone pair of electrons on oxygen.
These negative regions can be easily attracted by the positive potential regions of the metal ions
and form strong complex. More the negative charge over the surface higher the possibility of
catalytic reaction. Similarly, in case of complex (Figure 7), metal ion and aliphatic region gains
positive potential which arises from positive charge over metal and low electron density on these
regions. The most positive potential area (show in dark blue) is located over the surface of metal
Figure 7. Electrostatic potential (ESP) mapping of Complex 1 & 2
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395
ion, where the global maximum point is located.
3. Conclusions
In summary, hydrazone based N- and O- donor bidentate Schiff base-ligated two new copper(II)
complexes, [Cu(L1)2] (1) and [Cu(L2)2] (2) were synthesized by the reactions of
Cu(CH3COO)2.H2O with Schiff base ligand 1-(4-nitrophenyl)ethylidene) benzohydrazonic acid
(HL1) and 1-(4-methoxyphenyl)ethylidene) benzohydrazonic acid (HL2), respectively. Both
complexes were fully characterized using elemental analysis, FT-IR, EPR, thermo-gravimetric
(TG) analysis and Cyclic Voltammetry. The single crystal X-ray diffraction studies revealed the
bidentate chelation of these ligands to the metal center through N- and O-donor atoms and a
distorted square planar geometry around the Cu(II) metal ion. The catalytic potential of both
complexes was demonstrated in the synthesis of a series of substituted thioethers and 5-
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403
404
substituted 1H-tetrazoles. Complex 1 was found to be better catalyst than the complex 2, and the
maximum yield was obtained up to 92% for substituted thioethers and 93% for 5-substituted 1H-
tetrazoles. The results of DFT calculations are consistent with the experimental bond lengths/
bond angles. The HOMO-LUMO energy difference calculated from the DFT is lower for
complex 1 than for complex 2. This theortical observation augers well for the higher catalytic
acitivity displayed by complex 1. The ease of synthesis, air- and moisture-insensitivity, and good
to excellent catalytic activities of the newly reported catalysts are some of the key features of the
present methodology which may capture wide attention of numerous researchers and scientists in
future.
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4. Experimental Section
4.1. Materials and physical measurements:
All reagents and solvents for the synthesis and analysis were commercially available and used as
received without further purification. The FT-IR spectra were recorded on a Perkin Elmer
Spectrometer (Model: Cary 660) in the range of 400-4000 cm-1 using KBr pellets in which MCT
used as a detector with scan number 20, and resolution 4 cm-1. The NMR spectra of complexes
were recorded in CDCl3/ DMSO-d6 on a Bruker 75 AvIII HD-400 MHz spectrometer using TMS
as the internal standard.
4.2. General procedure for the synthesis of ligands HL1 and HL2
In a 25 ml round-bottomed flask, ethanolic solutions (5 ml) of benzoylhydrazine (1.0 mmol) and
o
substituted acetophenone (R = 4-NO2 or 4-OCH3) (1.0 mmol) were stirred under reflux at 80 C
temperature in ethanol (5 ml) for 8 h. Upon cooling to 25 °C, precipitate was formed from the
reaction mixture. After this, solid was filtered, washed with cold ethanol and dried vacuum over
anhydrous CaCl2.
4.2.1. Schiff base ligand 1-[(4-nitrophenyl)ethylidene] benzohydrazide (HL1):
Benzoylhydrazine (0.136 g, 1.0 mmol), 4-nitro acetophenone (0.165 g, 1.0 mmol), and ethanol
(10 ml) afforded the title compound as a light yellow crystalline solid. Yield: 0.246 g, 87 %, m.p
= 202 oC; 1H NMR (DMSO-d6, 25 oC, 400 MHz):
δ 10.97 (s, 1H, NH), 8.28 (d, 2H, Ar H), 8.10
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(s, 2H, Ar H), 7.89 (s, 2H, Ar H), 7.60 (t, 1H, Ar H), 7.51-7.54 (m, 2H, Ar H), 2.43 (s, 3H,
13
o
CCH3); C NMR (DMSO-d6, 25 C, 100 MHz): 164.97 (-NHC=O), 152.53 (Ar C adjacent to
NO2 group), 148.07 (C=N), 144.82 (Ar C), 134.30 (Ar C), 132.18 (Ar C), 128.82 (Ar C), 128.02
(Ar C), 124.11 (Ar C), 14.90 (-CH3); Selected FT-IR (KBr), cm-1: 3187 (
1583 N=O),1519 ( C=N).
4.2.2. Schiff base ligand 1-[(4-methoxyphenyl)ethylidene] benzohydrazide (HL2)
νNH), 1667 (νC=O),
429
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432
433
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435
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437
438
439
440
441
442
443
444
445
446
447
448
(ν
ν
:
Benzoylhydrazine (0.136 g, 1.0 mmol), 4-methoxy acetophenone (0.150 g, 1.0 mmol), and
ethanol (10 ml) afforded the title compound as off white crystalline solid. Yield: 0.225 g, 83 %,
m.p = 142 oC, 1H NMR (DMSO-d6, 25 oC, 400 MHz):
7.56 (d, 1H, Ar H), 7.51 (t, 2H, Ar H), 6.99 (d, 2H, Ar H), 3.80 (s, 3H, OCH3), 2.33 (s, 3H,
CCH3); 13C NMR (DMSO-d6, 25 oC, 100 MHz):
164.06 (-NHC=O) , 160.96 (Ar C adjacent to
-OCH3 group), 156.52 (C=N), 134.58 (Ar C), 131.12(Ar C), 128.84 (Ar C), 128.31 (Ar C),
114.50 (Ar C), 55.77 (-OCH3), 15.00 (-CH3); Selected FTIR (KBr), cm-1: 3193
(N-H), 1643
(C=O), 1607 (C=N), 1539 (C=C).
4.3. Synthesis of copper(II) complexes:
δ 10.69 (s, 1H, NH), 7.85 (d, 4H, Ar H),
δ
ν
ν
ν
ν
A methanolic solution of Cu(CH3COO)2. H2O (0.5 mmol) was added drop-wise to a methanolic
suspension (5 mL) of the HL1 and HL2 Schiff base ligand (1.0 mmol) separately, at room
temperature. The reaction mixture was stirred for 12 h at room temperature to give greenish
precipitate which was filtered, washed with cold methanol and dried vacuum over anhydrous
CaCl2. The precipitate was re-crystallized from DMF. Suitable single crystals for X-ray
crystallography were grown over a period of few days from a concentrated solution of the
complex in DMF.
Complex 1 [Cu(L1)2]: Yield: 0.553 g, 88 %, Anal. Calc. for C30H24CuN6O6: C, 57.64; H, 3.75; N,
13.56. Found: C, 57.37; H, 3.85; N, 13.38; FTIR (KBr), cm-1: 2857-2931
ν (N=O), 1511 (C=N), 572 (Cu-O), 508 (Cu-N); giso = 2.0907.
Complex 2 [Cu(L2)2]: Yield: 0.508 g, 85 %, Anal. Calc. for C32H30CuN4O4: C, 64.45; H, 4.92; N,
9.30. Found: C, 64.26; H, 5.06; N, 9.37; FTIR (KBr), cm-1: 2812-2925
(CH2), 1591 ν(C=N),
1479 (C=Cring), 564 (Cu-O), 514 (Cu-N); g|| = 2.392, g⊥ = 2.066 and A|| = 13 mT.
4.4. General procedure for the synthesis of thioethers:
ν (CH2), 1585
449
450
451
452
453
454
455
ν
ν
ν
ν
ν
ν
ν
A mixture of aryl halide (1.0 mmol), thiophenol (1.2 mmol), 0.5 mol % Cu(II) catalyst and
K2CO3 (1.2 mmol) was stirred at 90 °C in ethylene glycol. The progress of the reaction was
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monitored by TLC. After the completion of the reaction, the reaction mixture was cooled to
room temperature and treated with water (3 ml) and ethylacetate (10 ml). The organic and
aqueous layers were then separated and the aqueous layer was extracted with ethyl acetate (5 ml)
for three times and dried with Na2SO4. The solvent was evaporated under vacuum to give crude
product which was purified by coloum chromatography using petroleum ether/ethyl acetate as
eluent. The spectra and physical properties of products were compared to those reported in the
literature (Fig. S13-S25).
4.5. General procedure for the synthesis of 5-substituted 1H-tetrazole derivatives:
A mixture of aldehyde (1.0 mmol), hydroxylamine hydrochloride (1.2 mmol) sodium azide (1.5
mmol), catalyst and DMF (3 mL) were taken in a 25 mL round bottomed flask and heated at
110 °C. After completion of the reaction (observed on TLC; petroleum ether: ethylacetate, 7:3),
the reaction mixture was cooled to room temperature. After that 2 (N) HCl (10 ml) added to the
solution and corresponding tetrazoles extracted with ethyl acetate (2×10 ml). The resultant
organic layer was washed with distilled water and dried over sodium sulphate. The solvent
removed under reduced pressure to give crude product which was purified by column
chromatography by using petroleum ether/ethyl acetate as an eluent. The products were
confirmed by melting point and NMR spectroscopic technique (Fig. S26-S39).
4.6. Crystallographic studies:
Diffraction quality crystals of the complexes (1 and 2) were grownup over a period of few days
from a concentrated solution of the complex in DMF and the structure of the complexes have
been illuminated by single-crystal X-ray diffraction. The X-ray di
measured at 103 K with a Bruker Kappa di ractometer equipped with a CCD detector,
employing Mo K radiation (
=0.71073 Å), with the SMART suite of programs.[45] All data
were processed and corrected for Lorentz and polarization e ects with SAINT and for absorption
ects with SADABS.[46] Structural solution and refinement were carried out with the
ffraction intensity data were
ff
α
λ
ff
eff
SHELXTL suite of programs.[47] The structures were refined (weighted least squares refinement
on F2) to convergence. All the non-hydrogen atoms in all the compounds were refined
anisotropically till convergence is reached. A summary of the crystallographic and refinement
data of these two copper complexes are given in Table 1.
4.7. Computational Study:
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Geometry optimization and initial DFT calculations of both the ligand (L1, L2) were performed
using Becke's three parametrized Lee-Yang-Parr (B3LYP) exchange-correlation function of
Gaussian 09 package. The other calculations including single point energy of the complexes viz.
Complex 1 and complex 2, as well as their vibration modes were performed utilizing hybrid
CAM-B3LYP functional for small atoms like C, H, N, O and LANL2DZ functional for atoms
with higher atomic number like Cu. CAM-B3LYP functional was considered instead of B3LYP
as significant charge transfer character were involved for the case of metal complex. We have
used 6-311G(d,p) basis set for all the atoms, which provides highly precise results on moderate
time scale. The electrostatic potential (ESP), total electron density (ED), and frontier molecular
orbitals (FMOs) were also studied using the DFT level by means of the B3LYP functional, to
obtain adequate information about the electronic characteristics.
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Supporting Information
CCDC 1585130 & CCDC 1585131 contains the supplementary crystallographic data for this
paper.
This
data
can
be
obtained
free
of
charge
via
http://www.ccdc.cam.ac.uk/conts/retrieving.html, or from the Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: (+44) 1223-336-033; or mail.
Supporting information includes characterization data and spectra for synthesized compounds.
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Acknowledgements
Authors are grateful to the SAIF Panjab University, SAIF IISER Bhopal for the analysis
of the samples and to NTU, Singapore for the single crystal X-ray structure
determination. Samaresh Layek and Bhumika Agrahari acknowledges the receipt of IIT
(ISM) senior research fellowship.
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References
[1] (a) M. B. Gawande, A. Goswami, F. X. Felpin, T. Asefa, X. Huang, R. Silva, X. Zou, R.
Zboril, R. S. Varma, Chem. Rev. 116 (2016) 3722; (b) M. M. Conejo, J. Cantero, A. Pastor, E.
Alvarez, A. Galindo, Inorg. Chimic. Acta 470 (2018) 113.
25

ACCEPTED MANUSCRIPT
513
514
515
516
517
518
519
520
521
522
523
524
525
526
527
528
529
530
531
532
533
534
535
536
537
538
539
540
541
542
543
[2] (a) K. Kiranmai, Y. Prashanthi, N. Subhashini, J. Chem. Pharm. Res. 2 (2010) 375; (b) A.
Warra, J. Chem. Pharm. Res. 3 (2011) 951; (c) M. Padmaja, J. Pragathi, C. G. Kumari, J. Chem.
Pharm. Res. 3 (2011) 602.
[3] K. Tummalapalli, V. C. S. P. Munusami, M. Pathak, M. M. Balamurali, Appl. Organometal.
Chem. 31 (2016) 3680.
[4] S. E. Allen, R. R. Walvoord, R. Padilla-Salinas, M. C. Kozlowski, Chem. Rev. 113 (2013)
6234.
[5] S. N. Zhao, X. Z. Song, S. Y. Song, H. Zhang, Coord. Chem. Rev. 337 (2017) 80.
[6] (a) X. Tang, W. Wu, W. Zeng, H. Jiang, Acc. Chem. Res. 2018, 51, 1092; (b) N. Panda, A.K.
Jena, Organic Chem Curr Res. 4 (2015) 1.
[7] (a) A. Sujatha, A. M. Thomas, A. P. Thankachan, G. Anil Kumar, ARKIVOC 2015, 1; (b) F.
Theil, Angew. Chem., Int. Ed. 38 (1999) 2345; (c) C. M. Rayner, Contemp. Org. Synth. 3 (1996)
499.
[8] (a) S. Roy, P. Phukan, Tetrahedron Lett. 56 (2015) 2426; b) L. Li, Y. Ding, Min. Rev. Org.
Chem., 2017, 14; (c) V. Saini, B. Khungar, New J. Chem. 42 (2018) 12796.
[9] (a) Yudin, A. K.; Hartwig, J. F. Catalyzed Carbon-Heteroatom Bond Formation; Wiley-VCH:
Weinheim 2010; (b) H. J. Xu, Y. Q. Zhao, T. Feng, Y. S. Feng, J. Org. Chem. 77 (2012) 2878;
(c) E. M. Beccalli, G. Broggini, M. Martinelli, S. Sottocornola, Chem. Rev. 107 (2007) 5318; (d)
F. Monnier, M. Taillefer, Angew. Chem., Int. Ed. 48 (2009) 6954.
[10] (a) J. E. Anthony, Chem. Rev. 106 (2006) 5028; (b) T. Mori, T. Nishimura, T. Yamamoto,
L. Doi, E. Miyazaki, I. Osaka, K. Takimiya, J. Am. Chem. Soc. 135 (2013) 13900; (c) P. S.
Herradura, K. A. Pendola, R. K. Guy, Org. Lett., 2 (2000) 2019; (d) P. Saravanan, P. Anbarasan,
Org. Lett. 16 (2014) 848.
[11] (a) G. Bastug, S. P. Nolan, J. Org. Chem. 78 (2013) 9303; (b) A. Thuillier, P. Metzner,
Sulfur Reagents in Organic Synthesis; Academic Press: New York 1994; (c) A. J. Caruso, A. M.
Colley, G. L. Bryant, J. Org. Chem. 56 (1991) 862; (d) J. Ham, I. Yang, H. Kang, J. Org. Chem.
69 (2004) 3236; (e) F. Ullmann, P. Sponagel, Ber. Dtsch. Chem. Ges. 38 (1905) 2211; (f) M.
Murata, S. L. Buchwald, Tetrahedron 60 (2004) 7397.
[12] (a) A. Correa, M. Carril, C. Bolm, Angew. Chem. Int. Ed. 47 (2008) 2880; (b) V. P. Reddy,
K. Swapna, A. V. Kumar, K. R. Rao, J. Org. Chem. 74 (2009) 3189; (c) P. Guan, C. Cao, Y. Liu,
Y. Li, P. He, Q. Chen, G. Liu, Y. Shi, Tetrahedron Lett. 53 (2012) 5987; d) A. Byeun, K. Baek,
26

ACCEPTED MANUSCRIPT
544
545
546
547
548
549
550
551
552
553
554
555
556
557
558
559
560
561
562
563
564
565
566
567
568
569
570
571
572
573
574
M. S. Han, S. Lee, Tetrahedron Lett. 54 (2013) 6712; (e) J. Mondal, A. Modak, A. Dutta, A.
Bhaumik, Dalton Trans. 40 (2011) 5228; (f) W. K. Huang, W. T. Chen, I.J. Hsu, C. C. Han, S. G.
Shyu, RSC Adv. 7 (2017) 4912; (g) C. Lai, H. Kao, Y. Wang, C. Lee, Tetrahedron Lett. 53
(2012) 4365; (h) C. F. Lee, Y. C. Liu, S. S. Badsara, Chem. Asian J. 9 (2014) 706; (i) Y. Wong,
T. T. Jayanth, C. Cheng, Org. Lett. 8 (2006) 5613; (j) E. Alvaro, J. F. Hartwig, J. Am. Chem.
Soc. 131 (2009) 7858; (k) F. Luo, C. Pan, L. P. Li, F. Chen, J. Cheng, Chem. Commun. 47
(2011) 5304; (l) G. T. Venkanna, H. D. Arman, Z. J. Tonzetich, ACS Catal. 4 (2014) 2941; (m)
S. N. Murthy, B. Madhav, V. P. Reddy Y. V. D. Nageswar, Eur. J. Org. Chem. 34 (2009) 5902;
(n) S. Mallick, S. Rana, K. Parida, Dalton Trans. 40 (2011) 9169; (o) J. Zhang, C. M. Medley, J.
A. Krause, H. Guan, Organometallics 29 (2010) 6393; (p) O. B. Pantaleon, S. H. Ortega, D. M.
Morales, Adv. Syn. Catal. 348 (2006) 236; (q) V. P. Reddy, A. V. Kumar, K. Swapna, K. R.
Rao, Org. Lett. 11 (2009) 1697; (r) S. Jammi, P. Barua, L. Rout, P. Saha, T. Punniyamurthy,
Tetrahedron Lett. 49 (2008) 1484; (s) F. J. Guo, J. Sun, Z. Q. Xu, F. E. Kühn, S. L. Zang, M. D.
Zhou, Catal. Commun. 96 (2017) 11.
[13] R. B. Nasir Baig, R. S. Varma, Chem. Commun. 48 (2012) 2582.
[14] J. V. Faria, M. Silva dos Santos, P. F. Vegi, J. C. Borges, A. M. R. Bernardino, Tetrahedron
Lett. 54 (2013) 5748.
[15] U. B. Patil, K. R. Kumthekar, J. M. Nagarkar, Tetrahedron Lett. 53 (2012) 3706.
[16] (a)V. A. Ostrovskii, G. I. Koldobskii, R. E. Trifonov, Comprehensive Heterocyclic
Chemistry III, Vol. 6, Elsevier, Oxford 2008, 257; (b) M. Khanmoradi, M. Nikoorajam, A.G.
Choghamarani, Appl. Organometal. Chem. 31 (2017) 3693.
[17] P. Moradi, A. G. Choghamarani, Appl. Organometal. Chem. 31 (2016) 1.
[18] Anuradha, S. Layek, B. Agrahari, D. D. Pathak, Chem. Select 2 (2017) 6865.
[19] A. Hantzsch, A. Vagt, Justus Liebigs Ann. Chem. 314 (1901) 339.
[20] (a) B. Sreedhar, A. S. Kumar, D. Yadav, Tetrahedron Lett. 52 (2011) 3565; (b) T. Jin, K. S.
Kitahara, Y. Yamamoto, Tetrahedron Lett. 49 (2008) 2824.
[21] V. Rama, K. Kanagaraj, K. Pitchumani, J. Org. Chem. 76 (2011) 9090.
[22] A. Kumar, R. Narayanan, H. Shechter, J. Org. Chem. 61 (1996) 4462.
[23] J. Bonnamour, C. Bolm, Chem. Eur. J. 15 (2009) 4543.
[24] G. Venkateshwarlu, A. Premalatha, K. C. Rajanna, P. K. Saiprakash, Synth. Commun. 39
(2009) 4479.
27

ACCEPTED MANUSCRIPT
575
576
577
578
579
580
581
582
583
584
585
586
587
588
589
590
591
592
593
594
595
596
597
598
599
600
601
602
603
604
605
[25] D. P. Matthews, J. E. Green, A. J. Shuker, J. Comb. Chem. 2 (2000) 19.
[26] M. L. Kantam, K. B. Shiva Kumar, C. Sridhar, Adv. Synth. Catal. 347 (2005) 1212.
[27] G. Baskaya, I. Esirden, E. Erken, F. Sen, M. Kaya, J. Nanosci. Nanotechnol. 17 (2017)
1992.
[28] L. Lang, B. Li, W. Liu, Li. Jiang, Z. Xu, G. Yin, Chem. Commun. 46 (2010) 448.
[29] S. Layek, R. Ganguly, D.D. Pathak, J. Organomet. Chem. 870 (2018) 16.
[30] (a) Y. Yıldız, I. Esirden, E. Erken, E. Demir, M. Kaya, F. Sen, Chem. Select 1 (2016) 1695;
(b) P. Moradi, A. G. Choghamarani, Appl. Organometal. Chem. 31 (2016) 3602; (c) M.
Nikoorazm, A. G. Choghamarani, M. Ghobadi, S. Massahi, Appl. Organometal. Chem. 31
(2017), 3848; (d) I. Esirdena, E. Erken, M. Kaya, F. Sen, Catal. Sci. Technol. 5 (2015) 4452; (e) E.
Erken, I. Esirden, M. Kaya, F. Sen, RSC Adv. 5 (2015) 68558.
[31] (a) C. Tao, B. Wang, L. Sun, J. Yi, D. Shi, J. Wang, W. Liu, J. Chem. Res. 41 (2016) 25; (b)
M. M. Heravi, A. Fazeli, H. A. Oskooie, Y. S. Beheshtiha, H. Valizadeh, Synlett 23 (2012) 2927;
(c) M. A. Alibeik, A. Moaddeli, New J. Chem. 2015, 39, 2116; (d) S. Behrouz, J. Saudi. Chem.
Soc. 21 (2017) 220.
[32] (a) S. Layek, S. Kumari, Anuradha, B. Agrahari, R. Ganguly, D. D. Pathak, Inorg. Chim.
Acta 453 (2016) 735; (b) S. Layek, Anuradha, B. Agrahari, D. D. Pathak, J. Organomet. Chem.
846 (2017) 105; (c) S. Layek, B. Agrahari, A. Tarafdar, C. Kumari, Anuradha, R. Ganguly, D. D.
Pathak, J. Mol. Struct. 1141 (2017) 428; (d) B. Agrahari, S. Layek, Anuradha, R. Ganguly, D. D.
Pathak, Inorg. Chim. Acta 471 (2017) 345; (e) Anuradha, S. Kumari, S. Layek, D. D. Pathak,
New J. Chem. 41 (2017) 5595; (f) B. Agrahari, S. Layek, S. Kumari, Anuradha, R. Ganguly, D.
D. Pathak, J. Mol. Struct. 1134 (2017) 85; (g) S. Layek, B. Agrahari, S. Kumari, Anuradha, D.
D. Pathak, Catal. Lett. 148 (2018) 2675; (h) B. Agrahari, S. Layek, R. Ganguly, N. Dege, D. D.
Pathak, J. Organometal. Chem. 890 (2019) 13.
[33] T. Maity, D. Saha, S. Koner, ChemCatChem 6 (2014) 2373.
[34] B.N. Bessy Raj, M.R. P. Kurup Spectrochim. Acta, Part A 66 (2007) 898.
[35] B. Agrahari, S. Layek, R. Ganguly, D. D. Pathak, New J. Chem. 42 (2018) 13754.
[36] K. Tummalapalli, C. S. Vasavi, P. Munusami, M. Pathak, M.M. Balamurali, Appl.
Organometal. Chem. 31 (2017) 3680.
[37] K. Venkateswarlu, M. P. Kumar, A. Rambabu, N. Vamsikrishna, S. Daravath, K. Rangan,
Shivaraj, J. Mol. Struct. 1160 (2018) 198.
28

ACCEPTED MANUSCRIPT
606
607
608
609
610
611
612
613
614
615
616
617
618
619
620
621
622
623
624
[38] (a) K. Majee, J. Patel, B. Das and S. K. Padhi, Dalton Trans. 46 (2017) 14869; (b) J. Cheng,
K. Wei, X. Ma, X. Zhou and H. Xiang, J. Phys. Chem. C, 117 (2013) 16552; (c) P. Zivec, F.
Perdih, I. Turel, G. Giester, G. Psomas, J. Inor. Biochem. 117 (2012) 35.
[39] (a) X. Dong, Y. Li, Z. Li, Y. Cui, H. Zhu, J. Inorg. Biochem. 108 (2012) 22; (b) M. P.
Kumar, S. Tejaswi, A. Rambabu, V. Kumar, A. Kalalbandi, Shivaraj, Polyhedron 102 (2015)
111.
[40] (a) M. Kazemnejadi, A. R. Sardarian, RSC Adv. 6 (2016) 91999; b) B. Mitra, S. Mukherjee,
G. C. Pariyar, P. Ghosh, Tetrahedron Lett. 59 (2018) 1385.
[41] S. H. Lee, N. Shin, S. W. Kwak, K. Hyun, W. H. Woo, J. H. Lee, H. Hwang, M. Kim, J.
Lee, Y. Kim, K. M. Lee, M. H. Park, Inorg. chem. 56 (2017) 2621.
[42] (a) O. Prakash, K. N. Sharma, H. Joshi, P. L. Gupta, A. K. Singh, Organometallics 33
(2014)
2535; (b) F. Saleem,G. K. Rao, A. Kumar, S. Kumar, M. P. Singh, A. K. Singh, RSC Adv. 4 (2014)
56102.
[43] T. P. Chiu, S. Rao, R. S. Mann, B. Honig, R. Rohs, Nucleic acids res. 45 (2017) 12565.
[44] F. Zhang, B. Liu, G. Liu, Y. Zhang, J. Wang, S. Wang, Sci. Rep. 8 (2018) 3131.
[45] SMART version 5.628; Bruker AXS Inc., Madison, WI, USA, 2001.
[46] Sheldrick, G. M. SADABS; University of Göttingen, Göttingen, Germany, 1996.
[47] SHELXTL version 5.1; Bruker AXS Inc., Madison, WI, USA, 1997.
29