Facile synthesis of 1- and 5-substituted 1H-tetrazoles catalyzed by recyclable ligand complex of copper(II) supported on superparamagnetic Fe 3O4@SiO2 nanoparticles

Article abstract of DOI:10.1016/j.molcata.2014.06.001

We report a new method for preparing functionalized superparamagnetic Fe₃O₄@SiO₂ possessing high saturation magnetization. Magnetite particles were prepared by simple co-precipitation method in aqueous medium, and then Fe₃O₄@SiO₂ nanosphere was synthesized by using nano Fe₃O₄ as the core, TEOS as the silica source and polyethylene glycol (PEG 1000) as the surfactant. Then, the silica-coated Fe₃O₄ nanoparticles were covered with ligand complex of Cu(II). The functionalized magnetic core-shell nanoparticles (MNPs) were investigated by Fourier transform infrared spectroscopy, transmission electron microscopy, scanning electron microscopy, X-ray diffraction, thermogravimetric analysis, dynamic light scattering and N₂ adsorption/desorption. Also, its Cu content was determined by inductively coupled plasma (ICP) analyzer. Then, the immobilized copper complex was used as an efficient catalyst for synthesis of 1- and 5-substituted 1H-tetrazoles from nitriles and amines in good to excellent yields. The results show that the supported catalyst could be conveniently recovered through the use of an external magnetic field and reused for subsequent reactions for at least 6 times with less deterioration in catalytic activity.

Full text of DOI:10.1016/j.molcata.2014.06.001

Accepted Manuscript
Title: Facile synthesis of 1- and 5-substituted 1H-tetrazoles
catalyzed by recyclable ligand complex of copper (II)
supported on superparamagnetic Fe3O4@SiO2 nanoparticles
Author: Mohsen Esmaeilpour Jaber Javidi Fatemeh Nowroozi
Dodeji Mehdi Mokhtari Abarghoui
PII:
S1381-1169(14)00247-7
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.molcata.2014.06.001
MOLCAA 9137
To appear in:
Journal of Molecular Catalysis A: Chemical
Received date:
Accepted date:
26-4-2014
2-6-2014
Please cite this article as: M. Esmaeilpour, J. Javidi, F.N. Dodeji, M.M.
Abarghoui, Facile synthesis of 1- and 5-substituted 1H-tetrazoles catalyzed
by recyclable ligand complex of copper (II) supported on superparamagnetic
Fe3O4@SiO2 nanoparticles, Journal of Molecular Catalysis A: Chemical (2014),
http://dx.doi.org/10.1016/j.molcata.2014.06.001
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Facile synthesis of 1- and 5-substituted 1H-tetrazoles catalyzed by
recyclable ligand complex of copper (II) supported on
superparamagnetic Fe3O4@SiO2 nanoparticles
Mohsen Esmaeilpour (1), Jaber Javidi (2)* Fatemeh Nowroozi Dodeji (2), Mehdi Mokhtari
Abarghoui (3)
(1) Chemistry Department, College of Science, Shiraz University, Shiraz, Iran
(2) Department of Pharmaceutics, School of Pharmacy, Shahid Beheshti University of
Medical Sciences, Tehran, Iran
(3) Department of Chemistry, Isfahan University of Technology, Isfahan, Iran
*Corresponding author. Tel.: +98 7116137738, fax: +98 7112286008.
E-mail address: Jaber Javidi@sbmu.ac.ir
Abstract
We report a new method for preparing functionalized superparamagnetic Fe3O4@SiO2
possessing high saturation magnetization. Magnetite particles were prepared by simple co-
precipitation method in aqueous medium, and then Fe3O4@ SiO2 nanosphere was synthesized
by using nano Fe3O4 as the core, TEOS as the silica source and polyethylene glycol (PEG
1000) as the surfactant. Then, the silica-coated Fe3O4 nanoparticles were covered with ligand
complex of Cu (II). The functionalized magnetic core–shell nanoparticles (MNPs) were
investigated by fourier transform infrared spectroscopy, transmission electron microscopy,
scanning electron microscopy, X-ray diffraction, thermogravimetric analysis, dynamic light
scattering and N2 adsorption/desorption. Also, its Cu content was determined by Inductively
Coupled Plasma (ICP) analyzer. Then, the immobilized copper complex was used as an
efficient catalyst for synthesis of 1- and 5-substituted 1H-tetrazoles from nitriles and amines
in good to excellent yields. The results show that the supported catalyst could be
conveniently recovered through the use of an external magnetic field and reused for
subsequent reactions for at least 6 times with less deterioration in catalytic activity.
Keywords
1- and 5-substituted 1H-tetrazoles, Core–shell, Supported catalyst, Magnetic separation.
1. Introduction
The chemistry of heterocycles has acquired immense importance recently [1].
Tetrazoles which represent a significant class of heterocycles have attracted
considerable interest in recent years because of their wide utility [2,3]. Among them,
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1-substituted-1 H-tetrazoles and 5-substituted-1H-tetrazoles have received much
attention and have been found in variety of synthetic and medicinal chemistry
applications as well as in material science including propellants and explosives [4-6].
Particularly, this functional group show strong activities as antihypertensive drugs [7],
sedatives [7], antiallergic [7], anti-imflammatory [8], antifungal [9], antibacterial [10],
antimicrobial [11], hormonal [12], carboxylic acid isosteres [13], photography [14],
herbicides [15] and diuretics activity [16]. Furthermore, tetrazoles have already been
successfully used in various material sciences and synthetic organic chemistry as
analytical reagents [17] and synthons [18].
Tetrazole rings can be prepared in several ways. The routes to 1-substituted tetrazoles
include acid-catalyzed cycloaddition between isocyanides and trimethyl azide [19],
acetic acid or trifluoroacetic acid catalyzed cyclization between primary amines, or
their salts, with an orthocarboxylic acid ester and sodium azide [20], acid-catalyzed
cycloaddition between hydrazoic acid and isocyanides [21], and cyclizations from an
amine, triethyl orthoformate, and sodium azide using SSA [22], In(OTf)3 [23],
[HBIm]BF4 [6], Yb(OTf)3 [24], PCl5 [25], and recently natrolite zeolite as a catalyst
[26].
The most convenient rout for the preparation of 5-substituted 1H-tetrazoles is via
[3+2] cycloaddition of azide to the corresponding nitriles. In earlier synthetic
methods, the homogeneous catalysts were used, such as a stoichiometric amount of
inorganic salts or metal complex as a catalyst, trimethylsilyl azide (TMSN3) and
tetrabutylammonium fluoride (TBAF) instead of metal salts under the solvent-free
condition, or in micellar media and ionic liquid [27–29].
Also, different homogenous and heterogeneous catalysts such as FeCl3-SiO2 [30],
nano CuFe2O4 [31], ZrOCl2 [32], nano ZnO/Co3O4 [33], γ-Fe2O3 [34], CdCl2 [35],
ZnO [36], Fe(OAc)2 [28], Zn/Al hydrotalcite [37], Pd(OAc)2/ZnBr [38], natural
zeolite [39], and Zeolite and sulfated zirconia [40] have been reported for the
promotion of reaction between nitrile and NaN3 or TMS-N3.
However, each one of these methods has more than one of these drawbacks: harsh
reaction conditions, long reactions times, use of toxic and corrosive reagents,
difficulty in separation and recovery of the catalyst, low yields, tedious work-ups,
expensive moisture sensitive reaction conditions, and the presence of hydrazoic acid,
which can be highly toxic and explosive along with volatile. Thus, the development of
simple, convenient, and environmentally benign methods for the synthesis of
tetrazoles remains required.
Magnetic nanoparticles have been the focus of much research recently because they
possess attractive properties that could potential used in catalysis, drug delivery,
magnetic resonance imaging contrast enhancement, data storage, targeted drug,
magnetic bioseparation, gene manipulation and immunoassay, enzyme immobilization
and environmental remediation because of its excellent properties of
superparamagnetism, low toxicity, high magnetic susceptibility, biocompatibility, and
high saturation magnetization [41-48]. However, pure magnetic particles are likely to
form a large aggregation and alter magnetic properties. Therefore, an appropriate
coating is important to avoid such limitations from occurring [49].
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Recently, magnetic core–shell materials, which combine features of cores and various
functional shells for different applications, have gained much attention and undergone
intensive investigation for their unique magnetic responsively, low cytotoxicity
[50,51], good stability [52], potential applications in medicinal [53,54], chemically
modifiable surface [55,56], optical [57], environmental [58], biological [59] and
chemical areas [60,61]. On the other hand to the issue observed in recovering and
reusing most solid catalysts, core–shell nanostructure magnetic catalysts could be
easily retrieved under the influence of a magnetic field and used in subsequent
reactions. As a result of this property, using magnetic core–shell structure composites
as catalysts has been recommended in literature [62,63]. Moreover, silica coating
endows the magnetic nanoparticles with easily modifiable surface, which may be used
to graft various desirable functional groups.
Nowadays, the functionalization of magnetic core–shell structure has attracted
particular interest, mainly due to potential applications of those materials in catalysis,
drug delivery, and adsorption [64-68].
Therefore, in this work, we report the preparation of Fe3O4@SiO2/ligand/Cu (II) as
illustrated in Scheme 1 and its use as a magnetic nanocatalyst for facile construction
of 5-substituted-1H-tetrazoles, and 1-substituted-1H-tetrazole ring systems in high
yields.
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Scheme1: Preparation process of Cu(II) complex functionalized Fe3O4@SiO2 nanoparticle.
2. Experimental
2.1. General procedure
Solvents were purified by conventional methods. All reagents were purchased from
Aldrich. The 1H and 13C NMR spectra were recorded on a Bruker Avance DPX 250
MHz spectrometer (using CDCl3 or DMSO-d6 with TMS as the standard). Fourier
transform infrared (FT-IR) spectra were recorded on Shimadzu FT-IR 8300
spectrometer using pressed KBr pellets. X-ray powder diffraction (XRD) analysis was
conducted on a Bruker AXS D8-advance X-ray diffractometer using Cu Kα radiation
(λ = 1.5418). Transmission electron microscopy (Philips EM208) with an accelerating
voltage of 100 kV was used to examine morphology and size of the nanoparticles and
field emission scanning electron microscopy (FE-SEM) images were obtained on
HITACHI S-4160. Magnetic characterization was carried out on a vibrating sample
magnetometer (BHV-55) at room temperature and dynamic light scattering (DLS)
were recorded on a HORIBA-LB550. BET surface area and porosity of catalysts were
determined from nitrogen physisorption measured on a Micromeritics ASAP 2000
instrument at 196oC. The amount of Cu nanoparticles supported on Fe3O4@SiO2/
ligand was measured by ICP analyzer (Varian, Vista-pro) and atomic absorption
spectroscopy. All products were identified by comparison of their spectral data and
physical properties with those of the authentic sample and all yields refer to isolated
products. The progress of the reaction was monitored by TLC and purification was
achieved by silica gel column chromatography.
2.1.1. Preparation of Fe3O4 nanoparticles
Fe3O4 nanoparticles were prepared by chemical co-precipitation of Fe3+ and Fe2+ ions
with a molar ratio of 2:1. Typically, a solution was prepared from FeCl2.4H2O (3.7
mmol, 736 mg) and FeCl3.6H2O (7.4 mmol, 2 g) in deionized H2O (30 mL) under an
Ar atmosphere and 400 mg of polyethylene glycol (PEG 1000) were added. The
resultant solution was left to be stirred for 30 min in 80oC. Then 25% aqueous NH3
was added drop wise with vigorous stirring to produce a black solid product when the
reaction media reaches pH 10. The dropping rate was controlled with a constant
dropper at 1 mL/min.
The resultant mixture was heated on water bath for 2 h at 60 oC and the black
magnetite solid product was washed with deionized H2O, filtered, dried and calcined
at 600oC for 6 h.
2.1.2. Preparation of Fe3O4@SiO2 core–shell
The core–shell Fe3O4@SiO2 nano spheres were prepared via hydrolysis of
tetraethylorthosilicate (TEOS) in basic solution via Stober method [69] with minor
modification. 40 mL of ethanol (98%), 10 mL of deionized water, and 1.5 mL
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ammonia (25 wt %) were mechanically stirred for 10 min before addition of TEOS.
Then, 0.10 g of freshly prepared iron oxide was added. After 30 min mixing, 2 ml of
TEOS was added and the mechanical stirring was continued for 8 h. The obtained
particles were sequentially washed with water and ethanol, and dried at 60°C for 6 h.
2.1.3. General procedure for the preparation of functionalized Fe3O4@SiO2
nanoparticle with3-(triethoxysilyl)-propylamine(Fe3O4@SiO2-NH2)
Fe3O4@SiO2 (0.5 g) was added to the solution of 3-(triethoxysilyl)-propylamine (1
mmol, 0.176 g) in ethanol (5 mL) and the resultant mixture was under reflux for 12 h
under nitrogen atmosphere. After refluxing, the mixture was cooled to room
temperature, filtered by an external magnet and the product was washed with ethanol
and water to remove unreacted species and dried at 80oC for 6 h.
2.1.4. General procedure for the preparation of the ligand functionalized
magnetite@silica nanoparticles (Fe3O4@SiO2/ ligand)
The modification of Fe3O4@SiO2-NH2 with isatin was carried out via ligand formation
between the amino group and the active carbonyl group of isatin as presented in
Scheme 1. A suspension of isatin (1mmol, 0.147g) and Fe3O4@SiO2-NH2 (0.5 g) in
ethanol (10 ml) was refluxed with continuous stirring under inert atmosphere for 16 h.
Then the product was isolated by filtration and thoroughly washed several times with
ethanol and distilled water, and then finally dried in a vacuum oven at 70◦C
2.1.5. General procedure for Cu (II) complex functionalized magnetite@silica
nanoparticles (Fe3O4@SiO2/ligand/Cu (II))
Fe3O4@SiO2/ ligand (0.5 g) was added to the solution of Cu (OAc)2 (1 mmol,0.182 g)
in ethanol (10 mL) and the resultant mixture was under reflux for 6 h. The catalyst
was separated from the crude product using an external magnet and washed with
ethanol and water. Then, it was dried in vacuum at 70oC for 6 h and kept under
desiccator.
2.2. Typical procedure for the synthesis of 1-substituted- 1H-tetrazoles
A mixture of amine (1 mmol), sodium azide (1 mmol), triethyl ortho-formate (1.2
mmol) and catalyst (0.01g, 0.4 mol% of Cu(II)) was taken in a round-bottomed flask
and stirred at 100ºC. The progress of the reaction was followed by thin-layer
chromatography (TLC). After completion of the reaction, the reaction mixture was
cooled to room temperature and diluted with ethyl acetate (2×20 mL). The catalyst
was removed by using magnetic field and then the resulting solution was washed with
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water, dried over anhydrous Na2SO4 and was evaporated. The residue was
concentrated and recrystallized from EtOAc–hexane (1:10).
2.3. Typical procedure for the synthesis of 5-Substituted 1H-Tetrazoles
A mixture of nitrile (1 mmol), sodium azide (1.5 mmol), Cu complex catalyst (0.4 mol
%) and DMF (3 mL) was taken in a round-bottomed flask and stirred at 110oC
temperature. After completion of the reaction the catalyst was separated from the
reaction mixture with an external magnet and reaction mixture was treated with ethyl
acetate (2×20 mL) and 1 N HCl (20 mL). The resultant organic layer was separated
and the aqueous layer was again extracted with ethyl acetate (2×15 mL). The
combined organic layers were washed with water, concentrated, and the crude
material was chromatographed on silica gel (Hexane-EtoAc, 1:1) to afford the pure
product.
3. Results and discussion
Fig. 1 shows the FTIR spectra of Fe3O4 nanoparticles (MNPs), Fe3O4@SiO2,
Fe3O4@SiO2-NH2, Fe3O4@SiO2/ligand and Fe3O4@SiO2/Ligand/Cu (II) particles. The
bands centered around 3400 cm-1 and 1620 cm-1 are, respectively, assigned to the O-H
stretching and deforming vibrations of adsorbed water. The IR spectrum of pure Fe3O4
(Fig. 1(a)) shows the peak at 578 cm-1 corresponding to the Fe-O vibration. The
adsorption peaks at 1080 and 805 cm−1 corresponds to the antisymmetric and
symmetric stretching vibration of Si-O-Si bond in oxygen-silica tetrahedron,
respectively (Fig1b). Evidently, it indicates that the silica has been successfully coated
on the surface of superparamagnetic Fe3O4 NPs (Fig1b). Figure 1c shows the FT-IR
spectrum of Fe3O4@SiO2–NH2 nanoparticles; the peaks at 581, 1000–1150, 1400–
1410 and 1543 cm-1 are attributed to Fe–O (stretching vibration), Si–O–Si
(asymmetric stretching), C–N (stretching vibration) and N–H (bending), respectively.
Also, the presence of several bands with medium intensity in 2810–2986 cm-1 and
3050–3250 regions are allocated to C–H stretching of the propyl group and N–H
stretching (Fig. 1c). In the FT-IR spectrum of the Fe3O4@SiO2/ligand, a new band is
observed at 1651 cm-1 due to the C=N stretch of the newly formed azomethine group
and another new band appears around 1497 cm-1 because of the aromatic C=C stretch.
These bands prove that isatin has been successfully grafted onto the Fe3O4@SiO2-NH2
nanoparticles (Fig. 1d). The C=O stretch of the amide group occurs at 1712 cm-1 and
O-H stretching band is found at 3400 cm-1 (Fig. 1d). The free ligand exhibits a ν(C=N)
stretch at 1651 cm−1 while in the complex, this band shifts to lower frequency and
appears at 1628cm−1 due to the coordination of the nitrogen with the metal (Fig1e).
From the IR spectra presented in Fig. 1e, the absorption peaks at 580cm−1 belonged to
the stretching vibration mode of Fe-O bonds in Fe3O4, the absorption peak presented
at 1000-1150cm−1 due to stretching vibration of framework and terminal Si–O-Si
groups. The presence of vibration bands in 3400 (O-H stretching), 2870-3080 (CH
stretching), 1697 (C=O amide), 1628 (C=N), 1480-1600 (C=C aromatic ring
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stretching) and 1478 (CH2 bending) demonstrates the existence of ligand complex of
Cu (II) on Fe3O4@SiO2 nanoparticles in the spectrum (Fig.1e).
Fig.1: FT-IR spectra a) Fe3O4, b) Fe3O4@SiO2 c) Fe3O4@SiO2-NH2, d) Fe3O4@SiO2/ligand,
e) Fe3O4@SiO2/ligand/Cu(II).
Fig. 2 shows the XRD patterns of Fe3O4, Fe3O4@SiO2 and Fe3O4@SiO2/ligand/Cu
(II). As presented in Fig. 2, six characteristic diffraction peaks (2Ө = 30.1◦, 35.4◦,
43.1◦, 53.4◦, 57◦ and 62.6◦ correspond to (220), (311), (400), (422), (511) and (440)
reflections of inverse spinel Fe3O4 NPs, respectively. it can be seen that the Fe3O4
obtained has highly crystalline cubic spinel structure which agrees with the standard
Fe3O4 (cubic phase) XRD spectrum (PDF#88-0866). The characteristic diffraction
peaks of Fe3O4@SiO2 are at about 30.2, 35.5, 43.3 and 62.8, just like those of pure
Fe3O4 (JCPDS:00-003-0862),indicating that the embedded Fe3O4 cores retain their
magnetite crystalline structures after the silica coating, while the silica exists in an
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amorphous state (Fig.2b). The same set of characteristic peaks were also observed for
Fe3O4@SiO2 and Fe3O4@SiO2/ligand/Cu (II), indicating the stability of the crystalline
phase of Fe3O4 nanoparticles during silica coating and surface functionalization (Fig2,
Table1). From Fig. 2b, we can see the XRD pattern of Fe3O4@SiO2 showing an
obvious diffusion peak at 2Ө = 15–25o, generally considered as the diffusion peak of
amorphous silica. For Fe3O4@SiO2/ligand/Cu (II) nanoparticles, the broad peak was
transferred to lower angles due to the synergetic effect of amorphous silica. The
broadening of each peak in XRD mean crystallite size was calculated by applying
Scherrer’s equation: D=Kλ/βcosӨ, where K is a constant (K = 0.9 for Cu-Kα), D is
the average diameter in A°, β is the broadening of the diffraction line measured at half
of its maximum intensity in radians, λ is the wavelength of the X-rays and Ө is the
Bragg diffraction angle. The particle sizes of the magnetite calculated using the
Scherrer equation were 14.1, 26.8.0, and 38.8 nm for Fe3O4, Fe3O4@SiO2, and
Fe3O4@SiO2/ligand/Cu (II), respectively (Table 1).
Fig. 2: XRD patterns of a) Fe3O4, b) Fe3O4@SiO2 and c) Fe3O4@SiO2/ligand/Cu (II).
Fig. 3 displays the TEM (a–c) and SEM (d–f) images of Fe3O4, Fe3O4@SiO2 and
Fe3O4@SiO2/ligand/Cu (II). As shown in Fig. 3a,d, The TEM and SEM images shows
that Fe3O4 particles were spherical with a mean diameter of 15nm (Table1), were of
uniform size, and showed good dispersity. Actually, in depths consider the TEM
image indicated that large particles consisted of agglomeration of small particles.
Subsequently, it shows spherical morphology after being coated with dense silica shell
and mesoporous silica shell as shown as the FE-SEM images (Fig3e). According to
the result calculated by Scherrer equation, it was found that the diameter of
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Fe3O4@SiO2 nanoparticles obtained was about 25 nm (Table1) due to the
agglomeration of Fe3O4 inside nanospheres and surface growth of silica on the shell.
The mesoporous silica shell on the surface of Fe3O4 is quite homogeneous and
exhibits good monodispersity with an estimated thickness of 10 nm (Fig3b). As shown
in Fig. 3c, a basically core–shell structure (dark colored core for Fe3O4@SiO2
nanoparticles and light-colored shell for ligand) was obtained. The samples still
remained monodisperse, and total average increase in diameter was approximately 40
nm (Table1). The morphology of Fe3O4@SiO2/ligand/Cu (II) nanoparticles was also
observed by FE-SEM (Fig. 3f). The nanoparticles are approximately spherical shapes
with a smooth surface morphology. The diameter of the nanoparticles is found to be
approximately 50 nm. The FE-SEM images indicate the successful coating of the
magnetic Fe3O4 particles.
The hydrodynamic diameter of Fe3O4, Fe3O4@SiO2 and Fe3O4@SiO2/ligand/Cu (II)
nanoparticles is determined by the DLS technique (Fig. 3). This size distribution is
centered at a value of 14, 26 and 40 nm for Fe3O4, Fe3O4@SiO2 and Fe3O4@SiO2/
ligand/Cu (II), respectively (Fig. 3 g-i). The theoretical curve of standard distribution
from our studies was calculated by means of Microsoft Excel.
Fig. 3: TEM images of Fe3O4 (a), Fe3O4@SiO2 (b), Fe3O4@SiO2/Ligand/Cu (II) (c) and FE-SEM and
DLS images Fe3O4 (d, g), Fe3O4@SiO2 (e, h) and Fe3O4@SiO2/Ligand/Cu (II) (f, i), respectively.
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N2 adsorption–desorption isotherms were conducted to investigate the porous
structure and surface area of the bare Fe3O4 NPs, Fe3O4@SiO2 and the Fe3O4@SiO2/
Ligand/Pd (II). The measured BET surface areas are 438.0, 430.3, and 353.6 m2/g for
Fe3O4, Fe3O4@ SiO2, and Fe3O4@SiO2/ligand/Cu (II) nanoparticles, respectively
(Table 1).
Table.1: Selected properties of Fe3O4, Fe3O4@SiO2, and Fe3O4@SiO2/ligand/Cu (II)
nanoparticles.
Sample
crystal structure
BET surface area
(m2/g)a
Magnetite particle size
(nm)
XRDb
TEMc
Fe3O4
Cubic spinel
Cubic spinel
Cubic spinel
438.0
430.3
353.6
14.1
26.8
38.8
15
25
40
Fe3O4@SiO2
Fe3O4@SiO2/ligand/Cu(II)
aDetermined by N2 adsorption using the Brunauer–Emmett–Teller method.
bCalculated by the Scherrer equation based on powder X-ray diffraction patterns.
cAverage particle size observed from the transmission electron microscopy images.
For investigation on the amount of the catalyst loading and stability of the materials,
thermogravimetric analysis was used. Fig.4a shows the typical TGA curve of
Fe3O4@SiO2/ligand/Cu (II). The weight loss of 4.1% below 150◦C for the sample is
apparently owing to loss of adsorbed water or the water that formed from the
condensation of hydroxyl groups. The weight loss between 150 and 780°C in Fig.4a
was assigned to the decomposition of covalently bonded ligand (about 24.1%). Thus,
the TGA curve confirmed the successful functionalization of magnetic nanoparticles
Fe3O4@SiO2 with complex ligand of Cu (II).
The magnetic properties of Fe3O4 (a) and the Fe3O4@SiO2/ligand/Cu (II) (b) were
examined by vibrating sampling magnetometry (VSM) at room temperature (Fig. 4b).
The saturation magnetization of Fe3O4 (a) and the Fe3O4@SiO2/ligand/Cu (II) were
around 66.1 and 30.7 emu/g, respectively. Obviously, the saturation magnetization of
Fe3O4 NPs gradually decreased with the increase of SiO2 and ligand complex (Fig.4b).
This figure shows almost zero coercivity, which proves the superparamagnetic
properties of the synthesized magnetic nanoparticles. Superparamagnetic particles do
not have permanent magnetic moments in the absence of an external field but can
respond to an external magnetic field.
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Fig.4: (a) Thermogravimetric analysis of Fe3O4@SiO2/ligand/Cu (II) nanoparticles. (b)
Magnetization curves at 300 K for c) Fe3O4 and d) Fe3O4@SiO2/ligand/Cu (II) nanoparticles.
In summary therefore, the Fe3O4@SiO2/ligand/Cu (II) NPs were highly susceptible to
an external magnetic field. This idea is also supported by Fig.5. In Fig.5a, the particles
were well dispersed in DMF under normal conditions. These high saturation
magnetization values suggest that the NPs can be effective carriers movable under a
low/moderate strength magnetic field.
Fig.5: Photographs of the separation and redispersion processes of Fe3O4@SiO2/ligand/
Cu(II): without external magnetic field (a), and with external magnetic field (b).
Determination of the Pd content was carried out by inductively coupled plasma (ICP)
analysis on the digested catalyst in refluxing aq. HCl (37%). The obtained results
revealed that 0.38 mmol per 1 g of Cu is immobilized on Fe3O4@SiO2/ligand.
In order to evaluate the optimum amount of catalyst required for synthesis of 1-
substituted 1H-tetrazoles, the reaction was carried out in the presence varying amount
of the catalysts and the results are presented in Table 2. The best result was achieved
by carrying out the reaction with (0.4mol%, 1mmol, 1mmol, 1.2 mmol) ratio of
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Fe3O4@SiO2/ligand/Cu (II) catalyst, aniline, sodium azide and triethyl orthoformate
under solvent-free conditions at 100oC (Table2, entry5). The results show clearly that
catalyst is effective for this transformation and in the absence of it; the reaction did
not take place even after higher reaction time (Table2, entry1). Use of a higher amount
of catalyst did not improve the yield (Table2, entry6) while a decrease in the amount
of catalyst decreases the yield (Table2, entries 2-4).
The effect of temperature was studied by carrying out the model reaction at different
temperatures under solvent-free condition (room temperature, 60oC, 100oC and
110oC) and the best results were obtained at 100oC (Table2, entries5, 7-9). Then, the
reactions were conducted in refluxing MeOH, EtOH, CH3CN, DMSO and DMF as
solvents and under solvent-less conditions (Table2, entries5,10-14). When the reaction
was performed in solvent-free, the progress of the reaction was higher in comparison
with solvent conditions. Therefore, the solvent-free condition was used for the
synthesis of 1-substituted 1H-tetrazoles.
Table.2: Optimization of different proportions of Fe3O4@SiO2/ligand/Cu (II) nanocatalyst
and also effect of solvents and temperature on formation of 1-substituted 1H-tetrazoles.a
Entry Solvent/catalyst amount (mol%)
Temp. (oC)
120
Time (h)
Yieldb (%)
10
8
1
2
3
4
5
6
7
8
Solvent-free/None
Solvent-free/0.1
Solvent-free/0.2
Solvent-free/0.3
Solvent-free/0.4
Solvent-free/0.5
Solvent-free/0.4
Solvent-free/0.4
Solvent-free/0.4
MeOH/0.4
100
100
100
100
100
r.t
60
110
Reflux
Reflux
Reflux
Reflux
Reflux
2
2
1
0.75
1
4
2
1
2
2
2
2
2
32
66
90
93
92
17
61
92
65
58
54
73
81
9
10
11
12
13
14
EtOH/0.4
CH3CN/0.4
DMSO/0.4
DMF/04
a Conditions: aniline (1 mmol), triethyl orthoformate (1.2 mmol), and sodium azide (1 mmol).
b Yields refer to isolated pure product.
A variety of amines such as substituted anilines, heteroaromatic amines, and an
aliphatic amine were employed to investigate the scope and generality of this process.
The results are recorded in Table3. Amines carrying different functional groups were
subjected to the coupling reactions and in all cases the desired product was obtained in
high yields. It was observed that under similar conditions, a wide range of anilines
containing electron withdrawing as well as electron donating groups such as bromo,
chloro, nitro, acetyl, methoxy, and methyl and an aliphatic butan-1-amine easily
underwent condensation with triethyl orthoformate and sodium azide to give 1-
substituted- 1H-1,2,3,4-tetrazoles in short reaction times with excellent isolated yields.
(Table 3).
12
Page 12 of 24

Table.3: Preparation of 1-substituted 1H-tetrazoles in the presence of Fe3O4@SiO2/ligand/Cu(II).a
Substrate
Product
Time Yieldb Mp. (◦C) (Lit.)c Ref
.
(h)
0.75
1
(%)
N
N
N
93
62-63 (63-64)3
170-171 (170)70
153-154 (153)70
1
2
3
4
5
NH2
N
N
N
N
91
Br
Cl
NH2
N
N
Br
Cl
N
N
1.5
2.5
1.5
88
NH2
NH2
N
N
N
83
201-2002 (200)70
177 (175-177)3
O2N
N
O2N
H3COC
N
N
N
N
90
H3COC
NH2
N
N
N
N
1
1
2
97
97
86
92 (92)71
114-115 (115)3
78-79 (77)3
6
7
8
Me
NH2
NH2
N
Me
N
N
MeO
N
MeO
N
N
N
N
NH2
N
N
N
N
N
87
166 (166)70
9
NH2
N
2
N
N
N
Me
Me
130-132 (130)70
2
3
89
83
10
11
CH2NH2
N
N
N
N
N
N
143 (142-144)3
N
NH2
N
aConditions: amines (1 mmol), triethyl orthoformate (1.2 mmol), and sodium azide (1 mmol).
bYields refer to isolated pure product.
cMelting points reported in the parenthesis refer to the literature melting points.
Hence, we investigated the effects of different reaction parameters on the catalytic
activity in order to optimize the protocol for formation of 5-substituted 1H-tetrazoles.
13
Page 13 of 24

In the first, we chose the reaction benzonitrile (1mmol) with NaN3 (1mmol) as model
reaction; the results were summarized in Table 4. It was noted that in the absence of
Fe3O4@SiO2/ligand/Cu (II) nanocatalyst, there was no detectable amount of the
desired product formed (Table4, entry 1). The results show clearly that catalyst is
effective for this transformation. Various catalyst concentrations was also tested and
use of a higher amount of catalyst did not improve the yield (Table4, entry6) while 0.4
mol% gave the best result (Table4, entry5). When the reaction temperature was
increased to 110oC the yield was also increased while lowering the temperature to
80oC and room temperature led to decrease in reaction yields (Table4, entries 5,7,8).
Then, the reactions were conducted in present variation solvent such as MeOH, EtOH,
CH3CN, DMSO, NMP, THF, water, toluene and DMF. A good yield of 92% was
given in DMF in 4 h (Table4, entry5). We selected DMF as the solvent in the presence
of 0.4 mol% of the catalysts at 110°C as the best conditions for this reaction.
Table.4: Optimization of different proportions of Fe3O4@SiO2/ligand/Cu(II) nanocatalyst
and also effect of solvents and temperature on formation of 5-substituted 1H-tetrazoles.a
Entry
1
2
3
4
5
6
7
8
Solvent/catalyst amount (mol%) Temp. (oC)
Time (h)
Yieldb (%)
120
12
Trace
DMF/None
DMF/0.1
DMF/0.2
DMF/0.3
DMF/0.4
DMF/0.5
DMF/0.4
DMF/0.4
DMF/0.4
Toluene/0.4
Water/04
THF/04
110
110
110
110
110
r.t
80
120
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
6
6
6
4
4
12
8
4
6
12
12
8
8
12
12
17
67
88
92
91
Trace
53
92
38
Trace
Trace
64
80
55
9
10
11
12
13
14
15
16
NMP/04
DMSO/04
EtOH/0.4
MeOH/0.4
58
aConditions: benzonitrile (1 mmol) and NaN3 (1 mmol).
bYields refer to isolated pure product.
The scope and generality of this reaction have been explored by the reaction of
various nitrile compounds, with NaN3 (Table5). Based on the optimal conditions
obtained, various substrates such as benzonitrile and heteroaromatic benzonitrile were
then examined. As shown in Table5 under similar conditions a wide range of nitrile
compounds carrying different functional groups gave the desired products in good to
excellent yield. Nitriles compound carrying electron-donating groups provided high
yields of the desired products (Table5, entries 2-4,16,17). It is noticeable that,
compared to electron-rich nitriles, nitriles bearing electron withdrawing groups
14
Page 14 of 24

provided the corresponding products in shorter reaction time and comparatively higher
reaction yields (Table5, entries 5-7, 9,11). Steric effect also shows its hindrance upon
the rates and yields of the reactions. For example phthalonitrile reacted with azide
within 5 h with the isolation of the desired product in 90% (Table5, entry 8).
Table. 5: Preparation of 5-substituted 1H-tetrazoles in the presence of Fe3O4@SiO2/ligand/
Cu(II).a
Substrate
CN
Product
Time Yieldb
Mp. (◦C) (Lit.)c Ref
.
(h)
(%)
N
N
N
4
92
213-215 (215)70
249 (248-249)71
1
2
3
N
H
N
N
N
6
8
88
89
Me
CN
Me
N
H
N
N
232-234 (231-233)71
233-234 (234-235)2
266-267 (265-266)3
262 (261-263)3
MeO
CN
MeO
N
N
H
N
N
N
6
3
4
91
92
93
4
5
6
HO
Br
CN
HO
Br
N
H
N
N
N
CN
N
H
N
N
N
Cl
CN
Cl
N
H
N
N
4
94
254-256 (256)3
7
NC
CN
NC
N
N
H
CN
CN
CN
210-211 (208-210)71
217-219 (219-220)71
N
5
4
90
96
N
N
8
9
N
H
N
N
O2N
CN
O2N
N
N
H
15
Page 15 of 24

O2N
O2N
N
N
N
5
93
178 (178-179)71
CN
10
N
H
O2N
F3C
O2N
F3C
N
N
N
CN
5
4
91
94
221-223 (220-222)31
205(204-206)31
11
12
N
H
CN
N
N
N
N
H
N
N
4
5
93
92
211-212 (211)70
238 (239)3
13
14
CN
CN
N
N
N
H
N
N
N
N
N
N
H
N
CN
10
87
214-216 (215)70
15
N
N
N
N
H
H3CO
CN
H3CO
H3CO
N
6
8
89
92
206-207 (204-206)31
N
N
16
17
N
H
OCH3
OCH3
H3CO
H3CO
CN
H3CO
201 (202-203)31
N
N
N
H3CO
N
H
H3CO
8
83
123-124 (123-124)71
18
CH2CN
N
N
N
N
H
16
Page 16 of 24

aReaction conditions: nitrile compounds (1 mmol), NaN3 (1 mmol), Fe3O4@SiO2/ligand/Cu(II) (0.4
mol%), DMF, 110 ºC
bIsolated yield.
cMelting points reported in the parenthesis refer to the literature melting points.
Proposed mechanism for the formation of 1-substituted 1H-tetrazol (a) and 5-
substituted 1H-tetrazol (b) is shown in Scheme2. Initially of
Fe3O4@SiO2/Shiffbase/Cu (II) nanocatalyst reacts with azide to produce the
[Fe3O4@SiO2/Shiffbase/Cu(II)]-N3 (I) catalytic species. The role of catalytic species
(I) is activation of ethoxy groups and cleavage of C-O bonds. Generated carbenium
ions can stable with resonance by neighboring hetero atom O/N or sequential
nucleophilic displacements by amine and cyclization with azide (intermediates (II)-
(IV)). Elimination of ethanol from (IV) leads to the final heterocycle.c(b)- Formation
of [Fe3O4@SiO2/Shiffbase/Cu(II)]-N3 (I) is similar to (a). The [3+2] cycloaddition
takes place between the C-N bond of nitrile and (I) to form the intermediate (II) (III).
Precoordination of the nitrogen atom of the CN group of 2 with (I) to form complex
(II) would enhance this cyclization step.
Scheme.2. Proposed mechanism for the formation of 1-substituted 1H-tetrazol (a) and 5-substituted
1H-tetrazol (b).
Several reports attributed to reaction of benzonitrile and NaN3 with different catalyst
have established. For comparison, several reports have been summarized in table6.
It seems that the Fe3O4@SiO2/Shiffbase/Cu (II) nanocatalyst is active catalyst for this
reaction. Short time and high yield high confirm this statement.
Table.6: Comparison of various catalysts in synthesis of 5-substituted 1H-tetrazoles.a
Entry
Catalyst
ZnS hollow spheres
FeCl3–SiO2
Nano CuFe2O4
Sulfated zirconia
BaWO4
Conditions
DMF,120oC
DMF,120oC
DMF,120oC
DMF,110–120oC
DMF,120oC
DMF,120oC
Yieldb (%)
Time (h)
36 h
12h
Ref.
[72]
[30]
[31]
[40]
[73]
[73]
1
2
3
4
5
6
86
79
82
90
75
74
12h
24h
24h
24h
CaWO4
17
Page 17 of 24

7
8
9
ZnWO4
Zn/Al
DMF,120oC
75
84
92
24h
12h
4h
[73]
[37]
This work
DMF,120–130oC
Fe3O4@SiO2/ligand/Cu(II) DMF,110oC
aConditions: benzonitrile (1 mmol) and NaN3 (1 mmol).
bYields refer to isolated pure product.
Recycling of the catalyst is an important process from different aspects such as
environmental concerns, costs of the catalyst and its toxicity. However, Pd salts are
expensive; some of them are toxic, which makes the amounts of their leaching into the
reaction mixture a serious worry. Therefore, we studied the recycling of the
Fe3O4@SiO2/Salen Cu (II) catalyst for synthesis of 1- and 5-substituted 1H-tetrazoles
under optimized conditions (Fig.6). The catalyst was recovered by a magnetic field
and was washed with ethyl acetate (2×10 mL), dried and the catalyst reused for
subsequent reactions for at least 6 times without observation of appreciable loss in its
catalytic activity.
Fig.6: Recyclability of Fe3O4@SiO2/ligand/Cu(II) (A) in the synthesis of 1-substituted-1H-
1,2,3,4-tetrazoles (B) and in the synthesis of synthesis of 5-substituted 1H-tetrazoles.
AReaction conditions: aniline (1 mmol), triethyl orthoformate (1.2 mmol), and sodium azide (1 mmol),
Fe3O4@SiO2/ligand/Cu(II) (0.4 mol%), solvent-free, 100ºC.
BReaction conditions: benzonitrile (1 mmol) and NaN3 (1 mmol), Fe3O4@SiO2/ligand/Cu (II) (0.4 mol%), DMF,
110ºC.
To investigate the Cu leaching in these reactions, the filtrate of the reaction between
of p-methoxy aniline, triethyl orthoformate, and sodium azide after completion was
analyzed by ICP technique. The amount of Cu leaching after the first run was
determined by ICP analysis to be only 0.4%, and after 6 repeated recycling was 3.2%.
4. Conclusion
In summary, Fe3O4 was successfully prepared by co-precipitation with FeCl2 and
FeCl3 as reaction substrate, polystyrene (PS) as surfactant and aqueous NH3 as
precipitant. The core-shell Fe3O4@SiO2 nanospheres were prepared by a modified
18
Page 18 of 24

Stober method. Then, Fe3O4@SiO2 was coated with ligand complex of Cu (II). Then,
we have developed a mild, convenient, and efficient protocol for the synthesis of 1-
and 5-substituted 1H-tetrazoles from nitriles and amines using magnetically separable
Fe3O4@SiO2/ligand/Cu(II) nanoparticles as an efficient and recyclable catalyst. This
method gives notable advantages such as easy separation of the catalyst by external
magnetic field; excellent yields, short reaction times, non-toxic metal catalyst, and
simplicity of operation make this method a facile tool for the synthesis of tetrazoles.
Furthermore, the catalyst is magnetically separable and eliminates the requirement of
catalyst filtration after completion of the reaction, which represents a major advantage
for reactions from an economic and environmental point of view. In addition,
nanocatalyst can be easily recycled by applying an external magnetic field while
maintaining the catalytic activity without significant decrease even after running 6
times.
Acknowledgments
The authors are grateful to the council of Iran National Science Foundation and
University of Shiraz for their unending effort to provide financial support to undertake
this work.
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Figure Captions:
Fig.1: FT-IR spectra a) Fe3O4, b) Fe3O4@SiO2 c) Fe3O4@SiO2-NH2, d) Fe3O4@SiO2/ligand,
e) Fe3O4@SiO2/ligand/Cu(II).
Fig. 2: XRD patterns of a) Fe3O4, b) Fe3O4@SiO2 and c) Fe3O4@SiO2/ligand/Cu(II).
Fig. 3: TEM images of Fe3O4 (a), Fe3O4@SiO2 (b), Fe3O4@SiO2/Ligand/Cu(II) (c) and FE-
SEM and DLS images Fe3O4 (d, g), Fe3O4@SiO2 (e, h) and Fe3O4@SiO2/Ligand/Cu(II) (f, i),
respectively.
Fig.4: (a) Thermogravimetric analysis of Fe3O4@SiO2/ligand/Cu(II) nanoparticles. (b)
Magnetization curves at 300 K for c) Fe3O4 and d) Fe3O4@SiO2/ligand/Cu(II) nanoparticles.
Fig.5: Photographs of the separation and redispersion processes of Fe3O4@SiO2/ligand/
Cu(II): without external magnetic field (a), and with external magnetic field (b).
Fig.6: Recyclability of Fe3O4@SiO2/ligand/Cu(II) (A) in the synthesis of 1-substituted-1H-
1,2,3,4-tetrazoles (B) and in the synthesis of synthesis of 5-substituted 1H-tetrazoles.
Table Captions:
Table.1: Selected properties of Fe3O4, Fe3O4@SiO2, and Fe3O4@SiO2/ligand/Cu(II)
nanoparticles.
Table.2: Optimization of different proportions of Fe3O4@SiO2/ligand/Cu(II) nanocatalyst
and also effect of solvents and temperature on formation of 1-substituted 1H-tetrazoles.a
Table.3: Preparation of 1-substituted 1H-tetrazoles in the presence of
Fe3O4@SiO2/ligand/Cu(II).a
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Table.4: Optimization of different proportions of Fe3O4@SiO2/ligand/Cu(II) nanocatalyst
and also effect of solvents and temperature on formation of 5-substituted 1H-tetrazoles.a
Table. 5: Preparation of 5-substituted 1H-tetrazoles in the presence of Fe3O4@SiO2/ligand/
Cu(II).a
Table.6: Comparison of various catalysts in synthesis of 5-substituted 1H-tetrazoles.a
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Graphical abstract
A new magnetically separable catalyst consisting of complex of Cu(П) supported on
superparamagnetic Fe3O4@SiO2 nanoparticles was prepared. Then, the immobilized copper
complex was used as an efficient catalyst for synthesis of 1- and 5-substituted 1H-tetrazoles
from nitriles and amines in good to excellent yields.
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Research highlight
Preparation of the novel magnetic nanocatalysts 
Ligand complex of Cu(П) functionalized magnetite@silica nanoparticles 
 Identification of catalyst by XRD, TEM, DLS, FE-SEM, FT-IR, BET, TGA and VSM
Catalyst recycling by external magnetic field 
 The synthesis of 1- and 5-substituted 1H-tetrazoles from nitriles and amines
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