Multi-component one-pot reaction of aldehyde, hydroxylamine and sodium azide catalyzed by Cu-MCM-41 nanoparticles: A novel method for the synthesis of 5-substituted 1H-tetrazole derivatives

Article abstract of DOI:10.1039/c4nj01042f

A simple and efficient procedure for the synthesis of 5-substituted 1H-tetrazole derivatives has been developed using a one-pot, three-component reaction of various aldehydes, hydroxylamine and sodium azide in the presence of a catalytic amount of Cu-MCM-41, as a nanostructured, heterogeneous and reusable catalyst. In this research, Cu-MCM-41 nanoparticles with three Cu/Si molar ratios were prepared and characterized using various techniques. The characterization and optimization results show that the catalyst with a Cu/Si molar ratio of 0.050 has the best catalytic activity.

Full text of DOI:10.1039/c4nj01042f

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Multi-component one-pot reaction of aldehyde, hydroxylamine and
sodium azide catalyzed by Cu-MCM-41 nanoparticles: A novel
method for the synthesis of 5-substituted 1H-tetrazole derivatives
a,∗
a
Mohammad AbdollahiꢀAlibeik , Ali Moaddeli
a
Department of Chemistry, Yazd University, Yazd 89158ꢀ13149, Iran
Simple and efficient procedure for the synthesis of 5ꢀsubstituted 1Hꢀtetrazole derivatives has
been developed by oneꢀpot threeꢀcomponent reaction of various aldehydes, hydroxylamine and
sodium azide in the presence of catalytic amount of CuꢀMCMꢀ41 as a nanostructured,
heterogeneous and reusable catalyst. In this research, CuꢀMCMꢀ41 nanoparticles with three
Cu/Si molar ratios were prepared and characterized by various techniques. The characterization
and optimization results show that the catalyst with Cu/Si molar ratio of 0.050 has the best
catalytic activity.
Keywords: 5ꢀsubstituted 1Hꢀtetrazoles; multiꢀcomponent; heterogeneous catalyst; CuꢀMCMꢀ41;
nanoparticle.
Introduction
Tetrazoles are an important class of the synthetic heterocyclic compounds with wide range of
practical applications in major areas of sciences such as medicine, chemistry and material
sciences. From pharmaceutical chemistry viewpoint, tetrazole derivatives have many biological
1
2
3
4
5
activities such as antihypertensive, antiꢀallergic, antibiotic, antiꢀdiabetic, antiꢀarrhythmic,
activity and have also potential for drug development as inhibitor for HIV or other immune
∗
Corresponding author
Mohammad AbdollahiꢀAlibeik, Department of Chemistry, Yazd University, Yazd 89158ꢀ13149, Iran
Tel.: +98ꢀ35ꢀ31232659; fax: +98ꢀ35ꢀ38210644
Eꢀmail address: abdollahi@yazd.ac.ir; moabdollahi@gmail.com
1

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6
, 7
diseases.
The high physiological activity of tetrazoles, such as lower toxicity and higher
lipophilicity makes them as substances of versatile biochemical and pharmaceutical destinations
especially in drugs as isosteric replacement of carboxylic acid moiety.8 Moreover, this functional
group has significant roles as ligand in coordination chemistry,9 in photography and specialty
10
1
1, 12
in explosives.
General method for the synthesis of 5ꢀsubstituted 1Hꢀtetrazole derivatives is based on the [2+3]
cycloaddition (twoꢀcomponent reaction) of various nitriles with sodium azide (NaN ) or
3
trimethylsilylazide (TMSN ) in polar aprotic solvents.13ꢀ15 Many catalysts have been used for this
3
type of reaction such as Brønsted acids,16 Lewis acids including BF .OEt ,17 AlCl3, metal
18
3
2
oxides such as Cu O, ZnO, clays and modified clays,21 Zn/Al hydrotalcite and Amberlystꢀ
1
9
20
22
2
2
3
1
5 as polymeric catalyst.
Many of submitted methods for this type of reaction suffer from some disadvantages such as the
use of strong Lewis acids, expensive reagents, toxic metals and also the in situ generation of
highly toxic and explosive hydrazoic acid. Indeed, design of safe and environmentally friendly
protocols for the synthesis of tetrazoles from simpler and more available precursors is still highly
desirable.
In recent years, tendency to the heterogeneous catalysts have received much attention because of
being recyclable and environmentally benign. Mesoporous materials have unique properties such
as high surface area and acidic sites that have been applied as heterogeneous solid acid catalyst
2
4
for many organic transformations. Mesoporous silicas are the widest members of mesoporous
materials that have been applied as heterogeneous catalyst and support in many organic
processes. These materials have high surface area and uniform tubular channels with tunable
2
5
pore diameters in the range of 2–10 nm. These properties provide good transportation channels
for reactants especially for the large molecules to access active centers and for products to move
out. In particular, modified mesoporous materials based on SiO containing various transition
2
metals such as Fe,26 Cu,27 Co and Pd have emerged as a useful heterogeneous catalysts due to
their versatile applications in synthesis and catalysis. Among them, copperꢀmodified molecular
sieves have shown excellent catalytic behavior that have been prepared in variety structures such
28
29
3
0
31, 32
27
as CuO/MCMꢀ48, Cu/MCMꢀ41
and Cu/SBAꢀ15.
2

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Recently, Negarkar and coꢀworkers have reported a new method for the synthesis of 5ꢀ
substituted 1Hꢀtetrazole by the reaction of organic oxime with sodium azide (NaN ) in the
3
3
3
presence of copper acetate (Cu(OAc) ) as catalyst.
2
Considering the importance of tetrazoles, we report another novel method for the synthesis of
this nucleus by oneꢀpot multiꢀcomponent reaction of a wide variety of aldehydes, hydroxylamine
and sodium azide into the corresponding tetrazoles in the presence of CuꢀMCMꢀ41 as reusable
solid acid catalyst (Scheme 1). A simple procedure was also developed for the synthesis of Cuꢀ
MCMꢀ41 as a novel method under mild condition to produce spherical nanoparticles.
Scheme 1 The reaction of aldehydes, hydroxylamine and sodium azide in the presence of Cuꢀ
MCMꢀ41.
Experimental
Catalyst preparation
The synthesis of nanoꢀsized CuꢀMCMꢀ41 was carried out by method of direct insertion of copper
ion in solꢀgel preparation step at room temperature using tetraethyl orthosilicate (TEOS) as the Si
source, cetyltrimethylammonium bromide (CTAB) as the template, ammonia as the pH control
agent and Cu(OAc) .H O as the copper source with the gel composition (mole ratio) of SiO :
2
2
2
CTAB: NH OH: H O: Cu(OAc) .H O = 1.00:0.127:0.623:508:0.1, 0.05 and 0.033 for the
4
2
2
2
preparation of CuꢀMCMꢀ41(0.100), CuꢀMCMꢀ41(0.050) and CuꢀMCMꢀ41(0.033) respectively.
Cetyltrimethylammonium bromide (1.04 g) was dissolved in deionized water (200 mL) under
stirring, and temperature was adjusted to 60 °C for 15 min. To this solution, tetraethyl
orthosilicate (5 mL) was added dropwise and then a solution of Cu(OAc) .H O (appropriate
2
2
amount of copper precursor in 5 mL of deionized water) was added dropwise under vigorous
3

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stirring. Then pH of the solution was adjusted to 10.5 by adding 25 wt% ammonia solution. The
mixture was stirred for 12 h at r.t. The gel was recovered by centrifuging and washed with
ethanol (3 ꢀ 5 mL) and deionized water (3 ꢀ 10 mL). The obtained solid was dried at 120 °C
for 2 h and calcined in air at 550 °C for 4 h. The obtained samples with Cu/Si molar ratio of
0.100, 0.050 and 0.033 were denoted as CuꢀMCMꢀ41(0.100), CuꢀMCMꢀ41(0.050) and Cuꢀ
MCMꢀ41(0.033) respectively.
General procedure for the synthesis of 5-substituted 1H-tetrazoles 4a-o
A mixture of aldehyde (1 mmol), hydroxylamine hydrochloride (1 mmol) sodium azide (1.5
mmol), catalyst (30 mg) and DMF (3 mL) was taken in a 5 mL round bottomed flask and heated
at 140 °C. After completion of the reaction (observed on TLC; nꢀhexane:ethyl acetate, 7:3) the
reaction mixture was cooled to r.t. and separated from the catalyst by centrifugation. The solvent
was removed under reduced pressure and residue was dissolved in water (5 mL) and acidified
with HCl (37%). The precipitate was filtered and crystallized in mixture of water and ethanol.
Further purification with column chromatography was not necessary.
Catalyst characterization
XRD analysis was carried out on a BRUKER D8 ADVANCE using Cuꢀkα (1.54056 Å) radiation
1
13
and the diffractograms were recorded in 0–10 º and 10ꢀ70 º ranges of 2θ. H and C NMR were
recorded in DMSOꢀd on a BRUKER DRXꢀ400 AVANCE spectrometer. Fourier transform
6
infrared (FTꢀIR) spectra were recorded on a BRUKER EQUINOX 55 single beam spectrometer
−
1
at ambient conditions using KBr disks, with a nominal resolution of 4 cm . Scanning Electron
Microscopy (SEM) was obtained using KYKYꢀEM3200 Instrument. Potentiometric data was
collected using pH/mV meter, AZ model86502ꢀpH/ORP. Atomic absorption spectroscopy
analysis was performed by analytic jena nova 300 model 330 Germany.
Analytical Data for 5-(3,5-dimethoxyphenyl)-1H-tetrazole(4l)
1
H NMR (400 MHz, DMSOꢀd ): δ (ppm) = 3.84 (s, 6 H), 6.72 (t, 1 H), 7.21 (d, 2 H), 16.86 (br s,
6
1
3
NH). C NMR (100 MHz, DMSOꢀd ) δ (ppm) = 55.5, 103.0, 104.8, 125.7, 161.0. IR (KBr): ν =
6
4

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645, 680, 753, 846, 931, 1019, 1070, 1166, 1208, 1259, 1285, 1405, 1478, 1559, 1605, 2498,
–1
2
635, 2770, 2939, 3101 cm .
Results and discussion
In this research a new method was developed for the synthesis of 5ꢀsubstituted 1Hꢀtetrazoles by
multiꢀcomponent reaction of aldehydes, hydroxylamine and sodium azide in the presence of Cuꢀ
MCMꢀ41 as reusable solid acid catalyst. CuꢀMCMꢀ41 with Cu/Si molar ratios of 0.100, 0.050
and 0.033 were prepared and their catalytic and textural properties were characterized by XRD,
SEM, FTꢀIR, pyridine adsorption method and potentiometric titration.
Catalysts characterization
The low angle XRD patterns of CuꢀMCMꢀ41 samples with Cu/Si molar ratio of 0.100, 0.050 and
0.033 are shown in Fig. 1. The intensity of the main peak of CuꢀMCMꢀ41 samples was decreased
and the width of the peak was increased with increasing in copper content of the catalysts. Due to
the incorporation of copper into the framework of MCMꢀ41, a decrease in the longꢀrange order
of the hexagonal mesoꢀstructure of MCMꢀ41 was observed and this indicate that copper loading
destroy the crystalline structure of MCMꢀ41. It might be expected that with increasing in ion/Si
molar ratio, the main peak shift to the lower 2θ , but a certain trend is not observed in the various
literatures for other types of metal modified MCMꢀ41 because of using various sol gel methods
3
4, 35
and different size of ions and preparation conditions.
As shown in Fig. 1 high angle XRD pattern of CuꢀMCMꢀ41(0.100) shows slight extent of CuO
in tenorite phase. A lower distinct tenorite phase is also appeared in the pattern of CuꢀMCMꢀ
41(0.050). This fact show high dispersion of copper ions in the MCMꢀ41 framework especially
for CuꢀMCMꢀ41(0.050) relative to CuꢀMCMꢀ41(0.100).
5

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Fig. 1 The XRD patterns of a) CuꢀMCMꢀ41(0.033), b) CuꢀMCMꢀ41(0.050) and c) CuꢀMCMꢀ41(0.100)
Mesostructure of the CuꢀMCMꢀ41 was further studied by TEM. Porosity of the CuꢀMCMꢀ41
(0.050) is well observed in range of the mesoporousity definition. Partial disordered mesoporous
structure respect to hexagonal structure of nude MCMꢀ41 and also nonꢀuniform pore size
distribution is related to the incorporation of Cu in to the MCMꢀ41 framework that confirms by
XRD data.
6

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Fig. 2 TEM image of the CuꢀMCMꢀ41(0.050)
The FTꢀIR absorption spectra of pure silica MCMꢀ41 and Cuꢀincorporated MCMꢀ41 samples
ꢀ1
with different loading amounts of copper are shown in Fig. 3. In the range of 400–1600 cm ,
ꢀ1
ꢀ1
ꢀ1
MCMꢀ41 shows three peaks at 460 cm , 808 cm , and 1089 cm corresponding to the rocking,
bending (or symmetric stretching), and asymmetric stretching of the interꢀtetrahedral oxygen
ꢀ1
atoms in SiO of CuꢀMCMꢀ41, respectively and also the peak at 966 cm is assigned to the
2
ꢀ1
silanol group (Fig. 3a). A slight red shift to of the vibration absorption band at 1089 cm ,
assigned to υ(Si–O–Si), to the lower frequencies in the spectra of CuꢀMCMꢀ41 samples indicates
the formation of SiꢀOꢀCu bond and incorporation of Cu in the framework of MCMꢀ41.
Fig. 3
FTꢀIR spectra of a) MCMꢀ41, b) CuꢀMCMꢀ41(0.100), c) CuꢀMCMꢀ41(0.050) and
d) CuꢀMCMꢀ41(0.033)
Fig. 4 represents the results of scanning electron microscopy (SEM) in order to investigate the
particle size and morphology of the catalysts. The SEM of CuꢀMCMꢀ41 shows spherical
nanoparticles with sizes of <100 nm.
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Fig. 4 SEM image of CuꢀMCMꢀ41(0.050)
In order to obtain a clear distinction between Lewis and Brønsted acid sites, FTꢀIR analysis of
pyridine adsorbed on the catalyst surface were carried out and results are displayed in Fig. 5. The
FTꢀIR spectrum of pyridine adsorbed CuꢀMCMꢀ41(0.050) before heat treatment (Fig. 5b) shows
ꢀ1
the contribution of pyridine adducts in the region of 1400ꢀ1650 cm . In this spectrum, the peaks
ꢀ1
at 1448 and 1598 cm are attributed to pyridine bonded Lewis acid sites of the CuꢀMCMꢀ
ꢀ1
4
1(0.050). The weak peak at 1543 cm , that so hard to find in current zoom, assigned to
Brønsted acid sites (corresponds to protonation of pyridine on Brønsted acid sites). The weak
ꢀ1
peak at 1491 cm is attributed to the combination mode. As shown in Fig 5cꢀg, with increasing
ꢀ1
in temperature, Lewis acidity characteristic peaks are still remained at 1448 and 1598 cm .
These results show that Lewis acidity of the catalyst is stronger than its Brønsted acidity.36
8

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1.2
1.0
0.8
0.6
0.4
0.2
0.0
a)
b)
1
543
c)
d)
e)
f)
g)
1
599 1491
448
1
-0.2
-
0.4
1
800
1600
1400
Wavenumber (cm
1200
1
)
1000
-
Fig. 5 FTꢀIR spectra of a) CuꢀMCMꢀ41(0.050), b) pyridine adsorbed CuꢀMCMꢀ41(0.050) at
ambient temperature and pyridine adsorbed CuꢀMCMꢀ41(0.050) heated at c) 100 °C, d) 200 °C,
e) 300 °C, f) 400 °C and g) 500 °C.
The catalyst acidity characters, including the acidic strength and the total number of acid sites
were determined by potentiometric titration. According to this method, the initial electrode
3
7
potential (Ei) indicates the maximum acid strength of the surface sites. Therefore, a suspension
of the catalyst in acetonitrile was potentiometrically titrated with a solution of 0.02 M nꢀ
butylamine in acetonitrile. As shown in Fig. 6, CuꢀMCMꢀ41(0.050) displays higher strength than
the other samples.
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20
0
-20
-40
-60
-80
Cu-MCM-41(0.100)
Cu-MCM-41(0.050)
Cu-MCM-41(0.033)
-100
-120
-140
-160
-180
0.00
0.10
0.20
meq/g
0.30
0.40
0.50
Fig. 6 Potentiometric titration of (ꢀ) CuꢀMCMꢀ41(0.100), (•) CuꢀMCMꢀ41(0.050) and (ꢀ) Cuꢀ
MCMꢀ41(0.033)
In order to determine effective Cu/Si molar ratios in the products, the prepared catalysts was
analyzed by AAS and calculations show that CuO/SiO molar ratios of the CuꢀMCMꢀ41(0.100),
2
CuꢀMCMꢀ41(0.050) and CuꢀMCMꢀ41(0.033) is 0.093, 0.046 and 0.030 respectively. However,
for simplicity, the sample names were presented by gel composition molar ratios.
Activity measurements
The catalytic activity was investigated in the synthesis of 5ꢀsubstituted 1Hꢀtetrazole through
threeꢀcomponent reaction of aldehyde, hydroxylamine and sodium azide.
To optimize the reaction conditions, initially, the reaction of benzaldehyde, hydroxylamine and
sodium azide was selected as model reaction. The reaction conditions and media have large
effects on the yield and time due to the hard reaction conditions for the synthesis of tetrazoles. In
this research, the solvent and temperature was found to play an important role in promoting of
1
0

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the reaction. The reaction was optimized for various parameters such as temperature, solvent and
catalyst loading. In the all of experiments the reactions were monitored by TLC based on the
consumption of oxime because in the presented method oxime formation is faster than its
reaction with azide for prudution of tetrazole. To investigate the effect of temperature, the
reaction was performed at room temperature and the oxime (from the reaction of hydroxylamine
and aldehyde) was formed rapidly but the corresponding product was not observed in this
temperature. The reaction was also performed at 120, 130, 140 and 150 °C (Table 1, entries 1ꢀ3)
and the best result was obtained at 140 °C. To optimize the catalyst amount, the model reaction
was performed in the presence of various amounts of the catalyst and according to the obtained
results (Table 1, entries 4ꢀ6) 30 mg of the catalyst was chosen as the best catalyst amount. The
effect of solvent was also investigated by performing the model reaction in the presence of 30
mg catalyst in various solvents (Table 1, entries 11ꢀ13). Among them, DMF was found to be the
best solvent (Table 1, entry 3) in terms of the time and yield of desired product. In a blank
reaction, without the catalyst, moderate yield of the product was achieved after long time (Table
1, entry 8). Moderate yield was also obtained while MCMꢀ41 and CuO were applied as the
catalyst (Table 1, entries 9, 10). These result show that copper in MCMꢀ41 lattice play important
catalytic role in this reaction.
To investigate the catalytic activity of CuꢀMCMꢀ41(0.100) and CuꢀMCMꢀ41(0.033), the model
reaction was performed in the presence of these samples in the optimized conditions and results
(Table 1, entries 6, 7) show that these catalysts have considerable lower catalytic activity relative
to CuꢀMCMꢀ41(0.050).
a
Table 1 Screening of the reaction parameters for the synthesis of 5ꢀsubstituted 1Hꢀtetrazole
Reaction
Cu/Si molar
ratio
Catalyst
amount (mg)
30
b
c
Entry
1
Solvent
DMF
Time (h)
Yield (%)
43
temp. (°C
)
120
0.050
24
24
12
12
12
2
3
4
5
130
140
150
140
0.050
0.050
0.050
0.050
30
30
30
20
DMF
DMF
DMF
DMF
64
90
90
75
1
1

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6
7
8
9
140
140
140
140
140
140
140
140
140
140
0.050
0.100
0.033
ꢀ
50
30
30
0
DMF
DMF
12
12
12
24
24
24
24
24
24
24
90
75
60
DMF
d
DMF
45
e
1
0
1
2
3
4
5
CuO
8
DMF
40
35
52
0
1
1
1
1
1
MCMꢀ41
30
30
30
30
30
DMF
DMSO
Ethanol
0.050
0.050
0.050
0.050
H O
2
0
ꢀ
0
a
Reaction conditions: aldehyde (1 mmol), NaN (1.5 mmol), hydroxylamine hydrochloride (1mmol).
Reactions time is based on the consumption of oxime monitored by TLC.
Isolated yield
Reaction performed without catalyst.
3
b
c
d
e
The reaction was carried out in the presence of 10 mol% of CuO.
Thereafter, the above optimized reaction conditions were explored for the synthesis of 5ꢀ
substituted 1Hꢀtetrazole derivatives and the results are summarized in Table 2. As exemplified in
Table 2, this protocol is rather general for a wide variety of electronꢀrich as well as electronꢀ
deficient aromatic aldehydes. The better results were observed for aldehydes containing electronꢀ
donating substituent. Steric hindrance of substrate is an important factor in yield and time of the
reaction. For instance, time and yield of the reaction for 4ꢀchloro benzaldehyde and 2ꢀchloro
benzaldehyde show this fact.
a
Table 2 CuꢀMCMꢀ41 catalyzed synthesis of 5ꢀsubstituted 1Hꢀtetrazole
1
2

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b
c
ref
Entry
Substrate 1
Product 4
Time
Yield
(%)
90
M.p. (°C)
(h)
3
9
3
3
3
8
a
b
c
d
e
12
218ꢀ219
3
H
12
12
9
91
85
92
80
251ꢀ252
N
N
N
N
9
9
9
231ꢀ232
252ꢀ253
137ꢀ139
11
4
4
0
1
f
18
10
80
88
180ꢀ182
154ꢀ156
g
1
4
9
0
h
i
12
10
85
94
218ꢀ220
154ꢀ155
1
4
9
2
j
14
10
87
85
234ꢀ235
224ꢀ225
k
1
3

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3
9
l
10
85
210ꢀ213
4
4
3
3
3
4
8
8
m
n
5
5
82
87
85
75
205ꢀ206
199ꢀ201
212ꢀ214
154ꢀ156
o
13
12
p
a
Reaction conditions: aldehyde (1 mmol), NaN (1.5 mmol), hydroxylamine hydrochloride (1 mmol), CuꢀMCMꢀ
3
4
1(0.050) (30 mg) and temperature (140 ºC).
b
Reactions time is based on the consumption of oxime monitored by TLC.
Isolated yield
c
One of the most important features of our method is easy workup and purification of products.
After completion of the reaction, the catalyst was separated and the solvent was evaporated.
Thereafter, the residue was acidified and product crystallized in mixture of water and ethanol.
Further purification with column chromatography was not necessary.
Regeneration and reusability of the catalyst
The most important benefit of the applied catalyst is reusability. Thus the recovery and
reusability of the catalyst was investigated in the model reaction under the optimized reaction
conditions. The catalyst was separated from the reaction mixture by centrifugation and reused
three times with moderate loss of the catalytic activity (Table 3). Partial loss of the catalyst
activity is probably due to the coke depositions and slight amount of copper leaching from the
catalyst.
Table 3 Reusability of CuꢀMCMꢀ41(0.050) in the model reaction.
Entry
Fresh
90
Cycle 1
85
Cycle 2
80
Cycle 3
78
Yield (%)
Time(h)
12
12
12
12
1
4

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Conclusion
We introduced a simple method for the synthesis of copper modified molecular sieves with
MCMꢀ41 structure at room temperature without using hydrothermal condition. Three different
CuꢀMCMꢀ41 with Cu/Si molar ratios of 0.100, 0.050 and 0.033 was prepared and characterized
by XRD, FTꢀIR, SEM, pyridine adsorption and potentiometric titration. The catalysts were
applied in a novel method for the synthesis of 5ꢀsubstituted 1Hꢀtetrazoles through oneꢀpot multiꢀ
component reaction of aldehyde, hydroxylamine and sodium azide with excellent to good yields.
The results show that CuꢀMCMꢀ41(0.050) has the best catalytic activity in agreement with the
characterization results. The simple experimental procedure, using aldehydes as simpler starting
materials than the nitriles, easy workup, ease of the catalyst recovery and reusability make this
method attractive for the synthesis of tetrazoles.
Acknowledgment
We are thankful to the Yazd University Research Council for partial support of this work.
References
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New Journal of Chemistry
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DOI: 10.1039/C4NJ01042F
A new method was developed for the synthesis of 5-substituted 1H-tetrazoles in the presence of copper
modified MCM-41, as the heterogeneous and reusable nano structured catalyst .