The influence of ultrasonic irradiation on catalytic performance of ZnO nanoparticles toward the synthesis of chiral 1-substituted-1H-tetrazolederivatives from α-amino acid ethyl esters

Article abstract of DOI:10.1002/aoc.5758

In this work, a simple and greener protocol for the synthesis of 1-substituted 1H-tetrazole derived from α-amino acid ethyl esters was demonstrated in the presence of zinc oxide nanoparticles (ZnO NPs) under conventional conditions, with heating (at 60 and 80°C and under reflux) compared with ultrasonic. The effect of solvent was investigated to reveal that the solvent system CH₃CN/H₂O was optimum to obtain 1-substituted 1H-tetrazole in high yield. In addition, the effect of irradiation power was studied, which showed that the yield of the reaction was improved at 200 W and the reaction time was shortened to be 30 min. Also, an improvement in the rate of the reaction and the yield of the products was observed when reactions were carried out under sonication conditions in the presence of ZnO NPs compared with conventional methods using various zinc salts as catalysts. The yields of tetrazole compounds 2a–i under sonication were determined (88–96percent). Furthermore, the investigated heterogeneous catalytic system was recycled and reused for five runs with significant production of tetrazole 2a as a model target compound in excellent yields at each reaction cycle. In general, the investigated synthetic strategy for the heterocyclization of α-amino acid ethyl ester derivatives to 1-substituted 1H-tetrazoles was in agreement with the green chemistry point of view.

Full text of DOI:10.1002/aoc.5758

Received: 3 February 2020
DOI: 10.1002/aoc.5758
Revised: 10 April 2020
Accepted: 12 April 2020
F U L L P A P E R
The influence of ultrasonic irradiation on catalytic
performance of ZnO nanoparticles toward the synthesis of
chiral 1-substituted-1H-tetrazolederivatives from α-amino
acid ethyl esters
Yasser Mahmoud A. Mohamed1
| Yasser A. Attia2
1Photochemistry Department, National
Abstract
Research Center, Dokki, Giza, 12622,
Egypt
In this work, a simple and greener protocol for the synthesis of 1-substituted
1H-tetrazole derived from α-amino acid ethyl esters was demonstrated in the
presence of zinc oxide nanoparticles (ZnO NPs) under conventional condi-
tions, with heating (at 60 and 80ꢀC and under reflux) compared with ultra-
sonic. The effect of solvent was investigated to reveal that the solvent system
CH3CN/H2O was optimum to obtain 1-substituted 1H-tetrazole in high yield.
In addition, the effect of irradiation power was studied, which showed that the
yield of the reaction was improved at 200 W and the reaction time was short-
ened to be 30 min. Also, an improvement in the rate of the reaction and the
yield of the products was observed when reactions were carried out under son-
ication conditions in the presence of ZnO NPs compared with conventional
methods using various zinc salts as catalysts. The yields of tetrazole com-
pounds 2a–i under sonication were determined (88–96%). Furthermore, the
investigated heterogeneous catalytic system was recycled and reused for five
runs with significant production of tetrazole 2a as a model target compound in
excellent yields at each reaction cycle. In general, the investigated synthetic
strategy for the heterocyclization of α-amino acid ethyl ester derivatives to
1-substituted 1H-tetrazoles was in agreement with the green chemistry point
of view.
2National Institute of Laser Enhanced
Sciences, Cairo University, Giza, 12613,
Egypt
Correspondence
Yasser Mahmoud A. Mohamed,
Photochemistry Department, National
Research Center, Dokki, Giza 12622,
Egypt.
Email: y.m.a.mohamed@outlook.com
Yasser A. Attia, National Institute of Laser
Enhanced Sciences, Cairo University,
Giza, 12613, Egypt.
Email: yasserniles@niles.edu.eg
K E Y W O R D S
nanocatalysts, tetrazoles, ultrasonic-assisted, ZnO NPs, α -amino acid ethyl esters
1 | INTRODUCTION
several studies have reported that the sonication of mul-
ticomponent reactions can lead to accelerated reaction
The sonochemical approach in the synthesis of heterocy-
clic rings has received significant attention in recent
years.[1,2] The strategy of ultrasound offers many advan-
tages to promote the design and development of sensitive
molecules and it has also assisted in obtaining the prod-
ucts in high yields and selectivity.[3,4] In recent years,
rates via the formation and adiabatic collapse of transient
cavitation bubbles. The ultrasonic effect induces very
high local pressure and temperatures inside the bubbles
and enhances mass transfer and turbulent flow in the liq-
uid.[5–8] Another important factor that affects the results
of chemical reactions is the use of heterogeneous
Appl Organomet Chem. 2020;e5758.
wileyonlinelibrary.com/journal/aoc
© 2020 John Wiley & Sons, Ltd.
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https://doi.org/10.1002/aoc.5758

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MOHAMED AND ATTIA
catalysts that could offer many advantages from both eco-
nomic and environmental points of view.[9] ZnO
nanoparticles have been considered one of the most
promising nanocatalysts because of their wide band-gap
energy, physical and chemical stability, high oxidative
capacity, low cost and ease of availability.[10,11] As a con-
tinuation of our previous work on the development of
heterogeneous catalytic systems for the synthesis of bene-
ficial organic compounds,[12–16] we aimed in this study to
synthesize a series of 1-substituted-1H-tetrazoles derived
from some α-amino acid ethyl ester derivatives through
the utility of zinc oxide nanoparticles (ZnO NPs) as an
efficient nanocatalyst under sonication conditions. Cur-
rently, scientists are seeking to develop new methods for
the synthesis of tetrazole and its derivatives through fac-
ile, eco-friendly and low-cost approaches to testing these
tetrazoles in applications. Hence, new synthetic
approaches for the rational design of polyfunctional
materials based on a tetrazole nucleus to improve the
classical procedures for the preparation of tetrazole deriv-
atives have been reported in various studies.[17–21]
Tetrazoles were first synthesized the heterocycle in 1885
through the reaction of hydrazoic acid and hydrogen cya-
nide under pressure.[22] In 1961, the Ugi-azide procedure
was developed, which yielded 1,5-disubstituted tetrazole
derivatives through a multicomponent reaction.[23] A rel-
atively simple synthetic method for the preparation of
1-substituted tetrazoles was developed in 1973 that
included the heterocyclization reaction of primary
amines and their salts with orthoesters and sodium azide
in the presence of acetic acid[24] (Scheme 1).
Afterward this, research on the synthesis of tetrazole
compounds began to develop rapidly and tetrazole deriv-
atives have attracted interest.[25–29] Few reports on the
application of heterogeneous catalysts in the direct syn-
thesis of 1-substituted-1H-tetrazoles have been described
in the literature,[30–32] although there are some studies
related to the preparation of 1-substituted-1H-tetrazoles
from amines using various conditions, especially using
heterogeneous nanocatalysts.[33–38] Hence, the develop-
ment of efficient heterogeneous catalytic systems for the
promotion of the cyclization of primary amines to
tetrazoles is much needed.
2 | EXPERIMENTAL
2.1 | Materials and methods
All chemicals were obtained from Sigma-Aldrich and
used without further purification. Thin-layer chromatog-
raphy was performed using silica gel plates (60 GF254)
and cellulose plates (20 × 20 cm). The infrared spectra
were recorded as a thin film on a PerkinElmer Fourier
transform infrared (FTIR) spectrometer. The nuclear
magnetic resonance (NMR) spectra were obtained on a
1
Bruker Avance DPX (300 MHz for H and 75 MHz for
and 13C). The chemical shift data are reported in parts
SCHEME 1 Synthetic
strategies in the synthesis of
tetrazoles

MOHAMED AND ATTIA
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per million (ppm) downfield from tetramethylsilane.
DMSO-d6 was as a partially deuterated-NMR solvent.
High-resolution mass spectrometry (HRMS) analysis was
performed using a 6230 series accurate-masstime-of-flight
liquid chromatography (LC)/MS system. To resolve the
enantiomers, an LC/MS-compatible mobile phase system
was used on an Astec Chirobiotic® T column. UV–vis
spectra were recorded on a Hewlett-Packard 8452A
diode-array spectrophotometer. X-ray diffraction (XRD)
measurements were performed using a Philips PW1710
X-ray diffractometer using Cu Kα radiation (k = 1.54186
Å). The XRD patterns were recorded from 20 to 70ꢀ 2H,
with a step size of 0.020ꢀ 2H and collecting 10 s per step.
Transmission electron microscopy (TEM) micrographs of
the colloidal particles were measured using a Jeol JEM-
2100 of 200 kV with a magnification range of 1000× to
50,000×. The TEM samples were prepared and placed on
a copper grid by mixing one dilute drop of prepared aque-
ous particles dispersed in 5 ml acetone to produce a
slightly turbid solution that was allowed to dry thor-
oughly. Scanning electron microscopy (SEM) images
were obtained with a Zeiss FE-SEM ULTRA Plus
(equipped with an EDX analyzer) microscope with a
Philips CM20 microscope, operating at an accelerating
voltage of 200 kV. Several drops from the sample disper-
sion were deposited onto an aluminum pin stub and left
to evaporate at room temperature.
(1.5 mmol) and triethyl orthoformate (1.0 mmol). The
reaction mixture was performed under the following con-
ditions: (a) stirred at room temperature for 24 h; (b)
stirred at different temperatures—60 and 80ꢀC—and
under reflux conditions for 24 h; and (c) subjected to son-
ication using a multiwave ultrasonic generator operating
at 20 kHz with a maximum power output of 200 W for
30 min. The reaction was monitored by thin-layer chro-
matography. The reaction mixture was extracted with
ethyl acetate (3 × 15 ml). Under vacuum, the combined
organic layers were dried over sodium sulfate, filtered
and concentrated. The residue was purified using cold
crystallization (ethyl acetate/hexanes) to afford tetrazole
compounds 2a–i in excellent yields.
2.3.2 | Ethyl 2-(1H-tetrazol-1-yl)acetate
(2a)
1H NMR (300 MHz, DMSO-d6) δ (ppm): 1.33 (t, 3H,
J = 6.8 Hz), 3.56 (q, 2H, J = 6.8 Hz), 4.12 (s, 2H), 8.09 (s,
1H tetrazole); 13C NMR (75 MHz, DMSO-d6) δ (ppm):
14.0, 52.7, 62.9, 148.8, 172.9; m/z (HRMS): calcd for
C5H8N4O2: 156.0647; found: 157.1071 [M + H]+.
2.3.3 | (R)-Ethyl2-(1H-tetrazol-1-yl)
propanoate (2b)
2.2 | Synthesis of ZnO nanoparticles[39]
1H NMR (300 MHz, DMSO-d6) δ (ppm): 1.29 (t, 3H,
J = 6.8 Hz, CH3), 2.55 (d, 3H, J = 5.6 Hz, CH3), 3.54 (q,
1H, J = 5.6 Hz, CH), 4.11 (q, 2H, CH2, J = 6.8 Hz), 8.11
(s, 1H tetrazole); 13C NMR (75 MHz, DMSO-d6) δ (ppm):
14.1, 14.3, 54.5, 61.9, 146.6, 176.4; m/z (HRMS): calcd for
C6H10N4O2: 170.0804; found: 171.0974 [M + H]+.
Zinc oxide nanoparticles were prepared by a chemical
reduction of zinc precursor, using ascorbic acid,
trisodium citrate and NaOH. Briefly, 100 ml deionized
water containing 50 mM trisodium citrate and 4 mM
ascorbic acid was brought to boiling under stirring condi-
tions. To this solution, 3 ml of 2.5 M zinc sulfate solution
was added drop-wise at the rate of 0.2 ml/min. The color
of the solution changed from pale to bright white. By the
addition of 1.0 ml of 2 M NaOH solution, the color chan-
ged to white, indicating the onset of ZnO NP synthesis.
The ZnO NP suspension was centrifuged at 9000 rpm for
15 min followed by washing of the pellet two or three
times with Milli-Q water.
2.3.4 | (R)-Ethyl-3-methyl-2-(1H-tetrazol-
1-yl)butanoate (2c)
1H NMR (300 MHz, DMSO-d6) δ (ppm): 1.09 (m, 6H,
2CH3), 1.42 (t, 3H, J = 6.8 Hz, CH3), 2.64–2.76 (m, 1H,
CH), 4.18 (q, 2H, J = 6.8 Hz), 4.92 (t, 1H, J = 4.2 Hz, CH),
8.24 (s, 1H tetrazole); 13C NMR (75 MHz, DMSO-d6) δ
(ppm): 13.6, 18.7, 20.3, 24.5, 69.7, 145.1, 175.7; m/z (HRMS):
calcd for C8H14N4O2: 198.1116; found: 199.1209 [M + H]+.
2.3 | Synthesis of tetrazole derivatives
2.3.1 | Optimized reaction conditions
2.3.5 | (R)-4-Methyl-2-(1H-tetrazol-1-yl)
pentanoic acid (2d)
To a mixture of appropriate α-amino acid ethyl ester
hydrochloride salts (1.0 mmol) and ZnO NPs (5 wt%) in
CH3CN (3 ml) and H2O (3 ml), was added solid NaN3
1H NMR (300 MHz, DMSO-d6) δ (ppm): 0.87–1.01 (m,
6H, 2CH3), 1.46 (t, 3H, J = 6.8 Hz, CH3), 1.82–2.03 (m,

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MOHAMED AND ATTIA
1H, CH), 4.17 (q, 2H, J = 6.8 Hz), 4.88 (t, 1H, J = 4.2 Hz,
CH), 8.66 (s, 1H tetrazole); 13C NMR (75 MHz, DMSO-
d6) δ (ppm): 13.6, 21.4, 24.0, 25.8, 42.7, 67.1, 144.7, 176.1;
m/z (HRMS): calcd for C9H16N4O2: 212.1273; found:
213.1197 [M + H]+.
m/z (HRMS): calcd for C9H12N6O2: 236.1022; found:
236.1274 [M + H]+.
2.3.10 | (R)-3-(1H-indol-3-yl)-2-(1H-
tetrazol-yl)propanoic acid (2i)
2.3.6 | (R)-ethyl 3-hydroxy-2-(1H-tetrazol-
1-yl)propanoate (2e)
1H NMR (300 MHz, DMSO-d6) δ (ppm): 1.39 (t, 3H,
J = 6.8 Hz, CH3), 3.72–3.87 (m, 2H, CH2), 4.16 (q, 2H,
J = 6.8 Hz), 4.97 (dd, J = 4.2 Hz, 1H, CH), 6.81–6.94 (m,
4H, indole ring), 7.29–7.43 (m, 1H, indole), 8.64 (s, 1H
tetrazole), 10.16 (br, s, 1H, NH); 13C NMR (75 MHz,
DMSO-d6) δ (ppm): 13.8, 28.7, 62.8, 109.2, 111.8, 116.1,
118.4, 121.3, 122.9, 126.3, 136.5, 144.3, 175.2; m/z
(HRMS): calcd for C14H15N5O2: 285.1266; found:
286.1502 [M + H]+.
1H NMR (300 MHz, DMSO-d6) δ (ppm): 1.27 (t, 3H,
J = 6.8 Hz, CH3), 2.37 (br, s, 1H, OH), 3.65 (q, 2H,
J = 6.8 Hz), 3.91 (d, J = 4.2 Hz, 2H, CH2), 4.62 (t, 1H,
J = 4.2 Hz, CH), 8.21 (s, 1H tetrazole); 13C NMR
(75 MHz, DMSO-d6) δ (ppm): 13.6, 44.3, 53.2, 60.7, 148.5,
176.8; m/z (HRMS): calcd for C6H10N4O3: 186.1710;
found: 187.2023 [M + H]+.
2.4 | Catalyst recyclability
2.3.7 | (R)-ethyl 3-phenyl-2-(1H-tetrazol-
1-yl)propanoate (2f)
After completion of the reaction, the mixture was diluted
by H2O–EtOAc (v/v, 1:1, 10 ml), stirred at ambient tem-
perature (20 min) and filtered to collect the catalyst. The
solid catalyst was dried at room temperature under
reduced pressure to obtain almost quantitatively ZnO
nanoparticles.
1H NMR (300 MHz, DMSO-d6) δ (ppm): 1.39 (t, 3H,
J = 6.8 Hz, CH3), 3.25 (d, J = 4.2 Hz, 2H, CH2), 4.18 (q,
2H, J = 6.8 Hz, CH2), 4.61 (t, J = 4.2 Hz, 1H, CH), 7.29–
7.56 (m, 5H), 8.19 (s, 1H tetrazole); 13C NMR (75 MHz,
DMSO-d6) δ (ppm): 13.9, 44.3, 53.4, 60.9, 127.6, 128.9,
129.8, 131.9, 146.4, 143.5, 175.6; m/z (HRMS): calcd for
C12H14N4O2: 246.1117; found: 247.1610 [M + H]+.
3 | RESULTS AND DISCUSSION
3.1 | Catalyst preparation and
characterization
2.3.8 | (R)-ethyl 3-(4-hydroxyphenyl)-
2-(1H-tetrazol-1-yl)propanoate (2g)
The TEM image of ZnO NPs is depicted in Figure 1. It
was observed that ZnO NPs have a spherical structure
with a mean diameter ranging from 35 to 44 nm
(Figure 1a). SEM images with the mapping of the
ZnO NPs are shown in Figure 1b–d, confirming the
results from the TEM image. The chemical composi-
tion of ZnO NPs was analyzed by energy dispersive
spectrometry on an SEM (Figure 1e). The result
shows the peaks of O, and Zn at 28.42 and 72.58 wt%,
respectively, confirming that the sample is of high
purity.
1H NMR (300 MHz, DMSO-d6) δ (ppm): 1.32 (t, 3H,
J = 6.8 Hz, CH3), 3.14 (d, J = 4.2 Hz, 2H, CH2), 4.11 (q,
2H, J = 6.8 Hz), 4.72 (t, J = 4.2 Hz, 1H, CH), 5.64 (br, s,
1H, OH), 7.21–7.53 (m, 4H), 8.14 (s, 1H tetrazole); 13C
NMR (75 MHz, DMSO-d6) δ (ppm): 14.1, 46.3, 54.5, 61.6,
128.6, 129.3, 134.5, 146.23, 155.2, 177.6; m/z (HRMS):
calcd for C12H14N4O3: 262.1066; found: 263.1185
[M + H]+.
2.3.9 | (R)-ethyl 3-(1H-imidazol-4-yl)-
2-(1H-tetrazol-1-yl)propanoate (2h)
The UV–vis spectrum of the prepared ZnO NPs is
shown in Figure 2a. It is clear that ZnO NPs are semi-
conductors with a wide bandgap (3.3 eV) that makes
them a suitable absorber of UV radiation exhibiting a
sharp band at 375 nm.[14] The XRD pattern of the as-pre-
pared ZnO NPs is depicted in Figure 2b. The diffraction
peaks are quite similar to those of bulk ZnO, which can
be indexed as the hexagonal wurtzite structure ZnO
(a = 3.249 Å, c = 5.206 Å) and diffraction data were in
1H NMR (300 MHz, DMSO-d6) δ (ppm): 1.39 (t, 3H,
J = 6.8 Hz, CH3), 3.39–3.43 (m, 2H, CH2), 4.16 (q, 2H,
J = 6.8 Hz), 4.91 (dd, J = 4.2 Hz, 1H, CH), 5.11 (br, s, 1H,
NH), 6.35 (s, 1H, imidazole ring), 7.39 (s, 1H imidazole),
8.36 (s, 1H tetrazole); 13C NMR (75 MHz, DMSO-d6) δ
(ppm): 13.8, 30.6, 64.7, 116.8, 133.6, 134.5, 145.2, 176.8;

MOHAMED AND ATTIA
5 of 12
FIGURE 1 Transmission electron microscopy image of the synthesized zinc oxide nanoparticles (ZnO NPs) (a) and scanning electron
microscopy images of ZnO NPs (b–d) with energy dispersive spectrometry analysis of ZnO NPs (e)
FIGURE 2 Absorption spectrum (a), X-ray diffraction pattern (b) and Fourier transform infrared spectrum (c) of ZnO nanoparticles
agreement with the JCPDS card for ZnO (JCPDS
36-1451). No other peaks were detected, implying that
the prepared nanostructure materials are pure ZnO.[40]
The XRD pattern of the as-prepared ZnO NPs is shown
in Figure 2b and shows the presence of wurtzite ZnO
owing to presence of three distinct features: the first at
2θ = 36.252ꢀ is due to (101) reflection of planes and
2θ = 34.440ꢀ and 56.555ꢀ are due to (200) and (011)
reflection of planes, respectively. The FTIR spectrum of
ZnO NPs was recorded in the range 390–4000 cm−1
(Figure 2c). A significant vibration band ranging from
400 to 500 cm−1 was assigned to the characteristic
stretching mode of the Zn–O bond. The broad peak
3434 cm−1 (stretching) indicates the presence of hydroxyl
groups of absorbed H2O molecules.
3.2 | Catalytic performance of ZnO NPs
towards the synthesis of 1-substituted-1H-
tetrazole derivatives from α-amino acid
ethyl esters
Various parameters were studied, such as solvent system,
irradiation power, catalyst loading and irradiation time,
and a comparison was made between the catalytic activity
of ZnO NPs and other Zn precursors to obtain the

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MOHAMED AND ATTIA
optimum reaction conditions for heterocyclization of some
of α-amino acid ethyl esters to their corresponding
tetrazoles.
contrast to the other solvents used in this protocol that
could attenuate these waves.[43]
3.2.2 | The influence of ultrasound
irradiation powers on progress of the
reaction
3.2.1 | Effect of solvent and temperature
on the synthesis of tetrazoles
The initial step of this synthetic protocol was started by
exploring optimized reaction conditions. In the first series
of experiments, our effort was focused on determining an
appropriate solvent for performing the reaction. Thus,
the reaction of glycine ethyl ester (1a) with triethyl
orthoformate [HC (OEt)3] and sodium azide (NaN3) in
the presence of ZnO NPs (1 wt%) was selected as a model
reaction. Initially, the effect of different solvents under
three different reaction conditions—room temperature,
heating and sonication—was screened for preparation of
the corresponding ethyl 2-(1H-tetrazol-1-yl)acetate (2a)
(Scheme 2 and Table 1).
The effect of the ultrasound power irradiation on the
yield of the product 2a was investigated by performing
the reaction at different irradiation powers from 0 to
200 W at 20 kHz. It was demonstrated that, as seen from
Table 2, the increase in ultrasonic power to 200 W led to
a relatively higher yield (90%) at a shorter reaction time
(60 min). From these results, it was indicated that the
rate of the reaction increased when the irradiation power
increased.
3.2.3 | Effect of catalyst loading
In this protocol, when the model reaction was
employed under solvent-free conditions after 24 h at
room temperature and at 100ꢀC, or even if the reaction
was performed under sonication conditions for 8 h, the
reaction was not conducted (entry 1). It was also found
that the solvents like DMF, THF, EtOH and H2O were
inappropriate for the progress of this reaction (Table 1,
entries 3–6). As observed in Table 1, different solvents
were used under various conditions. However, the
highest yield of product 2a was obtained in 76 and 87%,
respectively, when the CH3CN and CH3CN–H2O solvents
were used under ultrasound irradiation (entry 7). The
reaction temperature was taken into account during the
progress of the reaction. It was demonstrated that com-
pound 2a was obtained in low to moderate yields when
the reaction was performed at room temperature or
under elevated temperatures (60 and 80ꢀC and under
reflux condition) (Table 1, entries 2–7). This indicated
that the increase in the reaction temperature had no dis-
tinguishable effect on the progress of the model reaction.
However, the yield of 1H-tetrazole (2a) was dramatically
improved when CH3CN/H2O solvent was used under the
sonication conditions. This enhancement of the reaction
yield resulted because the dielectric constant of CH3CN
was 38.8[41] and the dielectric constant of water is 78.4 at
25ꢀC.[42] Hence, the CH3CN/H2O system could be
affected in the acceleration of longitudinal ultrasonic
waves and consequently the ZnO nanoparticles, in
To investigate the ideal conditions, the effect of ZnO NPs
loading at irradiation power 200 W was studied (Table 3).
In Table 3, it is shown that the yield of product 2a
was dramatically improved. The increase in the catalyst
loading to 7 wt% (Table 3, entry 6) led to the same yield
as obtained in the case of catalyst loading (5 wt%). This
indicated that the best yield of product 2a was obtained
when the amount of catalyst was 5 wt% (Table 3, entry
5). The results indicated that merging between ultra-
sound irradiation method and ZnO nanoatalyst method
ameliorates the product yield and reaction time.
3.2.4 | Investigation of the relationship
between the irradiation time and the yield
of the product
The effect of sonication time on the yield of the product
2a was also investigated by carrying out six experiments
in which the reaction mixture was exposed to ultrasound
irradiation for appropriate times (0, 5, 10, 15, 20, 25 and
30 min). These experiments revealed that the increase in
irradiation time led to a relatively higher yield (Table 4).
A possible explanation for the positive association
between yield and time of ultrasound irradiation is that
the increase in the exposure time could increase the yield
of the product. In other words, the number of active
SCHEME 2 Model reaction

MOHAMED AND ATTIA
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TABLE 1
Effect of solvents under room temperature, heating method or sonication conditions (75 W) on the synthesis of ethyl
2-(1H-tetrazol-1-yl)acetate (2a) from glycine ethyl ester (1a)a zinc oxide nanoparticles (ZnO NPs) as a catalyst
Reaction conditions
Room temperature, time (h)/
yield (%)c
Heating method, T (ꢀC)/time (h)/
yield (%)c
Sonication, time (h)/yield
(%)c
Entry Solvent
1
Solvent
freeb
24/NRd
100/24/NR
8/NR
2
CH3CN
DMF
24/18
60/24/39
8/76
8/45
80/24/43
reflux/24/52
60/24/traces
80/24/27
3
24/tracese
Reflux/24/28
60/24/38
4
5
6
THF
EtOH
H2O
24/12
8/43
8/25
8/34
Reflux/24/40
60/24/19
24/NR
24/NR
Reflux/24/22
60/24/26
80/24/26
Reflux/24/28
60/24/69
7
CH3CN/
H2O
24/39
8/87
80/24/74
reflux/24/83
DMF; dimethylformamide, THF; tetrahedrofuran, EtOH; ethanol.
aReaction conditions: α-amino acid ethyl ester, 1 mmol; sodim azide, 1.5 mmol; HC(OEt)3, 1 mmol; ZnO NPs, 1 wt%; solvent, 6 ml.
bThe reaction was tested in a sealed tube.
cIsolated yield.
dNo reaction.
eTrace = the yield of the product was <10%.
synthesis of 1H-tetrazoles. Zinc chloride was used to
synthesize amino-tetrazole compounds from cyana-
mides under ultrasound conditions at 70–80ꢀC to
afford products in 73–80% isolated yields after 15 h.[44]
Also, it was reported that commercial ZnO was used in
stoichiometric amounts to promote the synthesis of
TABLE 2
The effect of ultrasonic irradiation power on the
synthesis of 2a using ZnO NPs (1 wt%) and CH3CN/H2O solvent
Power (W)
Yield (%)a
Time (min)
0
0
75
87
150
88
200
90
480
480
120
60
aIsolated yields.
TABLE 3
Effect of ZnO nanocatalyst loading under
cavitation bubbles and the size of the individual bubbles
are both expected to result in higher maximum collapse
temperature and accelerated respective reaction[21]
(Figure 3).
sonication conditions (200 W) in CH3CN/H2O solvent system
ZnO NPs loading
Entry (wt%)
Time
Yield (%)
a
(min)
1
2
3
4
5
6
1
2
3
4
5
7
60
60
45
45
30
30
90
92
92
93
96
96
3.2.5 | Catalytic activity of ZnO NPs vs.
zinc salts
A comparison was made between our investigated
methodology in this study and previously reported
methods in which zinc was used as the catalyst for the
aIsolated yields.

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MOHAMED AND ATTIA
TABLE 4
The effect of ultrasonic irradiation (200 W) time on
TABLE 5
A comparison between the catalytic potency of ZnO
the synthesis of 2a using ZnO NPs (5 wt%) and CH3CN/H2O
NPs with commercial ZnO and zinc salts under ultrasonic
irradiation (200 W) for 30 min
solvent
Entry
Time (min)
Yield (%)a
Entry
Catalyst
ZnO NPs
ZnO
Yield (%)a
1
2
3
4
5
6
7
0
5
0
38
45
53
76
92
96
1
2
3
4
5
6
7
96
49
43
37
38
36
35
10
15
20
25
30
ZnCl2
ZnBr2
ZnI2
ZnSO4
Zn (OAc)2
aIsolated yields.
aIsolated yield.
tetrazole under conventional methods at 120ꢀC to pro-
duce tetrazoles in 73–8% isolate yields at 2 h.[45] In our
method, product formation was completely pure and
solely regioselective 1-substituted-1H-tetrazoles from
some α-amino acid ethyl esters were obtained without
the need for chromatographic separation. Hence, a
series of experiments were performed to confirm the
potential catalytic activity of ZnO NPs (5 wt%) as het-
erogeneous nanocatalysts in comparison with com-
mercial zinc oxide (5 wt%) (Table 5, entry 2) and
different zinc salts (5 wt%) (Table 5, entries 3–7) under
the optimized reaction conditions at 30 min.
3.3 | Recyclability of ZnO nanocatalyst
Recycling of the catalyst from the reaction is one of
the important benefits of green chemistry. We studied
the recovery and reusability of catalyst. The reaction
was carried out with glycine ethyl ester, triethyl
orthoformate and sodium azide as a model reaction in
the presence of ZnO NPs under optimized conditions.
The reusability of catalysts was investigated and they
were reused five times with a minimal loss of activity
(Table 6).
Interestingly, product 2a was obtained in 96, 49,
43, 37, 38, 36 and 35, respectively, for the use of ZnO
NPs, commercial ZnO, ZnCl2, ZnBr2, ZnI2, ZnSO4 and
Zn (OAc)2 (Table 5, entries 1–7). It can be postulated
that the surface of ZnO NPs can provide suitable bind-
ing sites for the reactants which has a significant role
in reaction progress compared with the commercial
ZnO and other zinc salts that do not possess large sur-
face area, as in the case of ZnO NPs.
3.4 | Reaction mechanism
A proposed reaction mechanistic aspect for the pre-
sent work is depicted in Scheme 3. It is obvious that
ZnO NPs was coupled with triethyl orthoformate (A)
to produce intermediate (B). The second step was the
formation of intermediate (C) through the attack of
the amine group present in α-amino acid ethyl ester.
FIGURE 3 Relationship between the times
of irradiation and the obtained yield of
compound 2a

MOHAMED AND ATTIA
9 of 12
TABLE 6
The reusability of ZnO NPs (5 wt%) for the
3.5 | Ultrasound-assisted series of
1-substituted-tetrazoles derived from α-
amino acid ethyl ester derivatives
synthesis of 2a under ultrasonic irradiation (200 W)
Run no.
Yield (%)a
1
2
3
4
5
96
95
94
92
92
The investigated method was employed for the synthesis
of other 1-substituted-tetrazoles derived from L-alanine
ethyl ester (2b), L-valine ethyl ester (2c), L-leucine ethyl
ester (2d), L-serine ethyl ester (2e), L-phenylalanine ethyl
ester (2f), L-tyrosine ethyl ester (2 g), L-histidine ethyl
ester (2 h) and L-tryptophan ethyl ester (2i) under opti-
mum reaction conditions (catalyst, 5 wt%), as well as
ethyl ester of α-amino acid (1.0 mmol) and sodium azide
(1.5 mmol in MeCN/H2O, 6.0 ml, 1:1) under ultrasound
irradiation (200 W) for 30 min to obtain compounds 2b–
2i in excellent yields (Scheme 4). The yields of the
obtained products are shown in Table 7. It was observed
that the reactions of amino acid ethyl ester substrates
were performed without loss of optical purity. The chiral-
ity was determined using chiral HPLC, which showed
that the as-prepared tetrazole analogs were optically pure
within limits of detection (Table 7).
As seen from the results, different substitutions on
tetrazole ring could be developed through the utility of
an ultrasonication procedure in the presence of recycla-
ble ZnO nanocatalyst under the investigated optimal
reaction condition. These results were in accordance with
reported method in which zinc sulfide nanoparticles were
used for heterocyclization of some primary amines to 1H-
tetrazole derivatives under ultrasound.[48] It can be stated
that ZnO NPs can provide heterocyclization of α-amino
acid ethyl esters in a mild, clean, fast, novel and safe
sonochemical procedure for synthesis of 1-substituted
1H-tetrazole derivatives.
aIsolated yield.
Then the reaction could proceeded rapidly to produce
intermediate (F), which underwent heterocyclization
to yield tetrazole compound (G) (Scheme 3). This pos-
tulated mechanism was in accordance with the previ-
ous report.[46] However, this strategy facilitates
synthesisis of tetrazole derivatives from α-amino acid
ethyl esters under mild reaction conditions through
the combination of ultrasound irradiation with ZnO
nanoparticles, which has advantages from environ-
mental and economical points of view over the
reported synthetic pathway that was used for Cu
nanoparticles which were produced through complex
methods to perform heterocyclization of α-amino acid
ethyl esters to tetrazoles at 80ꢀC in 64–90% isolated
yield at 1–7 h.[47]
Hence, the present study provided a green, simple
and eco-friendly approach for the formation of
1-substituted-1H-tetrazoles derived from α-amino acid
ethyl ester.
SCHEME 3 Postulated
mechanism for producing
tetrazoles from α-amino acid
ethyl ester derivatives

10 of 12
MOHAMED AND ATTIA
SCHEME 4 Synthesis of
some tetrazoles derived from
some of α-amino acid ethyl ester
derivatives
TABLE 7
The catalytic activity of the ZnO NPs towards the synthesis of teterazoles 2b–i from α-amino acid ethyl esters 1b–i under
optimized reaction conditionsa
Entry
Product
Enantiomeric ratiob
[α]D25 (c = 1, MeOH)
Yield (%)c
1
16:1
+18.46
95
2
3
19:1
16:1
+21.30
+19.43
91
88
4
5
25:1
25:1
+16.83
+20.57
92
89
6
50:1
+14.17
93

MOHAMED AND ATTIA
11 of 12
TABLE 7 (Continued)
Entry
Product
Enantiomeric ratiob
[α]D25 (c = 1, MeOH)
Yield (%)c
7
8
25:1
19:1
+2.23
92
95
+12.96
aReagents and reaction conditions: α-amino acid ethyl esters 1b–i (1.0 mmol), NaN3 (1.5 mmol), HC (OEt)3 (1.0 mmol), catalyst (5 wt%)
under sonication for 30 min.
bDetermined by chiral HPLC.
cIsolated yield.
4 | CONCLUSIONS
FUNDING
This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.
In this report, an efficient ultrasound-assisted and green
protocol for the three-component reaction of a series of
α-amino acid ethyl esters, triethyl orthoformate and
sodium azide in the presence of ZnO nanocatalysts to
produce chiral 1-substituted-1H-tetrazole analogs under
optimum conditions was investigated. The main features
of this approach are the use of mild reaction conditions
that excluded the formation of HN3, no production of
side products, easy work-up and high yields. Recovery
and reuse of the nanocatalysts were also satisfactory,
which demonstrates the cost efficiency and green aspect
of our methodology.
ORCID
Yasser Mahmoud A. Mohamed https://orcid.org/0000-
0003-4678-9767
Yasser A. Attia https://orcid.org/0000-0002-5830-2250
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How to cite this article: Mohamed YMA,
Attia YA. The influence of ultrasonic irradiation on
catalytic performance of ZnO nanoparticles toward
the synthesis of chiral 1-substituted-1H-
tetrazolederivatives from α-amino acid ethyl esters.
Appl Organomet Chem. 2020;e5758. https://doi.org/
10.1002/aoc.5758
[31] S. Bahari, Letters Org. Chem. 2013, 10, 527.