Humic acid as an efficient and reusable catalyst for one pot three-component green synthesis of 5-substituted 1: H -tetrazoles in water

Article abstract of DOI:10.1039/c9ra08523h

Humic acid is a non toxic, inexpensive, easily available high-molecular weight polymer. A simple and facile one pot three-component synthesis of 5-substituted 1H-tetrazoles from aldehydes, hydroxyamine hydrochloride and sodium azide using humic acid as an efficient catalyst in water is described. The method reported has several advantages such as high to excellent yields, easy work-up, mild reaction conditions, use of water as a green solvent, and a commercially available, nontoxic and reusable catalyst.

Full text of DOI:10.1039/c9ra08523h

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Humic acid as an efficient and reusable catalyst for
one pot three-component green synthesis of 5-
substituted 1H-tetrazoles in water†
Cite this: RSC Adv., 2020, 10, 784
a
b
a
a
a
Hongshe Wang, * Yichun Wang, Yinfeng Han, Weixing Zhao and Xiaomei Wang
Humic acid is a non toxic, inexpensive, easily available high-molecular weight polymer. A simple and facile
one pot three-component synthesis of 5-substituted 1H-tetrazoles from aldehydes, hydroxyamine
hydrochloride and sodium azide using humic acid as an efficient catalyst in water is described. The
method reported has several advantages such as high to excellent yields, easy work-up, mild reaction
conditions, use of water as a green solvent, and a commercially available, nontoxic and reusable catalyst.
Received 18th October 2019
Accepted 23rd December 2019
DOI: 10.1039/c9ra08523h
rsc.li/rsc-advances
Nowadays, one pot multicomponent reactions (MCRs) have
received much attention for the synthesis of diverse compounds
Introduction
Tetrazoles are synthetic nitrogen-rich compounds with a wide and contribute to sustainability by simplifying the synthetic
18
range of applications that are receiving considerable attention route. MCRs combine three or more starting reagents at a time
1
among the stable heterocycles. They play important roles in in the same pot to create the target molecule since there is no
2
3
energetic materials, pharmaceuticals and coordination need of separating intermediate which help to reduce the
4
chemistry. Because of their potent usefulness, various energy consumption, solvent waste and reaction time and thus
synthetic methods have been developed for the construction of have the advantages of synthetic efficiency, simplicity, atom
tetrazole frameworks, such as the reactions of aryl halides with economy. Compared with the conventional multistep synthetic
5
potassium ferrocyanide, primary amides with triazido- routes, MCRs are more powerful procedures in the diversity-
6
7
chlorosilane, and oximes with sodium azide or diphenyl oriented convergent synthesis of organic heterocycles from
8
phosphorazidate. Traditional synthesis of 5-substituted 1H- simple and easily available substrates.
tetrazole has been reported to proceed via [3 + 2] cycloaddition
Humic acid is a high-molecular weight polymer that is
9
of azide ions with expensive and toxic nitrile. In view of the primarily derived from biodegradation of dead organic matter
availability, lower toxicity and ease of handling of aldehydes as and appears mostly in peat, soil, coal, upland streams,
compared to nitriles, the application of aldehydes for the dystrophic lakes and well water. Because humic acid is non
synthesis of tetrazole derivatives is a highly attractive and toxic, inexpensive and easily available, the study of its catalytic
advantageous strategy. From the literature survey, we came to activity may be very important. Humic acid is an acidic catalyst
know that some methods were reported for the synthesis of 5- owing to the presence of abundant carboxyl and phenolic
substituted 1H-tetrazole from aldehyde and the catalysts used hydroxyl groups in the structure of it. There are only very few
1
0
11
12
were (NH ) Ce(SO ) $2H O, TiCl3, Cu(OAc)2, PVA@Cu reports in which catalytic activity of humic acid has been
4
4
4 4
1
2
14
3
15
19,20
Schiff base complex, I , Cu-MCM-41, [bmim]N /Cu(OAc)
2
ref. 16) and P O . Although each of the above methods has its potential of humic acid as a catalyst, herein, we report an
described.
In view of the efforts toward development of the
2
3
17
(
2
5
own merit, most of these methods are associated with certain efficient one pot three-component synthesis of 5-substituted
disadvantages including the use of commercially unavailable 1H-tetrazoles from less expensive and easily available starting
catalysts, toxic organic solvents and high reaction temperatures. material aldehydes along with hydroxylamine hydrochloride
To avoid such drawbacks, development of more simple and and sodium azide (Scheme 1).
efficient protocols is still in demand.
a
College of Chemistry and Chemical Engineering, Baoji University of Arts and Sciences,
Baoji 721013, China. E-mail: baojizwx@126.com
b
College of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang 712046,
China
†
Electronic supplementary information (ESI) available. See DOI:
0.1039/c9ra08523h
Scheme 1 Humic acid catalyzed one pot three-component synthesis
of 5-substituted 1H-tetrazoles.
1
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a
Table 1 Effect of solvent on the synthesis of 5-phenyl 1H-tetrazole
(Table 3, entry 1). However, the productivity increased on
raising the temperature. The increase of reaction temperature
will accelerate the thermal movement of molecules and increase
the probability of intermolecular collision, thus, the rate of the
reaction is improved. Different research groups established that
c
Entry
Solvent
CH CN
DMF
DMSO
EtOH
Yield (%)
b
1
3
43
81
64
31
0
2
3
4
using high temperature is necessary for cycloaddition reac-
b
10–12
tions,
so it seems reasonable to think that increasing the
5
6
7
Toluene
reaction temperature would be a good choice for improvement
H
2
O
92
0
in the yield. The best result for this reaction was obtained at
Solvent-free
ꢀ
1
00 C (Table 3, entry 5).
a
Reaction condition: benzaldehyde (1 mmol), hydroxylamine
hydrochloride (1.2 mmol), sodium azide (1.5 mmol), solvent (2 mL),
humic acid (0.1 g) at 100 C for 4 h. Reaction was performed under efficiency and generality of this methodology, aldehydes were
Aer optimization of the reaction conditions, to expand the
ꢀ
b
c
reux condition. Isolated yield.
treated with hydroxylamine hydrochloride and sodium azide in
ꢀ
the presence of 0.1 g of humic acid in water at 100 C and a large
variety of tetrazole derivatives were formed. The results are
summarized in Table 4. This strategy applies to all types of
Results and discussion
aldehydes (aromatic, heterocyclic and aliphatic). Aromatic
aldehydes containing both electron-donating and electron-
withdrawing groups reacted successfully to give the corre-
sponding tetrazoles in good to excellent yields irrespective of
the electronic nature and substituent position on the aromatic
ring (Table 4, 2a–2r). Heterocyclic aldehydes also reacted well to
give corresponding products in high yields (Table 4, 2s and 2t).
In addition, good results were also obtained with aliphatic
aldehydes (Table 4, 2u–2w). From the above results, it is
concluded that humic acid is an excellent catalyst for the
synthesis of 5-substituted 1H-tetrazoles which tolerate a wide
range of substituents.
One of the most signicant features of a catalyst is its ability
for reusability. Thus, we studied the reusability of the catalyst
humic acid for the synthesis of 5-phenyl 1H-tetrazole (2a) under
the optimized reaction conditions. The catalyst was separated
from the reaction mixture by convenient ltration. According to
the data presented in Table 5, the catalyst was reusable for ve
consecutive runs without any signicant reactivity loss.
A comparison among humic acid and other catalysts re-
ported in the literature for the preparation of 5-phenyl 1H-tet-
razole reveals the advantages of humic acid over most of the
other catalysts in terms of higher yield and shorter reaction
time (Table 6).
In order to determine the best reaction conditions, the effect of
solvent (Table 1), catalyst loading (Table 2) and temperature
(Table 3) were examined in the reaction of benzaldehyde,
hydroxylamine hydrochloride and sodium azide. This reaction
was very dependent on the nature of the solvent utilized. It was
observed that the use of high boiling point polar solvents such
as DMF and DMSO resulted in moderate conversion to the
cycloaddition product (Table 1, entries 2 and 3). But no product
was formed with weak polar solvent toluene (Table 1, entry 5), it
may be due to the poor solubility of hydroxylamine hydrochlo-
ride and sodium azide in toluene. An additional disadvantage of
DMF and DMSO is their solubility in both organic solvents and
water, thus removing DMF and DMSO from tetrazole is difficult.
Water was the best solvent for this protocol in terms of yield
(Table 1, entry 6). However, no reaction was observed under
solvent-free conditions (Table 1, entry 7). The reaction did not
proceed with no catalyst (Table 2, entry 1). Decreasing the
catalyst concentration resulted in lower yields under the same
conditions (Table 2, entries 2 and 3). The best result was ach-
ieved by carrying out the reaction with 0.1 g of humic acid
(
Table 2, entry 4). Further increase in catalyst concentration did
not show any signicant effect on yields (Table 2, entries 5 and
). At room temperature a useful conversion was not observed
6
A plausible mechanism for the synthesis of 5-substituted 1H-
tetrazole is represented in Scheme 2. Aer the activation of the
Table 2 Effect of catalyst loading on the synthesis of 5-phenyl 1H-
a
tetrazole
Table 3 Effect of temperature on the synthesis of 5-phenyl 1H-
tetrazole
a
b
Entry
Catalyst loading (g)
Yield (%)
ꢀ
b
Entry
Temp. ( C)
Yield (%)
1
2
3
4
5
6
None
0.04
0.07
0.10
0.13
0.16
0
48
76
92
92
93
1
2
3
4
5
6
Room temp.
19
22
43
55
79
92
40
55
70
85
100
a
Reaction condition: benzaldehyde (1 mmol), hydroxylamine
O (2 mL),
a
hydrochloride (1.2 mmol), sodium azide (1.5 mmol), H
catalyst humic acid at 100 C for 4 h. Isolated yield.
2
Reaction condition: benzaldehyde (1 mmol), hydroxylamine
ꢀ
b
hydrochloride (1.2 mmol), sodium azide (1.5 mmol), H O (2 mL),
humic acid (0.1 g) at different temperature for 4 h. Isolated yield.
2
b
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a,b
Table 4 Synthesis of 5-substituted 1H-tetrazoles catalysed by humic acid
a
ꢀ
Reaction conditions: aldehydes (1 mmol), hydroxylamine hydrochloride (1.2 mmol), sodium azide (1.5 mmol), humic acid (0.1 g), 100 C, H
2
O (2
b
mL). Isolated yields.
carbonyl group of aldehyde catalyzed by protic acids on the oxygen atom of aldehyde oxime assists to activate C]N bond to
humic acid surface and the nucleophilic attack of the nitrogen form intermediate for nucleophilic addition of NaN . The
3
atom of hydroxylamine to the active carbonyl group, aldehyde reaction proceeds via [3 + 2] cycloaddition pattern. Finally, the
oxime is obtained. The coordination of the protic acids with elimination of water and acidic hydrolysis give the
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a
Table 5 Reusability of the catalyst humic acid
Conclusions
Run
1
2
3
4
5
In conclusion, we have disclosed that humic acid works as a non
toxic, inexpensive and efficient catalyst for one pot three-
component synthesis of 5-substituted 1H-tetrazoles from alde-
hydes, hydroxylamine hydrochloride and sodium azide in
water. Advantages of this methodology are use of commercially
available and reusable catalyst and water as a green solvent,
simple experimental and work-up procedure, high yields and
environment friendly. This environmentally friendly method to
synthesizing 5-substituted 1H-tetrazoles holds promising
potential for future applications in both academic and indus-
trial research.
b
Yield (%)
92
92
92
91
90
a
Reaction condition: benzaldehyde (1 mmol), hydroxylamine
O (2 mL),
hydrochloride (1.2 mmol), sodium azide (1.5 mmol), H
2
ꢀ
b
humic acid (0.1 g) at 100 C for 4 h. Isolated yield.
corresponding 5-substituted 1H-tetrazole. The active site on the
humic acid represented as –COOH is considered in the
mechanism.
Micellar catalysis provides a means for synthesizing novel
and conventional materials in aqueous media, resulting in
improved reaction rates and eliminating the need for organic
solvents. Humic acid generally forms micelle-like structure in
aqueous environment, which is an effective way to realize [3 + 2]
Experimental
Materials and instrumentation
cycloaddition of aldehydes, hydroxyamine hydrochloride and Humic acid and other chemicals were all purchased from
sodium azide, and the addition of inorganic electrolyte Aladdin Reagent Company and used as received unless
(
hydroxyamine hydrochloride and sodium azide) into the mentioned otherwise. Melting points were determined on an
21
aqueous phase can markedly promote the catalysis effect. The XT4A electrothermal apparatus equipped with a microscope
critical micelle concentration (CMC) value of the humic acid and are uncorrected. NMR spectra were recorded on a Bruker
À1
used in this study was 5.11 Æ 0.10 g L
.
Avance 400 spectrometer in DMSO-d . Elemental analyses were
performed on a PerkinElmer 240-C instrument.
6
Table 6 Comparison of various catalysts used in synthesis of 5-phenyl 1H-tetrazole from benzaldehyde, hydroxylamine hydrochloride and
sodium azide
Entry
Conditions
Yield (%)
Ref.
a
1
(NH
TiCl
Cu(OAc)
PVA@Cu Schiff base complex (0.43 mol%), H
4
)
4
Ce(SO
(20 mol%), DMF, reux, 4 h
(20 mol%), choline chloride–urea, 100 C, 12 h
O, r.t., 7 min
Cu-MCM-41 (30 mg mmol ), DMF, 140 C, 12 h
4
)
4
$2H
2
O (20 mol%), DMF, reux, 5 h
72
86
90
98
90
90
92
10
11
12
13
15
17
a
2
3
a
ꢀ
3
2
b
4
2
b
À1
ꢀ
5
a
6
P
2
O
5
(200 mol%), DMF, reux, 9 h
a
À1
ꢀ
7
Humic acid (0.1 g mmol ), H
2
O, 100 C, 4 h
This work
a
b
Commercially available catalyst. Commercially unavailable catalyst.
Scheme 2 Plausible mechanism for the synthesis of 5-substituted 1H-tetrazoles.
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General procedure for the synthesis of 5-substituted 1H-
tetrazoles
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ꢀ
water (2 mL) and the mixture was heated at 100 C for requisite
time. The progress of reaction was monitored by TLC. Aer
completion of reaction, the mixture was ltered to separate out
the catalyst. The ltrate was treated with HCl (4 N, 10 mL),
extracted with ethylacetate, and washed by water a few times.
The extract was dried over anhydrous Na SO , puried by col-
5
6
7
8
9
2
4
umnchromatography on silica-gel (60–120 mesh) using petro-
leum ether/ethyl acetate (75 : 25) as eluent to give the
corresponding pure product. All the products were character-
1
13
ized by H NMR and C NMR spectroscopy.
A gram scale synthesis of 5-phenyl 1H-tetrazole (2a)
To a 200 mL round-bottomed ask equipped with a magnetic
stirrer was added benzaldehyde (10.6 g, 0.1 mol), hydroxylamine
hydrochloride (4.2 g, 0.1 mol), NaN (0.5 g, 0.11 mol), humic
3
acid (10.0 g) and water (100 mL). Then the reaction mixture was
ꢀ
heated to 100 C with vigorous stirring. Aer completion of
reaction (4 h), as detected by TLC, the mixture was cooled to
room temperature and ltered to separate out the catalyst. The

ltrate was adjusted pH to 1.0 with concentrated HCl and
extracted with ethylacetate (3 Â 50 mL). The combined organic
phases were washed with water (2 Â 100 mL), dried over
2 4
anhydrous Na SO and evaporated under reduced pressure to
give the pure product 5-phenyl 1H-tetrazole as a white solid
13.2 g, 90% yield).
(
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Conflicts of interest
3
There are no conicts to declare.
4
Acknowledgements
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