Choline chloride–ZnCl2: Recyclable and efficient deep eutectic solvent for the [2+3] cycloaddition reaction of organic nitriles with sodium azide

Article abstract of DOI:10.1080/00397911.2017.1285033

Herein we report first time choline chloride–zinc chloride based deep eutectic solvent is a green and efficient reaction medium for the [2+3] cycloaddition reaction of organic nitriles with sodium azide to afford the corresponding 5-substituted 1H-tetrazo

Full text of DOI:10.1080/00397911.2017.1285033

Choline Chloride-ZnCl2: Recyclable and Efficient Deep Eutectic Solvent for the
[2+3] Cycloaddition Reaction of Organic Nitriles with Sodium Azide
Swapnil A. Padvi1, Dipak S. Dalal1
1School of Chemical Sciences, North Maharashtra University, Jalgaon, MS, India
Corresponding author Dipak S. Dalal E-mail: dsdalal2007@gmail.com
Abstract
Herein we report first time choline chloride-zinc chloride based deep eutectic solvent is a
green and efficient reaction medium for the [2+3] cycloaddition reaction of organic
nitriles with sodium azide to afford the corresponding 5-substituted 1H-tetrazoles. The
present method provides an environment-friendly route, short reaction times with
excellent yields, safe process and simple workup which make this method an attractive
and useful contribution to the existing conventional processes for synthesis of 5-
substituted 1H-tetrazoles.
Graphical Abstract
1

KEYWORDS: Tetrazoles; Choline chloride; Deep eutectic solvent; Green chemistry;
Click chemistry
INTRODUCTION
The chemistry of tetrazoles has been grown tremendously in the past few years because
tetrazoles are important and useful class of heterocyclic compounds which have a
widespread applications such as anticancer,[1] antimicrobial,[2–4] analgesics,[5]
antibacterial,[6] antifungal,[7] antihypertensive and anti-allergic[8] drugs in medicinal
chemistry. Furthermore, tetrazoles have application in material sciences as explosives,[9]
rocket propellants,[10–13] and in information recording systems.[14,15] In addition to this,
they have a wide range of application in coordination chemistry as a ligand.[16–18]
The [2+3] cycloaddition of sodium azide to organic nitriles in a temperature range of
typically 100-150°C is a most convenient route for the synthesis of 5-substituted 1H-
tetrazoles derivatives.[19,20] The ‘‘click chemistry’’ approach for the synthesis of 5-
substituted 1H-tetrazoles by [2+3] cycloaddition of corresponding nitriles and NaN3
under water as a solvent and stoichiometric amounts or 50 mol% of Zn(II) salts is an
alternative method developed by Sharpless.[21] After that much work has been done by
many scientist and reports the several catalytic system for the synthesis of 5-Substituted
1H-tetrazoles such as homogeneous catalysts like TBAF under solvent-free conditions,[22]
ionic liquid,[23]. Heterogeneous catalytic system using various catalyst such as Fe2O3,[24]
Zn hydroxyapatite,[25] mesoporous ZnS hollow sphere,[26] and CSMIL,[27] ZnO
nanoflakes,[28] Fe3O4@SiO2,[29] AgNPs,[30] Grapheneoxide/ZnO nanocomposite,[31]
2

Numerous lewis acid catalyst such as CdCl2,[32] ZnCl2,[33,34] InCl3,[35] B(C6F5)3,[36]. Some
natural zeolite Montmorillonite K-10 clay,[37] and CoY,[38] zeolite also reported. These
synthetic strategies give good results in many instances, still the search for greener
method is progressively in demand for the synthesis of 5-substituted 1H-tetrazoles.
Deep eutectic solvents (DESs) have emerged over the current decade as a novel class of
green reaction media.[39,40] The physical and chemical properties of DESs similar to the
ionic liquids (ILs) such as low vapor pressure, non-volatility, high thermal stability and
recyclability. As compared to ILs, DES are cheaply available, low-toxic, and
biodegradable.[41–43] These unique features of DESs have interesting and impressive in
many fields such as polymerizations,[44] enzyme-catalyzed reactions,[45,46]
electrochemical processes,[47,48] biochemical process,[49,50] nanotechnology,[51] and
organic synthesis.[52] While the ability of deep eutectic solvent as catalyst and reaction
medium in organic synthesis have appreciable attention in recent years. which makes
them predominantly required for large-scale applications effectively in industrial
production. [53–58]
Recently our group has developed an efficient catalytic system [59,60] for the synthesis of
5-substituted 1H-tetrazoles. In continuation to this research work, we have report choline
chloride-ZnCl2 based deep eutectic solvent is a green and efficient reaction medium for
the synthesis of 5-substituted 1H-tetrazoles.
RESULT AND DISCUSSION
3

The thermal properties of ChCl-ZnCl2 were investigated using thermogravimetric
analysis (TGA) and the observed result shown in Figure 1. The TGA curve of
ChCl:ZnCl2 shows three step degradation in that the first weight loss of water started
from 29-157°C (2.67%) and second weight loss of Choline chloride started from 157-
417°C (25.94%) and third weight loss began in the range of 418-762°C (68.11%). The
ChCl:ZnCl2 exhibit good thermal stability at 341°C.
In optimized the reaction conditions and role of ChCl-ZnCl2 (1:2) as a catalyst and
reaction medium, the reaction between benzonitrile, NaN3 has been selected as a model
reaction for synthesis of 5-phenyl 1H-tetrazole. Not many organic solvents are stable at
high temperature (sometimes as high as 140°C), and for this reason DESs is used at high
temperature. To develop the organic processes, among the several solvents were
examined at variable temperature listed in Table 1, Without any solvent, this reaction is
does not proceed within 24 hours. A rate of cycloaddition reaction is little beat increase
on changing the solvents polar aprotic such as DMF, DMSO (Table 1, entry 2-3). While
the polar aprotic solvent such as dioxane, DCM does not give the product. Thus, glycerol
was identified as most effective solvent for this reaction due to good solubility of both
organic nitriles as well as sodium azide at 140 °C but leads to lower yields (Table 1, entry
4) while protic solvents such as water, methanol, ethanol and acetic acid, toluene does not
lead to expected product. Among all solvents, including six different types of choline
chloride based deep eutectic solvent, choline chloride-ZnCl2 (1:2) proved to be the most
efficient media for the target product 3a preparation in practically good yields. The yield
of the model reaction in choline chloride-ZnCl2 (1:2) at 80 °C in 3.5 hours was fair (63
4

%). Next, the reaction was performed in higher temperature, 80-160 °C (Table 2, entries
1-5), the best result is obtained at 140 °C thus, 140 °C was selected as optimized
temperature and based on these result, we then investigated the amount of DES required
for the reaction, and found that 10 mL of DESs (Table 3, entries 5), gives excellent yield.
If the amount of DES was decreased from 10 mL to 1 mL (Table 3, entries 1-5), the time
of reaction increase and yield was also decreased thus, 10 mL of DES was chosen as the
optimum amount for the reactions. The recycling of DES was also examined under
optimized conditions. After reaction was completed, cold water (10 mL) was added to the
reaction mixture, stirred vigorously and solid was separated by filtration. Finally, DES
was recovered by evaporating the water at 80 °C under vacuum and was reused for the
next run and recycled again (Fig. 2).
A diversity of structurally different nitriles possessing a wide range of functional groups
was selected to understand the range and simplification of the ChCl-ZnCl2 (1:2)
promoted [2+3] cycloaddition reaction to form 5-substituted 1H-tetrazoles and the results
are summarized in Table 4. For all nitriles, ChCl-ZnCl2 (1:2) was used as a catalyst and
solvent and the reaction was conducted at 140 °C. In all cases, the conversion was
completed within 0.5-7 h with good to excellent yields. Further increase in reaction time
has no significant effect on yields. Aromatic nitriles containing both electron releasing
and electron withdrawing groups were smoothly converted in to the product. The nitriles
having electron releasing substituents give slower reaction (Table 4, entry 3d, 3e, 3g, and
3h). The benzyl nitriles require longer reaction times than benzonitriles (Table 4, entry 3i,
3j). The longer reaction time of 7 h was required with 88% yield for heterocyclic nitrile
5

(Table 4, entry 3h); this might be steric hindrance of rings. The 90% of yield was
obtained for benzonitrile (Table 4, entry 3a) within very short reaction time of 0.5 h. we
have extended the scope of this system to aliphatic nitriles but the aliphatic nitriles does
not proceed in ChCl-ZnCl2 (1:2) (Table 4, entry 3m and 3l).
All synthesized compounds were characterized by IR, 1H NMR, 13C NMR and Mass
spectroscopy and compared with literature data. Finally, the role of ChCl-ZnCl2 (1:2) for
the synthesis of 5-phenyl 1H-tetrazole has been compared with previous reported
catalysts (Table 5). This comparison clearly shows that the present method supportive to
several of the others in terms of high product yield, short reaction time, no need of toxic
metals and expensive reagents and hazardous solvent, easy isolation of final products by
simple work-up.
CONCLUSION
In summary, the first time, we have attempted the [2+3] cycloaddition reaction of organic
nitriles with sodium azide affords the corresponding 5-substituted 1H-tetrazoles in six
different types of choline chloride based deep eutectic solvents under mild reaction
condition. Choline chloride: ZnCl2 (1:2) showed the best results for the synthesis of 5-
substituted 1 H-tetrazoles as important pharmacophore in medicinal chemistry. This
method reduces the disadvantages such as: the use of toxic metals and expensive
reagents, drastic reaction conditions and the presence of dangerous hydrazoic acid. The
approach provides environment-friendly, short reaction times, good to excellent yields;
6

safe process and simple workup make this method an attractive and useful contribution to
present green organic synthesis of 5-substituted-1H-tetrazoles.
EXPERIMENTAL SECTION
Typical Experimental Procedure For Synthesis Of 5-Substituted 1H-Tetrazoles (3a-
3k)
NaN3 (0.975 g, 15 mmol) was dissolved in DES (10 mL) at room temperature by stirring
until a clear solution was formed. Then benzonitrile (10 mmol) was added. The reaction
mixture was constantly stirred at 140 °C and monitored by TLC. After completion of the
reaction, the reaction mixture was cooled to room temperature and poured into the cold
water (10 mL). The solid was obtained and filtered. The obtained solid is taken into cold
water (10 mL). Then it was acidified carefully to pH 5 with 5 M HCl. The organic
material was extracted thrice with ethyl acetate; the resultant organic layer was washed
with distilled water, dried over anhydrous sodium sulfate, and concentrated to give the
crude solid crystalline 5-substituted 1H-tetrazole. The resulting product, although evident
as a single compound by TLC, was purified by simple recrystallization from aqueous
ethanol giving pure 5-substituted 1H-tetrazoles.
SUPPORTING INFORMATION
Supplementary material includes full experimental details, IR, 1H NMR, 13C NMR and
Mass spectra of the product (3a-3k) for this article.
ACKNOWLEDGMENT
7

One of the authors, Swapnil A. Padvi, is sincerely thankful to the University Grants
Commission, New Delhi, India for the award of “Rajiv Gandhi National Fellowship”
(RGNF). We are also thankful to the University Grand Commission, New Delhi, India for
facilities under the UGC-SAP-DSA-I programme to North Maharashtra University
(NMU) and SAIF, Punjab University, for providing necessary characterization facilities.
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Table 1. Formation of 5-phenyl 1H-tetrazole (3a) using various reaction conditions a
Sr. No. Solvent (10 mL)
Time (hrs) Yield (%)b
1
-
24
24
24
3
NR
<20
<20
60
2
DMF
3
DMSO
4
Glycerol
5
Acetic Acidc
14
24
18
14
2
40
6
Choline chloride-urea (1:1)
Choline chloride-malonic acid (1:1)
Choline chloride-PTSA (1:1)
Choline chloride-glycerol (1:1)
Choline chloride-ZnCl2 (1:2)
Trace
72
7
8
68
9
70
10
11
30 min
90
Choline chloride-ZnCl2-1ml H2O (1:2) 30 min
90
aReaction was carried out with benzonitrile (10 mmol), NaN3 (15 mmol).
bIsolated yields.
cReflux.
13

Table 2. Formation of 5-phenyl 1H-tetrazole 3a at various reaction temperaturea
Sr. No. Temperature (°C) Time (min) Yield (%)b
1
2
3
4
5
80
210
120
50
63
82
86
90
90
100
120
140
160
30
30
aReaction was carried out with benzonitrile (10 mmol), NaN3 (15 mmol) and Choline
chloride-ZnCl2 (1:2) (10 ml).
bIsolated yields.
14

Table 3. The effect of amount of DES on the reaction yield and timea
Sr. No. DES (mL) Time (min) Yield (%)b
1
2
3
4
5
1
120
60
40
30
30
80
82
86
88
90
3
5
8
10
aReaction was carried out with benzonitrile (10 mmol), NaN3 (15 mmol) at 140 °C.
bIsolated yields.
15

Table 4. Synthesis of 5-substituted 1H-tetrazoles using (ChCl-ZnCl2)a
entry Reactant
Product
Time (min) Yield b (%)
3a
30
90, 60c
3b
3c
3d
50
94
80
94
82
5 hrs
3e
3f
90
70
86
78
16

3g
3h
45
80
88
7 hrs
3i
4. 3 hrs
3hrs
88
3j
82
3k
3l
4 hrs
76
12hrs
12hrs
NR
NR
3m
17

Table 5. Comparison of various reported catalysts for synthesis of 5-phenyl 1H-tetrazole
Entry Catalyst Temp. (°C) Time (h) Yield, (%) Ref.
1
2
3
4
5
6
7
ZnBr2
100
120
100
125
24
12
8
76
78
84
87
86
85
90
21
ZnHAP
25
ZnCl2
33
ZnO nanoflakes
14
36
1
28
ZnS hollow sphere 120
26
ZnCl2
50
34
DES
140
0.5
This Work
18

Figure 1. TGA thermograms of ChCl:ZnCl2
19

Figure 2. Recyclability of deep eutectic solvent (DES)
20