Ag2CO3-catalyzed cycloaddition of organic azides onto terminal alkynes: A green and sustainable protocol accelerated by aqueous micelles of CPyCl

Article abstract of DOI:10.1016/j.tetlet.2019.03.036

Using catalytic amount of Ag₂CO₃ a simple, efficient and copper free green protocol has been developed to synthesize 1,4-disubstituted 1,2,3-triazoles regioselectively. Here, the cationic surfactant, cetylpyridinium chloride (CPyCl) in water provides a micellar media and accelerates the subsequent Ag(I)-catalysed azide-alkyne cycloaddition (AgAAC) reaction by increasing the concentration of reactants in the micellar pseudophase. Our method is found to be environmentally friendly from E-factor measurement. The surfactant, CPyCl is found to be nontoxic.

Full text of DOI:10.1016/j.tetlet.2019.03.036

Accepted Manuscript
Ag CO -catalyzed cycloaddition of organic azides onto terminal alkynes: A
2
3
green and sustainable protocol accelerated by aqueous micelles of CPyCl
Jasmin Sultana, Nageshwar D. Khupse, Srijita Chakrabarti, Pronobesh
Chattopadhyay, Diganta Sarma
PII:
S0040-4039(19)30254-0
https://doi.org/10.1016/j.tetlet.2019.03.036
TETL 50677
DOI:
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
11 January 2019
11 March 2019
13 March 2019
Please cite this article as: Sultana, J., Khupse, N.D., Chakrabarti, S., Chattopadhyay, P., Sarma, D., Ag CO -
2
3
catalyzed cycloaddition of organic azides onto terminal alkynes: A green and sustainable protocol accelerated by
aqueous micelles of CPyCl, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.03.036
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Ag(I)-catalyzed cycloaddition of organic
azides onto terminal alkynes: A green and
sustainable protocol accelerated by aqueous
micelles of CpyCl
Leave this area blank for abstract info.
a
b
c
c
a,
Jasmin Sultana , Nageshwar D. Khupse , Srijita Chakrabarti , Pronobesh Chattopadhyay , and Diganta Sarma *

1
Tetrahedron Letters
Ag CO -catalyzed cycloaddition of organic azides onto terminal alkynes: A green
2
3
and sustainable protocol accelerated by aqueous micelles of CPyCl
a
b
c
c
Jasmin Sultana , Nageshwar D. Khupse , Srijita Chakrabarti , Pronobesh Chattopadhyay , and Diganta
Sarma 
a,
a
Department of Chemistry, Dibrugarh University, Dibrugarh-786004, Assam, India
b
Center for Materials for Electronics Technology, Pashan Road, Pune- 411008, India
c
Defence Research Laboratory, Tezpur - 784001, Assam, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
2 3
Using catalytic amount of Ag CO a simple, efficient and copper free green protocol has been
developed to synthesize 1,4-disubstituted 1,2,3-triazoles regioselectively. Here, the cationic
surfactant, cetylpyridinium chloride (CPyCl) in water provides a micellnar media and
accelerates the subsequent Ag(I)-catalysed azide-alkyne cycloaddition (AgAAC) reaction by
increasing the concentration of reactants in the micellar pseudophase. Our method is found to be
environmentally friendly from E-factor measurement. The surfactant, CPyCl is found to be
nontoxic.
Available online
Keywords:
AgAAC
CPyCl
2
009 Elsevier Ltd. All rights reserved.
Non-toxic surfactant
Negligible E-factor
—
——

Corresponding author. Tel.: +91 373-2370210; e-mail: dsarma22@dibru.ac.in

2
Introduction
essential. These prominent demerits of the earlier reports
strongly demand development of some simple and greener
protocols towards AgAAC. Here, we have reported a new
strategy for AAC reaction using readily available and relatively
inexpensive Ag CO catalyst in aqueous micelles of CPyCl.
The increasing awareness towards greener and sustainable
technologies has paid tremendous attention on efficient green
methodologies for synthesis of chemicals and pharmaceuticals.
Therefore, by utilizing the twelve principles of green chemistry,
continuous efforts have been made to develop sustainable and
effective strategies for organic synthesis. The use of organic
solvents for chemical transformation is one of the most important
issues in green chemistry because of their harmful effects on
2
3
Absolute solubility of the starting materials, very often, is the
crucial factor for better reactivity. For aqueous reactions
surfactant incorporation can show growing reactivity by forming
micelles. Micelle formation shows a general advancement over
the pure aqueous medium by increasing solubility and contact
between the starting reagents. TPGS-750-M in water forms
recyclable nanomicelles and was used for nitro group reduction
and Suzuki-Miyaura coupling reaction reported by Bruce H.
1
health and environment. Considering environmental impact and
safety measurement, replacement of these deleterious solvents by
environmentally benign solvents such as water, ionic-liquids or
supercritical carbon dioxide becomes the foremost aspect of
sustainable chemistry. Water is the first choice of green solvent
as it is non-destructive, cheap, non-flammable, and abundantly
1
8
Lipshutz. For synthesis of substituted 1,2,3-triazoles only a few
1
9
number of works have been carried out in micellar media. Here
we present a new method using the versatile cationic surfactant,
CPyCl in water as the accelerating media for AgAAC.
2
available in pure form. Water is a polar compound and is called
as the “universal solvent” for its ability to dissolve many
substances. Molecular structure and capability of forming
extensive hydrogen bonding are responsible for its unique
physicochemical properties such as high dielectric constant,
optimum oxygen solubility, high heat capacity and high cohesive
Results and discussion
3
energy density. The heterocyclic chemistry becomes a very
To follow the objective, we began our optimization with
important field in the organic or pharmaceutical chemistry. As
we are totally dependent on the drugs derived from heterocyclic
rings, enormous attention has been paid to develop some new
advanced methodologies to synthesize heterocycles. After the
benzyl azide (1a) and phenyl acetylene (2a) as representative
substrates in toluene using Ag CO as catalyst at room
2 3
temperature. After 24 hours, the exhilarating conversion of the
starting reagents to the corresponding 1,4-disubstituted 1,2,3-
triazole product encouraged us for further analysis (Table 1,
entry 1). The search for a green solvent system for this newly
synthesized protocol showed that use of both water and ethylene
glycol (EG) gives very good results (97%) after 24 hours (Table
1, entries 2 and 3).
establishment of copper catalyzed azide-alkyne cycloaddition
4
(
CuAAC) by Sharpless and Meldal in 2002, the 1,2,3-triazole
moiety has become one of the most important and well known
synthetic nitrogen containing heterocyclic rings having extensive
use in different fields including material science, drug discovery,
polymer chemistry, chemical synthesis and supramolecular
5
Table 1.a Optimization of reaction conditions for Cu-free
AgAAC
chemistry. In medicinal chemistry, the importance of triazolic
compounds is undeniable as many 1,2,3-triazole containing drugs
are used as anti-HIV, anticancer, antitubercular, antifungal,
6
antibacterial, anti-influenza and antiepileptic agents. Aromatic
character, high thermal and chemical stability, participation in
hydrogen bonding and strong dipole moment make this moiety
widely applicable.
7
b
Entry
Catalyst (mol%)
Additive
Solvent
Time
h)
Yield
(%)
50
97
97
80
85
90
87
(
Copper-catalyzed azide-alkyne cycloaddition (CuAAC) for
synthesis of 1,4-disubstituted 1,2,3-triazole and ruthenium-
1
2
3
4
5
6
7
8
9
Ag
Ag
Ag
Ag
Ag
Ag
Ag
2
2
2
2
2
2
2
CO
CO
CO
CO
CO
CO
CO
3
3
3
3
3
3
3
(10 %)
(10 %)
(10 %)
(10 %)
(10 %)
(10 %)
(10 %)
(10 %)
(10 %)
(10 %)
-
-
-
-
-
-
-
MePh
EG
24
24
24
24
24
24
24
2
8
catalyzed azide-alkyne cycloaddition (RuAAC) for synthesis of
H
2
O
complementary 1,5-disubstituted 1,2,3-triazole circumvented the
problems of high thermal necessity and poor regioselectivity of
DMF
DMSO
DCM
9
ordinary Huisgen 1,3-dipolar cycloaddition reaction. Plenty of
works have been done using different copper sources because of
CuAAC’s high yield in aqueous media, no need of elevated
temperature, exclusive regioselectivity and wide substrate scope.
Apart from these advantages, the CuAAC reactions have certain
limitations also. Cu(I) is cytotoxic in nature and therefore it is
t-BuOH
Ag
2
CO
3
CPyCl
CTAB
SLS
H
2
O
O
O
98
65
43
Ag
Ag
2
CO
CO
3
H
H
2
2
2
1
0
2
3
2
1
0
incompatible with living cells. Excessive copper intake can
cause some side effects like hepatitis, neurological disorders,
1
1
1
1
2
3
Ag
2
Ag
2
Ag
2
CO
CO
CO
3
3
3
(10 %)
(10 %)
(10 %)
SDBS
NaDC
Triton X-
100
CPyCl
CPyCl
CPyCl
CPyCl
CPyCl
CPyCl
H
2
H
2
H
2
O
O
O
2
2
2
81
80
20
1
1
kidney damage and Alzheimer’s disease. Another disadvantage
of CuAAC reaction is alkyne homocoupling, called Glaser Hay
coupling to form dialkynes in presence of copper salts. Therefore,
development of alternative methods for AAC reaction is of great
demand. Recently, several Ag(I) sources have found to display
huge potential towards the synthesis of 1,4-disubstituted 1,2,3-
triazoles. The indispensable metal, silver has gained growing
demand in industries due to its exclusive catalytic, sensing,
optical and antimicrobial properties. McNulty et al. identified the
first purely silver catalyzed click reaction using P, O-type silver
14
15
16
17
18
19
AgCl (10 %)
AgBr (10 %)
AgNO (10 %)
3
H O
2
2
2
2
2
2
2
45
23
<10
88
82
0
H
2
H
2
H
2
H
2
H
2
O
O
O
O
O
Ag
2
Ag
2
Ag
2
CO
3
(5 %)
(1 %)
(0 %)
CO
CO
3
3
a
Reagents and conditions: Azide (0.34 mmol, 1.0 equiv), alkyne (0.34
mmol, 1.0 equiv), Ag-catalyst, additive (10 mol%) and solvent (2 mL) were
1
2
13
complexes. Further, Ag-graphene nanocomposite, Ag O
b
2
allowed to react at room temperature. Isolated yields of 3a.
1
4
15
NPs, combination of AgOTf and Cu(0) catalyst, silver
nanoparticle supported on Al O @Fe O , AgN(CN) /DIPEA
1
6
17
Apparently, other organic solvents like DMF, DMSO, DCM
and t-BuOH were found to play a suitable role for AgAAC
(Table 1, entries 4-7). Further experiments were conducted in
water as it is environment friendly, cheap and easily available. In
order to minimize the time requirement we analyzed the reaction
2
3
2
3
2
were employed in order to get triazole products. However, in
these protocols inert atmospheric condition, toxic organic
solvents, elevated temperature, stabilizing ligands, bases and
additives and also the formation of silver complexes were

3
with different types of surface active agents (cationic, anionic
and non ionic). The cationic surfactant, cetylpyridinium chloride
product by AgAAC with phenylacetylene. 2-azidofuran and 2-
azidobenzofuran were found to be ineffective for AgAAC.
(CPyCl) accelerated the reaction rate and interestingly an
impressive yield was observed after 2 hours (Table 1, entry 8).
Cetyltrimethylammonium bromide (CTAB) was used and found
to be less effective than that of the previous one (Table 1, entry
9
). Besides, the use of anionic surfactants such as sodium lauryl
(
a)
sulphate (SLS), sodium dodecyl benzene sulphonate (SDBS) and
sodium deoxycholate (NaDC) showed relatively lower reactivity
(
a)
(
Table 1, entries 10-12). A non ionic surfactant, Triton X- 100
was found to be least efficient for our newly developed strategy
Table 1, entry 13). Considering CPyCl as the best promoter and
(
water as the suitable solvent media the reaction was further
screened with different silver salts. AgCl, AgBr and AgNO were
3
tested and observed to be inferior to Ag CO as they afforded
2
3,
lower yields of the desired products (Table 1, entries 14-16).
Further investigations were concerned with the catalyst loading.
A remarkable change was ascertained while reducing the catalyst
loading from 10 mol% to 5 mol% and further to 1 mol% (Table
(
b)
(c)
Figure1. (a) Specific conductivities of CPyCl as a function of concentration
at 302.15 K. [CMC of CPyCl in pure water = 0.90 mM]. Optical micrograph
of CPyCl in water before (b) and after (c) the addition of reactants. [Scale
bar= 1-10 μm]
1
, entries 17,18). The reaction did not proceed at all in absence
of catalyst (Table 1, entry 19).
Table 2. Screening of surfactant concentration.
b
Entry
1
2
3
4
5 a
Surfactant
CPyCl
CPyCl
CPyCl
CPyCl
Amount (mol%)
Yield (%)
0.25
0.51
2
5
10
67
79
83
89
98
CPyCl
Reaction conditions: Azide (0.34 mmol, 1.0 equiv), alkyne (0.34 mmol,
CO (10 mol%) were allowed to react in 2 mL of water at
different CPyCl concentrations. [Here, 0.51 mol%= 0.90 mM]. Isolated
yields.
1
.0 equiv), Ag
2
3
b
The surfactant concentration is
a notable factor that
substantially affects the rate of a chemical reaction. Considering
this, the impact of different CPyCl concentrations on reactivity
was also studied and the findings are shown in Table 2.
Reactivity was found to increase with increase in the amount of
CPyCl. We have determined the critical micelle concentration
(CMC) of the surfactant in water by conductometric method
[
Figure 1, (a)] and the calculated value (0.90 mM) was found to
2
0
match with the reported value. A lower yield of the product was
observed bellow CMC and the yield gradually increased due to
increase in aggregation of monomeric species and the size of the
colloidal cluster above CMC.
Next, we evaluated the generality and scope of our optimized
Cu-free AgAAC system towards synthesis of various 1,4-
disubstituted 1,2,3-triazoles. In this aspect, a variety of azides
(benzyl, aliphatic and aromatic) were allowed to react with
different alkynes (both aromatic and aliphatic) under the
established conditions. As demonstrated in Table 3, the reactions
worked suitably and afforded the corresponding 1,4-
disubstituted-1H-1,2,3-triazoles in good to excellent yields under
our catalytic conditions. The findings indicated that both
aromatic and aliphatic alkynes reacted effectively with benzyl
azide and provided the corresponding triazoles in excellent yields
(
Table 3, entries 3a-g). Functional group bearing benzyl azides
are also tolerated under our established conditions (Table 3,
entries 3h-j). A variety of phenyl azides bearing electron
donating or electron withdrawing functional groups were tested
and it was noticed that all reactions proceeded efficiently in the
direction of click conversion producing the respective triazole
products (Table 3, entries 3k-p). Octyl azide and phenethyl
azide also showed higher reactivity towards phenyl acetylene
under these conditions (Table 3, entries 3q, r). The heterocyclic
azide, 2-azidothiophene provided 79% yield of the desired
a
Reaction conditions: Azide (0.34 mmol, 1.0 equiv), alkyne (0.34
mmol, 1.0 equiv), Ag CO (10 mol%) were allowed to react in 2
2
3
b
mL of water at 10 mol% CPyCl concentration. Isolated yields of
the products.
We have analyzed two samples of CPyCl surfactant in distilled
water through an inverted microscope, one is prior to the addition
of reactants and the other is after the addition of reactants. Both

4
the samples indicated the formation of spherical shaped micelles
in water [Figure 1 (b), (c)]. It was observed that the size of the
spherical shaped micelles became more uniform in presence of
reacting substances.
The hydrophobic and electrostatic interactions of organic
reagents with the surfactant are believed to enhance the effect of
CPyCl micellar solution in water. The high interfacial energy
between the polar water molecules and the non polar
hydrocarbon chains of surfactant molecule serves as the force
governing the association process and leads to the formation of a
colloidal sized spherical cluster. As the non polar hydrocarbon
chains of the surfactants are pointing towards the interior, the
inner part of these spherical droplets behaves as hydrophobic
reaction site. Organic reagents are pushed towards the
hydrophobic region of the micelles as their solvation is better in
the non-polar core of the micelle than in the polar bulk water.
Thus, increase in concentration of reagents inside the micelle
favours more effective collisions among themselves which act as
a driving force for rate enhancement in water. We have suggested
a possible mechanism of the reaction on the basis of literature
1
2, 23
reports (Scheme 1).
In order to measure the greenness of our AgAAC protocol
Environmental Factor (E-factor) was determined. The concept of
E-factor was introduced by R. Sheldon and it is the weight of raw
materials minus the weight of desired product, divided by the
Scheme 1. Schematic diagram representing the role of CPyCl and
the plausible reaction mechanism.
Conclusion
In summary, Ag CO in aqueous micelles of CPyCl has been
2
1
weight of the product out. A comparative study was done with
earlier reported methods and the results are illustrated in Table 4.
E-factors with lower values are preferable. Moreover, the
additive CPyCl is found to be non toxic. The cytotoxicity effect
of CPyCl (1mg/100μl) is determined in primary hepatocytes by
2
3
employed for the first time as an efficient and alternative protocol
for regioselective synthesis of 1,4-disubstituted-1H-1,2,3-
triazoles at room temperature. From synthetic viewpoint, this
versatile method emerges as simple, mild and highly selective for
,2,3-triazole synthesis and hence it has huge significance in
various synthetic applications.
2
2
using MTT assay. The hepatocyte cells are found to be 51.14%
viable from absorption measurement at 750 nm by using a
microplate reader. Thus our system will be more environmental
friendly in comparison to the previous methods.
1
Acknowledgments
Table 3. Substrate scope of azides and alkynes for
AgAAC
a
D.S. is thankful to DST, New Delhi, India for a research grant
[
No. EMR/2016/002345]. Authors thank the Department of
Science and Technology for financial assistance under DST-FIST
programme and UGC, New Delhi for Special Assistance
Programme (UGC-SAP) to the Department of Chemistry,
Dibrugarh University.
Table 3. Comparative study of E-factors for measuring
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6




Simplest Cu-free protocol for azide-alkyne
cycloaddition reaction reported so far.
Non toxic cationic surfactant, CPyCl speeded
up the reaction.
Negligible E-factor as compared to literature
reports.
Wide substrate scope with good to excellent
yields.