AlCl3Br: An efficient novel ionic liquid for synthesis of novel 1,2,4-triazolidine-3-thiones in water

Article abstract of DOI:10.1039/c3ra46916f

An efficient novel ionic liquid, [C₁₆MPy]AlCl₃Br has been synthesized and explored as a catalyst for an eco-friendly synthesis of novel 1,2,4-triazolidine-3-thiones in water at ambient temperature. A variety of aldehydes undergo smooth reaction with thiosemicarbazide and substituted thiosemicarbazides. In the case of substituted thiosemicarbazides the corresponding 1,2,4-triazolidine-3-thiones are obtained as products instead of 1,3,4-oxadiazoles. A broad variety of functional groups are tolerated and a large number of substrates can be applied with this protocol. Rapid eco-friendly reactions with high yields, use of ambient temperature and water as a solvent, easy work-up procedure as well as isolation of product, excellent catalyst recyclability, high atom economy, novelty of ionic liquid as well as the protocol are the auxiliary advantages of the protocol. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c3ra46916f

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[C16MPy]AlCl3Br: an efficient novel ionic liquid for
synthesis of novel 1,2,4-triazolidine-3-thiones in
water†
Cite this: RSC Adv., 2014, 4, 14314
Received 21st November 2013
Accepted 6th March 2014
*
Jayavant D. Patil and Dattaprasad M. Pore
DOI: 10.1039/c3ra46916f
www.rsc.org/advances
An efficient novel ionic liquid, [C16MPy]AlCl3Br has been synthesized scientists. Thus, recently, the synthesis of task-specic ionic
and explored as a catalyst for an eco-friendly synthesis of novel 1,2,4- liquids (TSILs) has become an attractive eld.9
triazolidine-3-thiones in water at ambient temperature. A variety of
Triazoles are an important class of heterocycles, the interest in
aldehydes undergo smooth reaction with thiosemicarbazide and their synthesis stems from their wide range of applications10 in
substituted thiosemicarbazides. In the case of substituted thio- pharmaceuticals, agro chemicals, dyes, photographic materials,
semicarbazides the corresponding 1,2,4-triazolidine-3-thiones are corrosion inhibition, etc. and biological activities such as anti-
obtained as products instead of 1,3,4-oxadiazoles. A broad variety of viral,11 antiepileptic,12 antiallergic,13 anticancer,14 anti HIV,15 anti-
functional groups are tolerated and a large number of substrates can microbial activities against Gram positive bacteria and
be applied with this protocol. Rapid eco-friendly reactions with high b3-adrenergic receptor agonist.16 Due to these multifarious appli-
yields, use of ambient temperature and water as a solvent, easy work- cations, there is a need for novel, procient and green approaches
up procedure as well as isolation of product, excellent catalyst recy- to synthesize triazoles by using readily available precursors.
clability, high atom economy, novelty of ionic liquid as well as the
As a part of our ongoing research programme, stimulated by
the development of green methods for bioactive heterocycles,17
the present investigation was undertaken. In continuation with
our work on 1,2,4-triazolidine-3-thiones,17e herein we report an
expeditious for green synthesis of 1,2,4-triazolidine-3-thiones
from aldehydes and thiosemicarbazides/substituted thio-
semicarbazides using catalytic amount of [C16MPy]AlCl3Br in
water at ambient temperature (Scheme 1).
Initial attempts were focused on synthesis of novel acidic
ionic liquid which creates micelles by self-aggregation in water
thus achieved the highest level of green chemistry. Geng et al.
quoted that a remarkable decrease in the CMC values with
increasing the hydrocarbon chain length leads to stronger
hydrophobic interactions between the hydrocarbon chains.
Hence, the micelles can form easily and the CMC values
decreases.18 As reported for conventional surfactants, the CMC
is approximately halved with each addition of one carbon atom
to the hydrocarbon chain.19 In this context we design the
protocol are the auxiliary advantages of the protocol.
In the past decade, aqueous-mediated reactions have been
extensively pursued due to their efficiency, atom-economy, non
toxic nature, economy, ease isolation of product and green
credentials.1 By utilization of their unique physical and chem-
ical properties it would be possible to realize reactivity or
selectivity that cannot be attained in organic solvents.2 The
signicant enhancement in the rate of the reaction in water has
been attributed to hydrophobic packing,3 solvent polarity,4
hydration,5 and hydrogen bonding.6 Previously the scant solu-
bility of the reactants and the sensitivity of chemical groups
towards hydrolytic degradations were the main reasons that
ruled this solvent out from studies.7 One of the solutions to
circumvent this issue comprises the addition of a phase transfer
agent or ionic liquids having surfactant property,8a as surfactant
increase the reactivity of aqueous mediated reactions via the
formation of vesicular cavities or micelles with hydrophobic
core and hydrophilic corona at ambient conditions.8b If these
surfactants based ionic liquids possess special features
required for a particular reaction will attract attention of
Department of Chemistry, Shivaji University, Kolhapur 416 004, India. E-mail:
p_dattaprasad@rediffmail.com; Fax: +91 231 2692333; Tel: +91 231 2690571
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c3ra46916f
Scheme 1 Synthesis of combinatorial library of 1,2,4-triazolidine-3-
thiones.
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presence of acidic catalysts which also required ethanol as a
solvent (entries 5–11; Table 1). It is surprising that in the pres-
ence of commercially available surfactants such as Triton X-100
in water the corresponding product was obtained in compara-
tively good yield in 1 h (entry 12, Table 1). The effect of
surfactant ionic liquid was studied and observed nearly same
results (entries 14 and 15; Table 1). The best result was obtained
by using [C16MPy]AlCl3Br in water at room temperature in very
short time (10 min) (entries 16; Table 1), this may be due to
[C16 MPy]AlCl3Br bear hydrophilic corona, hydrophobic core
and Lewis acid cites. Thus from Table 1 and green chemistry
perspective, [C16MPy]AlCl3Br is the ideal choice for present
transformation.
Fig. 1 [C16MPy]AlCl3Br.
synthesis of [C16MPy]AlCl3Br which possess hydrophobic core,
hydrophilic corona required for creation of vesicular cavities or
micelles and Lewis acidic counter ion essential to accelerate
rate of reaction as well as improve yields [Fig. 1].
Encouraged by these results, the effect of load of the catalyst
on the reaction rate was studied. It was observed that the 10 mol
% of [C16MPy]AlCl3Br was sufficient to push this reaction
forward (entries 16–19; Table 1).
The synthesis of TSIL, [C16MPy]AlCl3Br was carried out by
reaction of AlCl3 and [C16MPy][Br] obtained from N-methyl
pyrrolidine and 1-bromohexadecane (Scheme 2). The structure
of which was in full agreement with H and 13C NMR.
1
It is noteworthy that, the workup for these very clean reac-
tions involves only a ltration and a simple washing with EtOH
resulted highly pure desired product. Identication of which is
ascertained by IR, 1H, 13C NMR and MS. In the IR spectrum, the
absorption bands at 1710 cmꢀ1 due to carbonyl of aldehyde and
3350 due to primary amines disappears while band at
1594 cmꢀ1 is observed corresponding to thiocarbonyl of 1,2,4-
triazolidine-3-thiones. 1H NMR spectrum indicates three D2O
exchangeable protons at d ¼ 7.91, 8.10, 11.31 of secondary
amine, respectively. In 13C NMR, signal due to carbonyl of
aldehyde get disappeared and exhibit signal at d ¼ 178 due to
thiocarbonyl conrm the structure of product 3a.
Having the optimized reaction conditions in hand, we
extended the scope of the reaction by using various structurally
diverse aldehydes (alicyclic, cyclic, aromatic, heteroaromatic
and organometallic) with thiosemicarbazides as illustrated in
Table 2.21 Furthermore, aromatic aldehydes bearing simple and
electron-donating as well as electron-withdrawing groups were
Aer this primary success the attention was focused towards
optimization of reaction conditions for synthesis of novel 1,2,4-
triazolidine-3-thiones. In the pilot experiment, the reaction of
anisaldehyde (1 mmol) and thiosemicarbazide (1 mmol) was
investigated as the model reaction for optimization of reaction
parameters such as, choice of catalyst, mole ratio of catalyst and
solvent at ambient temperature. Comparison of the catalytic
activity of [C16MPy]AlCl3Br with basic, acidic catalysts and
surfactants under the optimal reaction conditions, showed that
it has the highest catalytic activity (Table 1, entries 2–16). Due to
scant solubility of aldehydes, reactions in water under catalyst-
free conditions are sticky resulted into low yield of desired
product (entry 1, Table 1). When ethanol is used as solvent the
yield of the desired product increased upto 80% (entry 2, Table
1). For basic catalysts such as [BMIM] OH and K3PO4, ethanol is
required as solvent with very high reaction time (entries 3 and 4;
Table 1). We observed that rate of reaction is inuenced in
Table 1 Screening of catalysts in the formation of 3aa
Sr. no
Catalyst
Catalyst load (mol%)
Solvent
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
—
—
—
—
20
20
20
20
20
20
20
20
20
20
20
20
20
20
15
10
5
Water
2
2
12
10
1
1
2
2
2
1.5
1.5
1
0.58
1
57
80
79
75
81
82
85
75
78
85
75
85
89
88
90
97
97
96
70
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Water
Water
Water
Water
Water
Ethanol
Water
Water
Water
Water
[BMIM]OH
K3PO4
[PySoPy][HSO4]2
[HSO3(CꢀH2)4MIM] [HSO4]
Gly-NO3
[PySoPy][HSO4]2
[HSO3(CH2)4MIM] [HSO4]
p-TSA
NaPTSA
Triton X 100
AlCl3
[C16MIM]Br
[C16Mpy]Br
[C16Mpy]AlCl3Br
[C16Mpy]AlCl3Br
[C16Mpy]AlCl3Br
[C16Mpy]AlCl3Br
9
10
11
12
13
14
15
16
17
18
19
1
0.167
0.167
0.167
0.5
Water
Water
a
Reaction conditions: anisaldehyde (1 mmol), thiosemicarbazide (1 mmol), specied catalyst in 5 ml water at room temp. b Isolated yield.
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Table 2 Synthesis of combinatorial library of 1,2,4-triazolidine-3-thionea
Entry
a
Thiosemicarbazide (1)
Aldehyde (2)
Product (3)
Time (min)
Yieldb (%)
10
96
b
c
5
5
90
96
d
e
10
10
90
96
f
45
10
94
95
g
h
10
96
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Table 2 (Contd.)
Entry
Thiosemicarbazide (1)
Aldehyde (2)
Product (3)
Time (min)
Yieldb (%)
i
10
94
j
10
96
k
10
10
94
96
l
a
Reaction conditions: aldehydes (1 mmol), thiosemicarbazide/4-substituted thiosemicarbazide (1 mmol), catalyst (10 mol%), water, room temp.
Isolated yield.
b
performed smoothly and the corresponding 1,2,4-triazolidine-3-
thiones are attained in excellent yields. Interestingly, excellent
yields were observed with heteroaromatic aldehydes such as
thiophene-2-carboxyaldehyde (entry (i), Table 2). Fascinatingly,
ferocene-2-carboxyldehyde worked well yielded desired product
in excellent yield (entries (f), Table 2). Remarkably, the alicyclic
aldehydes reacted with thiosemicarbazides resulting the corre-
sponding 1,2,4-triazolidine-3-thiones in excellent yields (entry
(b), Table 2).
It is worthy to note that in case of substituted thio-
semicarbazides the corresponding 1,2,4-triazolidine-3-thiones
are obtained as products instead of 1,3,4-oxadiazoles20 (entries
(g), (i–l), Table 2).
Finally, we decided to study the scope of the reaction with
isophthalaldehyde as well as terephthalaldehyde and realized
that the reaction worked well with thiosemicarbazide Scheme 3
(entries (e) and (h); Table 2).
The reaction in ionic liquid is more advantageous as it can be
recycled and reused in subsequent reactions. Aer completion
Scheme 2 Synthesis of novel TSIL, [C16MPy]AlCl3Br.
supported by UV visible analysis for which the ltrate aer each
cycle of 0.1 ml have been analyzed by recording UV-vis spectrum
in water and compared with that of thiosemicarbazide, and
fresh ionic liquid (Fig. 2). The absorption at 236 nm due to
thiosemicarbazide disappeared from the reaction mixture
indicates its complete utilization. From Fig. 2 it seems that
there is no change in properties of ionic liquid at least up to ve
cycles.
Experimental
General
of reaction the product was separated by simple ltration and Various aldehydes (Sigma-Aldrich) and thiosemicarbazide (Alfa
the ltrate was washed with diethyl ether and used for next Aesar) were used as received. M.P. recorded were determined
cycle. Filtrate was used for ve cycles without any substantial and are uncorrected. The absorption spectrum was recorded at
loss in activity, while the reactivity gradually decreases for the room temperature on a UV 3600 Shimadzu UV-vis-NIR spec-
next few cycles afforded 96, 95, 95, 94 and 93%, respectively over trophotometer with the use of a 1.0 cm quartz cell. NMR spectra
ve cycles. The efficiency of catalyst while reusability study was were recorded on Bruker AC-300 (300 MHz for 1H NMR and
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Scheme 3 Synthesis of bis-1,2,4-triazolidine-3-thione.
75 MHz for 13C NMR) spectrometer in DMSO-d6 using TMS as
an internal standard and d values are expressed in ppm and
mass spectra were recorded on a Shimadzu QP2010 GCMS.
Thus, we conclude that the present manuscript explicates
the synthesis of novel 1,2,4-triazolidine-3-thione from alde-
hydes and thiosemicarbazide in presence of catalytic amount of
[C16MPy]AlCl3Br in water at ambient temperature. This reaction
covers a great range of substrates with excellent yield of 1,2,4-
triazolidine-3-thiones within short time. It is noteworthy that in
case of substituted thiosemicarbazides the corresponding 1,2,4-
triazolidine-3-thione are obtained instead of 1,3,4-oxadiazoles.
This protocol provides a sustainable route for the synthesis of
novel 1,2,4-triazolidine-3-thione as it is simple, rapid, high-
yielding, involve room temperature, use of water as solvent,
reusable novel ionic liquid catalyst, high atom economy and
does not involve any purication techniques like column
chromatography.
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Acknowledgements
16 L. L. Brockunier, E. R. Parmee, H. O. Ok, M. R. Candelore,
M. A. Cascieri, L. F. Colwell, L. Deng, W. P. Feeney,
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Author DMP thank UGC, New Delhi for nancial assistance [F.
no. 42-394/2013 (SR)].
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triazolidine-3-thione [3]: A mixture of aldehyde (1
mmol), thiosemicarbazide/substitutedthiosemicarbazide
(1 mmol) and 10 mol% of [C16MPy]AlCl3Br in water
(5 ml) was stirred at ambient temperature for the time
specied in Table 2. The progress of reaction was
monitored by TLC. Aer completion of the reaction, the
precipitated product was isolated by simple ltration.
All products 3a–l were characterized (1H, 13C NMR, IR
and MS).
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