A task-specific biodegradable ionic liquid: a novel catalyst for synthesis of bicyclic ortho-aminocarbonitriles

Article abstract of DOI:10.1007/s13738-018-1315-1

Abstract: Herein, we report a novel method for synthesis of bicyclic ortho-aminocarbonitriles catalyzed by biodegradable ionic liquid. The biodegradability (BOD analysis) of all the ionic liquids that are used to carry out the reaction is studied, and the

Full text of DOI:10.1007/s13738-018-1315-1

Journal of the Iranian Chemical Society
https://doi.org/10.1007/s13738-018-1315-1
ORIGINAL PAPER
A task‑specifc biodegradable ionic liquid: a novel catalyst
for synthesis of bicyclic ortho‑aminocarbonitriles
D. S. Gaikwad1 · K. A. Undale1 · D. B. Patil1 · A. A. Patravale1 · A. A. Kamble2
Received: 13 June 2017 / Accepted: 27 January 2018
© Iranian Chemical Society 2018
Abstract
Herein, we report a novel method for synthesis of bicyclic ortho-aminocarbonitriles catalyzed by biodegradable ionic liquid.
The biodegradability (BOD analysis) of all the ionic liquids that are used to carry out the reaction is studied, and these ester-
functionalized ionic liquids showed better degradability as compared to the rest of the ILs. The IL used in the reaction was
recycled six times very efectively, and the method developed is efcient in terms of green chemistry metrics calculations
(AE, RME, MI, CE, TON and TOF) also. High yield, less time and no column chromatography are the added advantages
of the protocol.
Graphical Abstract
O
R
N
OH-
N
+
O
O
CN
CN
NH2
CHO
+
CN
CN
CN
CN
IL (20 mol%)
+
R
+
EtOH:H2O (1:1)
60 oC
CN
Keywords Ionic liquid · Atom economy · Reusability · Green chemistry
Introduction
green chemistry principals. In addition to this, sustainable
chemistry environment can also be adopted by the accom-
plishment of various chemical transformations in a single
step so that minimization of time will also be followed [1,
2]. Considering these green parameters, recently one-pot
condensation, i.e., multicomponent reaction (MCR), has
become a promising area which is attracting young research-
ers [3, 4]. This booming technology is becoming attractive
because of its ability to generate two or more carbon–car-
bon and carbon–hetero bonds in the synthesis of plethora of
heterocycles [5–7] and natural products [8, 9]. Over the past
decade, there have been signifcant and promising devel-
opments in MCRs, of which one of the most important is
the use of ionic liquid (IL) as a solvent or catalyst for car-
rying out the reaction [10, 11]. ILs have many advantages
over the traditional solvents or catalyst such as reusability,
negligible vapor pressure, inertness, stability, non-volatility,
The development of environmentally benign, eco-friendly
and sustainable routes for pharmaceutically or biologically
important compounds has become a momentous area in the
organic synthesis. This can be achieved by adopting the
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s13738-018-1315-1) contains
supplementary material, which is available to authorized users.
* D. S. Gaikwad
dgchemistry@gmail.com
1
Department of Chemistry, Vivekanand College, Kolhapur,
Maharashtra 416003, India
2
Department of Chemistry, Bharatratna Indira Gandhi College
of Engineering, Kegaon, Solapur, Maharashtra 413 255,
India
Vol.:(0123456789)
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Journal of the Iranian Chemical Society
non-fammability and most importantly their biodegrada-
bility in the environment [12–15]. Biodegradation is one
method of analysis to determine and predict how a molecule
interacts with the environment. The earlier literature articles
and some reviews reveal that some of the ionic liquids are
biodegradable, especially ester-functionalized ILs [15–18].
It is an immense need and a challenging job to discover
an efcient, inexpensive, easily accessible and environmen-
tally friendly organocatalysts. For the synthesis of diferent
molecules in greener way in the current manuscript, we have
synthesized diferent task-specifc ionic liquids (TSILs) with
evaluations of their biodegradability (in terms of their BOD
evaluation) and application in catalyzing MCRs to synthe-
size bicyclic ortho-aminocarbonitriles derivatives.
O
OH
+
O
N
N
N
N
N
+
-
OH-
COO
N
H
IL 1
IL 2
O
+
N
NH2
OH
NH2
N
N
N
Br-
3-
PO4
IL 3
IL 4
O
+
N
N
N
OH-
O
Cl-
The bicyclic ortho-aminocarbonitriles moiety has gained
much signifcance owing to its multifarious applications as
an important intermediate in organic synthesis [19, 20]. In
addition to this, these are extensively used in the preparation
of diverse heterocyclic compounds [21, 22]. Earlier, some
authors group has studied and reported bicyclic ortho-ami-
nocarbonitriles, but each method has its own disadvantage
[23–25]. So in continuation to our interest in developing
new methods for the synthesis of heterocyclic compounds
[26, 27] herein, we describe a highly efcient protocol for
the synthesis of bicyclic ortho-aminocarbonitriles via MCR
approach using biodegradable ester-functionalized TSIL.
IL 5
IL 6
Fig. 1 Diferent ionic liquids (ILs) studied
with some traditional basic catalyst such as K3PO4, K2CO3.
(Table 1, entries 12, 13). Hence, IL proved to be the best for
the present transformation.
Having established the optimum reaction conditions in
hand for this one-pot reaction, next we investigated the efect
of substrate scope (Scheme 2). Reaction with both electron-
withdrawing and electron-donating substituted aromatic
aldehydes along with cyclohexanone and malononitrile gave
excellent yield. All the results are summarized in Table 2.
A plausible mechanism for the formation of bicyclic
ortho-aminocarbonitriles in the presence of basic ionic liq-
uid is shown in Scheme 3. Initially, the carbonyl group of
the aldehyde and cyclohexanone reacts with malononitrile
to form the Knoevenagel products 5 and 6. Then, followed
by vinylogous Michael addition reaction of intermediates
between 6 and 5 to give intermediate 7. Then, the proton
from carbon attached to two cyano groups is abstracted to
generate carbanion, which on subsequent intramolecular
attack on cyano group to give the desired product via inter-
mediate 8.
Results and discussion
Initially, we synthesized some diferent TSILs (Fig. 1) (for
synthesis, see the supplementary information) from the ear-
lier reported literature [28–31]. In order to test the catalytic
activity of diferent ILs and to ascertain the feasibility of
the transformation, an initial reaction using benzaldehyde
(1 mmol), cyclohexanone (1 mmol) and malononitrile
(2 mmol) was chosen as a simple model substrate to opti-
mize the reaction conditions (Scheme 1) (Table 1).
To achieve the best reaction conditions, we used synthe-
sized TSILs as a catalyst. At the start, we carried out reac-
tion at ambient temperature under catalyst- and solvent-free
condition, but after a prolonged time for 12 h no formation
of desired product was observed (Table 1, entry 1). Even
though the same reaction was carried out at 60 °C, no prom-
ising yield (50%) was observed. Hence, we decided to carry
out the reaction with IL as catalyst and ethanol/H2O (1:1)
solvent system. Amazingly, the reaction completed suc-
cessfully with an excellent yield of 93% (Table 1, entry 5).
Another phosphate anionic IL got smaller quantity yield as
compared with strong basic IL (Table 1, entry 8). Inferior
results are obtained when carrying out the reaction by using
IL 2, IL 3 and IL 5 even under heating conditions (Table 1).
Reaction also gave much lower yield when carrying out
Green metric calculations
Further, we performed green metrics calculations which
state the efciency of the present protocol in terms of green
chemistry. The green metrics were calculated using the pro-
cedures reported in the literature [32, 33]. Their defnitions
are given as follows:
Mass intensity (MI) = total mass used in a process or pro-
cess step (g)/mass of product (g); reaction mass efciency
(RME) = (Ʃ mass of products/Ʃ mass of reactants) × 100;
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Journal of the Iranian Chemical Society
Scheme 1 Optimization for
bicyclic ortho-aminocarboni-
triles
O
2
Catalyst
Solvent
CN
CN
NH2
CHO
CN
CN
+
+
+
RT or
CN
3
CN
3
CN
4
1
Table 1 Screening of catalyst and optimization of reaction conditions
TON = mole of product/IL mole; TOF = TON/time in h.
All the results are summarized in Fig. 2. The present proto-
col is highly efcient in terms of its carbon efciency (CE),
atom economy (AE) and reaction mass efciency (RME).
All these calculations reveal that the protocol is near to
ideal condition in terms of green chemistry. Along with the
reusability of the catalyst and in addition to this, we have
also calculated the turnover number (TON) and turnover
frequency (TOF) of the used catalyst.
S. no.
Catalyst (mol%)
Temp.
Time in h
% Yieldc
a
1
2
3
4
5
6
7
8
–
–
RT
60 °C
RT
12
12
12
12
2
–
50a
55b
65b
93
55
50
70
40
70
91
70
62
IL 1 (20)
IL 1 (20)
IL 1 (20)
IL 2 (20)
IL 3 (20)
IL 4 (20)
IL 5 (20)
IL 6 (20)
IL 6 (20)
K3PO4
RT
60 °C
60 °C
60 °C
60 °C
60 °C
RT
60 °C
60 °C
60 °C
5
5
5
8
12
2
4
6
Literature survey discloses that ILs are non-hazardous
and they can play a duel role as catalyst and solvent [27, 28]
as they catalyze reactions and enhance the rate of reaction
attributed to typical properties of ILs such as high polar-
ity and the ability to solubilize both inorganic and organic
compounds [29]. Taking into consideration the use of ILs
in organic synthesis and commercialization of ILs, it is nec-
essary to evaluate its hazardousness to environment and
to other aquatic organisms. The assessment of the ILs can
be done in accordance with the guidelines provided by the
organization for economic co-operation and development
(OECD) [30, 31]. In general, these tests are separated into
three groups: efects on biotic systems, health efects, and
degradation and accumulation. In the present study, we
decided to carry out the study of biological oxygen demand
(BOD) [18, 32] of ILs used. The BOD represents the amount
of oxygen consumed in the biodegradation of the organic
matter in the aquatic environment by biological processes.
We carried out the BOD analysis of ILs used during the
reaction by following a reported standard procedure by
9
10
11
12
13
K2CO3
Reaction conditions: benzaldehyde (1 mmol), malononitrile
(2 mmol), cyclohexanone (1 mmol), ethanol/water (1:1) 5 mL
aWithout catalyst and solvent
bWithout solvent
cIsolated yield
Bold represents the entry No. 5 is the best reaction condition and high
yield
carbon efciency (CE) = [(no. of moles of product × no. of
carbons in product)/Ʃ (no. of moles of reactant × no. of car-
bons in reactant)] X 100; atom economy (AE) = [molecular
weight of product/Ʃ molecular weight of reactant] × 100.
R
O
IL (20 mol%)
CN
CHO
CN
CN
EtOH:H2O (1:1)
60oC
CN
+
+
+
R
CN
3
CN
3
NH2
1
CN
4
2
Scheme 2 Synthesis of Bicyclic ortho-aminocarbonitriles
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Journal of the Iranian Chemical Society
Table 2 Substrate scope for the
synthesis of bicyclic ortho-
aminocarbonitriles
Entry
Aldehyde R
MW of product
Time in h
Product yield Product yield (g)
a
%
1
2
3
4
5
6
7
8
H
300.37
330.39
344.42
334.81
334.81
346.39
316.37
325.38
318.36
314.39
390.45
379.26
328.42
2
2
2
3
3
4
3
4
4
2
3
4
2
93
90
90
86
83
86
85
92
84
93
89
84
91
0.280
0.300
0.312
0.290
0.280
0.291
0.275
0.304
0.273
0.295
0.350
0.320
0.300
4-OMe
4-OEt
4-Cl
2-Cl
3-OMe,4-OH
4-N(CH3)3
4-CN
4-F
4-Me
3,4,5-(OMe)
4-Br
2,5-Me
9
10
11
12
13
Reaction conditions: aldehyde (1 mmol), malononitrile (2 mmol), cyclohexanone (1 mmol), IL (20 mol %),
ethanol/H2O(1:1) 5 mL
aIsolated yield
Scheme 3 Plausible mechanism
for the formation of bicyclic
ortho-aminocarbonitriles
NC
-
CN
6
CN
CN
-H2O
CN
5
-H2O
N
CN
-
HO
NC
OH
CN
CN
CN
CN
+
O
O
H
7
N
N
+
N
N
O
O
O
OH-
OH-
O
3
H
CN
CN
CN
H
CN
CN
CN
2
NH
2
CN
1
8
CN
CN
NH2
CN
4
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Journal of the Iranian Chemical Society
Reusability of ionic liquid
After completion of the reaction as monitored by TLC, the
solid product formed was fltered from the reaction mix-
ture. The fltrate remained was evaporated, washed with
ethyl acetate and dried at 70 °C to get the IL pure. The
recovered IL was used for the subsequent reaction, and it
was found that it can be used efectively at least six times
without any signifcant loss in yield of the product (fg. 4).
Conclusion
In conclusion, we have described a handy, efcient method
for the rapid synthesis of bicyclic ortho-aminocarboni-
triles using ester-functionalized IL as an inexpensive cata-
lyst. High yields along with simple reaction conditions as
well as easy work-up procedure augur well for the applica-
tion of this strategy. The green metrics calculations of all
the reactions also reveal the efciency of the protocol. We
have also studied the biodegradability of diferent TSILs.
Among these, ILs with ester functionality showed promis-
ing results.
Fig. 2 Green metrics calculations (for exact values, please see sup-
porting information). MI mass intensity, % RME percentage reaction
mass efciency, % CE percentage carbon efciency, % AE percent-
age atom economy. The solvent used in the purifcation step was not
considered. The amount of catalyst was not used in the calculations
because it is recoverable as it can be reused
OECD. After analyzing the data obtained during the study,
we concluded that ester-functionalized ILs are more bio-
degradable than the rest of the functionalized ILs (Fig. 3).
Previous literature reports are also available saying that
ester-functionalized ILs are having excellent biodegrada-
bility than other ILs [33–43]. For comparison, we choose
sodium dodecyl sulfate as a standard.
Experimental
NMR spectra were recorded on a BrukerAC-400 spec-
trometer in DMSO-d6 using trimethylsilane as internal
standard.
Fig. 3 Biodegradability study of ILs (BOD analysis)
Fig. 4 Reusability of ionic liquid
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Journal of the Iranian Chemical Society
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