Novel ionic liquid [2-Eim] HSO4 as a dual catalytic-solvent system for preparation of hexahydroquinolines under green conditions

Article abstract of DOI:10.1039/c5ra09666a

A novel Bronsted acidic ionic liquid 2-ethylimidazolium hydrogen sulfate, [2-Eim] HSO₄, was synthesized. Its structure was investigated using FT-IR, ¹H NMR, ¹³C NMR, UV, TGA and DTA spectroscopy. This ionic liquid was util

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ARTICLE
Novel ionic liquid [2-Eim] HSO4 as a dual catalytic-solvent system
for preparation of hexahydroquinolines under green condition
M. Ghorbani*, a, S. Nouraa, M. Oftadeha, E. gholamia, M. A. Zolfigolb
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
A novel Brønsted acidic ionic liquid 2-ethyl imidazolium hydrogen sulfate, [2-Eim] HSO4, was synthesized. Its structure was
investigated using FT-IR, 1H NMR, 13C NMR, UV, TGA and DTA spectra. This ionic liquid is utilized as a highly efficient and
homogeneous catalyst for the promotion of hexahydroquinolines via one-pot multi-component condensation of aromatic
aldehydes, dimedone, ethyl acetoacetate, and ammonium acetate at room temperature and neat conditions. Also,
optimization of the reaction conditions was investigated using the response surface method {Central Composite Design
(CCD)}. This new method consistently has the advantages of excellent yields and short reaction times. Further, the catalyst
could be reused and recovered at least four times without appreciable loss of activity.
www.rsc.org/
optimum conditions for desirable responses14. The above
mentioned subjects encouraged us to synthesize a new ionic
liquid with Brönsted acidic property, named as 2-ethyl
imidazolium hydrogen sulfate, [2-Eim] HSO4, for the first time
(Scheme 1), and its characterization by using FT-IR, 1H NMR,
13C NMR, UV, thermal gravimetric analysis (TGA) and
differential thermal analysis (DTA). Our investigations showed
that this reagent can be used as an efficient catalyst in the
Hantzsch reaction. The method is easy and the products are
obtained in high yields and short reaction times (Scheme 2).
1. Introduction
Ionic liquids, ILs, (based imidazolium or other organic cations)
have received considerable interest as eco-friendly solvents,
catalysts and reagents in green synthesis because of their
unique properties, such as low volatility, nonflammability, high
thermal stability, negligible vapor pressure and ability to
dissolve a wide range of materials 1-4. Recently ionic liquids
have been successfully employed as dual reagents (solvents +
catalysts) for a variety of the reactions, but their use as
catalyst under solvent-free conditions needs to be given more
attention5. Among them, Brønsted acidic ionic liquids have
designed to replace solid acids and traditional mineral liquid
acids like sulfuric acid and hydrochloric acid in chemical
procedures6. On the other hand, in recent years, an increasing
interest has been focused on the synthesis of 1,4
dihydropyridine compounds owing to their significant
biological activities7. In particular, dihydropyridine drugs such
as nifedipine, nicardipine and amlodipine (Fig. 1) are effective
cardiovascular agents for the treatment of hypertension8. In
view of the importance of polyhydroquinoline derivatives,
many
classical
methods
for
the
synthesis
9-13
of
polyhydroquinoline derivatives were reported
.
Also
response surface method (RSM) is collection of mathematical
and statistical techniques useful for designing experiments,
building models, evaluating relative significance of several
independent variables and their interactions, and determining
Fig. 1. Typical dihydropyridine drugs.
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Scheme. 1. The synthesis of 2-ethyl imidazolium hydrogen
sulfate, [2-Eim] HSO4
Fig. 2. FT-IR spectra of 2-ethyl imidazole (top), and [2-Eim]
HSO4 (down)
2.1.2. H NMR and 13C NMR studies. 1H and 13C NMR spectra
of [2-Eim] HSO4 ionic liquid are presented in Fig. 3. As Figure 3,
1
1
indicates that, the important peak of H NMR spectra of ionic
Scheme. 2. The one-pot multi-component preparation of ethyl
4-(aryl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-
3-carboxylate derivatives catalysed by [2-Eim] HSO4
liquid catalyst is linked to the acidic hydrogens (NH groups on
imidazolium ring and hydrogen sulfate) which is observed in δ
= 10.71 ppm. To confirm that this peak (10.71 ppm) is really
related to the (NH groups on imidazolium ring and hydrogen
sulfate) in the compound, not hydrogen of H2SO4 (its
unreacted starting material) H2SO4: 1H NMR (DMSO-d6, 300
MHz, ppm): δ=12.54 (s, 1H) 15 was investigated. The difference
between the peaks of the acidic hydrogens in [2-Eim] HSO4 and
H2SO4 15 confirmed that the peak observed in 10.71 ppm of the
1H NMR spectra of [2-Eim] HSO4 is correctly related to the
acidic hydrogens of this compound. The structure of [2-Eim]
HSO4 confident to accept that this reagent can act as an
efficient catalyst in reactions that needs acidic reagents to
speed up. Our investigations clarified that this prediction is
correct and can act as a promotion of the synthesis of
hexahydroquinolines (Scheme 2).
2. Results and discussion
2.1. Characterization of the catalyst
2.1.1. FT-IR studies. FT-IR (KBr, cm-1) υmax: 582, 761, 867, 1048,
1191, 1462, 1509, 1623, 2500-3500 cm-1. The corresponding
FT-IR spectral data of [2-Eim] HSO4 are presented in Fig. 1.
Spectrum of the ionic liquid indicated an abroad peak at 3112
cm−1 which can be related to N–H stretching group on
imidazolium ring. The strong absorptions at 582, and 867 in [2-
Eim] HSO4 ionic liquid were assigned to the stretching and
bending for S–O vibrations of hydrogen sulfate, also the
absorption at 1191 and 1048 cm−1 is related to O=S=O
asymmetric and symmetric stretching peaks that were absent
in 2-ethyl imidazole. In addition, C=N, N-H, and C=C vibrations
are observed at 1623, 1509, and 1462 cm-1, respectively. The
broad and strong bands at 2400–3600 cm−1 can be arising
from the stretching of the hydroxyl group in the ionic liquid
catalyst. These special IR peaks indicated that hydrogen sulfate
was successfully assembled by 2-ethyl imidazole molecule as
an anion for corresponding ionic liquid.
2 | J. Name., 2012, 00, 1-3
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subject confirmed that the catalyst is one-system, not binary
systems. In binary systems, the thermogravimetry (TG)
diagrams must be showed weight losses in two or more steps.
Moreover, the TGA and DTA diagrams of [2-Eim] HSO4 are
different. Therefore, the molecular decomposition of the ionic
liquid occurred above 319.8 °C.
Fig. 4. The TG/DTG diagrams of [2-Eim] HSO4
Molecular self-assembly including intramolecular and
intermolecular, is the process by which molecules adopt a
defined arrangement without guidance or management from
an outside source. Most often the term molecular self-
assembly refers to intermolecular self-assembly, and assembly
of molecules is directed through non-covalent interactions
(such as hydrogen bonding, metal coordination, hydrophobic
forces, van der Waals forces, π–π interactions and
electrostatic) as well as electromagnetic interactions16. The
specific structure of [2-Eim] HSO4 as a functional Brønsted
acidic ionic liquid with hydrogen-bond donor, can give it the
ability to produce a molecular self-assembly through hydrogen
bonds (Fig. S1†).
On the basis of the structure of [2-Eim] HSO4, it can act as an
efficient catalyst in reactions which need the use of acidic
catalysts to accelerate the rate of reaction. These functional
groups provide the ability to produce a molecular self-assembly
through intermolecular hydrogen bonds (Fig. S2†) and as a result
go up its thermal stability.
Fig. 3. 1H NMR and 13C NMR of 2-ethyl imidazolium hydrogen
sulfate, [2-Eim] HSO4.
2.1.4. UV spectra. UV–vis (DMSO): λmax 295 nm; UV spectra was
another evidence to confirm that [2-Eim] HSO4 was really
synthesized. For this purpose, UV–vis spectra of 2-ethyl
imidazole and [2-Eim] HSO4 were recorded. At first, some
solutions of the mentioned compounds in DMSO with the same
1
Spectral data of [2-Eim] HSO4 viscous pale yellow oil; HNMR
(400.22 MHz, DMSO-d6): δ (ppm) 1.262 (t, J = 7.6, 3H, CH3),
2.899-2.956 (m, J = 7.6, 2H, CH2), 7.486 (s, 2H), 10.712 (s, 3H);
13C NMR (100.64 MHz, DMSO-d6): (ppm) 11.88, 19.28, 119.20,
149.07.
concentration were prepared. The concentration of these
1
. The
compounds in DMSO for UV study was 0.005molL−
maximum absorptions of 2-ethyl imidazole (at 268, 293 nm) and
[2-Eim] HSO4 (at 295 nm) appeared, at 0.1082, 0.2978 and
0.1940 respectively. The difference between maximum
absorptions of 2-ethyl imidazole and [2-Eim] HSO4 confirmed the
preparation of the catalyst Fig. 5.
2.1.3. Study on thermal gravimetric analysis (TGA) of [2-Eim]
HSO4. The corresponding diagrams are shown in Fig. 4. As it
can be seen in Fig. 4, TGA and differential thermal analysis
(DTA) of the catalysts showed weight losses in one step; [2-
Eim] HSO4 was decomposed above 319.8 °C in one step. This
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optimization. The CCD is an effective design that provides
reasonable amount of information for testing the goodness of fit.
This method does not require large number of design points so
20
reducing the overall cost associated with the experiment. After
the characterization of [2-Eim] HSO4, we tested the catalytic activity
of it to promote the preparation of hexahydroquinolines. For this
purpose, a mixture of dimedone, 4-methoxybenzaldehyde, ethyl
acetoacetate and ammonium acetate in the present of [2-Eim] HSO4
under solvent-free condition was chosen as model reaction,
optimization of the reaction condition was investigated using the
response surface method {Central Composite Design (CCD)} with
four replicate at central point for developing a second order model
with 12 runs (Table S1†). Two variables that can effect on yield and
time of the reaction are catalyst (A with levels of the variables 3.6
to 11.5 mol%) and amount of ammonium acetate (B with levels of
the variables 10 to 10.6mmol). Yield and time of the reaction were
used as the dependent variables and were fitted to a quadratic
polynomialmodel. After programming optimization (Table S2† and
S3†), two polynomial response surface models based on significant
levels and actual values for time and yield were obtained.
Time = +8.22 – 6.84A – 1.08B + 2.60A2 (1)
Yield = +93.00 + 9.82A + 1.19B – 6.31A2 – 1.81B2 (2)
Fig. 5. UV spectra of a) 2-ethyl imidazole and b) [2-Eim] HSO4 at
room temperature in DMSO (the concentration of these
compounds in DMSO was 0.005molL−1).
Figs. 7-8 show the three-dimensional response surfaces, as well as
contour plots of the relationship between different parameters at
the optimized values. According to the models, interactions
between variables have significant effects on the responses;
therefore, results were presented and discussed in terms of
2.1.5. Measuring pH in aqueous media. The pH profile was
investigated and its corresponding diagram was shown in Fig. 6. At
first, a solution of the mentioned compound in water was also
prepared. The concentration of this compound in water for pH
study was 0.05molL−1. The pH was found 2.218 (at 25 oC). For
approaching overall to this main scope we have titrated the
solution by NaOH 0.05 N. The result is summarized in Fig. 6.
interactions
.
Fig. 6. pH Control, titrated aqueous media by NaOH 0.05N
2.1.6. Catalyst activity. RSM is one of the relevant multivariate
techniques which can deal with multi variant experimental design
18-19
strategy, statistical modeling and process optimization.
RSM
usually contains three steps: (1) design and experiments; (2)
response surface modeling through regression; and (3)
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actual values of Yield. The clustering of the points around the
diagonal line indicates a satisfactory correlation between the
experimental data and the predicted values, confirming the
robustness of the model.
Fig. 7. Contour plot and response surface for the effect of factors on
the reaction time.
Fig. 9. Predicted vs. actual values of Yield
For finding of accurate optimum area, with using of obtained
equations and calculation of desirability functions, the results
showed that accurate optimal operational conditions was (A = 7.55
mol%, B = 10.3 mmol). It should be mentioned that corresponding
maximum prediction conversion was 98.44% in introduced optimal
point. In the next step, the accuracy of the theoretical results, were
examined by empirical research. For this purpose, as model
reaction,
a
mixture of dimedone (10 mmol), 4-
methoxybenzaldehyde (10 mmol), ethyl acetoacetate (10 mmol)
and ammonium acetate (10.3mmol), was stirred in the presence 7.5
mol% of [2-Eim] HSO4 under solvent-free condition. The respective
result is displayed in Table 1. As it can be seen in Table 1, indicates
that (7.5 mol%) of [2-Eim] HSO4 was suitable to catalyze the
reaction at room temperature. In this reaction condition, the
desired hexahydroquinoline was efficiently prepared in 93% yield
within 8 min (Table 1) which is in a good accordance with the
response surface method.
Table 1
Optimization conditions for the one-pot synthesis of ethyl 4-
(4-methoxyphenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8
hexahydroquinoline-3-carboxylate in the presence of [2-Eim]
HSO4 under solvent-free conditions .
Catalyst
Temp (oC)
Time (min)
Yielda (%)
(mol%)
7.5
25
8
93
Fig. 8. Contour plot and response surface for the effect of factors on
the reaction Yield.
aYields refer to the pure isolated products based on the
reaction of 4-methoxybenzaldehyde (10 mmol), dimedone
(10 mmol), ethyl acetoacetate (10 mmol) and ammonium
acetate (10.3 mmol).
2.1.7 Determination of model adequacy. It should be noted that
polynomial models are reasonable approximations of the true
functional relationship over relatively small regions of the entire
space of independent variables17. Fig. 9. represents predicted vs.
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Further investigation shows that 7.5 mol% of catalyst at room
temperature is optimum condition and the yield of products was
excellent. To investigate the generality of present protocol, we
also run the various aldehydes that were converted to
hexahydroquinolines under the optimum condition (Table 2).
242–
244/242
–24421
6
9
93
Table 2
190-
192/191
-19323
Synthesis of ethyl 4-(aryl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-
hexahydroquinoline-3-carboxylate derivatives catalyzed by
[2-Eim]HSO4.
7
7
94
M.P/M.
Time
(min)
Yielda
(%)
Entry
Product
P
[ref](℃)
206-
208/
205-
20622
8
7.5
95
255–
257/255
–25615
1
9
92
232-
234/232
–23322
9
11
10.5
11
92
91
92
263–
265/262
–26422
2
9.5
91
218-
220/
10
256–
258/257
–25921
(220)24
3
4
5
8
93
94
90
195-
197/196
-19823
204-
206/205
–20722
11
8
a
Yields refer to the isolated pure products. The desired
known pure products were characterized by comparison of
their physical data (melting points, IR, 1H NMR) with those of
known compounds.
229–
231/228
–23021
10
Considering the reaction mechanism (Scheme 3), it can be
proposed that in the first step of reaction dimedone is converted
to its enol form by using [2-Eim] HSO4 and readily undergoes
Knoevenagel condensation with benzaldehyde to generate a 2-
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benzylidenedimedone (1). On the other hand, the activated β- group. The obtained results relating of intermediates are
ketoester (by the catalyst) with liberation of ammonia from agreement with those reported in the literatures. Thus our
NH4OAc
gives
enamine
(2).
Afterward,
the
2- suggested mechanism was confirmed with experimental data
benzylidenedimedone (1) and enamine (2) react together by and also by the literatures 15, 25-26
michael addition to afford intermediate (3). The intermediate (3)
is converted to intermediate (4) by tautomerization, and the
.
intermediate (4) affords intermediate (5) by intramolecular
nucleophilic attack of the NH2 group to the activated carbonyl
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Scheme. 3. Plausible mechanism for the catalytic synthesis of ethyl 4-(phenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-
3-carboxylate derivatives catalyzed by [2-Eim] HSO4.
2.1.8. Catalyst recycling. An important aspect of catalysts in amount of H2O decreased their activity. This can be attributed to
partial protonation of water as H3O+ instead of substrates.
large scale production is the recyclability and reusability of
applied catalysts. In order to examine the recyclability of the [2-
Eim] HSO4, the reaction between 4-methoxybenzaldehyde,
dimedone, ethyl acetoacetate, and ammonium acetate was
chosen Fig. 10. For recycling experiment, the reaction was
carried out in the same condition. At the end of the reaction, it
was cooled to room temperature. Then, 3 mL of water was
methoxybenzaldehyde, dimedone, ethyl acetoacetate and
added to the mixture. The ionic liquid was dissolved in water,
Table 3
Effect of impurities of water on the condensation of 4-
ammonium acetate.
and filtered for separation of the crude product. The separated
Water amount
Entry
Time (min)
Yielda (%)
product was washed twice with water (2×3 mL). For recycling
the catalysts, after washing the solid products with water
completely, the water containing the ionic liquid (IL is soluble in
water) was evaporated under reduced pressure and the ionic
liquid was recovered and reused. The solid product was purified
by recrystallization procedure in ethanol. All of the desired
product(s) were characterized by comparison of their physical
and spectral data (melting points, IR, 1H NMR) with those of
known compounds. 15, 27-28
(mmol)
1
1
3
9
93
92
90
90
88
81
2
12
17
28
33
40
3
5
4
7
5
9
6
11
a Isolated Yield
2.1.10. Comparison catalyst synthesized with reported results
in another literatures. In order to show the accessibility of the
present work in comparison with reported results in the
literatures, some of the results for the preparation of
hexahydroquinolines were summarized in Table 4. The results
show that [2-Eim] HSO4 as catalyst is the most efficient catalysts
with respect to the reaction time, low temperature, and exhibits
broad applicability in terms of the obtained yields.
Table 4
comparison the results of 2-ethyl imidazolium hydrogen sulfate, [2-
Eim] HSO4 with other catalysts reported in the literature in the
synthesis of ethyl 4-(4-methoxyphenyl)-2,7,7-trimethyl-5-oxo-
1,4,5,6,7,8-hexahydroquinoline-3-carboxylate
Yield(%)[r
ef]
Amount
of the
catalyst
Entry
Time
(min)
Catalyst
Conditions
93(the
present
work)
1
[2-Eim]
HSO4
Solvent-
free , r.t
Fig. 10. The investigation of the reusability of the ionic
liquid under solvent-free conditions using a model reaction
of 4-methoxybenzaldehyde, dimedone, ethyl acetoacetate,
and ammonium acetate in the presence of reused [2-Eim]
HSO4 as catalyst.
7.5 mol%
8
2
3
9127
9529
[DSim]H
SO4
Solvent-
free, 50 oC
3 mol%
3 mol%
32
10
[Pyridine
-SO3H]Cl
solvent
free, 50oC
2.1.9. Effect of impurity of water on the catalytic activity of 2-ethyl
imidazolium hydrogen sulfate
The ionic liquid is sensitive to moisture and water. To study effect of
silica
sulfuric
acid
solvent
free, 60 oC
or MW
4
9430
0.20
mmol
30
impurity of water on the catalyst activity, the condensation of 4-
methoxybenzaldehyde (10 mmol), dimedone (10 mmol), ethyl
acetoacetate (10 mmol) and ammonium acetate (10.3 mmol), using
[2-Eim] HSO4 (7.5 mol%) was examined in the presence of various
amounts of H2O at room temperature. (Table 3). As Table 3
indicates, 11 mmol of H2O did not affect significantly on the
catalytic activity of [2-Eim] HSO4; however, more increasing the
(SSA)
5
6
7
9631
9332
9233
HClO4-
SiO2
Solvent-
free, 50 oC
50 mg
10
55
8
[(CH2)4S
O3HMIM
][HSO4]
0.25
mmol
reflux,
EtOH
Solvent-
free, 60 oC
[Bsim]Cl
10 mol%
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nanoꢀγ ꢀ
Fe
SO
(MSAIm)
HSO4
In this research, Brønsted acidic ionic liquid [2-Eim] HSO4 as a
novel, highly efficient, general and homogeneous catalyst for the
one-pot multi-component reaction between various aldehydes,
dimedone, ethyl acetoacetate, and ammonium acetate leading
to hexahydroquinolines. The synthesized catalyst showed
8
9
9334
8935
8836
Solvent-
free, 60 oC
0.031gr
3.8 mol%
2 mol%
90
22
2
O ꢀ
3
3
H
Solvent-
free, 50 oC,
[MPIm][
HSO4]@S
BA-15
excellent
activity
in
the
synthesis
of
various
10
H2O, 45 oC
180
hexahydroquinolinein a green way. Also, optimization of the
reaction condition was investigated using the response surface
method {Central Composite Design (CCD)} which was in a good
accordance with empirical research. In addition, catalyst was
recycled four times without the significant loss of activity. In the
view of green chemistry the present protocol could find
industrial application.
3. Experimental
3.1. Materials
All chemicals were purchased from Merck or Fluka chemical
companies. All yields refer to the isolated products. Products
were characterized by their physical constants and comparison
with authentic samples. The purity determination of the
substrates and the reaction monitoring were accompanied by
TLC using silica gel SIL G/UV 254 plates.
Acknowledgements
The authors gratefully acknowledge partial support of this work
by the University of Payame Noor (Grant No. 62370) and Bu-Ali
Sina University.
3.2. Instrumentation
Notes and references
Melting points were measured using a Galen Kamp melting point
apparatus and are uncorrected. 1H NMR spectra were recorded
by Bruker Avance 400.22 using DMSO-d6 as the solvent and TMS
as the internal standard. FT-IR spectra were recorded with
PerkinElmer Spectrum Version 10.00.00. TG and DTA data were
1
2
3
B.C. Ranu, L. Adak, S. Banerjee, Can. J. Chem., 2007,
85, 366–371.
V.I. Parvulescu, C. Hardacre, Chem. Rev., 2007, 107,
2615–2665.
R.D. Rogers, K.R. Seddon, Ionic Liquids: Industrial
Applications to Green Chemistry, ACS, Washington, DC,
2002.
H. R. Shaterian, S. Noura, RSC Adv., 2014, 4, 60543
M. A. Zolfigol, A. Khazaei, A.R. Moosavi-Zare, A. Zare,
Zh. Asgari, V. Khakyzadeh, A. Hasaninejad, Industrial
and Eng. Chem., 2013, 19, 721–726.
obtained by
spectra were recorded by
spectrophotometer.
a PerkinElmer pyris diamond TG-DTA. UV–vis
a
Shimadzu UV-mini-1240V
4
5
3.3. Procedure for the preparation of ionic liquid [2-Eim] HSO4
To a round-bottomed flask (100 mL) containing 2-ethyl imidazole
(0.9613 g, 10mmol) in dry CH2Cl2 (50 mL), was added sulfuric
acid (0.9808 g, 10mmol) dropwise over a period of 10 min at
room temperature. After the addition was completed, the
reaction mixture was stirred for 50 min, stand for 5min, and the
CH2Cl2 was decanted. The residue was washed with dry CH2Cl2
(3×50 mL) and dried under vacuum to give [2-Eim] HSO4 as pale
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General
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