Compatibility of supported ionic liquid phase catalysts under ultrasonication

Article abstract of DOI:10.1016/j.molliq.2018.06.039

Various supported ionic liquid phase (SILP) catalysts containing hexafluorophosphate anion have been prepared by covalent grafting of imidazolium ionic liquid in the matrix of cellulose, silica and Merrifield resin followed by anion metathesis reaction. T

Full text of DOI:10.1016/j.molliq.2018.06.039

Accepted Manuscript
Compatibility of supported ionic liquid phase catalysts under
ultrasonication
Megha Jagadale, Dolly Kale, Rajashri Salunkhe, Mohan Rajmane,
Gajanan Rashinkar
PII:
S0167-7322(18)30941-3
doi:10.1016/j.molliq.2018.06.039
MOLLIQ 9237
DOI:
Reference:
To appear in:
Journal of Molecular Liquids
Received date:
Revised date:
Accepted date:
22 February 2018
5 June 2018
10 June 2018
Please cite this article as: Megha Jagadale, Dolly Kale, Rajashri Salunkhe, Mohan
Rajmane, Gajanan Rashinkar , Compatibility of supported ionic liquid phase catalysts
under ultrasonication. Molliq (2017), doi:10.1016/j.molliq.2018.06.039
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ACCEPTED MANUSCRIPT
Graphical Abstract
Compatibility of supported ionic liquid phase catalysts under ultrasonication
a
a
a
b
a
Megha Jagadale , Dolly Kale , Rajashri Salunkhe , Mohan Rajmane , Gajanan Rashinkar *
aDepartment of Chemistry, Shivaji University, Kolhapur, 416004, M.S., India
bSadguru Gadge Maharaj College, Karad, 415110, M.S., India
E-mail: gsr_chem@unishivaji.ac.in
∗Corresponding author. Tel.: +91 231 260 9169; fax: +91 231 2692333.
Graphical abstract
1

ACCEPTED MANUSCRIPT
Compatibility of supported ionic liquid phase catalysts under ultrasonication
a
a
a
b
a
Megha Jagadale , Dolly Kale , Rajashri Salunkhe , Mohan Rajmane , Gajanan Rashinkar *
aDepartment of Chemistry, Shivaji University, Kolhapur, 416004, M.S., India
bSadguru Gadge Maharaj College, Karad, 415110, M.S., India
E-mail: gsr_chem@unishivaji.ac.in
∗Corresponding author. Tel.: +91 231 260 9169; fax: +91 231 2692333.
Abstract: Various supported ionic liquid phase (SILP) catalysts containing hexafluorophosphate
anion have been prepared by covalent grafting of imidazolium ionic liquid in the matrix of
cellulose, silica and Merrifield resin followed by anion metathesis reaction. The compatibility of
SILP catalysts in the synthesis of 1,4-dihydropyridines under ultrasonication is investigated. The
results revealed that SILP catalysts can be effectively used under ultrasonication without
physical, chemical and structural changes as evidenced from various analytical techniques.
Keywords: Ionic Liquids; Supported ionic liquid phase; hexafluorophosphate anion;
dihydropyridine; reusability.
1
. Introduction
The advent of green chemistry principles has spurred unique interest in ultrasound
assisted organic synthesis as it offers clean as well as energy conserving protocol [1]. It has
potential benefits over conventional methods that include product selectivity, reduction in cost,
energy and waste [2]. Mechanistic process of ultrasonication involves acoustic cavitation, which
comprises generation, growth, oscillation and implosive collapse of bubbles inside the reaction
medium leading to rate enhancement [3]. Recently, synergistic effect of Ionic Liquids (ILs) with
2

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ultrasound has attracted considerable interest in the scientific community. Their combination is
being increasingly exploited in diverse fields such as material science, organic synthesis,
biomass processing, micro-extraction, waste water treatment and electrochemistry [4a]. Use of
ILs with ultrasound as a non-conventional energy source offers diverse benefits in terms of
energy economy, diminution in processing time and enhancement in mass transfer. Application
of ILs as reaction media in sonochemical transformations is attributed to their negligible vapor
pressure by the virtue of which efficiency of acoustic cavitation in bulk is altered noticeably that
forces the substrates to collapse more violently, ultimately leading to acceleration in the rate of
reactions [5]. However, despite these advantages the use of ILs under sonication has not
progressed significantly as many of the ILs under ultrasound irradiation undergo decomposition
into precursor azoles, alkyl halides, gaseous organic products and hydrocarbons [4]. In addition,
physical effect of ultrasound on ILs leads to production of radicals at high frequency along with
the rapid degradation. Moreover, the sonication of ILs leads to darkening of color as a function
of time, which displays serious issues for industrial application as purification and decolorization
steps of ILs result into poor E-factor [4a].
The concept of supported ionic liquid phase (SILP) catalysis involving immobilization of
ILs onto surface of porous high-area support material has been recently introduced to circumvent
the drawbacks associated with ILs. This new class of heterogenized version of ILs offer benefits
chief of which is the ease of separation of catalyst simply by filtration as well as facilitating
significant advances in selectivity, stability, recycling reproducibility and activity, decreases
mass transfer limitation due to wide diffusion of reactants in highly viscous ILs [6]. Moreover,
chemical transformations using SILP catalysts can be conducted under unusual conditions
3

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employing fixed bed technology [7]. These advantageous properties have sparked significant
interest in organic synthesis by employing SILP catalysts instead of ILs.
The scrutiny of literature reveals no report on the use as well as compatibility of SILP
catalysts under ultrasonication. As the field of SILP catalysis is still in its infancy, we envisioned
that such a study requires urgent attention as it can open new avenues for contemporary research
in green chemistry. In continuation of our research in green chemistry [8], we herein report our
pilot studies on the structural compatibility of SILP catalyst under ultrasonication.
2
. Experimental
2
.1 General remarks
All reactions were carried out under air atmosphere in dried glassware. Ultrasonication was
performed in EN 50 US Enertech Make ultrasound cleaner with a frequency of 33 kHz and an
output power of 120W. Infrared spectra were measured with a Perkin-Elmer one FT-IR
spectrophotometer. The samples were examined as KBr discs~5% w/w. Raman spectroscopy
was done by using Bruker FT-Raman (MultiRAM) spectrometer. The elemental compositions of
material were analyzed by an energy-dispersive X-ray spectra (EDS) attached to the field
1
emission scanning electron microscope (FE-SEM, Model Hitachi S 4800, Japan). H NMR and
1
3
1
13
C NMR spectra were recorded on a Bruker AC (300 MHz for H NMR and 75 MHz for C
NMR) spectrometer using CDCl as solvent and tetramethylsilane (TMS) as an internal standard.
Chemical shifts are expressed in δ parts per million (ppm) values and coupling constants are
3
1
3
expressed in hertz (Hz). The CP-MAS C NMR spectrum was recorded with a JEOL-ECX400
type FT-NMR spectrometer under prescribed operating condition. Mass spectra were recorded
on a Shimadzu QP2010 GCMS. The morphology of materials were analysed by SEM using a
JEOL model JSM with 5 kV and 20 kV accelerating voltage. Melting points were determined on
4

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MEL-TEMP capillary melting point apparatus and are uncorrected. Aerogel silica, cellulose,
alumina, Merrifield resin, potassium hexafluorophosphate and all other chemicals were obtained
from local suppliers and used without further purification.
2
.2 Preparation of chloropropyl aerogel silica (3)
A mixture of activated aerogel silica (1) (5.0 g) and 3-chloropropyltriethoxy silane (2) (5.0 mL,
2.7 mmol) in 25 mL of toluene was refluxed at 100 °C in an oil bath. After 24 h, reaction
2
mixture was cooled and the product was filtered and repeatedly washed with toluene (3×5 mL)
and dried under reduced pressure at 100 °C for 8 h to produce 3 (4.9 g).
2
.3 Preparation of [SilImi]Cl (5)
A mixture of 3 (4g) and 1-N-methyl-imidazole (4; 5.0 mL, 8 mmol) in 25 mL of DMF was
heated at 80 °C in an oil bath. After 72 h, the insoluble product was filtered, washed with DMF
(
3 x 50 mL), MeOH (3 x 50 mL), CH
2
Cl (3 x 50 mL) and dried under vacuum at 50 °C for 24 h
2
to afford 5. IR (KBr, thin film): υ = 3422, 2940, 2034, 1870, 1636, 1574, 1463, 1136, 806, 648,
-1
6
21, 572, 465 cm ; Raman: υ = 3068, 2999, 2959, 2897, 2711, 2406, 1916, 1786, 1724, 1595,
-1
1
483, 1417, 1336, 1156, 1022, 893, 791, 680, 480 cm ; Elemental analysis observed: % C 8.34,
-
1
%
H 1.34, % N 2.07; Loading: 0.73 mmol imidazolium unit g of silica.
(6)
A mixture of 5 (3g) and 7% aqueous KPF
2
.4 Preparation of [SilImi]PF
6
6
solution (25 mL) was vigorously stirred at ambient
temperature. After 24 h, the insoluble product was filtered, washed with copious amount of water
and dried under vacuum at 50 °C for 24 h to afford 6. IR (KBr, thin film): υ = 3451, 2955, 2008,
-
1
1
2
1
873, 1633, 1575, 1419, 1154, 841, 649, 622, 558, 489, 426, 408 cm ; Raman: υ = 3035, 2967,
921, 2899, 2839, 2768, 2702, 2662, 2519, 2491, 1925, 1782, 1730, 1527, 1456, 1379, 1146,
-1
052, 787, 745, 648, 461 cm ; Elemental analysis observed: % Si 28.42, % O 45.10, % N 1.89,
5

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-
1
%
C 16.56, % P 1.21, % F 6.81; Loading: 0.40 mmol functional group g of silica.
.5 Preparation of Cell-Al composite (8)
Blend of microcrystalline cellulose (7, 15 g), aluminum chloride hexahydrate (15 g) in water
200 mL) was stirred for 12 h. The mixture was subsequently filtered and resultant solid was
2
2
O
3
(
exposed to ammonia. Finally, it was washed with water and dried under vacuum at room
temperature to get 8. The amount of aluminum was determined by calcining 0.300 g of 8 to 600
°
C for 8 h and the residue weighed as Al
2
3
O , which was found to be 3.24 wt%, corresponding to
-
1
0
2
.67 mmol g aluminum.
.6 Preparation of chloropropyl cellulose (9)
A mixture of 8 (10.0 g) and (3-chloropropyl)triethoxysilane (2; 9.6 mL, 43.6 mmol) in 25 mL of
toluene was refluxed in an oil bath. After 24 h, reaction mixture was cooled, the product was
filtered and washed with toluene (3 × 5 mL) and dried under vacuum at room temperature for 8 h
to produce 9. IR (KBr, thin film): υ = 3366, 2898, 1623, 1427, 1335, 1204, 1160, 1109, 1056,
-1
-1
1
032, 707, 667 cm ; Loading: 0.67 mmol functional group g of cellulose.
2
.7 Preparation of [CellIMi]Cl (10)
A mixture of 9 (7.0 g) and 1-N-methyl-imidazole (4; 8.84 mL, 14 mmol) in DMF (25 mL) was
o
heated at 80 C in an oil bath. After 72 h, the solid was filtered, washed with DMF (3 × 50 mL),
o
MeOH (3 × 50 mL), CH
2
Cl
2
(3 × 50 mL) and dried under vacuum at 50 C for 24 h to afford 10.
IR (KBr, thin film): υ = 3346, 2902, 2129, 1642, 1574, 1371, 1317, 1281, 1245, 1061, 897, 665,
−
1
6
1
5
19, 579 cm ; Raman: υ = 3163, 3071, 2896, 2597, 2446, 2370, 2249, 1893, 1728, 1576, 1468,
−
1
377, 1337, 1119, 1095, 785, 515 cm ; Elemental analysis observed: % C 39.78, % N 1.84, % H
-1
.96; Loading: 0.65 mmol imidazolium unit g of cellulose.
6

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2
.8 Preparation of [CellImi]PF
6
(11)
A mixture of 10 (5.0 g) and 7% aqueous KPF
6
solution (40 mL) was stirred at room temperature
for 24 h. Afterwards, the mixture was filtered and the residue was washed with water and dried
under vacuum at 50 °C for 24 h to afford 11. IR (KBr, thin film): υ = 3356, 2902, 2130, 1640,
-1
1
429, 1371, 1336, 1317, 1281, 1246, 1113, 1059, 837, 707, 665, 617, 599 cm ; Raman: υ =
3
157, 2894, 2652, 2583, 2498, 2391, 2200, 2128, 1885, 1729, 1591, 1467, 1380, 1339, 1290,
−
1
1
119, 1095, 777, 734, 617 cm ; Elemental analysis observed: % Si 0.44, % Al 0.49, % N 6.78,
-1
%
C 61.71, % P 1.63, % F 9.43, % O 19.53; Loading: 0.54 mmol functional group g of
cellulose.
.9 Preparation of [MerImi]Cl (13)
2
A mixture of Merrifield resin (12; 1.0 g) and 1-N-methyl-imidazole (4; 1.26 mL, 2.0 mmol) in 15
mL of DMF was heated at 80 °C in an oil bath. After 72 h, the polymer was filtered, washed with
DMF (3 × 20 mL), MeOH (3 × 20 mL), CH
2
Cl
2
(3 × 20 mL) and dried under vacuum at 50 °C
for 48 h to afford 13. IR (KBr, thin film): υ = 3398, 3025, 2919, 2850, 1731, 1600, 1568, 1492,
−
1
1
1
444, 1364, 1156, 904, 750, 691, 612 cm ; Raman: υ = 3054, 2904, 2852, 2404, 1815, 1601,
−
1
449, 1332, 1185, 1155, 1029, 1000, 790, 619 cm ; Elemental analysis observed: % C 78.76, %
-1
H 7.30, % N 4.34; Loading: 1.55 mmol imidazolium unit g of resin.
.10 Preparation of [MerImi]PF (14)
MerImi]Cl (13; 1.0 g) was suspended in 7% aqueous solution of KPF
2
6
[
6
(10 mL) The reaction
.
mixture was stirred for 24 h at room temperature, Afterwards the polymer was filtered and
washed with water and dried under vacuum at 50 °C for 24 h to afford 14. IR (KBr, thin film): υ
=
3398, 3025, 2919, 2850, 1731, 1600, 1568, 1492, 1444, 1364, 1156, 1019, 826, 750, 691, 612
−
1
cm ; Raman: υ = 3056, 2901, 2851, 2541, 2477, 2406, 2320, 2191, 2144, 2006, 1602, 1448,
7

ACCEPTED MANUSCRIPT
−
1
1
7
2
325, 1186, 1078, 1028, 1000, 793, 780, 739, 619 cm ; Elemental analysis observed: % C
-1
5.20, % N 11.00, % P 1.92 and % F 11.88; Loading: 0.64 mmol functional group g of resin.
.11 General procedure for the synthesis of 1,4-dihydropyridines
A mixture of aldehyde (15; 1.0 mmol), ethyl acetoacetate (16; 2.0 mmol), ammonium acetate
17; 1.0 mmol) and [MerImi]PF (14; 100 mg) in ethanol (5 mL) was sonicated at ambient
(
6
temperature. After completion of the reaction as monitored by TLC, the reaction mixture was
filtered to remove insoluble catalyst. Evaporation of solvent in vacuuo followed by column
chromatography over silica gel using petroleum ether/ethyl acetate afforded pure 1,4-
dihydropyridine derivatives.
3
. Results and Discussion
The most striking approach for the synthesis of SILP catalysts involve covalent
attachment of IL like units on high area porous support materials since it reduces probability of
leaching. The commonly employed supports are those which are easily accessible, insoluble in
common solvents, non-toxic, cost effective, biocompatible and have excellent thermal and
chemical stability. In this regard, silica, cellulose and Merrifield resin have been widely used as
supports in the synthesis of SILP catalysts [9]. This prompted us to employ silica, cellulose and
Merrifield resin as supports in the synthesis of SILP catalysts in the present work. The SILP
catalysts were synthesized by covalent attachment of imidazolium units containing
hexafluorophosphate anion. Our interest in the incorporation of PF as a counter anion is
6
rationalized on the basis of wide applicability of ILs containing hexafluorophosphate anion in the
organic synthesis [10].
The synthesis of silica SILP catalyst is outlined in Scheme 1a. Initially,
organofunctionalization of silica was achieved by reacting the activated silica (1) with (3-
8

ACCEPTED MANUSCRIPT
chloropropyl)triethoxysilane (2) to yield chloropropyl silica (3). Synthetically active chloro
group in 3 allowed installation of IL like unit in silica matrix via quaternization of 1-N-methyl
imidazole (4) to produce heterogeneous azolium salt acronymed as [SilImi]Cl (5). The anion
metathesis reaction of 5 with aqueous potassium hexafluorophosphate solution resulted in the
formation of desired silica SILP catalyst containing hexafluorophosphate anion acronymed as
[
SilImi]PF (6).
6
OEt
EtO Si
OEt
+
Cl
Silica (1) 3-Chloropropyltriethoxysilane (2)
Toluene
o
1
00 C
O
O Si
Cl
O
Chloropropyl silica (3)
DMF
N N
o
8
0 C 1-N-methyl imidazole (4)
O
O Si
N N
Cl-
O
[SilImi]Cl (5)
KPF6 H O, rt
2
O
O Si
O
N N
PF6
[
SilImi]PF (6)
6
Scheme 1a. Synthesis of silica supported ionic liquid phase catalyst containing
hexafluorophosphate anion, [SilImi]PF (6)
6
9

ACCEPTED MANUSCRIPT
The preparation of cellulose SILP is summarized in Scheme 1b. Initially, Cell-Al
2
O
3
composite (8) was prepared by uniform dispersal of alumina on the cellulose matrix (7).
Reaction of Si-OEt group of (3-chloropropyl)triethoxysilane (2) with surface Al-OH groups of 8
allowed facile synthesis of chloropropyl cellulose (9). 1-N-methyl imidazole (4) was then grafted
on 9 to afford SILP catalyst precursor acronymed as [CellIMi]Cl (10). Finally, the anion
metathesis reaction of 10 with aqueous potassium hexafluorophosphate solution yielded the
desired cellulose SILP catalyst containing hexafluorophosphate anion acronymed as
[
CellImi]PF (11).
6
Cellulose (7)
AlCl 6H O
3
.
2
OEt
EtO Si
Cell/Al2O3
Cl
+
OEt
Cell-Al O composite (8)
2
(2)
3
o
Toluene 100 C
O
O Si
O
Cell/Al2O3
Cl
Chloropropyl cellulose (9)
DMF
N N
o
8
0 C
1-N-methyl-imidazole (4)
O
O Si
Cl
Cell/Al2O3
N N
O
[CellImi]Cl (10)
H O, rt
2
KPF6
O
O Si
O
PF6
Cell/Al2O3
N N
[CellIMi]PF (11)
6
Scheme 1b. Synthesis of cellulose supported ionic liquid phase catalyst containing
hexafluorophosphate anion, [CellImi]PF (11)
6
1
0

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The synthesis of Merrifield resin SILP catalyst is depicted in Scheme 1c. Initially, 1-N-
methyl imidazole (4) was covalently anchored on Merrifield resin (12) to yield heterogeneous
azolium salt acronymed as [MerImi]Cl (13). The anion metathesis reaction of 13 with aqueous
potassium hexafluorophosphate solution resulted in the desired Merrifield resin SILP catalyst
containing hexafluorophosphate anion acronymed as [MerImi]PF (14).
6
*
X
y
z
+
N
N
Cl
Merrifield resin (12)
1-N-methyl imidazole (4)
o
DMF, 80 C
Cl-
N
Cl-
N
N
N
N
N
Cl-
N
N
N
PS
N
Cl-
Cl-
N
N
N
N
Cl-
Cl-
[MerImi]Cl (13)
H O, rt
2
KPF6
PF -
6
PF -
N
6
N
N
N
N
N
PF -
6
N
PS
N
N
N
PF -
PF -
6
6
N
N
N
N
PF -
PF -
6
6
[
MerImi]PF (14)
6
Scheme 1c. Synthesis of Merrifield resin supported ionic liquid phase catalyst containing
hexafluorophosphate anion, [MerImi]PF
6
(14)
The successful synthesis of [SilImi]PF (6), [CellImi]PF
6
6
(11), [MerImi]PF (14) was
6
confirmed by Fourier transform-Raman (FT-Raman), Fourier transform-infrared (FT-IR) and
1
1

ACCEPTED MANUSCRIPT
1
3
cross-polarization magic angle spinning (CP-MAS) C NMR spectroscopy. The FT-Raman
analysis of 6, 11, 14 displayed characteristic peaks due to out-plane C-H bending vibrations of
imidazolium ring [787 cm−1 for 6, 777 cm−1 for 11, 793 cm−1 for 14], in-plane wagging
−
1
−1
−1
vibrations of alkyl chain [1052 cm for 6, 1095 cm for 11, 1078 cm for 14], symmetrical
−
1
−1
−1
stretching vibrations of alkyl chain [2899 cm for 6, 2894 cm for 11, 2901 cm for 14] and
anion [745 cm for 6, 734 cm for 11, 739 cm−1 for 14]
−
1
−1
symmetric P–F stretching of PF
6
supporting the formation of desired SILP catalysts. In addition, the FT-IR spectra exhibited
−
1
typical peaks due to in-plane C-H deformation vibrations of imidazolium ring [1154 cm for 6,
−
1
−1
−1
1
113 cm for 11, 1156 cm for 14], C-H bending vibrations of –CH
3
[1419 cm for 6, 1429
−
1
−1
cm for 11, 1444 cm for 14], in-plane C-N stretching vibrations of imidazolium ring [1633
−
1
−1
−1
cm for 6, 1640 cm for 11, 1592 cm for 14] and the characteristic peaks of P–F stretching of
−1
−1
−1
PF anion [841 cm for 6, 837 cm for 11, 826 cm for 14] suggesting the formation of desired
6
SILP catalysts.
The formation of 14 was further corroborated by recording the CP‐MAS 13C NMR
spectrum which demonstrated sharp peak at 41.0 (–CH
3
of imidazolium ring), 52.9 (-CH group
2
between imidazolium and benzene ring), 128.3, 137.1, 146.2 (imidazolium Cs), 120-146 (peaks
due to C atoms of aromatic polystyrene framework overlapped with peaks of imidazolium Cs)
confirming the proposed structure.
The quantification of IL like units was ascertained on the basis of EDX analysis. The
-1
-1
loading of 0.40 mmol functional group g of silica for 6, 0.54 mmol functional group g of
-
1
cellulose for 11 and 0.64 mmol functional group g of resin for 14 was observed.
The thermogravimetric analysis (TGA) of [SilImi]PF (6), [CellIMi]PF
MerImi]PF (14) is displayed in Fig. 1-3. The TGA curves of 6 and 11 displayed initial weight
6
6
(11) and
[
6
1
2

ACCEPTED MANUSCRIPT
o
o
loss of 2.55% (26-239 C) and 5.17% (26-83 C) due to desorption of physically adsorbed water.
o
o
Additionally, two subsequent weight losses of 8.20% (239-251 C) and 4.39% (251-304 C) for
o
o
[
SilImi]PF
observed due to collective combustion of surface bound organic scaffolds. The decomposition of
IL like unit resulted in further weight loss of 12.39% for [SilImi]PF and 21.81% for
(11). Finally, the large residual weight is ascribed to the formation of silica for
(6) and decomposition of cellulose units through the formation of levoglucosan and
(11). TGA thermogram of [MerImi]PF (14)
6
(6) while 53.66% (195-390 C) and 3.36% (390-400 C) for [CellIMi]PF (11) were
6
6
[
[
CellIMi]PF
6
SilImi]PF
6
other volatile compounds for [CellIMi]PF
6
6
o
o
displayed initial weight loss of 59.17% (248 C to 464 C) due to collective loss of organic
o
moiety and IL like units confined on Merrifield resin. Second weight loss of 13.10% (464 C to
o
5
92 C) is ascribed to the decomposition of Merrifield resin backbone. Finally the residual
weights correspond to formation of carbonaceous matter and generation of carbonates due to
incomplete combustion of polymeric material.
Fig. 1. Thermogravimetric analysis (TGA) curve of [SilImi]PF (6)
6
1
3

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Fig. 2. Thermogravimetric analysis (TGA) curve of [CellImi]PF (11)
6
Fig. 3. Thermogravimetric analysis (TGA) curve of [MerImi]PF (14)
6
1
4

ACCEPTED MANUSCRIPT
Fig. 4. FE-SEM images of (a) [SilImi]PF
d) Aerogel silica; (e) Cellulose; (f) Merrifield resin
The field emission scanning electron microscopy (FE-SEM) analysis of [SilImi]PF
CellIMi]PF (11), [MerImi]PF (14) and their corresponding supports (1, 7 and 12) is
6
(6); (b) [CellImi]PF
6
(11); (c) [MerImi]PF
6
(14);
(
6
(6),
[
6
6
exemplified in Fig. 4. FE-SEM image of 6 (Fig. 4(a)) display uniform arrangement of ultrafine
microparticles similar to pristine silica. The particles of 11 (Fig. 4(b)) appear irregular in shape
with micrometer size similar to pristine cellulose. Moreover, the Merrifield resin beads in 14
(Fig. 4(c)) did not appear spherical like original Merrifield resin. The bead degradation was
observed which may be created due to grafting of IL like units [11].
1
5

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3
2
1
0000
0000
0000
0
30000
25000
20000
3
2
9000
6000
3000
0
2
2
1
15000
1
1
10000
1
5000
0
0
10
20
30
40
50
60
70
80
0
10
20
30
40
50
60
70
80
0
10
20
30
40
50
60
70
80
2


2

5a
5b
5c
Fig. 5a: (1) XRD of [SilImi]Cl (5), (2) [SilImi]PF (6); 5b: (1) XRD of [CellImi]Cl (10),
6
(
2) [CellImi]PF (11); 5c: (1) XRD of [MerImi]Cl (13), (2) [MerImi]PF (14),
6
6
(
3) Reused [MerImi]PF (14)
6
X-ray diffraction (XRD) patterns of [SilImi]PF
6
(6), [CellIMi]PF
6
(11), [MerImi]PF (14)
6
o
are demonstrated in Fig. 5 and reveal strong diffraction peaks centred at angle 2θ = 22 for silica
o
o
o
o
[
12a], 16 , 22 , 34 for cellulose [12b], 19 for polystyrene [12c] signifying that the structural
integrity of basic support material is retained in SILP catalysts [12c]. Moreover, absence of any
characteristic reflection of hexafluorophosphate anion in the XRD patterns of 6, 11, 14 suggests
uniform distribution of PF
6
anions in the SILP catalysts.
(6), [CellIMi]PF
The catalytic efficiency of [SilImi]PF
6
6
(11), [MerImi]PF (14) was
6
screened in the synthesis of 1,4-Dihydropyridines (1,4-DHPs) (Scheme 2), which are privileged
scaffolds in medicinal chemistry with diverse pharmacological and therapeutical properties.
Many of their derivatives exhibited anticancer [13a], antidiabetic [13b-c], anti-inflammatory
[
13d] and photosensitizing activity [13e]. Due to their fascinating structural features these are
employed as anti-HIV protease inhibitor [13f], neuroprotective agents [13g] and also, these are
frequently used in the treatment of Alzheimer’s disease [13h], cardiovascular disease [13i].
Potential of several 1,4-DHPs has been explored in clinically significant drugs such as
1
6

ACCEPTED MANUSCRIPT
nifedipine, amlodipine, felodipine, nicardipine, nitrendipine, nislodipine and nimodipine [13j].
Due to diverse pharmacological properties, a plethora of distinct synthetic methodologies have
been reported for synthesis of 1,4-DHPs which include bis-cinchona mediated reaction of
malanonitrile and enamine derivatives [14a], reaction of N,N-dimethyl enaminones and amines
by oxidative mode [14b], iodine catalyzed reaction of primary amine, dialkyl acetylene
dicarboxylates, aldehyde and pyruvic acid [14c], copper (II) triflate mediated cyclizations of
alkynes, amines and α,β-unsaturated aldehydes [14d], reaction of aldehyde, β-keto ester and
different sources of ammonia employing variety of catalytic systems [15], reaction of diketene,
primary amines, malononitrile with aldehydes [14e]. Amongst these, reaction of aldehyde, β-keto
ester and different sources of ammonia represents most elegant protocol. A variety of catalytic
systems has been reported to improve the efficiency of this protocol [15]. However, despite of
impressive progress, there is still scope for improvement especially toward developing an energy
efficient protocol using synergistic effect of ultrasound and SILP catalysts. This prompted us to
evaluate catalytic activity of SILP catalysts ([SilImi]PF
14)) under ultrasound in the synthesis of 1,4-DHPs.
6
(6) / [CellIMi]PF
6
(11) / [MerImi]PF
6
(
R1
O
O
O
O
CHO
[MerImi]PF (14)
6
NH OAc
R2
+
2 R2
+
4
R2
R1
EtOH, ))))
N
H
17
18a-l
15a-l
16
Scheme 2. Synthesis of 1,4-dihydropyridines from aldehyde, ethyl acetoacetate and ammonium
acetate using [MerImi]PF (14)
Initial studies to examine the effect of solvent and catalyst loading were carried out using
model reaction between 4-nitrobenzaldehyde (15a), ethyl acetoacetate (16) and ammonium
6
1
7

ACCEPTED MANUSCRIPT
acetate (17). We observed that catalyst loading had a profound influence on the course of
reaction. When the amount of [SilImi]PF
6
(6), [CellIMi]PF
6
(11), [MerImi]PF (14) was
6
increased from 50 mg to 100 mg, the yield of corresponding product diethyl-2,6-dimethyl-4-(4-
nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxlate (18a) raised considerably (from 65% to 87%
for 6, 67% to 89% for 11, 70% to 96% for 14; Table 1, entries 3-4). However, further increase in
the catalyst amount did not substantially improve yield of product (Table 1, entries 5-6).
In order to identify solvent of choice, a variety of solvents were screened. Evident from
the basic screening process (Table 1), the reaction proceeds well in a polar protic solvents like
water, methanol, and ethanol (Table 1, entries 1-6). The reaction afforded moderate yields in
polar aprotic solvents such as DMSO, DMF, THF and CH CN (Table 1, entries 7-10).
3
Eventually, it was found that the relatively lower yields were acquired in non-polar solvents such
as dichloromethane, toluene, 1,4-dioxane, chloroform (Table 1, entries 11-14). Amongst all the
screened solvents, ethanol was adopted as the solvent of choice because it led to a short reaction
time and furnished maximum yield of anticipated product (Table 1, entries 3-6). The results of
optimization study revealed that [MerImi]PF
6
(14) exhibited highest catalytic activity in the
synthesis of 1,4-DHPs and hence it was used for further studies.
1
8

ACCEPTED MANUSCRIPT
Table 1. Optimization of catalyst loading and solvent in synthesis of 1,4-dihydropyridinesa
[
SilImi]PF (6)
NO2
6
Or
[
CellImi]PF (11)
6
O
O
Or
CHO
+
O O
EtO
OEt
[
MerImi]PF (14)
6
2EtO
+ NH4OAc
O N
N
H
2
Solvent, ))))
15a
16
17
18a
Entry Solvent
Amount
of
Time (Min.)
Support@PF
Yield (%)b
Support@PF
6
6
catalyst
(mg)
[
SilImi]PF
6
[CellImi]PF
6
[MeImi]PF
6
(6) (11) (14)
(
6)
(11)
45
30
30
15
15
15
55
60
70
50
55
70
45
(14)
35
25
20
10
10
10
65
55
65
40
55
61
35
1
2
3
4
5
6
7
8
9
H
2
O
100d
50
35
25
20
25
25
45
65
75
60
65
72
55
57
81
65
87
90
90
45
40
38
37
25
15
10
61
85
67
89
91
91
48
42
40
39
25
20
15
65
87
70
96
97
97
50
47
45
49
35
25
10
MeOH 100d
EtOH
EtOH
EtOH
EtOH
50c
100d
150e
200f
DMSO 100d
DMF
THF
100d
100d
1
0
1
2
3
CH
CH
Toluene 100d
3
CN 100d
Cl
100d
1
1
1
2
2
1,4-
100d
dioxane
1
4
CHCl
3
100d
77
75
70
25
27
30
a
Reaction conditions: 4-Nitrobenzaldehyde (1.0 mmol), ethyl acetoacetate (2.0 mmol), ammonium acetate (1.0 mmol), solvent (5
mL). Isolated yields after chromatography. c % Loading of catalyst per 50 mg: (0.020 mmol of [SilImi]PF
b
), (0.027 mmol of
6
d
[
[
[
[
CellImi]PF
CellImi]PF
CellImi]PF
CellImi]PF
6
6
6
6
), (0.032 mmol of [MerImi]PF
), (0.064 mmol of [MerImi]PF
), (0.096 mmol of [MerImi]PF
6
6
6
). % Loading of catalyst per 100 mg: (0.040 mmol of [SilImi]PF
). % Loading of catalyst per 150 mg: (0.060 mmol of [SilImi]PF
). % Loading of catalyst per 200 mg: (0.080 mmol of [SilImi]PF
6
), (0.054 mmol of
), (0.081 mmol of
), (0.108 mmol of
e
6
6
f
6
), (0.128 mmol of [MerImi]PF ).
With the optimized reaction conditions in hand, we probed the general applicability of
protocol by reacting variety of aromatic aldehydes 15 (1.0 mmol) with ethyl acetoacetate 16 (2.0
mmol) and ammonium acetate 17 (1.0 mmol) in the presence of 14 (100 mg) in ethanol (5 mL)
under ultrasonic irradiation at room temperature for synthesis of library of 1,4-DHPs. The
1
9

ACCEPTED MANUSCRIPT
reactions proceeded efficiently forming the desired products in high yields within short time and
the results were summarized in Table 2. Aldehydes with electron withdrawing group (Table 2,
entries 15a,c) furnished the higher yields than aldehydes bearing electron donating group (Table
2
, entries 15e-f). Sterically hindered aldehydes (Table 2, entries 15b,d) such as o-
nitrobenzaldehyde and o-anisaldehyde also performed well affording moderate yields of the
anticipated products. Heteroaromatic aldehydes such as 2-furaldehyde, 2-
thiophenecarboxaldehyde, pyridin-2-aldehyde, pyridin-3-aldehyde and pyridin-4-aldehyde
reacted efficiently forming the anticipated products in good yields (Table 2, entries 15h-l).
Table 2. [MerImi]PF
(14) catalyzed synthesis of 1,4-dihydropyridinesa
6
R1
CHO
+
O O
[
MerImi]PF (14)
O
O
6
2 R2
+ NH4OAc
R1
R2
R2
EtOH, ))))
N
H
15a-l
16
17
18a-l
Aldehyde
15)
Product
(18)
Time
(min.)
Yieldb
(%)
Entry
a
(
NO2
NO2
O
O
O
O
O
1
1
0
2
96
87
CHO
N
H
NO2
O
O
b
c
NO2
CHO
O
N
H
NO2
NO2
O
O
O
O
10
94
CHO
N
H
2
0

ACCEPTED MANUSCRIPT
O
O
O
d
e
O
CHO
O
O
2
1
0
5
79
90
N
H
O
O
O
O
O
O
O
O
O
O
CHO
N
H
f
15
89
87
CHO
CHO
N
H
O
O
O
O
O
O
g
O
O
O
O
O
O
1
0
N
H
O
S
h
i
O
S
CHO
2
2
0
2
90
86
N
H
CHO
N
H
N
N
O
O
O
O
j
N
O
O
O
O
2
1
5
5
85
86
89
CHO
N
H
N
k
l
CHO
N
H
N
N
O
O
O
O
18
CHO
N
H
a
Reaction conditions: Aldehyde (1.0 mmol), ethyl acetoacetate (2.0 mmol), ammonium acetate (1.0 mmol), ethanol (5 mL),
b
[
MerImi]PF
6
(100 mg); Isolated yields after chromatography.
2
1

ACCEPTED MANUSCRIPT
1
13
The identity of all the compounds was ascertained on the basis of IR, H NMR, C NMR
and mass spectroscopy. The physical and spectroscopic data are in harmony with the proposed
structures and are in well agreement with the literature data.
PS
N N
PF -
6
O
O
O HO
O
O
CH COONH
4
H
R
3
O
.
.
CH COOH + NH
PF -
6
3
3
N N
H
PS
..
O
NH2
O
O
R
O
O
(
I)
(II)
O
O
R
OH
O
O
O
NH O
2
(III)
R
O
O
O
H N
2
..
-
H O
2
R
O
O
O
O
N
H
Scheme 3. A plausible mechanism for [MerImi]PF (14) mediated synthesis of 1,4-
6
dihydropyridines
A plausible mechanism for [MerImi]PF
in Scheme 3. Initially, PF anion coordinates with enolic form of ethyl acetoacetate [16a].
Further, the hydrogen bond bonding ability of C -H of imidazolium ring activates carbonyl group
6
(14) catalyzed synthesis of 1,4-DHPs is depicted
6
2
2
2

ACCEPTED MANUSCRIPT
of aldehyde [16b]. This facilitates Knoevenagel condensation between 1,3-dicarbonyl compound
and aryl aldehydes yielding α,β-unsaturated carbonyl compound (I). Further, the enamine
intermediate (II) that is formed initially by reaction of 1,3-dicarbonyl compound with ammonia
undergo Michael addition with I yielding III. Lastly, the subsequent cyclization following by
dehydration results into formation of 1,4-DHPs.
To determine whether the [MerImi]PF (14) is really heterogeneous, we performed a split
6
test using a model reaction. While performing such a test, 14 was filtered off after 50% of the
reaction was completed (GC-MS analysis) and the liquid phase of the reaction mixture was
sonicated at room temperature for additional time. Interestingly, no considerable progress (GC-
MS analysis) was observed.
1
00
8
6
4
2
0
0
0
0
0
0
1
2
3
4
5
6
No. of cycles
Fig.6. Reusability of [MerImi]PF
6
(14) in 1,4-dihydropyridine synthesis
The recyclability of [MerImi]PF (14) was accessed by employing the model reaction for
6
synthesis of 18a. In brief, after each cycle the catalyst was filtered and washed with ethanol and
dried in vacuuo indicate that the reaction occurs under heterogeneous condition. Following this
2
3

ACCEPTED MANUSCRIPT
procedure, the recovered catalyst was reused for six times as illustrated in Fig. 6. The studies
revealed minimal loss in catalytic activity on successive cycles under optimized reaction
conditions.
Impact of ultrasound on the chemical, physical nature and stability of [MerImi]PF (14)
6
1
3
has been studied with help of FT-Raman, FT-IR and CP-MAS C NMR spectroscopy as well as
XRD, SEM, EDX and TGA analysis. The FT-Raman analysis of reused 14 displayed the
−
1
characteristic peaks due to out-plane C-H bending vibration of imidazolium ring (782 cm ), in-
−
1
plane wagging vibration of alkyl chain (1080 cm ), symmetrical stretching vibration of alkyl
−
1
−1
chain (2903 cm ) and the symmetric P–F stretching of PF anion (739 cm ). FT-Raman
6
analysis revealed that fresh and reused catalysts have the same patterns, indicating that reused 14
was stable even after ultrasonic irradiation. The FT-IR spectrum of reused 14 exhibited in-plane
-1
-1
C-H deformation (1446 cm ), in-plane C-N stretching vibration of imidazolium ring (1599 cm )
-1
and aliphatic C-H stretching vibration (2913 cm ). The characteristic peak of P–F stretching of
-1
PF
groups present in pristine 14 is retained in the reused catalyst even after recycling. CP‐MAS C
NMR spectrum of reused 14 demonstrated the peaks at 41.0 (-CH of imidazolium ring), 53.4 (-
CH group between imidazolium and benzene ring), 128.7, 138.0, 146.4 (imidazolium Cs), 120-
46 (peaks due to C atoms of aromatic polystyrene framework overlapped with peaks of
imidazolium Cs) and which is similar to the pristine 14.
6
anion was observed at 820 cm , which is convincing evidence for the fact that functional
13
3
2
1
2
4

ACCEPTED MANUSCRIPT
Fig. 7. Thermogravimetric analysis (TGA) curve of reused [MerImi]PF (14)
6
XRD pattern of reused [MerImi]PF
c). The EDX analysis of reused 14 revealed that there was no significant alteration in
composition of pristine and reused 14. The TGA analysis of reused 14 is shown in Fig. 7. TGA
6
(14) mimicked the XRD pattern of pristine 14 (Fig.
5
o
o
thermogram exhibited an initial weight loss of 55.60% (246 C to 438 C) due to decomposition
of organic moieties confined on Merrifield resin and loss of IL like unit. Consecutive weight loss
o
o
of 16.49% (438 C to 561 C) is ascribed to decomposition of Merrifield resin backbone. Finally
residual weights correspond to the formation of carbonates due to incomplete combustion of
polymeric material or generation of carbonaceous matter. The FE-SEM analysis of reused 14
(Fig. 8) revealed that the morphology of catalyst is preserved even after reuse. These results
reveal that structural rigidity of 14 is conserved even after reuse, confirming that SILP catalysts
do not undergo physical and chemical changes under ultrasonic irradiation.
2
5

ACCEPTED MANUSCRIPT
a
Fig. 8. FE-SEM image of (a) reused [MerImi]PF (14)
6
4
. Conclusion
In conclusion, we have investigated the compatibility of Merrifield resin, silica and cellulose
supported ionic liquid phase catalysts in the synthesis of bioactive 1,4-dihydropyridines under
ultrasonic irradiation. The impact of ultrasonication on the properties of SILP catalysts was
evaluated using various analytical techniques. The FT-Raman, FT-IR, CP‐MAS 13C NMR
analysis of reused SILP catalysts displayed the characteristic peaks similar to fresh SILP
catalysts. The XRD and TGA patterns of reused catalysts mimicked with fresh SILP catalysts.
The EDX analysis of reused SILP catalysts did not show that substantial alteration in
composition of fresh and reused SILP catalysts. The FE-SEM analysis of reused SILP catalysts
revealed that the morphology is conserved even after continuous reuse. The results reveal that
sonication of SILP catalysts does not lead to physical, chemical and structural changes unlike
traditional ILs confirming that SILP catalysts are stable even after ultrasonic irradiation. The
synergistic effect of ultrasound and SILP catalysts is likely to emerge as promising research
avenue worth broad interest for development in future.
Acknowledgements
The author is deeply gratitude to Indian Institute of Sciences (IISc), Bangalore and Sophisticated
Analytical Instrumental Facility, Indian Institute of Technology, Madras (IITM) for providing
2
6

ACCEPTED MANUSCRIPT
spectral facilities and Shivaji University Kolhapur for providing Departmental Research
Fellowship.
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