Ultrasound-assisted and efficient knoevenagel condensation reaction catalyzed by silica sodium carbonate nanoparticles

Article abstract of DOI:10.5562/cca3261

An efficient and ultrasound-assisted route to the synthesis of arylidene malononitriles/methylciano- or ethylciano acetates in a one-pot reaction catalyzed by silica sodium carbonate nanoparticles (SSC NPs) is described. In this reaction, SSC NPs demonstrated high efficiency as catalyst to obtain target products. By this achievement, a wide range of α,β-unsaturated compounds as Knoevenagel condensation products with good to excellent yields are obtained from reaction between numerous arylaldehydes, and malononitrile, methyl cianoacetate or ethyl cianoacetate. Target products which prepared in high yield and high purity can be candidate as important biologically active molecules. This method is an easy, cheap, rapid and highly efficient for the synthesis of desired products. In addition, capability of catalyst to separate from reaction mixture and reuse in further runs and being compatible with green chemistry are considered as other advantages of this procedure. All products were deduced from their FT-IR and FT-NMR spectroscopic and elemental analysis data.

Full text of DOI:10.5562/cca3261

O R I G I NA L S C I E N T I F I C P A P E R
Croat. Chem. Acta 2018, 91(1), 19–28
Published online: March 3, 2018
DOI: 10.5562/cca3261
Ultrasound-assisted and Efficient Knoevenagel
Condensation Reaction Catalyzed by Silica
Sodium Carbonate Nanoparticles
Yaghoub Pourshojaei,1,2,* Maryam Nikzad,1 Khalil Eskandari,1,* Mohammad-Hossein Darijani,1
Abdolreza Hassanzadeh,1 Ehsan Faghih-Mirzaei,1 Ali Asadipour1
1
2
Department of Medicinal Chemistry, Faculty of Pharmacy & Pharmaceutics Research Center, Kerman University of Medical Sciences, Kerman, Iran
Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
Corresponding author’s e-mail address: y.pourshoja@kmu.ac.ir; khalileskandari@yahoo.com
*
RECEIVED: December 4, 2017
REVISED: January 30, 2018
ACCEPTED: February 1, 2018
Abstract: An efficient and ultrasound-assisted route to the synthesis of arylidene malononitriles/methylciano- or ethylciano acetates in a one-
pot reaction catalyzed by silica sodium carbonate nanoparticles (SSC NPs) is described. In this reaction, SSC NPs demonstrated high efficiency
as catalyst to obtain target products. By this achievement, a wide range of α,β-unsaturated compounds as Knoevenagel condensation products
with good to excellent yields are obtained from reaction between numerous arylaldehydes, and malononitrile, methyl cianoacetate or ethyl
cianoacetate. Target products which prepared in high yield and high purity can be candidate as important biologically active molecules. This
method is an easy, cheap, rapid and highly efficient for the synthesis of desired products. In addition, capability of catalyst to separate from
reaction mixture and reuse in further runs and being compatible with green chemistry are considered as other advantages of this procedure.
All products were deduced from their FT-IR and FT-NMR spectroscopic and elemental analysis data.
Keywords: nanocatalyst, silica sodium carbonate nanoparticles, Knoevenagel reaction, active methylene compounds.
Knoevenagel condensations have attracted much
interest by chemists and pharmacologists. Its reason may
INTRODUCTION
LEFINS, also called alkenes, are very important class
of organic compounds that numerous natural prod-
be related to importance of this reaction in organic
synthesis and chemical industries. Over the past few
decades, several methods have been proposed and
developed by chemists for Knoevenagel condensation
reactions. For instance, running the reaction in the
presence of Lewis acids or bases,[12,13] ionic liquids,[14]
green solvents,[15] microwave assistance,[16] ultrasound
irradiation,[17] solid-phase reactions,[18] grinding
methods,[19] solvent-free microwave assisted conditions,[20]
and using biocatalysts,[15,21] organocatalysts[22] or poly-
oxometalates[23] could be countered as these met-
hodologies. Furthermore, there are a few reports that have
been applied to Knoevenagel condensation under different
conditions including continuous flow synthesis,[24] or
fluorous biphasic system.[25] Nevertheless, the attempts
to find and propose new and efficient protocols to
O
ucts, herbal medicines and significant pharmacological ac-
tive compounds such as vital, essential and necessary drugs
may be classified into their category.[1–3] Furthermore, ole-
fins can be found in chemical structure of α,β-unsaturated
compounds. Up to date, numerous medicines and natural
products have been recognized that belong to α,β-unsatu-
rated compounds.[4,5] One of the organic reactions which
lead to obtain α,β-unsaturated compounds is Knoevenagel
condensation reaction.[6–8] So far this reaction extensively
has been applied to the synthesis of a wide range of organic
and biological active compounds.[9,10] Also, this reaction has
sometimes been used to evaluate strength of different
solid basic catalysts considering the fact that pKa value of
active methylene compounds are about to 9–11.[11]
This work is licensed under a Creative Commons Attribution 4.0 International License.

20
Y. POURSHOJAEI et al.: Ultrasound-assisted and Efficient Knoevenagel Condensation Reaction …
Knoevenagel condensation reaction have been continued
by chemists because all above mentioned techniques
tolerate some drawbacks such as use of expensive and non-
recyclable catalysts, harsh thermal conditions, use of toxic
solvents and catalysts, non-compatible with green
chemistry aspects, not economically viable, and long reac-
tion times.[7,8,26]
So far various attempts and evaluations on biological
and pharmaceutical activities of α,β-unsaturated com-
pounds formed from Knoevenagel condensation reactions
have been performed. For instance there are several re-
ports that demonstrate these compounds could be consid-
significant interest because of their unique advantages
including easy separation from the reaction mixture and re-
usability,[37–39] easy handling and storing, avoiding the
generation of residual salts, nontoxicity, low solubility, in-
creasing selectivity of the reactions, and high stability.[40-42]
Very recently a green and recyclable inexpensive
Brønsted base prepared and called silica sodium carbonate
(SSC) 3,[43] via a cascade two steps method from silica gel
(1) and silica chloride 2 (Scheme 1). SSC has several im-
portant advantages including environmentally benign, re-
usability, easy handling, high perdurability, and
convenience work-up.
O
O
O
O
O
O
2
2
2
i
ii
Si
Si
Si
O
O
O
O
OH
Cl
ONa
O
S i O
S i O
S i O
SO2 HCl
HCl
,
1
2
3
NaHCO n-Hexane,
24
SOCl Reflux, 48 ii)
Reflux,
h
,
,
h;
i)
2
3
Scheme 1. Two steps route to preparation of SSC.
ered as anti-nociceptive agents modulating the TREK-1
channel,[27,28] inhibitors of 12-Lipoxygenase,[29] new group
of fungicidal and acaricidal agents,[30] a new class of antag-
onists at the glycine site of the NMDA receptor,[31] an ingre-
dient in sunscreens and cosmetics,[32] herbicidally active
compounds,[33] and also a therapeutic agent for diseases of
the circulatory system.[34] Also the importance of
Knoevenagel condensation products can be more realized
by considering to the fact that some of these molecules
have been recognized as molecular rotors[35] which were
subjected to 2016’s noble prize awarded to Sauvage,
Stoddartand, Feringa for their design and production of
Further to our last studies on the designing new pro-
tocols to high efficient catalytic green synthesis of novel or-
ganic compounds,[44] and investigation of their biological
activities[45] herein we wish to report a highly efficient and
practical approach to Knoevenagel condensation reaction
between a wide range of arylaldehydes 1 and malononitrile
or methyl(ethyl)cianoacetate 2 using SSC NPs as an eco-
friendly heterogeneous recyclable catalyst (Scheme 2). In
addition, it is notable to mention that in this work by a slight
modification on previous reported method,[43] we prepared
SSC nanoparticles instead of bulk one and applied it suc-
cessfully in Knoevenagel condensation reaction (Scheme 2).
EWG
H
O
G
H
NPs mol%)
(2
Sonication
EWG
SSC
N
N
CH3CN, 70 °C
G
1
2
3
2H5
EWG: CN, COOCH3 COOC
,
Scheme 2. Knoevenagel condensation reaction catalyzed by SSC NPs.
molecular machines. These disclosed properties encourage
chemists and pharmacologists to design and synthesize of
newly prepared molecules exhibiting pharmacological and
biological activities which may be applied in treatment of
human diseases as new medicines in the future.[9,10,36]
Recently, solid supported catalysts have attracted
EXPERIMENTAL SECTION
All chemicals were purchased from Sigma-Aldrich and
Merck chemical companies. Melting points were measured
on an electrothermal IA9100 melting point apparatus fixed
at 1 °C / min. IR spectra were recorded by Brucker FT-IR
Croat. Chem. Acta 2018, 91(1), 19–28
DOI: 10.5562/cca3261

Y. POURSHOJAEI et al.: Ultrasound-assisted and Efficient Knoevenagel Condensation Reaction …
21
Tensor 27 infrared spectrophotometer with KBr as matrix.
A cylindrical planetary ball mill apparatus with a 500 mL jar
volume made of welded steel supplied with three 19 mm
General Procedure for the Preparation
of Corresponding Aldehydes 1
Corresponding aldehydes containing alkylamine ethers was
synthesized according to the procedure reported in the lit-
erature,[45a] and all structures were confirmed by compari-
son with their physical and chemical data reported in
literature. Also p-benziloxybenzaldehyde derivatives were
prepared by treated with 4-hydroxybenzaldehyde with ap-
propriate benzylchloride/bromide derivatives in the pres-
ence of K2CO3 as catalyst. The physical and chemical
properties of all obtained substrates were compared with
the ones reported in literature and all of their structures
were confirmed.[46]
diameter hardened steel balls (DECO-SIO-0.5L, Hunan,
1
Mainland) was used for grinding silica gel. H NMR and 13
C
NMR spectra were recorded on a FT-NMR Bruker Avance
Ultra Shield Spectrometer at frequencies of 400.13 and
100.62 MHz respectively in CHCl3 as solvent. Elemental
analyses (C, H, N, S) were performed on a Heraeus Rapid
analyzer and the results were found in good agreement
(±0.3 %) with the calculated values. Scanning electron mi-
croscopy (SEM) evaluations of the nano-catalyst were per-
formed on a JEOL JEM 3010 instrument operating at an
accelerating voltage of 300 kV. Transmission electron mi-
croscopy (TEM) investigations of the nano-catalyst were
performed on a JEOL JEM 3010 instrument operating at an
accelerating voltage of 300 kV. TLC was performed on TLC-
Grade silica gel-G/UV 254 nm plates EtOAc/n-hexane (1:1)
as eluent. All products were isolated, purified and deduced
Typical Procedure to the Synthesis of 3c
4-morpholinobenzaldehyde (1 mmol, 0.191 g) was added
to a stirred mixture of malononitrile (1.5 mmol, 0.099 g),
and catalytic amount of SSC NPs (0.012 g, 2 mol%) in ace-
tonitrile (10 mL). It was allowed to the mixture to stir at 70
°C under sonication about 25–60 minutes. After completion
of the reaction (the reaction progress was monitored by
TLC using EtOAc/n-hexane (1:1) as eluent), the reaction
mixture was filtered to separate precipitate. Next, the pre-
cipitate was dissolved in boiling ethanol and then was fil-
trated to separate catalyst. Finally, pure crystalline product
was obtained from filtrate. Since the catalyst is reusable, at
the end of the reaction, it was washed by boiling methanol
three times (3 × 2 mL), dried at 90 °C for 2 h and re-used in
further cycles. Also, in the following, we explain more details
about reusability results of the catalyst on model reaction.
1
from their IR, H NMR, and 13C NMR spectral data along
with elemental analyses (C, H, N). The products were iso-
lated and characterized by physical and spectral data and
for known compounds they were compared with authentic
samples (Table 2).
Typical Procedure for the
Preparation of SSC NPs
Silica gel 60 (63–200 μm) (15 g) was grinded by a planetary
ball mill apparatus under dry milling conditions for 6 h with-
out using any milling additives to obtain a much finer pow-
der. Afterwards resulted finer SiO2 was dried at 120 °C for
6 h. In the next step, dried finer SiO2 (7 g) was added to a
100 mL two necked round bottom flask put previously into
an ice bath. Then, thionyl chloride (28 mL) was added drop-
wise to the flask (caution). One of the flask’s necks was con-
nected to a pot of water by a hose for smoking out of
produced HCl(g). When the addition of thionyl chloride was
completed, the other flask’s neck was connected to a reflux
condenser and it was allowed to the reaction mixture to stir
for 0.5 h at room temperature and then for 48 h under re-
flux conditions respectively. Afterwards, the reaction mix-
ture was cooled to room temperature and filtered to obtain
silica chloride. In second step, obtained silica chloride (5 g)
which was previously dried at 120 °C for 6 h was added to
a stirred 100 mL round bottom flask containing sodium bi-
carbonate (5 g) and dry n-hexane (20 mL) under reflux con-
ditions. After enough time passing (24 h), the reaction
mixture was filtered to separate the catalyst. Then to re-
move the remaining sodium bicarbonate, the catalyst was
washed with 5 mL of distilled water for ten times (10 × 5
mL) so the filtrate was neutral. Finally the catalyst was dried
at 90 °C for 6 h and then was grinded again by a ball mill for
1 h to obtain SSC NPs.
Representative Spectral Data
2-(4-Morpholinobenzylidene)malononitrile (3c): m.p. 198–
200 °C; IR (KBr) (νmax / cm–1): 3008, 2955, 2921, 2889, 2217,
1606, 1568, 1518, 1446, 1397, 1238, 1196, 928, 824, 621.
1H NMR (300 MHz, CDCl3) δ / ppm: 7.85 (2H, d, J = 9 Hz,
CHAr), 7.51 (1H, s, CHvinyl), 6.89 (2H, d, J = 9 Hz, CHAr), 3.88
(4H, t, J = 6 Hz, CH2OCH2), 3.45 (4H, t, J = 6 Hz, CH2NCH2).
13CNMR (75 MHz, CDCl3) δ / ppm: 158.2, 154.7, 133.7,
121.2, 115.5, 114.4, 113.2, 74.4, 66.3, 46.6. Anal. Calcd.
w / % for C14H13N3O (239.28): C, 70.28; H, 5.48; N, 17.56;
Found: C, 70.35; H, 5.41; N, 17.44.
2-(4-(Piperidin-1-yl)benzylidene)malononitrile (3d): m.p.
134–135 °C; IR (KBr) (νmax / cm–1): 2939, 2858, 2824, 2215,
1607, 1566, 1515, 1441, 1362, 1246, 1198, 1127, 932, 853,
606. 1H NMR (300 MHz, CDCl3) δ / ppm: 8.04 (1H, s, CHvinylic),
7.82 (2H, d, J = 9 Hz, CHAr), 7.05 (2H, d, J = 9 Hz, CHAr), 3.54
(4H, brs, CH2NCH2), 1.58 (6H, brs, 3 × CH2). 13CNMR (75
MHz, CDCl3) δ / ppm: 159.1, 154.6, 134.3, 119.6, 116.7,
115.9, 113.4, 69.6, 47.8, 25.6, 24.4. Anal. Calcd. w / % for
C15H15N3 (237.31): C, 75.92; H, 6.37; N, 17.71; Found: C,
75.88; H, 6.35; N, 17.80.
DOI: 10.5562/cca3261
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Y. POURSHOJAEI et al.: Ultrasound-assisted and Efficient Knoevenagel Condensation Reaction …
2-(4-(4-Phenylpiperidin-1-yl)benzylidene)malononitrile (3e):
m.p. 127–128 °C; IR (KBr) (νmax / cm–1): 3008, 2930, 2883,
2215, 1605, 1561, 1509, 1447, 1406, 1355, 1196, 1073,
1053, 964, 820, 606. 1HNMR (300 MHz, DMSO-d6) δ / ppm:
8.05 (1H, s, CHvinylic), 7.82 (2H, d, J = 9 Hz, CHAr), 7.32–7.17
(5H, m, CHPh), 7.05 (2H, d, J = 9 Hz, CHAr), 4.10 (2H, d, J = 12
Hz, CH2), 2.95 (2H, t, J = 12 Hz, CH2), 1.89–1.82 (1H, m,
CHBn), 1.65 (2H, d, J = 12 Hz, CH2), 1.24–1.11 (2H, m, CH2).
13CNMR (75 MHz, DMSO-d6) δ / ppm: 159.1, 154.5, 140.4,
134.3, 129.4, 128.6, 126.3, 119.7, 116.7, 115.8, 113.5, 69.8,
47.0, 42.4, 37.8, 31.6. Anal. Calcd. w / % for C21H19N3
(313.40) C, 80.48; H, 6.11; N, 13.41; Found: C, 80.57; H,
6.09; N, 13.49.
1013, 828, 798, 594. 1HNMR (300 MHz, DMSO-d6) δ / ppm:
8.41 (1H, s, CHvinylic), 7.99 (2H, d, J = 9 Hz, CHAr), 7.53–7.46
(4H, m, CHAr), 7.27 (2H, d, J = 9 Hz, CHAr), 5.26 (2H, s, OCH2).
13CNMR (75 MHz, DMSO-d6) δ / ppm: 163.6, 160.8, 135.5,
133.8, 133.2, 130.2, 129.0, 124.8, 116.4, 115.7, 115.2,
114.3, 77.6, 69.4. Anal. Calcd. w / % for C17H11ClN2O
(294.74): C, 69.28; H, 3.76; N, 9.50; Found: C, 69.25; H, 3.77;
N, 9.55.
2-(3-((4-Chlorobenzyl)oxy)benzylidene)malononitrile (3j):
m.p. 100–103 °C; IR (KBr) (νmax / cm–1): 3040, 2926, 2224,
1602, 1585, 1493, 1451, 1378, 1270, 1185, 1015, 801, 675.
1H NMR (300 MHz, CDCl3) δ / ppm: 7.76 (1H, s, CHvinylic), 7.59
(1H, s, CHAr), 7.52–7.41 (6H, m, CHAr), 7.30–7.24 (1H, m,
CHAr), 5.13 (2H, s, OCH2). 13CNMR (75 MHz, CDCl3) δ / ppm:
159.7, 159.0, 134.4, 134.2, 132.1, 130.7, 128.9, 124.5,
122.2, 114.8, 113.6, 112.6, 83.1, 69.5. Anal. Calcd. w / % for
C17H11ClN2O (294.74): C, 69.28; H, 3.76; N, 9.50; Found: C,
69.33; H, 3.71; N, 9.61.
2-(4-(2-Morpholinoethoxy)benzylidene)malononitrile (3f):
m.p. 228–229 °C; IR (KBr) (νmax / cm–1): 3005, 2970, 2938,
2571, 2538, 2449, 2221, 1603, 1587, 1557, 1511, 1430,
1268, 1182, 1080, 943, 831, 612. 1HNMR (300 MHz, DMSO-
d6) δ / ppm: 8.45 (1H, s, CHvinylic), 8.01 (2H, d, J = 9 Hz, CHAr),
7.25 (2H, d, J = 9 Hz, CHAr), 4.53 (2H, t, J = 6 Hz, OCH2), 3.84
(4H, t, J = 6 Hz, CH2OCH2), 3.40 (2H, brs, CH2N), 3.15 (4H,
brs, CH2NCH2). 13CNMR (75 MHz, DMSO-d6) δ / ppm: 163.1,
160.9, 133.7, 125.1, 116.3, 115.2, 114.3, 77.8, 64.3, 64.0,
55.5, 52.5. Anal. Calcd. w / % for C16H17N3O2 (283.33) C,
67.83; H, 6.05; N, 14.83; Found: C, 67.87; H, 6.00; N, 14.89.
2-(4-((4-Bromobenzyl)oxy)benzylidene)malononitrile (3k):
m.p. 187–190 °C; IR (KBr) (νmax / cm–1): 3029, 2220, 1604,
1582, 1555, 1507, 1432, 1272, 1236, 1176, 1070, 1010, 827,
609. 1HNMR (300 MHz, CDCl3) δ / ppm: 8.41 (1H, s, CHvinylic),
7.99 (2H, d, J = 9 Hz, CHAr), 7.62 (2H, d, J = 9 Hz, CHAr), 7.44
(2H, d, J = 9 Hz, CHAr), 7.27 (2H, d, J = 9 Hz, CHAr), 5.25 (2H,
s, OCH2). 13CNMR (75 MHz, CDCl3) δ / ppm: 163.6, 160.8,
135.9, 133.8, 131.9, 130.5, 124.8, 121.8, 116.4, 115.2, 114.3,
77.6, 69.5. Anal. Calcd. w / % for C17H11BrN2O (339.19): C,
60.20; H, 3.27; N, 8.26; Found: C, 60.25; H, 3.19; N, 8.31.
2-(3-(2-Morpholinoethoxy)benzylidene)malononitrile (3g):
m.p. 225–226 °C; IR (KBr) (νmax / cm–1): 3005, 2972, 2925,
2663, 2455, 2228, 1572, 1450, 1270, 1185, 1128, 922, 860,
1
684. HNMR (300 MHz, DMSO-d6) δ / ppm: 8.56 (1H, s,
CHvinylic), 7.61–7.56 (3H, m, CHAr), 7.39–7.36 (1H, m, CHAr),
4.51 (2H, t, J = 6 Hz, OCH2), 3.90 (4H, brs, CH2OCH2), 3.52
(2H, brs, CH2N), 3.28 (4H, brs, CH2NCH2). 13CNMR (75 MHz,
DMSO-d6) δ / ppm: 161.7, 158.3, 133.0, 131.3, 123.8, 121.2,
116.7, 114.6, 113.6, 82.6, 63.8, 63.4, 55.2, 52.2. Anal. Calcd.
w / % for C16H17N3O2 (283.33) C, 67.83; H, 6.05; N, 14.83;
Found: C, 67.89; H, 5.97; N, 14.85.
2-(3-((4-Bromobenzyl)oxy)benzylidene)malononitrile (3l):
m.p. 104–105 °C; IR (KBr) (νmax / cm–1): 3037, 2929, 2223,
1601, 1574, 1487, 1451, 1272, 1185, 1070, 1013, 844, 806,
1
786, 619. HNMR (300 MHz, CDCl3) δ / ppm: 8.51 (1H, s,
CHvinylic), 7.62 (1H, s, CHAr), 7.60–7.55 (4H, m, CHAr), 7.43
(2H, d, J = 6 Hz, CHAr), 7.38–7.34 (1H, m, CHAr), 5.16 (2H, s,
OCH2). 13CNMR (75 MHz, CDCl3) δ / ppm: 161.7, 158.8,
136.2, 132.9, 131.9, 131.2, 130.4, 123.6, 121.7, 121.2,
116.9, 114.6, 113.6, 82.4, 69.2. Anal. Calcd. w / % for
C17H11BrN2O (339.19): C, 60.20; H, 3.27; N, 8.26; Found: C,
60.27; H, 3.21; N, 8.33.
2-(4-(2-(Piperidin-1-yl)ethoxy)benzylidene)malononitrile (3h):
m.p. 195–198 °C; IR (KBr) (νmax / cm–1): 3002, 2944, 2859,
2612, 2449, 2388, 2226, 1603, 1585, 1559, 1459, 1260,
1190, 1018, 837, 613. 1H NMR (300 MHz, DMSO-d6) δ /
ppm: 8.45 (1H, s, CHvinylic), 7.99 (2H, d, J = 9 Hz, CHAr), 7.23
(2H, d, J = 9 Hz, CHAr), 4.50 (2H, t, J = 6 Hz, OCH2), 3.26 (2H,
brs, CH2N), 3.01 (4H, brs, CH2NCH2), 1.73 (4H, brs, 2CH2),
1.49 (2H, brs, CH2). 13CNMR (75 MHz, DMSO-d6) δ / ppm:
163.3, 160.9, 133.8, 124.9, 116.2, 115.2, 114.3, 77.7, 64.4,
55.5, 53.4, 23.6, 22.4. Anal. Calcd. w / % for C17H19N3O
(281.36) C, 72.57; H, 6.81; N, 14.94; Found: C, 72.65; H,
6.75; N, 14.97.
Methyl (E)-2-cyano-3-(4-morpholinophenyl)acrylate (3n):
m.p. 146–149 °C; IR (KBr) (νmax / cm–1): 2953, 2879, 2851,
2215, 1719, 1613, 1575, 1523, 1443, 1400, 1284, 1230,
1192, 1051, 925, 813, 614, 502. 1HNMR (300 MHz, CDCl3) δ
/ ppm: 8.12 (1H, s, CHvinylic), 7.97 (2H, d, J = 9 Hz, CHAr), 6.90
(2H, d, J = 9 Hz, CHAr), 3.92 (3H, s, OCH3), 3.88 (4H, t, J = 6
Hz, CH2OCH2), 3.40 (4H, t, J = 6 HZ, CH2NCH2). 13CNMR (75
MHz, CDCl3) δ / ppm: 164.2, 154.4, 154.1, 133.8, 121.6,
116.9, 113.5, 96.0, 66.4, 53.0, 46.9. Anal. Calcd. w / % for
C15H16N2O3 (272.30): C, 66.16; H, 5.92; N, 10.29; Found: C,
66.23; H, 5.87; N, 10.35.
2-(4-((4-Chlorobenzyl)oxy)benzylidene)malononitrile (3i):
m.p. 174–176 °C; IR (KBr) (νmax / cm–1): 3032, 2924, 2853,
2221, 1603, 1582, 1556, 1509, 1433, 1274, 1237, 1178,
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Methyl (E)-2-cyano-3-(4-(piperidin-1-yl)phenyl)acrylate (3o):
m.p. 96–99 °C; IR (KBr) (νmax / cm–1): 3022, 3002, 2936,
2851, 2215, 1714, 1612, 1573, 1523, 1416, 1361, 1281,
1226, 1182, 1131, 1092, 1015, 808, 759, 578, 496. 1H NMR
(300 MHz, CDCl3) δ / ppm: 7.98 (1H, s, CHvinylic), 7.83 (2H, d,
J = 9 Hz, CHAr), 6.77 (2H, d, J = 9 Hz, CHAr), 3.80 (3H, s, OCH3),
3.37 (4H, brs, CH2NCH2), 1.60 (6H, brs, 3 × CH2). 13CNMR (75
MHz, CDCl3) δ / ppm: 164.7, 154.4, 154.0, 134.2, 120.0,
117.4, 113.2, 94.0, 52.8, 48.1, 25.3, 24.3. Anal. Calcd. w / %
for C16H18N2O2 (270.33): C, 71.09; H, 6.71; N, 10.36; Found:
C, 71.15; H, 6.68; N, 10.33.
CDCl3) δ / ppm: 8.21 (1H, s, CHvinylic), 8.03 (2H, d, J = 9 Hz,
CHAr), 7.41 (4H, brs, CHAr), 7.07 (2H, d, J = 9 Hz, CHAr), 5.15
(2H, s, OCH2), 3.95 (3H, s, OCH3). 13CNMR (75 MHz, CDCl3) δ
/ ppm: 163.5, 162.6, 154.5, 134.3, 134.2, 133.7, 128.9,
128.8, 124.7, 116.1, 115.5, 99.2, 69.5, 53.2. Anal. Calcd.
w / % for C18H14ClNO3 (327.76): C, 65.96; H, 4.31; N, 4.27;
Found: C, 65.91; H, 4.25; N, 4.36.
Methyl (E)-3-(3-((4-chlorobenzyl)oxy)phenyl)-2-cyanoacrylate
(3t): m.p. 83–86 °C; IR (KBr) (νmax / cm–1): 2955, 2918, 2223,
1730, 1607, 1576, 1492, 1445, 1267, 1247, 1180, 1095, 804,
679. 1HNMR (300 MHZ, CDCl3) δ / ppm: 8.25 (1H, s, CHvinylic),
7.71 (1H, s, CHAr), 7.53 (1H, d, J = 9 Hz, CHAr), 7.44 (1H, t, J =
9 Hz, CHAr), 7.41–7.38 (4H, m, CHAr), 7.20 (1H, d, J = 9 Hz,
CHAr), 5.13 (2H, s, OCH2), 3.97 (3H, s, OCH3). 13CNMR (75
MHz, CDCl3) δ / ppm: 162.9, 158.8, 155.1, 134.7, 134.0,
132.6, 130.4, 128.9, 128.8, 124.9, 121.1, 115.5, 115.2,
102.8, 69.4, 53.4. Anal. Calcd. w / % for C18H14ClNO3
(327.76): C, 65.96; H, 4.31; N, 4.27; Found: C, 65.91; H, 4.25;
N, 4.36.
Methyl (E)-2-cyano-3-(4-(2-morpholinoethoxy)phenyl)acrylate
(3p): m.p. 203–207 °C; IR (KBr) (νmax / cm–1): 2957, 2925,
2224, 1726, 1599, 1512, 1434, 1274, 1212, 1185, 1127, 943,
1
838, 526. HNMR (300 MHz, DMSO-d6) δ / ppm: 8.33 (1H,
s, CHvinylic), 8.09 (2H, d, J = 9 Hz, CHAr), 7.20 (2H, d, J = 9 Hz,
CHAr), 4.32 (2H, t, J = 6 Hz, OCH2), 3.86 (3H, s, OCH3), 3.67
(4H, t, J = 6 Hz, CH2OCH2), 2.96 (2H, t, J = 6 Hz, CH2N), 2.71
(2H, brs, CH2N), 2.52 (2H, brs, CH2N). 13CNMR (75 MHz,
DMSO-d6) δ / ppm: 163.3, 163.0, 155.0, 134.0, 124.6, 116.7,
116.0, 98.9, 65.8, 65.5, 56.6, 53.6, 53.5. Anal. Calcd. w / %
for C17H20N2O4 (316.36): C, 64.54; H, 6.37; N, 8.86; Found:
C, 64.49; H, 6.43; N, 8.81.
Ethyl (E)-2-cyano-3-(4-(4-phenylpiperidin-1-yl)phenyl)acrylate
(3x): m.p. 115–116 °C; IR (KBr) (νmax / cm–1): 3021, 2992,
2933, 2208, 1727, 1609, 1563, 1510, 1274, 1226, 1172, 964,
812, 751, 705, 517; 1HNMR (300 MHZ, CDCl3) δ / ppm: 8.10
(s, 1H, CHVinylic), 7.96 (d, 2H, J = 9 Hz, CHAr), 7.36–7.18 (m,
5H, CHPh), 6.89 (d, J = 9 Hz, 2H, CHAr), 4.38 (q, J = 6 Hz, 2H,
OCH2), 3.99 (d, J = 9 Hz, 2H, CHAr), 2.93 (d.t, 2H, 1J = 9 Hz, 2J
= 3 Hz, 2CH), 2.61 (d, J = 6 Hz, 2H, CH2) 1.92–1.86 (m, 1H,
CH), 1.81 (d, J = 12 Hz, 2H, 2CH), 1.41 (t, J = 6 Hz, 3H, CH3),
1.35 (d, J = 3 Hz, 2H, 2CH). 13CNMR (75 MHz, CDCl3) δ / ppm:
164.2, 154.3, 153.9, 139.9, 134.1, 129.1, 128.4, 126.1,
120.3, 117.4, 113.4, 94.9, 81.9, 47.5, 42.9, 38.1. 31.5, 14.3.
Anal. Calcd. w / % for C24H26N2O2: C, 76.98; H, 7.00; N, 7.48;
Found: C, 77.01; H, 7.13; N, 7.51.
Methyl (E)-2-cyano-3-(3-(2-morpholinoethoxy)phenyl)acrylate
(3q): m.p. 180–183 °C; IR (KBr) (νmax / cm–1): 2953, 2923,
2852, 2224, 1734, 1610, 1580, 1437, 1243, 1130, 954, 684,
515. 1HNMR (300 MHz, DMSO-d6) δ / ppm: 8.40 (1H, s,
CHvinylic), 7.69 (1H, d, J = 9 Hz, CHAr), 7.67 (1H, s, CHAr), 7.53
(1H, t, J = 9 Hz, CHAr), 7.28 (1H, d, J = 9 Hz, CHAr), 4.25 (2H,
t, J = 6 Hz, OCH2), 3.88 (3H, s, OCH3), 3.67 (4H, t, J = 3 Hz,
CH2OCH2), 2.94 (2H, t, J = 6 Hz, CH2N), 2.70 (4H, brs,
CH2NCH2). 13CNMR (75 MHz, DMSO-d6) δ / ppm: 162.7,
158.9, 155.5, 133.0, 130.9, 123.7, 120.4, 116.9, 116.0,
103.0, 65.8, 65.2, 56.7, 53.8, 53.5. Anal. Calcd. w / % for
C17H20N2O4 (316.36): C, 64.54; H, 6.37; N, 8.86; Found: C,
64.61; H, 6.39; N, 8.92.
Ethyl (E)-2-cyano-3-(4-(2-morpholinoethoxy)phenyl)acrylate
(3y): m.p. 217–218 °C; IR (KBr) (νmax / cm–1): 3033, 2996,
2938, 2217, 1718, 1588, 1514, 1263, 1185, 940, 834, 517;
1HNMR (300 MHZ, CDCl3) δ / ppm: 8.32 (s, 1H, CHvinylic), 8.09
(d, J = 9 Hz, 2H, CHAr), 7.18 (d, J = 9 Hz, 2H, CHAr), 4.31 (q, J
= 6 Hz, 2H, OCH2), 4.30 (brs, 2H, CH2), 3.66 (brs, 4H, 2CH2),
2.92 (brs, 2H, CH2), 2.68 (brs, 4H, 2CH2), 1.32 (3H, t, J = 6 Hz,
CH3). 13CNMR (75 MHz, CDCl3) δ / ppm: 163.0, 162.8, 154.9,
133.9, 124.6, 116.7, 115.9, 99.2, 65.9, 65.6, 62.6, 56.7, 53.5,
14.5. Anal. Calcd. w / % for C18H22N2O4: C, 65.44; H, 6.71; N,
8.48. Found: C, 65.49; H, 6.68; N, 8.50.
Methyl (E)-3-(4-(4-bromobenzyl)oxy)phenyl)-2-cyanoacrylate
(3r): m.p. 129–132 °C; IR (KBr) (νmax / cm–1): 3027, 2948,
2218, 1724, 1590, 1514, 1434, 1311, 1268, 1214, 1184,
1
1094, 1070, 804, 759, 515. HNMR (300 MHz, CDCl3) δ /
ppm: 8.21 (1H, s, CHvinylic), 8.03 (2H, d, J = 9 Hz, CHAr), 7.57
(2H, d, J = 9 Hz, CHAr), 7.34 (2H, d, J = 9 Hz, CHAr), 7.07 (2H,
d, J = 9 Hz, CHAr), 5.13 (2H, s, OCH2), 3.95 (3H, s, OCH3).
13CNMR (75 MHz, CDCl3) δ / ppm: 163.5, 162.6, 154.5,
134.8, 133.7, 131.9, 129.1, 124.7, 122.3, 116.1, 115.5, 99.2,
69.5, 53.2. Anal. Calcd. w / % for C18H14BrNO3 (372.22): C,
58.08; H, 3.79; N, 3.76; Found: C, 58.11; H, 3.85; N, 3.81.
Ethyl (E)-3-(4-((4-bromobenzyl)oxy)phenyl)-2-cyanoacrylate
(3z): m.p. 140–142 °C; IR (KBr) (νmax / cm–1): 3027, 2948,
2218, 1724, 1590, 1514, 1434, 1381, 1311, 1268, 1214,
1
Methyl (E)-3-(4-((4-chlorobenzyl)oxy)phenyl)-2-cyanoacrylate
(3s): m.p. 142–145 °C; IR (KBr) (νmax / cm–1): 3028, 2951,
2219, 1725, 1589, 1515, 1433, 1387, 1311, 1267, 1214,
1184, 1093, 1005, 831, 759, 563, 514. 1HNMR (300 MHz,
1183, 1093, 1069, 1002, 832, 804, 759, 554, 515. HNMR
(300 MHz, CDCl3) δ / ppm: 8.20 (s, 1H, CHVinylic), 8.03 (d, J =
9 Hz, 2H, CHAr), 7.57 (d, J = 9 Hz, 2H, CHAr), 7.34 (d, J = 9 Hz,
2H, CHAr), 7.08 (d, J = 9 Hz, 2H, CHAr), 5.13 (s, 2H, OCH2),
DOI: 10.5562/cca3261
Croat. Chem. Acta 2018, 91(1), 19–28

24
Y. POURSHOJAEI et al.: Ultrasound-assisted and Efficient Knoevenagel Condensation Reaction …
4.40 (q, J = 6 Hz, 2H, OCH2), 1.42 (t, J = 6 Hz, 3H, CH3).
13CNMR (75 MHz, CDCl3) δ / ppm: 163.0, 162.5, 154.2,
134.8, 133.6, 131.9, 129.1, 124.8, 122.3, 116.1, 115.5, 99.8,
69.5, 62.5, 14.2. Anal. Calcd. w / % for C19H16BrNO3: C,
59.08; H, 4.18; N, 3.63; Found: C, 59.12; H, 4.11; N, 3.67.
RESULTS AND DISCUSSION
Silica sodium carbonate nanoparticles were synthesized by
a
slight modification of the solvothermal reported
method.[43] The FT-IR spectrum of SSC NPs are exactly same
as what reported in the literature[43] and strongly confirm
the catalyst’s structure. It should be mentioned that all im-
portant peaks centered at 3426, 1626, 1453, 1082, 880, 797
and 468 cm−1 are obviously seen in the FT-IR spectrum of
SSC NPs (supplementary materials).
The morphology of SSC NPs was studied by scanning
electron microscopy (SEM) (Figure 1). SEM image of SSC
NPs shows the silica sodium carbonate nanoparticles have
a diameter of about 30 nm without any amorphous or other
kinds of crystallized phase particles. In addition, the trans-
mission electron microscopy (TEM) image of silica sodium
carbonate nanoparticles was studied for more investigation
of SSC NPs morphology (Figure 2). TEM image of SSC NPs
clearly demonstrated the SSC NPs have a homogeneous di-
ameter size about 30 nm.
Figure 1. SEM image of SSC NPs.
In another investigation, to quantify the exact
amount of the sodium carbonate groups attached to the sil-
ica, the catalyst was titrated with HCl (0.01 N). Considering
to the molecular weight of CO3Na (83 g), the results demon-
strated that 0.006 g of SSC NPs was equivalent to 0.01
mmol CO3Na. In other words, 0.006 g of catalyst is contain-
ing 1 mol% of CO3Na group.
Also it is interesting to note that the reproducibility
of the SSC nanoparticle synthesis when considering the per-
centage of the attached sodium carbonate groups was very
good so that titration results with HCl (0.01 N) for repro-
duced catalysts were very close to previous one. From titra-
tion results on reproduced catalysts, it could generally be
concluded that 0.006 g of catalyst was equivalent to 0.01
mmol CO3Na.
Before starting to develop reaction scope by the use
of numerous arylaldehydes and malononitrile derivatives,
it was tried to find best condition to obtain products with
highest yield in shortest reaction time on model reaction
(compound 3a) and the results were summarized in Table 1.
First of all, the reaction was loaded in catalyst-free
conditions. It was observed that no remarkable product
was obtained in absence of catalyst. Among examined sol-
vents, target product was obtained with more yields in the
presence of acetonitrile. In addition, the application of son-
ication significantly leads to increase of reaction yield. As
Figure 2. TEM image of SSC NPs.
well as, the use of SSC NPs instead of SiO2 or SSC bulk re-
sulted to remarkably increase of reaction yield. As can be
seen from Table 1, among investigated of different condi-
tions, using SSC NPs (2 mol%) under sonication irradiation
at 70 °C was selected as the best condition to obtain prod-
ucts with highest yields.
After finding the optimum conditions for reaction
performance, the generality of the reaction was examined
by the use of a wide range of arylaldehydes and malono-
nitrile or methyl/ethyl cianoacetate in the presence of op-
timum amounts of SSC NPs as green, highly efficient and
recyclable nano-catalyst, and the results were summarized
in Table 2.[47-50]
Croat. Chem. Acta 2018, 91(1), 19–28
DOI: 10.5562/cca3261

Y. POURSHOJAEI et al.: Ultrasound-assisted and Efficient Knoevenagel Condensation Reaction …
25
Table 1. Investigation of different conditions on model reaction(a)
Entry
1
Catalyst
None
Conditions
CH2Cl2, 40 °C
Yield(b)
21
33
40
38
42
45
49
60
69
75
86
88
98
98
97
2
None
H2O, 70 °C
3
None
THF, 66 °C
4
None
EtOH, 50 °C
5
None
EtOH, 60 °C
6
None
EtOH, 70 °C
7
None
CH3CN, 70 °C
8
SiO2 (0.018 g)
SSC bulk (1 mol%)
SSC bulk (1 mol%)
SSC bulk (2 mol%)
SSC NPs (1 mol%)
SSC NPs (2 mol%)
SSC NPs (3 mol%)
SSC NPs (4 mol%)
CH3CN, 70 °C
9
CH3CN, 70 °C
10
11
12
13
14
15
CH3CN, Sonication, 70 °C
CH3CN, Sonication, 70 °C
CH3CN, Sonication, 70 °C
CH3CN, Sonication, 70 °C
CH3CN, Sonication, 70 °C
CH3CN, Sonication, 50 °C
(a)
(b)
Reaction time: 25 min
Isolated yield
As can be seen from Table 2, all products bearing
which it is indeed the significantly lower cost catalyst than
MCM-48 or SBA-15.
both electron donating/withdrawing groups on arylalde-
hyde rings under optimum conditions resulted to obtain
compound 3 with excellent yields. Also it may be noticed to
the reports on Knoevenagel condensation reactions cata-
lyzed by some standard commercially available mesopo-
rous silica such as functionalized MCM-48 or SBA-15.[51]
However MCM-48 or SBA-15 themselves are not as effi-
cient as SSC NPs in Knoevenagel condensation reaction but
when they would functionalize by amino groups or ionic
liquids they can almost act as good as SSC NPs in above
condensation reaction. However commercial samples of
MCM-48 or SBA-15 are rather expensive than SSC NPs
Reusability of the Catalyst
Because of the capability of catalyst to reuse makes it in-
dustrially and economically considerable and can be con-
sidered as one of the noteworthy aspects of this methodol-
ogy, the capability of SSC NPs to reuse was evaluated on
model reaction and the results were given in Figure 3. This
investigation reveals that SSC NPs can efficiently catalyze the
reaction up to six times without significant loss of activity.
CONCLUSION
In summary, an efficient nano-catalytic approach to the
synthesis of newly prepared arylidene malononitriles or
methy/ethyl cianoacetates was described by the use of SSC
NPs as a highly efficient nano-catalyst. By this achievement
some novel products were obtained which can be candi-
date as medicinally important compounds or even im-
portant drugs in the future. Therefore, this methodology
can attract the interest of chemists, biologists and pharma-
cologists in the future. In addition, a new application of SSC
NPs as a green, highly efficient, reusable, and easily han-
dled nano-catalyst to the synthesis of novel organic com-
pounds was successfully examined. All products were
isolated in excellent yields, and the catalyst efficiently
recovered and successfully reused in further cycles.
Figure 3. Reusability results of SSC NPs on model reaction
over six cycles; Reaction conditions: 4-nitrobenzaldehyde (1
mmol, 0.151 g), malononitrile (1.5 mmol 0.099 g), SSC NPs
(2 mol%), CH3CN (10 mL), Sonication, 70 °C.
DOI: 10.5562/cca3261
Croat. Chem. Acta 2018, 91(1), 19–28

26
Y. POURSHOJAEI et al.: Ultrasound-assisted and Efficient Knoevenagel Condensation Reaction …
Table 2. Highly efficient and practical synthesis of compounds 3a-z via Knoevenagel condensation reaction between
arylaldehydes and malononitrile or ethyl/methyl cianoacetate(a)
H3C
CH3
O
N
N
N
N
N
N
N
N
N
3a
Yield(b) (%)/(lit): 98/97
m.p. (°C) (lit): 163–165
(160–161)[47]
3b
N
N
N
Yield(b) (%)/(lit): 96/99
m.p. (°C) (lit): 185–186
(185–186)[48]
3c
3d
3e
Yield(b) (%): 94
Yield(b) (%): 93
Yield(b) (%): 95
m.p. (°C): 198–200(c)
m.p. (°C): 134–135(c)
m.p. (°C): 127–128(c)
O
Cl
N
N
Cl
O
O
O
O
O
N
O
N
N
N
N
N
N
N
N
N
N
3f
3g
3h
3i
3j
Yield(b) (%): 92
Yield(b) (%): 90
Yield(b) (%): 89
Yield(b) (%): 97
Yield(b) (%): 95
m.p. (°C): 228–229(c)
m.p. (°C): 225–226(c)
m.p. (°C): 195–198(c)
m.p. (°C): 174–176(c)
m.p. (°C): 100–103(c)
Br
O
H3C
CH3
N
N
N
Br
O
O
N
N
N
N
N
O
O
O
O
CH3
O
O
CH3
3m
3n
CH3
N
N
3k
3l
Yield(b) (%)/(lit): 95/91
m.p. (°C) (lit): 148–149
(145)[49]
Yield(b) (%)/(lit): 93/84
m.p. (°C) (lit): 146–149
(not reported)[50]
3o
Yield(b) (%): 95
Yield(b) (%): 93
Yield(b) (%): 90
m.p. (°C): 187–190(c)
m.p. (°C): 104–105(c)
m.p. (°C): 96–99(c)
O
Br
Cl
N
Cl
O
O
O
O
N
O
O
N
N
N
N
N
O
O
O
O
O
O
O
O
O
O
CH3
CH3
CH3
CH3
CH3
3p
3q
3r
3s
3t
Yield(b) (%): 91
Yield(b) (%): 90
Yield(b) (%): 95
Yield(b) (%): 94
Yield(b) (%): 93
m.p. (°C): 203–207(c)
m.p. (°C): 180–183(c)
m.p. (°C): 129–132(c)
m.p. (°C): 142–145(c)
m.p. (°C): 83–86(c)
O
Br
O
N
H3C
CH3
N
O
N
O
N
O
N
O
O
N
N
N
N
N
N
O
O
O
O
O
O
O
O
O
CH3
CH3
CH3
3u
3v
3w
CH3
CH3
CH3
Yield(b) (%)/(lit): 98/96
m.p. (°C) (lit): 127–129
(123–125)[48]
Yield(b) (%)/(lit): 94/86
m.p. (°C) (lit): 155–157
(not reported)[50]
Yield(b) (%)/(lit): 93/90
m.p. (°C) (lit): 90–92
(not reported)[50]
3x
3y
3z
Yield(b) (%): 95
m.p. (°C): 115–116(c)
Yield(b) (%): 93
Yield(b) (%): 98
m.p. (°C): 217–218(c)
m.p. (°C): 140–142(c)
(a)
Reaction conditions: SSC NPs (2 mol%), CH3CN (10 mL), Sonication, 70 °C.
(b)
(c)
Isolated yields.
Novel product.
Croat. Chem. Acta 2018, 91(1), 19–28
DOI: 10.5562/cca3261

Y. POURSHOJAEI et al.: Ultrasound-assisted and Efficient Knoevenagel Condensation Reaction …
27
Acknowledgment. Financial support from Pharmaceutics
Research Center, Institute of Neuropharmacology, Kerman
University of Medical Sciences is greatly acknowledged.
1998, 39, 8013; (b) G. Palmisano, F. Tibiletti, A.
Penoni, F. Colombo, S. Tollari, D. Garella, S.
Tagliapietra, G. Cravotto, Ultrason. Sonochem. 2011,
18, 652.
Supplementary Information. Supporting information to the
paper is attached to the electronic version of the article at:
http://doi.org/10.5562/cca3261.
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