Knoevenagel Condensation of Aldehydes and Ketones with Malononitrile Catalyzed by Amine Compounds-Tethered Fe3O4@SiO2 Nanoparticles

Article abstract of DOI:10.1007/s10562-016-1916-1

Abstract: A new magnetic nanoparticle supported-catalyst was developed for the Knoevenagel condensation between malononitrile and several aldehydes. The Fe₃O₄@SiO₂-3N (where 3N = N¹-(3-trimethoxysilylpropyl)diet

Full text of DOI:10.1007/s10562-016-1916-1

Catal Lett
DOI 10.1007/s10562-016-1916-1
Knoevenagel Condensation of Aldehydes and Ketones
with Malononitrile Catalyzed by Amine Compounds-Tethered
Fe3O4@SiO2 Nanoparticles
João Batista M. de Resende Filho1 · Gilvan P. Pires1 ·
João Marcos Gomes de Oliveira Ferreira1 · Ercules E. S. Teotonio1 · Juliana A. Vale1
Received: 12 September 2016 / Accepted: 9 November 2016
© Springer Science+Business Media New York 2016
Abstract A new magnetic nanoparticle supported-cat-
alyst was developed for the Knoevenagel condensation
between malononitrile and several aldehydes. The Fe3O4@
SiO2-3N (where 3N=N1-(3-trimethoxysilylpropyl)diethyl-
enetriamine) catalyst was characterized by XRD, infrared
spectroscopy, and thermogravimetric analysis. The reac-
tions provide excellent yields in a shorter reaction time in
relation to others reported in the literature. The catalyst was
easily recovered and reused until six times without signii-
cant loss of its catalytic capacity.
Graphical Abstract
Keywords Knoevenagel condensation · Magnetic
supported-catalyst · Heterogeneous catalysis
Electronic supplementary material The online version of this
article (doi:10.1007/s10562-016-1916-1) contains supplementary
material, which is available to authorized users.
1 Introduction
The Knoevenagel condensation [1] corresponds to aldol
organic reactions between active methylene and carbon-
ylated compounds such as aldehydes [2–5] and ketones
[6–8]. This reaction is commonly catalyzed by weak
* Juliana A. Vale
julianadqf@yahoo.com.br
1
Departamento de Química, Universidade Federal da Paraíba,
João Pessoa, PB 58051-970, Brazil
1 3

J. B. M. de Resende Filho et al.
bases such as amines under homogeneous conditions. The
proposed mechanism for the Knoevenagel condensation
involves deprotonation of the active methylene compound
by using a weak base, and subsequent attack of the result-
ing carbanion to the carbonyl group of the aldehyde or
ketone, concluding with a water elimination step [1]. This
kind of reactions is one of the most important methods to
perform new C–C bonds in organic compounds. Conse-
quently, it is present at least in one-step on the synthesis
of several molecules [9–11], drugs [12, 13] and total syn-
thesis [14–17]. For example, in the synthesis of (S)-(+)-
3-aminomethyl-5-methylhexanoic acid, the irst step is the
Knoevenagel condensation between isovaleraldehyde and
diethyl malonate (irst-generation Pregabalin manufactur-
ing process) [18, 19]. In addition, many other drugs have
been synthesized by using this condensation process, such
as atorvastatin [20], pioglitazone [21], entacapone [22],
coartem [23] etc.
Recently, some focus on the use of magnetic nanopar-
ticles for Knoevenagel condensation catalysis has been
reported [44–54]. These new catalysts have promoted good
yields, between 0.5 [51] to 18 [49] hours in mild conditions.
However, the reaction times have been relatively high and
their study with diferent substrates is still limited. There-
fore, this work presents the synthesis and characterization
of a new magnetic nanocatalyst, Fe3O4@SiO2-3N (where
3N=N1-(3-trimethoxysilylpropyl)diethylenetriamine), and
the catalytic activity test using a Knoevenagel condensa-
tion between carbonyl compounds (aldehydes and ketones)
and malononitrile, comparing with other similar catalysts
such as Fe3O4@SiO2-1N and Fe3O4@SiO2-2N (where
1N=(3-aminopropyl)trimethoxysilane, and 2N=N-[3-
(trimethoxysilyl)propyl]ethylenediamine), and some others
described in literature.
Throughout the years, several new catalysts for Knoev-
enagel condensation were developed to heterogeneous [24,
25] or homogeneous catalysis [26, 27]. Up to now, the main
researches were concerned in the preparation of new cata-
lysts that enable reactions in several media and substrates.
The catalysts were based on diferent materials such as
clays [28, 29], MOFs [30–32], organic compounds [33, 34],
enzymes [35, 36], composite oxides [37–39]. In particular,
the heterogeneous catalysts have received great attention in
the last decades [28–32, 37–54] owing to their capability
to overcome some diiculties on the catalysis, such as low
yield and catalyst recovery, due to the loss in the puriica-
tion process.
2 Experimental
2.1 Reagents and Instruments
Iron(III) chloride hexahydrate (FeCl3·6H2O, ACS reagent,
97%) iron(II) chloride tetrahydrate (FeCl2·4H2O, puriss.
p.a., ≥99%), sodium hydroxide (ACS reagent, ≥97.0%,),
silver nitrate (AgNO3, ACS reagent, ≥99.0%,), polyvi-
nylpyrrolidone (PVP, average molecular weight 40,000),
tetraethoxysilane (TEOS, reagent grade, 98%), pyridine
(ACS reagent, ≥99.0%), ethylenediaminetetraacetic acid
(EDTA, ACS, 99.4%), ammonium hydroxide solution
(NH4OH, ACS reagent, 28.0–30.0% NH3 basis), (3-ami-
nopropyl)trimethoxysilane 97% (H2N(CH2)3Si(OCH3)3),
Magnetic nanoparticles (MNPs) have been investigated
as inorganic supports for innumerous reactive species that
present potential application in organic catalysis. In this
case, a single material combines the properties assigned
to the MNPs such as the high surface area and its separa-
tion ability by applying an external magnet ield, with those
ones of the active catalyst covalently bonded on the surface
of the inorganic matrix. Consequently, the smart strategy
of using heterogeneous catalysis based on functionalized
MNPs is usually more efective than those ones involving
separation procedures such as iltration or centrifugation.
Most attention has been focused on the preparation of mag-
netic core–shell structures by coating magnetic nanoparti-
cles with a SiO2 shell in order to avoid degradation of the
naked MNPs in the reaction system or during the separa-
tion process. Furthermore, this inorganic shell became the
subsequent functionalization with the active species more
efective [55]. Over the last years, the use of magnetic nan-
oparticles as heterogeneous catalyst was reported in several
reactions: Michael addition [40, 56], Pechmann reaction
[41], Friedel–Crafts alkylation [40, 42], Mannich reaction
[43], Paal–Knorr reaction [57] among others [57–59].
N-[3-(trimethoxysilyl)propyl]ethylenediamine
97%
(H2N(CH2)2HN(CH2)3Si(OCH3)3), N1-(3-trimethoxysilyl-
propyl)diethylenetriamine technical grade (H2N(CH2)2HN
(CH2)2NH(CH2)3Si(OCH3)3), the aldehydes, and the malo-
nonitrile were obtained from Sigma-Aldrich Co. Ethanol
(200 Proof) was purchased from Tedia. All chemicals were
employed without further puriication. Pyridine was stored
over 3 Å molecular sieve.
Elemental analysis (C, H, and N) were carried out using
a Perkin Elmer 2400 elemental microanalyzer. The X-ray
difraction (XRD) patterns of all MNPs were recorded
with a Shimadzu Lab-X XRD-6000 difractometer, using
Cu-Ka radiation (λ=0.1541 nm). Measurements of mag-
netization curves at room temperature were performed by
using a Quantum Design Vibrating Sample Magnetom-
eter (VSM) under a test ield range of −15,000 to 15,000
Oe. The shape and nanostructural features were deter-
mined by transmission electron microscopy (TEM) using
a JEM-1200(JEOL) operating at 120 kV. Fourier-transform
infrared (FT-IR) spectra were carried out in a Shimadzu
IRTracer-100 FTIR spectrophotometer using KBr pellet
1 3

Knoevenagel Condensation of Aldehydes and Ketones with Malononitrile Catalyzed by Amine…
technique with a measuring range 400–4000 cm−1. Ther-
mogravimetric analysis (TGA) was performed on a Shi-
madzu DTG-60H thermal analyzer system at the heating
60 mL of ethanol it was added 3 g of PVP previously dis-
solved in 20 mL of deionized water. After this, the tem-
perature was raised to 60 °C, and 2.4 mmol of TEOS was
added to the reaction system, followed by the addition of
0.734 mL of NH4OH. This mixture was allowed to react
at a constant temperature of 60 °C for 8 h, and the par-
ticles produced were magnetically decanted. The result-
ing material was washed twice with 100 mL of deionized
water, then six times with 50 mL of ethanol, and dried
under reduced pressure at room temperature. To a sus-
pension of 0.5 g of this material in 50 mL of pyridine,
2.9 mmol of the silane N1-(3-trimethoxysilylpropyl)dieth-
ylenetriamine were added as well as 1.1 mL of NH4OH.
The mixture was constantly stirred by using a mechanical
stirrer for 24 h at room temperature. The resulting amino-
functionalized particles were magnetically decanted and
washed twice with 50 mL of deionized water and six
times with 50 mL of ethanol, and dried under reduced
pressure at room temperature. The Scheme 1 shows a
summary of the Fe3O4@SiO2-3N catalyst preparation.
The same procedures were used with the Fe3O4@SiO2-
1N and Fe3O4@SiO2-2N catalysts, changing only the
silane reagent, (3-aminopropyl)trimethoxysilane for the
irst and N-[3-(trimethoxysilyl)propyl]ethylenediamine
for the second, and these catalysts have been reported in
literature [46, 60]. The Fe3O4@SiO2-1N-EDTA catalyst
was synthesized according to the procedures as reported
in the literature [61].
1
rate of 10°C min−1 in N2 atmosphere. The H NMR spec-
tra was recorded on a VARIAN Mercury 200 MHz. The
chromatograms were recorded on a GC-QP2010-Shimadzu
equipped with FID detector and capillary Rtx-5 column
(30 m×0.25 mm×0.25 μm) and N2 as carry gas. Heating
gradient: 80–300°C (35°C min−1). From time to time an
aliquot of the reaction mixture was extracted with ethyl
acetate for analysis.
2.2 Preparation of the Catalyst
Fe3O4 nanoparticles were prepared by the chemical co-pre-
cipitation method. 7.2 mmol of FeCl3·6H2O and 3.6 mmol
of FeCl2·4H2O were mixed with 60 mL of deionized water.
The resulting solution was then brought to a reaction tem-
perature of 70°C. After that, 2.5 mol L−1 NaOH solution
was added dropwise until a pH of 11 was achieved. The
reaction system was kept under mechanical stirrer for 2 h
under N2 atmosphere.
The black solid was separated from the mixture by
using a magnet (Nd2Fe14B, N50, 50.8 × 50.8 × 25.4 mm)
and thoroughly washed with deionized water until no
more Cl− ions could be qualitatively detected by silver
nitrate test. The resulting material was dried for 12 h at
room temperature under reduced pressure. To a suspen-
sion containing 1 g of the magnetic nanoparticles in
Scheme 1 Synthesis of
the magnetic nanoparticle
supported catalyst, Fe3O4@
SiO2-3N
1 3

J. B. M. de Resende Filho et al.
2.3 General Procedure for Knoevenagel Condensation
(Ph), δ 142.50 (Ph), δ 146.99 (Ph–C=C), δ 189.02
(C=O), δ 190.29 (C=O).
A mixture of the aldehyde/ketone (0.1 mmol), compound
of active methylene group (0.1 mmol), catalyst (5 mg)
and solvent (toluene or water, 0.4 mL) was added in a
glass tube and mechanically stirred at 75 °C. The reac-
tion progress was monitored by Gas Cromatography with
FID detector. After the completion of this reaction, the
catalyst was removed by magnetic separation. For the
reactions in toluene, the mixture was puriied by using
column chromatography, and for the reactions in water,
the product was precipitated with cool water, iltrated and
dried under low pressure. All the products were charac-
terized by 1H NMR, and 13C NMR.
2.3.5 2-(4-Chlorobenzylidene)Malononitrile (5)
1H NMR (200 MHz, CDCl3): δ 7.85 (d, 2H, J=8.6 Hz), δ
7.74 (s, 1H), δ 7.52 (d, 2H, J=8.6 Hz); 13C NMR (50 MHz,
CDCl3) δ (ppm): δ 83.31 (–C=C–(CN)2), δ 112.34 (CN), δ
113.44 (CN), δ 129.25 (Ph), δ 130.07 (Ph), δ 131.84 (Ph),
δ 141.16 (Ph), δ 158.31 (Ph–C=C).
2.3.6 2-(4-Methoxybenzylidene)Malononitrile (6)
1H NMR (200 MHz, CDCl3): δ 7.92 (d, 2H, J=8 Hz), δ
7.66 (s, 1H), δ 7.02 (d, 2H, J=8 Hz), δ 3.92 (s, 3H); 13C
NMR (50 MHz, CDCl3) δ (ppm): δ 55.79 (H3C–O–), δ
78.55 (–C=C–(CN)2), δ 113.34 (CN), δ 114.43 (CN),
δ 115.12 (Ph), δ 124.01 (Ph), δ 133.46 (Ph), δ 158.89
(Ph–C=C), δ 164.80 (Ph).
2.3.1 2-Benzylidenemalononitrile (1)
1H NMR (200 MHz, CDCl3): δ 7.91 (d, 2H, J = 7.0 Hz),
δ 7.79 (s, 1H), δ 7.57 (m, 3H); 13C NMR (50 MHz,
CDCl3) δ (ppm): δ 82.56 (–C=C–(CN)2), δ 113.62 (CN),
δ 112.47 (CN), δ 130.61 (Ph), δ 130.77 (Ph), δ 134.54
(Ph), δ 159.97 (Ph–C=C).
2.3.7 2-(4-Nitrobenzylidene)Malononitrile (7)
1H NMR (200 MHz, CDCl3): δ 8.39 (d, 2H, J=8.8 Hz), δ
8.07 (d, 2H, J=8.8 Hz), δ 7.89 (s, 1H); 13C NMR (50 MHz,
CDCl3) δ (ppm): δ 87.48 (–C=C–(CN)2), δ 111.60 (CN), δ
112.64 (CN), δ 131.32 (Ph), δ 135.80 (Ph), δ 150.33 (Ph),
δ 156.94 (Ph–C=C).
2.3.2 Methyl 2-Cyano-3-Phenylacrylate (2)
1H NMR (200 MHz, CDCl3): δ 8.26 (s, 1H), δ 7.99 (d,
2H, J = 3.0 Hz), δ 7.52 (m, 3H), δ 3.94 (s, 3H); 13C NMR
(50 MHz, CDCl3) δ (ppm): δ 53.37 (–O=CH3), δ 102.60
(CQ–CN), δ 115.40 (CN), δ 129.28 (Ph), δ 131.08 (Ph),
δ 131.41 (Ph), δ 133.38 (Ph), δ 155.27 (Ph–C=C), δ
162.96 (C=O).
2.3.8 2-(3-Nitrobenzylidene)Malononitrile (8)
1H NMR (200 MHz, CDCl3): δ 8.67 (s, 1H), δ 8.48 (d, 1H,
J=8.0 Hz), δ 8.33 (d, 1H, J=8.0 Hz), δ 7.91 (s, 1H), δ 7.82
(d, 1H, J=8.0 Hz); 13C NMR (50 MHz, CDCl3) δ (ppm):
δ 86.75 (–C=C–(CN)2), δ 111.64 (CN), δ 112.66 (CN),
δ 125.59 (Ph), δ 128.25 (Ph), δ 131.01 (Ph), δ 131.98
(Ph–C=C), δ 134.82 (Ph), δ 148.61 (Ph–NO2), δ 157.01
(Ph–C=C).
2.3.3 Ethyl 2-Cyano-3-Phenylacrylate (3)
1H NMR (200 MHz, CDCl3): δ 8.25 (s, 1H), δ 7.99 (d,
2H, J = 3.6 Hz), δ 7.52 (m, 3H), δ 4.39 (q, 2H, J = 2.8 Hz),
δ 1.40 (t, 3H, J = 2.8 Hz),; 13C NMR (50 MHz, CDCl3)
δ (ppm): δ 14.14 (–CH3), δ 62.71 (O–CH2–), δ 103.08
(CQ–CN), δ 115.43 (CN), δ 129.25 (Ph), δ 131.04 (Ph),
δ 131.49 (Ph), δ 133.25 (Ph), δ 154.97 (Ph–C=C), δ
162.46 (C=O).
2.3.9 2-(2-Nitrobenzylidene)Malononitrile (9)
1H NMR (200 MHz, CDCl3): δ 8.45 (s, 1H), δ 8.35 (d, 1H,
J=7.8 Hz), δ 7.84 (m, 3H); 13C NMR (50 MHz, CDCl3) δ
(ppm): δ 88.55 (–C=C–(CN)2), δ 110.94 (CN), δ 112.19
(CN), δ 125.85 (Ph), δ 126.69 (Ph), δ 130.45 (Ph), δ
133.40 (Ph), δ 134.93 (Ph), δ 158.75 (Ph–C=C).
2.3.4 2-Benzylidene-2H-Indene-1,3-Dione (4)
2.3.10 2-(Heptylidene)Malononitrile (10)
1H NMR (200 MHz, CDCl3): δ 8.43 (m, 2H), δ 8.00 (m,
2H), δ 7.89 (s, 1H), δ 7.80 (m, 2H), δ 7.51 (m, 3H); 13C
NMR (50 MHz, CDCl3) δ (ppm): δ 123.33 (Ph), δ 128.78
(Ph), δ 129.13 (Ph), δ 133.04 (Ph–C=C), δ 133.19 (Ph),
δ 134.13 (Ph), δ 135.21 (Ph), δ 135.41 (Ph), δ 140.02
1H NMR (200 MHz, CDCl3): δ 0.90 (s, 3H), δ 1.55
(m, 8H), δ 7.34 (q, 2H, J = 7.5 Hz), δ 7.34 (t, 1H,
J = 8.0 Hz); 13C NMR (50 MHz, CDCl3) δ (ppm): δ
13.96 (–CH3), δ 22.39 (–CH2–), δ 27.53 (–CH2–), δ
28.74 (–CH2–), δ 31.27 (–CH2–), δ 32.98 (–CH2–), δ
1 3

Knoevenagel Condensation of Aldehydes and Ketones with Malononitrile Catalyzed by Amine…
Fig. 3 Magnetization curves at room temperature of a Fe3O4 and b
Fe3O4@SiO2-3N materials
Fig. 1 XRD patterns of a Fe3O4 and b Fe3O4@SiO2-3N samples
89.78 (–C=C–(CN)2), δ 110.54 (CN), δ 112.14 (CN), δ
110.94 (CN), δ 169.99 (–CH2–C=C).
2.3.12 2-(2-Furanylmethylidene)Malononitrile (12)
1H NMR (200 MHz, CDCl3): δ 7.79 (s, 1H), δ 7.50 (s,
1H), δ 7.34 (d, 1H, J=4.0 Hz), δ 6.70 (s, 1H); 13C NMR
(50 MHz, CDCl3) δ (ppm): δ 77.68 (–C=C–(CN)2), δ
112.56 (CN), δ 113.76 (CN), δ 114.42 (=C–O–), δ 123.38
(–C=C–C=C–), δ 143.04 (–C=C–C=C–), δ 148.08
(–S–C(CHC(CN)2)=C–), δ 149.51 (furanyl–C=C).
2.3.11 2-(2-Thiophenylmethylidene)Malononitrile (11)
1H NMR (200 MHz, CDCl3): δ 7.89 (s, 1H), δ 7.90
(d, 1H, J = 4.0 Hz), δ 7.82 (d, 1H, J = 4.0 Hz), δ 7.29
(m, 1H); 13C NMR (50 MHz, CDCl3) δ (ppm): δ 78.35
(–C=C–(CN)2), δ 112.93 (CN), δ 113.77 (CN), δ 129.01
(=C–S–), δ 135.38 (–S–C(CHC(CN)2)=C–), δ 136.90
(–C=C–C=C–), δ 138.15 (–C=C–C=C–), δ 151.09
(tiophenyl–C=C).
2.3.13 2-(2-Naphthylmethylidene)Malononitrile (13)
1H NMR (200 MHz, CDCl3): δ 7.93 (m, 5H), δ 7.62 (m,
2H), δ 8.28 (s, 1H). 13C NMR (50 MHz, CDCl3) δ (ppm):
Fig. 2 TEM images of a Fe3O4
and b Fe3O4@SiO2-3N samples
1 3

J. B. M. de Resende Filho et al.
Fig. 4 FT-IR spectra of a
Fe3O4 and b Fe3O4@SiO2-3N
samples registered in the range
400–4000 cm−1 using KBr
pellets
Fig. 5 TG–DTG analysis for a
Fe3O4 and b Fe3O4@SiO2-3N
materials
δ 82.18 (–C=C–(CN)2), δ 112.89 (CN), δ 114.03 (CN),
δ 124.18 (Naph), δ 127.75 (Naph), δ 128.04 (Naph),
δ 128.53 (Naph), δ 129.68 (Naph), δ 130.02 (Naph), δ
132.60 (Naph), δ 134.53 (Naph), δ 135.87 (Naph), δ
159.79 (Ph–C=C).
2.3.14 2-(1-Phenylehtylidene)Malononitrile (14)
1H NMR (200 MHz, CDCl3): δ 7.50 (m, 5H), δ 2.62 (s,
3H).
1 3

Knoevenagel Condensation of Aldehydes and Ketones with Malononitrile Catalyzed by Amine…
Table 1 The efect of diferent
types of nanoparticles based
Fe3O4 and SiO2
Entry
Catalyst
Timea/min
Conversiona/%
1
2
3
4
5
6
7
8
–
90
90
90
90
60
25
15
90
–
Fe3O4
–
Fe3O4@SiO2
SiO2
6
40
100
100
100
35
Fe3O4@SiO2-1N
Fe3O4@SiO2-2N
Fe3O4@SiO2-3N
Fe3O4@SiO2-1N-EDTA
Reaction conditions: benzaldehyde (0.1 mmol), malononitrile (0.1 mmol), 0.4 mL of THF, 10 mg of the
catalyst, 75°C
aThe reaction time and conversions were determined by GC analysis
(–CH2–), δ 27.98 (–CH2–), δ 34.77 (=C–CH2–), δ 105.00
(C=C(CN)2), δ 111.68 (CN), δ 185.10 (–C=C(CN)2).
Table 2 Optimization of solvent and amount of the catalyst in Kno-
evenagel condensation
Entry Solvent
Catalyst/mg Timea/min Conversiona/%
2.3.17 2-(3-Methylcyclohexylidene)Malononitrile (17)
1
THF
10
5
3
1
5
5
5
5
5
5
3
1
15
20
45
90
20
10
15
90
12
45
45
60
100
94
1H NMR (200 MHz, CDCl3): δ 2.28 (s, 1H, J = 2.2 Hz),
δ 2.03 (m, 2H), δ 1.83 (m, 3H), δ 1.55 (m, 1H), δ 1.25
(m, 2H); 13C NMR (50 MHz, CDCl3) δ (ppm): δ 17.74
(–CH3), δ 22.69 (–CH2–), δ 29.35 (–CH2–), δ 30.38
(–CH2–), δ 31.17 (–CH(Me)–), δ 38.52 (–CH2–), δ 78.67
(C=C–(CN)2), δ 107.75 (CN), δ 180.31 (C=C(CN)2).
2
THF
3
THF
84
4
THF
55
5
–
100
100
100
98
6
Toluene
Acetonitrile
Chloroformb
Distilled water
Ethyl acetate
Toluene
Toluene
7
8
9
100
100
94
10
11
12
3 Results and Discussion
54
3.1 Characterization of the Catalyst
Reaction conditions: benzaldehyde (0.1 mmol), malononitrile
(0.1 mmol), 0.4 mL of the solvent, Fe3O4@SiO2-3N catalyst, 75°C
aThe reaction time and conversions were determined by GC analysis
bReaction temperature: 60°C
The results of elemental analysis (C, H, and N) of the
catalyst Fe3O4@SiO2-3N show the loading of amine
on the surface of magnetic nanoparticle: C 14.70%, H
3.21%, and N 7.33%. The X-ray difraction (XRD) pat-
tern of Fe3O4 and Fe3O4@SiO2-3N particles are shown
in Fig. 1. The characteristic peaks of magnetite and rela-
tive intensity match well with the standard Fe3O4 sample
(JCPDS ile No. 19–0629). Furthermore, the broad peak
from 2θ = 20°–30° is in agreement with the siloxane lat-
tice grown on the surface of magnetic particles.
The Fig. 2 shows TEM images for Fe3O4 and Fe3O4@
SiO2-3N magnetic nanoparticles. As can be seen in
micrographs, the materials present the same granu-
lar structure, formed by submicron particles. In the
micrograph of Fe3O4@SiO2-3N sample, it is possi-
ble observe lower contrast edges, suggesting a efective
2.3.15 2-(Diphenylmethylene)Malononitrile (15)
1H NMR (200 MHz, CDCl3): δ 7.78 (m, 4H), δ 7.50
(m, 6H); 13C NMR (50 MHz, CDCl3) δ (ppm): δ 105.13
(CN), δ 128.28 (Ph), δ 130.06 (Ph), δ 132.44 (Ph), δ
137.55 (Ph), δ 196.84 ((Ph)2–C=C(CN)2).
2.3.16 2-Cyclohexylidenemalononitrile (16)
1H NMR (200 MHz, CDCl3): δ 2.64 (m, 4H), δ 1.79
(m, 6H); 13C NMR (50 MHz, CDCl3) δ (ppm): δ 25.04
1 3

J. B. M. de Resende Filho et al.
Table 3 Knoevenagel
condensation between
benzaldehyde and other
compounds with methylene
active groups using the Fe3O4@
SiO2-3N as catalyst in water
Entry
Compound with MAG
Time/mina
Isolated yield/%
1
2
12
30
100
80
NC
NC
CN
O
O
O
3
4
25
20
75
82
O
NC
O
O
Reaction conditions: benzaldehyde (0.1 mmol), compound with methylene active group (0.1 mmol),
0.4 mL of water, 5 mg of Fe3O4@SiO2-3N, 75°C
aThe reactions time were determined by GC analysis
silica coating of the Fe3O4 particles by siloxane network
(≡Si–O–Si≡), wich presents electronic density lower
than of the magnetite.
assigned to the asymmetric stretching modes νas(Si–O)
from ≡Si–O–Si≡ groups. Moreover, it is possible to see the
absorption band at ~1463 cm−1 and two bands at 2854 and
2626 cm−1 that may be ascribed to the δ(C–H) deformation
and ν(C–H) stretching vibration modes of the –CH2 groups
belong to ethylenediamine moieties on the nanoparticle
surfaces. These results give evidences of the operative coat-
ing of the Fe3O4 particles with SiO2 and of the functionali-
zation of these nanoparticles with the organic group.
The thermal stability of the active surface of the cata-
lyst was evaluated by TGA, as seen in the TG curves
shown in Fig. 5. Fe3O4@SiO2-3N undergoes the irst mass
loss below 120°C, which is due to the loss of adsorbed or
trapped solvent molecules (water or ethanol). It is observed
a mass loss of approximately 11% of the weight that is seen
in the temperature range of 150–540°C, which is related to
the decomposition of 3N amino group. Besides, the DTG
curve shows that the decomposition of the organic structure
mainly occurred as from 300 to 450°C, which is related to
the main weight loss of 6%. The peak in the DTG curve
shows that the fastest loss of the 3-aminopropyl group
occurred at 380°C. The results indicate that the catalyst is
stable in a nitrogen atmosphere up to 150°C.
Figure 3 shows the room temperature magnetization
curves of the materials as measured by a VSM. The hys-
teresis loops show nearly zero hysteresis indicating super-
paramagnetic properties. The values of the saturation mag-
netization (σs) for Fe3O4 and Fe3O4@SiO2-3N magnetic
materials are 83.6 and 10.0 emu g−1, respectively. The
lowest for the Fe3O4@SiO2-3N material may be attributed
to the success of the particles coating step, resulting in a
lower content of magnetite per gram of the Fe3O4@SiO2-
3N sample. Nevertheless, the catalyst Fe3O4@SiO2-3N still
maintained a suicient magnetization to allow the magnetic
separation with a regular magnet.
The FT-IR spectra for magnetic nanoparticles are pre-
sented in the Fig. 4. The spectrum for the Fe3O4 sample is
characterized by a strong band centered at 596 nm−1, which
may be attributed to ν(Fe–O) stretching vibration modes
involving the metallic ions in tetrahedral and octahedral
sites. On the other hand, the band at ~435 cm−1 is assigned
to the ν(Fe–O) stretching vibration modes for metal centers
in octahedral sites only [62]. The band around 1641 cm−1
can be assigned to the HO-H deformation δ(OH) and the
broad band at ~3387 cm−1 is due to O–H stretching vibra-
tions arising from hydroxyl ions or water molecules coordi-
nated to Fen+ ions, where n=2 or 3, of unsaturated surface
[63]. In addition to the Fe–O assignments, the FT-IR spec-
trum for Fe3O4@SiO2-3N also shows a band at ~1051 cm−1
3.2 Catalytic Activity Test
First, various catalyst based on nanoparticles Fe3O4 and
SiO2 (Table 1) were tested in order to identify the best
1 3

Knoevenagel Condensation of Aldehydes and Ketones with Malononitrile Catalyzed by Amine…
Table 4 Knoevenagel
condensation between
aldehydes and malononitrile
using the Fe3O4@SiO2-3N as
catalyst
Fe3O4@SiO2-3N
75°C, solvent
CN
CN
R1
R1
O
NC
CN
Timea/min
Toluene
Isolated yield/%
Entry
Aldehyde
Time/min–yield/% [lit]
480–99 [49]
Water
12
Toluene
100
Water
93
1
2
10
O
20
40
10
10
90
85
87
88
94
120–100 [61]
O
Cl
3
4
30
10
60–94 [46]
5–99 [64]
O
H3CO
100
O
O2N
O2N
5
6
25
45
30
30
97
96
95
60–98 [64]
90–98 [64]
O
100
O
NO2
b
7
8
15
10
22
4
80
87
72
71
–
O
5
120–89 [46]
120–71 [61]
S
O
9
5
4
83
93
90
96
O
O
b
10
45
20
–
O
Reaction conditions: aldehyde (0.1 mmol), malononitrile (0.1 mmol), 0.4 mL of toluene (or water), 5 mg of
Fe3O4@SiO2-3N, 75°C
aThe reactions time were determined by GC analysis
bNo reported any magnetic nanoparticles-supported catalyst reaction with the correspondent aldehyde
material for the Knoevenagel condensation catalysis and to
aid the reaction mechanism elucidation.
eiciency decays in comparison with the magnetic nano-
particle analog (entry 5, Table 1), suggesting a basic cataly-
sis due to the presence of amino group, in accordance with
previous papers [1, 44, 46]. The Knoevenagel condensa-
tion between benzaldehyde and malononitrile without cat-
alyst (entry 1, Table 1) and only with nanoparticle Fe3O4
as catalyst (entry 2, Table 1) does not happen until 90 min
time. This behavior suggests that the magnetic nanopar-
ticles work out only the magnetic separation; they do not
The results in Table 1 show that the Fe3O4@SiO2-3N
is the best catalyst, which may be explained by its high-
est number of the nitrogen sites (–NH– and –NH2), and
its longest distance between the –NH2 site and silica sur-
face. This last is notable when comparing the results of
the entries 5–7 in Table 1. When the EDTA group (entry
8, Table 1) is added in the nanoparticle, the catalysis
1 3

J. B. M. de Resende Filho et al.
Table 5 Knoevenagel
condensation between ketones
and malononitrile using the
Fe3O4@SiO2-3N as catalyst in
water
R
R
Fe3O4@SiO2-3N
75°C, water
CN
R
NC
CN
R
O
CN
Entry
1
Ketone
Time/ha
10
Isolated yield/%
81
O
2
3
4
72
3
75
82
83
O
O
O
4
Reaction conditions: ketones (0.1 mmol), malononitrile (0.1 mmol), 0.4 mL of water, 5 mg of Fe3O4@
SiO2-3N, 75°C
aThe reactions time were determined by GC analysis
participate efectively in the reaction. In the same period of
time, a small percentage of conversion was observed when
Fe3O4@SiO2 (entry 3, Table 1) and SiO2 (entry 4, Table 1)
were used as catalyst, suggesting that the silanol groups on
the silica surface act as acid site for the Knoevenagel con-
densation catalysis.
The reaction at room temperature is considering slower
than reaction with heating: 10 min for benzaldehyde and
malononitrile at room temperature and 120 min for the
same reaction at 75°C. Because of this, the following reac-
tions were performed under heating (75°C). To optimize
the Knoevenagel condensation conditions (solvent and the
amount of the catalyst), the reaction between benzaldehyde
and malononitrile was used as a model (Table 2).
Initially, the solvent was chosen randomly (THF) in
order to verify the best amount of the catalyst for the reac-
tion. As can be seen in Table 2 (entries 1–4), there is a con-
siderable increase in the GC yield from 55 to 100%, but no
signiicant diference between the entries 1 and 2 (Table 2)
is observed, suggesting that the amount of catalyst in entry
2 (Table 2) is the best choice, based on the reaction time
and conversion factors. After the determination of the best
amount of the catalyst, the inluence of solvent on the Kno-
evenagel condensation catalyzed by Fe3O4@SiO2-3N was
investigated (entries 2 and 5–10, Table 2). Good yield was
obtained for all the solvents used in this work; however it
was observed signiicant diferences in the reaction time.
For the solvents toluene (entry 6, Table 2), acetonitrile
(entry 7, Table 2), and water (entry 9, Table 2), a good time
reaction was observed (10–15 min.). The best result was
achieved by using toluene or water as solvent, considering
the relation between reaction time and yield. The reactions
with the Fe3O4@SiO2-1N and Fe3O4@SiO2-2N catalysts
in these solvents present a longer reaction time (in water:
20 min, 89% and 30 min; 90%, respectively; in toluene:
20 min, 93% and 40 min; 91%, respectively), conirming
the best result for Fe3O4@SiO2-3N. It is worth mentioning
that this reaction at room temperature inished in 120 min
(conversion 93%).
After the optimization of the conditions for the Knoev-
enagel condensations between benzaldehyde and malo-
nonitrile, we veriied the eiciency of this catalyst with
other compounds with methylene active groups (MAG),
using water as solvent, considering an ecofriendly approach
(Table 3). All the reactions showed good isolated yields in
considerable short reaction times. In comparison, the reac-
tions with these compounds are slower than reaction with
1 3

Knoevenagel Condensation of Aldehydes and Ketones with Malononitrile Catalyzed by Amine…
Fig. 6 Proposed mechanism for Knoevenagel condensation using Fe3O4@SiO2-3N as catalyst
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
1
2
3
4
5
6
Cycle
Fig. 8 Recycling performance of the Fe3O4@SiO2-3N in the Knoev-
enagel Condensation between benzaldehyde and malononitrile
aldehydes were reacted with malononitrile in the same
conditions (Table 4), using toluene (considering the best
time) or water (considering the short time and non-toxics
properties/“green” solvent) as solvent.
The reactions with several aldehydes with the catalyst
Fe3O4@SiO2-3N show good isolated yields and a fast reac-
tion time compared with other magnetic nanoparticles-
supported catalysts reported in the literature. In general,
the reactions in water or toluene were fast (in minutes),
and present close values, except the 4-chlorobenzaldehyde,
probable because it is insoluble in water (entry 2). In addi-
tion, it is possible to verify that some reactions in water
Fig. 7 Reused Fe3O4@SiO2-3N homogeneously dispersed in reac-
tional medium (a) and magnetically attracted to the wall of reaction
vessel (b)
malononitrile, as well expected considering the high acidity
of the α-carbon hydrogen.
The malononitrile is the most reactive compound with
MAG, considering the compounds tested. Then, several
1 3

J. B. M. de Resende Filho et al.
Fig. 9 FT-IR spectra of a
fresh Fe3O4@SiO2-3N and b
reused Fe3O4@SiO2-3N (six
times) registered in the range
400–4000 cm−1 using KBr
pellets
were considerable faster than toluene, suggesting a reaction
mechanism favored by a protic polar solvent.
The reactions with ketones are slower than reac-
tions with aldehydes, considering the low reactivity
of carbonyl group. The ketones with aromatic groups
(entries 1 and 2) shows times reaction slower than ali-
phatic ketones (entries 3 and 4), suggesting a high deac-
tivation of the carbonyl group by mesomeric efect. As
the aliphatic ketones present the same times reaction
any steric efect was observed with the cyclohexanones
monosubstituted.
The Fe3O4@SiO2-3N catalyst is easily produced and is
an unexpansive material and showed good results when
compared with other similar catalysts used in Knoev-
enagel condensation [44, 46]. A proposed mechanism
using the catalyst Fe3O4@SiO2-3N was showed in Fig. 6.
This mechanism is in agreement with others mecha-
nism reported in literature [50]. We suggest that the best
results with Fe3O4@SiO2-3N catalyst compared with oth-
ers materials it is probably due of (1) the great number of
nitrogen atoms tethered on nanoparticle surface and (2)
the distance between the terminal amigo group, –NH2,
and the nanoparticle surface.
The efect of substituents at the aromatic ring of the
aldehydes on the Knoevenagel condensation was inves-
tigated. The functionalized aromatic aldehydes with
electron-withdrawing group as substituent (such as
nitro and chloro group) at the 4-position (entries 2 and
4, Table 3) show good isolated yield and a faster reac-
tion time in comparison with the functionalized aromatic
aldehydes presenting an electron-donating group as sub-
stituent (such as methoxy group) at the 4-position (entry
3, Table 3). The times reaction with 2-NO2-benzaldehyde
(entry 6, Table 3) is lower than that one with 3-NO2-
benzaldehyde (entry 5, Table 3) which in turn is slower
than 4-NO2-benzaldehyde (entry 4, Table 3), suggesting
a higher steric hindrance. It is also interesting to note that
the reaction with aliphatic aldehyde (entry 7, Table 2)
presents similar reaction time and yield when compared
with the aromatic aldehydes. In addition, 2-naphthalde-
hyde (entry 10, Table 3) are slower than other aromatic
aldehydes, indicating a possible steric hindrance. The
reaction between a heteroaromatic aldehyde (such as
2-thiophenecarboxyaldehyde and furfural) and malononi-
trile also shows an excellent reaction time and a relatively
good yield (entries 8 and 9, Table 3), and there is not
identiication of polymerization with the furfural.
3.3 Recyclability Studies
The main advantage of magnetic catalysts is due to their
several reuses without mass loss (i.e. catalytic activity) dur-
ing the cycles owing to a simple magnetic separation step.
In this way, the catalyst was subjected to reuse and recycle
The catalyst was used in reactions with some ketones
and malononitrile using water as solvent (Table 5).
1 3

Knoevenagel Condensation of Aldehydes and Ketones with Malononitrile Catalyzed by Amine…
ME, Mishra RK, Harrison BL, Nyce PL, Rand CL, Goralski CT
(2000) Org Process Res Dev 4:477
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tests in Knoevenagel reaction of benzaldehyde and malo-
nonitrile. After each run, the catalyst was attracted to the
wall of reaction vessel by a magnet as shown in Fig. 7. The
recovered catalyst was used for the next cycle after simply
washing with toluene and removing the residue solvent
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number of cycles in which it retains its catalytic activity
(Fig. 9). These indings support the catalyst capabilities for
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4 Conclusions
The Fe3O4@SiO2-3N (where 3N=N1-(3-trimethoxysilyl-
propyl)diethylenetriamine) is an excellent recyclable cata-
lyst for the Knoevenagel condensation between aldehydes
and malononitrile in toluene at 75°C. Compared with
other catalysts and methods reported in the literature, the
Fe3O4@SiO2-3N catalyst shows better relation with reac-
tion time and isolated yield. In addition, the catalyst practi-
cally leaves no residue in the reaction medium (veriied by
GC analysis) and the puriication procedures are easier than
the conventional process, reducing the costs of a possible
production on an industrial scale.
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