Nanomagnetically modified vitamin B3 (Fe3O4@Niacin): An efficient and reusable green biocatalyst for microwave-assisted rapid synthesis of 2-amino-3-cyanopyridines in aqueous medium

Article abstract of DOI:10.1002/aoc.4103

Superparamagnetic nanoparticles of modified vitamin B₃ (Fe₃O₄@Niacin) represent a new, efficient and green biocatalyst for the one-pot synthesis of 2-amino-3-cyanopyridine derivatives via four-component condensation reaction between aldehydes, ketones, malononitrile, and ammonium acetate under microwave irradiation in water. This new magnetic organocatalyst was easily isolated from the reaction mixture by magnetic decantation using an external magnet and reused at least six times without significant degradation in the activity. The catalyst was fully characterized by FT-IR, XRD, SEM, VSM, UV–Vis, DLS and EDS. Excellent yield, very short reaction time (7–10?min), operational simplicity, easy work-up procedure, avoidance of hazardous or toxic catalysts and organic solvents are the main advantages of this green methodology which makes it more economic than the other conventional methods.

Full text of DOI:10.1002/aoc.4103

Received: 24 February 2017
DOI: 10.1002/aoc.4103
Revised: 22 May 2017
Accepted: 24 August 2017
F U L L P A P E R
Nanomagnetically modified vitamin B3 (Fe3O4@Niacin): An
efficient and reusable green biocatalyst for microwave‐
assisted rapid synthesis of 2‐amino‐3‐cyanopyridines in
aqueous medium
Mojgan Afradi1 | Sjjad Abbasi Pour2 | Maryam Dolat3 | Afshin Yazdani‐Elah‐Abadi4
1 Department of Chemistry, Tehran North
Superparamagnetic nanoparticles of modified vitamin B3 (Fe3O4@Niacin) rep-
resent a new, efficient and green biocatalyst for the one‐pot synthesis of 2‐
amino‐3‐cyanopyridine derivatives via four‐component condensation reaction
between aldehydes, ketones, malononitrile, and ammonium acetate under
microwave irradiation in water. This new magnetic organocatalyst was easily
isolated from the reaction mixture by magnetic decantation using an external
magnet and reused at least six times without significant degradation in the
activity. The catalyst was fully characterized by FT‐IR, XRD, SEM, VSM, UV–
Vis, DLS and EDS. Excellent yield, very short reaction time (7–10 min),
operational simplicity, easy work‐up procedure, avoidance of hazardous or
toxic catalysts and organic solvents are the main advantages of this green meth-
odology which makes it more economic than the other conventional methods.
Branch, Islamic Azad University, Tehran,
Iran
2 Department of Chemistry, Faculty of
Science, University of Sistan and
Baluchestan, Zahedan, Iran
3 Department of Chemistry, Saveh Branch,
Islamic Azad University, Saveh, Iran
4 Department of Biology, Science and Art
University, Yazd, Iran
Correspondence
Afshin Yazdani‐Elah‐Abadi, Department
of Biology, Science and Art University,
Yazd, Iran.
Email: afi_yazdani@yahoo.com
KEYWORDS
2‐amino‐3‐cyanopyridines, green chemistry, magnetic recyclable nanocatalyst, microwave irradiation,
multi‐component reactions (MCRs), vitamin B3
1 | INTRODUCTION
replacements of the conventional Lewis acid and base cat-
alysts in different organic synthetic processes.[8] Among
In the past few years, focusing on green chemistry using
the development of environment‐friendly, effective, and
economical methods for the synthesis of biologically
interesting compounds both in terms of selection of reac-
tions and for the study of solvent and catalyst effects
remains a considerable challenge in synthetic chemis-
try.[1,2] In this area, nanomaterial applications as hetero-
geneous catalyst have gained popularity in organic
synthesis due to the high surface area, surface modifica-
tion ability, excellent thermal and chemical stability,
simple work‐up procedures, environmentally benign
nature, reusability, low cost, and ease of synthesis and
isolation.[3–7] Magnetic nanoparticles have also gained
recognition as potential environmentally benign
them, non‐toxic magnetic nanoparticles (MNPs) such as
magnetite (Fe3O4) and maghemite (γ‐Fe2O3) catalyzed
organic processes are often considered to follow the prin-
ciples of green chemistry, i.e. these catalyzed processes
consume a minimum of energy and reagents or auxiliaries
and minimize waste.[9,10]
Immobilization of vitamins on the surface of the
nanoparticles[11,12] have received significant attention to
reduce the problems of using mineral acid catalysts (e.g.
H2SO4 and HCl) and solid acid catalysts such as clays,
zeolites, sulfated metal oxides and heteropolyacids.[13]
Vitamin B3 is one of 8 B vitamins. It is also known as nia-
cin (nicotinic acid)[14] and is a non‐hygroscopic white
crystalline powder, water‐soluble and generally very
Appl Organometal Chem. 2017;e4103.
wileyonlinelibrary.com/journal/aoc
Copyright © 2017 John Wiley & Sons, Ltd.
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https://doi.org/10.1002/aoc.4103

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AFRADI ET AL.
stable. Niacin has fundamental physiological roles as pre-
cursor of cofactors to many vital enzymes.[15,16] Also, it
has been found as a therapeutic agent capable of reducing
high blood levels of triglycerides, cholesterol and lipopro-
teins associated with atherosclerosis.[16] Niacin has two
other forms, niacinamide (nicotinamide) and inositol
hexanicotinate, which have different effects from nia-
cin.[17] So we have developed an efficient procedure to
tether VB3 on a magnetic surface.
anti‐microbial,[28]
cardiotonic,[29]
anti‐inflamma-
tory,[30,31] anti‐parkinsonism[32] and anti‐tumor proper-
ties.[33] Also, they have been identified as novel IKK‐β
inhibitors,[30] A2A adenosine receptor antagonists[32] and
potent inhibitor of HIV‐1 integrase.[34] Moreover, these
compounds serve as useful intermediates in preparing a
variety of heterocyclic compounds.[35]
For the above reasons and in continuation of our
research on multi‐component reactions and our ongoing
program for the synthesis of complex organic compounds
based on green chemistry protocols,[36–38] herein we were
intrigued by the possibility of applying nano and green
chemistry to the design of an efficient and reusable cata-
lyst (MNPs‐Niacin) for the synthesis of 2‐amino‐3‐
cyanopyridine derivatives under microwave irradiation
(180 W, max. 70°C) in H2O (Scheme 1).
On the other hand, in order to economic savings and
pollution prevention, multi‐component reactions (MCRs)
in which more than two components are combined in a
single synthetic operation, have considerable ecological
interest as a powerful strategy in the synthesis of chemi-
cally and biologically important organic frameworks.
These processes avoid the isolation and purification of
intermediates, higher productivity, minimize solvent
waste, and enhance the greenness of the transforma-
tions.[18,19] Also, microwave‐assisted organic synthesis
(MAOS) has become a very valuable tool, improving the
outcome of multi‐component reactions[20] because micro-
wave heating is able to minimize side reactions, increase
yields, reduce reaction times, improve reproducibility,
and even enable inaccessible reactions by conventional
heating and is particularly useful for the preparation of
various biologically active heterocyclic compounds.[21]
Therefore, the design of novel MCRs for the synthesis
of diverse heterocycles has remained as an important
topic for medicinal and organic chemists. The pyridine
nucleus is one of the most popular N‐heteroaromatics
found in pharmaceuticals and natural products.[22,23]
The pyridine ring systems are also involved in coordina-
tion chemistry,[24] materials and surfaces,[25] supramolec-
ular structures,[26] and organocatalysis.[27] Among them,
2‐amino‐3‐cyanopyridine derivatives have attracted sig-
nificant, because of their biological activities such as
2 | RESULTS AND DISCUSSION
2.1 | Preparation and characterization of
Fe3O4@niacin catalyst
Fe3O4 NPs were synthesized by the conventional co‐pre-
cipitation procedure.[39] In the first, Fe3O4 nanoparticles
prepared by co‐precipitation method from FeCl3.6H2O
and FeCl2.4H2O in ammonia medium and then nicotinic
acid coated on magnetic nanoparticles from reaction of
hydroxyl functional groups on the surface of Fe3O4 NPs
with carboxylic acid functional group of nicotinic acid in
water and room temperature (Scheme 2).
The morphology and particle size of MNPs‐Niacin cat-
alyst was demonstrated using the scanning electron
microscope (SEM), Figure 1. According to the Figure 1,
MNPs@Niacin has a mean diameter about 17 nm and
almost spherical shape.
SCHEME 1 One‐pot, four‐component
synthesis of 2‐amino‐3‐cyanopyridine
derivatives in the presence of MNPs‐niacin
as catalyst
SCHEME 2 Synthesis of MNPs‐Niacin
as new heterogeneous catalyst

AFRADI ET AL.
3 of 13
FIGURE 1 SEM image of MNPs‐Niacin
The energy dispersive X‐ray spectroscopy (EDS) result,
received from SEM analysis of MNPs‐Niacin, is depicted
in Figure 2 and clearly represents the attendance of N,
C, O, and Fe signals in magnetic nanoparticles catalyst
that indicate the iron oxidenanoparticles are functional-
ized by nicotinic acid groups.
According to the above analysis, it can be deduced
that the MNPs@Niacin have been successfully
synthesized.
To specify the crystalline structure of the MNPs‐
Niacin X‐ray powder diffraction (XRD) pattern was
accomplished Figure 3. In the basis of the XRD data of
the synthesized magnetic nanoparticles (Fe3O4@Niacin),
all diffraction peaks at 2 = 30.3, 35.7, 43.4, 53.8, 57.3,
62.9, and 74.5 which are assigned to the (220), (311),
(400), (422), (511), (440), and (533) crystallographic of
Fe3O4, respectively. The XRD pattern of nanocatalyst is
in accordance with the standard Fe3O4 spinal structure
(JCPDS file NO.19–0629), that indicate the retention/
survival of the crystalline spinel ferrite core structure
during the nicotinic acid coating process.
FIGURE 2 EDAX spectra of MNPs‐Niacin
FIGURE 3 XRD pattern of MNPs‐Niacin

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AFRADI ET AL.
X‐ray diffraction is a convenient method for estimat-
(DLS) spectrometer in an aqueous solution. Particle size
distribution curves showed that average particles size of
MNPs‐Niacin is 8.3 nm. The value of the zeta potential
is predictive of the colloidal stability. Nanoparticles with
Zeta Potential values greater than +25 mV or less than
−25 mV typically have high degrees of stability.[41] The
zeta potential of the MNPs‐Niacin in aqueous dispersion
Figure 4, were determined to be −26.3 mV that demon-
strate high stability of MNPs‐Niacin nanoparticles.
To evaluate magnetic properties of MNPs‐Niacin, a
vibration sample magnetometer (VSM) was used in an
applied field of approximately 10000 Oe at room tempera-
ture. On the basis of Figure 5, the saturation magnetiza-
tion (MS) quantity for MNPs and MNPs‐Niacin catalyst
is approximately 66 emu/g and 55 emu/g, respectively.
The saturation magnetization of Fe3O4@Niacin catalyst
in compared to the uncoated Fe3O4 MNPs (67.22 emu/g)
exhibited evident decrease because of the increasing
amount of organic compound on the nanoparticles sur-
face.[42] The strong magnetization of the MNPs was spec-
ified by means of an external magnet (Figure 5, right inset
in the MNPs‐Niacin diagram) suggesting that the synthe-
sized magnetic nanoparticles had a superb magnetic
responsibility, which prevents composite microspheres
ing the average size of nano crystallites in nano crystalline
bulk materials. The first scientist, Paul Scherrer, pub-
lished his results in a paper that included what became
known as the Scherrer equation in 1981.[40] This can be
attributed to the fact that ‘crystallite size’ is not synony-
mous with ‘particle size’, while X‐Ray diffraction is sensi-
tive to the crystallite size inside the particles. From the
well‐known Scherrer formula the average crystallite size,
D, is:
D ¼ kλ= βcos
where
λ is the X‐ray wavelength in nanometer
(0.154 nm), β is the peak width of the diffraction peak
profile at half maximum height resulting from small crys-
tallite size in radians and K is a constant related to crys-
tallite shape, normally taken as 0.9 and corresponds to
the Bragg diffraction angle of the (311) powder peak in
degrees. According to the Scherer's equation, the crystal-
line size of the MNPs‐Niacin was specified to be
10.68 nm, which is smaller than the size determined by
SEM analysis.
The particle size distribution and zeta potential of the
MNPs‐Niacin was determined by dynamic light scattering
FIGURE 4 Particle size distribution (a) and zeta potential (b) of MNPs‐Niacin assessed by DLS
MNPs
80
60
40
20
0
-10000 -5000 -20 0
5000
10000
-40
-60
-80
Applied Field (Oe)
FIGURE 5 VSM diagrams of MNPs and MNPs‐Niacin, right inset in the MNPs‐Niacin diagram: The picture displays the catalyst was
dispersed in liquid and captured by the outer magnet

AFRADI ET AL.
5 of 13
for aggregation and enable them to redispersed quickly
when the magnetic field is removed.
Fe3O4@Niacin are demonstrated in the Figure 7. Niacin
represents two peaks in UV region at 214 and 262 nm
due to both conjugated (π)‐bonding systems (π‐π*
transition) and nonbonding electron system (n‐π*
transition) in the compound. Fe3O4 nanoparticles do not
The FT‐IR spectra of niacin, Fe3O4 and Fe3O4@Niacin
are depicted in Figure 6, in the wave number range
4000–400 cm−1. The FT‐IR spectrum of nicotinic acid
(niacin) was represented in Figure 6a, the characteristic
signal at 3160 cm−1 and 3367 cm−1 is due to the C‐H
and O‐H groups and furthermore, the particular band
at 1698 cm−1 and 1617 cm−1 is attributed to the
C = O and C = N bands, respectively. The FT‐IR spec-
trum of Fe3O4 nanoparticles represents particular IR
absorption band in the area of 585 cm−1 which is
ascribed to the stretching vibration of the Fe‐O band
(Figure 6b) and the weak peak at 1615 cm−1 is because
of the twisting vibration mode of H‐OH that was
adsorbed on the Fe3O4 surface. FT‐IR analysis
(Figure 6c) was accomplished to characterize the pres-
ence of the niacin compound on the MNPs. According
to (Figure 6c), the FT‐IR spectra of Fe3O4@Niacin was
clearly different from those of niacin (Figure 6a) and
Fe3O4 (Figure 6b). For niacin functional group, the
band apperceived at 1718 cm−1, which are due to the
COO‐Fe band, approve the complexation between the
carboxylate moiety of nicotinic acid group and ions on
the magnetic nanoparticles surface.[43] The presence of
C‐H stretching vibration, C‐O and Fe‐O groups is con-
firmed by the attendance bands at 3125 cm−1, approxi-
mately 1011 cm−1 and 585 cm−1 regions, respectively.[44]
Overall, the above data, demonstrate that the func-
tional groups were successfully grafted on to the surface
of the magnetic Fe3O4 nanoparticles.
show any UV–Vis peaks characteristics
but
Fe3O4@Niacin nanoparticles, similar to niacin, exhibited
two peaks at 214 and 262 nm. The results obviously
confirm that niacin has been successfully conjugated to
the surface of Fe3O4 nanoparticles.
To evaluate the amount of niacin loaded on the
surface of Fe3O4 nanoparticles, UV spectrophotometer
(UV 1800, Shimadzu) at 262 nm was applied. For this
work, different specific concentrations of niacin, as a
standard solution, was prepared. Then, standard
calibration curve on the basis of absorbance of niacin
solutions was earned and washing solution was compared
with the obtained results (Figure 7). The quantity of
niacin immobilized per one gram nanoparticles was
determined about 196.196 mg (i.e. 1.65 mmol niacin per
one gram Fe3O4@Niacin nanoparticles).
2.2 | Synthesis of 2‐amino‐3‐
cyanopyridines
Considering the importance of pyridine derivatives, we
were willing to find a practical and general method for
their synthesis in high yields and purities. Owing to
the development of efficient and environmentally
friendly synthetic procedures is always desirable, we
decided to peruse whether those pyridines could be pre-
pared by condensation of aldehydes, ketones,
malononitrile, and ammonium acetate under microwave
irradiation, which would increased the yields, reduce the
The conjugations of niacin to the surface of the mag-
netic nanoparticles were determined by UV–Vis spectros-
copy. The UV–Vis spectra of Fe3O4, niacin and
FIGURE 6 FT‐IR spectra: (a) Niacin, (b) MNPs and (c) MNPs‐Niacin

6 of 13
AFRADI ET AL.
amount of waste material and was beneficial for short-
ening the reaction period. For this purpose, the conden-
sation reaction between benzaldehyde 1 (1 mmol),
butanone 2 (1 mmol), malononitrile 3 (1 mmol) and
ammonium acetate 4 (1.5 mmol) for the synthesis of
compound 5a was selected as a model reaction in the
presence of different catalytic systems under microwave
irradiation in H2O (Scheme 3) and the results are
summarized in Table 1. After extensive screening, we
found that the optimized best yields and time profiles
were obtained when the reaction was carried out in
(a)
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
199
249
299
349
399
the presence of 0.03
g of Fe3O4@Niacin under
microwave irradiation at 180 W (max. 70°C) in H2O,
which afforded the corresponding 2‐amino‐5,6‐
dimethyl‐4‐phenylnicotinonitrile 5a in 7 min with 94%
of yield (Table 1, entry 8). Increasing the amount of
Fe3O4@Niacin to more than 0.06 g showed no substan-
tial improvement in the yield, whereas the yield
decreased by decreasing the amount of the catalyst to
0.015 g. Moreover, the reaction did not proceed effi-
ciently in the absence of Fe3O4@Niacin even after
20 minutes under microwave irradiation. In this
1.2
1
y = 0.0225x + 0.0379
R² = 0.9982
0.933
0.826
0.72
0.8
0.6
0.4
0.2
0
0.607
0.483
0.369
0.286
0.135
(b1)
0
10
20
30
40
50
1.2
1
y = 0.0235x + 0.0168
R² = 0.9985
0.954
TABLE 1 Optimization of reaction conditions of compound 5aa
0.836
0.731
0.8
0.6
0.4
0.2
0
Time
(min)
Yield
(%)c
0.592
Entry
Catalyst (g)
Powerb
0.492
1
Niacin (0.03)
180
10
10
10
10
10
7
82
43
50
68
94
92
84
94
90
95
81
34
0.354
0.27
10
2
FeCl3.6H2O (0.03)
Bulk‐Fe3O4 (0.03)
Nano‐Fe3O4 (0.03)
Fe3O4@Niacin (0.03)
Fe3O4@Niacin (0.03)
Fe3O4@Niacin (0.03)
Fe3O4@Niacin (0.03)
Fe3O4@Niacin (0.03)
Fe3O4@Niacin (0.06)
Fe3O4@Niacin (0.015)
‐
180
180
180
180
300
100
180
180
180
180
180
0.127
3
(b2)
4
0
20
30
40
50
5
1.2
1
6
y = 0.0235x + 0.0176
R² = 0.9994
0.944
7
20
7
0.847
0.728
8
0.8
0.6
0.4
0.2
0
0.603
9
5
0.488
0.366
0.258
10
11
12
7
0.129
7
(b3)
20
0
10
20
30
40
50
aThe reaction was carried out under microwave irradiation conditions (MW)
in H2O
Concentration
bThe reaction was tested at different microwave powers (100–300 W) at range
of 40–100 °C
cIsolated yields
FIGURE 7 (a) UV–Vis spectroscopy of niacin, Fe3O4 and
Fe3O4@Niacin. (b) Calibration curve of niacin in 3 step b1, b2 and
b3 with error bars and the fitting formula
SCHEME 3 Synthesis of 2‐amino‐5,6‐
dimethyl‐4‐phenylnicotinonitrile 5a

AFRADI ET AL.
7 of 13
experiment no other solvents were tested because of the
green chemistry concept.
investigated the recycling of the MNPs‐Niacin under
microwave irradiation (180 W, max. 70°C) in H2O using
a selected model reaction of benzaldehyde, butanone,
malononitrile and ammonium acetate in the presence of
MNPs‐Niacin (Table 2, entry 1). After completion of the
reaction, the reaction mixture was diluted with hot ethanol
and the catalyst was easily separated from the reaction mix-
ture using an external magnetic field, washed with hot eth-
anol dried in air and reused for a similar reaction. The
recovered catalyst was reused for six consecutive cycles
without any significant loss in catalytic activity (Figure 8).
After recycling the catalyst for six runs, to show the
stability of the catalyst under microwave irradiation and
To explore the scope of the reaction further, the pres-
ent study is extended to various aldehydes and ketones
using these optimized conditions. All the reactions have
proceeded efficiently and resulted in higher yields without
the formation of any side products and the observed
results are presented in Table 2. As shown in Table 2,
the reactions were efficiently promoted using
arylaldehydes with electron‐withdrawing groups and
increased yields rather than substitutions of electron‐rich
groups on the benzene ring. The desired pure products
were characterized by comparison of their physical data
1
(melting points, IR and H NMR) with those of known
compounds in the literature.
Structural assignments of these new compounds have
1
been made on the basis of IR, H NMR, 13C NMR and
elemental analysis. The mass spectra of these compounds
displayed molecular ion peaks at the appropriate m/z
values.
The recovery and reuse of the catalysts is an important
advantage in green chemistry and heterogeneous cataly-
sis; and also important from an industrial point of view
in the large scale operations and commercial applications.
In this regard, we also for recyclability of the catalyst,
FIGURE 8 Reusability of the nanocatalyst
TABLE 2 Preparation of 2‐amino‐3‐cyanopyridine derivatives in the presence of MNPs‐niacin (0.03 g) as catalyst under microwave irra-
diation (180 W, max. 70°C) conditions in H2O
Entry
R1
R2
R3
Product
5a
Time (min)
Yield (%)a
MP (Obs) (°C)
MP (lit) (°C)
243–244[45]
1
Ph
CH3
CH3
7
94
244–245
2
4‐NO2C6H4
3‐NO2C6H4
4‐ClC6H4
4‐BrC6H4
4‐CH3C6H4
4‐CH3OC6H4
n‐C3H7
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
Ph
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
5b
5c
7
10
7
95
92
94
88
90
87
73
92
89
86
90
85
93
91
319–321
230–232
271–272
279–281
259–261
275
Present work
Present work
Present work
Present work
259–260[45]
275–276[45]
Present work
235–236[45]
256–257[45]
186–187[45]
233–235[22]
177–178[45]
234–235[45]
225–226[45]
3
4
5d
5e
5
10
7
6
5f
7
5 g
5 h
5i
7
8
10
10
10
7
183–184
235–236
256–258
188
9
Ph
10
11
12
13
14
15
4‐CH3C6H4
Ph
H
5j
H
5 k
5 l
5 m
5n
5o
4‐ClC6H4
4‐CH3C6H4
Ph
Ph
H
7
237–238
178–180
234–235
227–229
Ph
H
7
‐(CH2)4‐
‐(CH2)5‐
10
10
Ph
aIsolated yields

8 of 13
AFRADI ET AL.
FIGURE 9 FT‐IR spectra spent MNPs‐Niacin
approve the recoverability of the catalyst, we again ana-
lyzed the spent MNPs‐Niacin catalyst using FT‐IR, UV–
Vis, SEM, EDS, XRD and VSM techniques.
According to FT‐IR (Figure 9), the bands at the
regions 3111 cm−1, 1712 cm−1, 1021 cm−1 and 588 cm−1
approve the presence of C‐H, C = O, C‐O and Fe‐O groups
respectively.
Also, to figure out the attendance of the niacin on the
surface of NMPs after microwave irradiation, UV–Vis
spectrophotometer in the range 210–400 nm was applied
(Figure 10). For this aim, a reaction system containing
the heterogeneous catalyst without the starting material
components was treated with the microwave irradiation
0.2
0.15
0.1
0.05
0
210
260
310
nm.
360
FIGURE 10 UV–Vis spectroscopy of spent Fe3O4@Niacin after
each recovery
FIGURE 11 SEM image of spent MNPs‐Niacin

AFRADI ET AL.
9 of 13
(180 W, max 70 °C in H2O). Afterward the heterogeneous
catalyst system was filtered while hot and finally the
absorbance of the heterogeneous catalyst was evaluated
using UV–Vis spectroscopy. Base on the Figure 10, the
specific peaks at 262 nm and 214 nm (after each using
under microwave irradiation for 6 recovery) in com-
pared with the niacin, confirm the attendance of niacin
on the surface of the Fe3O4 nanoparticles. Regarding to
FT‐IR and UV–Vis analyses, the presence of niacin on
the surface of magnetic Fe3O4 nanoparticles was
approved.
On the basis of SEM images, spherical shape for the
spent MNPs@Niacin was accepted (Figure 11) with mean
diameter approximately 31 nm. It is remarkable that the
aggregation and more size in spent MNPs@Niacin after
six recoveries, in compared with unused catalyst is related
to the increasing quantity of organic compound on the
surface of nanoparticles. Also the existence of N, C, O,
and Fe elements in the spent catalyst using EDS tech-
nique was represented (Figure 12).
Vibration sample magnetometer was used to appraise
the magnetic properties of used MNPs‐Niacin. The satura-
tion magnetization (MS) amount for used MNPs catalyst
is about 50 emu/g. The saturation magnetization of spent
catalyst in compared with the uncoated MNPs (66 emu/g)
and unused MNPs‐Niacin (55 emu/g) represented
decrease due to the increasing amount of organic com-
pound on the nanoparticles surface after continuous
applying (Figure 14).
In this study, we also evaluated the effect of diverse pow-
ers of microwave irradiation on the stability of niacin in the
MNPs@Niacin catalyst. As can be seen in Figure 15, with
increase the power of microwave irradiation, the presence
of niacin was decreased on the surface of MNPs. Absence
of specific peaks at 214 nm and 262 nm approve the absence
of the niacin at 400 W and 500 W.
In order to assess the efficiency and generality of this
methodology, the obtained result from the reaction of
benzaldehyde, butanone, malononitrile and ammonium
acetate by this method has been compared with those of
the previously reported methods (Table 3). It was found
that the present method is convincingly superior to the
reported methods with respect to reaction time and
exhibits broad applicability in terms of yields.
The crystalline structure of the spent Fe3O4@Niacin
was evaluated using XRD technique. According to
Figure 13, diffraction peaks at 2θ = 30.4, 35.8, 43.4, 53.7,
57.3, 62.9, and 74.4 demonstrate the stableness of the
crystalline spinel ferrite core structure after using the
catalyst.
60
40
20
0
-10000
-5000
0
5000
10000
-20
-40
-60
Applied Field (Oe)
FIGURE 14 VSM diagram of spent MNPs‐Niacin
FIGURE 12 EDS spectra of spent MNPs‐Niacin
0.4
0.35
0.3
500
311
400
0.25
0.2
300
0.15
0.1
440
220
200
100
0
511
400
422
0.05
0
533
210
260
310
nm.
360
10
20
30
40
50
60
70
80
Position [º2 Theta]
FIGURE 15 Effect of different power of microwave irradiation on
the MNPs‐Niacin
FIGURE 13 XRD pattern of spent MNPs‐Niacin

10 of 13
AFRADI ET AL.
TABLE 3 Comparison of the efficiency of L‐proline with other reported catalysts in literature
Entry
Catalyst/Condition
Time (min)
Yield (%)a
Ref.
1
No catalyst/Benzene, Reflux
240 min
65
Previous work[45]
Previous work[22]
Previous work[46]
Present work
2
3
4
Yb(PFO)3/EtOH, Reflux
240 min
360 min
10 min
86
80
94
No catalyst/Trifluoroethanol, Reflux
Fe3O4@Niacin/H2O, MWb (180 W, max. 70°C)
aIsolated yields.
bThe reaction was carried out under microwave irradiation (MW) conditions.
SCHEME 4 Proposed mechanism for the synthesis of 2‐amino‐3‐cyanopyridine derivatives
In order to determine the catalytic behavior of MNPs‐
Niacin, the suggested mechanism for the formation of the
products is shown in Scheme 4. The first step is the
formation of the two reaction intermediates. Imine (A)
was produced from the addition of ketone 3 to ammo-
nium acetate 4, and the alkylidenemalononitrile (B) was
formed by the Knoevenagel condensation of the respec-
tive aldehyde with malononitrile catalyzed by
Fe3O4@Niacin. In the second step, imine (A) reacts with
alkylidenemalononitrile (B) to prepare 6, followed by
cycloaddition, isomerization, aromatization leads to the
formation of 2‐amino‐3‐cyanopyridine 5.
the low loading of reusable, nontoxic, easy to handle
catalyst, shorter reaction time without any byproduct,
avoidance of hazardous organic solvents and easy
workup (the catalyst can be easily separated from the
reaction mixture by an external magnet), may find a
wide range of applications.
4 | EXPERIMENTAL
4.1 | General
All melting points were determined on an Electrothermal
9100 apparatus and are uncorrected. The IR spectra were
recorded on Perkin Elmer FT‐IR spectrometer‐
SpectrumRX1. Elemental analyses for C, H, and N were
performed using a Heraeus CHN‐O‐Rapid analyzer at
Iranian Central Research of Petroleum Company. Mass
spectra were recorded on an Agilent Technology (HP)
spectrometer operating at an ionization potential of
3 | CONCLUSIONS
In summary, we synthesized superparamagnetic nanopar-
ticles of modified vitamin B3 (Fe3O4@Niacin) as a new,
efficient, and reusable catalyst and characterized the cata-
lyst by FT‐IR, SEM, XRD, UV–Vis, DLS, EDS, and VSM
spectroscopy. This newly synthesized catalyst was applied
as a green heterogeneous biocatalyst for the efficient
1
70 eV. The H and 13C NMR spectra were recorded on a
Bruker DRX‐300 and 400 Avanve instrument with CDCl3
and DMSO‐d6 as solvent and using TMS as internal
reference at 300, 400, 75, and 100 MHz, respectively. All
reactions were carried out using a laboratory microwave
oven (MicroSYNTH, Milestone Company, Sorisole, Italy).
Thin‐layer chromatography (TLC) was performed on
silica‐gel Polygram SILG/UV 254 plates. Elemental
synthesis
of
2‐amino‐3‐cyanopyridine
derivatives
through single‐pot four‐component condensation reac-
tion between aldehydes, ketones, malononitrile, and
ammonium acetate under microwave irradiation in
water. The environmentally friendly methodology with
excellent green chemistry credentials, such as use of

AFRADI ET AL.
11 of 13
compositions were determined with a Leo 1450 VP scan-
ning electron microscope equipped with an SC7620
energy dispersive spectrometer (SEM‐EDS) presenting a
133 eV resolution at 20 kV. Power X‐ray diffraction
(XRD) was performed on a Bruker D8‐advance Xray dif-
fractometer with Cu Kα (λ = 0.154 nm) radiation. All
reagents and solvent were purchased from Merck and
Aldrich and used without further purification.
microwave was programmed to give a maximum internal
temperature of 70°C. Upon completion of the reaction,
monitored by TLC, the reaction mixture was diluted with
hot ethanol and the catalyst was easily separated from the
reaction mixture by an external magnet, washed with hot
ethanol, dried and reused for a consecutive run under the
same reaction conditions. Then, the reaction mixture was
cooled to room temperature and the crude product
obtained was collected by filtration and washed with cold
ethanol to give the pure solid 5.
4.2 | Nanocatalyst preparation
4.2.1 | Synthesis of Fe3O4 magnetite
nanoparticles
4.4 | The analytical and spectroscopic data
for the unknown compounds
Synthesis of magnetite nanoparticles was accomplished
by chemical co‐precipitation procedure. In a three‐necked
round‐bottom flask (250 ml), ferric chloride hexahydrate
(FeCl3.6H2O, 98%) and ferrous chloride tatrahydraye
(FeCl2.4H2O, 99%) with the molar ratio of 4:2 were dis-
solved in 150 ml deionized water and resulting solution
was heated at 80–85 °C with mechanical stirring for 1 h.
To adjust the pH of the solution, ammonium hydroxide
solution (25 wt %) was added continually and slowly to
above solution over a 20 min period. After sequential stir-
ring for 4 h at 80–85 °C, the resulting magnetic precipi-
tates were washed several times with distilled water to
remove chloride ions. Eventually, the black precipitate
(Fe3O4) was collected with a permanent magnet and dried
in vacuum at 70 °C for 24 h.
2‐Amino‐5,6‐dimethyl‐4‐(4‐nitrophenyl)nicotinonitrile (5b)
Cream solid; yield 95%, 0.255 g; mp 319–321 °C; IR
(KBr) (νmax, cm−1): 3363, 3170, 2212, 1652, 1526, 1360,
1101, 503; 1H NMR (400 MHz, CDCl3): δH 2.44, 2.47
(2 s, 6H, 2CH3), 5.14 (s, 2H, NH2), 7.17 (d, 2H,
J = 8.0 Hz, Ar‐H), 7.31 (d, 2H, J = 7.6 Hz, Ar‐H); 13C
NMR (100 MHz, CDCl3): δC 14.9 and 22.1 (2CH3), 82.4
(CN), 103.1, 127.6, 128.1, 128.3, 128.9, 141.3, 152.9, 161.3
and 169.0 (9Carom); MS (m/z, %): 268 (M+, 9); Anal. Calcd
for C14H12N4O2: C, 62.68; H, 4.51; N, 20.88%. Found: C,
62.95; H, 4.76; N, 21.10%.
2‐Amino‐5,6‐dimethyl‐4‐(3‐nitrophenyl)nicotinonitrile
(5c) Cream solid; yield 92%, 0.247 g; mp 230–232 °C; IR
(KBr) (νmax, cm−1): 3500, 3099, 2211, 1680, 1526, 1354,
1
923, 486; H NMR (400 MHz, CDCl3): δH 2.20, 2.63 (2 s,
6H, 2CH3), 5.42 (s, 2H, NH2), 7.66–8.43 (m, 4H, Ar‐H);
13C NMR (100 MHz, CDCl3): δC 25.7 and 28.0 (2CH3),
93.1 (CN), 111.8, 120.3, 125.0, 126.3, 127.3, 127.9, 128.2,
129.5, 132.6, 153.0 and 153.1 (11Carom); MS (m/z, %): 268
(M+, 5); Anal. Calcd for C14H12N4O2: C, 62.68; H, 4.51;
N, 20.88%. Found: C, 62.91; H, 4.73; N, 20.97%.
4.2.2 | Synthesis of nanocatalyst
Fe3O4@Niacin
Fe3O4 MNPs (1.0 g) were initially dispersed in 100 ml of
deionized water for nearly 60 min at room temperature
by ultrasonic vibration. Niacin (Nicotinic acid, 98%) was
added at a concentration of 50 mg/ml to the above solu-
tion under vigorous stirring, and then resulting solution
was mechanically stirred continuously for 12 h. Thereaf-
ter, the modified magnetite nanoparticles were collected
by magnetic separation and washed with deionized water
three times to remove excess coating agent and finally
dried under vacuum at 80 °C for 24 h.
2‐Amino‐4‐(4‐chlorophenyl)‐5,6‐dimethylnicotinonitrile
(5d) Cream solid; yield 94%, 0.242 g; mp 271–272 °C; IR
(KBr) (νmax, cm−1): 3381, 3190, 2217, 1654, 1557, 1250,
1
1089, 1003, 557; H NMR (300 MHz, DMSO‐d6): δH 1.07,
1.79 (2 s, 6H, 2CH3), 5.17 (s, 2H, NH2), 8.15–8.86 (2 m,
4H, Ar‐H); 13C NMR (100 MHz, CDCl3): δC 22.1 and
25.9 (2CH3), 82.4 (CN), 108.0, 125.6, 126.1, 126.3, 126.9,
138.3, 154.9, 161.9 and 166.5 (9Carom); MS (m/z, %): 257
(M+, 12); Anal. Calcd for C14H12ClN3: C, 65.25; H, 4.69;
N, 16.30%. Found: C, 65.57; H, 4.54; N, 16.52%.
4.3 | General experimental procedure for
the synthesis of 2‐amino‐3‐cyanopyridine
derivatives (5a–o)
2‐Amino‐4‐(4‐bromophenyl)‐5,6‐dimethylnicotinonitrile
(5e) Cream solid; yield 88%, 0.266 g; mp 279–281 °C; IR
(KBr) (νmax, cm−1): 3412, 3163, 2212, 1651, 1558, 1236,
1
Fe3O4@Niacin (0.03 g) was added to a mixture of alde-
hyde 1 (1 mmol), ketone 2 (1 mmol), malononitrile 3
(1 mmol), and ammonium acetate 4 (1.5 mmol) in H2O
(10 mL) and this mixture was irradiated in a microwave
oven at 180 W for the times reported in Table 2. The
999, 701; H NMR (300 MHz, DMSO‐d6): δH 1.17, 1.49
(2 s, 6H, 2CH3), 5.10 (s, 2H, NH2), 7.31 (d, 2H,
J = 7.2 Hz, Ar‐H), 8.15–8.19 (m, 2H, Ar‐H); 13C NMR
(100 MHz, CDCl3): δC 17.5 and 24.6 (2CH3), 94.1 (CN),
106.8, 132.0, 133.3, 134.3, 134.9, 135.5, 138.6, 149.6,

12 of 13
AFRADI ET AL.
154.8, 160.5 and 168.8 (11Carom); MS (m/z, %): 302 (M+,
7); Anal. Calcd for C14H12BrN3: C, 55.65; H, 4.00; N,
13.91%. Found: C, 55.89; H, 3.89; N, 14.15%.
[15] H. M. Said, S. M. Nabokina, K. Balamurugan, Z. M. Moham-
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2‐Amino‐5,6‐dimethyl‐4‐propylnicotinonitrile (5 h)
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[17] Institute of Medicine (IOM), Dietary Reference Intakes for Thia-
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1
994, 502; H NMR (300 MHz, DMSO‐d6): δH 0.84 (t, 3H,
J = 7.0 Hz, CH3), 1.06, 1.16 (2 s, 6H, 2CH3), 3.27–3.34
(m, 2H, CH2), 3.82–3.95 (m, 2H, CH2), 4.83 (s, 2H, NH2);
13C NMR (75 MHz, DMSO‐d6): δC 11.9, 18.2 and 27.8
(3CH3), 54.1 and 55.3 (2CH2), 81.2 (CN), 123.3, 123.5,
130.2, 142.2 and 147.9 (5Carom); MS (m/z, %): 189 (M+,
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22.20%. Found: C, 70.08; H, 8.23; N, 22.46%.
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ACKNOWLEDGEMENTS
Cintas, Med. Chem. Commun. 2013, 4, 1323.
We gratefully acknowledge financial support from the
Research Council of the University of Science and Arts
of Yazd, Iran.
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ORCID
[24] D. Bora, B. Deb, A. L. Fuller, A. M. Z. Slawin, J. D. Woollins, D.
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Afshin Yazdani‐Elah‐Abadi
8162-280X
http://orcid.org/0000-0002-
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How to cite this article: Afradi M, Pour SA,
Dolat M, Yazdani‐Elah‐Abadi A. Nanomagnetically
modified vitamin B3 (Fe3O4@Niacin): An efficient
and reusable green biocatalyst for microwave‐
assisted rapid synthesis of 2‐amino‐3‐
cyanopyridines in aqueous medium. Appl
Organometal Chem. 2017;e4103. https://doi.org/
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