Synthesis and characterization of fluconazole-functionalized magnetic nanoparticles as a catalyst for the synthesis of 3-aryl and 3-amino-imidazo[1,2-a]pyridines

Article abstract of DOI:10.1039/c5ra05246g

Fluconazole was successfully immobilized on the surface of chloropropyl-modified Fe₃O₄-SiO₂ core-shell nanoparticles and was found to exhibit unique catalytic activity for the synthesis of 3-aryl-imidazo[1,2-a]pyridines in water. This catalyst also showed great activity in a multi-component reaction for the synthesis of 3-amino-imidazo[1,2-a]pyridines under solvent-free conditions. The magnetically-recoverable catalyst was found to be capable of repeated reuse without significant loss of activity.

Full text of DOI:10.1039/c5ra05246g

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Synthesis and characterization of fluconazoleꢀfunctionalized magnetic nanoparticles as
a catalyst for the synthesis of 3ꢀaryl and 3ꢀaminoꢀimidazo[1,2ꢀa]pyridines
Mohammad Jafarzadeh,a* Ebrahim Soleimani,a,b Heshmatollah Sepahvand,a Rohana Adnanc
aDepartment of Organic Chemistry, Faculty of Chemistry, Razi University, Kermanshah 67149ꢀ67346, Iran
bDepartment of Chemistry, College of Sciences, Kermanshah Branch, Islamic Azad University, Kermanshah, Iran
cSchool of Chemical Sciences, Universiti Sains Malaysia, 11800 Minden, Penang, Malaysia
*Corresponding author (M. Jafarzadeh): Email: mjafarzadeh1027@yahoo.com
Abstract
Fluconazole was successfully immobilized on the surface of chloropropylꢀmodified Fe3O4ꢀSiO2 coreꢀshell
nanoparticles and was found to exhibit unique catalytic activity for the synthesis of 3ꢀarylꢀimidazo[1,2ꢀ
a]pyridines in water. This catalyst also showed great activity in a multiꢀcomponent reaction for the synthesis
of 3ꢀaminoꢀimidazo[1,2ꢀa]pyridines under solventꢀfree conditions. The magneticallyꢀrecoverable catalyst
was found to be capable of repeated reuse without significant loss of activity.
Keywords: Fluconazole, Magnetic silica nanoparticles, Triazole, Imidazo[1,2ꢀa]pyridine
1. Introduction
Magnetic silica nanoparticles have recently received significant attention due to their chemical inertness,
magnetic properties, nontoxicity, and excellent thermal stability.1 These favorable properties allow
nanoparticles (NPs) to be widely used as a catalyst or catalyst support for organic syntheses.2 However, a
major drawback in using homogeneous catalysts is the difficulty of catalyst isolation from the reaction
media and their reusability. Heterogenation of organic catalysts through immobilization on the surface of
inert materials is a common way to overcome these problems. Organoꢀfunctionalization of silica allows
researchers to customize the surface with a wide variety of active organic compounds and organic catalysts.
For catalytic applications, the reaction of silicaꢀbased materials with organohalotrialkoxysilane is a common
method for the initial functionalization of the support by a postꢀmodification process.3 The covalent linkage
of the organic groups to the silica surface by reaction with organohalotrialkoxysilane has been widely
reported in the literature.4
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Fluconazole (FLU) or 2ꢀ(2,4ꢀdifluoroꢀphenyl)ꢀ1,3ꢀbisꢀ[1,2,4]triazolꢀ1ꢀylꢀpropanꢀ2ꢀol, is a bisꢀtriazole
antifungal commonly utilized to treat invasive infections.5 The structure of FLU consists of two triazole
rings, with the nitrogen atoms of the triazoles demonstrating nucleophilic behavior through their lone pair
electrons. It is expected that the reaction between the nitrogen of the triazole ring and the halogen functional
group of the organosilane can be carried out via a nucleophilic substitution reaction, and that the
functionalized silica materials can be employed as a catalyst in organic synthesis.
A variety of materials such as organic amines, inorganic bases, and ionic liquids have been used as catalysts
for the synthesis of imidazo[1,2ꢀa]pyridines, respectively.6 Bangade et al. reported synthesis of 3ꢀarylꢀ
imidazo[1,2ꢀa]pyridines in the presence of 1,4ꢀdiazabicyclo[2.2.2]octane (DABCO) under an aqueous
medium.6b Shaabani et al. prepared 3ꢀaminoꢀimidazo[1,2ꢀa]pyridines in an ionic liquid medium6c and Daemi
et al. applied the cationic polyurethane dispersion in this reaction.6f In our work, the grafting of FLU onto
the surface of magnetic silica coreꢀshell nanostructures is carried out. The catalytic activity of these
nanostructures is examined for the synthesis of 3ꢀaryl and 3ꢀaminoꢀimidazo[1,2ꢀa]pyridines and the catalyst
is separated from the reaction mixture using a magnet and reused for several cycles. The use of FLU as a
homogeneous or heterogeneous catalyst has not been previously reported.
2. Experimental
Tetraethoxysilane (TEOS, 99%), chloropropyltriethoxysilane (CPTES, 99%) and absolute ethanol (EtOH,
99%) were purchased from Merck and used without further purification. Fluconazole was purchased from
Pars Daru Company.
2.1. Preparation of modified silica coated magnetite NPs (Fe3O4@SiO2~Cl)
Magnetite (Fe3O4) nanoparticles (NPs) were prepared according to the reported method (coꢀprecipitation)7
and coated with silica in the presence of 2ꢀpropanol (solꢀgel method8). In brief, 0.036 mol of FeCl3.6H2O
and 0.018 mol of FeCl2.4H2O were dissolved in 20 mL deionized water under nitrogen gas with vigorous
stirring. Then, NH3 (25%) was added into the solution until the pH of the solution reached 11. Stirring was
continued for 1 h at 60 ºC. The color of the bulk solution turned from orange to black immediately. The
magnetite precipitate was separated from the solution using a magnet, washed several times with deionized
water and ethanol, and left to dry in air. Then, 30 mg asꢀsynthesized Fe3O4 NPs were mixed with 50 mL
isopropyl alcohol in a sealed threeꢀneck flask by ultrasonic treatment for 30 min. 10 mL deionized water, 0.3
mL TEOS (silica precursor), and 1.70 mL ammonia (25 wt%) were added into the mixture of Fe3O4 and
isopropyl alcohol at 30 °C under mechanical agitation. After 12 h, the final product (Fe3O4@SiO2) was
collected, washed with ethanol and deionized water and dried at 50 ºC. The silica coated Fe3O4
(Fe3O4@SiO2) NPs were then functionalized using
a
postꢀmodification method with 3ꢀ
2

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chloropropyltriethoxysilane (CPTES)9 by refluxing in anhydrous toluene at 110 oC for 24 h
(Fe3O4@SiO2~Cl).
2.2. Immobilization of fluconazole on the surface of modified silicaꢀcoated magnetite NPs
(Fe3O4@SiO2~Flu)
The fluconazole (3 g, 10.79 mmol) was added into a suspension of Fe3O4@SiO2~Cl powder (1.0 g) in dry
o
DMF (30 mL). The reaction mixture was refluxed at 140 C in an oil bath for 24 h. The solid phase was
filtered and washed with DMF, followed by distilled water. Finally, the solid sample was dried at 100 oC for
24 h.
2.3. Characterization techniques
Infrared spectra were recorded using a Ray Leigh Wqfꢀ510 Fourier Transform Infrared (FTIR)
spectrophotometer. Morphological studies measurements were performed using a Transition Electron
Microscopy (TEM, Philips CM10) operated at an 80 kV electron beam accelerating voltage. Scanning
electron microscopy (SEM) and EDX were performed on a Philips XLꢀ300 instrument. The sample was
sputtered by gold to avoid undesirable electron charging. Xꢀray diffraction was conducted using a Philips
X’pert Pro (PW 3040) Xꢀray diffractometer with monochromatic CuꢀKα radiation (k = 1.54056 Å, 40 kV,
30 mA). Particle size distribution and zeta potential were obtained using a Malvern Zetasizer (Nano ZS
series ꢀ Model: ZEN3600). Ultravioletꢀvisible (UVꢀVis) absorption spectra were recorded on a PerkinꢀElmer
Lambda 25. Thermogravimetric analyses were investigated using a TG/DTA6300 instrument, at a heating
o
rate of 20 C minꢀ1 under nitrogen flow. Elemental analysis was performed with a CHN machine (Perkin
1
Elmer Series II, 2400). H and 13C NMR spectra were recorded on a Bruker DRXꢀ400 spectrometer at 400
and 100 MHz, respectively.
2.4. General procedure for the synthesis of 3ꢀarylꢀimidazo[1,2ꢀa]pyridines
A mixture of phenacyl bromide (1 mmol), 2ꢀaminopyridine (1 mmol), and an appropriate amount of
Fe3O4@SiO2~FLU was stirred in water (5 mL) at 60–70 oC for 1 h. The reaction progress was monitored by
TLC (Thin Layer Chromatography) using silica gel polygram SIL G/UV 245 plates. After the completion of
the reaction, the catalyst was separated by applying an external magnet and extracted with ethyl acetate (3×5
mL). The combined organic layer was washed with brine solution, dried over anhydrous Na2SO4 and
concentrated under reduced pressure. All known products were characterized by comparison of their spectral
data and physical properties (including the melting point) with those reported in the literature. The new
1
derivative compounds were characterized by H and 13C NMR. The following is the spectral data of 3ꢀ
phenylꢀ7ꢀmethylꢀimidazo[1,2ꢀa]pyridine (3b) and 3ꢀ(4ꢀbromo phenyl)ꢀ7ꢀmethylꢀimidazo[1,2ꢀa]pyridine
(3f), which were prepared via reaction of 2ꢀaminoꢀ3ꢀmethylpyridine with phenacyl bromide and 4ꢀ
bromophenacyl bromide, respectively (refer to Table 2 in Part 3.2).
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1
8ꢀMethylꢀ3ꢀphenylHꢀimidazo[1,2ꢀa]pyridine (3b): Yellow solid. mp 144ꢀ146 C; H NMR (400 MHz,
DMSOꢀd6): δH (ppm) 2.66 (3H, s, CH3), 7.4 (1H, s, CH of imidazole ring), 7.73–7.56 (4H, m, HꢀAr), 7.99
(2H, m, HꢀAr), 8.75 (2H, m, HꢀAr). 13C NMR (100 MHz, DMSOꢀd6): δC (ppm) 16.3 (CH3), 111.6, 116.9,
126.4, 126.7, 127.5, 128.6, 129.3, 130.1, 131.9, 133.9, 141.6.
1
6ꢀBromoꢀ8ꢀmethylꢀ3ꢀphenylHꢀimidazo[1,2ꢀa]pyridine (3f): Yellow solid. mp 152–154oC; H NMR (400
MHz, DMSOꢀd6): δH (ppm) 2.66 (3H, s, CH3), 7.4 (1H, s, CH of imidazole ring), 7.82–7.97 (4H, m, HꢀAr),
8.71 (2H, m, HꢀAr). 13C NMR (100 MHz, DMSOꢀd6): δ= 16.3 (CH3), 111.8, 116.3, 126.2, 126.6, 128.3,
129.4, 130.7, 132.1, 136.3, 151.6, 156.0.
2.5. General procedure for the synthesis 3ꢀaminoꢀimidazo[1,2ꢀa]pyridines.
To the mixture of aldehyde (1.0 mmol), 2ꢀaminopyridine (1.0 mmol), and isocyanide (1.2 mmol), 0.1 g of
Fe3O4@SiO2~FLU NPs was added. The resulting mixture was stirred at 60 ˚C under solventꢀfree conditions.
After completion of the reaction, as indicated by TLC (ethyl acetate/nꢀhexane, 2:1), ethanol was added to the
reaction mixture, and an external magnet was applied to separate the catalyst. The solvent was removed
under vacuum and the residue was crystallized from ethyl acetate to obtain the product.
All known products were characterized by comparison of their spectral data and physical properties with
those reported in the literature.
2.6. Recovery of the catalyst
After the catalyst was separated from the reaction medium by applying an external magnetic field, it was
thoroughly washed with ethanol and activated by heating at 100 °C for 1 h in an oven. The catalyst was
found to retain most of its catalytic activity after recycling and recovering. The supported organocatalyst
stability and catalyst regeneration were determined by FTIR.
3. Results and discussion
3.1. Preparation and characterization of the catalyst
The Fe3O4@SiO2~FLU nanocatalyst was prepared with a multiꢀstep reaction ꢀ initially by preparing iron
oxide as a magnetic core for coating by a silica layer through solꢀgel process. For immobilization of the
organic catalyst on the surface of inorganic support, the surface was first modified using an appropriate
coupling agent to make covalent bonds with the catalyst. It is known that organosilanes can act as a linker
between the organic catalyst and the support. In this work, chloropropyltriethoxysilane was used. Scheme 1
illustrates the process of catalyst preparation. A part of the linker’s chloride was replaced by nitrogen of the
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triazole via an SN2 nucleophilic substitution reaction. This is because the chloropropyl group provides type 1
alkyl halide, allowing the nucleophile (triazole) to attack the carbon containing Cl, and to release the
chloride as a leaving group. Each step of the catalyst preparation procedure was monitored using techniques
such as FTIR to ensure the presence of new functional groups.
There is also the potential for both triazole rings to attach to the surface. The chloride ions resulting from the
nucleophilic substitution by nitrogen of triazole are formed from ammonium/chloride ion pairs. The
quaternary ammonium, with its corresponding counter ion, can form ionic liquid (IL) on the surface. This
type of solid supported ionic liquid (i.e. Supported Ionic Liquid Phase (SILP) catalysts10,11) is expected to
show specific task, as a catalyst/medium, in organic synthesis. The central carbon of FLU is prochiral,
which can be converted to chiral centers upon the immobilization of FLU on the surface of the support. The
formation of stereoisomeric carbon in the center of the FLU structure also has potential applications in
asymmetric syntheses.12,13 Work is currently underway in our lab to develop this catalyst in asymmetric
synthesis and other synthetic methodologies.
F
N
N
N
F
EtO
EtO
HO
Si
Cl
N
O
O
O
N
EtO
Fe3O4
Si
Cl
Fe3O4
N
Reflux in dry toluene
SiO2
Reflux inDMF, 140oC
SiO2
F
F
F
F
N
Cl
N
HO
HO
N
N
N
N
N
N
N
N
N
Cl
N
O
Cl
O
O
O
O
O
O
O
HO
O
Fe3O4
O
O
SiO2
S O
HO
i
O
OH
HO
Cl
Cl
N
N
N
N
N
N
OH
F
F
Scheme 1. The schematic pathway for immobilization of fluconazole on the surface of Fe3O4@SiO2~Cl
coreꢀshell nanoparticles.
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The crystalline structure of magnetite nanoparticles (before and after silica coating) was identified with the
XRD technique. Figure 1 shows the XRD patterns of Fe3O4, Fe3O4@SiO2, Fe3O4@SiO2~Cl, and
Fe3O4@SiO2~FLU. For Fe3O4 diffraction peaks at different angles (2θ) were attributed to the corresponding
planes of cubic spinel Fe3O4, and are in good agreement with the reported XRD patterns of Fe3O4 NPs.14
The silica–coating process and further functionalization with CPTES and FLU did not influence the
crystalline structure of the Fe3O4 core. Therefore, similar XRD pattern to that of Fe3O4 were also observed
for Fe3O4@SiO2, Fe3O4@SiO2~Cl and Fe3O4@SiO2~FLU. The (311) XRD peak was used to determine the
mean nanoparticle diameter by Scherrer’s equation D = 0.9 λ/(β cosθ), where D is the average crystalline
size, λ is the wavelength (Cu Kα, 1.54 Aº), β is the angular line width of halfꢀmaximum intensity (full width
at the halfꢀmaximum FWHM), and θ is the Bragg’s diffraction angle in degrees.15 The mean crystallite size
calculated was 27 nm.
d
c
b
a
10
20
30
40
50
60
70
80
2θ(degree)
Figure 1. XRD patterns of (a) Fe3O4, (b) Fe3O4@SiO2, (c) Fe3O4@SiO2~Cl and (d) Fe3O4@SiO2~FLU NPs.
Figure 2 shows the particle size distribution obtained using Dynamic Light Scattering (DLS). The zꢀaverage
hydrodynamic diameter of Fe3O4, Fe3O4@SiO2~Cl, and Fe3O4@SiO2~FLU NPs dispersed in ethanol were
about 174 nm (87 r.nm; radius nanometer, PdI=1.00), 438.6 nm (219.3 r.nm, PdI=0.405), and 470.0 nm
(235.0 r.nm, PdI=0.331), respectively. These results indicated that there is aggregation among NPs in
colloidal form. The diameters measured by DLS for modified magnetite NPs were larger than the initial
magnetic NPs due to differences in their dispersion properties in ethanol. After organoꢀfunctionalization, the
nature of the surface varied from hydrophilic to hydrophobic and thus the type of interaction between the
catalyst surface and the solvent (ethanol) changed upon modification. The difference between the DLS and
XRD diameters were due to differences in size measurement techniques and sample preparations; the size
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calculated by XRD was related to the size of crystallites, whereas DLS gave the dynamic size of aggregated
and agglomerated particles. The DLS generally shows larger particle size than that in TEM and it was
inferred that this was a result of the surface charge of the nanoparticles affecting the hydrodynamic size
measurement of the sample in colloidal form. In contrast, dried samples are generally used for TEM
analysis.16 By increasing the number of hydrophilic groups on the surface, the probability of undesirable
agglomeration among nanoparticles increases. In addition, the existence of ionic bonds between quaternary
ammonium of triazole rings and chloride groups (ionic liquid form) in Fe3O4@SiO2~FLU NPs further
enhance the polarity of the shell.
Figure 2. Particle size distribution of (a) Fe3O4, (b) Fe3O4@SiO2~Cl and (c) Fe3O4@SiO2~FLU NPs.
Transmission electron microscopy (TEM) was used to observe the morphology of the threeꢀstage synthesis
of the catalyst. Figure 3(a) shows that the NPs have a coreꢀshell structure with a distinct contrast between
silica shells and Fe3O4 cores, implying that silica shells (Fe3O4@SiO2) successfully coated the hydrophilic
Fe3O4 NPs. The average size of the cores was found to be ~25ꢀ30 nm – a result consistent with the crystallite
size of 25 nm for Fe3O4 NPs obtained from XRD. The thickness of the silica shell was estimated to be
around 10ꢀ15 nm. Therefore, the average size of magnetiteꢀsilica coreꢀshell nanoparticles was determined to
be around ~35ꢀ45 nm Similarly, the TEM images of Fe3O4@SiO2~Cl, and Fe3O4@SiO2~FLU are shown in
Figures 3(b) and 3(c), respectively. These images reveal that the modified magnetic silica nanoparticles and
Fe3O4@SiO2~FLU are similar in size (~40ꢀ45 nm) and are spherical in shape. The Scanning Electron
Microscopy (SEM) image of Fe3O4@SiO2~FLU in Figure 3(d) show the granular and spherical morphology
for these nanoparticles. The average size of 44±9.3 nm obtained by SEM analysis is consistent with the
TEM results. The slight size differences between TEM and SEM results could be related to the different
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sample preparations techniques, which applied to TEM (colloidal form of dried sample) and SEM (powder
form with Gold thin layer sputtering).
(a)
(b)
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(c)
(d)
Figure 3. TEM images of (a) Fe3O4@SiO2, (b) Fe3O4@SiO2~Cl and (c) Fe3O4@SiO2~FLU and (d) SEM
image of Fe3O4@SiO2~FLU.
In addition, the stages of the catalyst formation were tracked by FTIR spectroscopy. Figure 4(a) shows the
FTIR spectra of the Fe3O4, the silicaꢀcoated Fe3O4, and the Fe3O4@SiO2~Cl NPs. The peaks appearing at
645 cm−1, 591 cm−1 and 445 cm−1 are ascribed to the stretching vibrations of Fe–O bonds, while the
absorption peak at 3253 cm−1 is the OH stretching vibration characteristic peak, indicating the presence of
some amount of ferric hydroxide in Fe3O4.17 At room temperature, Fe2+ and Fe3+ are converted into
hydroxide compounds with a pH above 10 (required pH for magnetite preparation is 11), while at elevated
temperature (e.g. 60 ºC within magnetite preparation) they are crystallized to Fe3O4 slowly.18 Silicaꢀcoated
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Fe3O4 is expected to produce a corresponding peak of Fe–O–Si bonds at 584 cm−1 resulting from the
adsorption of silica on the magnetite surface, while this band was overlapped with the Fe–O vibration. In
other words, the formation of FeꢀOꢀSi bonds upon silica coating affected the position of FeꢀO bands, and a
peak shift occurred.19 The Si–O–Si stretching and bending vibrations appeared at 1088 cm−1 and 463 cm−1,
respectively. The absorption bands at 3460 cm−1, 1100 cm−1 and 960 cmꢀ1 are attributed to the stretching,
asymmetric stretching, and bending of silanol groups (Si–OH) on the silica surface, respectively.20
Vibrations at 3500–3400 cm−1, 1637 cm−1 and 800 cm−1 correspond to the adsorbed water (H–OH,
stretching vibration), residual intermolecular water (H–OH, bending), and moisture (H–OH, bending) in the
samples.3a The spectrum of the Fe3O4@SiO2~Cl shows peaks at 2847 cm−1 and 2926 cm−1 due to C–H
bonds of CPTES stretching vibrations, while peaks at 638 cm−1 and 689 cm−1 indicate the presence of C–Cl
bonds in CPTES.
The FTIR spectra of fluconazole and Fe3O4@SiO2~FLU are shown in Figure 4(b). The spectrum of the
commerciallyꢀavailable sample of the fluconazole showed some broad and sharp bands due to OꢀH
stretching vibration at 3434 cmꢀ1, aromatic C=N stretching vibration at 1620 cmꢀ1, aromatic C=C stretching
vibration at 1516 cmꢀ1, and CꢀF stretching vibration at 1273 cmꢀ1.5 Furthermore, the absorbance of CꢀN and
aromatic CꢀF were apparent at 1040 cmꢀ1 and 1236 cmꢀ1, respectively. For Fe3O4@SiO2~FLU, the major
peaks of FLU overlapped with broad and strong bands of SiꢀOꢀSi, intermolecular water and moisture (H–
OH, bending) in the samples. Therefore, CHN, EDX and TGA analyses were required to confirm the
functionalization processes and the presence of FLU on the surface.
Fe3O4
Fe3O4@SiO2
Fe3O4@SiO2~Cl
(a)
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3400
2900
2400
1900
1400
900
400
Wavenumber (cm-1)
(b)
Figure 4. FTIR spectra of (a) Fe3O4, Fe3O4@SiO2, Fe3O4@SiO2~Cl, and (b) Fe3O4@SiO2~FLU (red line)
and fluconazole.
From the elemental analysis (CHN) in Table 1, it is observed that there is an increase in carbon content and
also in hydrogen and nitrogen content after functionalization of the Fe3O4@SiO2~Cl with fluconazole. This
indicates the successful attachment of organic fragments (FLU) onto the surface of the modified
nanoparticles. Furthermore, the Energy dispersive Xꢀray spectroscopy (EDX) in Figure 5 confirmed the
presence of FLU with elemental analysis of Fe (74.41%), Si (3.13%), O (17.86%), C (2.76%), N (0.91%), F
(0.30%), and Cl (0.63%).
Table 1. The CHN results for Fe3O4@SiO2~Cl and Fe3O4@SiO2~FLU.
Fe3O4@SiO2~Cl
Elements (mg/g)
Fe3O4@SiO2~FLU
0
5.712
N
C
H
30.232
2.071
43.912
6.426
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Figure 5. EDX spectrum of Fe3O4@SiO2~FLU.
Thermogravimetric analysis and derivative curves (TGA/DTG) of Fe3O4@SiO2~Cl and Fe3O4@SiO2~FLU
o
nanoparticles are presented in Figure 6. The initial % wt losses below 150 C are related to the adsorbed
moisture in the samples. The decomposition temperature, which started at ~415 oC, and continued until ~540
oC, is associated with the decomposition of the organic chains. The organic species decomposed completely
at temperatures higher than 600 oC and the residual weights of Fe3O4@SiO2~Cl and Fe3O4@SiO2~FLU were
~90% and ~86%, respectively, at 700 oC. In other words, the results demonstrate percentages of ~4% and
~9% for organic groups on the surface of Fe3O4@SiO2~Cl and Fe3O4@SiO2~FLU, respectively. The
differences between these two values confirm the successful immobilization of FLU on the surface of
chloropropylꢀmodified silica coated magnetite nanoparticles. Fe3O4@SiO2~FLU also exhibited a slight
o
weight loss in the temperature range of ~200ꢀ300 C that can be related to the partial degradation of FLU.
This phenomenon was not observed for Fe3O4@SiO2~Cl.
(a)
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Fe3O4@SiO2~Cl
102
100
98
96
94
92
90
88
86
486.3
Fe3O4@SiO2~FLU
0
100
200
300
400
500
600
700
temperature (oC)
(b)
Figure 6. (a) TGA and (b) DTG curves of Fe3O4@SiO2~Cl before and after FLU functionalization.
The measurement of zeta (ζ) potential was performed in order to study the variation of surface charge after
the modification of silica with chloropropyltriethoxysilane and immobilization of FLU. The zeta potential is
the electric potential in the interfacial double layer between the dispersion medium and the stationary layer
of fluid besides the dispersed particles.21 The surface charge of silica in Fe3O4@SiO2 was negative, arising
from Si–O– groups, and the zeta potential was ꢀ2.26. These values reduced to ꢀ1.96 and ꢀ1.72 upon
functionalization of the silica surface with CPTES and FLU groups, respectively. This further confirms the
introduction of organic groups onto the silica surface, and that the nature of the surface changed from
hydrophilic to hydrophobic depending on the quantity of surface modification. The observed negative
charge after modification might be due to the existence of unꢀmodified silanol (Si–OH) groups, the effect of
steric hindrance of organic chain to avoid further surface modification, and also on the existence of ionic
liquid nature on the surface upon FLU immobilization. Due to the large structures in FLU and the existence
of three rings that cause hindrance and steric repulsion between the FLU molecules, the replacement of all
chlorides is impossible. In other words, after attachment of FLU to the CPTES, the proximity of further FLU
to the surface is constrained. Therefore, limited immobilization of FLU on the surface leads to a slight
reduction in surface charge. In contrast, the formation of ionic pairs between the triazole ring of FLU and
the chloride released upon immobilization enhances the surface charge.
3.2. Catalytic activity of Fe3O4@SiO2~FLU in organic synthesis
The fluconazoleꢀimmobilized magnetic nanocatalyst was employed for the synthesis of 3ꢀarylꢀimidazo[1,2ꢀ
a
]pyridines. Scheme 2 demonstrates the reaction between phenacyl bromides and 2ꢀaminopyridine in the
presence of the catalyst at 60 oC in water. To find the optimum conditions, different amounts of the catalyst
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(0.03ꢀ0.1 g) were used for the model synthesis (entry 1ꢀ4, Table 2). The highest yield (92%) was obtained
within 1 h using 0.07 g of the catalyst. Although 0.07 g of the catalyst produced the highest yield, poor
reusability and lower yield in subsequent runs were observed with this amount, due to higher agglomeration
and aggregation of the catalyst during isolation. Instead, the amount of 0.05 g, producing a reasonable yield
(90%), was finally selected for further studies. Different derivatives of the starting materials were employed
to generalize this synthetic protocol. Phenacyl bromides with electronꢀwithdrawing groups showed higher
yield than the compound with electronꢀdonating groups. Furthermore, the steric effect arising from the
presence of methyl groups in R2 of aminopyridine lowered the reactivity of the amine group in the reaction.
The catalyst was successfully recycled and reused several times without significant loss of its activity, as
demonstrated in Figure 7.
R3
R3
O
NH2
N
Br
Fe3O4 @SiO2~Flu
H2O, 60 oC
+
N
N
R2
R2
R1
1
2
R1
Scheme 2. Synthesis of 3ꢀarylꢀimidazo[1,2ꢀa]pyridines.
Table 2. Optimization of the reaction condition for the synthesis of 3ꢀarylꢀimidazo[1,2ꢀa
]pyridines.a
Entry
R1
H
H
H
H
R2
H
H
H
H
H
H
Me
H
H
R3
H
H
H
H
Me
H
H
H
Me
H
Catalyst (g)
0.03
Product
3a
Time (h)
Yield (%)b
1
1
1
1
2
1.5
1.5
1
2
1
1
2
3
4
5
6
7
8
9
70
90
92
92
94
82
85
94
96
96
91
0.05
0.07
0.10
0.05
0.05
0.05
0.05
0.05
H
3b
3c
3d
3e
3f
3g
3h
MeO
MeO
Br
Br
NO2
10
11
H
Me
0.05
0.05
NO2
H
1
aReaction condition: phenacylbromide (1 mmol), 2ꢀaminopyridine (1.2 mmol) and the catalyst in H2O (5 mL) at
60 oC. bIsolated yields
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90
90
90
89
88
87
86
85
84
83
82
88.4
87
85
reused time
Figure 7. Reusability of the catalyst for synthesis of 3ꢀphenylꢀimidazo[1,2ꢀa]pyridine (model reaction: entry
3, Table 2).
The FLUꢀimmobilized magnetiteꢀmodified silica coreꢀshell nanocatalyst was also utilized for the synthesis
of 3ꢀaminoꢀimidazo[1,2ꢀa]pyridines. A multiꢀcomponent reaction involving condensation of benzaldehydes,
2ꢀaminopyridines, and isocyanide was carried out for this synthesis. To determine the optimum reaction
parameters, benzaldehydes, 5ꢀmethylꢀ2ꢀaminopyridines, and cyclohexylꢀisocyanide were chosen as a model
reaction in the presence of different amounts of the catalyst (0.03ꢀ0.15 g) at 60 ˚C in solventꢀfree conditions
(Scheme 3). The results show a 98% yield by using only 0.1 g of the catalyst (Fe3O4@SiO2~FLU) after 1 h
of reaction time (entry 3, Table 3). A variety of different benzaldehydes, with electronꢀwithdrawing and
electronꢀdonating groups, exhibited good yields (94ꢀ99%). Tertꢀbutyl isocyanides required longer reaction
times to afford a yield above 90%. The supported catalyst was easily recovered by applying an external
magnetic field, and successfully reused several time without significant loss of reactivity (Figure 8).
O
NH2
N
R1
H
Fe3O4 @SiO2~Flu
60 oC
R3
N
C
+
+
N
N
R2
R2
R1
R3
HN
1
2
4a-g
3
Scheme 3. Synthesis of 3ꢀaminoꢀimidazo[1,2ꢀa]pyridines.
Table 3. Optimization of the reaction condition for the synthesis of 3ꢀaminoꢀimidazo[1,2ꢀa]pyridine.a
Entry
R1
R2
R3
Catalyst (g)
Product
Time (h)
Yield (%)b
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1
2
3
4
5
6
7
8
9
H
H
H
Me
Me
Me
Me
Me
Me
Me
Br
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
tert-Butyl
0.03
0.05
0.10
0.15
0.10
0.10
0.10
0.10
0.10
0.10
1
1
1
1
1
1
1
1
1.5
1.5
60
75
98
90
99
94
97
98
93
90
4a
H
Me
Cl
NO2
H
H
Me
4b
4c
4d
4e
4f
Me
Me
10
tert-Butyl
4g
aReaction condition: benzaldehyde (1 mmol), aminopyridine (1 mmol), isocyanide (1 mmol) and Fe3O4@SiO2~FLU at
60oC in solventꢀfree condition. bIsolated yields
98
98
98
98
96
94
92
90
88
86
93
90
1
2
3
4
5
reused time
Figure 8. Reusability of the catalyst for synthesis of 3ꢀaminoꢀimidazo[1,2ꢀa]pyridine (model reaction: entry
3, Table 3).
Catalyst stability
Comparison between the FTIR spectra of the asꢀprepared (fresh) catalyst and the reused catalyst in Figure 9
demonstrated great stability of the catalyst in both of the preceding syntheses, without change in surface
functionality.
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After 5 time used
3400
2900
2400
1900
1400
900
400
Wavenumber (cm-1)
Figure 9. FTIR spectra of fresh and reused catalyst.
Proposed mechanism
The proposed mechanism for the synthesis of 3ꢀarylꢀimidazo[1,2ꢀa]pyridines from the reaction between
phenacyl bromides and 2ꢀaminopyridine in the presence of catalytic amounts of FLUꢀfunctionalized
magnetic heterogeneous nanocatalyst (0.03 g) is summarized in Scheme 4. The nucleophilic and basic
natures of the triazole22,23 corresponded with reactivity of the catalyst in nucleophilic substitution of bromide
in phenacyl bromide and hydrogen abstraction of the intermediate compounds to afford an imidazole ring
via a ring closure process.
N
O
O
Cat.
N
Br
N
N
Cat.
N
N
H2N
N
1
5
2
N
O
NH
N
N
N
HO
N
H
3
6
7
N
Cat.
N
N
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F
F
N
O
O
O
OH
N
FFee OO
33 44
Si
N
N
N
SiO2
Cat.
Scheme 4. Possible mechanism of the synthesis of 3ꢀarylꢀimidazo[1,2ꢀ
a
]pyridines in the presence of
Fe3O4@SiO2~FLU.
4. Conclusion
This work reported on the preparation of Fe3O4@SiO2~FLU via functionalization of silicaꢀcoated magnetic
nanoparticles with chloropropyltriethoxysilane (CPTES) as a linker for the immobilization of fluconazole. A
Supported Ionic Liquid Phase (SILP) catalyst was also formed upon FLU immobilization. The coreꢀshell
nanoparticles were stable and reusable, and the nonꢀtoxic and inexpensive heterogeneous nanocatalyst
prepared has great potential for applications in organic syntheses. The Fe3O4@SiO2~FLU nanoparticles
were developed as a basic/nucleophilic catalyst for the synthesis of different 3ꢀarylꢀimidazo[1,2ꢀa]pyridines
with phenacyl bromides and 2ꢀaminopyridines in water as a solvent. In addition, the catalytic system was
applied in a oneꢀpot, threeꢀcomponent coupling reaction of aromatic aldehyde, 2ꢀaminopyridine, and
isocyanide in a solventꢀfree condition to afford substituted 3ꢀaminoꢀimidazo[1,2ꢀa]pyridines with excellent
yields. The existence of ionic liquid as a medium on the surface (in the absence of a common solvent) may
accelerate the accessibility of reactants to catalytic sites (particularly in oneꢀpot/threeꢀcomponent reactions),
leading to excellent yields (90ꢀ99%). The major advantage of this catalyst was its ease of the recovery,
allowing it to be reused without significant change in its catalytic activity.
Acknowledgements
The authors gratefully acknowledge the financial support and technical support from Razi University,
University Sains Malaysia (through the USM Short Term Grant no 304/PKIMIA/6312088) and Universiti
Malaysia Sabah.
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