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Biological synthesis of ZnO nanoparticles using C. albicans and studying their catalytic performance in the synthesis of steroidal pyrazolines
⁎Corresponding author. Tel.: +91 941003465. shamsuzzaman9@gmail.com (Shamsuzzaman) shams_chem@rediffmail.com (Shamsuzzaman)
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Received: ,
Accepted: ,
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.
Peer review under responsibility of King Saud University.
Abstract
In this study, we describe a green and simple procedure for biosynthesis of ZnO nanoparticles using Candida albicans as eco-friendly reducing and capping agent. The synthesized ZnO nanoparticles were characterized by UV–vis spectroscopy, powder X-ray diffraction, scanning electron microscopy (SEM), transmission electron microscopy (TEM), photoluminescence (PL), thermo gravimetric analysis (TGA) and differential thermal analysis (DTA). The prepared nano-particles were used as catalyst for the fast and efficient synthesis of steroidal pyrazolines (4–9) from α, β-unsaturated steroidal ketones (1–3). The target molecules were obtained in good to excellent yields applying the current method.
Keywords
ZnO
Nanoparticles
C. albicans
Steroid
Pyrazoline
1 Introduction
Green chemistry can be recognized as pioneering research, which widely reports intrinsic atom economy, energy savings, waste reduction, easy work ups and the avoidance of hazardous chemicals (Kumar et al., 2012). The development of a simple, eco-friendly reaction protocol for the synthesis of highly functionalized compound libraries of medicinal motifs is an attractive area of research in both academia and the pharmaceutical industry (Domling, 2006). Nano-chemistry is an up growing research area due to its unique properties (Xia et al., 2003). The usage of nanomaterials as catalyst has gained a significant role in organic synthesis due to simple work-up procedure, environmentally benign nature, reusability, low cost, and ease of isolation. Recently, nano-crystalline inorganic oxides exhibited enormous opportunities and attracted the interest of several research groups because of their different topical characteristics and wide range of particle sizes (Hadjipanayis and Siegel, 1994). Of late, catalysis by nanomaterials has become an area of interest, as these materials exhibit better catalytic activity compared to their bulk sized counterparts (Beydoun et al., 1999; Zhang et al., 2007). Zinc oxide as a non-toxic, inexpensive, and non-hygroscopic polar inorganic crystalline material is very economical, safe, and easily available Lewis acid catalyst, which has gained much interest in various organic transformations, sensors, piezoelectrics, transparent conductors, and surface-acoustic-wave devices (Bahrami et al., 2011; Tayebee et al., 2010; Chanaewa et al., 2012; Hosseini et al., 2008; Jayaraj et al., 2000; Gorla et al., 1999). Zinc oxide nano-particles have very different physical and chemical properties compared to the bulk material (Kim and Varma, 2004). The induced catalytic performance of nano-sized ZnO with reference to the commercial analog in catalysis could be a result of the increased surface area and changes occurred in surface properties. Therefore, nano-ZnO has been potentially utilized as a heterogeneous catalyst for various organic reactions (Mascolo et al., 2005; Moghaddam et al., 2008). Pyrazolines are an interesting group of compounds, many of which possess wide spread pharmacological properties such as analgesic, antipyretic and antiandrogenic activities (Jung et al., 2005; Amr et al., 2005). Pyrazolines also possess antidepressant, anti-inflammatory, antirheumatic, antidiabetic and antitumor activities (Havrylyuk et al., 2012; Ahn et al., 2004; Bansal et al., 2001; Palaska et al., 2001; Hammam et al., 2000). In the view of considerable importance of pyrazoline derivatives, several protocols have been developed for the synthesis of these scaffolds over a period of time. The conventional methods reported in the literature have their own advantages but also suffer from some bottlenecks, such as use of acidic/basic catalyst, modest yields, low reaction rate and tedious work-up procedure (Karthikeyan et al., 2007; Bashir et al., 2011; Rathish et al., 2009; Amir et al., 2008). Therefore, these drawbacks prompted us to examine a new catalyst for the environmentally benign synthesis of steroidal pyrazoline derivatives. Inspired by the above catalytic activity of ZnO nanoparticles, we examined the ZnO nanoparticles as a heterogeneous catalyst in the synthesis of steroidal pyrazoline derivatives. We, in continuation of our program on the synthesis of new steroidal heterocyles (Shamsuzzaman et al., 2013), aimed to investigate a very facile, efficient and high yielding new protocol for the synthesis of steroidal pyrazoline derivatives (4–9) employed by the union of cholest-5-en-7ones (1–3), and hydrazine hydrate/phenyl hydrazine hydrate in the presence of ZnO nanoparticles as an environmentally benign and heterogeneous catalyst under reflux conditions. Although there are reports about the synthesis of steroidal pyrazolines (Abdalla et al., 2012; Ivanyi et al., 2012; Choudhary et al., 2011), no literature precedants were found describing the synthesis of steroidal pyrazolines through the strategy we have employed. The structure of the synthesized compounds has been established on the basis of their elemental analysis and spectral data. UV–vis spectroscopy, XRD, SEM, TEM, PL, TGA and DTA have been used to characterize the structure and morphology of the catalyst.
2 Experimental
2.1 General experimental
All the chemicals used were purchased from Sigma Aldrich and Merck as analytical grade. The solvents were purified prior to use. Zinc oxide nanoparticles were prepared by biological method from Candida albicans. The optical absorbance spectra were taken by using UV–vis double beam Perkin–Elmer LAMDA 35 spectrophotometer at room temperature in the wavelength range of 250–800 nm. X-ray diffraction (XRD) patterns of the samples were obtained at room temperature, with a step of 0.02°, using Bruker D8 ADVANCE X-ray diffractometer with Cu Kα radiation (λ = 1.54178 Ǻ) in the range of 0° ⩽ 2θ ⩽ 100° at 40 kV. SEM images were obtained using a field emission scanning electron microscope (JSM-7600F, JEOL, Tokyo Japan) at an accelerating voltage of 15 kV and TEM images were obtained with ultra-high resolution FETEM (JEOL, JEM-2100F) at an accelerating voltage of 200 kV. Photoluminescence (PL) spectra were measured using a Cary Eclipse EL06063917 fluorescence spectrophotometer with a xenon arc lamp as the light source. The thermal studies were carried out using TGA/DTA-60H instrument (SHIMADZU) at a heating rate of 20 °C min−1. Melting points were recorded on Riechert Thermover instrument and are uncorrected. IR spectra (KBr disks) were recorded on Interspec 2020 FT-IR Spectrometer Spectro Lab and only noteworthy absorptions were noted, its values are given in cm−1. 1H and 13C NMR spectra in dilute CDCl3 solutions at 303 K were run on a Bruker Avance DRX 500 NMR spectrometer equipped with a 5 mm diameter broad band inverse probehead working at 500 MHz for 1H and at 125 MHz for 13C, respectively. 1H chemical shifts were referenced to the trace signal of CHCl3 (7.26 ppm from int. TMS). Following abbreviations were used to indicate the peak multiplicity s -singlet, d - doublet, t - triplet, m - multiplet and values are given in parts per million (ppm) (δ) and coupling constants (J) are given in Hertz and 13C chemical shifts to the center peak of the solvent signal (77.00 ppm from int. TMS). Mass spectra were recorded on a JEOL D-300 mass spectrometer. Elemental analyses were carried out by the instrumentation lab at the Department of Chemistry, Indian Institute of Technology Roorkee, Roorkee, India within 0.04% of the theoretical values. The progress of all reactions was monitored by thin layer chromatography (TLC) plates with 0.5 mm layer of silica gel G, light petroleum ether refers to a fraction of b.p. 60–80 °C, and exposed to iodine vapors to check the purity as well as the progress of reaction. Sodium sulfate (anhydrous) was used as a drying agent. All described compounds showed the characteristic spectral data of cyclopentanoperhydrophenanthrene nuclei of cholestane series that were similar to those reported in the literature (Bhacca and Williams, 1964). For the nomenclature of steroid derivatives we used the definitive rules for the nomenclature of steroids published by the Joint Commission on the Biochemical Nomenclature (JCBN) of IUPAC.
2.2 Synthesis of ZnO nanoparticles
The ZnO nanoparticles were prepared by using some modification in the methods (Jayaseelan et al., 2012). C. albicans cells were allowed to grow as a suspension culture in sterile distilled water containing nutrient broth media for 24 h and treated with 1.0% NaCl. Twenty-five mL of culture was taken and diluted four times by adding 75 mL of sterile distilled water containing nutrients. This diluted culture solution was again allowed to grow for another 24 h. Twenty mL aqueous solution of 1 mM zinc oxide (ZnO) was added to the culture solution and it was kept at 30 °C for 24 h until white deposition starts to appear at the bottom of the flask, indicating the initiation of transformation. The culture solution was cooled and allowed to incubate at room temperature in the laboratory ambience. After 15 h, the culture solution was observed to have distinctly makeable coalescent white clusters deposited at the bottom of the flask. The reaction mixture was subjected to centrifugation for 15 min. The resulting pellet was stored in the dark until further used.
2.3 General procedure for synthesis of 5α-cholestano [5, 7-cd] pyrazoline derivatives 4–9
A mixture of α, β-unsaturated steroidal ketones (Dauben and Takemura, 1953) (1–3) (1 mmol), hydrazine hydrate (1 mmol)/phenyl hydrazine hydrate and ZnO nanoparticles catalyst (0.003 g), in ethanol (5 mL) was refluxed for 3 h. The progress of the reaction was followed by TLC. After completion of the reaction, the mixture was filtered to remove the catalyst and the filtrate was taken in ether, washed with water and dried over anhydrous sodium sulfate. Removal of solvent gave the crude product which was recrystallized from methanol to obtain the pure compounds.
2.4 Spectral data of the synthesized compounds
2.4.1 3β-Acetoxy-5α-cholestano[5,7-cd]pyrazoline (4)
Yield (80%); mp. 137–139 °C; Anal. Calcd for C29H48N2O2: C, 76.27, H, 10.59, N, 6.13; found; C, 76.24, H, 10.55, N, 6.9; IR (KBr) ν cm−1 3270 (NH), 1736 (OCOCH3), 1655 (C⚌N), 1265 (C–N), 1235 (C–O); 1H NMR (CDCl3, 500 MHz) δ 5.3 (s, 1H, NH), 4.7 (m, 1H, C3α-H, W ½ = 15 Hz, A/B trans), 2.5 (s, 2H, C6-CH2), 2.03 (s, 3H, OCOCH3), 1.18 (s, 3H, C10-CH3), 0.70 (s, 3H, C13-CH3), 0.97 & 0.83 (other methyl protons); 13C NMR (CDCl3, 125 MHz) δ 172, 156, 74, 66, 48, 47, 46, 43, 42, 41, 40, 39, 36, 35, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 16. MS (EI): (m/z) 456 [M+].
2.4.2 3β-Chloro-5α-cholestano[5,7-cd]pyrazoline (5)
Yield (82%); mp. 140–142 °C; Anal. Calcd for C27H45ClN2: C, 74.87, H, 10.47, N, 6.47; found; C, 74.85, H, 10.48, N, 6.44; IR (KBr) ν cm−1 3265 (NH), 1650 (C⚌N), 1254 (C–N), 776 (C–Cl); 1H NMR (CDCl3, 500 MHz) δ 5.4 (s, 1H, NH), 3.9 (m, 1H, C3α-H, W ½ = 17 Hz, A/B trans), 2.65 (s, 2H, C6-CH2), 1.19 (s, 3H, C10-CH3), 0.75 (s, 3H, C13-CH3), 0.97 & 0.80 (other methyl protons); 13C NMR (CDCl3, 125 MHz) δ 159, 64, 60.2, 48, 47, 46, 43, 42, 41, 40, 39, 36, 35, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 19, 16; MS (EI): (m/z) 432/434 [M+].
2.4.3 5α-Cholestano[5,7-cd]pyrazoline (6)
Yield (82%); mp. 134–136 °C; Anal. Calcd for C27H46N2: C, 81.34, H, 11.63, N, 7.03; found; C, 81.37, H, 11.66, N, 7.05; IR (KBr) ν cm−1 3267 (NH), 1657 (C⚌N),1268 (C–N); 1H NMR (CDCl3, 500 MHz) δ 5.2 (s, 1H, NH), 2.32 (s, 2H, C6-CH2), 1.19 (s, 3H, C10-CH3), 0.75 (s,3H, C13-CH3), 0.96 & 0.83 (other methyl protons); 13C NMR (CDCl3, 125 MHz) δ 157, 65, 48, 47, 46, 43, 42, 41, 40, 39, 36, 35, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 16; MS(EI): (m/z) 398 [M+].
2.4.4 3β-Acetoxy-2′-pheny-5α-cholestano[5,7-cd]pyrazoline (7)
Yield (80%); mp. 180–182 °C; Anal. Calcd for C35H52N2O2: C, 78.90, H, 9.84, N, 5.62; found; C, 78.88, H, 9.82, N, 5.58; IR (KBr) ν cm−1 1734 (OCOCH3), 1630 (C⚌N), 1242 (C–N), 3130, 1564, 1394 (aromatic ring), 1239 (C–O); 1H NMR (CDCl3, 500 MHz) δ 7.30–7.34 (m, 2H), 7.1–7.2 (m, 2H), 6.9 (m,1H), 4.6 (m, 1H, C3 α-H, W ½ = 15 Hz, A/B trans), 2.32 (s, 2H, C6-CH2), 1.19 (s, 3H, C10-CH3), 0.75 (s, 3H, C13-CH3), 0.96 & 0.83 (other methyl protons); 13C NMR (CDCl3, 125 MHz) δ 172,156, 145, 130, 129, 120, 116, 114, 74, 66, 48, 47, 46, 43, 42, 41, 40, 39, 36, 35, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 16; MS(EI): (m/z) 532 [M+].
2.4.5 3β-Chloro2′-pheny-5α-cholestano[5,7-cd]pyrazoline (8)
Yield (76%); mp. 170–172 °C; Anal. Calcd for C33H49ClN2: C, 77.84, H, 9.70, N, 5.50; found; C, 77.88, H, 9.72, N, 5.54; IR (KBr) ν cm−1 1635 (C⚌N), 3129, 1590, 1407 (aromatic ring) 1235 (C–N), 743 (C–Cl); 1H NMR (CDCl3, 500 MHz) δ 7.31–7.32 (m, 2H), 7.1–7.2 (m, 2H), 6.8 (m,1H), 3.9 (m, 1H, C3 α-H, W ½ = 17 Hz, A/B trans), 2.32 (s, 2H, C6-CH2), 1.19 (s, 3H, C10-CH3), 0.75 (s,3H, C13-CH3), 0.96 &0.83 (other methyl protons); 13C NMR (CDCl3, 125 MHz) δ 159, 146, 128, 126, 119, 115,114, 64, 60, 48, 47, 46, 43, 42, 41, 40, 39, 36, 35, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 19, 16; MS(EI): (m/z) 508/510 [M+].
2.4.6 2′-Pheny-5α-cholestano[5,7-cd]pyrazoline (9)
Yield (70%); mp. 185–187 °C; Anal. Calcd for C33H50N2: C, 83.84, H, 10.62, N, 5.90; found; C, 83.87, H, 10.66, N, 5.92; IR (KBr) ν cm−11640 (C⚌N), 3095, 1590, 1406 (aromatic ring), 1233 (C–N); 1H NMR (CDCl3, 500 MHz) δ 7.34–7.32 (m, 2H), 7.2–7.1 (m, 2H), 6.8 (m,1H), 2.32 (s, 2H, C6-CH2), 1.19 (s, 3H, C10-CH3), 0.75 (s,3H, C13-CH3), 0.96 & 0.83 (other methyl protons); 13C NMR (CDCl3, 125 MHz) δ 157, 147, 131,130, 122, 115, 113, 65, 48, 47, 46, 43, 42, 41, 40, 39, 36, 35, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 16; MS(EI): (m/z) 474 [M+].
3 Results and discussion
3.1 Characterization of catalyst
3.1.1 UV spectrophotometry study
The UV–vis absorption spectrum findings demonstrate a novel technique for the preparation of ZnO nanoparticles (Fig. 1), by dispersing ZnO nanoparticles in distilled water and using distilled water as the reference. An absorption peak focused at 381 nm (3.26 eV) was found, which is in good agreement with the previous work (Ni et al., 2005).
UV–visible spectra of ZnO nanoparticles.
3.1.2 XRD analysis
X-ray diffraction is taken in order to further confirm ZnO phase of the nanoparticles. The XRD patterns of the obtained ZnO nanoparticles are shown in Fig. 2. Powder XRD of the product was carried out with Cu Kα radiation (λ = 0.1540 nm), employing a scanning rate of 0.02° s−1 and 2θ ranges from 20° to 80° for ZnO. All the peaks of XRD are very well matched with the hexagonal phase (wurtzite structure) by comparison with the data from JCPDS card No.89-7102 and no indication of a secondary phase. The strong and narrow diffraction peaks indicate that the product has good crystalline structure. The crystallite size of the nanoparticles was calculated using Debye Scherrer formula
where, K is constant, λ is the wavelength of employed X-rays (1.54056 Å), β is corrected full width at half maximum and θ is Bragg’s angle. The 2θ value from the equation comes out to be at 35.815 and therefore the calculated crystallite size of the powder particles is about 25 nm.
XRD image of the ZnO nanoparticles.
3.1.3 SEM and TEM analysis
The conformation of the nanostructure morphology of ZnO particles comes from the analysis of SEM and TEM micrographs. SEM micrograph (Fig. 3) showed the average size of nanoparticles between 15 and 25 nm.
SEM image of the ZnO nanoparticles.
The size and morphology of ZnO particles analyzed by TEM is represented in Fig. 4. This image reveals that most of the ZnO nanoparticles are quasi-spherical and their diameter is about ∼20 nm. This result is in accordance with the value calculated from the X-ray diffraction.
TEM image of the ZnO nanoparticles.
3.1.4 Photoluminescence analysis
The PL spectrum of ZnO nanoparticles consists of two emission peaks (Fig. 5). A weak deep-level emission at 2.3 eV in the visible range is caused by a structural defect (Soares et al., 2008). The other peak in the UV range at 3.04 eV which can be explained by the direct combination of excitons through an exciton–exciton collision process and the lower energy peak in the asymmetric UV emission is associated with band-to-acceptor transitions due to the large binding energy of ZnO (Ha et al., 2000).
The PL spectrum of ZnO nanoparticles.
3.1.5 Thermal stability
The differential thermal analysis and thermo gravimetric analysis (DTA/TGA) have been performed on the
biosynthesis of ZnO nanoparticles. TGA curve in Fig. 6 indicates that the weight loss starts at ∼200 °C because of the evaporation of water, the major weight loss occurs between 340 and 550 °C, which is around 40% of the original weight due to the removal and decomposition of organic groups present in the sample during the biosynthesis. No decomposition or reaction occurs at temperatures above 700 °C. The exothermic peak observed in the DTA plot as shown in Fig. 6 between 370 and 520 °C illustrates the maxima at ∼435 °C which exemplifies the burn-out of organic composition. Apart from this, no other exothermic or endothermic peak is present in DTA curve.
TGA and DTA curves of ZnO nanoparticles.
3.2 The catalytic performance of ZnO in the synthesis of steroidal pyrazolines
As expected, the catalytic system is influenced by various reaction parameters, such as amount of the catalyst employed, effect of catalyst and solvent system. 3β-Acetoxy cholest-5-en-7-one and hydrazine hydrate in ethanol were selected as model substrates for carrying out the optimization studies for synthesis of steroidal pyrazolines.
3.2.1 Catalytic loading
The effect of catalyst loading on the synthesis of model reaction was investigated by varying the catalyst amount from 0 to 10 mol% (Table 1).
It was found that 5 mol% of the catalyst was sufficient to get optimum yields in less reaction time while less than 5 mol% of the catalyst increased the reaction time. Use of more than 5 mol% of the catalyst did not show any profound effect on the reaction rate as well as the yield this may be attributed to the coagulation of ZnO nanoparticles which decreased the effective surface area of the catalyst (Bhattacharyya et al., 2012).
3.2.2 Effect of solvent
We then tried to screen the reaction in various organic solvents in order to optimize the reaction conditions using ZnO nanoparticles as catalyst (Table 2).
The solvent screening experiments revealed that the reaction yield is dependent on the polarity and the coordinating ability of the solvents. The polar solvents afforded better yield than the nonpolar ones and the best result was obtained in ethanol in which ZnO nanoparticle catalyst worked most efficiently by phasing out of the desired product. In order to investigate the scope of this reaction, a variety of different steroidal compounds were subjected to this reaction (Scheme 1).![Synthesis of 5α-cholestano [5, 7-cd] pyrazoline derivatives over ZnO nanoparticles.](/content/184/2017/10/2_suppl/img/10.1016_j.arabjc.2013.05.004-fig7.png)
Synthesis of 5α-cholestano [5, 7-cd] pyrazoline derivatives over ZnO nanoparticles.
All the reactions proceeded smoothly and the reaction was completed within 3 to 3.5 h to afford the products (4–9) in excellent yields (75–82%).
3.2.3 Recyclability of catalyst
After completion of the model reaction in specified time, the catalyst was recovered by filtration, washed with dichloromethane and methanol and dried at 150 °C for 4 h and used for the subsequent cycle (Ghomi and Ghasemzadeh, 2012). The results revealed that the catalyst exhibited good catalytic activity up to five cycles (Table 3).
3.2.4 Superiority of ZnO nanoparticles over some other metal oxide nanoparticles
Various catalysts were employed to evaluate the capability and efficiency of the catalyst (Table 4). Initially, the model reaction was performed in the absence of any catalyst and the reaction proceeded very slowly and the expected product was in a very small quantity (entry 1) and when the model reaction was examined with MgO, CaO, Fe2O3 and Al2O3 nanoparticles using 5 mol% of each catalyst separately the reaction took longer time period for completion with lower yield of the product (entry 2–5). With ZnO nanoparticles the reaction was accelerated and yield of the desired product was maximum (Table 4, entry 6).
These observations may be explained by the HSAB (hard and soft acid base) concept. Unlike Zn2+ which is a borderline Lewis acid, all the rest of nanoparticles are classified as hard Lewis acids and the first step of the reaction is the formation of intermediate by the interaction of Lewis acid catalyst with rather soft Lewis base carbonyl group which was assumed to be efficient for ZnO nanoparticles than the other (Kantam et al., 2012).
3.2.5 Proposed reaction pathway for the synthesis of steroidal pyrazolines
With these excellent results in our hand, we are now in a position to propose the mechanism of the reaction which involves Michael addition and then intramolecular cyclization catalyzed by ZnO nanoparticles as presented in Scheme 2. In the first step, ZnO nanoparticles increase the electrophilicity of the carbonyl group which in turn accelerates the Michael addition step. At the time of cyclization, the particular catalyst plays the key role where ZnO acts as a mild acid and activates the ketone group by polarization (through coordination) and hence facilitates the intramolecular nucleophilic attack by the NH2 group leading to the ring closure which ultimately forms the final product and again the catalyst enters into the catalytic cycle.![Proposed mechanism of the formation of 5α-cholestano [5, 7-cd] pyrazoline derivatives catalyzed by ZnO nanoparticles.](/content/184/2017/10/2_suppl/img/10.1016_j.arabjc.2013.05.004-fig8.png)
Proposed mechanism of the formation of 5α-cholestano [5, 7-cd] pyrazoline derivatives catalyzed by ZnO nanoparticles.
4 Conclusions
In conclusion, we have reported biological synthesis of ZnO nanoparticles using C. albicans as a green, reusable, nontoxic and inexpensive heterogeneous catalyst. The synthesized nanoparticles were used as catalyst for the fast and efficient synthesis of steroidal pyrazolines. The attractive features of this protocol are simple reaction procedure, short reaction time and easy products. To the best of our knowledge, this is the first report about the synthesis of steroidal pyrazolines using nano metal oxide as a catalyst.
Acknowledgements
Authors thank the Chairman, Department of Chemistry, A.M.U., Aligarh, for providing necessary research facilities. Facilities provided by SAP (DRS-I) for their generous research support are also gratefully acknowledged. The authors would also like to thank Dr. Khalid Mujasam Batoo, King Abdullah Institute for Nanotechnology, King Saud University, Saudi Arabia, for providing SEM and TEM facilities.
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