In the present work, magnetic nanoparticles (MNPs) supported by Tin and Magnesium nanomagnetic catalysts were synthesized by a facile synthetic method under aerobic conditions using inexpensive chemicals. This nanomagnetic catalyst was characterized by various characterization techniques such as FE-SEM, XPS, and XRD. The catalytic activity of nanoparticles was tested for the synthesis of various substituted coumarins in good to excellent yields (70-95%). The new method demonstrated is more efficient in terms of the time required and yield obtained compared to methods reported in the literature. The catalyst was found to be reusable for up to five cycles.
Research Article
Study for Coumarin Synthesis by Magnetically Recoverable Metal Deposited Ferromagnetic Nano-Green Catalyst
https://doi.org/10.21203/rs.3.rs-3758168/v1
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Nano-catalysis
MNPs
Green catalyst
Coumarins synthesis
Nowadays researchers are keenly interested in the development of environmentally benign reactions using magnetic nanoparticles (MNPs) because these are safe and fulfill the green catalyst property. In recent decades, magnetic nanoparticles have gained much attention in the chemical field due to their physical and chemical properties [1]. Various methods have been developed to gain control over their size, composition and morphology [2]. MNPs-supported catalysts have been shown to catalyze the syntheses of various organic molecules with less reaction time and improved yield [3]. Fe3O4 MNPs are also being used in the biomedical field due to their magnetic nature, so they can be guided manually by applying an external magnetic field for site-specific drug delivery [4].
The catalytic activity of Fe3O4 is dependent on the particle size and the surface area. They are superior to the conventional heterogeneous catalysts mainly because of their magnetic properties which lead to their easy separation from the reaction mixture. MNPs can also act as a support for other active elements on their surface which leads to enhanced catalytic activity [5]. Surface-functionalized Fe3O4 MNPs were used in organic conversions like cyanation of aryl halides with K4[Fe(CN)6] using palladium over Fe3O4 [7], Ligand-Free Suzuki − Miyaura Coupling of Aryl Carbamates and Sulfamates using nickel over Fe3O4 [8], Suzuki and Heck cross-coupling reactions using palladium over Fe3O4 [9] and enantioselective Henry Reaction using Fe3O4 − Silica Nano particles [10].
A literature survey revealed that researchers are paying much of their attention to the synthesis of coumarin and its derivatives due to their broad range of biological activity. Coumarin derivatives are important building blocks in the development of new therapeutic agents. [11]. Coumarins are associated with a variety of pharmacological activities such as being anti-oxidant, anti-bacterial, anti-fungal, anti-viral, anti-proliferative, anti-inflammatory, anti-diabetics, anticoagulant and anti-neurodegenerative [12] A recent study has shown by functionalizing different substituents on Coumarin can give significant anticancer activity [13]. Hence, considering their wide biological activities chemists are trying to develop facile and efficient methods of their synthesis. One of the most promising and effective methods is the Pechmann reaction [14] which involves condensation of phenols with β-keto esters in the presence of an acid [trifluoroacetic acid (TFA)] as a catalyst [15].
Solvent-free Coumarin synthesis has gained much traction in the past few decades. An example of solvent-free synthesis is the synthesis of Coumarin using SO42−/CexZr1−xO2 as a catalyst [16]. In another report, sulphated zirconia is a used catalyst alternative for the mineral acid yst [17]. On the other hand, numerous reports reveal an effective utilization of Fe3O4 MNPs catalyzing the Coumarin Synthesis. One such report shows bis-ethylferrocene-modified Fe3O4 MNPs as a catalyst for the synthesis of Coumarins [18]. Recently pyrrole fused coumarins have been synthesized using MNPs under solvent-free conditions [19]. In the past few years, researchers have focused on the Pechmann condensation reaction for the synthesis of Coumarin derivatives using various MNP-supported catalysts such as g-Fe2O3@HAp-Ag[20], Cu(II)-OHPC-Fe3O4 [21] and Fe3O4@C@OSO3H [22]. Recently, a new core-shell magnetic silica functionalized with 3,4-diaminobenzoic acid nanocatalyst (Fe3O4@SiO2@PTSDABA) was successfully used for the green synthesis of biologically active pyrano[2,3-c]pyrazole and benzylpyrazolyl coumarin derivatives [23]. Researchers have also synthesized the benzylamino coumarin derivatives using the Mannich reaction which was catalyzed by Fe3O4@ZrO2/SO42- [24]. A recent literature survey revealed that researchers have taken a keen interest in the green synthetic strategy for coumarin derivatives using differently doped Fe3O4 MNPs, due to its catalytic sustainability [25].
In the present work, we have set out to develop a method for the synthesis of coumarins using an inexpensive and non-polluting catalyst that can be easily separated by a simple magnetic decantation method. The catalyst retains its activity even after five consecutive cycles. We report here a method for the preparation of coumarins A using Sn-doped Fe3O4 and Mg-doped Fe3O4 as catalysts in the Pechmann reaction of a neat mixture of phenols and β-keto esters.
Preparation of Fe3O4 MNPs
FeCl3.6H2O (5.4 g) and urea (3.6 g) were dissolved in water (200 mL) at 85-90 °C for 2 h, resulting in a brown-coloured solution. The solution was cooled down to room temperature to which FeSO4.7H2O (2.8 g) was added followed by the addition of 0.1 M NaOH until pH 10. The molar ratio of Fe (III) to Fe (II) in the above system was taken as 2:1. Resulting hydroxides were treated by ultrasound in a sealed flask at 30 to 35°C for 30 min. After aging for 5 hrs, a black precipitate of Fe3O4 was washed with water and ethanol and subsequently dried to obtain in the powder form.
Preparation of Fe3O4-Sn MNPs
Aqueous solution of Fe3O4 nanoparticles (2g in 50mL) & SnCl2 (5%wt of Sn on ferrite) were stirred for 1 hour at room temperature. After mixing, the pH of the solution was raised to 12-13 by the addition of 1M NaOH and stirred further for 20 hours. The solid thus obtained was washed with distilled water and ethanol several times with ultrasonication for 10min during each wash. The resulting MNPs were dried to obtain in the powder form and were characterized using XRD, and FESEM.
Preparation of Fe3O4-Mg MNPs
Aqueous solution of Fe3O4 nanoparticles (2g in 50 mL) and MgCl2 (5%wt of Mg on ferrite) were stirred for 1 hour at room temperature. After mixing, the pH of the solution was raised to 12-13 by the addition of 1M NaOH and stirred further for 20 hours. The solid thus obtained was washed with distilled water and ethanol several times with ultrasonication for 10min during each wash. The Resulting MNPs were dried to obtain in the powder form and were characterised using XRD, and FESEM.
Field Emission-Scanning Electron Microscopic (FE-SEM) analysis
The FESEM analysis was carried out to understand the surface morphology and size distribution of the MNPs. Most of the particles were found to be big chunks (>500 nm) of aggregated nanoparticles with sizes ranging from 10-100 nm. The majority of the particles appeared to be spherical along with others having polymorphic shapes. Since the metal is dispersed over Fe3O4 support, the difference in the contrast from certain regions of FE-SEM images indicates the distinction in elemental composition on the surface of particles.
X-ray diffraction (XRD) analysis
Fig 2. displays XRD patterns of Mg-Fe3O4 and Sn-Fe3O4. In which five distinctive peaks were found at 30o, 35o, 43o, 53o, and 63o that corresponded to the (220), (311), (400), (511), and (440) crystal planes of a pure Fe3O4 sample match well with standard JCPDS file no. 65-3107. The diffraction peaks at 28.54° could be attributed to the (511) planes of MgFe2O4. The diffraction peaks at 31.15°, 47.02°, and 54.88° might be attributed to (220), (400), and (422) crystal planes of MgO, respectively. Furthermore, no diffraction peaks of Sn or SnO2 can be observed since the content is may low to be detected by XRD. These findings are similar to those published in the literature.[26] Indexed XRD data of magnetite was obtained from the American Mineralogist Crystal Structure Database purpose of comparison and is shown using black arrows in Fig 2. XRD patterns of all doped Fe3O4 samples show a broadening of prominent peaks. The average crystallite size of ~20 nm was thus calculated for the sample Mg-Fe3O4 by applying the Debye-Scherrer formula to the [311] peak. The approximate crystallite size was generalized to other samples also. Positions of prominent peaks were well preserved even after the doping.
X-ray photoelectron spectroscopy (XPS) Analysis
X-ray photoelectron Spectra of Sn-doped Fe3O4 were obtained to confirm the presence of Sn on the surface of Fe3O4 MNPs. Fig 3 (on left) shows the survey scan which confirms the presence of Sn as strong characteristic signals are observed in the Sn 3d region of binding energies. Signals in the Sn 3d region were deconvoluted and fitted. Oxidation states of Sn were identified (Sn2+ and Sn4+) after comparing the binding energies of respective 3d5/2 and 3d3/2 energy levels [27].
Synthesis of coumarin using doped Fe3O4 MNPs as catalyst
Catalyst-1: Fe3O4-Sn
A 100 mL RBF was charged with Resorcinol (1.1gm) and β-keto ester (Ethyl Acetoacetate) (1.3 gm) to mix thoroughly in 4 mL of ethanol. To this reaction mixture 1mL of 1M HCl was added followed by the addition of Fe3O4-Sn nano-catalyst (10% w/w) at room temperature. Then the reaction mixture was subjected to sonication. The progress of the reaction was monitored by TLC. After completion of the reaction (~20 min), the solution was then poured into the crushed ice and washed with cold water. The resulting product was filtered off and purified by recrystallization using ethanol to afford the pure product. The structure of the synthesized compounds was confirmed by spectral studies.
Catalyst-2: Fe3O4-Mg
Resorcinol (1.1 gm) and β-keto ester (ethyl acetoacetate) (1.3 gm) were mixed thoroughly in RBF containing 4 ml ethanol. 1M HCl (1mL) was added to this solution followed by the addition of Fe3O4-Mg nano-catalyst (10% w/w) at room temperature. After sonicating for 20 minutes, the reaction mixture was then poured into the crushed ice and washed with cold water. The resulting crude product was filtered off and re-crystallized using ethanol to give the pure product.
Catalyst Recyclability study
To investigate the catalytic green sustainability of MNPs; the reusability of Sn-Fe3O4 and Mg-Fe3O4 MNPs was tested in the synthesis of Coumarin. After the first run, the reaction content was dissolved in acetone with ultrasonication treatment and the nanocatalyst was separated with the external magnet. In the first cycle used catalyst was activated for the next run by washing and drying. The liquid phase containing the product was obtained by simple evaporation. After each reaction cycle, the separated Sn-Fe3O4 and Mg-Fe3O4 MNPs were cleaned thoroughly with acetone and dried under the vacuum. With the recovered nanocatalyst, the synthesis of coumarin was passed up to five times. Remarkably, we experiential that the catalytic activity of Sn-Fe3O4 and Mg-Fe3O4 MNPs was altered only to a small extent even after five times recycling, which is evident from the isolated yield of coumarin which changed from 89 to 72% only (Fig 4).
Optimization of reaction Conditions
a Reaction Conditions:
i) Equivalent mole (1.0 mmol) of substituted Phenol and ethyl acetoacetate with 1M HCl (1 mL) was heated at reflux for 220-240 min.
ii) Equivalent mole (1.0 mmol) of substituted Phenol and ethyl acetoacetate with Fe3O4-Sn or Fe3O4-Mg (10% w/w) was sonicated for 20-30 Min.
b Isolated yield.
Recycled Sn doped Fe3O4 catalyst after 5th run was analyzed by X-ray Photoelectron spectroscopy. The XPS spectra showed the presence of Sn (Sn+4 & Sn+2) on the surface of the catalyst. Comparing the XPS spectra before (Fig 3) and after catalytic cycles (Fig 5). indicate that elemental composition remained unaffected even after 5th run which suggests use of the catalyst for further cycles is possible
Infrared (IR) Spectroscopy
Infrared Spectroscopy was performed to analyze the products obtained from the chemical transformations using conc. H2SO4 (CMRF), Sn-Fe3O4 (SNCM) and Mg-Fe3O4 (MGCM) as catalysts. The fingerprint region of all three spectra was compared. It was found that, the IR spectra of the products- SNCM and MGCM, obtained by using Sn-Fe3O4 and Mg-Fe3O4 as catalysts match well with that of the product which was obtained from the standard Coumarin synthesis performed using Conc. H2SO4 as a catalyst.
To further confirm the structure of products, NMR spectra were obtained for all three samples.
1H NMR, 13C NMR, and HRMS data
The Structural analysis of the products was conducted using 1H NMR, 13C NMR, and HRMS spectroscopy.
A1 (CM_RES): 1H NMR (500 MHz DMSO-d6): d 2.33, s, 3H (-CH3), d 6.08, s, 1H (=C-H), d 6.68, J=2.3Hz, d, 1H (Ar-H), d 6.76, J=2.3Hz, dd, 1H (Ar-H), d 7.53, J=8.65Hz, d, 1H (Ar-H), d 10.48, s, 1H (-OH); 13C NMR (500 MHz DMSO-d6): d 17.97, (Ar-CH3), d 102.07, 110.15, 111.90, 112.73, 128.2, 153.33, 154.73 (Ar-C), d 160.18, (=C-OH), d 161.06, (-C=O); HRMS (ES+) m/z: 177.0553.
A2 (CM_MET): 1H NMR (500 MHz CDCl3): d 2.39, s, 3H (-CH3), d 3.86, s, 3H (-CH3), d 6.11 s, 1H (=C-H), d 6.78, J=2.45Hz, d, 1H (Ar-H), d 6.84, J=2.45Hz, dd, 1H (Ar-H), d 7.47, J=8.8Hz, d, 1H (Ar-H); 13C NMR (500 MHz CDCl3): d 18.64, (Ar-CH3), d 55.73, (Ar-O-CH3), d 100.84, 111.89, 112.20, 113.55, 125.54, 152.60, 155.26 (Ar-C), d 161.24, (Ar-C-O), d 162.64, (-C=O); HRMS (ES+) m/z: 191.070.
A3 (CM_MCR): 1H NMR (500 MHz CDCl3): d 2.40, s, 3H (-CH3), d 2.43, s, 3H (-CH3), d 6.20 s, 1H (=C-H), d 7.09 to 7.47, m, 3H (Ar-H); 13C NMR (500 MHz CDCl3): d 18.55, (Ar-CH3), d 21.56, (Ar-CH3), d 113.92, 117.11, 117.54, 124.28, 125.35, 142.90, 152.47, 153.54 (Ar-C), d 161.06, (-C=O); HRMS (ES+) m/z: 175.0781.
The catalysts Fe3O4-Sn and Fe3O4-Mg were found to be very efficient for the synthesis of substituted coumarins using Pechmann condensation. The catalytic consistency of the nano-catalysts was proved by synthesizing various substituted coumarins. The reusability of the catalysts is shown up to five cycles without a significant decrease in efficiency. They are also easy to separate from the reaction mixture. The reaction was demonstrated to work in mild reaction conditions.
Author Contribution
A.S., R.M., and Y.B. synthesize and characterize the nano-catalyst using FE-SEM, XPS, and XRD.A.J., R.D., and S.S. optimize and synthesize the Coumarin derivatives using Ferromagnetic Nano-Catalyst.A.S. and S.S. wrote the manuscript's abstract, introduction, and characterization data. R.D. and R.M. prepared all figures and tables. All authors reviewed the manuscript.
Acknowledgment
This work was funded by the Seed Money Project by R.B.N.B. College, Shrirampur, Dist: Ahmednagar (MS), India.
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Scheme 1 is available in the Supplementary Files section.
No competing interests reported.
- Scheme1.jpg
Scheme 1. Synthesis of coumarin
- SupportingInformation.pdf
