Zirconia-based catalyst for the one-pot synthesis of coumarin through Pechmann reaction

Coumarins play an important role in drug development with diverse biological applications. Herein, we present the synthesis of coumarin through Pechmann reaction by using zirconia-based heterogeneous catalysts (ZrO2-TiO2, ZrO2-ZnO, and ZrO2/cellulose) in a solvent-free condition at room temperature. ZrO2-TiO2, ZrO2-ZnO, and ZrO2/cellulose were identified through spectroscopic techniques such as FESEM, X-ray, EDS, XPS, and FT-IR. ZrO2-TiO2 showed the best catalytic performance while ZrO2/cellulose was inactive. The kinetic parameters were observed in a solvent-free condition as well as in toluene and ethanol. The temperature effect was extensively studied which revealed that increasing the temperature will increase the rate of reaction. The rate of reaction in a solvent-free condition, ethanol, and toluene were 1.7 × 10−3, 1.7 × 10−2, and 5.6 × 10−3 g mol−1 min−1, respectively.


Background
Heterogeneous catalysts play an extremely important role in the chemical industry which shows its applicability in our daily life [1]. Recently, scientists greatly reverted their attention towards the application of heterogeneous catalyst in the synthesis of important pharmaceutical scaffolds. It was estimated that more than 90 % of the chemical manufacturing depends on the catalytic processes [1]. The design and development of a catalyst with unique morphological and structural characteristics are the main focus in the field of catalysis [2]. The catalytic performance of a catalyst largely depends on the structural features and chemical composition, which in turn affect the active site of the catalyst, approachability of the molecules to the pore size of the catalyst and reactant product mass transport of the molecules [3][4][5][6][7]. A number of transition and normal element metal oxides (s and p blocks element) was largely used in various fields. Among transition metal oxide, zirconia (ZrO 2 ) played an important role as heterogeneous catalyst, due to its dual nature (both acidic and basic) and semiconductor behavior. These properties attributed the use of zirconia in a number of industrially important chemical reactions (Fig. 1) [8].
Various zirconia-based catalysts were reported for the synthesis of coumarin through Pechmann reaction. Coumarin belongs to a class of flavonoids and a type of benzo-2-pyrone, which is a plant secondary metabolite isolated from natural plants and some microorganisms. For instance, the antibiotic novobiocin, coumermycin A 1 , and chlorobiocin were isolated from microorganisms [1,2]. Coumarin acts as a safeguard against viral, bacterial, and fungal attacks, wounds, and stress by a process called phytoalexins [3,4]. The potential biological applications of coumarin were reported as platelet aggregation inhibition, antibacterial, anticancer, and antioxidant [7,8]. Coumarin and its derivatives are widely used in synthetic, pharmaceutical, and agrochemicals industries and also used as optical brightening agents, insecticidal, additive in perfumes, and cosmetics [5,6]. Coumarine serves as an intermediate in the synthesis of several organic reactions, i.e., furocoumarins, chromenes, coumarones, and 2-acylresorcinols [9]. Calanolides, a polycyclic coumarin, exhibited potent anti-HIV (NNRTI) activity and was isolated from genus Calophyllum [10].
The bioavailability of coumarin is sessional and environment dependent, so its production is variable at large scale from the natural resources. However, the remarkable application of coumarin and its derivatives needs it at large scale in medicinal, pharmaceutical, synthetic, and several other industries. Coumarin has been prepared through various strategies such as Perkin [11], Pechmann [12], Reformatsky [11], Knoevenagel [13], Wittig reactions [14], and flash vacuum hydrolysis [15]. Among all these reactions, Pechmann reaction was found as the most effective for this synthesis. Formerly, concentrated H 2 SO 4 was employed for the synthesis of coumarin in Pechmann reaction. Several inorganic reagent and Lewis acid such as P 2 O 5 , FeCl 3 , ZnCl 4 , POCl 3 , AlCl 3 , PPA, HCl, phosphoric acid, trifluoroacetic acid, and montmorillonite clays were used for the synthesis of this scaffold [9]. A number of other catalysts were also successfully reported in the literature for this condensation reaction, i.e., Nafion-H, W/ZrO 2 solid acid, zeolite H-BEA, montmorillonite clay, ionic liquids, and Amberlyst-15 [10].
The Pechmann reaction is an acid-catalyzed reaction that proceeds through three main steps. The first step is transesterification, which involved an exchange between phenol and β-ketoester followed by intramolecular hydroxyl alkylation in the second step and elimination of a water molecule in the third step as depicted in Fig. 8 [10,16]. Therefore, the yield of an acid catalyzes reactions depends on the acidic strength of the catalyst [17].
A large number of reactions are preceded in the presence of hazardous catalysts that deteriorate the climatic condition. Therefore, an environmentally benign alternative catalyst is needed for those reactions that are catalyzed by expensive ionic liquid, hazardous acid, and toxic catalyst [18][19][20]. This need can be fulfilled by the use of a catalyst that not only furnishes the required targets but also is ecofriendly. At present, zirconia got much attention as a solid acid catalyst in terms of their acidic strength, recyclability, and environmental benignity.
Based on the acidic strength of zirconia, we carried out Pechmann reaction with different zirconia-based catalyst (ZrO 2 -TiO 2 , ZrO 2 -ZnO, ZrO 2 /cellulose) that acts as a solid acid catalyst. The reaction was carried out under the solvent-free condition as well as in ethanol and toluene solvent. The kinetics of the reaction was studied for the first time for this reaction. The structures of the mentioned catalyst were determined by field emission electron microscope (FESEM), energy dispersive X-rays spectrometry (EDS), X-ray diffraction (XRD), and Fourier transform infrared spectroscopy (FT-IR). This method has several advantages such as simplicity of the reaction, solvent-free condition, room temperature, inexpensive starting material, no side product, high yield, high reaction rate, and no toxic waste material.

Materials
Reagents such as a salt of zinc and zirconium nitrates, NaOH, cellulose acetate, and TiO 2 were purchased from Sigma-Aldrich. Departmental Millipore-Q water purification assembly was used for deionized water. Ethyl acetoacetate and phenols (resorcinol and catechol) were taken from Koch-Light Laboratories Ltd.

Synthesis of ZrO 2 -TiO 2
The nanoparticle ZrO 2 -TiO 2 was synthesized according to our previous reports [21][22][23][24]. The commercially available TiO 2 was treated with the aqueous solution of Zr(NO 3 ) 2 . The solution was basified with 0.1 M NaOH solution till the pH reached 9. The reactants were stirred vigorously for 24 h and the supernatant was removed by centrifugation to isolate the precipitate of ZrO 2 -TiO 2 . The procedure of centrifugation is repeated for three times by washing with ethanol. Finally, the resultant precipitate was washed with 1:1 water/ethanol solvent mixture for several times and dried at 50°C for 24 h in an oven.

Synthesis of ZrO 2 -ZnO
The ZrO 2 -ZnO flowers were synthesized by the same method as employed for ZrO 2 -TiO 2 . An equimolar

Synthesis of ZrO 2 /Cellulose
ZrO 2 nanoparticle was grown on the surface of cellulose by adding 1:1 mixture of cellulose and Zr(NO 3 ) 2 [25]. The solution mixture was basified with 0.1 M NaOH solution in order to facilitate the formation of the nanoparticle. Finally, the precipitate was centrifuged and washed with 1:1 H 2 O:C 2 H 5 OH mixture and dried at 50°C in the oven for 24 h.

Characterization of Nanomaterials
The nanomaterials (ZrO 2 -TiO 2 , ZrO 2 -ZnO , and ZrO 2 / cellulose) were extensively studied through spectroscopic techniques. FESEM, JEOL (JSM-7600F, Japan), was used to find the morphology and average size of the nanomaterials. EDS oxford-EDS system was employed to investigate the elemental composition of the nanomaterials. The structures of nanomaterials were further analyzed by ARL X'TRA X-ray Diffractometer. The functional group in nanomaterial was characterized by FT-IR (Thermo scientific), while kinetics of the reactions were studied by UV/Visible spectrophotometer (Thermo scientific), and the product was identified through melting point (Buchi).

Results and Discussion
Structure Characterization of Nanoparticles The morphology of ZrO 2 -TiO 2 , ZrO 2 -ZnO, and ZrO 2 /cellulose was largely characterized by FESEM. ZrO 2 -TiO 2 was grown in the form of particles (Fig. 2a-2c) while the ZrO 2 -ZnO was grown in flower shape (Fig. 2d, 2e). ZrO 2 -ZnO was basically grown in the form of nanoparticles with an average size of 25-30 nm which aggregate to make a flower-shaped structure. In the case of ZrO 2 /cellulose, ZrO 2 was grown in the form of particles on the surface of cellulose as shown in Fig. 2f.
The elemental composition of ZrO 2 -TiO 2 , ZrO 2 -ZnO, and ZrO 2 /cellulose were performed by EDS spectroscopy as indicated in Fig. 3a-3c. The EDS spectrum of By the bombardment of X-ray, the number of electrons ejected from the surface of the sample was determined by X-ray photoelectron spectroscopy (XPS) as shown in Fig. 6a-6c. ZrO 2 -TiO 2 exhibited peaks for oxygen, titanium, and zirconium (O 1s, Ti 2p, Zr 3P, Zr 3d, and Zr 4P) while ZrO 2 -ZnO showed peaks for zinc, zirconium, and oxygen (O 1s, Zn 2P, Zn 3P, Zr 3P, Zr 3d and Zr 4p). Similarly, ZrO 2 /cellulose exhibited peaks for O 1s, C 1s, Zr 3P, and Zr 4P. Ti 2P, Zn 2P, and Zn 3P appeared in the XPS spectra at binding energies of 500.0, 1076, and 91.9 eV, respectively, as depicted in Fig. 6a. Zr 4P, Zr 3d, and Zr 3P appeared in the XPS spectra having binding energies of 350, 329, 37.9, and 1072.3 eV. Similarly, O 1s and C 1s were displayed at 535 and 185.0 eV in the XPS spectra as shown in Fig. 6a. The expanded XPS detailed spectra for all the materials are shown Fig. 6b. One can obviously see in these figures that Zr 3p peaks are shifted towards lower binding energies in both ZrO 2 -TiO 2 and ZrO 2 -ZnO as compared to Zr 3p peak position in ZrO 2 /cellulose. Similar shift behavior has been reported [27] and can be attributed to the formation of ZrO 2 -TiO 2 and ZrO 2 -ZnO binary oxides.

General Description for the Synthesis of Coumarin
The reaction was carried out between resorcinol and ethyl acetoacetate (1:2) by using 50 mg of the catalyst ZrO 2 -TiO 2 in three-neck round-bottom flask in solventfree condition at room temperature. The resultant product was formed without side product with a m.p. of 184-187°C. The diagrammatic view of the reaction is depicted in Fig. 1. The reaction was also carried out between resorcinol and ethyl acetoacetate without a catalyst at 80°C, but no product is formed as shown in Table 1.   Table 1. Due to the strongest catalytic performance of ZrO 2 -TiO 2 with resorcinol and ethyl acetoacetate, we further select this catalyst for the detailed study of this reaction. The reaction between resorcinol and ethyl acetoacetate (1:2) with 50 mg of the catalyst ZrO 2 -TiO 2 was studied in a polar solvent (ethanol) and non-polar solvent (toluene) by varying the temperature condition ( Table 2). The use of solvent-free condition is a better way while using a heterogeneous catalyst. Prior to the use of a catalyst, the reaction was carried out between resorcinol and ethyl acetoacetate in the absence of a catalyst in a solvent-free condition, toluene, and ethanol, but no product is formed. This confirms that solvent or temperature have no role; only catalyst played a central role in this reaction.

Temperature Effect
The temperature effect was observed on the reaction ZrO 2 -TiO 2 (50 mg) in the presence of toluene and ethanol. It was observed that increasing the temperature will decrease the time for reaction completion as indicated in Tables 3 and 4. Ethyl acetoacetate and resorcinol (1:2) was used as starting materials for the synthesis of coumarin along with 50 mg of the catalyst.

UV/Visible Data
The increase in product concentration was monitored gradually by taking the UV/Visible spectra periodically. A bathochromic shift was observed for the product, due to an increased conjugation as compared to the reactant. However, the product showed a different bathochromic shift in ethanol and toluene solvent. The bathochromic shift (increase in wavelength) was observed in ethanol at 372 nm while the same product appeared at 317 nm in toluene. In the presence of non-polar solvent (toluene), polar molecule showed hypsochromic shift due to n-π transition because it stabilizes the ground state more as compared to the excited state; therefore, a high amount of energy is   required to promote an electron from the highest occupied molecular orbital (HOMO) of non-bonding orbital to the lowest unoccupied molecular orbital (LUMO) of antibonding π orbital, and so the wavelength is decreased. However, polar solvent (ethanol) forms hydrogen bonding to the excited state of the product (coumarin), which stabilizes the transition state of the product more as compared to the ground state. Therefore, less amount of energy is required to promote an electron from HOMO of non-bonding orbital to the LUMO of the antibonding π orbital and thus increasing the wavelength as shown in Fig. 7a.

Kinetics of the Reaction
The kinetics was studied in solvent-free condition, ethanol, and toluene in the presence of ZrO 2 -TiO 2 catalyst. The rate of reaction in solvent-free condition at room temperature was 1.7 × 10 −3 g mol −1 min −1 , while at 60°C the rate of reaction in ethanol is 1.7 × 10 −2 g mol −1 min −1 and toluene 5.6 × 10 −3 g mol −1 min −1 as shown in Fig. 7a-7c.

Mechanism of the Reaction
Several mechanisms were put forward for the synthesis of coumarin. In the whole scenario, one C-O and one C-C bond are generated by the reaction of phenol with β-ketoester [28]. During C-C bond formation, the metal in the nanocatalyst chelates with β-ketoester, followed by Friedel-Craft cyclization in which the π-electron of the benzene ring of phenol attacks the carbonyl carbon of βketoester to form an unstable anti-aromatic species (4n electron system). This highly unstable anti-aromatic species restore its aromaticity (4n + 2π electron system) by losing hydrogen atom. Transesterification occurred in the next step followed by condensation to form C-O bond as depicted in Fig. 8.

Conclusions
In the present study, zirconia-based catalysts (ZrO 2 -TiO 2, ZrO 2 -ZnO, ZrO 2 /cellulose) were synthesized for the onepot synthesis of coumarin. The ZrO 2 -TiO 2 showed strongest catalytic performance for this reaction as compared to ZrO 2 -ZnO. At room temperature, the rate of reaction in solvent-free condition is 1.7 × 10 −3 g mol −1 min −1 . However, at 60°C, the rate of reaction in ethanol is 1.7 × 10 −2 and toluene 5.6 × 10 −3 g mol −1 min −1 . The rate of reaction was increased by increasing the temperature of the reaction. The bathochromic shifts was observed in the UV/Visible spectrum of the ethanol. The product appeared at λ max 372 nm in the presence of the ethanol as it stabilized the excited state of the polar molecule (coumarin). Similarly, the product appeared at λ max 317 nm in toluene solvent as it stabilizes the ground state of the polar molecule (coumarin).