Photocatalytic Synthesis of Quinazolinone Derivatives as Mediated by Titanium Dioxide (TiO2) Nanoparticles Greenly Synthesised via Citrus limon Juice

Abstract In this study, we focused on the ultrasonic synthesis of titanium dioxide (TiO2) nanoparticles via a green chemistry process using Citrus limon (lemon) juice. XRD diffractograms and Raman spectroscopy revealed the anatase structure of TiO2, SEM analysis showed nanometric particle sizes, and FTIR spectroscopy confirmed the presence of the synthesized nanoparticles. The catalytic performance of the biosynthesised nanoparticles was evaluated for the synthesis of sulphur-substituted quinazolinone derivatives under UV irradiation. The final products were achieved in 6–8 h with good yields (79–91%). Graphical Abstract


Introduction
Nanoscience and nanotechnology both include scientific and technological activities performed at a nanometric scale, as the names imply.Nanotechnology attracts attention because, at the nanometric level, the behavior of objects is completely disrupted, and the new properties make the creation of more efficient materials possible.Furthermore, the development of synthetic techniques now allows rapid production on a large scale. 1,2Nanomaterials are distinguished by their very high surface-to-volume ratios, which are responsible for their surface properties and interactions with surrounding mediums.Nowadays, these materials occupy an increasingly large space and are used in various high-tech fields, such as electronics, catalysis, and energy, as well as in our daily lives (e.g.cosmetics and food).
The miniaturization of objects to the nanometric scale is a field of research that focuses the attention of a large community of scientists.In particular, titanium dioxide (TiO 2 ) is one of the most widely used nanomaterials.4][5] TiO 2 is generally recognized as inert and harmless; however, on a nanoscale, it gains increased surface reactivity.There are various routes to TiO 2 nanoparticles synthesis, but all can be categorized into two main approaches: top-down or bottom-up.
The basic principle of the top-down approach is to start with a massive amount of material with the desired nature and break it down gradually into smaller and smaller pieces.The most common technique used for this is planetary milling.The aim of the bottom-up approach is to build a nanomaterial atom by atom or molecule by molecule.The major advantage of this approach is that it is possible, by modulating parameters, to control the size, morphology, and structure of the resultant NPs.Several such synthetic techniques include the sol-gel process 6,7 and the hydrothermal, 8 solvothermal, 9,10 precipitation, 11 and electrochemical methods. 12ver the past 10 years, several scientific research articles have been published on the green production of NPs through the use of bacteria or plant leaf and fruit extracts. 13Recently, articles have been written on the green synthesis of TiO 2 nanostructures using extracts from various plants, such as Annona squamosal (sugar apple), 14 Eclipta prostrata (false daisy), 15 Catharanthus roseus (Madagascar periwinkle), 16 Mangifera indica L. (mango), 17 Aloe vera, 18 Echinacea purpurea (purple coneflower), 19 Cicer arietinum L. (chickpea), 20 alcea (hollyhocks), 21 thyme, 22 Glycyrrhiza glabra (liquorice), 23 and other medicinal plants. 24n its nano-form, TiO 2 has been shown to be a good catalyst in organic chemistry due to its high efficacy, availability, ease of reuse, non-toxicity, stability, high oxidizing power, and Lewis acidity. 25,26Indeed, nano-TiO 2 has been used for the synthesis of 2-indolyl-1-nitroalkane derivatives, 27 the preparation of Hantzsch ester and polyhydroquinoline derivatives, 28 and the synthesis of bis-(indolyl)methane 29 and acetamidocetone. 30It has also been used in the preparation of xanthene scaffolds, 31 indoles alkylation, 32 and the synthesis of quinazolinone, 33 imines, 34 and quinoxalines. 35Moreover, metal catalysts supported on TiO 2 have been used in different inorganic and organic processes such as the Suzuki-Miyaura coupling reaction, 36 the Mizoroki-Heck reaction, 37 the Liebeskind-Srogl coupling reaction, 6 and hydrogenation. 38he present study focuses on one green route for TiO 2 synthesis using Citrus limon (lemon) juice as a biosource of citric acid that acts as a reducing agent as well as favor the hydrolysis of precursor molecules to increase specific surface area, pore volume, and pore size.The prepared TiO 2 catalyst was characterized using different analytical techniques, including Fourier-transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), Raman spectroscopy, X-ray photoelectron spectroscopy (XPS), and scanning electron microscope (SEM) techniques.We also studied the catalytic performance of the greenly prepared TiO 2 when synthesizing quinazolinone derivatives under UV light irradiation.

Reagents and chemicals
Tetrabutyl titanate (C 16 H 36 O 4 Ti) was used as the precursor compound for both the chemical and green processes.All chemicals and solvents were purchased from the Shanghai Chemical Reagent Company (China) and were used without further purification.C. limon was purchased from the local market.

Biosynthesis of TiO 2 nanostructures
The following method was used to synthesize green TiO 2 nanoparticles (G-TiO 2 ): first, 23 mL of C 16 H 36 O 4 Ti was dissolved in 23 mL of ethanol.Next, the solution was ultrasonically irradiated for 15 min.Then, under sonication, 23 mL of C. limon juice was added dropwise to the solution until the desired TiO 2 nanopowder had fully precipitated.The mixture was dried at 80 C in an incubator.Finally, the dried powder was calcined at 600 C for 2 h.

Characterization techniques
Structural investigations were performed using an Ultima IV XRD apparatus (Rigaku Corporation).The diffractometer was equipped with a Cu Ka radiation source that provided a wavelength of k ¼ 1.54056 Å. Spectroscopic studies were performed with a SENTERRA II Raman microscope (Bruker) equipped with a laser source providing an excitation wavelength of 532 nm.Surface topography investigations of the TiO 2 nanoparticles were conducted using an Inspect F50 scanning electron microscope.The chemical composition of the as-prepared TiO 2 samples was achieved with a Thermo Scientific K-Alpha XPS system with an Al Ka radiation source that emitted 1486.6 eV.

Synthesis of compound 3
First, 1 mmol of 5-methylanthranilic acid was mixed with 1 mmol of 4-fluorophenylisothiocyanate via stirring in the presence of 20 mL of pure ethanol, and then 1.1 mmol of triethylamine (0.11 g) was added.The reaction was refluxed for 1.5 h until thin layer chromatography (TLC) verified its completion.The crude product was filtered and recrystallized in ethanol to obtain pure compound 3.

Synthesis of quinazolinone derivatives (5a-h)
To prepare compound 5, in the presence of 10 mL of acetone containing 1 mmol of alkyl-or benzyl-bromide and 1.5 mmol of G-TiO 2 , 1 mmol of compound 3 was irradiated for the appropriate amount of time.Then, the reaction was filtered and the solvent was evaporated in vacuo.The crude product was recrystallized in ethanol to finally obtain quinazolinone derivative type 5.

Raman characterisation
In conjunction with XRD analysis, a Raman spectroscopy investigation was conducted to gather more information about the phase structure of the synthesized TiO 2 samples.Figure 2 shows five intense Raman peaks located at 143 cm À1 (E g ), 197 cm À1 (E g ), 396 cm À1 (B 1g ), 519 cm À1 (A 1g þB 1g ), and 639 cm À1 (E g ) (anatase phase). 5,13Figure 2's inset is a magnification of the dashed region, which shows a small peak at 447 cm À1 (E g ) (rutile phase), 5,13 confirming that the biosynthesised TiO 2 was largely in the anatase phase but had evidence of the rutile phase.

Elemental analysis
Further investigation of the prepared TiO 2 samples was conducted using XPS.The survey spectra corresponding to the biosynthesized G-TiO 2 and the high-resolution spectra corresponding to the different elements identified in the samples are depicted in Figures 3 and 4.
The surveys of the chemical and biosynthesized TiO 2 samples revealed characteristic peaks corresponding to Ti2p and O1s.Both spectra showed a peak located at 287 eV, which was attributed to the C1S state of the adventitious carbon from environmental contaminations.This result indicated the synthesized samples' purity.
The deconvolution of the high-resolution scan of Ti2p in the chemical sample presented two peaks located at 459.78 eV and 465.48 eV, corresponding to the Ti2p3/2 and Ti2p1/2 spin orbit's splitting and separating by 5.7 eV, which matched well with the reported values for TiO 2 .Similarly, the deconvolution of the high-resolution plot of Ti2p in the biosynthesized sample presented two peaks, located at 459.3 eV and 465 eV, corresponding to the Ti2p3/2 and Ti2p1/2 spin orbit's splitting and separating by 5.3 eV.Moreover, the fitting of the O1s peak in the biosynthesized sample showed a core peak at 530.35 eV, which was attributed to TiO 2 's oxygen lattice.There was also a slight peak at 531.39 eV, which was assigned to the adsorbed Ti-OH hydroxyl groups. 39

Morphologic analysis
The morphological features of G-TiO 2 , achieved using SEM, are shown in Figure 5; the sample appears to have a porous, spherically-shaped structure.

Infrared spectroscopy
Figure 6 shows the FTIR spectrum of greenly synthesized TiO 2 .A broad band around 3200 cm À1 can be seen, which is characteristic of OH stretching vibrations, as well as a band at 1650 cm À1 , which corresponds to the stretching of the hydroxyl group. 41][44] The identification of the different functional groups in our prepared material confirmed the existence of secondary metabolites within the C. limon juice.These metabolites were responsible for the reduction of TiTp to attain the TiO 2 nanoparticles.

Optimization of reaction conditions
The optimization study was conducted by reacting intermediate 3 with 1-bromopropane in different solvents at room temperature in the presence or absence of a catalyst and the presence or absence of a light source (Table 1).
First, we found that the product was not achievable with the lack of both a light and a catalyst (Table 1, entry 1).The experiment was repeated with a catalyst but no light; again, no product was obtained (entry 2).In the third attempt, a 300 nm wavelength light source was used, but with the absence of a solvent, the product was not achieved (entry 3).Next, we tried using the same 300 nm wavelength light source in the presence of a catalyst and different solvents.The target product was achieved with a 14% yield in the presence of the G-TiO 2 catalyst and water (entry 4); in other solvents-THF, DMSO, CHCl 3 , Me 2 CO, MeCN, and DMF-the product was obtained with yields varying from 21-54% (entries 5-10).Using acetone resulted in a yield of 84% (entry 11).
The optimization investigation revealed that not only was a catalyst necessary to facilitate a reaction, but also the reaction yield was dependent on the light source's wavelength (entry 12).We found that a 300 nm wavelength was suitable for the completion of the reaction (entry 13).Furthermore, the G-TiO 2 catalyst, compared to the chemically prepared nano-TiO 2 , enabled higher efficiency (entries 10 and 14).However, K 2 CO 3 gave a result similar to G-TiO 2 (entry 15).We also found that alkylbromide gave better results than alkylchloride when used as a reactant (entries 11 and 16).

Application of the methodology
Through the optimization experiment, the scope of the reactions between compound 3 and different alkyl and aromatic halides was investigated (Table 2). 45We reacted intermediate 3 and a stoichiometric amount of reactant 4 in 10 mL of acetone, using G-TiO 2 (5 mol%) as a catalyst.Each mixture was kept under a light source (or not, as was the case in several trials) for an appropriate amount of time.Alkylation was successfully performed, and the final derivatives were obtained after purification by recrystallization.The isolated products were obtained with yields varying from 79-91% after a reaction time of 6-8 h.The aryl and alkyl groups encouraged the reactions and boosted the resultant products' yields, which were also linked to the presence of the G-TiO 2 and UV illumination.

Proposition of the reaction mechanism
Based on the results obtained of experiments of optimization, the reaction mechanism is proposed in Figure 8. Basically, under UV illumination, electrons jump from the valence band of POLYCYCLIC AROMATIC COMPOUNDS TiO 2 to its conduction band, forming an electron-hole pair.Therefore, this pair recombines very rapidly within the TiO 2 semiconductor; thus, photoexcited electrons participate in the catalytic reaction and help in the formation of the C-C bond.87% (6 h) a Yield of pure isolated product.Reaction conditions: Compound 3 (1 equiv.),RBr (1 equiv.),Catalyst (5% equiv.),solvent (10 mL).b Isolated yields.

Conclusion
Titanium dioxide (TiO 2 ) nanoparticles were prepared via ultrasonic green chemistry, using C. limon juice as a capping/reducing agent.The prepared catalyst was analyzed via different analytical techniques.Finally, the photocatalytic potential of the greenly synthesized nanoparticles was investigated in the synthesis of quinazolinone derivatives under UV irradiation with the sulphursubstitution method.

Figure 5 .
Figure 5. SEM images of the chemical and biomediated TiO 2 samples.
a b Isolated yields.

Table 2 .
Reactivity of derivative type 3 with different reactants 4a-h.