Microwave-assisted Multi-component Reaction for the Green Synthesis of Novel 4-(5-hydroxybenzo[a]phenazin-6-yl)-5-phenyl-1, 3-dihydro-2H-imidazol-2-one Using H3PW12O40@nano-TiO2 as Recyclable Catalyst

ABSTRACT In this context, we have demonstrated a highly efficient and green process for the preparation of various potentially biologically active functionalized 4-(5-hydroxybenzo[a]phenazin-6-yl)-5-phenyl-1,3-dihydro-2H-imidazol-2-one derivatives via a one-pot, the four-component cyclo-condensation reaction in the presence of catalytic amounts of phosphotungstic acid supported on TiO2 as a nontoxic, highly reactive, and eco-friendly solid acid catalyst under MWI in solvent-free conditions. The crystallinity and the crystallite size nano-TiO2 were fabricated and characterized by X-ray diffraction (XRD), Transmission electron microscopy (TEM), scanning electron microscopy (FESEM), Thermogravimetric Analysis (TGA), Fourier transform infrared (FT-IR), Brunauer-Emmett-Teller (BET), and atomic force microscopy (AFM). We believe that this work can provide new insights into the fabrication of high-performance photocatalysts and facilitate their practical application in environmental issues. GRAPHICAL ABSTRACT


Introduction
Multi-component reactions (MCRs) have considerable ecological interest for use in the synthesis of biologically important compounds. The design of novel MCRs for the synthesis of diverse heterocycles has become an important topic for medicinal and organic chemists (1). Reducing laboratory time and costs is an important benefit of multicomponent reactions (MCRs) (2,3). In most multicomponent reactions, the largest number of atoms participating in the reaction are present in the product. One of the most important aspects of multi-component reactions is their high synthetic efficiency (4)(5)(6)(7).
In addition to their wide application in pharmaceutical sciences and drug synthesis, multi-component reactions are used in other fields, including materials science and the synthesis of environmentally friendly compounds, or the preparation of chiral stationary phases in chromatography (8)(9)(10)(11). Multi-component reactions can also be used for the artificial synthesis of amino acids and peptide macromolecules or in the polymer industry and the production of a variety of polymers such as polysaccharides (12)(13)(14).
Since 1986, materials have been synthesized using the microwave (15). Microwave heating is one of the most important applications of these waves. This is an application that has been used well in recent decades to perform various chemical reactions and has led to the emergence of a branch of chemistry called microwave chemistry (16)(17)(18). The microwave method has become increasingly used in the synthesis of various reactions due to its properties such as uniform heat distribution, selective heating, increasing reaction speed and reducing time, the energy required to walk, and improving the physical and chemical properties of synthesized particles (19)(20)(21).
In biology, the active site is the region of an enzyme where substrate molecules bind and undergo a chemical reaction. The active site consists of amino acid residues that form temporary bonds with the substrate (binding site) and residues that catalyze a reaction of that substrate (catalytic site). Although the active site occupies only ∼10-20% of the volume of an enzyme, is the most important part as it directly catalyzes the chemical reaction (22).
Due to its chemical and physical stability under reaction conditions and non-toxicity, titanium dioxide, in addition to its various applications in pigments and ceramics, has been widely used as a photocatalyst in the removal of environmental pollutants (23,24). TiO 2 has many functional properties in the crystalline phase of anatase. The form of anatase has a high photocatalytic activity and therefore has been used to eliminate organic and inorganic pollutants in the environment (25)(26)(27).
The application and efficiency of TiO 2 are strongly influenced by its crystal structure, shape, and particle size. Therefore, many efforts have been made to produce TiO 2 nanoparticles with controlled size, shape, and porosity for use in thin films, ceramics, composites, and catalysts (28)(29)(30).
TiO 2 is used in a variety of fields such as paints, plastics, cosmetics, inks, papers, and sensors. The increasing use of TiO 2 nanoparticles in the field of catalysts, photocatalysts, and sensors has intensified the need to use precision equipment for their synthesis (31)(32)(33).
Phenazines are a large group of nitrogen-containing heterocyclic compounds that differ in chemical and physical properties. Phenazines are a class of redox-active secondary metabolites produced by a few clades of bacteria, most notably pseudomonads,20,22 but not cyanobacteria. Bacteria are the only known source of phenazines, and more than 100 types of these compounds have been identified. Their potential impact on bacterial interactions and biotechnological processes has been considered ( Figure 1) (34,35). Natural phenazines are considered biologically active and are used in pigments and have many biological properties such as antioxidants (36), anti-AIDS (HIV) (37,38), anti-tumor (39,40), and the treatment of Alzheimer's and schizophrenia (40,41).

General Procedures
All reagents and solvents were purchased from Merck and Aldrich and used without further purification. Melting points were taken in open capillaries and are uncorrected. IR spectra were recorded on a Perkin-Elmer-1420 spectrophotometer. 1H NMR spectra (DMSO) were recorded on a Gemini-500 MHz spectrophotometer with TMS as the internal standard. Elemental analyses for C, H, and N were performed using a Costech ECS 4010 CHNS-O analyzer. Mass spectra were recorded on an Agilent Technology (HP) spectrometer operating at an ionization potential of 70 eV. 2.1.1. Preparation of nanocomposite TTIP (2 mL) and different amounts of H 3 PW 12 O 40 were added into isopropanol, respectively, and then mixed under vigorous stirring. After that, diluted hydrochloric acid was added to adjust the pH value. The mixture was stirred at room temperature until the gelatin was formed. After aging for 12 h, the resulting gelatin was transferred into a Teflon-lined stainless-steel autoclave and maintained at 200 0 C for 2 h with a heating rate of 2 0 C /min. The obtained white product was denoted as x-H 3 PW 12 O 40 /TiO 2 , in which x represented the H 3 PW 12 O 40 loading amount (wt%) in the composite photocatalyst (42,43).
A 25 mL reaction flask was charged with a mixture of Arylglyoxals 4 (1 mmol), urea 5 (1 mmol), and 0.03 gr of H 3 PW 12 O 40 @nano-TiO 2 nanoparticles Then, this mixture was stirred under thermal conditions at 100°C or it was transferred to a microwave oven at 300 W (max. 100°C) for a specific time. Upon completion of the reaction, monitored by TLC, the reaction mixture was allowed to cool to room temperature. Then, 10 mL of water was added to the mixture and filtered for separation of the crude product ( Table 1). The separated product was washed twice with water (2×5 mL) (46).

Results and Discussion
The phase structure, crystal size, and crystallinity are the essential factors of the composite catalyst. Figure 2 shows the XRD patterns of the catalysts. Peaks at angles 25.3°, 37.8°, 48.0°, 54.4°, 62.7°, 69.3°, and 75.2°, respectively (JCPDS 21-1272). As for HPA@Nano-TiO 2 , the same characteristic peaks as those of pristine TiO 2 were also observed, indicating that the anatase phase of TiO 2 was preserved well in the composite photocatalyst. No diffraction peaks of the H 3 PW 12 O 40 appeared, which presumably was due to the low content incorporation of H 3 PW 12 O 40 (38).
The FT-IR spectra of H 3 PW 12 O 40 /TiO 2 were characterized and presented in  (Figure 4(c)). Figure 4(d) gives the TEM micrograph of nanocrystalline H 3 PW 12 O 40 /TiO 2 , whose crystallite size was in the range of 10-20 nm. As can be seen in (Figure 4(b)), TiO 2 nanoparticles present spherical shapes being agglomerated in asymmetric formations. The TEM and HRTEM images reveal that the HPW/TiO 2 sample possesses disordered microporous structures, and the macropores are preserved throughout the entire material (Figure 4(c-e)). Figure 4(c) displays that partly macropores are connected by the holes on the wall of the macropores. This result could be due to the shrinkage of the HPW/ TiO 2 composite during calcination. Figure 4(c) evidences the existence of ordered mesopores in the macropore walls. The mesopore and macropore structures are further confirmed by transmission electron microscopy (TEM) micrographs, showing that the HPW/TiO 2 sample represents macropores, which are interconnected through hexagonally ordered mesopores of ca. 10-20 nm.
Atomic force microscopy (AFM) analysis of the nanocatalyst confirms the presence of spherical particles in the final catalyst ( Figure 5). The higher the effective level, the higher the catalyst activity or efficiency in product synthesis. The AFM image showed the presence of nanoparticles whose particle size and morphology were close to SEM images.
The thermal behavior of representative samples H 3-PW 12 O 40 /nano-TiO 2 sample was investigated via TG analyses ( Figure 6). A decrease in the weight percentage of the catalyst of about 100°C is due to the removal of water molecules and another decrease of 280°C is observed, which indicates the high thermal stability of the catalyst.
To investigate the surface areas and pore size distributions of H 3 PW 12 O 40 @nano-TiO 2 composite photocatalyst, the N 2 adsorption-desorption isotherms were analyzed, as presented in Figure 7. The pore size distributions indicated that TiO 2 presented a relatively  narrow distribution ranging from 35 nm to 45 nm. Taking into account the morphology of the material observed by TEM, the small pores should be the intra nanoparticle pores. The BET surface area of the prepared TiO 2 nanoparticles was 186.25 m 2 .g −1 and the BET surface area of the commercial was 50 m 2 .g −1 . A larger surface area provides more surface-active sites for the adsorption of the reactive molecules, which leads the photocatalytic process to be more efficient. We can conclude that the nanoparticles prepared by us might have good photocatalytic activities. BET surface area (177.9 m 2 .g −1 ), pore volume (0.4390 cm 3 .g −1 ), and average pore size (3.84 nm) of H 3 PW 12 O 40 /nano-TiO 2 were higher than those of TiO 2 (158.6 m 2 .g −1 ; 0.4240   Using the relation σ = 1/ρ the electrical conductivity of the material can be obtained, as shown in Figure 8. The electrical conductivity increases with temperature from σ = 3.78·10 −8 S cm −1 at 145 K to σ = 6.04·10 −7 S cm −1 at 300 K. XPS analysis is applied to investigate the chemical state of the H 3 PW 12 O 40 @nano-TiO 2 catalyst. As shown in Figure 9(a), the survey scan XPS spectrum displays that the composites contain Ti, O, P, and W, Peaks appeared at approximately 464.4 and 458.8 eV can be attributed to the binding energies of O 1s, Ti 2p 1/2 , and Ti 2p 3/2 , originated from lattice oxygen of TiO 2 (Figure 9(b and c)) Moreover, the characteristic 4f 5/2 and 4f 7/2 peak of W atom in Figure 5(d) can be found at 37.6 and 35.6 eV, suggesting the WVI oxidation state. The high-resolution P 2p and W 4f XPS spectra also indicate the introduction of HPW in the catalyst (Figure 9(e)).

Catalyst recyclability
We also examined catalyst recycling using an option ( Figure 10). After the reaction, 5 ml of water was added and filtered to separate the precipitate. After complete washing of the solid product, the water evaporates under pressure and is used again. The results showed that the catalyst can be reused 6 consecutive times ( Table 2). One of the advantages of heterogeneous catalysts is their reusability. The recycled catalyst was reused six times in similar reaction conditions. The results show that recyclability has not significantly decreased the catalytic performance.
A hot filtration test was performed by separating the H 3 PW 12 O 40 /TiO 2 catalyst from the reaction mixture after 5 min in the first cycle of the reaction. The recovered nanocatalyst was collected and then dried at 100 0 C. This may lead to a slight increase of the yield to 59% from 55% after the hot filtration test. Furthermore, disruptions, such as hot filtration, may deactivate an existing active dissolved metal, leading to the incorrect conclusion that there are no active homogeneous catalytic species before the filtration ( Figure 11).     Table 3 After extensive screening, we found that the optimized best yields and time profiles were obtained when the reaction was carried out in the presence of 0.03 g of 60% H 3 PW 12 O 40 @ nano-TiO 2 under      Scheme. 2. a Proposed mechanism for the synthesis of novel 4-(5-hydroxybenzo[a]phenazin-6-yl)−5-phenyl-1, 3-dihydro-2H-imidazol-2-one derivatives via a single-pot.

Effect of tungstophosphoric acid loading on TiO 2
MWI at 300 W under solvent-free, which afforded the corresponding 4-(5-hydroxybenzo[a]phenazin-6-yl)−5phenyl-1, 3-dihydro-2H-imidazol-2-one in 10 min with 95% of yield (Table 3, entry 12). Increasing the amount of 60% H 3 PW 12 O 40 @ nano-TiO 2 to more than 0.06 g showed no substantial improvement in the yield, whereas the yield decreased by decreasing the amount of the catalyst to 0.015 g. Moreover, the reaction did not proceed efficiently in the absence of H 3 PW 12 O 40-@nano-TiO 2 even after 60 min under MWI. In this experiment, no other solvents were tested because of the green chemistry concept.
In this context, we have demonstrated a highly efficient and green process for the preparation of various potentially biologically active functionalized 4-(5-hydroxybenzo[a]phenazin-6-yl)-5-phenyl-1, 3dihydro-2H-imidazol-2-one derivatives via a single-pot, two-step, four-component cyclo-condensation reaction using H 3 PW 12 O 40 @nano-TiO 2 , highly reactive, and ecofriendly solid acid catalyst under MWI in an aqueous medium. To determine the catalytic behavior of H 3 PW 12-O 40 -nano-TiO 2 , the suggested mechanism for the formation of the products is shown in Scheme 2. Based on this mechanism, at first, 2-hydroxynaphthalene-1,4dione 1 tautomerizes to intermediate 11. The primary condensation of 4-hydroxy-1,2-naphthoquinone 11 with benzene-1,2-diamine 2 obtain benzo[a]phenazin-5-ol 3. A reaction pathway involves the formation of an intermediate (A) medium when reacted with the urea group after being added to the carbonyl group or the replacement of the side-chain hydroxy group. Based on the second route, Arylglyoxal and Urea developed the open shaft (B), which is made after reacting with the intermediate middle (A) benzo [a] phenazine-5-ol, which is caused by loss of water during the ringing process the desired product is obtained.

Conclusion
In summary, we have described a simple, efficient, and environment-friendly one-pot procedure for the synthesis of 4-(5-hydroxybenzo[a]phenazin-6-yl)-5-phenyl-1, 3-dihydro-2H-imidazol-2-one derivatives by using catalytic amount under microwave irradiation conditions. Short reaction times, high yields, high atom economy, excellent chemoselectivity, simple experimental procedure, and the easily work-up procedure associated with the efficiency of the synthesized nanocatalyst are the highlighted points of the present method. Moreover, this sequential protocol includes some important aspects like the use of MWI as a partially renewable energy source for the direct heating of the reaction mixture and the application of H 3 PW 12 O 40 @nano-TiO 2 as a reusable and recoverable catalyst.