Synthesis and Characterization of Graphitic Carbon Nitride Supported Tris(Hydroxymethyl)Aminomethanem) G-C 3 N 4 / THAM) as Novel Catalyst for the Synthesis of Poly Hydroquinoline and Pyranopyrazole Derivatives

Here, an impressive heterogeneous catalytic system, graphitic carbon nitride supported tris(hydroxymethyl)aminomethanem) g-C 3 N 4 / THAM) is presented. The novel g-C 3 N 4 / THAM nanocatalysts was characterized by analyzing methods such as FT-IR, EDX, XRD, TGA, and FESEM. Afterward, the performance of fabricated nanocatalyst g-C 3 N 4 / THAM was suitably investigated in multicomponent reactions (MCRs) for the synthesis of 1,4-dihydropyridine and pyranopyrazole derivatives. By optimizing reported nanocatalyst, the corresponding reaction products were obtained with excellent eciency and then the reversibility process was exanimated. The g-C 3 N 4 / THAM nanocatalyst is environmentally friendly and was catalyzed the reactions in the presence of ethanol as a green solvent.


Introduction
Graphitic carbon nitride (g-C 3 N 4 ) this astounding material, is certainly one of the oldest economical and nontoxic polymeric catalyst 1 .The g-C 3 N 4 is made easily and large-scale by thermal polymerization (hydrothermal method) from inexpensive precursors such as melamine, dicyandiamide, urea, etc. without the use of organic solvent and is considered a green method [2][3][4][5] .The g-C 3 N 4 due to its characteristics such as having a small bandgap (2.7 v), non-toxicity, porous structure, high thermal stability, large surface area, remarkable mechanical properties as a catalytic support for many heterogeneous catalytic application processes [6][7][8] .Due to the special morphology and available surface of polymeric g-C 3 N 4 , it is extremely easier to modify the structures of g-C 3 N 4 .As a consequence, The g-C 3 N 4 became a hot topic for study,and Its surface can be modi ed with different functional groups to achieve the desired application.
Many reactions have been done with modi ed carbon nitride, such as oxygen reduction reaction 9 , carbonylation reaction 10 , electrooxidation of alcohols 11 , photocatalyst 12 , and multi-component reactions like the synthesis of imidazole derivatives 13 , quinoxaline derivatives 14 , and polysubstituted pyridine 15 .
Tris (hydroxymethyl) aminomethane (THAM) molecule can be described as consisting of three CH 2 OH groups and an NH 2 functional group.The THAM molecule particular structure enriches it with donoracceptor groups 16 .This structure is a creative and very interesting combination that broadly used in molecular biology, biochemistry and chemistry 17,18 .One of the things that has attracted the attention of chemists to this molecule is its non-toxicity, cost-effectiveness, degradability and biocompatibility of the compound 19 .
The use of multicomponent reactions (MCRs) paves the way for us to synthesize complex compounds with more con dence 20 .In many multi-component reactions with the change of one substance new compounds would synthesis.Simple puri cation of products, mild reaction conditions, and high yields are the bene ts of these reactions 21 .
Despite their complexity, MCRs have been identi ed since the beginning of organic chemistry in the nineteenth century 22 .Up to date, more than a dozen MCRs have been developed, many of them named after people.Many basic MCRs, for instance, Passerini 23 , Ugi 24 , Biginelli 25 , Strecker 26 , Pictet-Spengler 26 , Hantzsch 27 , Mannich 28 , Kabachnik−Fields 29 , and Döbner 30 are named reactions.
Among them, the Hantzsch reaction is one of the oldest, most famous, and challenging multicomponent reactions and it was discovered in 1882 31,32 .Hantzsch derivatives are one of the signi cant heterocyclic compounds due to their pharmacology properties such as antitumor 33 , calcium channel blockers 34 , analgesic 35 , and neuroprotective 36 and still is on progress.One-pot condensation of aldehydes, dimedone, ammonium acetate, and ethyl acetoacetate in re ux condition is the classical method of synthesis unsymmetric 1,4-dihydropyridines.This previous method also has some problems such as long reaction time, use of toxic solvents, and low yields that scientists are trying to solve 37,38 .pyranopyrazole are another functional and important compound that is more easily synthesized by MCRs 39 .Due to various properties of pyranopyrazole derivatives such as anticancer 38 , anti-in ammatory 40 , antimicrobial 41 , anti-HIV, and biological activities their synthesis is interesting.Also, many bioactive compounds that have agrochemical and medical activities containing pyranopyrazole ring.Due to these compounds' remarkable properties, scientists are doing their best to synthesis pyranopyrazole derivatives with several methods 42 .The reported methods have disadvantages such as long reaction time, complex and hard work-up process, and also the destructive environment 43 .
In this report, we have introduced a new catalyst, g-C 3 N 4 / Pr/THAM composite that shown in scheme 1 and used it as novel nanocatalyst in the synthesis of 1,4-dihydropyridine and pyranopyrazole derivatives.Some advantages of using this catalyst are high yields, mild reaction conditions, use of non-toxic solvents, short reaction time, and simple puri cation.To prepare this nanocatalyst, g-C 3 N 4 is synthesized as a substrate and its surface modi ed with THAM ligand to create a synergistic effect.Mentioned ligand was placed on the substrate surface with 1,3-dibromopropane linker.

Experimental
General All chemicals were purchased by the Merck Company and used without further puri cation.The melting points of the prepared derivatives were measured by an electrothermal 9100 apparatus.Al-plates supported by silica gel F254 were used for monitoring reaction progress.The X-ray diffraction (XRD) pattern was obtained using PHILIPS-PW 1800 diffractometer with monochromatized Cu Kα radiation (λ=1.542Å).Fourier transform infrared (FT-IR) spectra of compounds were performed on a Bruker Tensor27 FT-IR spectrometer.thermal stability of samples was studied by Thermogravimetric analysis (TGA) using the STA504 analyzer system.energy-dispersive X-ray (EDX) spectroscopy for elemental studying of the catalyst was recorded on Oxford Instrument (ZEISS-Sigma VP).Field emission scanning electron microscopy (FESEM) were carried out on MRIA3 TESCAN-XMU.The purity of the obtained products was con rmed by Varian Inova 500 NMR Spectrometer in DMSO-d6.

Synthesis of bulk g-C 3 N 4 and g-C 3 N 4 nanosheets
The bulk g-C 3 N 4 was synthesized by heating melamine with a rate of 2.5 ℃ min -1 using a mu e furnace and kept for 2 h at 550 ℃ with the ramp for 4h.After cooling down to ambient temperature, bulk g-C 3 N 4 was ground into light yellow color and ne powder.For the preparation of the g-C 3 N 4 nanosheets, rst 1.0 g bulk g-C 3 N 4 was added into 20 mL of H 2 SO 4 under stirring for 1 h at 90 ℃.After 5h, 200.0 mL ethanol was added to the mixture and stirred at room temperature yielding a white mixture.The reaction was complete after 2 h.The white precipitate was formed which was separated by simple ltration, then it was washed several times with deionized water, and dried in the oven at 60℃.

Synthesis of sheet g-C 3 N 4 /Pr/tris(hydroxymethyl)aminomethane composite
In the rst step, a mixture of 0.027 g sodium iodide, 0.028 g potassium carbonate, 0.026 g tris(hydroxymethyl)aminomethane, 0.5 ml 1,3-dibromopropane, and 20 ml dry toluene as solvent was added in a round bottom ask and re uxed for 12h.Then, the product was ltered and washed with ethyl acetate.
In the next step, in a round bottom ask, a mixture of the obtained salt product, 0.027 g sodium iodide, g-C 3 N 4 (0.1 g), and 20 ml dry toluene was added and re uxed for 12h.Finally, the product was ltered and washed with ethyl acetate and water to remove unreacted materials (scheme 2).

Results And Discussion
To investigate the surface functionalization g-C 3 N 4 substrate characterized by Fourier transform infrared (FT-IR), energy-dispersive X-ray (EDX) spectroscopy indicates the type of elements present in the g-C 3 N 4 /Pr/ THAM nanocatalyst.X-ray diffraction (XRD) pattern is shown to investigate the crystal structure of the compound and the eld emission scanning electron microscope (FESEM) analysis indicates the morphology of the synthesized catalyst surface.Finally, the heat resistance of the desired compound is characterized by Thermogravimetric analysis (TGA).

FT-IR spectroscopy
According to the spectrum presented in Figure 1, a broad peak has appeared in the range of 3000-3300 cm -1 , which is related to the stretching vibration of NH bonds; the peak width can be assigned to NH groups involved in the hydrogen bond or the existence of the OH group.The stretching vibrational peak C =N is observed at 1602 cm -1 .Peaks 1303 and 1082 cm -1 are attributed to the tensile vibration of C-N bonds formed between triazine and N-H groups, and the stretching vibration of C-N bonds in the ring in 1448 and 1379 cm -1 is easily visible.Also, the peak is 786 cm -1 due to the vibration of tri-s-triazine units.
The presence of C-H stretching peaks (2800-3000 cm -1 ) con rms the synthesis of the desired composite.

EDS analysis
In this section, we will go to the EDS spectrum to con rm the synthesis of the g-C 3 N 4 /THAM nanocatalyst compound.As shown in Figures 2, presence elements such as C, N, O con rms the synthesis of g-C 3 N 4 / THAM nanocatalyst.Very small amounts of sodium, potassium and iodine are observed in the analysis, all of which are related to substances that added to the reaction to modify the surface carbon dioxide.Due to many elements and their disintegration, the names of the elements are not mentioned in the device's intermediate diagram; they are listed in the quantitative table shape.

XRD analysis
The structure of the g-C 3 N 4 /Pr/ THAM nanocatalyst was characterized using by XRD pattern.As observed in Figure 3, the broad and intense re ection peaks at 2θ= 27.4 were assigned to the re ection peak of graphitic carbon nitride with Card No. JCPDS 87-1526.The new couriers have corresponded to the surface modi cation and nanocatalyst synthesis.

FE-SEM analysis
FESEM analysis was used to study the morphology and particle size distribution of the synthesized nanocomposite.Figure 4(a-d) has demonstrated images of nano-sheets g-C 3 N 4 and nano-sheets g-C 3 N 4 / Pr/THAM nanocatalyst by FE-SEM studies.As expected, FE-SEM images of graphitic carbon nitride (a,b) are smooth and are almost neatly linked and placed on each other due to being graphitic.In nano-sheets g-C 3 N 4 / Pr/THAM nanocatalyst images (c,d), g-C 3 N 4 plates are not smooth and have particles on them that exhibited the synthesis of the nanocomposite.Also, carbon nitride nano-sheets have become irregular.

TGA analysis
These observations also agree with the thermogravimetric analysis (TGA). Figure 5 shows the thermal stability of synthesized graphitic carbon nitride/ tris(hydroxymethyl)aminomethane composite which was carried out by TGA.The resulting catalyst as evidenced by TGA has displays high-temperature resistance up to approximately 400 °C.The mass-loss curve presents an in ection point at 400 °C.From 400°C, the diagram exhibits a gentle slope which is probably due to the decomposition of the composite before entering a nearly sharp slope being attributed to the thermal decomposition of carbon nitride.

Catalyst application of the g-C 3 N 4 /Pr/ THAM nanocatalyst in MCRs
The catalytic activity of the g-C 3 N 4 /Pr/ THAM nanocatalyst was studied in two MCRs for the synthesis of 1,4-dihydropyridine and pyranopyrazole derivatives to obtain the highest performance.To achieve the best result, different experimental conditions such as temperature, solvent, and amount of catalyst must be examined.To optimize the reaction conditions and performance evaluation of the g-C 3 N 4 /Pr/THAM nanocatalyst in Hantzsch reaction for the synthesis of 1,4-dihydropyridine derivatives, a one-pot four components reaction of chlorobenzaldehyde (1 mmol), ethyl acetoacetate (1 mmol), dimedone (1 mmol), and ammonium acetate (1 mmol) were investigated as a model reaction.Also, for the synthesis of pyranopyrazole derivatives a four-component reaction ethyl acetoacetate (1 mmol), hydrazine hydrate (1 mmol),4-chlorobenzaldehyde (1 mmol), and malononitrile (1 mmol) in ethanol was considered as the model reaction.Both model reactions showed almost the same behavior.One of the crucial factors in multicomponent reactions is solvent selection due to the different yields of each catalyst in different solvents.therefore, we have examined different solvents (protic and aprotic) to observe the effect.First, optimization experiments were conducted in ethanol, methanol, acetonitrile, DCM, DMF, DMSO, THF, toluene, water, ethanol/water (3:1), methanol/water (3:1), and solvent-free conditions as green conditions in both model reaction and the best e ciency were obtained in ethanol (Table 1, entries 1).Among these solvents, just MeOH, DCM, and ACN gave the intended product for 92, 60, and 66% yield, respectively (Table 1, Entries 2-4).Protic solvents have shown great progress in model reactions in comparison to aprotic solvents.In aprotic solvents, the intended product has not been seen in TLC even after 1h.Thus, we have desired to use protic solvents more than aprotic solvents.Unfortunately, model reactions showed no intended product in TLC in water as solvent (Table 1, entry 9).The insolubility of organic compounds in water could be the reason for this event.Therefore, we have used the combination of water and ethanol (Table 1, entries 10-11).The results showed that the existence of water would decrease the yields.We also tried model reactions in solvent-free conditions.In these conditions, the intended product has not been seen in TLC even after 1h.After concluding the results, ethanol was the best solvent among the others and was selected as the constant solvent for further studies.
The subsequent model reaction was performed without catalyst and in the presence of ethanol, the yield of this MCRs was not considerable (Table 1, entries 14).Another critical factor in multicomponent reactions is the amount of catalyst in the reaction.By adding the g-C 3 N 4 /Pr/ THAM nanocatalyst to the model reaction in the presence of a solvent, the e ciency increased dramatically and the yield was reached about 91%.Thus, we have examined the different amounts of the catalyst to nd the optimum amount, and the results have shown in Table 1.Hence, we have added 0.01 g of catalyst to the reaction mixture.The TLC monitoring showed that the intended product is produced (Table 1, Entry 15).For optimizing catalyst amount, we have increased the amount by 30 mg.As a result, it showed that the amount of catalyst upper 0.02 g does not affect the yield of the intended product.(Table 1, Entry 18).Accordingly, it was observed that 0.02g nanocatalyst is su cient to conduct this MCRs.(b) Reaction of ethyl acetoacetate (1 mmol), hydrazine hydrate (1 mmol), 4-chlorobenzaldehyde (1 mmol) and malononitrile (1 mmol), catalyst (0.01-0.03 g), the yields relate to the isolated product.
After the optimization process, the generality of the procedure was evaluated by the reaction of different aromatic aldehydes with different types of electron-donating and electron-withdrawing groups.As observed in Table 2 and 3, all desired product was obtained with high yields in short reaction times.After optimizing the reaction conditions, we investigated the limitation and generality of the presented procedure using different aromatic aldehydes (Table 2 and 3).  a The yields relate to the isolated product.
The Hantzsch reaction widely used for direct synthesis of 1,4-dihydropyridine (DHPs) derivatives.Based on previous studies 57,58 , we propose the following mechanism for the synthesis of 1,4-dihydropyridine derivatives.We know that the surface of our g-C 3 N 4 /Pr/THAM catalyst plays an important role for the synthesis of desired derivatives.).These compounds are formed by the reactions Michael addition, 6-exo-dig cyclization respectively.In the last step, by proton transfer and tautomerization of molecule (IV), the desired pyranopyrazole derivatives were obtained.Then g-C 3 N 4 /Pr/THAM nanocatalyst was returned to the reaction cycle to reuse.

Reusability
Reusability is one of the most important factors in any catalyst system, which highlights them as an e cient system due to time savings and economic bene ts.The reusability of this synthesized catalyst was investigated in two MCRs.Initially, the heterogeneous catalyst was separated from the reaction mixture with lter paper.Then, it was washed several times with water and ethanol and dried in an oven at 80 ° C. It was observed that the catalyst can be reused at least ve times without signi cantly reducing its activity (Figure 6).

Conclusion
In this paper, we have successfully synthesized g-C 3 N 4 / tris(hydroxymethyl)aminomethane that have -OH functions.Next, we used this catalyst in two different multicomponent reactions to investigate the catalytic properties in various reactions.As shown, the yields of the pure products either in the Hantzsch reaction or in the synthesis of pyranopyrazole derivatives were excellent and high.Also, the intended products have been puri ed by simple recrystallization.The advantages of using this catalyst in organic reactions are high yield, non-toxic, easy separation, and reusability.

Table 1 .
Optimizing the reaction conditions in the synthesis of 1,4-dihydropyridine a and pyranopyrazole b derivatives

Table 2 .
The synthesis of 1,4-dihydropyridine derivatives in optimized condition using g-C 3 N 4 /Pr/ a The yields relate to the isolated product.

Table 3 .
The synthesis of pyranopyrazole derivatives in optimized condition using the g-C 3 N 4 /Pr/ 43,57ihydropyridine derivatives are synthesized by two slightly different methods.In the rst method which presented in Scheme 3, the critical intermediate (I) formed through Knoevenagel condensation of benzaldehyde and dimedone in the presence of g-C 3 N 4 /Pr/THAM.On the other hand, the nucleophilic attack of the nitrogen of the ammonium acetate and the condensation of ethyl acetoacetate and ammonium acetate generated the intermediate (II).The next step involves Michael addition of (II) to (I), ring closing, and water elimination produced 1,4-dihydropyridine derivatives.But there is another mechanism for this reaction, In the second method, the reaction between dimedone and ammonium acetate in the presence of catalyst would obtain intermediate (III).The reaction between ethyl acetoacetate and aldehyde would obtain intermediate (IV).Eventually, by the reaction of two intermediates, the corresponding product would obtain and the g-C 3 N 4 /Pr/ THAM nanocatalyst was returned to reaction cycle.Also, the essential role of the catalyst is shown.To form the pyranopyrazole derivatives, the g-C 3 N 4 /Pr/THAM nanocomposite as a bifunctional catalyst was utilized.According to reported articles43,57,we have proposed a plausible reaction mechanism for the preparation of pyranopyrazole derivatives which is outlined in Scheme 4. First, the carbonyl groups were subjected to the nucleophilic attack of hydrazine hydrate with two nucleophilic sites.At this stage, by removing water and ethanol molecules respectively and also tautomerization intermediate (I) is formed.On the other hand, intermediate (II) was produced via Knoevenagel condensation reaction and with loss of H 2 O between catalyst-activated aromatic aldehyde and malononitrile.In the second stage, two intermediate pyrazolone ring and 2-phenylidenemalononitrile catalyzed with g-C 3 N 4 /Pr/ THAM compound and produced intermediate (III) and (IV