Molybdenum trioxide as a newer diversified economic catalyst for the transformation of nitroarenes to arylamine and 5-substituted-1H-tetrazole

The present work has developed a straightforward, gentle, and effective approach for synthesizing arylamines and 5-substituted-1H-tetrazole derivatives, and among the two tested catalysts, molybdenum trioxide (MoO3) proved to be highly effective. The selective hydrogenation of nitroarenes to arylamines presents a significant challenge due to the complex reaction mechanism and the competitive hydrogenation of other reducible functional groups. It facilitated the transfer hydrogenation of nitrobenzene using hydrazine hydrate-produced amino compounds and enabled the [3 + 2] cycloaddition of sodium azide with aromatic nitriles to yield 5-substituted-1H-tetrazoles. The structure of compound 5-(4-bromophenyl)-1H-tetrazole (5k) was verified through single-crystal X-ray analysis, and the calculation of Green Chemistry Metrics showed the optimal range. Notably, the MoO3 catalyst can be reutilized for up to seven cycles with minimal loss of effectiveness. These attributes make molybdenum trioxide particularly attractive for industrial applications. This methodology offers several advantages over traditional synthetic methods.


Introduction
Catalysis is integral to numerous chemical processes, serving as the foundation for countless synthetic transformations in research and industrial contexts.Numerous catalytic reagents can signicantly enhance the reaction yield and selectivity while allowing for more easily controlled reaction conditions. 1 Signicant advancements have been made in heterogeneous and homogeneous catalysis over the twentieth century.Heterogeneous catalysis offers the advantage of easy catalyst separation at the end of the reaction, while homogeneous catalysis is known for achieving higher catalytic activity. 2ransition metal oxides have been extensively explored for their applications in various environmental, industrial, and technological elds.Transition metal catalysts were rst demonstrated by Busch in 1929, who used Pd/CaCO 3 , 3 and later Pietra, 4 who used Pd/C for the hydrazine-facilitated transfer hydrogenation (TH) of nitro-aromatics.Catalytic transfer hydrogenation (CTH) presents an appealing alternative for converting nitroarenes to anilines.It involves the addition of hydrogen from a hydrogen donor compound such as hydrazine, 5 formic acid, 6 isopropanol, 7 or sodium borohydride (NaBH 4 ), 8 to an organic molecule, and has recently become a signicant research focus. 9 recent study has investigated molybdenum oxide-based catalysts for this reaction. 10,11Studies have suggested that reactive hydrogen species, in the forms of H d− and H d+ , are active in reducing nitrobenzene when using MoO x catalysts. 10hese hydrogen species are believed to form through hydrazine (N 2 H 4 ) activation, particularly at low oxidation state molybdenum sites, such as Mo 4+ and Mo 3+ , which serve as adsorption sites. 10,11olybdenum oxides (MoO x ) have demonstrated potential as catalysts due to their various oxidation states, including Mo 4+ , Mo 5+ , and Mo 6+ .They have been utilized in numerous applications such as CO 2 hydrogenation, water splitting, [12][13][14] and the reduction of nitrobenzene to aniline.The most effective active sites for the hydrogenation of nitrobenzene are reported to be the acidic sites associated with the low oxidation states of molybdenum, such as Mo 5+ , Mo 4+ , and Mo 3+ .This aligns with observations that molybdenum trioxide (MoO 3 ) has signicantly inferior performance to MoO x 10,15 due to the presence of Mo 6+ .Molybdenum trioxide (MoO 3 ) can exist in various phases, including a-(orthorhombic), b-(monoclinic), and h-(hexagonal) forms while MoO 3 primarily consists of less active Mo 6+ species; these can be reduced to lower oxidation states, altering the catalyst's structure.The in situ reduction of Mo 6+ during catalytic reactions has been reported, namely,

RSC Advances
PAPER dehydroaromatization in methane using Mo-loaded HZSM-5 16,17 and MoO 3 /HMCM-49. 18The reduction of Mo 6+ by CH 4 leads to the formation of Mo 2 C, which is proposed to be the active phase for this reaction. 19This process can be observed in the reaction proles as an induction period. 17Recent studies have demonstrated that Mo 6+ can be reduced to Mo 5+ or Mo 4+ in the presence of hydrazine. 20The formation of Mo 4+ is signicant as it is proposed to be the active site for decomposing N 2 H 4 into reactive hydrogen species. 10This reduction has been observed during the hydrogenation of nitrobenzene to aniline over [FeMo]S x using N 2 H 4 , forming Mo 4+ . 15ccording to literature reports, aromatic amines serve as essential components in synthesizing pharmaceuticals, dyes, pigments, polymers, and agrochemicals. 21,22It is also observed that nearly one-fourth of all pharmaceutical amine-containing drugs, such as procaine and phentermine, are widely used (Fig. 1). 23,24hese drugs are clinically used for the treatment of local anesthetics and treat conditions like attention decit hyperactivity disorder (ADHD) and narcolepsy, and the reduction of pchloronitrobenzene and 8-nitroquinoline into p-chloroaniline and 8-aminoquinoline, respectively.These compounds serve as essential intermediates in the synthesis of paludrine and primaquine, which are important antimalarial drugs (Fig. 1). 25everal methods suffer from drawbacks in synthesizing anilines from nitrobenzene, including harsh reaction conditions, low yields, high temperatures, long reaction times, and costly reagents.Additionally, the catalysts used can be toxic, less accessible, thermally unstable, and exhibit poor functional group tolerance, oen leading to side product formation.The preparation and use of these reagents also demand strict conditions.Therefore, signicant room remains for improving and developing new, simple, and efficient reagents to address and mitigate these issues. 26,27Following research into metal oxide catalysts, we found that molybdenum trioxide (MoO 3 ) is exceptionally effective at stabilizing hydride and proton when using hydrazine as a hydrogen source.
Tetrazoles are heterocyclic compounds comprising a vemembered ring of one carbon atom and four nitrogen atoms.These compounds can exist in two tautomeric forms: 1H-tetrazole and 2H-tetrazoles.In solution, the 1H-tetrazole form is   more stable and commonly found, while the 2H-tetrazole form is more stable in the gas phase. 28][30][31][32][33] Medications incorporating tetrazole compounds are employed in diverse therapeutic areas, encompassing antibacterial, 34 antifungal, 35 anticancer, 36 antitubercular, 37 peptides inhibitor, 38 and antimalarial treatments. 39The tetrazole moiety is a constituent in several widely utilized drugs, such as losartan, valsartan, cefazolin, irbesartan, and azosemide (Fig. 2). 40ue to their excellent adaptability and broad utility, there has been signicant interest in exploring the catalytic synthesis of tetrazole derivatives.Due to their widespread applications, 5substituted tetrazoles have been a focal point in fundamental research. 41,42Previous research on various catalytic systems has enabled scientists to develop methods containing transition metals with precisely dened sizes, which are known as outstanding catalysts.
Keeping the above facts and applications in mind, we made efforts to explore the catalytic use or property of MoO 3 in the synthesis of diversied compounds hydrazine-mediated transfer hydrogenation of nitroarenes to arylamines and synthesis of 5-substituted-1H-tetrazoles.The synthesized arylamines and 5substituted-1H-tetrazoles were characterized by NMR, IR, and HRMS, and a single-crystal XRD study was done for compound 5-(4-bromophenyl)-1H-tetrazole (5k).

Materials and methods
All the reagents and solvents were acquired from E. Merck (India), Avra, CDH, and Sigma-Aldrich and were used directly without additional processing.The reactions were monitored using thin-layer chromatography (TLC) on a pre-coated silica gel 60 F254 mesh.The results were observed using UV light or an iodine chamber.Merck silica gel (230-400 mesh) was employed for column chromatography.The compounds melting points were ascertained using the open capillary method, the results of which were uncorrected.The NMR spectra were collected on a Bruker Ascend 600 MHz spectrophotometer operating at 600 MHz for 1 H and 151 MHz for 13 C experiments.The chemical shis are reported on a ppm scale concerning CDCl 3 (7.269ppm) for 1 H and (77.00 ppm) for 13 C NMR and DMSO-d 6 (2.5 ppm), 1 H (3.5 ppm) for moisture, and (40.39 ppm) for 13 C NMR as an internal standard.The abbreviations are s = singlet, d = doublet, t = triplet, q = quartet, dd = double doublet, and m = multiplet.The chemical shis were gauged in parts per million (ppm) on the delta (d) scale with tetramethylsilane (TMS) acting as the internal reference.The mass spectra were recorded on a Sciex X500R QTOF mass spectrometer.FT-IR spectra were recorded in KBr pellets in the 4000-400 cm −1 range at room temperature using a PerkinElmer400 FT-IR spectrometer.The single crystal X-ray analysis further veried the synthesized tetrazole compound 5k.Crystals were formed via the slow evaporation of the solution with methanol in the solution technique.The graphite monochromatized Cu-Ka radiation (l = 1.54184Å) was used to measure the X-ray diffraction intensity data at 293 K using the X-ray scan method on a Rigaku XtaLAB Synergy-i Single Crystal X-ray Diffractometer with a CCD detector (HyPix-Bantam).

General procedure for the synthesis of amine derivatives
The synthesis of amine derivatives was carried out using the literature procedure. 43Nitroarene (1 mmol) and N 2 H 4 $H 2 O (4 equiv.)were dissolved in 3 mL of DMSO in an oven-dried 25 mL round bottom ask.MoO 3 (22.75mg, 25 mol%) was added to the reaction mixture and stirred at 120 °C for 15 min.Aer the completion of the reaction, as monitored by TLC (mobile phase, ethyl acetate : hexane = 50 : 50), the solution was cooled to room temperature, and the catalyst was removed by centrifugation.The reaction mixture was extracted with ethyl acetate (5 mL × 3).The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.The nal product was puried by silica gel column chromatography using ethyl acetate : hexane (25 : 75) as the eluent, and amine derivatives were obtained with a yield of 85-90%.

General procedure for the synthesis of 5-substituted-1Htetrazole derivatives
A methodology from the literature was used to synthesize 5substituted-1H-tetrazole derivatives. 44Benzonitrile (1 mmol)    dehydrated with anhydrous sodium sulfate and evaporated in vacuo.The solid mass of 5-phenyl-1H-tetrazole derivatives was obtained with a yield of 85-91%.
3 Results and discussion

Optimization for the transfer hydrogenation of nitrobenzene
The catalytic efficiency of the catalyst (MoO 3 and MoO 2 ) was assessed in the transfer hydrogenation (TH) of nitroarenes employing N 2 H 4 $H 2 O.At rst, the reaction was done using nitrobenzene as a benchmark substrate in the absence of the catalyst and N 2 H 4 $H 2 O (6 equiv.) in methanol at 50 °C for 24 h.The reaction did not proceed (entries 1 and 2, Table 1), as monitored by TLC.Under the next optimized reaction conditions, the catalyst (MoO 3 and MoO 2 ) (5 mol%) and N 2 H 4 $H 2 O (6 equiv.)were added in methanol at 50 °C for 24 h and the yield was 11% and 10%, respectively (entries 3 and 4, Table 1).On increasing the amount of the catalyst (MoO 3 , 10 mol%) and using N 2 H 4 $H 2 O (6 equiv.) in ethanol at 60 °C, a yield of 20% was obtained in 24 h (entry 5, Table 1).Under another optimized reaction condition, the amount of hydrazine hydrate was (4 equiv.)and DMSO was used as a solvent at 120 °C.The obtained yield was 45% in 4 h (entry 6, Table 1).Further, MoO 2 (10 mol%) was used as a catalyst with hydrazine hydrate (4 equiv.)and DMSO solvent at 120 °C to get a yield of 35% in 6 h (entry 7, Table 1).On enhancing the amount of catalyst (MoO 3 , 15 mol%) and hydrazine hydrate used (6 equiv.) in DMF at 120 °C, 50% yield was obtained in 8 h (entry 8, Table 1).On further increasing the catalyst amount of both MoO 3 and MoO 2 using 20 mol%, and hydrazine hydrate (4 and 6 equiv.) in DMSO at 120 °C, the yield obtained was 60% and 42% in 5 h, respectively (entries 9 and 10, Table 1).In DMF solvent, MoO 3 was used at 25 mol% with 4 equiv. of hydrazine hydrate at 120 °C, and a yield of 80% was obtained in 2 h (entry 11, Table 1).With the same reaction, conditions were applied in DMSO to get a maximum yield of 90% in 15 min (entry 12, Table 1).Moreover, water was used as a solvent with an appropriate reaction condition at 80 °C but no changes were obtained (entry 13, Table 1).MoO 2 was used as 25 mol% in DMSO solvent at 120 °C to get a yield of 48% in 4 h (entry 14, Table 1).Thus, the maximum yield (90%) was observed in DMSO (3 mL) at 120 °C for 15 min (entry 12, Table 1).The scope for the TH of various nitroarenes was investigated (Table 2).Utilizing the optimized conditions, several para-and meta-substituted nitroarenes presented a good-to-excellent yield of nitroamines (85-90%).In the formation of compounds 2d, 2e, and 2h, the selective reduction of the nitro group occurred due to its stronger negative inductive effect compared to that of the CHO/COOH group present in the same substrate moiety.
Analogues of 2,4-dinitrophenol and picric acid exhibited pseudo-rst-order kinetics, as illustrated in Fig. 3(a-d).Upon comparison, it was observed that the rate constant for 2,4-dinitrophenol was higher than that of 2,4,6-trinitrophenol.This variation in the rate constants is attributed to the structural differences between the compounds, with steric hindrance playing a signicant role in the di-and tri-substituted derivatives.
In Fig. 4, the plausible mechanism representing the role of MoO 3 for synthesizing amine derivatives is shown using nitrobenzene as the representative substrate.The catalytic reduction of nitroarenes to anilines occurs by the reaction of MoO 3 with hydrazine hydrate.It forms a complex in situ that reacts with nitroarene to produce the nitroso derivative and diimide intermediate of MoO 3 .Both the above reacted and formed the hydroxylamine species and nitrogen complex of MoO 3 and then underwent reduction with hydrazine hydrate to form the nal product, i.e., amine derivative.

Optimization of the reaction conditions for the synthesis of 5-phenyl-1H-tetrazole
Our goal is to develop an improved catalytic system by evaluating molybdenum dioxide (MoO 2 ) and molybdenum trioxide (MoO 3 ) for their effectiveness in catalyzing the [3 + 2] cycloaddition between benzonitrile and sodium azide to synthesize 5phenyl-1H-tetrazole in dimethylsulfoxide (DMSO).We optimized the catalyst amount, solvent, and temperature to achieve a high yield of 5-phenyl-1H-tetrazole in a shorter reaction time.The outcomes of these experiments are summarized in Table 3.
In an initial attempt, the reaction was carried out without any catalyst using DMF and DMSO as solvents.However, no progress was observed aer 24 h at 140 °C and 120 °C, respectively (entries 1 and 2, Table 3).Thin-layer chromatography (TLC) was used to monitor the progress of the reaction.The effectiveness of MoO 2 and MoO 3 (2.5 mol%) as catalysts was tested in various solvents (DMSO and DMF) at 140 °C.This resulted in a meagre yield (25-30%) of the desired product aer 15 and 12 h, respectively (entries 3 and 4, Table 3).Further, the amount of the catalyst was increased (MoO 3 and MoO 2 ) and was taken at 5 mol% in DMSO solvent at 140 °C to get the product; the yield was (40-45%) aer 10 and 7 h of the reaction, respectively (entries 5 and 6, Table 3).Again, the reaction was attempted with an increased amount of catalyst (MoO 3 , 10 mol%) in various solvents (ethanol, acetonitrile, water, DMF, and DMSO) at different temperatures (78 °C, 80 °C, 90 °C, and 140 °C, respectively) (entries 7-11, Table 3).Among these conditions, the highest yield of 5-phenyl-1H-tetrazole (65%) was obtained when DMSO was used as the solvent at 140 °C for 5 h (entry 11, Table 3).Further, in the optimization process, MoO 2 (10 mol%) was used as a catalyst in DMSO solvent and a yield of 57% was obtained in 7 h at 140 °C (entry 12, Table 3).In the next step, a larger amount of the catalyst was added to the reaction (MoO 3 , 15 mol%) in DMF and DMSO solvent system at 140 °C, and the desired yield of the product obtained was 72% in 3 h and 91% in 1.5 h (entries 13 and 14, Table 3).Further, MoO 2 (15 mol%) was used in DMF and DMSO solvents and yields of 42% and 45% in 5 h at 140 °C (entries 15-16, Table 3).Thus, the optimized reaction condition was determined to be MoO 3 (15 mol%) as a catalyst in DMSO (3 mL) at 140 °C.Under this condition, the product 5-phenyl-1H-tetrazole was isolated with 91% yield aer 1.5 h of reaction.Aer establishing the optimal reaction conditions, we extended the substrate scope for synthesizing MoO 3 -catalyzed 5substituted-1H-tetrazole derivatives to include aromatic and heteroaromatic nitriles.The results, summarized in Table 4, show good to excellent yields (85-91%) of 5-substituted-1H-tetrazoles.Aromatic nitriles with electron-withdrawing groups yielded higher amounts of the corresponding 5-substituted-1Htetrazoles than those with electron-donating groups.Additionally, heteroaromatic nitriles produced the corresponding 5substituted-1H-tetrazoles with excellent yields (entry 5n, Table 4).
Fig. 5 illustrates a plausible mechanism for the role of MoO 3 in synthesizing 5-substituted-1H-tetrazoles using benzonitrile as a representative substrate.Initially, the nitrogen atom of the azide compound coordinates with MoO 3 to form an intermediate.This intermediate facilitates the [3 + 2] cycloaddition between the azide ion and the nitrile compound's (-C^N) The synthesis approach for 5-substituted-1H-tetrazoles was further validated using single-crystal X-ray analysis of compound 5k.X-ray quality crystals were grown in methanol using the slow evaporation method.Fig. 6 shows the ORTEP diagram of compound 5k, with additional single-crystal X-ray crystallographic details provided in Table 5.

Green chemistry parameters
A thorough evaluation of green chemistry metrics was done to assess the synthesis of 5-phenyl-1H-tetrazole (5g).Table S1 † presents the comprehensive calculations.Fig. 7 illustrates the outcomes in a radar plot, highlighting key variables pivotal in analyzing the cost-effectiveness of green organic synthesis, ideally under optimal conditions.The radar chart visually elucidates the synergistic correlation among parameters such as reaction mass efficiency, carbon efficiency, atom economy, and the E-factor, signifying the environment-friendly nature of this approach.

Reusability of the catalyst
The capability of a heterogeneous catalyst that demonstrates convenient recoverability and efficient reusability is crucial for its practical application in industry.In this present investigation, the recoverability and reusability of MoO 3 were scrutinized for the synthesis of amine and 5-phenyl-1H-tetrazole derivatives under the optimized reaction conditions.Following the completion of each cycle, MoO 3 could be effortlessly retrieved via centrifugation, washed with ethyl alcohol, and subsequently dried at 60 °C in an oven for 1 h, ready for reuse in the subsequent cycle.Remarkably, MoO 3 retained its catalytic activity over seven consecutive cycles without any signicant decline.The yields (%) obtained for the seven catalytic cycles for both reactions are depicted in Fig. 8(a and b).Furthermore, the purity of the products was conrmed by analyzing the 1 H NMR spectra of 4-chloroaniline (2f) and 5-phenyl-1H-tetrazole (5g) synthesized using the recovered catalyst aer the seventh cycle.

Previously reported catalyst for the transformation of nitroarenes to arylamine
Based on existing literature, various methodologies have been employed for the transformation of nitroarenes to arylamines (Table 6).

Previously reported catalyst for the synthesis of 5substituted-1H-tetrazole
Based on existing literature, various synthetic methodologies have been employed for the synthesis of 5-substituted-1H-tetrazoles (Table 7).

Conclusion
In this study, molybdenum dioxide (MoO 2 ) and molybdenum trioxide (MoO 3 ) were utilized as catalysts for two reactions: the Paper RSC Advances transfer hydrogenation of nitrobenzene to arylamine derivatives in DMSO at 120 °C for 15 min and the [3 + 2] cycloaddition between benzonitrile and sodium azide in dimethyl sulfoxide (DMSO) at 140 °C for 1.5 h.MoO 3 emerged as the superior catalyst, delivering higher yields and shorter reaction times for the synthesis of the target compounds.The green chemistry metrics for these reactions revealed an E-factor of 0.36 (the ideal value is 0).The identity and purity of the synthesized compounds were veried using various analytical techniques, including 1 H and 13 C NMR, HRMS, FT-IR, and single-crystal XRD.The key advantages of this methodology include reduced reaction times, a wide range of applicable substrates, milder reaction conditions, and the use of cost-effective catalysts, making it highly appealing for industrial applications.

Fig. 1
Fig. 1 Structures of the marketed drugs contain an amine functional group.

Fig. 2
Fig. 2 Structure of marketed drugs containing the tetrazole moiety.

Fig. 3
Fig.3(a) UV-vis spectra for the hydrogenation of 2,4-dinitrophenol and (b) relationship between ln(a t /a 0 ) and reaction time (min).(c) UV-vis spectra of the hydrogenation of picric acid and (d) relationship between ln(a t /a 0 ) and reaction time (min).

Fig. 4
Fig. 4 Plausible mechanism for the synthesis of amine derivatives using MoO 3 .
Paper RSC Advances and sodium azide (1.5 mmol) were dissolved in 3 mL DMSO in a 25 mL round bottom ask.MoO 3 (20.92mg, 15 mol%) was added to the reaction mixture and stirred at 140 °C for 1.5 h.Aer the completion of the reaction (as monitored by TLC, mobile phase = ethyl acetate : hexane = 50 : 50), the solution was cooled to room temperature.The catalyst was removed by centrifugation.Note that 5 mL of ice water was added, followed by the dropwise addition of 3 N HCl until the reaction mixture became strongly acidic (pH 2).The reaction mixture was extracted with ethyl acetate (6 mL × 3).The organic layer was Table 4 Substrate scope for the MoO 3 -catalyzed synthesis of 5-substituted-1H-tetrazoles a,c a Reaction condition: nitrile (1 mmol), NaN 3 (1.5 mmol), DMSO (3 mL) and MoO 3 (15 mol%) at 140 °C, 1.5 h.b Isolated yields.c Products were characterized using 1 H and 13 C NMR, IR spectroscopy and HRMS.

Fig. 7
Fig.7Illustrates the outcomes in a radar plot.

Table 1
Optimization for the transfer hydrogenation of nitrobenzene a b Isolated yields.

Table 5
Crystal data, data collection, and structure refinement details for compound 5k

Table 6
Previously reported catalysts for the transformation of nitroarenes to arylamine a a PW = present work.