Abstract
A series of azo-linked pyrazolophthalazine-5,10-diones (APPDs) were synthesized via multicomponent reaction of phthalic anhydride, synthetized azo-aldehyde, malononitrile, and hydrazine hydrate using the gabapentin (GBP) functionalized silica coated Fe3O4 magnetic nano composites (MT@SP@GBP MNCs) as a catalyst. All derivatives were characterized by FT-IR, 1H NMR, 13C NMR, and mass spectrometry. MT@SP@GBP MNCs was characterized by FT-IR, FE-SEM, TEM, TGA, XRD, EDX and VSM.
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Introduction
Pyrazolophthalazines (PPs) are one of the important groups of heterocyclic compounds with a pyrazole and a phthalazine ring fused to a hydrazine. PPs play a valuable role in the pharmaceutical and agricultural industries. PPs showed different biological activities such as anti-microbial1, muscle relaxant2, anti-fungal3, anti-convulsant and anti-tumor4, anti-bacterial5 anti-inflammatory and analgesic6, anti-cancer7 and anti-oxidant8.
As a result, the synthesis of nitrogen-containing heterocycles as well as PPs has attracted the attention of researchers because of their wide range of biological activities. Different synthetic procedures have been reported for the synthesis of PPs as ZnFe2O49, Fe3O4@ SiO2-imine/phenoxy-Cu(II)10, PbO11, CuO12, [Bu3NH][HSO4]13, 1-(Cu-ferrite-siloxypropyl)-3-methyl imidazolium polytungstate ionic liquid14, 2,2,2-trifluoroethanol15, diisopropyl ethyl ammonium acetate16, γ-Fe2O3/talc/CuII NPs17, CuI@KSF18, β-cyclodextrin15, 1,1,1,3,3,3-hexafluoro-2-propanol19, hercynite20, uric Acid21, extract of mango peel ash/microwave irradiation22, Fe3O4@GOQDs-N-(β-alanine)23, bovine serum albumin in water24, and [bmim]OH25. Among the various mentioned synthetic methods, nanocatalysts have received more attention compared to other catalysts. High efficiency, high safety, reusable and optimal use of raw materials are the advantages of nanocatalysts. In addition, nanocatalysts do not dissolve in the reaction solution due to their larger dimensions and can be easily separated26.
Azo compounds are the synthetic dyes that were utilized in textile dyeing, textile, leather, tanneries, plastic, and paint industries27,28,29,. In addition, different biological properties were reported for azo heterocycles. For example, M. Alsafy and Alrazzak reported synthesis and antibacterial activities of azo phthalazine30. Malleva et al. Reported azobenzene-nitrazepam as anion-selective Cys-loop receptors31, Mezgebe and Mulugeta reported different heterocycle azo derivatives as anti-viral, anti-convulsant, anti-microbial, anti-diabetic, anti-fungal, anti-inflammatory, and chemosensing agents32.
The application of nanocatalysts in the synthesis of organic compounds has seen a not able rise in recent years, primarily attributed to their straightforward isolation process. Furthermore, their substantial surface area has enhanced their utility in this domain33,34,35,. It is crucial to note that while nanomaterials may display comparable characteristics at the macroscopic level, they possess distinct properties at the nanoscale, and the catalytic efficiency of nanoparticles can be affected by the inherent properties of the nanomaterials36,37,38,39,40,. Nanocatalysts have been documented to exhibit enhanced reaction efficiency, elevated reaction rates, diminished by-product formation, and superior reaction selectivity. Furthermore, these materials have demonstrated comparable outcomes in optimizing the conditions for multicomponent reactions41,42,43,44,45,46,47,48,49,50.
Herein, on continuing of our study on the development of nanocatalysts in azo heterocycle compounds and synthetic procedures, we reported synthesis of APPDs via multicomponent reaction of azo-aldehydes, malononitrle, phthalic anhydride and hydrazine hydrate in MT@SP@GBP MNCs as catalyst (Fig. 1).
Experimental
Materials and instruments
The solvents and chemical materials were obtained from Fluka and Merck. FT-IR spectra were obtained on a Shimadzu (8400 S) spectrometer. Bruker DRX 500 spectrometer at 250 and 62.5 MHz were used for NMR spectrum. The m/e ratio of product ions was obtained by an Agilent instrument (70 eV). FESEM were done by MIRAII, and TEM were obtained on a Zeiss-EM10C (100 KV) scanning microscope. An energy dispersive analysis of X-ray (MIRA II, 20 kV) were applied for the compositional analysis. TGA was carried out at 25–700 °C on a Mettler Toledo apparatus. The BELSORP MINI II were applied for BET analysis and determination of the catalyst’s specific surface area and pore volume. Vibrating sample magnetometer (VSM) (Kavir Kashan company, 500-0.0005 emu, 2 teslas) were used for magnetic properties. Powder X-ray diffraction (XRD) was recorded by Philips Xpert in 0–80° (2θ) and CuKα, radiation, λ = 0.154056.
Preparation of MT@SP@GBP MNCs
The synthetized Fe3O4 & Fe3O4@SP-Cl MNPs were synthesized by research group, et al.51,52. In brief, first FeCl2 (2.0 g) and FeCl3 (2.0 g) were stirred in H2O (15 mL) and triethylamine (5 mL) for 24 h. Then, the desired mixture was stirred for half an hour under ultrasonic waves at room temperature. Then CPTES (15 mL) was added to the desired mixture and it was stirred for 24 h. Finally, Fe3O4@SP-Cl was obtained. Then, Fe3O4@SP-Cl MNPs (0.2 g), gabapentin (GBP) (0.2 g), and Et3N (5 mL) were added. It was stirred for 24 h. After stirring with the magnet, separation was performed and incubated in oven at 60 °C for 24 h. The structure of MT@SP@GBP MNCs obtained was confirmed by TEM, FE-SEM, TGAو DLS, VSM, Zeta Potential and FT-IR spectroscopy (Figs. 2, 3, 4, 5, 6, 7, 8 and 9).
Synthesis of APPDs 5a-i
Azo aldehydes (1 mmol), malononitrile (1 mmol, 0.066 g), hydrazine hydrate (1 mmol, 0.050 g), phthalic anhydride (1 mmol, 0.148 g) and MT@SP@GBP MNCs (0.1 g) was mixed and stirred at 25 °C. At the end of the reaction that determined with TLC, MT@SP@GBP MNCs was separated and was washed with hot water (2 × 5.0 mL) and ethanol (2 × 5.0 mL). The solid products were separated by filtration and were recrystallized from ethanol to produce pure products. The spectroscopic data for PPD compounds 5a-i were obtained as below:
(5a): Pale Red solid; Yield: 97%; m.p: 178–180 °C: FT-IR (KBr, cm-1); 3583, 3556 (NH2 stretch), 3413 (O-H stretch), 2952 (C-H stretch), 2259 (CN stretch), 1623 (C = O amide), 1579 (C = C stretch), 1377 (C-N stretch), 1234 (C-O stretch) cm-1. 1H NMR (DMSO-d6, 250 MHz): δH: 6.90 (s, 1H), 7.29 (s, 1H), 7.46 (s, 1H), 7.58 (s, 1H, Ar), 7.70 (s, 1H, Ar), 7.76 (s, br., 3 H, Ar), 8.11 (s, br., 3 H, Ar), 11.49 (s, 1H, OH) ppm; 13C NMR (DMSO-d6, 75 MHz): δC: 63.5, 119.2, 124.6, 125.5, 127.5, 128.9, 130.7, 132.7, 133.0, 135.4, 136.7, 147.0, 148.6, 154.9, 157.4, 160.2, 168.7, 204.0, 208.3; Anal. calcd for C24H14Cl2N6O3: C, 63.16; H, 3.28; N, 17.54. Found: C, 63.15; H, 3.25; N, 17.57.
(5b): Brown solid; Yield: 89%; m.p: 180–182 °C: FT-IR (KBr, cm-1); 3404 (O-H stretch), 2958(C-H stretch), 2255 (CN stretch), 1620 (C = O amide), 1587 (C = C stretch), 1517 and 1346 (NO2 stretch), 1228 (C-N stretch), 1143 (C-O stretch) cm-1. 1H NMR (DMSO-d6, 250 MHz): δH: 2.70 (s, 3 H, CH3), 6.78 (s, 1H), 7.33 (d, J = 6.2 Hz, 1H), 7.59–7.67 (m, 4 H), 7.96 (d, J = 6.2 Hz, 1H), 8.13 (s, 2 H), 8.25 (s, 2 H) ppm; 13C NMR (DMSO-d6, 100 MHz): δC: 22.5, 62.2, 113.2, 113.3, 117.0, 118.2, 119.4, 122.5, 124.1, 124.9, 125.9, 126.7, 128.8, 131.1, 138.6, 139.3, 148.7, 149.3, 152.7, 153.5, 154.0, 163.3, 208.9, 209,8; Anal. calcd for C25H17N7O5: C, 63.16; H, 3.28; N, 17.54. Found: C, 63.14; H, 3.31; N, 17.59.
(5c): Dark orange; Yield: 93%; m.p: 185–187 °C: FT-IR (KBr, cm-1); 3406 (OH stretch), 2129 (CN stretch), 1623 (C = O amide), 1515 and 1344 (NO2 stretch), 1278 (C-O stretch), cm-1. 1H NMR (DMSO-d6, 300 MHz): δH: 6.81 (S, 1H), 7.57–7.60 (m, 4 H), 7.77–7.80 (m, 4 H), 7.88–7.91 (m, 1H), 8.08–8.14 (m, 1H), 13.26 (s, 1H, OH) ppm; 13C NMR (DMSO-d6, 100 MHz): δC: 61.6, 125.2, 125.6, 125.9, 127.6, 128.6, 129.2, 129.5, 130.4, 131.1, 131.3, 131.4, 131.7, 132.5, 133.0, 133.6, 135.8, 136.7, 153.9, 159.1, 201.2, 202.7; Anal. calcd for C24H15N7O5: C, 58.22; H, 3.02; N, 12.93. Found: C, 58.25; H, 2.99; N, 12.90.
(5d): Orange; Yield: 90%; m.p: 186–188 °C: FT-IR (KBr, cm-1); 3407 (O-H stretch), 2241 (CN stretch), 1654 (C = O amide), 1564 (C = C stretch), 1371 (C-N stretch), 1240 (C-O stretch) cm-1. 1H NMR (DMSO-d6, 400 MHz): δH: 6.77 (s, 1H), 7.15 (s, 1H), 7.39–7.60 (m, 6 H, Ar), 7.72 (s, 1H), 7.96–8.08 (m, 4 H, Ar) ppm; 13C NMR (DMSO-d6, 100 MHz): δC: 61.56, 122.5, 122.9, 124.6, 125.1, 125.5, 125.8, 126.3, 128.6, 129.2, 129.9, 130.2, 131.0, 131.3, 131.6, 132.5, 132.9, 133.9, 136.6, 152.2, 200.0, 203.1; Anal. calcd for C24H16N6O3: C, 64.87; H, 3.37; N, 14.41. Found: C, 64.90; H, 3.39; N, 14.38.
(5e): Dark red; Yield: 89%; m.p: 181–183 °C: FT-IR (KBr, cm-1); 3429 (O-H stretch), 2956 (C-H stretch), 2252 (CN stretch), 1623 (C = O amide), 1521 (C = C stretch), 1344 (C-N stretch), 1230 (C-O stretch) cm-1. 1H NMR (DMSO-d6, 400 MHz): δH; 2.17 (s, 3 H, CH3), 6.76 (s, 1H), 6.97 (s, 1H), 7.28 (s, 2 H), 7.52 (s, 1H), 7.71–8.03 (m, 4 H, Ar), 8.27 (s, br, 3 H, Ar), 13.10 (s, 1H, OH) ppm; 13C NMR (DMSO-d6, 100 MHz): δC: 14.1, 61.5, 123.7, 125.2, 125.5, 127.6, 128.6, 129.2, 129.7, 130.0, 131.0, 131.4, 131.6, 133.0, 133.9, 135.0, 136.6, 155.1, 163.8, 168.9, 174.2, 201.9, 202.8; Anal. calcd for C25H18N6O3: C, 63.92; H, 3.66; N, 16.94. Found: C, 63.90; H, 3.63; N, 16.96.
(5f): Brown; Yield: 88%; m.p: 182–184 °C: FT-IR (KBr, cm− 1); 3413 (OH stretch), 2246 (CN stretch), 1668 (C = O amide), 1618, 1573 (C = C stretch), 1481 (C-N stretch), 1089 (C-O stretch) cm− 1. 1H NMR (DMSO-d6, 400 MHz): δH: δH; 6.84 (s, 1H), 7.53 (s, br, 3 H, Ar), 7.60 (s, br, 2 H, Ar), 7.74 (s, br, 2 H, Ar), 7.85 (s, br, 2 H, Ar), 8.04 (s, br, 2 H, Ar), 10.41 (s, 1H, OH) ppm; 13C NMR (DMSO-d6, 100 MHz): δC:61.56, 122.1, 124.7, 125.1, 125.5, 127.5, 128.1, 128.6, 129.4, 129.9, 130.2, 131.1, 131.6, 132.1, 133.0, 133.5, 136.6, 137.7, 151.5, 155.1, 202.0, 203.1; Anal. calcd for C24H15IN6O3: C, 64.87; H, 3.37; N, 14.41. Found: C, 64.84; H, 3.34; N, 14.43.
(5 g): Brown; Yield: 93%; m.p: 177–179 °C: FT-IR (KBr, cm− 1); 3475 (OH stretch), 2243 (CN stretch), 1660 (C = O amide), 1625(C = C stretch), 1529, 1348 (NO2 stretch), 1303 (C-N stretch), 1076 (C-O stretch) cm− 1. 1H NMR (DMSO-d6, 400 MHz): δH: 7.02 (s, 1H), 7.56–7.06 (m, 3 H), 7.69–7.92 (m, 4 H), 8.00-8.34 (m, 4 H) ppm; 13C NMR (DMSO-d6, 100 MHz): δC: 61.9, 125.1, 125.5, 125.7, 126.1, 128.6, 129.2, 129.9, 130.1, 131.1, 131.3, 131.6, 132.6, 132.9, 133.9, 136.5, 148.2, 148.7, 151.9, 156.2, 156.6, 163.8, 200.5, 202.1; Anal. calcd for C24H15N7O5: C, 64.87; H, 3.37; N, 14.41. Found: C, 64.90; H, 3.39; N, 14.38.
(5 h): Dark red; Yield: 94%; m.p: 196–198 °C: FT-IR (KBr, cm− 1); 3467 (N-H stretch), 3440 (OH stretch), 2196 (CN stretch), 1643 (C = O amide), 1568 (C = C stretch), 1288 (C-N stretch), 1072 (C-O stretch) cm− 1. 1H NMR (DMSO-d6, 400 MHz): δH: 6.71 (s, 1H), 7.32 (s, br, 1H), 7.55 (s, br, 1H), 7.78 (s, br, 1H), 7.91 (s, br, 1H), 8.07 (s, br, 1H, Ar) ppm; 13C NMR (DMSO-d6, 100 MHz): δC: 61.5, 113.2, 113.3, 118.1, 119.5, 124.8, 125.5, 128.6, 129.2, 131.1, 131.3, 131.6, 133.0, 133.4, 136.6, 148.9, 151.1, 152.2, 163.5, 169.0, 201.7, 202.3; Anal. calcd for C24H15BrN6O3: C, 52.52; H, 2.73; N, 11.67. Found: C, 52.55; H, 2.70; N, 11.70.
(5i): Brown; Yield: 93%; m.p: 178–180 °C: FT-IR (KBr, cm− 1); 3404 (OH stretch), 3082 (C-H stretch), 2966 (C-H stretch), 2189 (CN stretch), 1662, 1569 (C = O amide), 1404 (C-N stretch), 1278 (C-O stretch) cm− 1. 1H NMR (DMSO-d6, 400 MHz): δH: 1H NMR (DMSO-d6, 300 MHz): δH; 7.00 (s, 1H), 7.34 (d, J = 1.5 Hz, 1H), 7.56–7.63 (m, 4 H), 7.73–7.77 (m, 3 H), 7.85–7.89 (m, 2 H), 7.92–7.97 (m, 1H) ppm; 13C NMR (DMSO-d6, 100 MHz): δC: 61.6, 119.9, 123.9, 124.6, 125.1, 125.6, 128.8, 129.2, 129.3, 129.4, 130.0, 131.1, 131.8, 133.0, 133.5, 148.9, 150.7, 152.2, 163.8, 201.1, 202.6; Anal. calcd for C24H15ClN6O3: C, 71.73; H, 4.38; N, 15.21. Found: C, 71.72; H, 4.41; N, 15.20.
Results and discussion
Characterization of MT@SP@GBP MNCs
In our previous research, we reported synthesis of azo-linked heterocyclic compounds via eco-friendly protocols51,52,53,54,55,56,. So, in this study, after preparation of MT@SP@GBP MNCs, different technical analyses including FT-IR, FE-SEM, TEM, TGA, XRD, EDX, VSM and BET were used for nanocatalyst characterization.
The MT@SP@GBP MNCs was prepared and fully characterized as detailed in the Supplementary Materials. In brief, the MT@SP core-shell structures were subjected to sequential treatment with 3-chloropropyltriethoxysilane (CPTES) and GBP, resulting in the production of the desired MNC (Fig. 2).
FT-IR spectroscopy of MT@SP@GBP MNCs was performed to identify the functional groups of the synthesized nanoparticles. The vibrations of O-H band from -COOH group were observed in 2980–3490 cm− 1 and the strong intense band at 3524 cm− 1 is related to the N-H stretching vibrations of nano-catalyst, The band at 1638 cm− 1 is related to the C = O stretching vibrations of imine group, The bands at 1512 and 1463 cm− 1 are related to the C = C vibrations of aromatic part, The strong intense band at 1163 and 1029 cm− 1 is related to C-O and Si-O stretching vibrations respectively and vibrations of Fe-O band were observed in 639 cm− 1 (Fig. 3).
Synthesis of novel APPD 5a-i with MT@SP@GBP MNCs.
The synthesis of MT@SP@GBP MNCs.
The FT-IR spectra of (a) MT, (b) MT@SP, and (c) synthesized MT@SP@GBP MNCs.
The size and morphology of the MT@SP@GBP MNCs was studied by TEM and FE-SEM. The following figure shows the TEM images of the sample at different scales of 47 and 72 nm. TEM and FE-SEM images of the MT@SP@GBP MNCs reveal that MNCs are formed with nearly spherical morphology having a particle size of 47–72 nm. Furthermore, TEM images show some aggregation, which was illustrated the successful grafting of the GBP (Figs. 4).
Figure 5 displays the VSM plot of the MT@SP@GBP MNCs. Based on the VSM spectrum analysis of the specimen; results indicate that an elevation in external magnetic field intensity along the x-axis translates to a concurrent increase in the magnetic susceptibility of the material. At approximately 5300 Tesla, the magnetic property becomes saturated and attains a value of 39.83 as the Hysteresis saturated (Hs) value (Fig. 5).
Figure 6 displays TGA spectrum of MT@SP@GBP MNCs. Based on Fig. 6, in temperatures between 25 and 100 °C, MT@SP@GBP MNCs lost 11% of their weight after removing moisture absorbed on the surface. Then, the sample lost 32% of weight from organic carbon compounds (GBP) at 290–350 °C and in the temperature range of 430–450 °C, the weight loss (10%) is due to the melting of parts of the sample due to the breaking of oxygen-metal bonds. So, the sample has about 53% weight loss until its pure form at 450 °C. Therefore, the stability of the catalyst is 280 °C (Fig. 6).
(A) The TEM image and (B) FE-SEM images of MT@SP@GBP MNCs.
The VSM image of synthesized MT@SP@GBP MNCs.
The TGA image of synthesized MT@SP@GBP MNCs.
To check the structure of MT@SP@GBP MNCs more closely, DLS analysis and Zeta Potential were also performed. According to the data of DLS analysis, the nano particle size is 34.63 nm and according to Zeta Potential analysis, the surface tension of the composition is equal to 34.6 mV (Fig. 7).
The present study employs XRD analysis to examine the MT@SP@GBP MNCs in comparison to pure Fe3O4. The presented pattern showed that the Fe3O4 iron oxide phase attains the foremost ranking amidst other phases, thereby denoting its singular phase composition (Fig. 8).
The energy-dispersive X-ray spectrum (EDS) dedicated the C (13.16 w/w %), O (33.78 w/w %), N (3.89 w/w %), Si (6.33 w/w %) and Fe (42.83 w/w %) atoms in the structure of MT@SP@GBP MNCs (Fig. 9).
The DLS and Zeta potential of synthesized MT@SP@GBP MNCs.
The XRD of synthesized MT@SP@GBP MNCs.
The EDX of synthesized MT@SP@GBP MNCs.
In the continuing on our previous research and studying the efficiency of the MT@SP@GBP MNCs, the preparation of azo-linked PPDs via the one-pot reaction of hydrazine hydrate, phthalic anhydride, azo aldehydes and malononitrile by MT@SP@GBP MNCs were studied. At first, the reaction parameters were optimized and we used the reaction of 2-hydroxy-5-((2,4-dichlorophenyl)diazenyl)benzaldehyde 1a, malononitrile 2, phthalic anhydride 3 and hydrazine hydrate 4 as a model reaction.
Catalytic studies
To synthesize derivatives of PPDs via the reaction of 1a (1 mmol), malononitrile 2 (1 mmol), phthalic anhydride 3 (1 mmol) and hydrazine hydrate 4 (1 mmol) and 0.1 g of various catalysts were studied at a temperature of 60 °C (Table 1).
Influence of temperatures on reaction time
The synthesis of PPD 5a involved the reaction of 1a (1 mmol), malononitrile 2 (1 mmol), phthalic anhydride 3 (1 mmol) and hydrazine hydrate 4 (1 mmol) with MT@SP@GBP (0.1 g). This study was investigated via changing the temperatures and the results can be ascribed that the best temperature in this synthesis, is room temperature (Table 2).
Effect of MNCs catalyst value
The results of the investigation of the quantities of nanocatalyst were shown in Table 3. The findings confirmed that 0.1 g of the nanocatalyst per 1 mmol of azo-aldehyde resulted in higher yield and shorter reaction time (Table 3).
The recyclability and reusability of catalyst was studied in the model one-pot reaction among 1a (1 mmol), malononitrile 2 (1 mmol), phthalic anhydride 3 (1 mmol) and hydrazine hydrate 4 (1 mmol), and 0.1 g of MT@SP@GBP. The separated catalyst is reusable after the reaction by washing with warm EtOH and drying at 80 °C. MT@SP@GBP was used again for subsequent experiments under similar reaction conditions. The catalyst is reusable for the next cycle without noticeable loss of its activity. After six cycles of reusing the catalyst, yields of the product decreased only slightly. Experience has shown that reusing the catalyst for the seventh time greatly reduced the efficiency of the reaction (Table 4).
To evaluate the efficacy of the reported procedure, different azo-linked aldehydes, malononitrile, phthalic anhydride, hydrazine hydrate and MT@SP@GBP MNCs were applied to reaction in H2O at 25 °C (Fig. 1; Table 5).
Conclusions
In summary, we have reported a new protocol for the synthesis of novel azo-linked PPDs by reaction of azo-linked aldehydes, malononitrile phthalic anhydride, hydrazine hydrate with MT@SP@GBP MNCs. The reaction proceeds the in room-temperature to produce the PPDS in good yields (88–97%). Room temperature reaction conditions, easy separation, and recyclable MT@SP@GBP nanocatalyst are the notable aspects of this study.
Data availability
All data generated or analysed during this study are included in this published article [and its supplementary information files].
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Financial support from the Research Council of Rasht Branch, Islamic Azad University, Rasht, Iran is sincerely acknowledged.
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Alizadeh, Z., Nikpassand, M., Mokhtary, M. et al. Preparation, characterization and application of MT@SP@GBP and their use for synthesis of novel pyrazolophthalazine-5,10-diones. Sci Rep 15, 35351 (2025). https://doi.org/10.1038/s41598-025-19325-8
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DOI: https://doi.org/10.1038/s41598-025-19325-8
