Shabnam Rashidi and
Mohammad Soleiman-Beigi
*
Department of Chemistry, Basic of Sciences Faculty, Ilam University, 69315-516 Ilam, Iran. E-mail: m.soleimanbeigi@ilam.ac.ir; SoleimanBeigi@yahoo.com
First published on 16th July 2025
In this study, we successfully utilized natural asphalt as a natural carbon substrate for the synthesis of a novel heterogeneous Brønsted acid nanocatalyst, Re-NA–CH2CO2H. The –COOH functional groups present on the surface of Reduced Natural Asphalt Oxide (Re-NA-oxide) serve as catalytic sites for Brønsted acid. This arrangement, in addition to increasing acidity, also expands the surface area accessible for catalytic activity, positioning Re-NA-oxide as a viable option for a range of acid-catalyzed reactions. The synthesized catalyst was characterized using various methods, including FT-IR, TGA, SEM, EDX and TEM. This catalyst was employed in the synthesis of pyrano[2,3-c]pyrazole and 2-amino-3-cyanopyridine derivatives through four-component reactions involving ethyl acetoacetate, hydrazine hydrate, malononitrile, and various aldehydes, as well as ammonium acetate, malononitrile, aldehydes, and ketones, respectively. The final step of the reaction mechanism involved vinylogous anomeric-based oxidation. The high acidity of the Re-NA–CH2CO2H catalyst enhanced nucleophilic attacks on electrophiles, contributing to the efficiency of the reactions. It is noteworthy that this study uses a naturally derived catalytic support, emphasizing its sustainability. This research potentially enables the coupling of nucleophiles to natural asphalt for the development of new functional materials from this renewable resource. The reaction conversion rate is significantly influenced by the electron-donating and electron-accepting groups in the reactions of pyrano[2,3-c]pyrazole (90–97% yield in 20–50 min) and 2-amino-3-cyanopyridine (90–97% yield in 30–50 min). Furthermore, due to the use of water as the solvent, it is easy to separate and reuse, operational simplicity, and environmentally friendly. The catalyst exhibits exceptional recyclability and retains its activity for at least five cycles, outperforming currently available catalysts in terms of yield, reaction conditions, and overall efficiency.
The demand for stable, cost-effective, and eco-friendly catalysts has led researchers to explore alternatives to traditional mineral acids, which are often corrosive and challenging to regenerate. Heterogeneous Brønsted acid catalysts, characterized by their low corrosiveness, higher selectivity, and ease of separation from reaction systems, represent an attractive solution.7 Among various types of solid acids, heteropoly acids, metal oxides, sulfonated metal oxides, phosphates, and highly acidic resins exhibit promising catalytic activity and reusability in acid-catalyzed reactions. However, their limited specific surface area restricts substrate accessibility to active sites and increases diffusion barriers.8
Carbon-based materials act as catalysts or supports in chemical reactions like oxidation, hydrogenation, reduction and condensation, thanks to their excellent properties such as large surface areas, high porosity, excellent electron conductivity, and relative chemical inertness. They can be modified with metallic nanoparticles to improve catalytic abilities. These materials are promising for green, solvent-free catalysis, aiming for efficient synthesis and energy use. Future advancements depend on developing eco-friendly multifunctional catalysts from nanostructured carbon.9
Research is continually advancing the optimization of the properties of carbon-based materials for various catalytic uses. Several Brønsted acid catalysts exist, including p-toluene sulfonic acid (p-TsOH),10 silica-sulfuric acid (SSA),11 PPF–SO3H,12 sulfonated MCM-41 (MCM–SO3H),13 a magnetic solid acid catalyst derived from chitosan (CS–Fe3O4@SO3H),14 organosilane sulfonated graphene oxide (SSi–GO)15 and cellulose sulfuric acid (CSA),16 which offer benefits such as reusability, recyclability, high yield, quick reaction times, and straightforward separation. Nevertheless, they face challenges such as costly starting materials and reagents, intricate synthesis processes, low catalytic activity, and the use of toxic solvents for product separation.13–15
Traditional liquid–acid catalysts, such as sulfuric acid (H2SO4), hydrochloric acid (HCl), hydrobromic acid (HBr), and trifluoroacetic acid (CF3COOH), often deliver high effectiveness in a range of chemical reactions, especially in various processes. However, they bring about environmental and economic issues related to the generation of waste and separation procedures. The challenges associated with separation and recovery often result in substantial quantities of non-recyclable acid waste, which not only increases disposal expenses but also poses environmental risks. To address these problems, various approaches can be utilized, such as employing solid acid catalysts, exploring alternative reaction conditions, utilizing immobilization techniques, and implementing continuous flow systems. Solid acid catalysts are becoming increasingly favored due to their non-toxic characteristics, ability to be reused, cost-effectiveness, capability of operating under gentler conditions, environmental benefits, ease of handling, stability, and versatility across a variety of chemical reactions. They enhance reactions by creating a pathway that requires lower activation energy, thus accelerating reaction rates.17
Acids play a key role in many chemical processes in biology and industry. Recently, chiral Brønsted acids have quickly advanced for creating C–C and C–X bonds. Weakly acidic compounds like (thio)ureas, squaramides, and others that activate substrates through hydrogen bonding have become popular organocatalysts. Some of these have been used in anion binding catalysis and other new applications. Since phosphoric acids were introduced as asymmetric catalysts in 2004, Brønsted acid catalysis has gained attention for asymmetric synthesis.18,19 Carboxylic acids are common in organic chemistry and found in natural compounds. However, their use for substrate activation is less developed due to their weaker acidity, which limits the types of substrates that can be activated. However, selecting an acid catalyst with suitable acidity can be crucial for the effective activation of specific types of substrates.19,20
Heterogeneous Brønsted carboxylic acid catalysts, including simple, aromatic, long-chain, mixed carboxylic acids, and those with mineral structures, play a crucial role in diverse chemical transformations, ranging from the synthesis of pharmaceuticals and biological compounds to industrial chemicals. Their significance in green chemistry lies in their ability to optimize chemical processes, reduce energy consumption, minimize waste production, and enhance product quality.7,19,21
Multicomponent reactions (MCRs) have become increasingly important in modern synthetic chemistry due to their atom-efficient properties and ability to effectively construct complex molecular structures. MCRs offer an effective and environmentally friendly method for synthesis. Using sustainable solvents with MCRs helps reduce waste and improve safety. MCRs combine materials in one step to create final products, known for their efficiency, convergence, and high atom economy. By combining three or more reactants in a single step, MCRs provide a powerful tool for combinatorial synthesis, significantly increasing molecular diversity and complexity. The most important subclasses of heterocyclic chemistry are oxygen and nitrogen containing rings that are found in the skeletal structures of a variety of biologically active and pharmaceutical compounds.8,22–24 Among the oxygen and nitrogen containing heterocycles, pyrano[2,3-c]pyrazoles and 2-amino-3-cyanopyridines have anticancer, anticoagulant, anticonvulsant, antimicrobial, anti-HIV, antimalarial, antitumor, antibacterial, antifungal, and antitumor properties. Also 2-amino-3-cyanopyridines exhibit potent activities as IKK-β inhibitors and adenosine A2A receptor antagonists (Fig. 1).25
Natural asphalt, also known as uintaite or asphaltum, is a resinous hydrocarbon created over millions of years through geological processes. It mainly contains hydrocarbons, asphaltenes, resins, and minerals, and is highly soluble in organic solvents like trichloroethylene, carbon disulfide, and toluene. Natural asphalt consists of 70–80% carbon and about 15% hydrogen, with small amounts of oxygen, sulfur, and nitrogen. Key sources are in the U. S., Canada, and Iran. Its non-toxic nature allows for uses in producing coke, asphalt, dyes, drilling mud, and foundry industries, with research exploring its properties in organic reactions. Its benefits include availability, affordability, stability, and high carbon content, making it effective as a carbon support for catalysts. Often used in powder form due to its brittleness, natural asphalt is a candidate for creating sustainable materials, including heterogeneous catalysts.26–28
Continuing previous research, the aim of this study is to synthesize a new heterogeneous Brønsted acid catalyst derived from natural asphalt oxide and investigate its catalytic activity in the synthesis of multicomponent reactions pyrano[2,3-c]pyrazoles and 2-amino-3-cyanopyridines (Schemes 2 and 3) in line with the principles of green chemistry in aqueous solvent and mild conditions.
In this study, we present a significant innovation in the synthesis of a novel heterogeneous Brønsted acid nanocatalyst, Re-NA–CH2CO2H, using natural asphalt as a stable carbon support. The presence of –COOH functional groups on the surface of reduced natural asphalt oxide (Re-NA-oxide) increases the acidity and increases the surface area available for catalytic activities, making it an effective option for a variety of acid-catalyzed reactions. The high acidity of the catalyst facilitates nucleophilic attacks on electrophiles, thereby improving the overall efficiency of the reactions. Key advantages of this catalyst include high catalytic activity, operational simplicity, and environmental friendliness due to the use of water as a solvent.
Oxidized natural asphalt (NA-oxide) was synthesised utilizing the Hummers' method, as outlined in earlier research27 (Scheme 1). The resulting asphalt oxide underwent Soxhlet extraction with water for a duration of 24 hours. Subsequent to this, the NA-oxide was reduced using hydrazine hydrate. This procedure involved dispersing 0.3 g of NA-oxide in 50 mL of ethanol and placing the mixture in an ultrasonic bath for 30 minutes to ensure thorough exfoliation and uniform distribution. Following this, 2.5 mL of hydrazine hydrate was introduced into the solution, and the mixture was stirred under reflux conditions for 24 hours to promote the reduction reaction. Upon completion of the reaction, the black precipitate of reduced asphalt oxide (Re-NA-oxide) was collected through vacuum filtration on filter paper. The precipitate was then washed multiple times with distilled water and ethanol to eliminate any unreacted substances or by-products. Ultimately, the product was dried in an oven at 50 °C. Next, 0.3 g of Re-NA-oxide was combined with 30 mL of tetrahydrofuran (THF) as a solvent and 0.15 g of sodium hydride (NaH) in a 100 mL flask. The mixture was stirred for 30 minutes, after which 0.3 g of chloroacetic acid was added. The reaction continued for 24 hours under reflux with ongoing stirring. Subsequently, 2 mL of 37% HCl was incorporated, and the mixture was stirred for an additional 2 hours. The resulting precipitate was filtered, thoroughly washed with water and ethanol, and then dried in an oven at 50 °C. The FT-IR spectrum of the final precipitate was recorded for characterization purposes.
Fourier-transform infrared spectroscopy (FT-IR) was employed to confirm the functional groups present in the catalyst, providing evidence for the successful immobilization of chloroacetic acid. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) were utilized to examine the morphology and particle size distribution of the catalyst, revealing a well-defined and uniform structure. Thermal stability was assessed through thermogravimetric analysis (TGA), which demonstrated the catalyst's resilience under elevated temperatures. Additionally, energy-dispersive X-ray spectroscopy (EDX) was performed to determine the elemental composition, further confirming the successful incorporation of chloroacetic acid into the catalyst framework.
These comprehensive analyses not only validated the successful synthesis of Re-NA–CH2CO2H but also provided detailed insights into its structural and thermal properties, laying a solid foundation for its application in catalytic processes.
Entry | Catalyst (mg) | Solvent | Temperature (°C) | Yieldb (%) |
---|---|---|---|---|
a Conditions: benzaldehyde (1 mmol), malononitrile (1 mmol), ethyl acetoacetate (1 mmol), hydrazine hydrate (1 mmol), catalyst Re-NA–CH2CO2H (mg), solvent (3 mL) and time: 20 min.b Isolated yield.c Catalyst NA, 4 h.d Catalyst NA-oxide.e N.P.: not product. | ||||
1 | 30 | Water | 90 | 90 |
2 | 30 | Ethanol | Reflux | 87 |
3 | 30 | Water![]() ![]() ![]() ![]() |
90 | 89 |
4 | 30 | Ethyl acetate | Reflux | 87 |
5 | 30 | Dimethylformamide | 90 | 88 |
6 | 30 | Water | 70 | 92 |
7 | 30 | Water | 50 | 95 |
8 | 30 | Water | 25 | 95 |
9 | 15 | Water | 25 | 95 |
10 | 10 | Water | 25 | 97 |
11 | 10 | Water | 25 | N.R.c |
12 | 10 | Water | 25 | 30d |
13 | 5 | Water | 25 | 86 |
14 | — | Water | 25 | N.R. |
15 | — | Water | 90 | N.P.e |
The best performance of the product 5k is obtained by the reaction in an aqueous solvent, at room temperature and in the presence of 10 mg of Re-NA–CH2CO2H (Table 1, entry 10). To verify the catalytic activity, we extended the reaction to a series of aromatic aldehydes and ethyl acetoacetate, hydrazine hydrate and malononitrile under optimal reaction conditions, and the results are reported in Table 2. Derivatives synthesized with electron-withdrawing aldehyde groups showed higher yields compared to those with electron-donating groups.
Entry | Product | Time (min) | TOF (min−1) | TON | Yieldb (%) | Mp (°C) | Mp (°C) ref. |
---|---|---|---|---|---|---|---|
a Reaction conditions: aldehydes 5a–5k (1 mmol), malononitrile (1 mmol), ethyl acetoacetate (1 mmol), hydrazine hydrate (1 mmol), catalyst Re-NA–CH2CO2H (10 mg) in H2O at 25 °C.b Isolated yield. | |||||||
1 | ![]() |
25 | 1.02 × 104 | 2.54 × 105 | 96 | 231–233 | 230–232 (ref. 29) |
2 | ![]() |
50 | 4.76 × 103 | 2.38 × 105 | 90 | 234–236 | 234–236 (ref. 29) |
3 | ![]() |
25 | 1.02 × 104 | 2.54 × 105 | 96 | 178–180 | 179–181 (ref. 30) |
4 | ![]() |
30 | 4.76 × 103 | 2.38 × 105 | 92 | 234–236 | 229–231 (ref. 31) |
5 | ![]() |
25 | 9.95 × 103 | 9.95 × 103 | 94 | 238–241 | 240–242 (ref. 32) |
6 | ![]() |
20 | 1.23 × 104 | 2.46 × 105 | 93 | 219–221 | 218–220 (ref. 29) |
7 | ![]() |
20 | 1.24 × 104 | 2.49× 105 | 94 | 211–213 | 209–211 (ref. 33) |
8 | ![]() |
25 | 1.01 × 104 | 2.51 × 105 | 95 | 215–217 | 214–216 (ref. 34) |
9 | ![]() |
40 | 5.96 × 103 | 2.38 × 105 | 90 | 217–220 | 218–220 (ref. 35) |
10 | ![]() |
25 | 1.02 × 104 | 2.54 × 105 | 96 | 200–203 | 200–202 (ref. 29) |
11 | ![]() |
20 | 1.28 × 104 | 2.57 × 105 | 97 | 241–243 | 241–243 (ref. 29) |
In catalyst-related studies, two key metrics are often discussed: Turnover Number (TON) and Turnover Frequency (TOF). The TON indicates the total number of substrate molecules that can be transformed into product by each molecule of catalyst, usually expressed as the yield (the quantity of product produced) divided by the amount of catalyst, measured in moles. This is represented in eqn (1).
![]() | (1) |
The TOF, on the other hand, measures how many substrate molecules a catalyst can convert into product per molecule of catalyst per unit of time. This is determined by dividing the Turnover Number (TON) by the duration of the reaction, as shown in eqn (2). A greater TOF value signifies a more effective catalyst, indicating that it can drive more reactions per active site in a given timeframe. Tables 2 and 4 display the TON and TOF values associated with pyrano[2,3-c]pyrazole and 2-amino-3 cyanopyridine derivatives.
![]() | (2) |
Entry | Catalyst (mg) | Solvent | Temperature (°C) | Yieldb (%) |
---|---|---|---|---|
a Reaction conditions: a mixture of benzaldehyde (1 mmol), acetophenone (1 mmol), malononitrile (1 mmol), ammonium acetate (1 mmol) and Re-NA–CH2CO2H (15 mg), solvent (3 mL) and 30 min.b Isolated yield.c Catalyst NA (15 mg), 4 h.d Catalyst NA-oxide (15 mg), 30 min. | ||||
1 | 30 | Water | 90 | 98 |
2 | 30 | Ethanol | Reflux | 85 |
3 | 30 | Water![]() ![]() ![]() ![]() |
Reflux | 89 |
4 | 30 | Ethyl acetate | Reflux | 86 |
5 | 30 | Dimethylformamide | 90 | 88 |
6 | 30 | n-Hexane | Reflux | 35 |
7 | 20 | Water | 90 | 96 |
8 | 15 | Water | 90 | 96 |
9 | 10 | Water | 90 | 92 |
10 | 15 | Water | 70 | 96 |
11c | 15 | Water | 70 | N.R.c |
12d | 15 | Water | 70 | 25d |
13 | 15 | Water | 50 | 89 |
14 | — | Water | 70 | N.R. |
Entry | Product | Time (min) | TOF (min−1) | TON | Yieldb (%) | Mp (°C) | Mp (°C) ref. |
---|---|---|---|---|---|---|---|
a Reaction conditions: aldehydes 8a–8l (1 mmol), acetophenone derivatives (1 mmol) malononitrile (1 mmol), ammonium acetate (1 mmol) and Re-NA–CH2CO2H (15 mg) in H2O at 70 °C.b Isolated yield. | |||||||
1 | ![]() |
35 | 7.29 × 103 | 2.55 × 105 | 97 | 168–170 | 170–172 (ref. 38) |
2 | ![]() |
50 | 4.74 × 103 | 2.37 × 105 | 90 | 237–239 | 239–241 (ref. 38) |
3 | ![]() |
35 | 1.02 × 104 | 2.42 × 105 | 92 | 160–163 | 164–166 (ref. 39) |
4 | ![]() |
30 | 8.07 × 103 | 2.42 × 105 | 92 | 197–199 | 198–200 (ref. 40) |
5 | ![]() |
35 | 7.1 × 103 | 2.47 × 105 | 94 | 218–220 | 219–221 (ref. 41) |
6 | ![]() |
35 | 6.99 × 103 | 2.44 × 105 | 93 | 173–175 | 173–174 (ref. 42) |
7 | ![]() |
40 | 5.99 × 103 | 2.39× 105 | 91 | 173–175 | 173–174 (ref. 43) |
8 | ![]() |
30 | 8.42 × 103 | 2.53 × 105 | 96 | 183–185 | 182–184 (ref. 38) |
9 | ![]() |
40 | 6.2 × 103 | 2.5 × 105 | 95 | 236–238 | 238–240 (ref. 44) |
10 | ![]() |
45 | 5.50 × 103 | 2.47 × 105 | 94 | 168–170 | 168–170 (ref. 41) |
11 | ![]() |
40 | 6.12 × 103 | 2.45 × 105 | 93 | 161–164 | 160–163 (ref. 45) |
12 | ![]() |
45 | 5.50 × 103 | 2.47 × 105 | 94 | 215–218 | 216–218 (ref. 46) |
In addition to the solubility of reactants and products, solvents can also affect reaction rates, pathways, selectivity, and yields. Thus, for reactions such as the synthesis of pyrano[2,3-c]pyrazole derivatives and 2-amino-3-cyanopyridine, solvents play a key role. Water, as a protic and polar solvent, stabilizes intermediates through hydrogen bonding, potentially lowering activation energy barriers and increasing reaction rates. “Chemistry on water” has shown that the use of an aqueous medium can sometimes improve reaction rates and yields. Water, as a solvent, can also affect the acidity and availability of protons from Brønsted acid catalysts. This effect can lead to an increase in the rate of the synthesis of pyrano[2,3-c]pyrazole and 2-amino-3-cyanopyridine by facilitating the protonation of nucleophiles or activating electrophilic centers.37
The results presented in Fig. 8 demonstrate that the Re-NA–CH2CO2H catalyst can be recovered and reused up to five times without significant loss of activity. This highlights the robustness and stability of the catalyst under reaction conditions, which aligns well with the principles of green chemistry by minimizing waste generation and reducing the need for fresh catalyst synthesis.
To further confirm the structural integrity of the catalyst after multiple cycles, an FT-IR spectrum was recorded for the recycled catalyst. As shown in Fig. 9, the FT-IR spectrum of the recovered catalyst closely matches that of the freshly synthesized material, indicating that the catalyst retains its functional groups and stability even after five stages of recycling and reuse. This finding underscores the durability and reusability of Re-NA–CH2CO2H, reinforcing its potential as a green and sustainable catalyst.
Entry | Catalyst | Experimental conditions | Time (min) | Yield (%) | Effa |
---|---|---|---|---|---|
a Eff = mmol of product formed per g of catalyst. | |||||
1 | Ag/TiO2 nano-thin films | H2O![]() ![]() ![]() ![]() |
30 | 88 (ref. 48) | |
2 | Nano-SiO2 (10 mol%) | H2O, 80 °C | 30 | 94 (ref. 49) | |
3 | Fe3O4@THAM–SO3H | Ethanol![]() ![]() |
5–25 | 82 (ref. 50) | |
4 | Borax (0.04 g) | H2O, reflux | 50 | 85 (ref. 30) | 21.25 |
5 | FSiPSS nano-catalyst (20 mg) | EtOH, 40 °C, ultrasonic | 80 (ref. 51) | 40 | |
6 | Re-NA–CH2CO2H (10 mg) | H2O, 25°C | 20 | 97 (This work) | 97 |
7 | Iron(III) phosphate (10 mol%) | EtOH, reflux | 240 | 82 (ref. 52) | |
8 | PDMAF-MNPs (40 mg) | EtOH (reflux) | 150 | 92 (ref. 53) | 23 |
9 | GO (10 mol%) | H2O, 80 °C | 300 | 96 (ref. 54) | |
10 | Na2CaP2O7 (0.05 g) | Solvent-free, 80 °C | 30 | 92 (ref. 55) | 18.4 |
11 | LDH@TRMS@NH2SO2(C2H4)SO2NH2@nano copper (50 mg) | Solvent-free, 60 °C | 12 | 88 (ref. 38) | 17.6 |
12 | Nanomagnetic catalyst bearing morpholine tags (14 mg) | Solvent-free, 80 °C | 20 | 85 (ref. 46) | 60.71 |
13 | Re-NA–CH2CO2H (15 mg) | H2O, 70°C | 30 | 96 (This work) | 64 |
The catalytic activity of Re-NA–CH2CO2H was evaluated in the synthesis of multicomponent reactions for the production of pyrano[2,3-c]pyrazole and 2-amino-3-cyanopyridine derivatives. The results demonstrated that the catalyst exhibits high efficiency, selectivity, and stability under mild reaction conditions, making it suitable for green chemistry applications. The catalyst showed excellent recyclability, maintaining its catalytic activity over five consecutive cycles without significant degradation. This highlights its potential for sustainable and cost-effective use in industrial processes. Water was employed as the reaction solvent, emphasizing the environmentally friendly nature of the methodology. Water's advantages include its wide availability, non-toxicity, non-flammability, and ability to enhance reactivity and selectivity compared to conventional organic solvents. The catalyst facilitated the synthesis of pyrano[2,3-c]pyrazole and 2-amino-3-cyanopyridine derivatives with high yields and short reaction times, even at low loadings (10–15 mg). These heterocyclic compounds possess significant pharmaceutical and biological activities, underscoring the practical importance of the developed methodology.
Overall, the successful synthesis of Re-NA–CH2CO2H demonstrates the versatility and effectiveness of natural asphalt as a renewable carbon source for preparing functionalized Brønsted acid catalysts. This work aligns with the principles of green chemistry by promoting sustainable practices, reducing waste, and minimizing environmental impact. The findings suggest that Re-NA–CH2CO2H is a promising candidate for the efficient and eco-friendly synthesis of pharmaceutically relevant heterocyclic compounds.
Footnote |
† Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d5ra03786g |
This journal is © The Royal Society of Chemistry 2025 |