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Article

Helical Airflow Synthesis of Quinoxalines: A Continuous and Efficient Mechanochemical Approach

State Key Laboratory of Environment-Friendly Energy Materials, School of Materials and Chemistry, Southwest University of Science and Technology, Mianyang 621010, China
*
Authors to whom correspondence should be addressed.
Chemistry 2025, 7(4), 121; https://doi.org/10.3390/chemistry7040121
Submission received: 2 July 2025 / Revised: 23 July 2025 / Accepted: 28 July 2025 / Published: 29 July 2025

Abstract

In this work, we report a novel mechanochemical synthesis method for the synthesis of quinoxaline derivatives—a spiral gas–solid two-phase flow approach, which enables the efficient preparation of quinoxaline compounds. Compared to conventional synthetic methods, this approach eliminates the need for heating or solvents while significantly reducing reaction time. The structures of the synthesized compounds were characterized using nuclear magnetic resonance (NMR), Fourier-transform infrared spectroscopy (FT-IR), ultraviolet-visible (UV–Vis) absorption spectroscopy, powder X-ray diffraction (XRD), differential scanning calorimetry (DSC), and high-performance liquid chromatography (HPLC). Using the synthesis of 2,3-diphenylquinoxaline (1) as a model reaction, the synthetic process was investigated with UV–Vis spectroscopy. The results demonstrate that when the total feed amount was 2 g with a carrier gas pressure of 0.8 MPa, the reaction completed within 2 min, achieving a yield of 93%. Furthermore, kinetic analysis of the reaction mechanism was performed by monitoring the UV–Vis spectra of the products at different time intervals. The results indicate that the synthesis of 1 follows the A4 kinetic model, which describes a two-dimensional diffusion-controlled product growth process following decelerated nucleation.

1. Introduction

Nitrogen-containing heterocyclic compounds are ubiquitous in pharmaceuticals, natural products, and biologically active molecules [1,2]. Among these, quinoxaline—a fused dinitrogen heterocycle—has attracted significant research interest due to its broad applications in medicinal chemistry, agrochemicals, and corrosion inhibition. For instance, 5,7-diamino-3-phenyl-2-benzylquinoxaline derivatives demonstrate potent growth inhibitory activity against cancer cells [3]. Similarly, 2,3-bis [2-(substituted benzylidene)hydrazinyl]quinoxaline derivatives exhibit remarkable antibacterial efficacy in vitro, positioning them as promising lead compounds for novel antibacterial drug development [4]. Furthermore, quinoxaline-based structures can effectively adsorb onto metal surfaces, suppressing corrosion [5]. Representative derivatives such as indeno [1,2-b]quinoxaline, acenaphtho [1,2-b]quinoxaline, and 2,3-diphenylquinoxaline have shown exceptional metal corrosion inhibition properties [6,7,8].
Quinoxaline derivatives are conventionally synthesized through condensation reactions of 1,2-diamines with various organic substrates. The reaction conditions exhibit significant substrate dependence: (1) α-dicarbonyl compounds typically require catalytic activation [9,10,11], (2) diol derivatives necessitate prolonged reaction durations [12,13], and (3) α-hydroxy ketone substrates demand elevated temperatures for effective cyclization [14,15,16]. Such energy-intensive and catalyst-dependent methodologies contravene fundamental principles of green chemistry [17].
Notably, mechanochemical synthesis has emerged as a sustainable alternative in the past decade, gaining substantial recognition within the chemical sciences community [18,19,20]. This innovative approach offers distinct advantages, including solvent-free conditions, enhanced reaction efficiency, and improved product yields, thereby addressing several limitations of conventional synthetic protocols. Based on the potential of mechanochemistry in synthesis, our team has proposed a novel mechanochemical approach—the spiral gas–solid two-phase flow method—and demonstrated its significant potential for synthetic applications [21,22].
In this work, we report for the first time the synthesis of quinoxaline derivatives via a spiral gas–solid two-phase flow (S-GSF) method, demonstrating that the S-GSF approach can be effectively employed for the continuous synthesis of quinoxaline compounds without the addition of any catalyst or organic solvent. The target compounds were obtained with high efficiency, yield, and purity. Using the reaction of benzil with o-phenylenediamine to produce 2,3-diphenylquinoxaline (1) as a model, the feasibility of applying S-GSF to the preparation of quinoxaline derivatives was investigated. The products were characterized by nuclear magnetic resonance (NMR), powder X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FT-IR), ultraviolet-visible (UV–Vis) absorption spectroscopy, and high-performance liquid chromatography (HPLC). Furthermore, the synthetic process conditions were optimized through UV–Vis absorption spectroscopy, and the reaction mechanism was kinetically studied by monitoring the UV–Vis absorption spectra of the products at different time intervals. Building on the synthesis of 1, the generality of the S-GSF method was further verified by synthesizing five additional quinoxaline derivatives (2–6) (Scheme 1).

2. Experimental Section

2.1. Chemicals and Apparatus

All chemicals are from Aladdin and Mackin, and they are of analytical grade without further purification. The gas–solid two-phase flow equipment used for chemical synthesis is shown in Figure S1 (The device plan is shown in reference [22]). In a typical process, simple premixed raw materials are fed into the feed funnel through the feeder, while the feed gas carries the reactants into the reaction chamber. When high-pressure carrier gas passes through four inclined nozzles arranged at a certain angle on the outer wall, a high-speed spiral flow field is generated inside the reaction chamber. When the raw materials enter the reaction chamber, they undergo high-speed spiral motion under the action of high-speed spiral flow, causing violent collisions and friction between particles. Under strong mechanical energy, the particle size is greatly reduced, the reaction performance is improved, and the strong mechanical energy is converted into the internal energy required for chemical reactions, thereby triggering chemical reactions to generate new products. After energy exchange, the gas leaves the reaction chamber through the outlet above the center and is filtered by high-efficiency collection filter bags before being discharged into the atmosphere. Finally, under the centrifugal force of the spiral flow field, the coarse particles will remain in the reaction chamber to continue the reaction, while the fine particles will slowly move to the center of the reaction chamber after gradually overcoming the centrifugal force of the flow field, and finally fall into the collection tank from the lower outlet. Under the strong mechanical energy of S-GSF, the reactants have been converted into products before leaving the reaction chamber, thus achieving efficient and continuous preparation of the products.

2.2. Synthesis of 1 by S-GSF

Benzil (1.32 g, 1.0 equivalent, 6 mmol) and o-phenylenediamine (0.68 g, 1.0 equivalent, 6 mmol) were premixed using a mortar. The carrier gas pressure and feed gas pressure were adjusted to 0.8 and 0.84 MPa, respectively, and the premixed raw materials were added to the feeding funnel through the feeder. The experiment was completed within 2 min, with the final product collected in the tank. After removing the byproduct water by vacuum drying, the product was used without further purification, yielding white powder with 93% yield.

2.3. Analysis and Characterization

All chemicals were purchased from Aladdin (Shanghai, China). PXRD experiments of the samples were performed on a Philips X’Pert Pro X-ray diffractometer (PANalytical, Lelyweg, The Netherlands) with Cu Ka1 radiation (λ = 0.15418 nm) at 80 mA and 40 KV. FT-IR spectra were measured on a Nicolet 5700 FT-IR spectrometer (US, KBr pellet in the range of 4000–400 cm−1. 1H-NMR spectra were recorded on Bruker Avance 600 spectrometers (Ettlingen, Germany) with deuterated chloroform (CDCl3) as the solvent and tetramethylsilane as the internal reference. UV–vis spectra were recorded with a UV-1800 spectrophotometer (Shimadzu, Japan) with ethanol as the solvent. Elite high-performance liquid chromatography (HPLC) P230 (China) was used for analysis. The separation was conducted on a UV detector, and sampling was conducted with an autosampler. Data collection for the chromatogram was conducted using N2000. The column used was Welchrom-C18 (250 mm × 4.6 mm) with a mobile phase of acetonitrile and water (the ratio of volume = 70:30) mixture solvent. Filtration of the mobile phase was carried out using a 0.45 μm membrane filter under the isocratic condition with a flow rate of 0.5 mL min−1, an injected volume of 20 μL, and elution monitored at 260 nm with a run time of 30 min.

3. Results and Discussion

3.1. Synthesis and Characterization

First, the 1 synthesized via the S-GSF method was characterized by NMR spectroscopy, preliminarily confirming the structural correctness of the product (Figure S4). Subsequently, the structure of the product was further verified by XRD, FT-IR spectroscopy, and UV–Vis spectroscopy. Figure 1 shows the XRD patterns of the starting materials and 1. The powdered product obtained from the collection vessel was directly analyzed using XRD and compared with the raw materials. The results revealed that the diffraction pattern of 1 exhibited distinct characteristic peaks differing from those of the two starting materials, confirming the conversion of the raw materials in the reaction chamber and demonstrating the successful synthesis of 1 via the S-GSF method. Furthermore, compared to the starting materials, the product exhibits significant diffraction peak broadening. This phenomenon can be attributed to the following mechanism: When initially formed in the reaction chamber, the product particles have relatively large sizes and thus experience weaker centripetal forces. At this stage, the product continues in a spiral motion with the carrier gas within the chamber. As the particle size decreases to a critical value, the centripetal force increases sufficiently to enable the product to descend into the collection vessel.
Figure 2 displays the FT-IR spectra of the starting materials and 1. For o-phenylenediamine, the peak at 3190 cm−1 can be assigned to the N–H stretching vibration, while the peak at 3029 cm−1 corresponds to the aromatic C–H stretching vibration. In the FT-IR spectrum of benzil, characteristic peaks at 3063 cm−1 and 1660 cm−1 are attributed to the Ar–H stretching vibration of the aromatic ring and the C=O stretching vibration, respectively. For 1, the disappearance of the N–H stretching band of o-phenylenediamine and the C=O stretching band of benzil indicates complete consumption of the starting materials. Meanwhile, the emergence of a new absorption peak at 1601 cm−1 is due to the C=N stretching vibration, confirming that the reactants successfully underwent transformation after passing through the S-GSF reaction system. The appearance of the characteristic C=N stretching vibration peak further verifies the structure of 1.
Figure 3 shows the UV–Vis absorption spectra of the starting materials and 1. The spectra reveal distinct absorption profiles between the two reactants and 1, reflecting structural differences. Notably, 1 exhibits a characteristic absorption peak at 344 nm, which is absent in the spectra of the starting materials. This observation confirms that the reactants underwent chemical transformation within the S-GSF system, and the observed peak can be attributed to the π-π* transition of the newly formed conjugated system in the cyclized product, further verifying the successful synthesis of 1.
Moreover, given the unique absorption feature of 1 at 344 nm, which clearly distinguishes it from the starting materials, UV–Vis spectroscopy was subsequently employed to investigate the reaction conditions and kinetics of this process.
Figure 4 displays the high-performance liquid chromatography (HPLC) profiles of 1 and the starting materials. The purity of 1 synthesized via the S-GSF method was directly analyzed using HPLC without additional purification. As evident from Figure 4, benzil and o-phenylenediamine exhibit retention times of 11 min and 6 min, respectively, while 1 elutes at 26 min. The absence of any peaks corresponding to the starting materials in the chromatogram of 1 confirms their complete conversion. Quantitative analysis demonstrates that 1 obtained through the S-GSF process achieves 99% purity without requiring any post-synthetic treatment.
Furthermore, to further validate the high efficiency of the S-GSF method, we compared the reactivity of the two starting materials under simple mechanical grinding and direct mixing in solution. Figure 5a presents the XRD pattern of the two precursors after manual grinding. The diffractogram clearly shows no characteristic peaks corresponding to 1, confirming that mechanical grinding alone—without solvents or catalysts—does not induce the reaction. The reaction behavior in solution was examined by UV–Vis spectroscopy (Figure 5b). After dissolving the two precursors in ethanol and allowing the mixture to stand for 12 h, no distinct absorption peak of 1 was observed at 344 nm, demonstrating that mere dissolution in ethanol without further treatment does not initiate the reaction. Comparative analysis of both scenarios (grinding and solution mixing) revealed that the formation of the target product occurs exclusively upon the intervention of the S-GSF system. This conclusively demonstrates that the S-GSF method supplies the requisite energy to drive the reaction, thereby underscoring its superior efficiency in synthetic applications.

3.2. Reaction Process Analysis

To determine the optimal process conditions for synthesizing quinoxaline derivatives via the S-GSF method, we systematically investigated the reaction parameters for 1. Using UV–Vis spectroscopy, we evaluated the effects of carrier gas type, carrier gas pressure, and reaction time on the yield of 1.
Figure 6 presents the UV–Vis absorption spectra of the reaction under varying carrier gas conditions. The results demonstrate that when nitrogen or argon is used as the carrier gas, the UV absorption peak intensity of 1 remains nearly identical, indicating that the reaction is unaffected by the carrier gas type. Thus, we conclude that the selection of inert gas does not significantly influence the reaction progression.
Figure 7 presents the UV–Vis spectra of products obtained within one minute at different carrier gas pressure levels, along with the relationship between conversion rate and pressure. Figure 7a demonstrates that the UV absorption peak at 344 nm gradually intensifies with increasing carrier gas pressure, indicating enhanced conversion of 1 at higher pressures. Figure 7b reveals a significant improvement in conversion rate when the pressure increases from 0.2 MPa to 0.6 MPa. The significant improvement in conversion rate can likely be attributed to the increased particle velocity under S-GSF conditions at higher carrier gas pressures, which enables the reactants to acquire greater reaction energy. Furthermore, as the carrier gas pressure increases, the deposited materials at the bottom of the reaction chamber gain kinetic energy that follows the flow field, thereby promoting enhanced dispersion among reactant particles. This phenomenon leads to an increased probability of effective collisions, improved mass transfer efficiency, and consequently higher conversion rates.
As the carrier gas pressure rises from 0.6 MPa to 0.8 MPa, the pressure-dependent increase in conversion rate of 1 becomes less pronounced. This plateau effect may occur because at these higher pressures, the two reactants achieve homogeneous dispersion within the reaction chamber with minimal material deposition at the bottom, leading to a dynamic equilibrium between collision probability and reaction rate. The results demonstrate that while increasing carrier gas pressure generally enhances the conversion rate of 1, the effect becomes marginal beyond 0.8 MPa. Therefore, from an energy efficiency perspective, the optimal carrier gas pressure is determined to be 0.8 MPa.
Figure 8 shows the UV–visible absorption spectra of 1 at different reaction times. As can be seen from the figure, the conversion rate of 1 increases with prolonged reaction time. When the reaction time is extended from 2 min to 3 min, the UV absorption peak intensity of 1 at 344 nm remains essentially unchanged, indicating that the substrate completes its conversion within 2 min with a yield of 93%.
After optimizing the reaction conditions, we evaluated the generality of this method by synthesizing various quinoxaline derivatives using nitrogen as the carrier gas at a regulated pressure of 0.8 MPa, as outlined in Scheme 1. The results demonstrate that all reactions were completed within 1–3 min with yields exceeding 90%, confirming that quinoxaline derivatives can be efficiently synthesized via the S-GSF method within an extremely short timeframe. These findings clearly illustrate the exceptional synthetic efficiency of the S-GSF approach.
Furthermore, to demonstrate that the S-GSF method serves as a green and sustainable alternative for chemical synthesis, we conducted a comparative analysis between this approach and conventional solution-phase methods. The green chemistry metrics of both S-GSF and solution-phase methods for synthesizing 2,3-diphenylquinoxaline were calculated and compared to evaluate and identify the more sustainable process, including environmental factor (E-factor), process quality intensity (PMI), and atom economy (AE). As shown in Table 1, the S-GSF method not only achieved significantly lower E-factor (0.26) and PMI (1.26) compared to the solution-phase method, but also higher AE (88.68%), demonstrating that the synthesis of 2,3-diphenylquinoxaline via S-GSF represents a more sustainable synthetic route with both environmental and economic benefits.

3.3. Kinetic Analysis

To investigate the reaction mechanism and kinetics, we studied the synthesis of 1 via the S-GSF method using UV–visible absorption spectroscopy. The sigmoidal curve of the UV absorption intensity of 1 at 344 nm over time (α = It/Imax, where It is the measured intensity at any point in time, and Imax is the maximum intensity vs. time plot) to 10 solid-sate reaction models: D1, D2, D3, and D4 diffusion models, geometrical contraction R2 and R3, Prout-Tompkins B1, and A2, A3, and A4 Avrami–Erofe’ev models [23]. The fitting results are shown in Figure S3.
For 1, fitting to the kinetic models revealed the best agreement with the A4 reaction model (Figure 9), indicating that its mechanism follows a nucleation-controlled process. Crystals possess localized energy fluctuations due to impurities, surfaces, edges, dislocations, cracks, and point defects. These defects serve as nucleation sites for the reaction because they exhibit the lowest activation energy. Most of these sites are located on particle surfaces. Once nuclei form, they grow inward via diffusion. As the reaction progresses, the starting material is gradually converted into the product.
The Avrami–Erofe’ev equation, one of the most widely used models for describing solid-state reaction processes, was employed to fit the experimental data of 1. The fitting results for the sigmoidal region of the curve are presented in Figure 10a, and the calculated coefficients are as follows: n = 1.57295, k = 0.957769 s−1, with R2 = 0.9293. The significantly larger rate constant (k) reveals the underlying reason for the rapid and highly efficient synthesis of quinoxaline derivatives via the S-GSF method. Within an extremely short timeframe, the reactants in the reaction chamber are subjected to intense mechanical energy, generating abundant surface defects. These defects serve as additional nucleation sites, thereby accelerating the reaction kinetics. This further validates the high energy input efficiency of the S-GSF method, highlighting its superior performance in driving solid-state reactions.
The Sharp−Hancock plot is the most facile way to check the authenticity of the kinetic model (Figure 10b). The linear fitting of the experimental data in the form of a Sharp−Hancock plot of ln [ ln ( 1 α ) ] versus ln t as shown in Figure 10b, and the R2 of the fitting result reached 0.88187. The results demonstrate the high reliability of this model.

4. Conclusions

In summary, this work successfully demonstrates that the S-GSF method can efficiently synthesize quinoxaline derivatives without solvents, catalysts, or purification steps within an exceptionally short timeframe. Through systematic analysis of the synthesis process for 1, we identified the optimal reaction conditions: nitrogen as the carrier gas at 0.8 MPa pressure. Under these conditions, six quinoxaline derivatives were synthesized within 1–3 min with yields exceeding 90%, confirming the remarkable efficiency of the S-GSF approach. Furthermore, kinetic studies using the Avrami–Erofe’ev model revealed that the synthesis of 1 follows the A4 kinetic model. The significantly large rate constant (K) further substantiates the high energy input efficiency of the S-GSF method in quinoxaline derivative synthesis, highlighting its unique advantages in mechanochemical applications. We conclude that the S-GSF method establishes a novel pathway for green and efficient synthesis of quinoxaline derivatives.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/chemistry7040121/s1, Figure S1: Spiral gas-solid two-phase flow device picture; Figure S2: At 0.3 MPa, the UV-Visible absorption spectra of 1 changed with time; Figure S3: The fitting of It/Imax for the reaction of compound 1 after linearization to nine different models of solidstate reactivity: (a) the D1 model; (b) the D2 model; (c) the D3 model; (d) the D4 model; (e) the B1 model; (f) the R2 model; (g) the R3 model; (h) the A2 model; (i) the A3 model; Figure S4-S9: Nuclear magnetic spectra of quinoxaline derivatives [11,24].

Author Contributions

Conceptualization, J.Z. and B.J.; Validation, J.Z.; Formal analysis, Z.X.; Date curation, J.Z.; Writing—original draft, J.Z.; Writing—review & editing, Q.H., Y.Z., B.J. and R.P.; Supervision, Q.H., Y.Z., B.J. and R.P.; Funding acquisition, B.J. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by Natural Science Foundation of China grant number 22275151.

Data Availability Statement

All data are available within the manuscript and Supplementary Materials.

Conflicts of Interest

There are no conflicts to declare.

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Scheme 1. Synthesis of six quinoxaline derivatives by S-GSF method.
Scheme 1. Synthesis of six quinoxaline derivatives by S-GSF method.
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Figure 1. XRD patterns of benzil, o-phenylenediamine, and 1 synthesized using S-GSF.
Figure 1. XRD patterns of benzil, o-phenylenediamine, and 1 synthesized using S-GSF.
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Figure 2. FT–IR spectra of benzil, o-phenylenediamine, and 1 synthesized using S-GSF.
Figure 2. FT–IR spectra of benzil, o-phenylenediamine, and 1 synthesized using S-GSF.
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Figure 3. UV–Vis spectra of benzil, o-phenylenediamine and 1 synthesized using S-GSF.
Figure 3. UV–Vis spectra of benzil, o-phenylenediamine and 1 synthesized using S-GSF.
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Figure 4. HPLC of 1 prepared by S-SGF and the raw material.
Figure 4. HPLC of 1 prepared by S-SGF and the raw material.
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Figure 5. (a) XRD patterns of grinding, benzil, o-phenylenediamine, and 1 synthesized using S-GSF; (b) The UV–Vis absorption spectra of 1 synthesized using the S-GSF method and standing in ethanol for 12 h after mixing the raw materials.
Figure 5. (a) XRD patterns of grinding, benzil, o-phenylenediamine, and 1 synthesized using S-GSF; (b) The UV–Vis absorption spectra of 1 synthesized using the S-GSF method and standing in ethanol for 12 h after mixing the raw materials.
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Figure 6. UV absorption spectra of 1 under different carrier gas conditions.
Figure 6. UV absorption spectra of 1 under different carrier gas conditions.
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Figure 7. UV–vis spectra of 1 under different carrier gases and the relationship between conversion rate and pressure within 1 min (a) UV–vis spectra of 1 under different carrier gases; (b) relationship between pressure and conversion rate of 1.
Figure 7. UV–vis spectra of 1 under different carrier gases and the relationship between conversion rate and pressure within 1 min (a) UV–vis spectra of 1 under different carrier gases; (b) relationship between pressure and conversion rate of 1.
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Figure 8. UV–vis spectroscopy of 1 with different reaction times at 0.8 MPa.
Figure 8. UV–vis spectroscopy of 1 with different reaction times at 0.8 MPa.
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Figure 9. Fitting curves of the A4 kinetic model.
Figure 9. Fitting curves of the A4 kinetic model.
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Figure 10. (a) The fit of the sigmoidal part of the intensity vs. time curve for the reaction of 1 to a general Avrami–Erofe’ev equation; (b) Sharp–Hancock plots of the sigmoidal parts of the kinetic curves.
Figure 10. (a) The fit of the sigmoidal part of the intensity vs. time curve for the reaction of 1 to a general Avrami–Erofe’ev equation; (b) Sharp–Hancock plots of the sigmoidal parts of the kinetic curves.
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Table 1. Comparison of the green metric of 1 prepared by the S-GSF and solution methods.
Table 1. Comparison of the green metric of 1 prepared by the S-GSF and solution methods.
E-Factor bPMI cAE (%) d
using S-GSF0.261.2688.68
in solution [11] a1.983.5961.83
a The calculated data for the solvent method takes into account 90% solvent recovery. b E-factor = total wasted (kg)/product (kg). c PMI = total mass (kg) used in the process/product quality (kg). d AE = (molecular weight of desired product/molecular weights of all reactants) ×100 %.
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Zhang, J.; Xiao, Z.; Huang, Q.; Zhao, Y.; Jin, B.; Peng, R. Helical Airflow Synthesis of Quinoxalines: A Continuous and Efficient Mechanochemical Approach. Chemistry 2025, 7, 121. https://doi.org/10.3390/chemistry7040121

AMA Style

Zhang J, Xiao Z, Huang Q, Zhao Y, Jin B, Peng R. Helical Airflow Synthesis of Quinoxalines: A Continuous and Efficient Mechanochemical Approach. Chemistry. 2025; 7(4):121. https://doi.org/10.3390/chemistry7040121

Chicago/Turabian Style

Zhang, Jiawei, Zeli Xiao, Qi Huang, Yang Zhao, Bo Jin, and Rufang Peng. 2025. "Helical Airflow Synthesis of Quinoxalines: A Continuous and Efficient Mechanochemical Approach" Chemistry 7, no. 4: 121. https://doi.org/10.3390/chemistry7040121

APA Style

Zhang, J., Xiao, Z., Huang, Q., Zhao, Y., Jin, B., & Peng, R. (2025). Helical Airflow Synthesis of Quinoxalines: A Continuous and Efficient Mechanochemical Approach. Chemistry, 7(4), 121. https://doi.org/10.3390/chemistry7040121

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