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. 2026 Mar 16;11(12):19171–19179. doi: 10.1021/acsomega.5c10335

Green Condensation of Aromatic Aldehydes and Barbituric Acid Enabled by Spiral Gas–Solid Flow

Zeli Xiao 1, Yong Song 1, Jiawei Zhang 1, Bangnian Cai 1, Xing Lan 1, Guangfu Lv 1, Rufang Peng 1, Bo Jin 1,*
PMCID: PMC13044827  PMID: 41939415

Abstract

This paper presents a novel spiral gas–solid two-phase flow (S-GSF) synthetic methodology for establishing carbon–carbon double bonds during mechanochemical synthesis, thus enabling the solvent-free continuous production of barbituric-acid-derived Knoevenagel adducts. The applicability of this method in the Knoevenagel condensation reaction was verified by the condensation of aromatic aldehydes with malononitrile. Employing the condensation product between veratraldehyde and barbituric acid (compound 1) as a model system, we confirmed that this approach is a viable alternative to conventional mechanochemical synthesis protocols. Structural elucidation of the synthesized barbiturate derivatives was accomplished through Fourier transform infrared spectroscopy, nuclear magnetic resonance spectroscopy, and ultraviolet–visible (UV–vis) absorption spectrometry. Analytical results confirmed the successful fabrication of compound 1 at a production rate of 1 g/min within a 3 min reaction interval, demonstrating a substantial temporal reduction compared to the 90 min duration required by twin-screw extrusion methodologies. Furthermore, we performed a kinetic evaluation of the reaction mechanism through time-dependent UV–vis spectral monitoring and found that the formation of compound 1 follows the Prout-Tompkins (B1) nucleation–growth kinetic paradigm. The S-GSF technique exhibits a remarkable capability to construct conjugated olefinic systems under solvent-free conditions, showing promising potential for advancement in organic synthesis applications and offering innovative solutions for continuous process intensification.

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1. Introduction

The Knoevenagel condensation reaction stands as one of the most important methods for constructing CC bonds. This reaction typically involves a dehydration-condensation process between the carbonyl group of aldehyde compounds and active methylene carbons under catalysis by weak Brønsted base catalysts. In recent decades, numerous efficient catalysts have been developed to enhance the reaction efficiency. However, practical industrial applications of these catalysts remain constrained due to limitations such as prolonged reaction times, the need for heating, high costs, and reliance on organic solvents. , Unsaturated organic compounds synthesized through Knoevenagel condensation function as crucial organic intermediates with broad applications in materials science and pharmaceutical fields. − Derivatives of barbituric acid exhibit enhanced reactivity because of the strong electron-withdrawing nature of their structural nucleus, which activates the C5 proton. This characteristic enables their participation in Knoevenagel condensation under mild conditions, and their unique structural features confer biological activity. , These barbituric acid derivatives provide versatile molecular frameworks that are extensively utilized in drug discovery, luminescent material development, and sensor design. −

Mechanochemistry, recognized as an excellent green chemical synthesis method, can substantially reduce or even completely eliminate solvent use. − By operating without bulk solvents, this approach has opened new possibilities for organic compound synthesis. Compared with conventional liquid-phase methods, mechanochemistry offers enhanced reaction selectivity, accelerated reaction rates, more stable yields, and simplified post-treatment procedures, leading to structurally stable molecules and materials with improved performance. − Traditional mechanochemical techniques primarily involve ball milling and twin-screw extrusion. In ball milling, mechanical energy is transferred to reactants through the reciprocal motion of grinding balls within a vessel. However, this method inevitably generates localized hot spots because of the friction between the balls and vessel walls, thereby complicating reaction kinetics analysis. In addition, a small amount of liquid is usually added to assist the reaction and achieve the desired reaction rate, a small amount of liquid is usually added to assist the reaction. Twin-screw extrusion, although useful for large-scale preparation, often requires supplemental heating because of insufficient pressure resulting from its structural limitations. These constraints highlight the challenges in developing novel mechanical energy input methods for chemical reactions.

Our research group has previously introduced an innovative mechanochemical approach called gas–solid two-phase flow technology. − Distinct from conventional grinding and ball milling methods, this technique utilizes airflow to transport solid reactants to the grinding chamber, where they undergo collisions with each other and the chamber walls. The method has several key advantages, including rapid mass transfer, continuous processing capability, and stable low-temperature operation. These features enable solvent-free, large-scale, high-efficiency continuous production, while providing potential benefits for kinetic analysis. Theoretical calculations and experimental studies have confirmed the feasibility of this approach. − Thus, this technology has the potential to continuously prepare compounds solely by mechanical force.

Our studies have demonstrated that spiral gas–solid flow (S-GSF) technology enables the continuous synthesis of barbituric acid derivatives without the requirement of organic solvents and additional catalysts. The products can be isolated through simple washing with a small amount of water, eliminating the need for extensive purification procedures. To validate this approach, we selected the formation of barbituric acid derivatives (Compound 1) from veratraldehyde and barbituric acid as a model reaction (Scheme ). Comprehensive characterization of the product was performed by using Fourier transform infrared (FT-IR) analysis, nuclear magnetic resonance (NMR) spectroscopy, and ultraviolet–visible (UV–vis) spectroscopy. Furthermore, we investigated the reaction kinetics via UV–vis spectroscopy and applied the methodology to synthesize four additional barbituric acid derivatives (compounds 2–5) by using different aldehyde substrates (Scheme ). In order to investigate the applicability of this method in the Knoevenagel condensation reaction, three aromatic aldehydes were randomly selected and reacted with malononitrile to obtain compounds 6–8. This work presents a novel solvent-free approach for CC bond formation, achieving remarkable advancement in organic synthesis methodologies. The continuous production capability of S-GSF has distinct advantages for the industrial-scale synthesis of these compounds. Implementation of this technology for chemical processes that traditionally require large-scale production, substantial organic solvent usage, or prolonged reaction times can substantially enhance the energy efficiency, reduce environmental effects, and promote sustainable development in chemical manufacturing.

1. Synthesis of Five Barbituric Acid and Malononitrile Derivatives by an S-GSF Method.

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2. Experimental Section

2.1. Chemicals and Equipment

Continuous synthesis of barbituric acid derivatives was conducted in an S-GSF device. In the device, reactant powders are premixed using a simple stirring method and introduced into the feeding funnel at a controlled rate via a feeder. A laval nozzle within the pipeline accelerates the feed gas to generate a high-speed stream, which transports the reactants to the reaction chamber at a defined angle. Simultaneously, high-pressure carrier gas flows through an angled acceleration channel on the reaction chamber’s outer wall, merging with the feed gas to form a high-speed spiral gas flow field. This configuration stabilizes the reaction temperature at low levels (15–20 °C).

The S-GSF apparatus for the continuous synthesis of barbituric acid derivatives is shown in Figure a. Figure b presents a diagram of the continuous preparation of chemicals by S-GSF technology. Inside the chamber, the reactant powders undergo rapid spiral motion driven by the airflow. The intense mechanical forces from particle collisions and the friction with the chamber walls drastically reduce the particle size, enhance reaction efficiency, and convert mechanical energy into the internal energy required to drive chemical reactions. The resulting product particles are further refined under the spiral flow field. Aerodynamic forces from the high-speed airflow overcome centrifugal effects, directing the particles toward the chamber’s center. The product then exits through the central outlet and accumulates in a tank via gravity. Exhaust gases exit the chamber through the outlet and are filtered by a high-efficiency dust bag before atmospheric release. Given the S-GSF system’s robust mechanical energy and rapid mixing capabilities, raw materials are converted into products with high efficiency and short reaction times, enabling continuous chemical production. The modular S-GSF design allows for interchangeable feed and carrier gases, facilitating studies on the effects of different gas environments on reaction outcomes.

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(Left) Schematic of the reaction equipment (1bag collector; 2exhaust outlet; 3high-efficiency collection filter bags; 4feed funnel; 5reaction chamber; 6collection tank; 7feeder; 8airflow distributor; 9total air inlet). (Right) Diagram of S-GSF continuous chemical synthesis.

2.2. General Procedure for Synthesizing Compounds by Using the S-GSF Method

Aldehyde (1 equiv, 0.05 mol) and barbituric acid (1 equiv, 0.05 mol) were mixed briefly and placed in the feeder. The pressure of the carrier gas was adjusted to 0.80 MPa. The feed gas pressure was slightly higher than the carrier gas pressure. When the device was running and negative pressure was generated in the feeding funnel, the feeding rate was adjusted to 1 g/min, and the raw materials were added to the feeding funnel. The feed gas loaded the raw materials into the reaction chamber for reaction. After the reaction, the product was collected in a collection tank. The powder product from the collection tank was obtained, washed with distilled water (10.0 mL) and anhydrous ethanol (5.0 mL), filtered, and dried to a constant weight in a 60 °C vacuum-drying oven to obtain the final product. The synthesis and characterization details of compounds 2–8 are provided in the Supporting Information.

2.3. Analysis and Characterization

H NMR spectra were acquired on a Bruker Avance 600 MHz spectrometer with deuterated dimethyl sulfoxide as the solvent and tetramethylsilane as the internal standard. UV–vis spectra were recorded on a Shimadzu UV-1800 spectrophotometer (Shimadzu Corporation, Japan) with a 1:1 (v/v) mixture of dichloromethane and methanol as the solvent. FT-IR spectra were collected on a Nicolet-5700 FT-IR spectrometer (Thermo Scientific) over the range of 4000–400 cm–1 by the potassium bromide (KBr) pellets method.

3. Results and Discussion

The model reaction for synthesizing compound 1 via S-GSF involves the reaction of veratraldehyde with barbituric acid (Scheme ). Initially, compound 1 was synthesized using the S-GSF device under the following conditions: veratraldehyde (0.05 mol, 8.21 g) and barbituric acid (0.05 mol,6.41 g) were mixed briefly and placed in the feeder, a feed rate of 1 g/min for 1 min, a carrier gas pressure of 0.8 MPa, and ambient low-temperature conditions. A yellow powder product was collected in the tank and preliminarily analyzed by thin-layer chromatography (TLC). Notably, the TLC plate displayed a distinct spot separate from the starting materials, confirming the successful synthesis of compound 1 under solvent-free, catalyst-free, and low-temperature S-GSF conditions. Previous studies have indicated that the reaction chamber maintains stable low temperatures throughout the process. Even if heat is released during the reaction, the temperature remains consistent, minimizing fluctuations and facilitating kinetic studies. For purification, the crude product was washed 2–3 times with distilled water to remove unreacted barbituric acid, followed by rinsing with anhydrous ethanol to eliminate residual veratraldehyde. The washed product was then dried to a constant weight in a 60 °C vacuum-drying oven.

2. Synthesis of Compound 1 by the S-GSF Method.

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Compound 1 was subsequently characterized by FT-IR, NMR, and UV–vis spectroscopy. Figure shows the FT-IR spectra of compound 1 and the starting materials. In the FT-IR spectrum of barbituric acid, the peak at 3187 cm–1 is assigned to the N–H stretching vibration, and the peak at 2877 cm–1 is assigned to the saturated C–H stretching vibration. Characteristic carbonyl (CO) stretching vibration appears at 1718 cm–1, and the peak at 773 cm–1 is attributed to the methylene bending vibration (C–H). For veratraldehyde, the peaks at 2838 and 1461 cm–1 are assigned to the saturated C–H stretching and asymmetric bending vibrations of the methoxy group’s methyl group, respectively. The aldehyde carbonyl (CO) stretching vibration is observed at 1681 cm–1, and the ether bond (C–O–C) vibration appears at 1132 cm–1. In the FT-IR spectrum of compound 1, the disappearance of the aldehyde stretching vibration peak from veratraldehyde and the methylene bending vibration peak from barbituric acid indicates the consumption of starting materials. The appearance of a new absorption peak at 1656 cm–1, which corresponds to the CC stretching vibration, confirms the formation of the target product. These FT-IR spectroscopic results demonstrate the successful preparation of compound 1. The 1H NMR and 13C NMR spectra provide definitive confirmation of the successful synthesis of compound 1 (Figures S1 and S2).

2.

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FT-IR spectra of veratraldehyde, barbituric acid, and compound 1 prepared by S-GSF.

To investigate the reaction kinetics and optimize the reaction conditions, we employed non-in situ UV–vis absorption spectroscopy to study the S-GSF preparation process of compound 1. The UV–vis spectrum of compound 1 differs substantially from those of the starting materials because of the formation of an extended conjugated system containing the newly formed CC bond (Figure a). This conjugated system in compound 1 has strong π→π* transition absorption at 400 nm, which serves as a characteristic peak for monitoring the reaction’s progress. To verify that no additional chemical transformations occurred during sample preparation for UV–vis analysis that could compromise data accuracy, we examined the reactivity of both starting materials in a 1:1 dichloromethane/methanol solution (Figure b). Even after 12 h at room temperature, no characteristic absorption at 400 nm was observed, confirming that the starting materials remained inert in this solvent system during the entire UV–vis measurement process. These results demonstrate that the condensation reaction did not proceed in this solvent mixture within the experimental time frame. Therefore, the solution-phase UV–vis measurements reliably reflect the actual reaction kinetics without interference from the solution-phase side reactions.

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(a) Room-temperature UV–vis spectra of veratraldehyde, barbituric acid, and pure compound 1 in a dichloromethane: methanol = 1:1 solution. (b) UV–vis spectra of veratraldehyde and barbituric acid at different mixing times in a dichloromethane:methanol = 1:1 solution at room temperature.

To investigate the influence of feed rate on reaction efficiency while seeking the optimal feed rate for the maximum reaction yield, we conducted experiments at 0.8 MPa by using feed rates of 1, 2, and 3 g/min for 30 s reaction durations. UV–vis absorption spectroscopy analysis of the products (Figure S24) revealed an inverse relationship between feed rate and reaction efficiency. As the feed rate increased, the airflow’s material loading capacity increased, whereas particle velocity decreased, resulting in a reduced mechanical energy input and low reaction rates. Nevertheless, the reaction remained viable even at higher feed rates, but the initial selection of 1 g/min was maintained as the standard condition in consideration of the overall efficiency.

Capitalizing on the gas-switchable capability of the S-GSF system, we examined four distinct gas sources and their effects on Knoevenagel condensation. Helium demonstrated superior performance, yielding a much higher characteristic absorption at 400 nm (Figure ) compared with the other gases while maintaining strong negative pressure at the feed inlet when the carrier pressure matched the feed pressure. This enhancement stems from fundamental gas dynamics: particle collision kinetic energy dictates that light helium atoms impart high velocity to reactant particles, thereby increasing the mechanical energy input. The resultant high-velocity effects provide dual benefits: (1) localized stress concentrations and lattice distortions effectively lower reaction activation barriers, enabling room-temperature reactions that normally require elevated temperatures, and (2) intensified particle collisions accelerate size reduction, dramatically increasing the specific surface area and improving mass transfer.

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UV–vis spectra of products synthesized under various atmospheric conditions; all reactions were conducted for 30 s at a constant feed rate of 1 g/min and grinding pressure of 0.8 MPa.

The Laval nozzle’s gas dynamics further explain helium’s advantage; under the same conditions, the outlet velocity of a Laval nozzle is inversely proportional to the gas density. While gas molecular type does not directly affect reaction chemistry, low-molecular-weight gases substantially boost mechanical energy transfer. Although helium demonstrates optimal performance, practical considerations of industrial scalability and cost make nitrogen the preferred choice, because it combines abundant availability with satisfactory reaction promotion. This comprehensive analysis confirms that gas selection in S-GSF systems primarily affects mechanical energy input rather than chemical pathways, with nitrogen representing the optimal balance between performance and practicality for large-scale applications.

Figure a displays the UV–vis spectra of products obtained at varying reaction times under a nitrogen atmosphere, with constant parameters of 1 g/min feed rate and 0.8 MPa carrier pressure. The characteristic absorption peak at 400 nm progressively intensified with prolonged reaction time, although the rate of peak enhancement diminished after a certain reaction duration was reached. The relationship between the reaction rate and time is shown in Figure b. As time passed, the rate gradually slowed down as it increased. The final product achieved a reaction rate of 96.2% within 3 min, which is much shorter than the reaction time for the twin-screw extrusion method (90 min).

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(a) UV–vis spectra of the products obtained at different reaction times under a fixed feed rate of 1 g/min and grinding pressure of 0.8 MPa. (b) Reaction rate relationship curve with different reaction times.

This kinetic behavior can be attributed to competing factors: (1) positive contributions from prolonged reaction time, including improved particle dispersion uniformity, expanded reactive surface area, increased effective contact sites, and sustained mechanical energy input through continuous gas flow and (2) limiting factors, such as declining mass transfer efficiency of residual reactant particles, substantial reduction in remaining raw material quantity, and diminished reaction effectiveness. These opposing effects manifest in the marginal 4.1% rate increase from 92.1% to 96.2% during the late stages.

These results conclusively demonstrate that although extended reaction time under constant pressure conditions effectively enhances the reaction rate, the incremental improvement becomes negligible when the reaction approaches completion, indicating a practical limit to the temporal optimization of this mechanochemical process.

Figure presents the pressure-dependent reaction characteristics. Figure a displays the UV–vis spectra of the products synthesized under varying carrier gas pressures, revealing nearly identical spectral profiles for products obtained at 0.8 and 0.9 MPa, both closely matching the absorption intensities of pure compound 1. These results demonstrate that although elevated pressure enhances reaction rates up to a threshold, further pressure increments yield diminishing returns. The quantitative analysis in Figure b shows only a 1.3% rate improvement (96.2% to 97.5%) when pressure increases from 0.8 to 0.9 MPa.

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(a) UV–vis spectra of the products obtained at different reaction times under a fixed feed rate of 1 g/min and a reaction time of 2.5 min. (b) Reaction rate relationship curve under different reaction pressures.

This pressure-dependent behavior arises from the following competing mechanisms: (1) enhanced mechanical energy input and accelerated mass transfer at high pressures promote reaction efficiency, and (2) the finite limit of particle size reduction establishes a maximum achievable mass transfer efficiency. Under S-GSF conditions, reactant particles attain extremely high velocities, and once they are refined to their minimum size, additional pressure cannot further improve mass transfer. Consequently, we posit that while increasing grinding pressure effectively accelerates reactions initially, the benefits plateau when particle refinement reaches completion; beyond this critical pressure, neither reaction rate nor required duration shows substantial improvement, indicating an optimization limit for pressure-based enhancement in this mechanochemical system.

S-GSF successfully and rapidly prepared compound 1, so we further investigated the reaction of barbituric acid with different substituted aldehydes. By optimizing the process conditions, we obtained the process parameters for compounds 2–8, which are summarized together with the process parameters for compound 1 in Table .

1. Process Conditions for the Synthesis of Compounds 1–8 by S-GSF.

product substituents of aldehydes feed rate (g/min) carrier gas pressure (MPa) reaction time (min) reaction rate (%)
compound 1 3-OCH3,5-OCH3 1.0 0.9 2.5 97.5
compound 2 4-Cl 1.0 0.9 3.0 97.1
compound 3 3-OCH3,4-OH,5-Br 1.0 0.9 3.0 96.7
compound 4 4-OH 2.0 0.9 2.0 98.3
compound 5 4-Ar 2.0 0.9 2.0 98.7
compound 6 3-Br,5-Br 2.0 0.9 2.0 98.5
compound 7 4-OH 2.0 0.9 2.0 98.6
compound 8 anthracene 2.0 0.9 2.0 98.1
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The data in Table reveal distinct reactivity patterns under the S-GSF conditions. During operation at 1 g/min feed rate and 0.9 MPa carrier pressure, compounds 2 and 3 required extended reaction times to 3 min to achieve satisfactory conversion rates of 97.1% and 96.7%, respectively. By contrast, compounds 4–8 maintained exceptional reactivity (>98% conversion) even at a doubled feed rate (2 g/min) with a reduced reaction duration. These results demonstrate that 4-hydroxybenzaldehyde and 4-biphenylbenzaldehyde exhibit superior reactivity compared with their counterparts bearing electron-withdrawing substituents, despite conventional organic chemistry principles predicting enhanced carbonyl carbon electrophilicity through such electronic effects.

This apparent contradiction suggests that in the S-GSF mechanochemical system, the electronic properties of aromatic substituents constitute only one component that affects the reactivity. The observed behavior may stem from complex interactions between molecular electronic effects and the inherent properties of solid materials including crystal stacking arrangements, solid-state morphology, and density characteristics. These solid-phase factors may considerably modulate mechanochemical reactivity in ways that differ fundamentally from solution-phase behavior. While this multifaceted interaction presents an intriguing research direction, its comprehensive investigation extends beyond the current scope of our study.

To comprehensively investigate the reaction mechanism and kinetic parameters of compound 1′s formation in the S-GSF system, we employed non-in situ UV–vis spectra to analyze the entire preparation process. We fitted the sigmoidal time dependence of the normalized compound 1 absorption intensities (α = It/I max, where It is the measured intensity at any point in time and I max is the maximum intensity vs time plot) to 10 solid-state reaction models: D1, D2, D3, and D4 diffusion models; geometrical contraction models R2 and R3; Prout–Tompkins B1; and A2, A3, and A4 Avrami–Erofe’ev models. ,,, The integral expressions are shown in Table , and the fitting results are given in Figure S25.

2. Solid-State Rate and Integral Expressions for Different Models.

category models integral form: g(α) = kt R 2
diffusion models 1D diffusion (D1) α2 0.97587
2D diffusion (D2) (1 – α) ln (1 – α) + α 0.98124
3D diffusion-Jander (D3) [1 – (1 – α)1/3]2 0.95654
Ginstling–Brounshtein (D4) 1 – 2α/3 – (1 – α)2/3 0.97730
geometrical contraction models contracting area (R2) 1 – (1 – α)1/2 0.98794
contracting volume (R3) 1 – (1 – α)1/3 0.98941
nucleation models Prout–Tompkins (B1) ln [α/(1 – α)] 0.99442
Avrami–Erofeyev (A2) [− ln (1 – α)]1/2 0.99285
Avrami–Erofeyev (A3) [− ln (1 – α)]1/3 0.99305
Avrami–Erofeyev (A4) [− ln (1 – α)]1/4 0.99186
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Kinetic analysis of compound 1 revealed excellent correlation with multiple nucleation reaction models (A2, A3, A4, and B1), as shown in Figure S14, with the B1 model demonstrating the best fit among them (Figure ). This finding confirms that the reaction mechanism follows a nucleation-controlled process. In crystalline systems, localized energy fluctuations occur because of structural imperfections, including impurities, surface defects, edges, dislocations, cracks, and point defects, which serve as preferential nucleation sites because of their reduced activation energy requirements. These reactive sites predominantly exist on particle surfaces, where initial nucleation occurs before subsequent diffusion and crystal growth. Progressive transformation of reactants into products is thereby achieved through this defect-mediated nucleation mechanism as the reaction time increases.

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Fitting curves of the B1 kinetic model.

The Avrami–Erofe’ev equation, representing the most widely adopted model for characterizing solid-state reaction kinetics, ,, was employed to analyze the formation of Compound 1. As demonstrated in Figure a, the experimental data exhibit excellent agreement with the theoretical S-shaped curve upon fitting to this fundamental kinetic model. The final calculated coefficients are n = 1.2077 and k = 0.958 s–1, with R 2 = 0.98. The Sharp–Hancock plot is the most facile way to check the authenticity of the kinetic model. The linear fitting of the experimental data in the form of a Sharp–Hancock plot of ln­[−ln­(1 – α)] versus lnt is shown in Figure b. Then, R 2 of the fitting result reached 0.97779, indicating that the model has good authenticity.

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(a) Fitting curves of the sigmoidal part of the intensity vs time curve for the reaction of compound 1 to a general Avrami-Erofe’ev equation. (b) Sharp–Hancock plots of the sigmoidal parts of the kinetic curves.

4. Conclusion

This work established S-GSF technology as a pioneering mechanochemical approach for efficient CC bond formation under completely solvent- and catalyst-free conditions, as demonstrated through the successful synthesis of compounds 1–8 with remarkably shortened reaction times that substantially outperform both twin-screw extrusion and conventional solution-phase methods. Comprehensive kinetic analysis using the Prout-Tompkins B1 nucleation model revealed that the reaction mechanism followed this kinetic framework, where the enhanced exposure of surface defects and increased abundance of reactive sites under S-GSF conditions accounted for the dramatically increased reaction rates. Notably, the large-scale continuous preparation of compounds 1–8 was easy to achieve in this study. Generally, carrier gas pressures above 1 MPa are easy to attain in the industry. The spiral jet mill used in S-GSF has various sizes in commercial applications, and employing large-scale equipment may result in high rates. These findings position S-GSF as a transformative platform that opens new possibilities for large-scale synthesis of Knoevenagel condensation derivatives and CC bond construction, offering an environmentally benign, operationally simple, highly efficient, and continuously operable mechanochemical technology with substantial potential for industrial applications across materials science and pharmaceutical synthesis.

Supplementary Material

ao5c10335_si_001.pdf (1.3MB, pdf)

Acknowledgments

This work was supported by the financial support received from the Natural Science Foundation of China (22275151), the Project of State Key Laboratory of Environment-friendly Energy Materials, Southwest University of Science and Technology (project no. 22fksy18).

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.5c10335.

  • Synthesis details of compounds 2–8; 1H NMR and 13C NMR spectra of compounds 1–8; FT-IR spectrum of compounds 2–8; UV–vis spectra of compound 1 obtained at different feed rates at a fixed carrier gas pressure of 0.9 MPa; and fitting diagram of 10 classical kinetic models (PDF)

The authors declare no competing financial interest.

References

  1. Kolagkis P. X., Serviou S. K., Stini N. A.. et al. Deciphering the Knoevenagel Condensation: Towards a Catalyst-Free and Water-Mediated Process. Org. Biomol. Chem. 2024;22(41):8293–8299. doi: 10.1039/D4OB01420K. [DOI] [PubMed] [Google Scholar]
  2. Chen Y., Ma X., Zhang C.. et al. TBD-Grafted Activated Carbon as An Efficient Solid Base Catalyst for Continuous Knoevenagel Reaction. J. Catal. 2025;448:116156. doi: 10.1016/j.jcat.2025.116156. [DOI] [Google Scholar]
  3. Chen W., Xu N., Qin L.. et al. A Hollowed-Out Heterometallic Cluster for Catalytic Knoevenagel Condensation. Angew. Chem., Int. Ed. 2025;64(9):e202420770. doi: 10.1002/anie.202420770. [DOI] [PubMed] [Google Scholar]
  4. Fei Y., Abazari R., Ren M.. et al. Defect Engineering in A Nanoporous Thulium-Organic Framework in Catalyzing Knoevenagel Condensation and Chemical CO2 Fixation. Inorg. Chem. 2024;63(40):18914–18923. doi: 10.1021/acs.inorgchem.4c03217. [DOI] [PubMed] [Google Scholar]
  5. Louzada L. D. T., Batalha P. N., de Almeida F. B.. Coordination Polymers as Catalysts in Knoevenagel Condensations-A Critical Review Analysis under Synthesis Conditions and Green Chemistry. Cryst. Growth Des. 2025;25(5):1708–1723. doi: 10.1021/acs.cgd.5c00033. [DOI] [Google Scholar]
  6. Lim E.. A Nonfullerene Acceptor Containing Rhodanine and Barbituric Acid End Groups for Use in Organic Photovoltaic Devices. Bull. Korean Chem. Soc. 2019;40(5):435–438. doi: 10.1002/bkcs.11739. [DOI] [Google Scholar]
  7. Zhang X., Man Lai E. S., Lai E. S. M., Martin-Aranda R.. An Investigation of Knoevenagel Condensation Reaction in Microreactors Using A New Zeolite Catalyst. Appl. Catal., A. 2004;261(1):109–118. doi: 10.1016/j.apcata.2003.10.045. [DOI] [Google Scholar]
  8. Ravikumar M. V., Raj A. K., Rao M. R., Lakshmi V.. Structure-Property Evaluation of Knoevenagel-Derived π-Conjugated Organic Systems. Eur. J. Org. Chem. 2025;28(13):e202401367. doi: 10.1002/ejoc.202401367. [DOI] [Google Scholar]
  9. Kuntze K., Pooler D. R. S., Di Donato M.. et al. A Visible-Light-Driven Molecular Motor Based on Barbituric Acid. Chem. Sci. 2023;14(32):8458–8465. doi: 10.1039/D3SC03090C. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Abiola T. T., Rioux B., Toldo J. M.. et al. Towards Developing Novel and Sustainable Molecular Light-to-Heat Converters. Chem. Sci. 2021;12(46):15239–15252. doi: 10.1039/D1SC05077J. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Ma L., Li S., Zheng H.. et al. Synthesis and Biological Activity of Novel Barbituric and Thiobarbituric Acid Derivatives Against Non-Alcoholic Fatty Liver Disease. Eur. J. Med. Chem. 2011;46(6):2003–2010. doi: 10.1016/j.ejmech.2011.02.033. [DOI] [PubMed] [Google Scholar]
  12. Ziarani G. M., Aleali F., Lashgari N.. Recent Applications of Barbituric Acid in Multicomponent Reactions. RSC Adv. 2016;6(56):50895–50922. doi: 10.1039/C6RA09874F. [DOI] [Google Scholar]
  13. Tyagi K., Kumari R., Venkatesh V.. Harnessing the Sulfur-for-Oxygen Shift: A Magic Bullet for Dynamic Photophysical and Anticancer Activities of Indole-Barbituric Acid Construct. ChemMedChem. 2025;20(7):e202400849. doi: 10.1002/cmdc.202400849. [DOI] [PubMed] [Google Scholar]
  14. Bulliard X., Lee G. H., Yagi T.. et al. Fused Terthiophene End-Capped with Barbituric Acid as Non-Fullerene N-type Small Molecule for An Organic Photo-Detector. Chem. Commun. 2025;61(27):5194–5197. doi: 10.1039/D5CC00671F. [DOI] [PubMed] [Google Scholar]
  15. Kawaura M., Aizawa T., Takahashi S.. et al. Fluorescent Supramolecular Polymers of Barbiturate Dyes with Thiophene-Cored Twisted π-systems. Chem. Sci. 2022;13(5):1281–1287. doi: 10.1039/D1SC06246H. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Howard J. L., Cao Q., Browne D. L.. Mechanochemistry as An Emerging Tool for Molecular Synthesis: What can It Offer? Chem. Sci. 2018;9:3080–3094. doi: 10.1039/C7SC05371A. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Bolt R. R. A., Leitch J. A., Jones A. C.. et al. Continuous Flow Mechanochemistry: Reactive Extrusion as An Enabling Technology in Organic Synthesis. Chem. Soc. Rev. 2022;51(11):4243–4260. doi: 10.1039/D1CS00657F. [DOI] [PubMed] [Google Scholar]
  18. Rensch T., Chantrain V., Sander M.. et al. Scale-Up of Solvent-Free, Mechanochemical Precursor Synthesis for Nanoporous Carbon Materials Via Extrusion. ChemSusChem. 2022;15(16):e202200651. doi: 10.1002/cssc.202200651. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Crawford D. E., Miskimmin C. K. G., Albadarin A. B.. et al. Organic Synthesis by Twin Screw Extrusion (TSE): Continuous, Scalable and Solvent-Free. Green Chem. 2017;19(6):1507–1518. doi: 10.1039/C6GC03413F. [DOI] [Google Scholar]
  20. Hou Y., Wang H., Xi J.. et al. Electromagnetic Mill Promoted Mechanochemical Palladium-Catalyzed Solid State Cyanation of Aryl Bromides Using Non-Toxic K4[Fe­(CN)6] Green Chem. 2023;25(6):2279–2286. doi: 10.1039/D2GC04506K. [DOI] [Google Scholar]
  21. Do J. L., Friščić T.. Mechanochemistry: A Force of Synthesis. ACS Cent. Sci. 2017;3(1):13–19. doi: 10.1021/acscentsci.6b00277. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Hernández J. G., Bolm C.. Altering Product Selectivity by Mechanochemistry. J. Org. Chem. 2017;82(8):4007–4019. doi: 10.1021/acs.joc.6b02887. [DOI] [PubMed] [Google Scholar]
  23. Štrukil V., Igrc M. D., Eckert-Maksić M., Eckert-Maksić M.. Click Mechanochemistry: Quantitative Synthesis of “Ready to Use” Chiral Organocatalysts by Efficient Two-Fold Thiourea Coupling to Vicinal Diamines. Chem. - Eur. J. 2012;18(27):8464–8473. doi: 10.1002/chem.201200632. [DOI] [PubMed] [Google Scholar]
  24. Wang G. W., Komatsu K., Murata Y., Shiro M.. Synthesis and X-ray Structure of Dumb-Bell-Shaped C120 . Nature. 1997;387(6633):583–586. doi: 10.1038/42439. [DOI] [Google Scholar]
  25. Burmeister C. F., Schmidt R., Jacob K.. et al. Effect of Stressing Conditions on Mechanochemical Knoevenagel Synthesis. Chem. Eng. J. 2020;396:124578. doi: 10.1016/j.cej.2020.124578. [DOI] [Google Scholar]
  26. Carta M., James S. L., Delogu F.. Phenomenological Inferences on the Kinetics of A Mechanically Activated Knoevenagel Condensation: Understanding the “Snowball” Kinetic Effect in Ball Milling. Molecules. 2019;24(19):3600. doi: 10.3390/molecules24193600. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Sun B. Y., He Y., Peng R. F.. et al. Air-Flow Impacting for Continuous, Highly Efficient, Large-Scale Mechanochemical Synthesis: A Proof-of-Concept Study. ACS Sustainable Chem. Eng. 2016;4(4):2122–2128. doi: 10.1021/acssuschemeng.5b01579. [DOI] [Google Scholar]
  28. Guo Z. L., Zhang Q. C., Cheng Z.. et al. Air-Flow Impacting Synthesis of Metal Organic Frameworks: A Continuous, Highly Efficient, Large-Scale Mechanochemical Synthetic Method. ACS Sustainable Chem. Eng. 2020;8(10):4037–4043. doi: 10.1021/acssuschemeng.9b05395. [DOI] [Google Scholar]
  29. Zhao J., Jin B., Peng R. F.. Gas-Solid Two-Phase Flow (GSF) Mechanochemical Synthesis of Dual-Metal-Organic Frameworks and Research on Electrochemical Properties. Nanoscale Adv. 2020;2(12):5682–5687. doi: 10.1039/D0NA00749H. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Zhang J., Zhao J., Jin B., Peng R.. Gas-Solid Two-Phase Flow Method for Preparing Trimesic Acid Series MOFs for Catalytic Thermal Decomposition of Ammonium Perchlorate. Dalton Trans. 2022;51(46):17620–17628. doi: 10.1039/D2DT02303B. [DOI] [PubMed] [Google Scholar]
  31. Song Y., Jin Z. Y., Zhang J. W.. et al. Manufacturing of Urea Co-Crystals by Spiral Gas-Solid Two-Phase Flow (S-GSF) Based on Spiral Jet Mills: A Continuous, Solvent-Free, and Scalable Mechanochemical Method. CrystEngComm. 2023;25(44):6215–6224. doi: 10.1039/D3CE00833A. [DOI] [Google Scholar]
  32. Song Y., Jin Z. Y., Li J. S.. et al. Low-Temperature Continuous Mechanochemical Synthesis of Hydantoin-Based Active Pharmaceutical Ingredients by Spiral Gas-Solid Two-Phase Flow. ACS Sustainable Chem. Eng. 2024;12(49):17739–17748. doi: 10.1021/acssuschemeng.4c06480. [DOI] [Google Scholar]
  33. Song Y., Jin Z. Y., Zhang J. W.. et al. Continuous, Solvent-Free, and Mechanochemical Synthesis of N-Acylhydrazone Derivatives by Spiral Gas-Solid Two-Phase Flow. ACS Sustainable Chem. Eng. 2024;12(4):1427–1436. doi: 10.1021/acssuschemeng.3c05316. [DOI] [Google Scholar]
  34. Song Y., Hao W. J., Li J. S.. et al. Continuous and Large-Scale Preparation of Hierarchical Porous HKUST-1 Via the “Nanofusion” Mechanism Using Liquid-Assisted Mechanosynthesis. Inorg. Chem. 2025;64(11):5579–5585. doi: 10.1021/acs.inorgchem.5c00025. [DOI] [PubMed] [Google Scholar]
  35. Fedorov D. M., Gogaev K. O., Radchenko O. K., Kolesnichenko Y.. Calculation of Geometrical Parameters of the Laval Nozzle and Gas Dynamic Spraying Conditions in the Production of Fine Tool Steel Powders. Powder Metall. Met. Ceram. 2022;61(7):389–397. doi: 10.1007/s11106-023-00326-z. [DOI] [Google Scholar]
  36. Khawam A., Flanagan D. R.. Solid-State Kinetic Models: Basics and Mathematical Fundamentals. J. Phys. Chem. B. 2006;110(35):17315–17328. doi: 10.1021/jp062746a. [DOI] [PubMed] [Google Scholar]
  37. Friščić T., Halasz I., Beldon P. J.. et al. Real-Time and in Situ Monitoring of Mechanochemical Milling Reactions. Nat. Chem. 2013;5(1):66–73. doi: 10.1038/nchem.1505. [DOI] [PubMed] [Google Scholar]
  38. Williams G. R., O’Hare D.. A Kinetic Study of the Intercalation of Lithium Salts into Al­(OH)3 . J. Phys. Chem. B. 2006;110(22):10619–10629. doi: 10.1021/jp057130k. [DOI] [PubMed] [Google Scholar]

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