Continuous flow reductive amination of cyclohexanone using Pd/C catalyst with high productivity

Abstract

Amines represent crucial intermediates in fine chemical synthesis, finding extensive applications across pesticide, dye, and pharmaceutical industries. N,N-Dimethyl tertiary amines can be efficiently synthesized through reductive amination of dimethylamine. We developed an environmentally benign continuous flow reductive amination system employing a micro-packed bed reactor (μ-PBR) with a Pd/C catalyst prepared via direct impregnation. This system successfully produces N,N-dimethylcyclohexylamine (DMCHA) in an aqueous system, achieving high selectivity (99.5%), impressive space–time yields (2.7 × 10⁴ g L⁻¹ h⁻¹), and operates without requiring additional additives. In addition, the reaction system demonstrated excellent stability during a 120-hour continuous test and proved suitable for both aromatic aldehydes and aromatic amines.

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1 Introduction

Tertiary amines constitute essential building blocks in pharmaceutical synthesis, with growing importance in drug development.¹ Various synthetic approaches have been established for amine production, including the amination of alcohols,^2–4 the reduction of cyano or nitro compounds,^5,6 and reductive amination of aldehydes, ketones and even alcohols.^7,8 Reductive amination employing molecular hydrogen as a reducing agent has emerged as a particularly attractive approach due to its huge advantages, such as a wide variety of raw materials, ease of use, and environmental friendliness, making it a critical approach for synthesizing tertiary amines.^9,10 DMCHA serves not only as a pharmaceutical intermediate but also as a modifying agent in chromatography and as a ligand in asymmetric catalysis.¹¹ The reductive amination mechanism begins with the nucleophilic attack of ammonia or amines on the carbonyl group of an aldehyde or ketone, resulting in the formation of imines or enamines, which is subsequently reduced to yield the desired amine.¹² Nonetheless, several challenges persist, including the self-condensation of carbonyl compounds, the hydrogenolysis of amines, and the hydrogenation of substrate carbonyl compounds, all of which can lead to the formation of unwanted alcohol by-products.^13,14 Consequently, the goal of inhibiting the production of alcohols while enhancing the selectivity for the desired amines has become a focal point of research.

Various catalysts have been employed in the reductive amination process, including non-noble transition metals such as Fe, Co, and Ni, as well as noble metals like Ru, Rh, Ir, Pd, and Pt.^15–18 Homogeneous catalysts are abundantly available; Chusov et al.¹⁹ evaluated Rh₂(OAc)₄ among several homogeneous and heterogeneous noble metal catalysts, achieving yields of up to 89% for secondary amines using carbon monoxide as a reducing agent. Similarly, Gross et al.²⁰ demonstrated improved outcomes in the reductive amination of aldehydes with ammonia employing a bimetallic homogeneous catalyst based on Rh/Ir, resulting in up to 97% selectivity for aniline. However, a notable challenge remains: the difficulty in separating and recovering these catalysts. Although Riemer et al.²¹ reported that Rh homogeneous catalysts lose less than 0.3% of Rh over extended cycles, the complexity of both the apparatus and the reaction system persists as a concern. For conventional heterogeneous catalysts, the metal atom's nature significantly influences selectivity; for instance, Ru, Ni, and Co tend to favor the synthesis of primary amines, while Pd and Pt are more likely to generate secondary and tertiary amines.²² Additionally, variations in the pathways for synthesizing primary and secondary amines versus tertiary amines, along with the acid–base environment and solvent effects²³ in the reaction system, are also important factors warranting further exploration. For instance, Baxter²⁴ suggested in 2004 that using a Lewis acid as an additive could enhance the electrophilicity of the carbonyl carbon atom, thereby facilitating the formation of imines.

Most industrial chemicals, including amines, are currently produced through batch reactions.²⁵ The micropacked-bed reactor significantly enhances the mixing of reactants and reduces the likelihood of side reactions due to shorter residence times. This is particularly advantageous for gas–liquid–solid multiphase reactions.²⁶ By addressing mass transfer limitations, the micropacked-bed reactor alleviates the primary factors that slow down reactions, leading to improved production efficiency. However, successful applications of μ-PBR remain limited.²⁷ For instance, Wernik et al.²⁸ employed triethylsilane as a reducing agent and Pd/C as a catalyst to continuously produce pharmaceutical intermediates on a gram scale after surfactant addition. Jumde et al.²⁹ developed a method for reducing amination using phenol at room temperature or under microwave conditions to synthesize cyclohexylamine. Nevertheless, current studies mainly focus on the reductive amination of aromatic substrates; further investigation of the reductive amination reactions of aliphatic aldehydes and ketones, as well as aliphatic amines, is needed.

Herein, an environmentally friendly micropacked-bed reaction system for continuous flow reductive amination was developed, and several loaded catalysts were screened using the reductive amination of cyclohexanone with dimethylamine as an exemplary reaction (Scheme 1). Optimal process conditions were also investigated. Using the prepared Pd/C catalysts, the substrates for the reaction were extended, all of which were accompanied by high selectivity. Furthermore, under the same conditions, the Pd/C catalyst in this continuous flow system showed a significant increase in the space–time yield compared with the kettle reactor.

Scheme 1 The simplified diagram of the H-flow system.

2 Experimental

2.1 Chemicals

Cyclohexanone (CHO, analytical grade, 99% purity), dimethylamine (DMA, 50 wt% aqueous solution), dimethylamine solution (2.0 M in THF), and dimethylamine solution (2.0 M in methanol) were obtained from Shanghai Aladdin Biochemical Technology Co. Hydrogen (H₂, 99.99%), nitrogen (N₂, 99.99%), catalyst support (spherical carbon, diameter 0.7–2 mm), precursor Pd(NO₃)₂·6H₂O solution, reductant NaBH₄ (analytical grade, 99% purity), ruthenium/carbon catalyst (Ru/C, 5 wt%), nickel/carbon catalyst (Ni/C, 5 wt%), and palladium/alumina catalyst (Pd/Al₂O₃, 5 wt%), and platinum/carbon catalyst (Pt/C, 5 wt%) were obtained from Shenyang Research Institute of Chemical Industry. The palladium/carbon pellet catalysts (Pd/C, 3 wt% and 5 wt%), were made in the laboratory.

2.2 General experimental procedures

The raw material dimethylamine (50 wt% in H₂O) and cyclohexanone were mixed in a closed container in a certain proportion. The mixture was added to the container with a rotor and stirred for 30 minutes at room temperature with a speed of 300 rpm to ensure complete homogeneity. The exhaust valve of the infusion pump should be opened first for exhaust operation, and then closed for supply once the operation is completed. Following the system operation instructions, open the hydrogen generator and nitrogen inlet ball valves. Then, complete the exchange of nitrogen and hydrogen to the system. Finally, set the parameters for preheating temperature, reactor temperature, and system pressure before starting the reaction. After a residence time of more than three cycles, samples can be taken and analyzed using gas chromatography to determine the conversion of CHO and the selectivity of DMCHA.

2.3 Catalyst preparation & characterization

Preparation of Pd/C catalysts. Spherical activated carbon (10 g) was first mixed with 100 mL deionized water in a round-bottom flask under stirring. Separately, palladium nitrate solution (3 g, containing 10 wt% Pd) was dissolved in 30 mL deionized water, which was then added dropwise into the flask. After complete addition, the pH was adjusted to 9 using 0.25 M sodium bicarbonate aqueous solution. The mixture was heated to 50 °C and maintained under stirring for 12 h. Subsequently, 0.1 g sodium borohydride was added to reduce Pd species. The resulting catalyst was thoroughly washed and filtered until the filtrate reached near-neutral pH (<8), yielding 3 wt% Pd/C catalyst. The 5 wt% Pd/C catalyst was prepared following the identical procedure.

The specific surface area and pore size distribution of the catalysts were measured by multipoint BET using a Micromeritics ASAP 2020 HD88 at 77.35 K. The samples were degassed at 200 °C for 6 hours prior to measurement. Samples were degassed at 200 °C for 6 hours prior to measurement. The active metal content of several catalysts used was evaluated by inductively coupled plasma photoemission spectroscopy (Thermo Fisher iCAP PRO, USA). The catalysts were morphologically analyzed by transmission electron microscopy (JEOL JEM-2100F, Japan).

2.4 Analytical method

The raw materials, products and by-products involved in this experiment have boiling points below 350 °C, making them suitable for quantitative analysis by gas chromatography (GC). For this purpose, an effective gas chromatography analysis method was developed in this experiment, and its detection conditions are as follows:

Gas chromatograph: AGILENT 7890A; chromatography column: DB-624; injection port temperature: 220 °C; detector temperature: 250 °C; heating program: initial 30 °C, heating rate: 30 °C min⁻¹, ramping to 220 °C and maintain for 10 minutes; solvent: DMF; carrier gas: nitrogen gas; injection volume: 1 μL; separation ratio: 10 : 1.

Using this GC method, the retention times of the major components of the reactants were as follows: dimethylamine 3.42 min; cyclohexanol (CHOL) 7.37 min; cyclohexanone 7.78 min; N,N-dimethylcyclohexylamine 8.34 min; in this experiment, H nuclear magnetic resonance spectra (¹H-NMR) and gas chromatography-tandem mass spectrometry (GC-MS) methods were used for qualitative analysis.

3 Results and discussion

3.1 Catalyst screening

We systematically evaluated the catalytic performance of various metal catalysts for the reductive amination process, categorizing them into non-noble (Ni, Co) and noble metal (Pd, Pt, Ru) systems. While some homogeneous catalysts demonstrate excellent performance, their poor separation and recovery often result in the loss of active metal components, which is detrimental to industrial production. Heterogeneous catalysts are frequently used in reductive amination reactions; although non-noble metal catalysts tend to be less expensive, they often require more stringent catalytic conditions, such as high temperatures and pressures,³⁰ which can compromise production safety. Consequently, precious metal catalysts have gained increasing importance in the industrial synthesis of amines due to their advantages at mild operating conditions. To optimize reaction pathways and product selectivity, it is essential to screen and develop suitable catalysts, as different active metals can directly influence these factors. Five catalysts, namely Pd/C, Pt/C, Ru/C, Ni/C, and Pd/Al₂O₃, were evaluated for their suitability in the reductive amination reaction. Catalytic performance was assessed based on two aspects: substrate (CHO) conversion and product (DMCHA) selectivity, with the results summarized in Table 1.

Table 1 Continuous reductive amination of CHO to DMCHA over different catalysts^a

Catalyst	T [°C]	Con. CHO^b	Sel. DMCHA^b	Sel. CHOL^b
a Reaction condition: substrate(CHO) concentration: 10 wt%, solvent: methanol, H2 pressure: 3 Mpa, liquid flow rate: 0.5 ml min^−1, hydrogen flow rate: 80 sccm. b Conversion and selectivity were calculated by GC using methanol as internal standard, similarly hereinafter.
Pd/Al2O3 (5%)	80	96.8%	96.2%	0.2%
	120	99.2%	96.3%	1.7%
Ni/C (5%)	80	24.2%	52.8%	4.6%
	120	34.0%	72.3%	9.6%
Ru/C (5%)	80	100%	24.4%	72.9%
	120	100%	43.5%	52.1%
Pd/C (5%)	80	94.4%	97.6%	Trace
	120	95.2%	99.3%	0.2%
Pt/C (5%)	80	94.7%	90.5%	6.3%
	120	99.0%	96.4%	3.1%
Pd/C (3%)	80	97.7%	98.0%	Trace
	120	98.9%	99.3%	Trace

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Catalytic screening revealed distinct performance patterns: Ru-based catalysts exhibited superior CHO conversion (100%) but poor DMCHA selectivity (24.4–43.5%), primarily generating cyclohexanol as the major product (72.9% selectivity at 80 °C). On the other hand, Pd and Pt catalysts are excellent for the preparation of tertiary amine by reductive amination. Pd catalysts are more selective for the product, although their catalytic activity is slightly lower than that of Pt catalysts. For the subsequent separation and purification of the product, it is recommended to select the Pd catalyst with fewer by-product CHOL. Additionally, it should be noted that different supports have varying effects on the catalytic process. Upon comparing the catalytic performance of the Pd/Al₂O₃ catalyst with that of the Pd/C catalyst, it is evident that the by-products generated under Pd/C catalysis are fewer than those of the Pd/Al₂O₃ catalyst, whether at 80 or 120 °C. The catalytic activity of the alumina support may be increased due to the presence of more L-acid sites.³¹ However, this may also promote the formation of CHOL. The Pd/C used in this study had a 3 wt% loading, which provides a cost advantage compared to other precious metal catalysts with 5% loading. The reaction using the non-noble metal Ni/C (5 wt%) catalyst did not proceed completely under milder conditions, resulting in only 34% conversion of CHO even at 120 °C. Therefore, it was not considered. In summary, 3 wt% Pd/C was chosen as the catalyst for subsequent experiments.

3.2 Reaction mechanism

Mechanistic studies using online Raman spectroscopy (characteristic peaks at 735, 765, and 825 cm⁻¹ for CHO, DMCHA, and CHOL, respectively) revealed few byproduct formation (Fig. 1). Only trace amounts of cyclohexanol were detected as a by-product when the Pd/C catalyst was utilized. Furthermore, employing CHOL as the sole feedstock resulted in a 20% conversion to DMCHA. Building on these observations, we proposed potential reaction pathways for the interaction of CHO with DMA, as illustrated in Scheme 2. The primary reaction pathway involved imine formation, wherein CHO undergoes nucleophilic attack by DMA, followed by hydrogenation to produce DMCHA, which constituted main of the product distribution. A minor portion of CHO was directly hydrogenated to form CHOL, which subsequently reacted with DMA at the catalyst's more acidic site to yield DMCHA.

Fig. 1 Product Raman shift using Pd/C catalyst at different residence time.

Scheme 2 Catalytic reductive amination of CHO with DMA and the possible accompanying side reactions.

3.3 Effect of temperature

Studies on temperature optimization have demonstrated significant effects on the reductive amination process. These studies have shown that increasing the temperature enhances the selectivity for DMCHA. This is due to the thermodynamic preference for tertiary amines.¹⁸ However, direct hydrogenation of CHO to CHOL often occurs as a side reaction within the reaction system, particularly at elevated temperatures.³² Temperature optimization studies (60–140 °C) revealed a strong correlation between reaction temperature and product distribution (Fig. 2). While increasing temperature enhanced DMCHA selectivity from 96.2% (60 °C) to 99.5% (120 °C), further elevation to 140 °C resulted in decreased selectivity (98.7%) due to competing hydrogenation pathways. Considering production cost savings, the optimal reaction temperature was identified as 120 °C.

Fig. 2 Product composition using Pd/C catalyst at different reaction temperatures. Reaction conditions: CHO concentration: 50 wt%, temperature: 80 °C, solvent: H₂O, H₂ pressure: 2 Mpa, gas flow rate:80 sccm, liquid flow rate: 0.5 ml min⁻¹, catalyst loading: 3.50 g, n(DMA) : n(CHO) = 1.2 reaction conditions: CHO concentration: 50 wt%, solvent: H₂O, H₂ pressure: 3 Mpa, gas flow rate:80 sccm, liquid flow rate: 0.5 ml min⁻¹, catalyst loading: 3.50 g, n(DMA) : n(CHO) = 1.2.

3.4 Effect of the hydrogenation pressure

System pressure emerged as a crucial parameter governing the hydrogenation kinetics. According to Le Chatelier's principle, increasing pressure shifts the hydrogenation equilibrium towards product formation. However, higher pressures may also promote unwanted side reactions.³³

Hydrogen pressure optimization (1–4 Mpa) demonstrated significant effects on product distribution (Fig. 3). Increasing pressure from 1 to 3 MPa improved DMCHA selectivity from 98.2% to 99.65%, while further pressure increase to 4 MPa provided marginal improvement (99.73%) at the expense of increased byproduct formation. To enhance the safety of the hydrogenation system, 3.0 Mpa is recommended as the optimal reaction pressure.

Fig. 3 Product composition using Pd/C catalyst at different H2 pressures. Reaction conditions: CHO concentration: 50 wt%, solvent: H₂O, temperature: 120 °C, gas flow rate: 30 sccm, liquid flow rate: 0.25 ml min⁻¹, catalyst loading: 3.50 g, n(DMA) : n(CHO) = 1.2.

3.5 Effect of gas/liquid ratio and space velocity

To achieve high selectivity in the reductive amination process without side reactions, a stoichiometric ratio of 1 mol of H₂ per 1 mol of carbonyl compound is recommended for the hydrogenation reaction. Increasing the gas–liquid ratio enhances H₂ adsorption on the catalyst surface and improves its contact with reactants in the liquid phase. The reductive amination reaction in the μ-PBR is a three-phase process involving gas, liquid, and solid phases.³⁴ The liquid flow rate determines both the residence time of the liquid phase on the catalyst surface and the degree of contact. Higher flow rates lead to shorter residence times, making complete conversion of the raw material challenging, whereas lower flow rates may promote side reactions.²⁸ Additionally, low space velocity increases the likelihood of side reactions and decreases production efficiency. Thus, determining the optimal airspeed is essential for a continuous flow reductive amination reaction.

This study evaluated the effect of various hydrogen flow rates (25, 30, 40, and 50 sccm) on reaction performance while maintaining a constant reaction liquid flow rate of 0.25 sccm. Additionally, experiments were conducted at different liquid flow rates (0.25, 0.5, 0.75, and 1.00 ml min⁻¹) to further explore the influence of the gas–liquid ratio on reaction performance. The resulting selectivity and conversion data are presented in Fig. 4. Fig. 4 demonstrates that, with a fixed liquid flow velocity (or residence time), the conversion of CHO initially increases but then declines as the gas–liquid ratio (100–200) rises. At a gas–liquid ratio (V) of 200 : 1, the conversion decreases to 98.43%, suggesting that an excessively high gas–liquid ratio reduces the retention time of the raw material on the catalyst surface, hindering complete conversion of CHO.

Fig. 4 Product composition using Pd/C catalyst at different liquid/gas flow rates. Reaction conditions: CHO concentration: 50 wt%, solvent: H₂O, temperature: 120 °C, H₂ pressure: 3 Mpa, catalyst loading: 3.50 g, n(DMA) : n(CHO) = 1.2.

The selectivity of DMCHA also varied with hydrogen flow rate, initially increasing and then decreasing. This variation can be attributed to the increased hydrogen concentration, which accelerated product removal but also occupied substantial space within the reactor.³⁵ Consequently, a significant portion of the substrate was displaced from the catalyst surface before adsorption. DMCHA selectivity remained steady at approximately 99.5%. After careful evaluation, a hydrogen flow rate of 40 ml min⁻¹ and a liquid flow rate of 0.25 ml min⁻¹ were identified as optimal, resulting in a total liquid–gas hourly space velocity (WLHSV) of 3.0 h⁻¹.

3.6 Effect of molar ratio of amine to ketones

The reductive amination of aldehydes or ketones generally requires high reaction temperatures and proper amine-ketone molar ratios. In this reaction, the carbonyl compound acts not only as a substrate for nucleophilic addition to form imines but also participates in various side reactions, such as self-polymerization and direct hydrogenation of the carbonyl group.^9,22 Increasing the molar ratio of DMA to CHO shifts the reaction equilibrium favorably toward the target product. In this study, we examined amine-to-ketone molar ratios of 1.0, 1.1, 1.2, 1.5, and 2.0. The results are presented in Fig. 5.

Fig. 5 Product composition using Pd/C catalyst at different DMA-CHO ratios. Reaction conditions: CHO concentration: 50 wt%, solvent: H₂O, temperature: 120 °C, H₂ pressure: 3 Mpa, gas flow rate: 40 sccm, liquid flow rate: 0.25 ml min⁻¹, catalyst loading: 3.50 g.

The results indicate that higher amine-ketone molar ratios favor the reaction, improving both DMCHA selectivity and CHO conversion. However, the impact of increasing the amine-to-ketone molar ratio on reaction performance is less pronounced than that of temperature increases. Considering production costs and post-processing purification requirements, the optimal molar ratio was determined to be 1.1.

3.7 Effect of solvents and substrate concentration

Solvents play a critical role in the reaction process within μ-PBR. Ideal solvents should exhibit high solubility for both the substrate and hydrogen to facilitate a smooth reaction^20,36 different solvents can sometimes cause variations in product composition for the same reaction. In this study, we examined the impact of three solvents (THF, methanol, and water) on reaction performance, and obtained the following results (Fig. 6). The results indicate that all three solvents result in effective conversion and selectivity. However, the main advantage of the two non-aqueous solvents is their higher conversion rate, likely due to their greater solubility for the CHO substrate compared to water. Conversely, the use of non-aqueous solvents increases the formation of unidentified by-products, Consequently, water remains a viable solvent option due to its cost-effectiveness.

Fig. 6 Product composition using Pd/C catalyst with different solvents. Reaction conditions: CHO concentration: 50 wt%, temperature: 120 °C, H₂ pressure: 3 Mpa, gas flow rate: 40 sccm, liquid flow rate: 0.25 ml min⁻¹, catalyst loading: 3.50 g, n(DMA) : n(CHO) = 1.1.

We subsequently examined the effect of varying substrate concentrations (10%, 20%, 30%, 40%, and 50% by weight) on the reaction, using water as the solvent under conditions of 120 °C, 3 Mpa, and a flow rate of 0.5/80 ml min⁻¹. The findings are presented in Fig. 7. The experimental results indicate that under the given conditions, an optimal concentration of 20 wt% yields the highest substrate conversion and selectivity for the product DMCHA.

Fig. 7 Product composition using Pd/C catalyst at different substrate concentrations. Reaction conditions: temperature: 120 °C, H₂ pressure: 3 Mpa, gas flow rate: 40 sccm, liquid flow rate: 0.25 ml min⁻¹, catalyst loading: 3.50 g, n(DMA) : n(CHO) = 1.1.

The series of experiments demonstrates a trend where CHO substrate conversion initially increases and then decreases with rising substrate concentration. However, this trend is observed only under the 0.5/80 ml min⁻¹ flow rate, where optimal mass transfer conditions are essential for achieving the best reaction performance. Notably, the reaction performance under the previously optimized conditions (gas–liquid flow rate of 0.25/40 ml min⁻¹ with a 50 wt% substrate concentration) still surpasses any results obtained in this series. Moreover, the productivity remains higher at the 50 wt% concentration than at the newly identified optimal condition, offering cost savings by eliminating the need for additional solvents, which can be derived directly from industrial raw materials. Therefore, a substrate concentration of 50 wt% remains the preferred optimal choice.

3.8 Catalyst stability

Long-term stability tests (Fig. 8) demonstrated exceptional catalyst durability, with no significant activity loss (<2% conversion decrease) or selectivity reduction (<1% change) observed during 120 hours of continuous operation at optimal conditions. The data clearly indicate no significant loss of activity, suggesting that the catalyst bed remains highly stable within this continuous-flow reductive amination system.

Fig. 8 Stability of Pd/C catalyst. Reaction conditions: CHO concentration: 50 wt%, temperature: 120 °C, H₂ pressure: 3 Mpa, gas flow rate: 40 sccm, liquid flow rate: 0.25 ml min⁻¹, catalyst loading: 3.50 g, n(DMA) : n(CHO) = 1.1.

3.9 Application on other substrates

The reaction of CHO with dimethylamine exhibited excellent performance in this continuous-flow reductive amination system. Consequently, efforts were made to broaden the range of carbonyl compounds, including aliphatic and aromatic aldehydes (entries 2 and 3 in Table S2). Under similar mild conditions (120 °C, 3 Mpa, 0.5/80 ml min⁻¹), both substrates achieved complete transformation with high selectivity. The amine species were also varied (entries 1 and 2), leading to the formation of a mixture of tertiary and secondary amines (entry 1). This outcome may be attributed to the steric hindrance of the secondary amine product, which restricts the amino group from further attacking the carbonyl carbon atom to form an imine. The product from entry 1 column 2 underwent purification by distillation under reduced pressure and column chromatography, resulting in a 62% conversion. Despite this, the system demonstrated remarkable selectivity for tertiary amines. The reaction was subsequently applied to the reductive amination of 1-pentanal, with satisfactory results for both 1-pentanal and benzaldehyde using dimethylamine. Overall, this Pd/C catalytic reductive amination system displays excellent selectivity for small-molecule tertiary amines with low steric hindrance and broad substrate compatibility.

Conclusions

We have successfully established an efficient continuous-flow reductive amination system using Pd/C catalyst, demonstrating the selective synthesis of tertiary amines from aldehydes and ketones without the need for additional solvents. The process mechanism was analyzed using online Raman spectroscopy, and the process was optimized to obtain the optimal reaction conditions: reaction temperature (120 °C), pressure (3.0 Mpa), liquid–gas hourly space velocity (WLHSV) of 3.0 h⁻¹, aldehyde/ketone-amine molar ratios (1.1), and solvent and substrate concentrations (50 wt%). Under optimal conditions, the results indicated a CHO conversion of 99.5% with high selectivity for DMCHA. Our findings provide new insights into the relationship between catalytic selectivity and structural modifications of the Pd/C catalyst. The substrate scope of the system was expanded, demonstrating applicability to other simple aliphatic and aromatic aldehydes and ketones. However, yields remain unsatisfactory for reactions involving significant steric hindrance, highlighting the need for further optimization. Additionally, the study confirms the stability of the catalyst within the system.

Author contributions

Hongbo Yu: investigation, data curation, and writing – original draft. Weixing Ming, Wei Wei: investigation, data curation. Xin Dong: investigation. Yanan Zhao, Xianguo Wu: writing – review & editing. Gaowu Qin: supervision, project administration, and funding acquisition. Dongmao Yan: resources, supervision, and funding acquisition.

Conflicts of interest

There are no conflicts to declare.

Data availability

The datasets generated during this study are fully available within the article and SI. The authors will supply any additional data in response to reasonable requests.

Supplementary information: the supplementary information (SI) for this work includes catalyst characterization, physical diagram of primary experimental devices for reference. See DOI: https://doi.org/10.1039/d5re00250h.

Acknowledgements

The authors are grateful for financial supports from the National Natural Science Foundation of China (U20A20143).

References

1. M. K. Saini, S. Kumar, H. Li, S. A. Babu and S. Saravanamurugan, ChemSusChem, 2022, 15, e202200107.
2. W. J. W. Hui and D. Zhengyin, Chin. J. Chem., 2017, 37, 1127–1138.
3. F. Niu, M. Bahri, O. Ersen, Z. Yan, B. T. Kusema, A. Y. Khodakov and V. V. Ordomsky, Green Chem., 2020, 22, 4270–4278.
4. J. Wang, W. Qiang, S. Ye, L. Zhu, X. Liu and T.-P. Loh, Catal. Sci. Technol., 2021, 11, 3364–3375.
5. S. Elangovan, C. Topf, S. Fischer, H. Jiao, A. Spannenberg, W. Baumann, R. Ludwig, K. Junge and M. Beller, J. Am. Chem. Soc., 2016, 138, 8809–8814.
6. Y. Liu, K. Zhou, M. Lu, L. Wang, Z. Wei and X. Li, Ind. Eng. Chem. Res., 2015, 54, 9124–9132.
7. Y. Wang, S. Furukawa, X. Fu and N. Yan, ACS Catal., 2019, 10, 311–335.
8. R. Apodaca and W. Xiao, Org. Lett., 2001, 3, 1745–1748.
9. W. Guo, T. Tong, X. Liu, Y. Guo and Y. Wang, ChemCatChem, 2019, 11, 4130–4138.
10. X. Dai and F. Shi, Curr. Opin. Green Sustainable Chem., 2020, 22, 1–6.
11. S. Bhattacharyya, Synth. Commun., 2000, 30, 2001–2008.
12. T. Senthamarai, K. Murugesan, J. Schneidewind, N. V. Kalevaru, W. Baumann, H. Neumann, P. C. J. Kamer, M. Beller and R. V. Jagadeesh, Nat. Commun., 2018, 9, 4123.
13. C. Dong, Y. Wu, H. Wang, J. Peng, Y. Li, C. Samart and M. Ding, ACS Sustainable Chem. Eng., 2021, 9, 7318–7327.
14. G. Hahn, P. Kunnas, N. de Jonge and R. Kempe, Nat. Catal., 2019, 2, 71–77.
15. N. K. Gupta, P. Palenicek, L. Nortmeyer, G. M. Meyer, T. Schäfer, T. Hellmann, J. P. Hofmann and M. Rose, ACS Sustainable Chem. Eng., 2022, 10, 14560–14567.
16. M. Li, C. Pischetola, F. Cárdenas-Lizana and M. A. Keane, Appl. Catal., A, 2020, 590, 117368.
17. K. Murugesan, V. G. Chandrashekhar, T. Senthamarai, R. V. Jagadeesh and M. Beller, Nat. Protoc., 2020, 15, 1313–1337.
18. N. M. Patil and B. M. Bhanage, Catal. Today, 2015, 247, 182–189.
19. D. Chusov and B. List, Angew. Chem., Int. Ed., 2014, 53, 5199–5201.
20. T. Gross, A. M. Seayad, M. Ahmad and M. Beller, Org. Lett., 2002, 4, 2055–2058.
21. T. B. Riemer, P. Lapac, D. Vogt and T. Seidensticker, ACS Sustainable Chem. Eng., 2023, 11, 12959–12966.
22. D. Luo, Y. He, X. Yu, F. Wang, J. Zhao, W. Zheng, H. Jiao, Y. Yang, Y. Li and X. Wen, J. Catal., 2021, 395, 293–301.
23. X. Zhou, J. Liu, L. Zhang, S. Wang, X. Jia, W. Fu and T. Tang, Appl. Organomet. Chem., 2023, 37, e7080.
24. E. W. Baxter and A. B. Reitz, Org. React., 2004, 1–714,  DOI:10.1002/0471264180.or059.01.
25. B. Laroche, H. Ishitani and S. Kobayashi, Adv. Synth. Catal., 2018, 360, 4699–4704.
26. M. B. Plutschack, B. Pieber, K. Gilmore and P. H. Seeberger, Chem. Rev., 2017, 117, 11796–11893.
27. A. Faridkhou, J.-N. Tourvieille and F. Larachi, Chem. Eng. Process.: Process Intesif., 2016, 110, 80–96.
28. M. Wernik, G. Sipos, B. Buchholcz, F. Darvas, Z. Novák, S. B. Ötvös and C. O. Kappe, Green Chem., 2021, 23, 5625–5632.
29. V. R. Jumde, E. Petricci, C. Petrucci, N. Santillo, M. Taddei and L. Vaccaro, Org. Lett., 2015, 17, 3990–3993.
30. A. S. Touchy, S. M. A. Hakim Siddiki, K. Kon and K.-i. Shimizu, ACS Catal., 2014, 4, 3045–3050.
31. M. Sun, X. Du, X. Kong, L. Lu, Y. Li and L. Chen, Catal. Commun., 2012, 20, 58–62.
32. K. Murugesan, T. Senthamarai, V. G. Chandrashekhar, K. Natte, P. C. J. Kamer, M. Beller and R. V. Jagadeesh, Chem. Soc. Rev., 2020, 49, 6273–6328.
33. V. V. Karve, D. T. Sun, O. Trukhina, S. Yang, E. Oveisi, J. Luterbacher and W. L. Queen, Green Chem., 2020, 22, 368–378.
34. M. Kitamura, D. Lee, S. Hayashi, S. Tanaka and M. Yoshimura, J. Org. Chem., 2002, 67, 8685–8687.
35. H. Yu, W. Ming, Q. Zhang, W. Wei, L. Ji, T. An, W. Sun, S. Li and D. Yan, ChemistrySelect, 2024, 9, e202303376.
36. J. Zhang, J. Yin, X. Duan, C. Zhang and J. Zhang, J. Catal., 2023, 420, 89–98.

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