Catalytic hydrogenation is a common method for reducing carbon-carbon or carbon heteropolybonds, and in traditional batch reactions, some heterogeneous *** such as ranny nickel, platinum, palladium and rhodium are often used as catalysts. Due to the applicability of this type of reaction, many research groups have developed continuous flow hydrogenation methods using heterogeneous catalysts. Hydrogenation reactions are carried out under flow conditions using a packed bed reactor or honeycomb reactor equipped with a catalyst, and as the mobile phase and hydrogen pass through the catalyst bed, the catalyst can mix well with them, exhibiting high diffusion efficiency and high reactivity.
Metal nanoparticle (NP) catalysts.
In most heterogeneous transition metal catalysts, the surface area of metal substances can be increased when they are present in the form of nanoparticles, further enhancing their catalytic capacity. In order to improve the activity and durability of metal nanoparticles, they are usually immobilized on organic or inorganic supports, for example, polymeric carriers can enhance the adsorption and permeability of organic substances in gas-liquid heterogeneous reactions; Aromatic groups in polymers such as polystyrene can play an important role in the immobilization of metal nanoparticle catalysts through electronic interactions. The development of novel carrier materials to enhance the activity of metal catalysts in hydrogenation reactions has become a research hotspot in recent years.
Hidekazu et al. [1] developed polysilane [poly(methylphenyl)silane, PMPSI; Poly(dimethyl)silane, DMPSI] supported palladium catalyst with high reactivity and high durability in continuous flow systems. The group reported the reductive hydrogenation of olefins, alkynes, nitriles, aromatic nitro compounds, and aliphatic nitro compounds.
Palladium polymers catalyze hydrogenation reactions in continuous flow systems.
Gericke et al. [2] reported the use of a Ru(NP) catalyst supported on hyperbranched polystyrene to achieve a reaction to prepare sorbitol from D-glucose under continuous flow conditions. Hyperbranched polystyrene (HPS) forms a highly porous structure by introducing methoxymethyl chloride as a linker for phenyl units in polystyrene. The catalytic hydrogenation activity of the catalyst for high-concentration glucose solution under continuous flow conditions is comparable to that of industrial Raney nickel catalyst, with a conversion rate of 99%.
RU HPS catalyzes glucose hydrogenation in a continuous flow system.
Goszewska et al. [3] also reported that PD, Ni, and Cu2Onps were loaded on some commercially available tentagel-S polymers, and the catalyst was used to hydrogenate olefins, unsaturated aldehydes, and p-nitrophenol respectively, resulting in high yields.
Because typical hydrogenation catalysts are acid-compatible, Furuta et al. mixed a hydroxyl-substituted sulfonic acid catalyst (Hosas) and PDC supported on silica in the same column and underwent a simultaneous dehydration and hydrogenation reaction to convert terpene-derived alcohols into basking mercane with high selectivity and high yield.
In a continuous flow system, the catalyst binds to the acid while catalyzing the dehydration and hydrogenation reactions.
Immobilized molecular catalysts.
Immobilization of highly active molecular catalysts on solid supports is another important method for heterogeneous catalysis under continuous flow conditions. Amara et al. [4-5] proposed the concept of using a "supported ionic liquid phase (SILP)" as the stationary phase, on which the catalyst can be loaded to convert the batch hydrogenation reaction into a continuous flow hydrogenation process. The research group dispersed phosphotungstic acid to the surface of the metal catalyst through a simple and effective method, the Agustin method, so that it acts as an anchor for the cationic organometallic complex rhodium-(s,s)-ethyldithiophosphine, and binds it firmly through the strong interaction between the charged metal center and the oxygen atom of phosphotungstic acid, and the phosphotungstic acid itself binds to it by forming hydrogen bonds with the carrier alumina, as shown in Figure 4. The key chiral intermediates of the active pharmaceutical ingredient can be obtained by asymmetric reduction of the enamine under flow conditions, and 1kg of product can be obtained by continuous reaction for 18 hours, and its conversion rate is 976% and an enantiomeric excess (EE) value of 988%, rhodium leaching less than 10ppm.
The molecular catalyst is anchored to a solid support by heteropolyacids.
Brenna et al. [6] reported a method for immobilizing a novel imidazolidin-based pyridinamide catalyst and applied it to the synthesis of chiral amines using trichlorosilanes under continuous flow conditions. The research group constructed a chiral scaffold based on L-tyrosine, and used the phenolic hydroxyl group as the binding site to immobilize the catalyst on a solid support (silica or polystyrene), and loaded it into a packed bed reactor, and obtained a product with high conversion rate and selectivity under flow conditions, with an EE value of 97%, and the catalyst dosage can be reduced to 001 equivalent, and successfully applied to the enantioselective synthesis of drug precursors such as rivastigmine and acrylamide (S)-A.
Metals: Reduction of organohydrides.
Although hydrogen is the most atomically efficient and cost-effective reagent used in reduction reactions, there are some drawbacks to the application of this gas molecule, as its low solubility in commonly used laboratory solvents will always result in the reactants in two-phase or even three-phase systems not being able to fully contact, reducing the reaction rate. Therefore, some salt or liquid hydrogen supply materials are used to replace hydrogen. Moderately reactive Si-H compounds are often used as stable and easy-to-handle hydride sources, and their reduced by-products are soluble in most organic solvents, making them suitable for flow reactions.
Asadi et al. [7] reported a thioesterification of acid chloride under multi-step continuous flow conditions, followed by the reduction of it to aldehydes using PD XAD-4 as a catalyst and triethylsilane as a hydrogen source, i.e., the Fukuyama reduction reaction. In their optimized system, a mixture of acyl chloride, dodecane thiol, and triethylsilane is first passed through an Amberlysta21 column to form the corresponding thioester intermediate, then flows through an isocyanate-loaded reactor to remove excess thiols, residual thioeesters and triethylsilanes flow through a reaction column equipped with a PD XAD-4 catalyst for selective reduction, trace metals are removed using a quadrapureida resin column, and finally ** "capture and release" on primary amine resin After purification, aromatic or fatty aldehydes are obtained in high yields. At 60, the flow system washes out all unwanted products, trapping only the desired aldehydes (imine form) and can release the captured imines by injecting a mixture of formic acid, methanol, and water to obtain the target product.
The Fukuyama reduction reaction is carried out in a continuous flow system.
The micro-reaction hydrogenation platform offers higher efficiency and selectivity. Scale-up in conventional reactors, especially at the level of industrial production, requires significant investment in equipment to build and install large reactors; But microchannel reactors can be easily used to scale up reactions, and the amplification effect is small. In terms of catalyst development, further development of microchannel reactors will meet the need for better selectivity and higher turnarounds, as well as improved stability.
The micro-reaction hydrogenation platform has the characteristics of high process safety, short reaction time and low catalyst cost, and has realized the automatic control of the whole process of hydrogenation reaction, real-time detection, automatic sample collection and other automatic control to monitor the reaction information in a timely and accurate manner. Through the monitoring of the reaction process, the collected data is used for continuous feedback and regulation, and the continuous optimization of the reaction process is realized, which will significantly improve the overall efficiency of process development.
The micro-reaction hydrogenation platform not only realizes the efficient hydrogenation process development and rapid screening of catalysts in the laboratory, but also realizes the customized production of hydrogenation kilogram products in the fume hood.
References
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