Construction Of Continuous Flow Microreactor And Its Research And Application In Multiphase Organic Synthesis

In recent years,continuous flow chemistry with microreactors as the core unit has attracted much attention in the field of organic synthesis.Microreactor is a small reaction system consisting of micro-channels in the range of microns to millimeters.Compared with the conventional reaction,continuous flow chemistry has advantages such as efficient mass and heat transfer,almost no amplification effect,safe and controllable,green and easy to integrate for automated control due to tiny microreactor channels and large specific surface area.Although microreactors are widely used in organic synthesis,most current continuous flow chemistry reactors are poorly versatile,expensive to customize and have long manufacturing cycles,which hinder the further development of continuous flow chemistry technology.In this paper,we aim to design and construct an efficient and safe continuous flow chemistry device for different multiphase reactions,and use its unique advantages to achieve efficient reactions in liquid-liquid,solid-liquid,and gas-liquid phases.Chapter 1:OverviewThis chapter first described the advantages of microreactor in organic synthesis.Secondly,the microreactors were classified according to their functions and applications and the types of microreactors that played an important role in organic synthesis were highlighted.After that,the structure and advantages of three-dimensional chip microreactor based on the ultra-limited manufacturing technology were introduced.In addition,we summarized the research progress of microreactors in multiphase reactions.Finally,the significance and research content of this paper were clarified.Chapter 2:Microreactor-based flow chemistry study and its application in liquid-liquid two-phase catalytic oxidation reaction for the preparation of benzaldehydeIn this chapter of work,we constructed an efficient liquid-liquid two-phase continuous flow chemical reaction device based on a three-dimensional chip microreactor.In this device,the phase transfer catalytic oxidation reaction of benzyl alcohol to benzaldehyde was studied with tetrabutylammonium bromide(TBAB)as the catalyst and sodium hypochlorite as the oxidant.The important parameters such as the concentration and p H value of sodium hypochlorite solution,the flow rate ratio and the phase transfer catalyst equivalent were optimized.The experimental results showed that the yield of benzaldehyde was 97.50%under the optimized conditions of temperature of 20℃,sodium hypochlorite concentration of 14.6%,p H of 9.5,TBAB concentration of 7.5%,Q_A/Q_O=2.5 and residence time of 3 min.Compared with the conventional microreactor,the reaction efficiency was significantly improved,which proved that the device could effectively increase the phase boundary area of liquid-liquid two-phase and improve the mass transfer rate.It has obvious advantages and potential broad application prospects in liquid-liquid two-phase reaction.Chapter 3:Microreactor-based flow chemistry study and its application in solid-liquid two-phase metal insertion reactions for the preparation of organozinc reagents andα-cyano carbonyl carbon compoundsA packed-bed reactor was integrated in a liquid-liquid two-phase continuous flow chemical reaction device,which was filled with zinc metal particles.2-bromo-2-methylpropiophe was in-situ synthesized into organozinc reagent through the packed-bed reactor,and then combined with the electrophilic cyanide reagent N-cyano-N-phenyl-p-toluenesulfonamide(NCTs)in the three-dimensional microchip reactor to generateα-cyano carbonyl compoundα,α-dimethyl-β-oxo-phenylpropanonitrile containing all-carbon quaternary center.The effects of temperature and residence time on the reaction were also inspected to investigate the optimal process conditions for the synthesis ofα-cyano carbonyl compounds in the microreactor.The optimal reaction parameters were as follows:reaction temperature of 60℃,residence time of 7.14 min,volume flow rate ratio of 2:1 and the yield was100%.The introduction of solid-phase reagents has greatly expanded the application of the microreactor in the synthesis of complex organic compounds,and the device can be easily modified for reactions involving multi-step synthesis,allowing flexible arrangement and on-demand building block synthesis.Compared with traditional synthesis methods,this two-step method highlights the advantages of high yield,high efficiency,green and safeChapter 4:Microreactor-based flow chemistry study and its application in the preparation of benzoic acid by gas-liquid two-phase carboxylation reactionThe reaction process of benzyl chloride substituents with magnesium metal was studied in a solid-liquid two-phase continuous flow chemical reactor by simply changing the metal filler type to prepare Grignard reagent,and finally Grignard reagent was successfully prepared by using benzyl chloride substituents which were less active than the corresponding bromides or iodides as substrates,effectively expanding the range of substrates while improving the selectivity of products.A platform of gas-liquid continuous flow chemical reaction was constructed based on the solid-liquid two-phase reaction in the first step,and the phenylmagnesium bromide Grignard reagent generated in situ in the first step was reacted with carbon dioxide gas in a three-dimensional chip microreactor,and the reaction conditions were also to be optimized.Finally,carboxylic acids were successfully prepared with a high yield(96%)at a temperature of 25℃and a residence time of 2.82 s.This demonstrated that the device could effectively mix carbon dioxide gas with the substrate solution thoroughly to improve the selectivity and yield of the reaction,showing the great potential for conducting gas-liquid reactions.