Synthesis Of Nitrogen-Containing Organic Compounds Based On Microdroplets

Micrometer-size liquid droplets are commonly generated by the atomization of bulk solutions with a turbulent nebulizing gas.Microdroplet reaction is a kind of reaction that between the compounds initiated by the fusion of micro-sized droplets.Compared with the solution phase reaction,the rate is significantly increased,because the compounds in the droplets exhibited acceleration of reacting speed and enhanced reaction efficiency.The key features include alteration of p H,accumulation of reagents on the microdroplet surface,evaporation of solvent,confinement of reagents,and high surface-to-volume ratio of microdroplets,which are believed to contribute to the reaction acceleration.Quinoxaline is one of the most important nitrogen-containing heterocyclic compounds,which has been widely used in the biological,medical and industrial area.The industrial synthesis of quinoxaline often uses compounds with amino groups and carbonyl groups as reaction materials,taking acids,alkalis or metals as catalysts.The bulk phase reaction is usually time consuming,which need several hours or days of reaction time.In this work,a simple prototype microdroplet device was built to synthesize quinoxaline derivatives by using condensation reaction in microdroplets,which produced by electrospray ionization.The condensation reaction is initiated by the rapid mixing of charged droplets,generated caused by turbulent nitrogen atomization and high-pressure jets.The charged droplets that contained diamino and dicarbonyl compounds.Our experimental results showed that a series of quinoxaline derivatives were synthesized in microdroplets without any catalyst.Compared with the bulk phase reaction,the yield of quinoxaline in the microdroplets is significantly improved,while the reaction time is greatly shortened.On-line mass spectrometry detection revealed that the products were formed in microseconds.Liquid mass spectrometry(LC-MS)was further conducted to confirm the higher efficiency of this microdroplet reaction than bulk phase.Moreover,the aza-Michael(aza-MR)reaction was also studied by this simple microdroplet device platform.The aza-Michael reaction is one commonly used method for the stereoselective formation of a C-N bond between an available NH nucleophile and an unsaturated electrophile.This reaction produces several important intermediates for synthesis of natural product analogs and active pharmaceutical ingredients.In this work,the reaction conditions of the aza-Michael reaction was optimized by the microdroplet device.Three kinds of NH containing nucleophiles and three kinds of unsaturated electrophilic reagents with different substituents were used as reaction substrates in the microdroplet condition.LC-MS results indicated that obvious absorption peak of reaction product has been appeared in microdroplet reaction without any catalyst.However,there was no product in bulk phase reaction.These results further highlight the high efficiency of the present microdroplet reaction.To conclude,our work clearly demonstrated that microdroplet is an efficient method for synthesis of nitrogen-containing organic compounds.The yield is significantly higher than solution phase reaction under the same reaction conditions,and the reaction time is greatly shortened.Our experimental results also reveal the high importance of microdroplets in organic synthesis reaction studies and they have high potentiality to be further applied in actual production.