C ร C coupling reactions catalyzed by palladium complexes with a variety of ligands in organic solvents are commonly used for the synthesis of natural products, pharmaceuticals, organic materials, and compounds with other applications. [1][2][3] The organic solvents and palladium complexes are essential for dissolving the organic substances and enhancing the reaction rate. [3] However, these conventional synthetic procedures involve high levels of energy consumption for satisfactory yields to be attained and place significant limits on the reaction rates. Additionally, the separation of the catalyst and the product from the homogeneous reaction mixtures is troublesome, costly, and chemically wasteful. To overcome these problems, C ร C coupling reactions in aqueous media have been investigated with the development of suitable catalysts. [4] However, reaction times of several hours are still required for the products to be formed in high yields with high selectivities. [5] To generate large volumes of the desired products in very short reaction times with simple separation, and thus in a green process suitable for application in industry, we have developed a water-mediated approach based on "step-by-step rapid mixing and heating" in a microfluidic system [6] for the well-known Sonogashira CรC coupling reaction. [7] Our copper-free methodology involves no organic solvents and no specific ligands for the palladium catalyst.
Chemical microprocessing is generally defined as continuous flow through regular domains with characteristic dimensions of the internal structures of fluid channels, typically in the submillimeter range; an enhancement of the rate of some chemical reactions is found in a microreactor. [8][9][10] The schematic images in Figures 1 and2 illustrate reactions under the conditions of step-by-step rapid mixing and heating in high-pressure and high-temperature water