Intensification of organic reactions with hybrid flow reactors

The intensification of chemical processes, which means improving their efficiency and cutting down energy consumption, requires more automation and non-conventional energy sources, as well as new, efficient and scalable protocols which need to be implemented in continuous flow reactors. We showed that flowing systems are advantageous when using conductive heating or non-conventional energy sources such as microwave (MW) and ultrasound (US) irradiation. We developed several hybrid flow reactors suitable for organic reactions with the aim of optimizing heat and mass transfer and achieving process intensification. Here we present a series of applications of a simple flow reactor that uses an HPLC pump, a column heater and suitable columns filled with a supported catalyst. Using the same column packed with a commercially available derivatized acidic silica we efficiently performed two reaction types: the nucleophilic opening of epoxides with a series of alcohols and the Friedländer quinoline synthesis. In both cases we obtained pure products in excellent yield in a few minutes. The set of experiments on the epoxide opening could be repeated on a hybrid flow reactor under sequential MW/US irradiation, though at lower temperature. A suitable combination of 1D and 2D NMR experiments (i.e. 1H–13C HMQC, 1H–1H COSY and 1H–1H NOESY) was applied to unambiguously assign the stereochemistry of hydroxyethers from the nuclephilic cleavage of limonene oxide.