Selective synthesis of phenylhydroxylamine under slug flow conditions using Bayesian optimization

Abstract

Phenylhydroxylamine (PHA) derivatives are key chemical intermediates of nitrogen-containing organic compounds, however, their selective synthesis is challenging. Using Bayesian optimization, we attempted to streamline the reaction conditions for synthesizing PHAs in a microreactor to improve the yield of the target compound. Based on the results obtained in our previous work, the photoreduction of nitrobenzene was used for the selective synthesis of PHA under slug flow conditions. Furthermore, we examined the key factors responsible for the high synthetic selectivity. The optimization method helped us to optimize the experimental conditions required to achieve a yield of over 90% with only seven synthetic experiments. These results suggest that it is important to achieve a high reaction rate. Furthermore, additional experiments, cyclic voltammetry measurements, and calculations indicated that it is crucial to maintain the high redox potential of PHA under slug flow conditions with ethyl acetate. Finally, a batch reaction of the two phases was attempted to synthesize the target compound in comparison with the results of the flow reaction. Although the target compound was obtained in moderate yield with few byproducts, a prolonged reaction time was required. The flow reaction of the two phases slightly improved the synthesis selectivity and shortened the reaction time. We expect this reaction achieved by the merits of flow reactions to be useful for the synthesis of unstable PHAs.