Automated Serendipity with Self-Optimizing Continuous-Flow Reactors

A self-optimizing approach is used as a tool for targeting known and unknown materials in the continuous reaction of aniline, dimethyl carbonate (DMC) and tetrahydrofuran (THF) in supercritical CO₂ on γ-Al₂O₃. The study led to the formation of methylated anilines or carbamate derivatives and unusual addition products with THF including pyrrolidines and N-alkylated anilines. The identification of these products leads to the development of a plausible mechanism for the reactions. The system not only demonstrates a high flexibility that the self-optimization approach provides, including the ability to optimize for a variety of products by using a single catalyst, but also the ability to discover unexpected and original synthetic reactions. Self-optimizing continuous-flow reactors have been used to investigate the reaction of aniline with THF and DMC. High-selectivity profiles were obtained for the synthesis of methylated anilines or N-phenylpyrrolidines. By combining the three components in a single reaction system, a tandem alkylation reactivity leading to diversely alkylated anilines was discovered.