Automated generation of photochemical reaction data by transient flow experiments coupled with online HPLC analysis

Abstract

The automated generation and acquisition of large-scale reaction data is crucial to recent progress in organic synthesis and pharmaceutical process development. To follow reaction progress over time, time-series of reaction data can be generated by transient flow experiments, which allow to investigate reactions in a short transient period between two steady-state operations of a continuous-flow microreactor. The acquisition of analytical data in this short transient period, however, remains challenging since separation techniques like HPLC – though able to cope with highly complex samples – are typically regarded as too slow for the required acquisition rates. We break the longstanding coupling between the timescale of the continuous-flow experiment and the acquisition rate of the analytical method with the introduction of the multiple heart-cutting interface, which allows for sample parking prior to sample analysis. Transient flow experiments are presented for the [2 + 2] cycloaddition between 1-methyl-2-quinolinone and coumarin. Competing homo- and crossdimerization reactions are quantitatively investigated in systematic reaction parameter screenings with more than 400 data points. Results provide precious insights into this complex photochemical system – not only for reaction optimization, but also for a more profound understanding of the involved chemical processes.