In-situ Bromine Generation for Photochemical Applications in Continuous Manufacturing

Continuous manufacturing enables options to generate hazardous or unstable reagents. This opens options to enable the use of hazardous reagents in a safe manner on manufacturing scale. In this study we present how in situ generated bromine can be used for a photochemical application. This combines the process intensification of a photochemical reaction with the in situ generation of the hazardous reagent bromine. The past decade has seen Photochemistry become a powerful tool in chemical synthesis. The development of efficient pseudo-monochromatic light sources enables a new efficient way for the energy supply. Continuous flow technology has been demonstrated as a solution to this problem, since narrow reaction channels can ensure homogeneous irradiation, alongside improved heat transfer and mass transfer (batch-to-conti). Benzyl bromides represent common photo-chemically accessible building blocks in the pharmaceutical and other industries, signifying that their scalable synthesis is of importance to multiple fields. The use of N-bromosuccinimide (NBS) instead is convenient, especially on lab scale since the associated risks are significantly lower and the crystalline solid is easier to handle. The trade-off when using NBS, however, is poorer reactivity, atom economy, and solubility.

In the current study that was conducted by the CCFlow Team in cooperation with our team, we can demonstrate a highly intensified process for photochemical benzylic bromination, using the chemical generator approach for in situ bromine formation. A commonly used oxidant is H₂O₂, but there are safety concerns associated with the storage and use of peroxides. Accordingly, we employed NaBrO₃, a crystalline solid with a high decomposition temperature of 310 °C, as a safer alternative. By using concentrated hydro bromic acid (one source for both bromide ions and protons), a concentrated sodium bromate solution and no organic solvent (substrate pumped neat), the bromine generator was considerably intensified. Modular plants enable a flexible use of the bromine generator in batch and in continuous applications.

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