Multikilogram per Hour Continuous Photochemical Benzylic Brominations Applying a Smart Dimensioning Scale-up Strategy

Abstract

Although continuous flow technology can facilitate the scale-up of photochemical processes it is not yet routinely implemented on production scale in the fine chemical industries. This can be attributed to additional challenges compared to thermal processes, mostly in the homogeneous irradiation of the flow reactor. Here, we detail the process of bringing a previously developed photochemical benzylic bromination, utilizing in situ bromine generation, from lab to pilot scale. The process setup is discussed in detail, alongside a comprehensive risk assessment and discussion of problems encountered in the investigation of key reaction parameters. Ultimately, an assay yield of 88% was obtained in 22 s irradiated residence time, resulting in a productivity of 4.1 kg h–1 (space-time yield = 82 kg L–1 h–1) representing a 14-fold scale-up versus the lab-scale process.

Scalability of photochemical reactions in continuous flow mode

“…Comparison of this methodology to the previously published FEP reactor [9] found the Firefly system to be almost 30% more power efficient which while not crucial on laboratory scale, is of prime importance for manufacturing. The majority of novel innovative reactor designs for kilogram-scale continuous flow photochemical synthesis have only been reported over the last decade [20,61,72,[75][76][77]. Many of these involve scaling up reactors that were designed for laboratory scale synthesis, such as the vortex reactor reported by Poliakoff, George and coworkers [22,76].…”

“…The direct use of molecular bromine for these reactions is unfavourable due to safety concerns on larger scales, and while N-bromosuccinimide can act as a safer alternative [84], its use is not ideal due to poorer reactivity and modest atom economy. Another strategy involves the in-situ generation of bromine [85], which was recently explored by the Kappe group [75]. The relatively green reaction between NaBrO 3 and hydrobromic acid provides access to Br 2 with the formation of water as a by-product [86].…”

“…This can be accounted for by the poorer heat and mass transfer provided by the single photochemical G3 FM, which was operated at a lower than recommended flow rate. Therefore, one would assume that this space-time-yield could be further increased through the use of 5 x G3 FMs which would be more comparable to the lab scale design [75]. This high space-time-yield highlights the advantages that can be achieved through continuous processing when compared to batch, in particular for processes that require both high mass transfer and photon flux.…”

A modular, low footprint and scalable flow platform for the expedient α-aminohydroxylation of enolizable ketones

“…65 With increasingly restrictive legislations both at the R&D and commercial scales, the use of reactive and potentially hazardous chemicals has become limiting if not impossible with conventional batch reactors. The concept of chemical generators under continuous flow conditions has been extensively documented by Kappe, [66][67][68][69][70][71][72] hence providing a robust answer for exploiting reactive intermediates yet benefiting from all the safety and process advantages of continuous flow operation. A continuous flow chemical generator actually relies on stable and widely available precursors and on the concatenation of upstream operations aiming at the preparation of unstable, toxic or reactive chemicals, which are next immediately consumed within downstream operations (Fig.…”

The PhotoFlexys: A Multi‐Purpose Reactor Platform to Simplify Process Intensification and Mechanistic Studies in Photochemistry

“…[25][26][27][28] In general, batch reactions are commonly conducted in standard glassware, which is irradiated from either the side [29] or the bottom. [30] Under continuous flow conditions, various approaches like the utilization of coiled capillary reactors, [31] plate-based microreactors, [32] falling-film [33] or vortex reactors [34] have been demonstrated. Further, different commercially available photoreactors have proven their applicability in either batch [35][36][37][38] or continuous flow photochemistry.…”