Rapid Optimization of Photoredox Reactions for Continuous-Flow Systems Using Microscale Batch Technology

Abstract

Photoredox catalysis has emerged as a powerful and versatile platform for the synthesis of complex molecules. While photocatalysis is already broadly used in small-scale batch chemistry across the pharmaceutical sector, recent efforts have focused on performing these transformations in process chemistry due to the inherent challenges of batch photocatalysis on scale. However, translating optimized batch conditions to flow setups is challenging, and a general approach that is rapid, convenient, and inexpensive remains largely elusive. Herein, we report the development of a new approach that uses a microscale high-throughput experimentation (HTE) platform to identify optimal reaction conditions that can be directly translated to flow systems. A key design point is to simulate the flow-vessel pathway within a microscale reaction plate, which enables the rapid identification of optimal flow reaction conditions using only a small number of simultaneous experiments. This approach has been validated against a range of widely used photoredox reactions and, importantly, was found to translate accurately to several commercial flow reactors. We expect that the generality and operational efficiency of this new HTE approach to photocatalysis will allow rapid identification of numerous flow protocols for scale.

Heterogeneous metallaphotoredox catalysis in a continuous-flow packed-bed reactor

“…Especially the combination with other transition metal catalysts (metallaphotoredox catalysis), such as nickel complexes, resulted in a vast number of new methods to achieve cross-couplings under mild conditions [ 10 ]. However, the conditions of these methods are often hard to translate to flow [ 11 – 12 ] and significant changes to the optimized batch protocol are usually required [ 13 – 14 ]. The most common obstacle in the batch-to-flow translation of metallaphotoredox reactions is their frequent heterogeneous nature, most commonly due to poorly soluble inorganic bases, catalysts or additives [ 5 , 15 ].…”

Photoredox Iridium–Nickel Dual Catalyzed Cross-Electrophile Coupling: From a Batch to a Continuous Stirred-Tank Reactor via an Automated Segmented Flow Reactor

“…MacMillan and co-workers recently demonstrated successful homogeneous condition tuning of a related photochemical transformationtargeted to scale upby increasing the tubing dimension of a modified plug-flow reactor (PFR) setup to enable solid handling capability. 15 approach to "homogeneous condition tuning" is to apply engineering design considerations to the handling of the solids, which can overcome suspensions in the charge feedstock or handle suspensions generated in situ. 16−21 Herein, we describe our efforts to develop homogeneous continuous processing conditions for a dual catalysis photoredox Br−Br cross-electrophile coupling to allow for its application in our microfluidic screening system to subsequently benefit from the above-mentioned advantages for homogeneous starting conditions for flow chemical processes.…”

“…In terms of scalability, this is often undesirable for productivity and reactor throughput. MacMillan and co-workers recently demonstrated successful homogeneous condition tuning of a related photochemical transformationtargeted to scale upby increasing the tubing dimension of a modified plug-flow reactor (PFR) setup to enable solid handling capability . An alternative approach to “homogeneous condition tuning” is to apply engineering design considerations to the handling of the solids, which can overcome suspensions in the charge feedstock or handle suspensions generated in situ. − …”

Photochemistry at Scale: Wireless Light Emitters Drive Sustainability in Process Research & Development

“…For flow systems a direct transfer of small-scale batch conditions is often challenging and often necessitate additional optimizations steps. [33] Once the reaction is transferred to the WLE system, adapting the reaction conditions to a larger scale pilot or production reactor can be done in a time and cost saving manner by simply keeping the fill factor constant.…”