Highly efficient and chemoselective singlet oxygen oxidation of unprotected methionine was performed in water using a continuous mesofluidic reactor. Sustainable process engineering and conditions were combined to maximize process efficiency and atom economy, with virtually no waste generation and safe operating conditions. Three water-soluble metal-free photosensitizers [Rose Bengal, Methylene Blue, and tetrakis­(4-carboxy­phenyl)­porphyrin] were assessed. The best results were obtained with Rose Bengal (0.1 mol %) at room temperature under white light irradiation and a slight excess of oxygen. Process and reaction parameters were monitored in real-time with in-line NMR. Other classical organic substrates (α-terpinene and citronellol) were oxidized under similar conditions with excellent performances.

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.

Development of a scalable continuous-flow process towards enriched threo-methylphenidate (Ritalin) hydrochloride.

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The method and results described herein concern the photosensitized addition of various alcohols to renewable platform fumaric and itaconic acids under scalable continuous-flow conditions in glass micro-and mesofluidic reactors. Alcohols were used both as reagents and as solvents, thus contributing to a reduced environmental footprint. Process parameters such as the temperature, light intensity, and the nature as well as amount of the photosensitizer were assessed under microfluidic conditions and, next, transposed to a lab-scale mesofluidic reactor connected with an in-line NMR spectrometer for real-time reaction monitoring. Substituted γ-butyrolactones, including spiro derivatives with unique structural features, were obtained with quantitative conversion of the starting materials and in 47−76% isolated yields. The model photoaddition of isopropanol to fumaric acid was next successfully transposed in a pilot-scale continuous-flow photoreactor to further demonstrate scalability.