M.W. (2015) 'Applying green chemistry to the photochemical route to artemisinin.', Nature chemistry., 7 (6). pp. 489-495. Further information on publisher's website:https://doi.org/10.1038/nchem.2261Publisher's copyright statement:Additional information: Use policyThe full-text may be used and/or reproduced, and given to third parties in any format or medium, without prior permission or charge, for personal research or study, educational, or not-for-prot purposes provided that:• a full bibliographic reference is made to the original source • a link is made to the metadata record in DRO • the full-text is not changed in any way The full-text must not be sold in any format or medium without the formal permission of the copyright holders.Please consult the full DRO policy for further details.

We report the construction and use of a vortex reactor which uses a rapidly rotating cylinder to generate Taylor vortices for continuous flow thermal and photochemical reactions. The reactor is designed to operate under conditions required for vortex generation. The flow pattern of the vortices has been represented using computational fluid dynamics, and the presence of the vortices can be easily visualized by observing streams of bubbles within the reactor. This approach presents certain advantages for reactions with added gases. For reactions with oxygen, the reactor offers an alternative to traditional setups as it efficiently draws in air from the lab without the need specifically to pressurize with oxygen. The rapid mixing generated by the vortices enables rapid mass transfer between the gas and the liquid phases allowing for a high efficiency dissolution of gases. The reactor has been applied to several photochemical reactions involving singlet oxygen (1O2) including the photo-oxidations of α-terpinene and furfuryl alcohol and the photodeborylation of phenyl boronic acid. The rotation speed of the cylinder proved to be key for reaction efficiency, and in the operation we found that the uptake of air was highest at 4000 rpm. The reactor has also been successfully applied to the synthesis of artemisinin, a potent antimalarial compound; and this three-step synthesis involving a Schenk-ene reaction with 1O2, Hock cleavage with H+, and an oxidative cyclization cascade with triplet oxygen (3O2), from dihydroartemisinic acid was carried out as a single process in the vortex reactor.

The development of a continuous flow process for asymmetric hydrogenation with a heterogenized molecular catalyst in a real industrial context is reported. The key asymmetric step in the synthesis of an API (active pharmaceutical ingredient) has been developed on a kilogram scale with constant high single-pass conversion (>95.0%) and enantioselectivity (>98.6% ee) through the asymmetric hydrogenation of the corresponding enamide. This performance was achieved using a commercially available chiral catalyst (Rh/(S,S)-EthylDuphos) immobilized on a solid support via strong interaction resulting from the requirement of electroneutrality. The factors affecting the long-term catalyst stability and enantioselectivity were identified using small-scale continuous flow setups. A dedicated automated software-controlled high-pressure pilot system with a small footprint was then built and the asymmetric hydrogenation on kilogram-scale was realized with a space time yield (STY) of up to 400 g L −1 h −1 at predefined conversion and enantiopurity levels. No catalyst leaching was detected in the virtually metalfree product stream, thereby eliminating costly and time-consuming downstream purification procedures. This straightforward approach permitted an easy and robust scale-up from gram to kilogram scale fully matching the pharmaceutical quality criteria for enantiopurity and low metal content, thus demonstrating the high versatility of fully integrated continuous flow molecular catalysis. ■ INTRODUCTIONContinuous processing has long been recognized as a promising method for process intensification in the chemical industry. Although continuous manufacturing is traditionally the realm of large scale production, it only recently has begun attracting increased attention from the pharmaceutical industry. 1−4 It is now clear that continuous flow processing can contribute to minimizing costs and intensifying production, 5 especially in the synthesis of complex molecules where constant quality standards are required and expensive catalyst and/or high pressure are needed. Small and flexible reactor systems can also allow the integration of multiple operations either consecutively or even simultaneously, 6 for example the incorporation of continuous workups and product extraction post-reaction. 7,8 Both upstream and downstream operations can be integrated into a single process unit rather than being separated in space or time, allowing a more efficient process. These technologies offer unique scale-up opportunities because of the improved control on mass and heat transfers and the possibility to scale out with relatively small reactor footprints. Such reactor systems can also be automated with online analysis allowing for faster optimization and better control of the overall performance. 9,10 The advantages of fully integrated continuous flow systems are best exemplified in the context of homogeneous catalysis where often additional purification steps are required to remove or potentially recycle an expensive organometallic catalyst. 6,11...

Developing cleaner chemical processes often involves sophisticated flow-chemistry equipment that is not available in many economically developing countries. For reactions where it is the data that are important rather than the physical product, the networking of chemists across the internet to allow remote experimentation offers a viable solution to this problem.

The industrial transition to more-sustainable chemical manufacturing requires the development of a variety of high-performance heterogeneous catalysts. Recently, new classes of heterogeneous and recyclable catalysts that exploit visible-light activation have emerged in the field of organic synthesis. Among these systems, sensitized semiconductors occupy a strategic place as they are able to initiate single electron transfer processes under heterogeneous conditions and using medium-to-low energy light activation. This technology can promote a range of synthetically useful reactions, such as oxidations, reductions, or additions, including C–C bond formation, under very mild conditions and with high selectivity. Sensitized semiconductors have been known for decades in solar cell technologies (the so-called “Dye-Sensitized Solar Cells”) but applications in organic synthesis are only very recent. This Review provides a comprehensive overview of the mechanisms, reactivity, and scope of this technology, with a focus on their new and promising synthetic applications.