A new immobilization scheme for enantioselective catalysts was developed by using a combination of ionic liquids and compressed CO2. Under continuous flow conditions, stable conversion and asymmetric induction was achieved over more than 60 h in the enantioselective Ni‐catalyzed hydrovinylation of styrene. While the ionic liquid dissolves and activates the organometallic catalyst in a tuneable manner, the presence of compressed CO2 greatly facilitates mass transfer and gives easy access to continuous processes (see the schematic representation).

A new and environmentally benign protocol for enzymatic reactions in ionic liquids is described using supercritical CO2 as the mobile phase; the products are obtained in solvent-free form and the enzyme/ionic liquid mixture can be recycled in batchwise or continuous flow operations.

Abstract:The combination of kinetic resolution in ionic liquids (IL) and selective extraction with supercritical carbon dioxide (scCO 2 ) provides a new approach for the separation of enantiomers as exemplified by the lipase-catalyzed esterification of chiral secondary alcohols. Excellent enantioselectivities are achieved upon conversion of alcohols 1a ± e to the corresponding acetates 4a ± e or laureates 5a ± e using various modifications of the lipase from Candida antarctica (CaL-B) in imidazolium-based ionic liquids. The anion of the ionic liquid has a significant influence on the performance of the bio-catalyst with bis(trifluoromethanesulfonamide) [BTA] giving the best results. The acetates 4a ± e can be extracted from the reaction mixture preferentially over the alcohols 1a ± e with scCO 2 under certain conditions, but preparatively useful selectivities would require advanced multi-step extraction procedures. In contrast, efficient separation is possible with relatively simple equipment if alcohols 1a ± e are extracted preferentially from their corresponding laureates 5a ± e. A ™green∫ continuous process for the resolution of racemic alcohols without the use of organic solvents was devised on the basis of these findings.

Readily available chiral phosphoramidites are a promising class of ligands for nickel-catalyzed asymmetric hydrovinylation of vinyl arenes. Cooperative effects are operative when ligands with more than one element of chirality are used. Choosing the proper stereochemistry in each part of the modular ligand system leads to high chemoselectivities and excellent enantioselectivities up to 94%. Moreover, the catalysts derived from these ligands proved extremely efficient and remarkably robust performing up to 8300 catalytic turnovers at an initial turnover frequency beyond 1000 h-1. The large potential for structural variation and their straightforward synthesis make the phosphoramidites currently the best lead structure for catalyst development in this field.

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...

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Organometallic catalysis is a powerful tool for chemical synthesis, and the field still evolves at a high pace continuously improving efficiencies and opening up new possibilities. However, despite increasing use in specialty and fine chemical production issues of catalyst recovery still hamper broader application and prevent tapping the full potential of this technology on industrial scale. Even though scientists have tackled this problem for decades practicable methods remained scarce. In this contribution we analyse the major challenges of performing organometallic catalysis in continuous flow from a conceptual point of view, and exemplify for recently developed concepts based on near- and supercritical fluids how the integration of molecular and engineering principles can offer new solutions to this persistent problem.

A continuous-flow process based on a chiral transition-metal complex in a supported ionic liquid phase (SILP) with supercritical carbon dioxide (scCO(2)) as the mobile phase is presented for asymmetric catalytic transformations of low-volatility organic substrates at mild reaction temperatures. Enantioselectivity of >99% ee and quantitative conversion were achieved in the hydrogenation of dimethylitaconate for up to 30 h, reaching turnover numbers beyond 100000 for the chiral QUINAPHOS-rhodium complex. By using an automated high-pressure continuous-flow setup, the product was isolated in analytically pure form without the use of any organic co-solvent and with no detectable catalyst leaching. Phase-behaviour studies and high-pressure NMR spectroscopy assisted the localisation of optimum process parameters by quantification of substrate partitioning between the IL and scCO(2). Fundamental insight into the molecular interactions of the metal complex, ionic liquid and the surface of the support in working SILP catalyst materials was gained by means of systematic variations, spectroscopic studies and labelling experiments. In concert, the obtained results provided a rationale for avoiding progressive long-term deactivation. The optimised system reached stable selectivities and productivities that correspond to 0.7 kgL(-1)h(-1) space-time yield and at least 100 kg product per gram of rhodium, thus making such processes attractive for larger-scale application.