Development of a Continuous‐Flow System for Asymmetric Hydrogenation Using Self‐Supported Chiral Catalysts

Well‐designed, self‐assembled, metal–organic frameworks were constructed by simple mixing of multitopic MonoPhos‐based ligands ( 3 ; MonoPhos=chiral, monodentate phosphoramidites based on the 1,1′‐bi‐2‐naphthol platform) and [Rh(cod)₂]BF₄ (cod=cycloocta‐1,5‐diene). This self‐supporting strategy allowed for simple and efficient catalyst immobilization without the use of extra added support, giving well‐characterized, insoluble (in toluene) polymeric materials ( 4 ). The resulting self‐supported catalysts ( 4 ) showed outstanding catalytic performance for the asymmetric hydrogenation of a number of α‐dehydroamino acids ( 5 ) and 2‐aryl enamides ( 7 ) with enantiomeric excess (ee) ranges of 94–98 % and 90–98 %, respectively. The linker moiety in 4 influenced the reactivity significantly, albeit with slight impact on the enantioselectivity. Acquisition of reaction profiles under steady‐state conditions showed 4 h and 4 i to have the highest reactivity (turnover frequency (TOF)=95 and 97 h^?1 at 2 atm, respectively), whereas appropriate substrate/catalyst matching was needed for optimum chiral induction. The former was recycled 10 times without loss in ee (95–96 %), although a drop in TOF of approximately 20 % per cycle was observed. The estimation of effective catalytic sites in self‐supported catalyst 4 e was also carried out by isolation and hydrogenation of catalyst–substrate complex, showing about 37 % of the Rh^I centers in the self‐supported catalyst 4 e are accessible to substrate 5 c in the catalysis. A continuous flow reaction system using an activated C/ 4 h mixture as stationary‐phase catalyst for the asymmetric hydrogenation of 5 b was developed and run continuously for a total of 144 h with >99 % conversion and 96–97 % enantioselectivity. The total Rh leaching in the product solution is 1.7 % of that in original catalyst 4 h .     

Catalytic Enantioselective Flow Processes with Solid‐Supported Chiral Catalysts

Sustainability concerns are the wind in the sails for the development of novel, more selective catalytic processes. Hence, chiral catalysts play a crucial role in the green production of enantioenriched compounds. To further increase the green profile of this approach, the use of solid‐supported catalytic species is appealing due to the reduced generation of waste, as well as the possibility of reusing the precious catalyst. Even more attractive is the implementation of flow processes based on these immobilized catalysts, a flexible strategy that allows to generate from milli‐ to multi‐gram amounts of chiral product with a reduced footprint set‐up. Herein, we will present the efforts devoted in our laboratory towards the immobilization of chiral catalysts and their use in single‐pass, highly enantioselective, flow processes. Proline, diarylprolinols, other aminocatalysts, squaramides, thioureas, phosphoric acids and even chiral ligands and metal‐based catalysts constitute our current toolkit of supported species for enantioselective catalysis.     

Iridium‐Catalyzed Enantioselective Hydrogenation of Oxocarbenium Ions: A Case of Ionic Hydrogenation

Ionic hydrogenation has not been extensively explored, but is advantageous for challenging substrates such as unsaturated intermediates. Reported here is an iridium‐catalyzed hydrogenation of oxocarbenium ions to afford chiral isochromans with high enantioselectivities. A variety of functionalities are compatible with this catalytic system. In the presence of a catalytic amount of the Brønsted acid HCl, an α‐chloroether is generated in situ and subsequentially reduced. Kinetic studies suggest first‐order kinetics in the substrate and half‐order kinetics in the catalyst. A positive nonlinear effect, together with the half kinetic order, revealed a dimerization of the catalyst. Possible reaction pathways based on the monomeric iridium catalyst were proposed and DFT computational studies revealed an ionic hydrogenation pathway. Chloride abstraction and the cleavage of dihydrogen occur in the same step.     

The Co‐Entrapment of a Homogeneous Catalyst and an Ionic Liquid by a Sol–gel Method: Recyclable Ionogel Hydrogenation Catalysts

Molecular hydrogenation catalysts have been co‐entrapped with the ionic liquid [Bmim]NTf₂ inside a silica matrix by a sol–gel method. These catalytic ionogels have been compared to simple catalyst‐doped glasses, the parent homogeneous catalysts, commercial heterogeneous catalysts, and Rh‐doped mesoporous silica. The most active ionogel has been characterised by transmission electron microscopy, X‐ray photoelectron spectroscopy, and solid state NMR before and after catalysis. The ionogel catalysts were found to be remarkably active, recyclable and resistant to chemical change.     

A Monolithic Hybrid Cellulose‐2.5‐Acetate/Polymer Bioreactor for Biocatalysis under Continuous Liquid–Liquid Conditions Using a Supported Ionic Liquid Phase

Mesoporous monolithic hybrid cellulose‐2.5‐acetate (CA)/polymer supports were prepared under solvent‐induced phase separation conditions using cellulose‐2.5‐acetate microbeads 8–14 μm in diameter, 1,1,1‐tris(hydroxymethyl)propane and 4,4′‐methylenebis(phenylisocyanate) as monomers as well as THF and n‐heptane as porogenic solvents. 4‐(Dimethylamino)pyridine and dibutyltin dilaurate (DBTDL), respectively, were used as catalysts. Monolithic hybrid supports were used in transesterification reactions of vinyl butyrate with 1‐butanol under continuous, supported ionic liquid–liquid conditions with Candida antarctica lipase B (CALB) and octylmethylimidazolium tetrafluoroborate ([OMIM⁺][BF₄^?]) immobilized within the CA beads inside the polymeric monolithic framework and methyl tert‐butyl ether (MTBE) as the continuous phase. The new hybrid bioreactors were successfully used in dimensions up to 2×30 cm (V=94 mL). Under continuous biphasic liquid–liquid conditions a constant conversion up to 96 % was achieved over a period of 18 days, resulting in a productivity of 58 μmol mg^?1(CALB) min^?1. This translates into an unprecedented turnover number (TON) of 3.9×10⁷ within two weeks, which is much higher than the one obtained under standard biphasic conditions using [OMIM⁺][BF₄^?]/MTBE (TON=2.7×10⁶). The continuous liquid–liquid setup based on a hybrid reactor presented here is strongly believed to be applicable to many other enzyme‐catalyzed reactions.     

A Solid‐Supported Organocatalyst for Highly Stereoselective,Batch, and Continuous‐Flow Mannich Reactions

The fast and highly stereoselective Mannich reaction of aldehydes and ketones with the N‐(p‐methoxyphenyl) ethyl glyoxylate imine catalyzed by polystyrene resins functionalized with (2S,4R)‐hydroxyproline is reported. The effect of the nature of the linker connecting proline with the polymeric backbone has been studied, and a 1,2,3‐triazole linker constructed from azidomethyl polystyrene and O‐propargyl hydroxyproline turns out to be optimal for catalytic activity and enantioselectivity. With aldehyde donors, fast reactions leading to complete conversion in 1–3 h are recorded in DMF. With ketone donors, the reactions tend to be slower, but can be efficiently accelerated (six‐membered ring cycloalkanones) by low‐power microwave irradiation. This approach, which greatly facilitates product isolation since the catalyst is removed by simple filtration, has allowed the implementation of the reactions of aldehyde substrates in a continuous‐flow, single‐pass system. In this manner, the continuous synthesis of the enantiomerically and diastereomerically pure adducts (syn/anti>97:3; ee>99 %) has been achieved at room temperature with residence times of 6.0 min. This methodology has allowed for the preparation of up to 7.8 mmol of the desired Mannich adduct through the use of 0.46 mmol of catalytic resin (5.9 mol %), in a greatly simplified experimental protocol that avoids purification steps.     

5‐(Pyrrolidin‐2‐yl)tetrazole‐Catalyzed Aldol and Mannich Reactions: Acceleration and Lower Catalyst Loading in a Continuous‐Flow Reactor

Continuous organocatalysis : Fast aldol and Mannich reactions require less catalyst when conducted in a microreactor. A proline tetrazole derivative (5–10 mol %) catalyzes asymmetric aldol reactions between various aromatic aldehydes and ketones in microreactor at 60 °C with reaction times ranging from 10 to 30 min.

     

Application of a Supramolecular‐Ligand Library for the Automated Search for Catalysts for the Asymmetric Hydrogenation of Industrially Relevant Substrates

A procedure is described for the automated screening and lead optimization of a supramolecular‐ligand library for the rhodium‐catalyzed asymmetric hydrogenation of five challenging substrates relevant to industry. Each catalyst is (self‐) assembled from two urea‐functionalized ligands and a transition‐metal center through hydrogen‐bonding interactions. The modular ligand structure consists of three distinctive fragments: the urea binding motif, the spacer, and the ligand backbone, which carries the phosphorus donor atom. The building blocks for the ligand synthesis are widely available on a commercial basis, thus enabling access to a large number of ligands of high structural diversity. The simple synthetic steps enabled the scale‐up of the ligand synthesis to multigram quantities. For the catalyst screening, a library of twelve new chiral ligands was prepared that comprised substantial variation in electronic and steric properties. The automated procedures employed ensured the fast catalyst assembly, screening, and direct acquisition of samples for analysis. It appeared that the most selective catalyst was different for every substrate investigated and that small variations in the building blocks had a major impact on the catalyst performance. For two substrates, a catalyst was found that provided the product with outstanding enantioselectivity. The subsequent automated optimization of these two leads showed that an increase of catalyst loading, dihydrogen pressure, and temperature had a positive effect on the catalyst activity without affecting the catalyst selectivity.     

Microwave Irradiation for the Facile Synthesis of Transition‐Metal Nanoparticles (NPs) in Ionic Liquids (ILs) from Metal–Carbonyl Precursors and Ru‐, Rh‐, and Ir‐NP/IL Dispersions as Biphasic Liquid–Liquid Hydrogenation Nanocatalysts for Cyclohexene

Stable chromium, molybdenum, tungsten, manganese, rhenium, ruthenium, osmium, cobalt, rhodium, and iridium metal nanoparticles (M‐NPs) have been reproducibly obtained by facile, rapid (3 min), and energy‐saving 10 W microwave irradiation (MWI) under an argon atmosphere from their metal–carbonyl precursors [M_x(CO)_y] in the ionic liquid (IL) 1‐butyl‐3‐methylimidazolium tetrafluoroborate ([BMIm][BF₄]). This MWI synthesis is compared to UV‐photolytic (1000 W, 15 min) or conventional thermal decomposition (180–250 °C, 6–12 h) of [M_x(CO)_y] in ILs. The MWI‐obtained nanoparticles have a very small (<5 nm) and uniform size and are prepared without any additional stabilizers or capping molecules as long‐term stable M‐NP/IL dispersions (characterization by transmission electron microscopy (TEM), transmission electron diffraction (TED), and dynamic light scattering (DLS)). The ruthenium, rhodium, or iridium nanoparticle/IL dispersions are highly active and easily recyclable catalysts for the biphasic liquid–liquid hydrogenation of cyclohexene to cyclohexane with activities of up to 522 (mol product) (mol Ru)^?1 h^?1 and 884 (mol product) (mol Rh)^?1 h^?1 and give almost quantitative conversion within 2 h at 10 bar H₂ and 90 °C. Catalyst poisoning experiments with CS₂ (0.05 equiv per Ru) suggest a heterogeneous surface catalysis of Ru‐NPs.     

Asymmetric Carbon–Carbon Bond Formation under Continuous‐Flow Conditions with Chiral Heterogeneous Catalysts

Catalytic asymmetric carbon–carbon bond‐forming reactions provide one of the most efficient ways to synthesize optically active compounds, and, accordingly, many chiral catalysts for these reactions have been developed in the past two decades. However, the efficiency of the catalysts in terms of turnover number (TON) is often lower than that of some other reactions, such as asymmetric hydrogenation, and this has been one of the obstacles for industrial applications. Although there are some difficulties in increasing the efficiency, the issues might be solved by using continuous flow in the presence of chiral heterogeneous catalysts. Indeed, continuous‐flow systems have several advantages over conventional batch systems. Here we summarize the recent progress in asymmetric C? C bond‐forming reactions under continuous‐flow conditions with chiral heterogeneous catalysts.     

CO2 Hydrogenation over Oxide‐Supported PtCo Catalysts: The Role of the Oxide Support in Determining the Product Selectivity

By simply changing the oxide support, the selectivity of a metal–oxide catalysts can be tuned. For the CO₂ hydrogenation over PtCo bimetallic catalysts supported on different reducible oxides (CeO₂, ZrO₂, and TiO₂), replacing a TiO₂ support by CeO₂ or ZrO₂ selectively strengthens the binding of C,O‐bound and O‐bound species at the PtCo–oxide interface, leading to a different product selectivity. These results reveal mechanistic insights into how the catalytic performance of metal–oxide catalysts can be fine‐tuned.     

Asymmetric Hydrogenation of α-Hydroxy Ketones: A Reaction Sensitive toward Electronic Effect of Substrates

以[RuCl2(benzene)]2 和 SunPhos为原料现场制备的催化剂,催化不对称氢化α-羟基酮类化合物可获得手性1, 2-二醇类化合物,ee值最高达99%。