The industrial production of chiral entities, estimated at over 10,000 tons, necessitates the development of catalysts exhibiting both excellent enantioselectivity and high turnover numbers (TONs) for asymmetric hydrogenation. Noyori-type catalysts, while achieving high enantioselectivities (>98% ee), typically exhibit limited TONs (a few million) and TOFs (hundreds) in the asymmetric hydrogenation of aryl alkyl ketones. This limitation is particularly pronounced for challenging nitrogen-containing ketones, crucial building blocks for high-value bioactive compounds, where reported TONs rarely exceed 10,000. This restricts their practical industrial application. In contrast to inner-sphere mechanisms, outer-sphere mechanisms, exemplified by Noyori-type catalysts (Ru(bisphos)(diamine), Ir-PNN complexes), avoid substrate contact with the metal center, promoting catalyst stability and enantioselectivity. While Zhou's tridentate Ir-PNN catalyst holds the record for TONs (4,550,000 at 98% ee), achieving ultra-efficient catalysts with 10-million TONs and biocatalysis-like TOFs remains a significant challenge. This necessitates a shift beyond the state-of-the-art NH/MH bifunctional catalysts. Inspired by highly reactive anionic reductants and multidentate Noyori-type catalysts, the researchers propose integrating anionic complexes and multidentate ligands to enhance catalyst efficiency, selectivity, and stability. Anionic complexes, with a formal negative charge, theoretically enhance hydricity and reaction rates, a concept demonstrated by previous anionic metal hydride catalysts. Multidentate ligands simultaneously stabilize the metal center through coordinative saturation, creating a well-defined chiral environment and promoting catalyst stability and selectivity.

The literature review extensively covers existing catalysts for asymmetric hydrogenation, particularly focusing on Noyori-type catalysts and their limitations in achieving high TONs and TOFs, especially for challenging substrates like nitrogen-containing ketones. The review highlights the advantages of outer-sphere mechanisms over inner-sphere mechanisms in terms of catalyst stability and selectivity. The authors specifically discuss the record-high TON achieved by Zhou's Ir-PNN catalyst, emphasizing the need for further advancements to reach biocatalysis-like efficiencies. The review also touches upon various aspects of catalyst design, including the roles of ligands, metal centers, and reaction mechanisms. Key challenges and limitations of existing catalysts are clearly outlined, setting the stage for the introduction of the researchers' novel catalyst.

The study begins with the optimization of the catalytic reaction using iridium catalysts based on a tetradentate PNNO ligand (f-phamidol). Initial experiments used a substrate/catalyst ratio of 2,000,000 with acetophenone as the benchmark substrate. Different bases were tested, and NaOtBu was identified as superior, leading to 99% conversion in 16 hours (1,980,000 TONs). Solvent addition proved crucial for achieving both high enantioselectivity and TON. Subsequent experiments systematically varied the substrate/catalyst ratio (5,000,000 to 15,380,000), revealing a steady increase in TONs while maintaining excellent enantioselectivities (99% ee). The highest TON (13,425,000) was achieved with 800 mmol of acetophenone at 100 bar H2 over 30 days, demonstrating exceptional stability and enantioselectivity. The initial TOF was determined from pressure-drop curves and reached an ultra-high value of 224 s−1, approaching biocatalytic efficiency. The catalyst's effectiveness was further evaluated using various substrates, including challenging nitrogen-containing ketones. Gram-scale experiments showed excellent results, even for substrates containing both amide and pyridine functionalities, which often deactivate catalysts. The key step in the synthesis of nicotine was successfully conducted at 40 kg scale. At an industrial scale, 500 kg batch reactions in a 2000 L reactor demonstrated full conversion and high enantioselectivity (98.9% ee) within 2 hours using KOH as the base. Further scale-up and process optimization, including using recycled solvents, allowed for the production of 40 tons of nicotine with 99% ee. The characterization of the catalyst involved HRMS, NMR, ATR-IR, Raman, XRD, and DFT calculations, revealing the formation of anionic Ir-complexes with a preferred ONa/MH bifunctional mechanism. Control experiments using modified ligands confirmed the crucial role of the tetradentate PNNO ligand and the anionic oxygen donor in achieving high TONs and selectivity. DFT calculations were used to explore the reaction mechanism, comparing ONa/MH and NNa/MH pathways. Kinetic studies unexpectedly revealed 1.9th order in H2 pressure and 1.5th order in iridium concentration, suggesting a complex mechanism requiring further investigation. The enhanced activity was attributed to orbital interactions between the Ir atom and hydride ligands, leading to increased hydricity.

The research produced a highly efficient anionic iridium catalyst for asymmetric hydrogenation, achieving unprecedented turnover numbers (TONs) and turnover frequencies (TOFs). Key findings include: 1. **Record-High TON and TOF:** The catalyst demonstrated a remarkable TON of 13,425,000 and a TOF of 224 s−1 for acetophenone hydrogenation, approaching biocatalytic efficiency. This far surpasses previously reported values for similar catalysts. 2. **Exceptional Performance with Challenging Substrates:** The catalyst also exhibited exceptional performance in the hydrogenation of challenging nitrogen-containing ketones, achieving TONs up to 1,000,000 and 99% ee, a significant improvement over existing technologies. 3. **Successful Industrial-Scale Application:** The catalyst was successfully implemented in a selective industrial route to enantiopure nicotine, producing 40 tons of product at a 500 kg batch scale. This demonstrates the catalyst's scalability and practical applicability. 4. **Novel Mechanistic Insights:** The study revealed a novel ONa/MH bifunctional mechanism, contrasting with the commonly observed NNa/MH mechanism. This was supported by in situ spectroscopy, DFT calculations, and kinetic experiments. The enhanced activity was attributed to increased hydricity of the metal-hydride due to orbital interactions. 5. **Detailed Catalyst Characterization:** The catalyst was characterized using various techniques including HRMS, NMR, ATR-IR, Raman, XRD, and DFT calculations. These provided crucial structural information and mechanistic insights. 6. **Control Experiments:** Control experiments using modified ligands confirmed the crucial role of the tetradentate PNNO ligand structure and the anionic oxygen donor for high TON, reaction rate, and selectivity.

The development of this ultra-efficient anionic Ir-catalyst represents a significant advancement in asymmetric hydrogenation catalysis. The achievement of 13-million TONs and biocatalysis-like TOFs for acetophenone hydrogenation, along with the high efficiency observed for challenging nitrogen-containing ketones, addresses the limitations of existing catalysts in terms of both activity and substrate scope. The successful industrial-scale application in nicotine synthesis showcases the catalyst's practical potential. The identification of the novel ONa/MH bifunctional mechanism contributes valuable fundamental understanding to the field. This work not only delivers a highly effective catalyst for industrial applications but also lays a foundation for further research in designing and optimizing anionic catalysts for a broader range of chemical transformations. The unexpected kinetic orders observed suggest a complex reaction mechanism warranting further investigation.

This research successfully developed and implemented an anionic iridium catalyst for asymmetric hydrogenation with record-breaking turnover numbers and frequencies, significantly advancing the field. The catalyst's exceptional performance was demonstrated through its application in the industrial-scale synthesis of chiral nicotine. Future research should focus on further mechanistic studies to fully elucidate the complex kinetics and on expanding the catalyst's applicability to other challenging substrates. Exploring different anionic ligands and metal centers could lead to even more efficient and versatile catalysts.

While the catalyst demonstrates remarkable performance, some limitations should be noted. The unusual kinetic orders observed (1.9th order in H2 pressure and 1.5th order in iridium concentration) suggest a more complex mechanism than initially assumed. Further investigation is needed to fully understand these kinetics and potentially optimize the reaction conditions. The study primarily focuses on acetophenone and nicotine synthesis; further research is necessary to determine the catalyst's effectiveness with a wider range of substrates. Finally, the long reaction times for some of the high-TON experiments might pose limitations for certain industrial applications. Further optimization of reaction conditions may be needed to reduce these times.