Engineering Single Atom Catalysts for Flow Production: From Catalyst Design to Reactor Understandings

ConspectusIn heterogeneous catalysis, the long-standing challenge is to achieve extremely high activity and chemoselectivity in liquid-phase organic transformations comparable to that of homogeneous or enzymatic processes. Single-atom catalysts (SACs) with atomically precise coordination are developed with the objectives to mimic the homogeneous pathways but face stability issues due to metal leaching or clustering. Additionally, the practical application of SACs in chemical production is hampered by the lack of standard preparation protocols and low conversion using laboratory batch reactors.This Account focuses on our recent studies in both catalyst design and reactor-level engineering for the flow synthesis of fine chemicals via SACs. At the catalyst and reaction level, we will discuss the intrinsic mechanism that controls reactivity and chemoselectivity in the SAC-catalyzed process and highlight examples where SACs outperform other catalytic approaches. Specifically, we reported the SAC-mediated preparation and late-stage functionalization of pharmaceutical drugs, including lonidamine, Tamiflu, cavosonstat, indomethacin, and many others by chemoselective transformations in a sequential or multicomponent manner. The ability of ultrahigh loading SACs in providing a multisite pathway for organic transformations involving two or more reactants is highlighted and contrasted with the single-site pathway in conventional SACs. Molecular-level understanding on the dynamic catalytic cycle obtained using operando X-ray absorption spectroscopies provides guidance for the design of more effective and leach resistant SACs. This also calls for the transformation of laboratory powder-based catalysts into industrially viable monolithic catalysts via formulation to further enhance the leach resistance. At the reactor level, we will highlight the importance of continuous-flow techniques in maximizing productivity and simplifying process transfer from laboratory to commercial production. Particularly, we discuss the use of fuel cell-type flow stacks for quantitative production of fine chemicals, including the synthesis of multifunctional anilines at a 5.8 g h–1 productivity using a Pt SAC module (3.2 mg Pt). Insight into multiscale reactor processes, for instance, the fluid diffusion kinetics, heat transfer, and influence of porosity and the gas–liquid–solid interface are provided by computational fluidic dynamics calculations as well as experimental techniques. In many cases, catalytic processes are more limited by mass diffusion than the intrinsic activity of the catalyst, calling for process optimization and engineering at the reactor level to enhance the productivity. Finally, we also identify technical barriers that need to be overcome in SAC research and offer our perspective on standardized and scalable protocols for mass production, the production cost analysis of typical SACs, high-throughput screening platforms, and novel flow reactor designs involving photochemical and electrochemical reactions for up-scaling chemical production by SACs.