has seen limited progress owing to their instability in solution and insufficient activation of reactants by single metal sites under ambient conditions. [4,5] Consequently, applications of SACs in organic synthesis were limited to certain hydrogenations, [6,7] oxidations, [8,9] and CC bond formations. [10] Very recently, we have reported the first SAC-catalyzed preparation of pharmaceuticals (Lonidamine etc., and their 15 N-labeled analogues) by selective hydrogenation to E-hydrazones and subsequent cyclization using Pt 1 /CeO 2 catalyst. [11] We have also developed the latestage functionalization of pharmaceuticals (Tamiflu) by chemoselective oxidation of sulfides using Co 1 -in-MoS 2 catalyst. [12] Despite excellent functional group tolerance and synthetic utility in both cases, the scope is limited by the use of complex starting materials (i.e., carboxylic esters mediated α-diazoesters synthesis and multifunctionalized sulfides), and the inaccessibility to synthesize multi-ring system as the reactions mainly involve simple hydrogenation/oxidation. [11,12] Quinolines, a major class of heterocycles, are widely occurring in natural and synthetic products with diverse pharmacological and physical properties. [13,14] Among the many methods to synthesize quinolines, the classical Friedländer condensation of an aromatic 2-amino-substituted carbonyl compound with another substituted carbonyl derivative is one of the simplest The production of high-value chemicals by single-atom catalysis is an attractive proposition for industry owing to its remarkable selectivity. Successful demonstrations to date are mostly based on gas-phase reactions, and reports on liquid-phase catalysis are relatively sparse owing to the insufficient activation of reactants by single-atom catalysts (SACs), as well as, their instability in solution. Here, mechanically strong, hierarchically porous carbon plates are developed for the immobilization of SACs to enhance catalytic activity and stability. The carbon-based SACs exhibit excellent activity and selectivity (≈68%) for the synthesis of substituted quinolines by a three-component oxidative cyclization, affording a wide assortment of quinolines (23 examples) from anilines and acetophenones feedstock in an efficient, atom-economical manner. Particularly, a Cavosonstat derivative can be synthesized through a one-step, Fe 1 -catalyzed cyclization instead of traditional Suzuki coupling. The strategy is also applicable to the deuteration of quinolines at the fourth position, which is challenging by conventional methods. The synthetic utility of the carbon-based SAC, together with its reusability and scalability, renders it promising for industrial scale catalysis.

Single-atom catalysts (SACs) offer many advantages, such as atom economy and high chemoselectivity; however, their practical application in liquid-phase heterogeneous catalysis is hampered by the productivity bottleneck as well as catalyst leaching. Flow chemistry is a well-established method to increase the conversion rate of catalytic processes, however, SAC-catalysed flow chemistry in packed-bed type flow reactor is disadvantaged by low turnover number and poor stability. In this study, we demonstrate the use of fuel cell-type flow stacks enabled exceptionally high quantitative conversion in single atom-catalyzed reactions, as exemplified by the use of Pt SAC-on-MoS2/graphite felt catalysts incorporated in flow cell. A turnover frequency of approximately 8000 h−1 that corresponds to an aniline productivity of 5.8 g h−1 is achieved with a bench-top flow module (nominal reservoir volume of 1 cm3), with a Pt1-MoS2 catalyst loading of 1.5 g (3.2 mg of Pt). X-ray absorption fine structure spectroscopy combined with density functional theory calculations provide insights into stability and reactivity of single atom Pt supported in a pyramidal fashion on MoS2. Our study highlights the quantitative conversion bottleneck in SAC-mediated fine chemicals production can be overcome using flow chemistry.

However, downsizing to single-atom level is not always beneficial to the catalytic process because the cooperative interaction between adjacent singleatom sites reduces with increasing distance from each other. [3,4] In the case of a reaction that requires activation of two (or more) reactants, a dinuclear type catalytic mechanism involving two metal atoms is often more efficient than the mononuclear mechanism. For low-density SACs, the majority of metal sites are isolated from each other and only a single-site mechanism is possible (Figure 1). [5][6][7][8][9][10] The use of few-atom clusters offers multisite pathways, however, this requires specific metal precursors like dimer or trimer complexes to avoid uncontrolled aggregation during heat treatment. [3,[11][12][13] The use of terms like low-density or high-density SACs (or low-loading and high-loading) is not sufficiently quantitative. A more quantitative and fundamental criterion involves the inter-atom distance between SAC that allows a switch from a single-site-catalyzed mechanism to a dinuclear-type mechanism. A systematic study of this problem would require a variation of the inter-atom distance to see if a two-reactant reaction, usually promoted mainly by metal-cluster-type catalytic system, works well for SAC that observes a minimum inter-atom distance. According to previous reports, high loading SACs showed higher activity than low loading counterparts, which was usually explained by the higher density of active sites and/or its distinctive electronic structure. [14][15][16][17][18] Only a handful of studies considered the relationship between performance and inter-atom distance. [14] Overall, there is a lack of understanding on how inter-atom distance influences bimolecular or more complex reactions.Herein, we investigate the efficiency of nitrile-azide cycloaddition as a function of the inter-atom distance of Cu 1 SACs supported on C 3 N 4 by tuning the loading of the SAC. At low loading of the SAC, poor activity was obtained as expected of the singlesite mechanism. At high loading level, Cu 1 -C 3 N 4 SAC enjoys an average inter-atom distance of 0.74 ± 0.13 nm. This is analogous to dinuclear copper intermediate and promotes the 1,3-dipolar cycloaddition. [19,20] The dinuclear-like pathway at high loading Cu 1 -C 3 N 4 SACs was evidenced by operando X-ray absorption (XAS) investigations, which include individual steps such as activation of sodium azide (NaN 3 ), dynamic ligand exchange between NaN 3 and benzylnitrile (PhCN), cycloaddition and formation of tetrazole compound on two nearby Cu sites.