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Geminal-atom catalysis for cross-coupling


Single-atom catalysts (SACs) have well-defined active sites, making them of potential interest for organic synthesis1,2,3,4. However, the architecture of these mononuclear metal species stabilized on solid supports may not be optimal for catalysing complex molecular transformations owing to restricted spatial environment and electronic quantum states5,6. Here we report a class of heterogeneous geminal-atom catalysts (GACs), which pair single-atom sites in specific coordination and spatial proximity. Regularly separated nitrogen anchoring groups with delocalized π-bonding nature in a polymeric carbon nitride (PCN) host7 permit the coordination of Cu geminal sites with a ground-state separation of about 4 Å at high metal density8. The adaptable coordination of individual Cu sites in GACs enables a cooperative bridge-coupling pathway through dynamic Cu–Cu bonding for diverse C–X (X = C, N, O, S) cross-couplings with a low activation barrier. In situ characterization and quantum-theoretical studies show that such a dynamic process for cross-coupling is triggered by the adsorption of two different reactants at geminal metal sites, rendering homo-coupling unfeasible. These intrinsic advantages of GACs enable the assembly of heterocycles with several coordination sites, sterically congested scaffolds and pharmaceuticals with highly specific and stable activity. Scale-up experiments and translation to continuous flow suggest broad applicability for the manufacturing of fine chemicals.

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Fig. 1: Synthesis and characterization of Cug/PCN.
Fig. 2: Substrate scope of Cug/PCN-catalysed cross-couplings.
Fig. 3: Proposed catalytic mechanism of C–O coupling over Cug/PCN.
Fig. 4: Advantages of geminal-atom catalysis for organic synthesis.

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Data availability

All data are available in the manuscript or in the Supplementary information. The data for the LCA analysis are deposited in the Zenodo repository:


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J. Lu acknowledges support from MOE Tier 2 (MOE-T2EP50121-0008) and the Agency for Science, Technology and Research (A*STAR) under its MTC IRG grant (project nos. M22K2c0082 and A20E5c0096). Y. Zhu acknowledges support from Pharma Innovation Programme Singapore (PIPS, A*STAR-IAF-PP A19B3a0016 and A20B3a0107). M.J.K. acknowledges support from MOE Tier 2 (MOE-T2EP10122-0003). R.Z. acknowledges financial support from the National Natural Science Foundation of China (grant 51825201). S.M., V.T., G.G.-G. and J.P.-R. acknowledge funding from NCCR Catalysis (grant 180544), a National Centre of Competence in Research funded by the Swiss National Science Foundation. Jun Li acknowledges financial support from the National Natural Science Foundation of China (grant 22033005), NSFC Center for Single-Atom Catalysis, National Key R&D Project (nos. 2022YFA1503900 and 2022YFA1503000) and the Guangdong Provincial Key Laboratory of Catalysis (no. 2020B121201002). Q.Y. acknowledges financial support by the Natural Science Basic Research Program of Shaanxi (2021JCW-20 and 2022KJXX-18). We acknowledge the computational resources supported by the Center for Computational Science and Engineering (SUSTech), Tsinghua National Laboratory for Information Science and Technology and the National Supercomputing Centre (NSCC) Singapore. Q.Y. is grateful for the hospitality of Tsinghua University during her sabbatical visit.

Author information

Authors and Affiliations



J. Lu supervised the project and organized the collaboration. X.H. and J. Lu conceived the research and proposed geminal-atom catalysis. X.H. designed the experiments and synthesized the materials. Jun Li and Q.Y. conceived the Cu–Cu bonding reaction mechanism and carried out quantum-chemical calculations. N.G. and C.Z. carried out theoretical calculations of the periodic structures. Y. Zhe., X.H. and Y. Zhu discovered the catalytic activity. M.J.K. and X. Luo conducted the comparison studies and synthetic applications. S.X. performed the XAFS measurement and structural analysis. X.Z. and Y.C. performed the electron microscopy experiments and data analysis. X.S. and X.P. performed the scanning tunnelling microscope experiments. J.W., X. Lo and M.W. performed the continuous-flow synthesis. V.T., J.P.-R. and G.G.-G. performed the LCA analysis and interpreted the results. S.M. and J.P.-R. advised on the experiments, methodologies and data presentation. L.R., Jing Li, P.H., H.L., J.S. and R.Z. assisted with materials characterization and data analysis. X.H. wrote the draft, with the assistance of Q.Y., Y. Zhe. and S.M. All authors discussed the results and edited and commented on the manuscript.

Corresponding authors

Correspondence to Shibo Xi, Javier Pérez-Ramírez, Ming Joo Koh, Ye Zhu, Jun Li or Jiong Lu.

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Nature thanks Jagadeesh Rajenahally and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data figures and tables

Extended Data Fig. 1 STM characterization of Cug/PCN.

a, Overview STM image after annealing PCN on Cu(111) at 370 K, V = 2.0 V, I = 20 pA. b, Corresponding constant-height STM image with a CO-functionalized tip (V = 5 mV, Δz = −20 pm; set point before turning off feedback, V = 5 mV, I = 200 pA).

Extended Data Fig. 2 Characterization of Cug/PCN.

a, High-resolution TEM image with the corresponding Fourier transform diffraction pattern inset. b, ADF-STEM image and corresponding elemental maps. c, Atomic force microscopy image of Cug/PCN with height profile inset. d, XRD patterns of PCN and Cug/PCN. e, Cu 2p XPS spectra of Cug/PCN. The peaks at 932.8 eV and 952.7 eV are assigned to Cu(I). The solid red line and dotted black line represent the experiment and fitting curves, respectively. f, EPR spectra of Cug/PCN and the reference CuCl2.

Extended Data Fig. 3 Comparison of the experimental and modelled Cu K-edge XANES spectra.

The corresponding DFT-modelled atomic structures are shown in the insets. Colour code: C, grey; N, blue; O, green; Cu, orange; H, white.

Extended Data Fig. 4 Substrate scope of Cug/PCN-catalysed cross-coupling and cycloaddition.

Product isolated yields obtained in Cug/PCN-catalysed C–N (5272) and C–O bond formations (7382). Products yields for Cug/PCN-catalysed azide–alkyne cycloadditions (8390) determined by gas chromatography.

Extended Data Fig. 5 Cug/PCN-catalysed pharmaceutical and biorelevant molecules.

a, Synthesis of pharmaceutical compounds (9193) in multisteps and one-pot manner. b, Synthesis of biorelevant molecules (9496) from natural products.

Extended Data Fig. 6 Characterization of Cu1/PCN with different Cu contents.

ADF-STEM images (scale bar, 1 nm) (a), FTIR spectra (b) and Fourier-transformed EXAFS spectra (c) of Cu1/PCN samples with different Cu contents. Red and yellow dashed lines encircle GAC and SAC sites, respectively.

Extended Data Fig. 7 Electronic structure of Cu1/PCN with different Cu contents.

Cu K-edge XANES (a) and Cu 2p XPS (b) spectra of Cu1/PCN samples with different Cu contents. c,d, Charge density distributions and PDOS of monomeric (c) and geminal (d) Cu sites, respectively. Colour code: Cu, pink; C, grey; N, blue; H, white.

Extended Data Fig. 8 In situ XANES and EPR spectra during C–O coupling reaction.

a,b, In situ Cu K-edge XANES (a) and Fourier-transformed EXAFS (b) spectra of Cug/PCN catalyst measured before and in the C–O coupling reaction, respectively. c, In situ EPR spectra of Cug/PCN recorded at different times in the C–O coupling reaction. The chemical state change of Cug/PCN during the C–O cross-coupling reaction cycle was clearly seen from Cu K-edge XANES. A distinct weakening of the feature peak at 8,983 eV and an increase of the main peak at 8,996 eV indicate that the valence state of Cu increases during the reaction, which is related to the successful adsorption of 4-iodotoluene or methanol. Correspondingly, the intensity of the main peak related to the first coordination sphere in the Fourier-transformed EXAFS spectra increases, evidencing the increased coordination number of Cu. The change in the chemical valence state of Cu during the reaction cycle is further explained by in situ EPR spectroscopy. EPR-silent Cu(I) is first oxidized to EPR-sensitive Cu(II) with a gradually enhanced signal intensity and then reduced to the original Cu(I) state during a complete reaction process, in line with the in situ XAFS results.

Extended Data Fig. 9 Stability of Cug/PCN in C–O coupling.

a, Cycling test for the coupling of 4-iodotoluene with ethanol to form C–O bond over Cug/PCN. FTIR spectra (b), XRD pattern (c), XPS spectra (d), Cu K-edge Fourier-transformed EXAFS (e) and XANES (f) spectra of the as-prepared Cug/PCN and the catalyst recovered after nine reaction cycles.

Supplementary information

Supplementary Information

Supplementary Figs. 1–23, Supplementary Tables 1–7 and NMR data.

Supplementary Video 1

Animation following the path for the C–O coupling reaction with the Cu GACs calculated by DFT.

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Hai, X., Zheng, Y., Yu, Q. et al. Geminal-atom catalysis for cross-coupling. Nature 622, 754–760 (2023).

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