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Shape-selective C–H activation of aromatics to biarylic compounds using molecular palladium in zeolites


The selective activation of inert C–H bonds has emerged as a promising tool for avoiding the use of wasteful traditional coupling reactions. Oxidative coupling of simple aromatics allows for a cost-effective synthesis of biaryls. However, utilization of this technology is severely hampered by poor regioselectivity and by the limited stability of state-of-the-art homogeneous Pd catalysts. Here, we show that confinement of cationic Pd in the pores of a zeolite allows for the shape-selective C–H activation of simple aromatics without a functional handle or electronic bias. For instance, out of six possible isomers, 4,4′-bitolyl is produced with high shape selectivity (80%) in oxidative toluene coupling on Pd-Beta. Not only is a robust, heterogeneous catalytic system obtained, but this concept is also set to control the selectivity in transition-metal-catalysed arene C–H activation through spatial confinement in zeolite pores.

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Fig. 1: Oxidative coupling of toluene with different additives.
Fig. 2: Variation of the reaction temperature in the oxidative coupling of toluene.
Fig. 3: Spectroscopic characterization of Pd-loaded zeolite Beta.
Fig. 4: Variation of the amount of H-Beta, kinetics and filtration test.
Fig. 5: Substrate scope.
Fig. 6: Proposed catalytic cycle for the oxidative coupling of toluene using H-Beta.

Data availability

The findings of this study are available in the main text or the supplementary materials. Atomic coordinates of optimized computational models and initial and final configurations of molecular dynamics trajectories are supplied in a Supplementary Data file. All data are available from the authors upon reasonable request.


  1. Hassan, J., Sévignon, M., Gozzi, C., Schulz, E. & Lemaire, M. Aryl−aryl bond formation one century after the discovery of the Ullmann reaction. Chem. Rev. 102, 1359–1469 (2002).

    Article  CAS  Google Scholar 

  2. Mondschein, R. J. et al. Synthesis and characterization of amorphous bibenzoate (co)polyesters: permeability and rheological performance. Macromolecules 50, 7603–7610 (2017).

    Article  CAS  Google Scholar 

  3. De Smit, E. et al., Hydroalkylation catalyst and process for use thereof. US patent 2014/0378697 (2014).

  4. Dakka, J. M. et al. Biphenyl esters, their production and their use in the manufacture of plasticizers. US patent 9,556,103 (2017).

  5. Chen, X., Engle, K. M., Wang, D. ‐H. & Yu, J. ‐Q. Palladium(II)-catalyzed C–H activation/C–C cross-coupling reactions: versatility and practicality. Angew. Chem. Int. Ed. 48, 5094–5115 (2009).

    Article  CAS  Google Scholar 

  6. Xu, B.-Q., Sood, D., Iretskii, A. V. & White, M. G. Direct synthesis of dimethylbiphenyls by toluene coupling in the presence of palladium triflate and triflic acid. J. Catal. 187, 358–366 (1999).

    Article  CAS  Google Scholar 

  7. Izawa, Y. & Stahl, S. S. Aerobic oxidative coupling of o‐xylene: discovery of 2‐fluoropyridine as a ligand to support selective Pd‐catalyzed C–H functionalization. Adv. Synth. Catal. 352, 3223–3229 (2010).

    Article  CAS  Google Scholar 

  8. Wang, D., Izawa, Y. & Stahl, S. S. Pd-catalyzed aerobic oxidative coupling of arenes: evidence for transmetalation between two Pd(ii)–aryl intermediates. J. Am. Chem. Soc. 136, 9914–9917 (2014).

    Article  CAS  Google Scholar 

  9. Wang, D. & Stahl, S. S. Pd-catalyzed aerobic oxidative biaryl coupling: non-redox cocatalysis by Cu(OTf)2 and discovery of Fe(OTf)3 as a highly effective cocatalyst. J. Am. Chem. Soc. 139, 5704–5707 (2017).

    Article  CAS  Google Scholar 

  10. Álvarez‐Casao, Y. et al. Palladium‐catalyzed cross‐dehydrogenative coupling of o‐xylene: evidence of a new rate‐limiting step in the search for industrially relevant conditions. ChemCatChem 10, 2620–2626 (2018).

    Article  Google Scholar 

  11. Yang, Y., Lan, J. & You, J. Oxidative C–H/C–H coupling reactions between two (hetero)arenes. Chem. Rev. 117, 8787–8863 (2017).

    Article  CAS  Google Scholar 

  12. Kuhl, N., Hopkinson, M. N., Wencel-Delord, J. & Glorius, F. Beyond directing groups: transition-metal-catalyzed C–H activation of simple arenes. Angew. Chem. Int. Ed. 51, 10236–10254 (2012).

    Article  CAS  Google Scholar 

  13. Sambiagio, C. et al. A comprehensive overview of directing groups applied in metal-catalysed C–H functionalisation chemistry. Chem. Soc. Rev. 47, 6603–6743 (2018).

    Article  CAS  Google Scholar 

  14. Leow, D., Li, G., Mei, T.-S. & Yu, J.-Q. Activation of remote meta-C–H bonds assisted by an end-on template. Nature 486, 518–522 (2012).

    Article  CAS  Google Scholar 

  15. Boursalian, G. B., Ham, W. S., Mazzotti, A. R. & Ritter, T. Charge-transfer-directed radical substitution enables para-selective C–H functionalization. Nat. Chem. 8, 810–815 (2016).

    Article  CAS  Google Scholar 

  16. Berger, F. et al. Site-selective and versatile aromatic C–H functionalization by thianthrenation. Nature 567, 223–228 (2019).

    Article  CAS  Google Scholar 

  17. Dey, A., Maity, S. & Maiti, D. Reaching the south: metal-catalyzed transformation of the aromatic para-position. Chem. Commun. 52, 12398–12414 (2016).

    Article  CAS  Google Scholar 

  18. Van Speybroeck, V. et al. Advances in theory and their application within the field of zeolite chemistry. Chem. Soc. Rev. 44, 7044–7111 (2015).

    Article  Google Scholar 

  19. Kosinov, N., Liu, C., Hensen, E. J. M. & Pidko, E. A. Engineering of transition metal catalysts confined in zeolites. Chem. Mater. 30, 3177–3198 (2018).

    Article  CAS  Google Scholar 

  20. Lawton, S. L., Leonowicz, M. E., Partridge, R. D., Chu, P. & Rubin, M. K. Twelve-ring pockets on the external surface of MCM-22 crystals. Micropor. Mesopor. Mat. 23, 109–117 (1998).

    Article  CAS  Google Scholar 

  21. Van Velthoven, N. et al. Single-site metal–organic framework catalysts for the oxidative coupling of arenes via C–H/C–H activation. Chem. Sci. 10, 3616–3622 (2019).

    Article  Google Scholar 

  22. Kaplan, G. Preparation of biphenols by oxidative coupling of alkylphenols using a recyclable copper catalyst. US patent 2003/0050515 (2003)

  23. Eckardt, M., Greb, A. & Simat, T. J. Polyphenylsulfone (PPSU) for baby bottles: a comprehensive assessment on polymer-related non-intentionally added substances (NIAS). Food Addit. Contam. A 35, 1421–1437 (2018).

    Article  CAS  Google Scholar 

  24. Davies, D. L., Macgregor, S. A. & McMullin, C. L. Computational studies of carboxylate-assisted C–H activation and functionalization at group 8–10 transition metal centers. Chem. Rev. 117, 8649–8709 (2017).

    Article  CAS  Google Scholar 

  25. Chen, B., Hou, X., Li, Y. & Wu, Y. Mechanistic understanding of the unexpected meta selectivity in copper-catalyzed anilide C–H bond arylation. J. Am. Chem. Soc. 133, 7668–7671 (2011).

    Article  CAS  Google Scholar 

  26. Deng, C., Zhang, J. & Lin, Z. Theoretical studies on Pd(ii)-catalyzed meta-selective C–H bond arylation of arenes. ACS Catal. 8, 2498–2507 (2018).

    Article  CAS  Google Scholar 

  27. Lane, B. S., Brown, M. A. & Sames, D. Direct palladium-catalyzed C-2 and C-3 arylation of indoles: a mechanistic rationale for regioselectivity. J. Am. Chem. Soc. 127, 8050–8057 (2005).

    Article  CAS  Google Scholar 

  28. Popp, B. V. & Stahl, S. S. Insertion of molecular oxygen into a palladium−hydride bond: computational evidence for two nearly isoenergetic pathways. J. Am. Chem. Soc. 129, 4410–4422 (2007).

    Article  CAS  Google Scholar 

  29. Konnick, M. & Stahl, S. S. Reaction of molecular oxygen with a PdII-hydride to produce a PdII-hydroperoxide: experimental evidence for an HX-reductive-elimination pathway. J. Am. Chem. Soc. 130, 5753–5762 (2008).

    Article  CAS  Google Scholar 

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We thank N. Van Velthoven for discussion. The XAS experiments were performed on beamline BM26A at the European Synchrotron Radiation Facility (ESRF), Grenoble, France. This work was funded by grants from FWO (1S17620N for J.V.; project G0D0518N, G0F2320N, G078118N; EoS BioFACT), the Flemish government (CASAS Methusalem programme for D.D.V.). V.V.S., J.H. and M.B. acknowledge the Research Board of Ghent University (BOF) and funding from the European Union’s Horizon 2020 research and innovation programme (consolidator ERC grant agreement No. 647755 – DYNPOR (2015-2020)). The computational resources and services used were provided by Ghent University (Stevin Supercomputer Infrastructure) and the VSC (Flemish Supercomputer Center), funded by the Research Foundation - Flanders (FWO). A.S. and A.B. acknowledge the funding from Russian Science Foundation (joint RSF-FWO grant No. 20-43-01015). A.K. and G.M. acknowledge the financial support from the Slovenian Research Agency (research core funding No. P1-0021 and project No. N1-0079).

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Authors and Affiliations



Under the supervision of D.D.V., J.V. was responsible for the conception, design and interpretation of the experiments. S.V.M. performed additional experiments. Under the supervision of V.V.S., J.H., S.N. and M.B. performed the DFT calculations. A.B. and A.S. conceived and performed the XAS experiments. A.K. and G.M. conceived and performed the NMR experiments. All authors discussed the results and commented on the manuscript.

Corresponding authors

Correspondence to Véronique Van Speybroeck or Dirk E. De Vos.

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Competing interests

J.V., P.T. and D.D.V. filed a patent application GB1804905.6 prior to an international patent application PCT/EP2019/057746.

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Supplementary information

Supplementary Information

Supplementary Methods, Discussion, Figs. 1–53, Tables 1–16.

Reporting Summary

Supplementary Data 1

Atomic coordinates of optimized computational models and initial and final configurations of molecular dynamics trajectories.

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Vercammen, J., Bocus, M., Neale, S. et al. Shape-selective C–H activation of aromatics to biarylic compounds using molecular palladium in zeolites. Nat Catal 3, 1002–1009 (2020).

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