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Unveiling the full reaction path of the Suzuki–Miyaura cross-coupling in a single-molecule junction

Nature Nanotechnology volume 16, pages 1214–1223 (2021)Cite this article

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Abstract

Conventional analytic techniques that measure ensemble averages and static disorder provide essential knowledge of the reaction mechanisms of organic and organometallic reactions. However, single-molecule junctions enable the in situ, label-free and non-destructive sensing of molecular reaction processes at the single-event level with an excellent temporal resolution. Here we deciphered the mechanism of Pd-catalysed Suzuki–Miyaura coupling by means of a high-resolution single-molecule platform. Through molecular engineering, we covalently integrated a single molecule Pd catalyst into nanogapped graphene point electrodes. We detected sequential electrical signals that originated from oxidative addition/ligand exchange, pretransmetallation, transmetallation and reductive elimination in a periodic pattern. Our analysis shows that the transmetallation is the rate-determining step of the catalytic cycle and clarifies the controversial transmetallation mechanism. Furthermore, we determined the kinetic and thermodynamic constants of each elementary step and the overall catalytic timescale of this Suzuki–Miyaura coupling. Our work establishes the single-molecule platform as a detection technology for catalytic organochemistry that can monitor transition-metal-catalysed reactions in real time.

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Fig. 1: Design of a single-molecule catalyst device.
Fig. 2: Preparation and characterization of a single-molecule catalyst device.
Fig. 3: Electrical characterization and signal attribution of the single-molecule Suzuki–Miyaura cross-coupling reaction.
Fig. 4: Intermediate-controlled experiments.
Fig. 5: Theoretical potential energy surface calculation of the single-molecule Suzuki–Miyaura cross-coupling reaction.
Fig. 6: Dynamic characterization of a single-molecule Suzuki–Miyaura cross-coupling reaction.

Data availability

The datasets used in this work are available online from the Zenodo repository at https://doi.org/10.5281/zenodo.4903414. Source data are provided with this paper.

References

  1. Coontz, R. Not so simple. Science 305, 957–957 (2004).

    Article  CAS  Google Scholar 

  2. Barkai, E., Jung, Y. & Silbey, R. Theory of single-molecule spectroscopy: beyond the ensemble average. Annu. Rev. Phys. Chem. 55, 457–507 (2004).

    Article  CAS  Google Scholar 

  3. Lu, H. P., Xun, L. Y. & Xie, X. S. Single-molecule enzymatic dynamics. Science 282, 1877–1882 (1998).

    Article  CAS  Google Scholar 

  4. Armani, A. M., Kulkarni, R. P., Fraser, S. E., Flagan, R. C. & Vahala, K. J. Label-free, single-molecule detection with optical microcavities. Science 317, 783–787 (2007).

    Article  CAS  Google Scholar 

  5. Li, Y., Yang, C. & Guo, X. Single-molecule electrical detection: a promising route toward the fundamental limits of chemistry and life science. Acc. Chem. Res. 53, 159–169 (2020).

    Article  CAS  Google Scholar 

  6. Aviram, A. & Ratner, M. A. Molecular rectifiers. Chem. Phys. Lett. 29, 277–283 (1974).

    Article  CAS  Google Scholar 

  7. Venkataraman, L. et al. Electronics and chemistry: varying single-molecule junction conductance using chemical substituents. Nano Lett. 7, 502–506 (2007).

    Article  CAS  Google Scholar 

  8. Su, T. A., Li, H., Steigerwald, M. L., Venkataraman, L. & Nuckolls, C. Stereoelectronic switching in single-molecule junctions. Nat. Chem. 7, 215–220 (2015).

    Article  CAS  Google Scholar 

  9. Miyaura, N. & Suzuki, A. Palladium-catalyzed cross-coupling reactions of organoboron compounds. Chem. Rev. 95, 2457–2483 (1995).

    Article  CAS  Google Scholar 

  10. Beletskaya, I. P., Alonso, F. & Tyurin, V. The Suzuki–Miyaura reaction after the Nobel prize. Coord. Chem. Rev. 385, 137–173 (2019).

    Article  CAS  Google Scholar 

  11. Thomas, A. A. & Denmark, S. E. Pre-transmetalation intermediates in the Suzuki–Miyaura reaction revealed: the missing link. Science 352, 329–332 (2016).

    Article  CAS  Google Scholar 

  12. Thomas, A. A., Wang, H., Zahrt, A. F. & Denmark, S. E. Structural, kinetic, and computational characterization of the elusive arylpalladium(II)boronate complexes in the Suzuki–Miyaura reaction. J. Am. Chem. Soc. 139, 3805–3821 (2017).

    Article  CAS  Google Scholar 

  13. Thomas, A. A., Zahrt, A. F., Delaney, C. P. & Denmark, S. E. Elucidating the role of the boronic esters in the Suzuki–Miyaura reaction: structural, kinetic, and computational investigations. J. Am. Chem. Soc. 140, 4401–4416 (2018).

    Article  CAS  Google Scholar 

  14. Lennox, A. J. J. & Lloyd-Jones, G. C. Transmetalation in the Suzuki–Miyaura coupling: the fork in the trail. Angew. Chem. Int. Ed. 52, 7362–7370 (2013).

    Article  CAS  Google Scholar 

  15. Matos, K. & Soderquist, J. A. Alkylboranes in the Suzuki–Miyaura coupling: stereochemical and mechanistic studies. J. Org. Chem. 63, 461–470 (1998).

    Article  CAS  Google Scholar 

  16. Carrow, B. P. & Hartwig, J. F. Distinguishing between pathways for transmetalation in Suzuki–Miyaura reactions. J. Am. Chem. Soc. 133, 2116–2119 (2011).

    Article  CAS  Google Scholar 

  17. Amatore, C., Jutand, A. & Le Duc, G. Kinetic data for the transmetalation/reductive elimination in palladium-catalyzed Suzuki–Miyaura reactions: unexpected triple role of hydroxide ions used as base. Chem. Eur. J. 17, 2492–2503 (2011).

    Article  CAS  Google Scholar 

  18. Braga, A. A. C., Ujaque, G. & Maseras, F. A DFT study of the full catalytic cycle of the Suzuki–Miyaura cross-coupling on a model system. Organometallics 25, 3647–3658 (2006).

    Article  CAS  Google Scholar 

  19. Gu, C. et al. Label-free dynamic detection of single-molecule nucleophilic-substitution reactions. Nano Lett. 18, 4156–4162 (2018).

    Article  CAS  Google Scholar 

  20. Guan, J. X. et al. Direct single-molecule dynamic detection of chemical reactions. Sci. Adv. 4, eaar2177 (2018).

    Article  Google Scholar 

  21. Polanyi, J. C. & Zewail, A. H. Direct observation of the transition-state. Acc. Chem. Res. 28, 119–132 (1995).

    Article  CAS  Google Scholar 

  22. Xin, N. et al. Concepts in the design and engineering of single-molecule electronic devices. Nat. Rev. Phys. 1, 211–230 (2019).

    Article  Google Scholar 

  23. Li, G. et al. Mechanistic study of Suzuki–Miyaura cross-coupling reactions of amides mediated by [Pd(NHC)(allyl)Cl] precatalysts. ChemCatChem 10, 3096–3106 (2018).

    Article  CAS  Google Scholar 

  24. Meconi, G. M. et al. Mechanism of the Suzuki–Miyaura cross-coupling reaction mediated by [Pd(NHC)(allyl)Cl] precatalysts. Organometallics 36, 2088–2095 (2017).

    Article  CAS  Google Scholar 

  25. Melvin, P. R., Balcells, D., Hazari, N. & Nova, A. Understanding precatalyst activation in cross-coupling reactions: alcohol facilitated reduction from Pd(II) to Pd(0) in precatalysts of the type (η3-allyl)Pd(L)(Cl) and (η3-indenyl)Pd(L)(Cl). ACS Catal. 5, 5596–5606 (2015).

    Article  CAS  Google Scholar 

  26. Zhou, T. et al. [Pd(NHC)(μ-Cl)Cl]2: versatile and highly reactive complexes for cross-coupling reactions that avoid formation of inactive Pd(I) off-cycle products. iScience 23, 101377 (2020).

    Article  CAS  Google Scholar 

  27. Balcells, D. & Nova, A. Designing Pd and Ni catalysts for cross-coupling reactions by minimizing off-cycle species. ACS Catal. 8, 3499–3515 (2018).

    Article  CAS  Google Scholar 

  28. Cao, Y. et al. Building high-throughput molecular junctions using indented graphene point contacts. Angew. Chem. Int. Ed. 51, 12228–12232 (2012).

    Article  CAS  Google Scholar 

  29. Gaudreau, L. et al. Universal distance-scaling of nonradiative energy transfer to graphene. Nano Lett. 13, 2030–2035 (2013).

    Article  CAS  Google Scholar 

  30. Rust, M. J., Bates, M. & Zhuang, X. Sub-diffraction-limit imaging by stochastic optical reconstruction microscopy (STORM). Nat. Methods 3, 793–795 (2006).

    Article  CAS  Google Scholar 

  31. Marion, N. et al. Modified (NHC)Pd(allyl)Cl (NHC = N-heterocyclic carbene) complexes for room-temperature Suzuki–Miyaura and Buchwald–Hartwig reactions. J. Am. Chem. Soc. 128, 4101–4111 (2006).

    Article  CAS  Google Scholar 

  32. Fantasia, S. & Nolan, S. P. A general synthetic route to mixed NHC-phosphane palladium(0) complexes (NHC = N-heterocyclic carbene). Chem. Eur. J. 14, 6987–6993 (2008).

    CAS  Google Scholar 

  33. Hruszkewycz, D. P., Balcells, D., Guard, L. M., Hazari, N. & Tilset, M. Insight into the efficiency of cinnamyl-supported precatalysts for the Suzuki–Miyaura reaction: observation of Pd(I) dimers with bridging allyl ligands during catalysis. J. Am. Chem. Soc. 136, 7300–7316 (2014).

    Article  CAS  Google Scholar 

  34. Hruszkewycz, D. P. et al. Effect of 2-substituents on allyl-supported precatalysts for the Suzuki–Miyaura reaction: relating catalytic efficiency to the stability of palladium(I) bridging allyl dimers. Organometallics 34, 381–394 (2015).

    Article  CAS  Google Scholar 

  35. Melvin, P. R. et al. Design of a versatile and improved precatalyst scaffold for palladium-catalyzed cross-coupling: (η3-1-tBu-indenyl)2(μ-Cl)2Pd2. ACS Catal. 5, 3680–3688 (2015).

    Article  CAS  Google Scholar 

  36. Comanescu, C. C. & Iluc, V. M. EH (E = N, O) bond activation by a nucleophilic palladium carbene. Polyhedron 143, 176–183 (2018).

    Article  CAS  Google Scholar 

  37. Grushin, V. V. & Alper, H. The existence and stability of mononuclear and binuclear organopalladium hydroxo complexes, [(R3P)2Pd(R′)(OH)]and [(R3P)2Pd2(R′)2(μ-OH)2]. Organometallics 15, 5242–5245 (1996).

    Article  CAS  Google Scholar 

  38. Moriya, T., Miyaura, N. & Suzuki, A. Synthesis of allenes by palladium-catalyzed cross-coupling reaction of organoboron compounds with propargylic carbonates: transmetalation of organoboron compounds with (alkoxo)palladium complexes under neutral conditions. Synlett 1994, 149–151 (1994).

    Article  Google Scholar 

  39. Sherwood, J., Clark, J. H., Fairlamb, I. J. S. & Slattery, J. M. Solvent effects in palladium catalysed cross-coupling reactions. Green Chem. 21, 2164–2213 (2019).

    Article  CAS  Google Scholar 

  40. Senn, H. M. & Ziegler, T. Oxidative addition of aryl halides to palladium(0) complexes: a density-functional study including solvation. Organometallics 23, 2980–2988 (2004).

    Article  CAS  Google Scholar 

  41. Milescu, L. S., Yildiz, A., Selvin, P. R. & Sachs, F. Maximum likelihood estimation of molecular motor kinetics from staircase dwell-time sequences. Biophys. J. 91, 1156–1168 (2006).

    Article  CAS  Google Scholar 

  42. Barrios-Landeros, F., Carrow, B. P. & Hartwig, J. F. Effect of ligand steric properties and halide identity on the mechanism for oxidative addition of haloarenes to trialkylphosphine Pd(0) complexes. J. Am. Chem. Soc. 131, 8141–8154 (2009).

    Article  CAS  Google Scholar 

  43. Ciampi, S., Darwish, N., Aitken, H. M., Diez-Perez, I. & Coote, M. L. Harnessing electrostatic catalysis in single molecule, electrochemical and chemical systems: a rapidly growing experimental tool box. Chem. Soc. Rev. 47, 5146–5164 (2018).

    Article  CAS  Google Scholar 

  44. Shaik, S., Danovich, D., Joy, J., Wang, Z. & Stuyver, T. Electric-field mediated chemistry: uncovering and exploiting the potential of (oriented) electric fields to exert chemical catalysis and reaction control. J. Am. Chem. Soc. 142, 12551–12562 (2020).

    Article  CAS  Google Scholar 

  45. Wolfe, J. P., Singer, R. A., Yang, B. H. & Buchwald, S. L. Highly active palladium catalysts for Suzuki coupling reactions. J. Am. Chem. Soc. 121, 9550–9561 (1999).

    Article  CAS  Google Scholar 

  46. Yang, C. et al. Electric field-catalyzed single-molecule Diels–Alder reaction dynamics. Sci. Adv. 7, eabf0689 (2021).

    Article  CAS  Google Scholar 

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Acknowledgements

We acknowledge primary financial support from the National Key R&D Program of China (2017YFA0204901), the National Natural Science Foundation of China (21727806, 21933001 and 21772003) and the Tencent Foundation through the XPLORER PRIZE. The research at UCLA was supported by the US National Science Foundation (CHE 1764328). S.Z. and Z.L. appreciate the support from the High-Performance Computing Platform of the Center for Life Science at Peking University.

Author information

Author notes

  1. These authors contributed equally: Chen Yang, Lei Zhang, Chenxi Lu.

Authors and Affiliations

  1. Beijing National Laboratory for Molecular Sciences, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University, Beijing, P. R. China

    Chen Yang, Shuyao Zhou, Yu Li, Zhirong Liu & Xuefeng Guo

  2. Department of Energy and Resources Engineering, College of Engineering, Peking University, Beijing, P. R. China

    Lei Zhang & Fanyang Mo

  3. Department of Chemistry and Biochemistry, University of California, Los Angeles, CA, USA

    Chenxi Lu, Yanwei Li & K. N. Houk

  4. Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, P. R. China

    Xingxing Li & Jinlong Yang

  5. Environment Research Institute, Shandong University, Qingdao, P. R. China

    Yanwei Li

  6. Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA, USA

    Yang Yang

  7. Center of Single-Molecule Sciences, Institute of Modern Optics, College of Electronic Information and Optical Engineering, Nankai University, Tianjin, P. R. China

    Xuefeng Guo

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Contributions

X.G., F.M. and K.N.H. conceived and designed the experiments. C.Y., L.Z. and Yu Li fabricated the devices and performed the device measurements. L.Z. carried out the molecular synthesis. C.L., S.Z., X.L., Yanwei Li, Z.L. and J.Y. built and analysed the theoretical model and performed the quantum transport calculations. X.G., F.M., K.N.H., Y.Y., C.Y. and L.Z. analysed the data and wrote the paper. All the authors discussed the results and commented on the manuscript.

Corresponding authors

Correspondence to K. N. Houk, Fanyang Mo or Xuefeng Guo.

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Peer review information Nature Nanotechnology thanks Nadim Darwish, Albert Poater and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Supplementary Sections 1–16, Figs. 1–39 and Tables 1–5.

Supplementary Data 1

Supplementary source data and original figures including compounds 1–3, Scheme 1, Figs. 1–39 and Tables 1–5.

Supplementary Video 1

Highly correlated fluorescent and current signals of the single-molecule catalyst site during the Suzuki–Miyaura cross-coupling.

Source data

Source Data Fig. 1

Original NMR data.

Source Data Fig. 2

Statistical source data and original figures.

Source Data Fig. 3

Statistical source data.

Source Data Fig. 4

Statistical source data.

Source Data Fig. 6

Statistical source data.

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Yang, C., Zhang, L., Lu, C. et al. Unveiling the full reaction path of the Suzuki–Miyaura cross-coupling in a single-molecule junction. Nat. Nanotechnol. 16, 1214–1223 (2021). https://doi.org/10.1038/s41565-021-00959-4

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