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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Coontz, R. Not so simple. Science 305, 957–957 (2004).
Barkai, E., Jung, Y. & Silbey, R. Theory of single-molecule spectroscopy: beyond the ensemble average. Annu. Rev. Phys. Chem. 55, 457–507 (2004).
Lu, H. P., Xun, L. Y. & Xie, X. S. Single-molecule enzymatic dynamics. Science 282, 1877–1882 (1998).
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).
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).
Aviram, A. & Ratner, M. A. Molecular rectifiers. Chem. Phys. Lett. 29, 277–283 (1974).
Venkataraman, L. et al. Electronics and chemistry: varying single-molecule junction conductance using chemical substituents. Nano Lett. 7, 502–506 (2007).
Su, T. A., Li, H., Steigerwald, M. L., Venkataraman, L. & Nuckolls, C. Stereoelectronic switching in single-molecule junctions. Nat. Chem. 7, 215–220 (2015).
Miyaura, N. & Suzuki, A. Palladium-catalyzed cross-coupling reactions of organoboron compounds. Chem. Rev. 95, 2457–2483 (1995).
Beletskaya, I. P., Alonso, F. & Tyurin, V. The Suzuki–Miyaura reaction after the Nobel prize. Coord. Chem. Rev. 385, 137–173 (2019).
Thomas, A. A. & Denmark, S. E. Pre-transmetalation intermediates in the Suzuki–Miyaura reaction revealed: the missing link. Science 352, 329–332 (2016).
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).
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).
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).
Matos, K. & Soderquist, J. A. Alkylboranes in the Suzuki–Miyaura coupling: stereochemical and mechanistic studies. J. Org. Chem. 63, 461–470 (1998).
Carrow, B. P. & Hartwig, J. F. Distinguishing between pathways for transmetalation in Suzuki–Miyaura reactions. J. Am. Chem. Soc. 133, 2116–2119 (2011).
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).
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).
Gu, C. et al. Label-free dynamic detection of single-molecule nucleophilic-substitution reactions. Nano Lett. 18, 4156–4162 (2018).
Guan, J. X. et al. Direct single-molecule dynamic detection of chemical reactions. Sci. Adv. 4, eaar2177 (2018).
Polanyi, J. C. & Zewail, A. H. Direct observation of the transition-state. Acc. Chem. Res. 28, 119–132 (1995).
Xin, N. et al. Concepts in the design and engineering of single-molecule electronic devices. Nat. Rev. Phys. 1, 211–230 (2019).
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).
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).
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).
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).
Balcells, D. & Nova, A. Designing Pd and Ni catalysts for cross-coupling reactions by minimizing off-cycle species. ACS Catal. 8, 3499–3515 (2018).
Cao, Y. et al. Building high-throughput molecular junctions using indented graphene point contacts. Angew. Chem. Int. Ed. 51, 12228–12232 (2012).
Gaudreau, L. et al. Universal distance-scaling of nonradiative energy transfer to graphene. Nano Lett. 13, 2030–2035 (2013).
Rust, M. J., Bates, M. & Zhuang, X. Sub-diffraction-limit imaging by stochastic optical reconstruction microscopy (STORM). Nat. Methods 3, 793–795 (2006).
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).
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).
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).
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).
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).
Comanescu, C. C. & Iluc, V. M. EH (E = N, O) bond activation by a nucleophilic palladium carbene. Polyhedron 143, 176–183 (2018).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Yang, C. et al. Electric field-catalyzed single-molecule Diels–Alder reaction dynamics. Sci. Adv. 7, eabf0689 (2021).
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.
The authors declare no competing interests.
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 Sections 1–16, Figs. 1–39 and Tables 1–5.
Supplementary source data and original figures including compounds 1–3, Scheme 1, Figs. 1–39 and Tables 1–5.
Highly correlated fluorescent and current signals of the single-molecule catalyst site during the Suzuki–Miyaura cross-coupling.
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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
Nature Nanotechnology (2021)