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Identifying palladium culprits in amine catalysis

The Original Article was published on 18 January 2021

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Fig. 1: Exploration of the active catalyst species in the Suzuki reaction.

Data availability

Crystal structure data have been deposited at the Cambridge Crystallographic Data Centre (CCDC 2070871 and 2070872) and crystallographic data are provided in the Supplementary Information. All other data are available from the corresponding authors upon reasonable request.


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

    Article  CAS  Google Scholar 

  2. Lennox, A. J. J. & Lloyd-Jones, G. C. Selection of boron reagents for Suzuki–Miyaura coupling. Chem. Soc. Rev. 43, 412–443 (2014).

    Article  CAS  Google Scholar 

  3. Xu, L. et al. The amine-catalysed Suzuki–Miyaura-type coupling of aryl halides and arylboronic acids. Nat. Catal. (2021).

  4. Arvela, R. K. et al. A reassessment of the transition-metal free Suzuki-type coupling methodology. J. Org. Chem. 70, 161–168 (2005).

    Article  CAS  Google Scholar 

  5. Yu, S., Saenz, J. & Srirangam, J. K. Facile synthesis of N-aryl pyrroles via Cu(II)-mediated cross coupling of electron deficient pyrroles and arylboronic acids. J. Org. Chem. 67, 1699–1702 (2002).

    Article  CAS  Google Scholar 

  6. Sapountzis, I. & Knochel, P. A new general preparation of polyfunctional diarylamines by the addition of functionalized arylmagnesium compounds to nitroarenes. J. Am. Chem. Soc. 124, 9390–9391 (2002).

    Article  CAS  Google Scholar 

  7. Bedford, R. B. & Cazin, C. S. J. High-activity catalysts for Suzuki coupling and amination reactions with deactivated aryl chloride substrates: importance of the palladium source. Organometallics 22, 987–999 (2003).

    Article  CAS  Google Scholar 

  8. Bedford, R. B., Cazin, C. S. J. & Hazelwood, S. L. Simple mixed tricyclohexylphosphane–triarylphosphite complexes as extremely high-activity catalysts for the Suzuki coupling of aryl chlorides. Angew. Chem. Int. Ed. 41, 4120–4122 (2002).

    Article  CAS  Google Scholar 

  9. Bedford, R. B., Hazelwood, S. L. & Limmert, M. E. Extremely high activity catalysts for the Suzuki coupling of aryl chlorides: the importance of catalyst longevity. Chem. Commun. 2002, 2610–2611 (2002).

    Article  Google Scholar 

  10. Novák, Z. et al. Curse or blessing? Influence of impurities on cross-coupling—guideline for elucidating catalysts. Preprint at ChemRxiv (2021).

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We thank S. Traxel and his team (Merck Element Analytics) for conducting and evaluating the ICP–MS analysis of 1a, D. S. Yufit (Durham) for the structure determination of 1a, A. N. Iashin for conducting NMR experiments (Moscow) and M. I. Sharikov for fruitful discussions. We thank the Chemical Synthesis Centre for Doctoral Training (funded by EPSRC (EP/L015366/1), AstraZeneca, GlaxoSmithKline, Syngenta, UCB, Ziylo and the University of Bristol) for the provision of a PhD studentship (B.J.S.R.); the Technology Enhanced Chemical Synthesis Centre for Doctoral Training (funded by EPSRC (EP/S024107/1), AstraZeneca, Astex, Bayer, GlaxoSmithKline, Syngenta, Vertex and the University of Bristol) for the provision of a PhD studentship (J.H.); GSK (iCASE studentship to M.A.); the EPSRC (PhD studentship to C.S.B., EP/T518001/1, project reference 2456710); the UK Catalysis Hub (support provided to R.B.B., A.J.J.L. and R.N.-S. for membership of the UK Catalysis Hub Consortium, funded by EPSRC grants EP/R027129/1 and EP/S018050/1)); the ERC (Advanced Grant 883786 to J.C.) and the Royal Society (University Research Fellowship to A.J.J.L.; Research Fellowship to M.O.K. (UF150536) and equipment grant (RGS\R2\180467)).

Author information

Authors and Affiliations



M.A., R.B.B., C.S.B., S.A.D., J.-C.E., G.P.G., J.H., K.A.K., J.K., P.S.K., N.E.P., R.N.-S., H.A.S., B.J.S.R., D.V.U., M.P.W. and H.J.W. performed and analysed experiments. R.B.B., J.C., G.P.G., I.V.H., M.O.K., D.B., A.J.J.L., A.Z.V. and M.P.W. designed and analysed the synthetic and catalytic experiments. R.B.B. designed the computational experiments. R.B.B. prepared the manuscript.

Corresponding authors

Correspondence to Robin B. Bedford, Jonathan Clayden, Georgy P. Goryunov, Ingo V. Hartung, Matthew O. Kitching or Alastair J. J. Lennox.

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Competing interests

The authors declare no competing interests.

Additional information

Peer review information Nature Catalysis thanks Nicholas Leadbeater and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Fig. 1 Computational investigation into the intramolecular acidolysis of the key proposed phenyl potassium intermediate (Int4).

Relaxed PES scan of proton (highlighted) migration to K-Ph from adjacent B-O-H group showing facile cluster rearrangement to Int4-R followed by proton transfer (via H-trans) to give the acidolysed product Int4-dp. Attempts to model the transition state associated with proton transfer were unsuccessful, which is unsurprising considering the almost flat PES landscape in the region of H-trans. The calculations were performed using Orca 4.2 at the B3LYP-D3BJ/def2-svp level of theory (see Computational Studies section, Supporting Methods for full details); E(elec) of Int4 set to same value as calculated for the ΔG in the literature for comparison purpose; amine group represented as simple tubes, the rest of the cluster as ball-and-stick.

Extended Data Fig. 2 Comparison of ΔG for intramolecular acidolysis of K-Ph by adjacent B-O-H group (highlighted in red) versus the originally proposed dissociation of the amine group and formation of Int5.

It is clear that acidolysis is far more favourable than the formation of Int5 and would occur before Int5 could participate in the proposed steps leading to the activation and coupling of the aryl bromide substrate. Calculations performed using Gaussian 16 at the B3LYP-D3BJ/6–311 + G** level of theory; Int4, Int5 and cat reoptimized from the literature coordinates; ΔG for Int4 set to same value as in the literature. See Computational Studies section, Supporting Methods for full details.

Supplementary information

Supplementary Information

Supplementary Methods, Figs. 1–133, Tables 1–9, Discussion and references.

Supplementary Data

Optimised Cartesian coordinates (B3LYP-D3BJ/6–311+G**) for Int4, Int5, Cat and Int4-dp.

CIF Data

Crystallographic determination of 1a.

CIF Data

Crystallographic determination of 5a.

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Avanthay, M., Bedford, R.B., Begg, C.S. et al. Identifying palladium culprits in amine catalysis. Nat Catal 4, 994–998 (2021).

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