The highly surprising behaviour of diphosphine ligands in iron-catalysed Negishi cross-coupling


Iron-catalysed cross-coupling is undergoing explosive development, but mechanistic understanding lags far behind synthetic methodology. Here, we find that the activity of iron–diphosphine pre-catalysts in the Negishi coupling of benzyl halides is strongly dependent on the diphosphine, but the ligand does not appear to be coordinated to the iron during turnover. This was determined using time-resolved in operando X-ray absorption fine structure spectroscopy employing a custom-made flow cell and confirmed by 31P NMR spectroscopy. While the diphosphine ligands tested are all able to coordinate to iron(ii), in the presence of excess zinc(ii)—as in the catalytic reaction—they coordinate predominantly to the zinc. Furthermore, combined synthetic and kinetic investigations implicate the formation of a putative mixed Fe–Zn(dpbz) species before the rate-limiting step of catalysis. These unexpected findings may not only impact the field of iron-catalysed Negishi cross-coupling, but potentially beyond to reactions catalysed by other transition metal/diphosphine complexes.

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Fig. 1: Generalized transition-metal-catalysed cross-coupling reactions.
Fig. 2: Activity of diphosphines in a representative iron-catalysed Negishi cross-coupling.
Fig. 3: Single-crystal X-ray structures of FeBr2–diphosphine adducts.
Fig. 4: Iron(i) versus iron(ii) in the Negishi coupling reaction.
Fig. 5: Time-resolved XAFS spectroscopy studies.
Fig. 6: Single-crystal X-ray structures of Zn(ii)–diphosphine adducts.
Fig. 7: Transmetallation studies.
Fig. 8: Schematic of a tentative suggestion for the role of chelating diphosphine in the catalytic reaction.

Data availability

Crystal structure data have been deposited at the Cambridge Crystallographic Data Centre (CCDC nos. 1836928–1836960 and 1868985) and crystallographic data are provided in the Supplementary Information. The spectroscopic, mass spectrometric, TEM and kinetic data that support the findings of this study are freely available in the University of Bristol data repository, data.bris, with the identifier


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The authors thank the following for supporting the project: the UK Catalysis Hub for resources and support provided via our membership of the UK Catalysis Hub Consortium and funded by EPSRC (grants nos. EP/K014706/2, EP/K014668/1, EP/K014854/1, EP/K014714/1 and EP/M013219/1); the EPSRC for funding (grant no. EP/K012258/1), the provision of a studentship through the EPSRC Centre for Doctoral Training in Catalysis (to S.L.J.L.) and for a part-studentship (to H.M.O’B.); AstraZeneca for CASE top-up funding (to H.M.O’B.) and CONACYT (studentship for O.H.F.). The authors thank Diamond Light Source and the UK Catalysis Hub for award of beamtime through the BAG allocation to B18 (SP15151). The authors thank N. Fey for provision of and discussions concerning Ligand Knowledge Base data and P. Lawrence for help with setting up NMR experiments.

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A.M.M., S.L.J.L., D.G., E.K.G., H.M.O’B., H.A.S., S.A.D., J.C., D.E., O.H.-F. and R.B.B. performed and analysed experiments. A.M.M. and P.P.W. designed the flow-XAFS cell. P.P.W., A.M.M., D.G., E.K.G. and J.C. designed XAFS experiments. A.M.M., S.L.J.L. and R.B.B. designed synthetic and mechanistic experiments. R.B.B. designed computational experiments. R.B.B., A.M.M., P.P.W. and S.L.J.L. prepared this manuscript.

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Correspondence to Robin B. Bedford.

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Supplementary Methods, Supplementary Figures 1–231, Supplementary Tables 1–25, Supplementary References

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Messinis, A.M., Luckham, S.L.J., Wells, P.P. et al. The highly surprising behaviour of diphosphine ligands in iron-catalysed Negishi cross-coupling. Nat Catal 2, 123–133 (2019).

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