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PALLADIUM CATALYSIS

Speciation controls selectivity

Nature Reviews Chemistry volume 5, page 517 (2021)Cite this article

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Dihalogenated heterocycles are easily accessible building blocks for pharmaceutical synthesis. When the same halogen is present at two inequivalent positions on a heterocycle, one of the two is often observed to undergo palladium-catalysed cross-coupling much more favourably. Such observations can sometimes be rationalized by considering the electronic environment at the two reactive sites. This is not always the case, however; 2,4-dibromopyridine, for example, cross-couples selectively at C2. A doodled resonance structure suggests that both carbon atoms should carry a partial positive charge, and steric arguments are equally unsatisfying given the flat nature of the molecule.

Now, Ian Fairlamb and co-workers from the University of York along with collaborators from Bayer AG (CropScience Division) and the University of Leeds have reported an unusual approach to obtaining regiodivergence. “We postulated that to switch the arylation selectivity from C2 to C4 would most likely require a change in mechanism through the operation of an alternative Pd catalyst species. That led to us wonder about Pdn clusters and nanoparticles and whether such species could alter the arylation selectivity,” says Fairlamb. To probe this hypothesis, they ran two typical palladium-catalysed cross-couplings with 2,4-dibromopyridine and a coupling partner, varying the ratio of palladium catalyst to phosphine ligands (which tend to slow down nanoparticle formation). Under reaction conditions with relatively high phosphine ratios, the C2 product was formed predominately, per the normal paradigm of homogeneous catalysis. Reaction conditions with a relatively lower phosphine concentration, where higher-order palladium species are formed easily, provided the alternative C4 cross-coupling product.

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References

Original article

  • Scott, N. W. J. et al. A dichotomy in cross-coupling site selectivity in a dihalogenated heteroarene: influence of mononuclear Pd, Pd clusters, and Pd nanoparticles—the case for exploiting Pd catalyst speciation. J. Am. Chem. Soc. 143, 9682–9693 (2021)

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  1. Assoicate Editor, Nature Communications http://www.nature.com/natrevchem/

    Jamal A. Malik

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  1. Jamal A. Malik
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Correspondence to Jamal A. Malik.

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Malik, J.A. Speciation controls selectivity. Nat Rev Chem 5, 517 (2021). https://doi.org/10.1038/s41570-021-00319-9

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  • DOI: https://doi.org/10.1038/s41570-021-00319-9

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