Investigating the mechanism and origins of selectivity in palladium-catalysed carbene insertion cross-coupling reactions

Gavin Lennon, Christina O'Boyle, Andrew I. Carrick, Paul Dingwall*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)
44 Downloads (Pure)


The mechanism of palladium-catalysed carbene insertion cross-coupling reactions was studied by variable time normalisation analysis (VTNA), NMR spectroscopy, tandem eletrospray ionisation-mass spectrometry (ESI-MS), and density functional theory calculations. VTNA revealed a zero-order dependence on benzyl bromide and base, a first-order dependence on diazo substrate and Pd, and a negative first-order dependence on the PPh3 ligand. These results suggest rate determining carbene formation and the existence of an off-cycle bisphosphine turnover determining intermediate prior to this step. A time-adjusted same excess protocol showed that, while the catalytic cycle was stable, an induction period was present when the Pd : PPh3 ratio was greater than 1 : 3. NMR spectroscopic study revealed a large degree of phosphorous speciation, with control experiments allowing each species present to be identified. The turnover determining intermediate implicated during kinetic studies was identified, along with a second, η3-benzyl, turnover determining intermediate placed off the catalytic cycle after carbene insertion but prior to β-hydride elimination. ESI-MS of the reaction mixture was conducted, providing additional evidence for the existence of both turnover determining intermediates. Theoretical investigations suggest carbene insertion as the origin of selectivity, rather than β-hydride elimination as is generally assumed. Selectivity during carbene insertion was found to be governed by frontier molecular orbital interactions which heavily favour (E)-selectivity. Energy span and degree of TOF control analysis strongly support experimental observations and mechanistic rationale, validating theoretical work. Beyond defining aspects of the mechanism of palladium carbene insertion reactions, this study reveals that, when a pendant migrating group is present, carbene insertion is the selectivity determining step. These results can be used to rationalise unexpectedly high selectivities reported for similar reactions in the literature, suggesting this to be a general model for selectivity in palladium-catalysed carbene insertion reactions.

Original languageEnglish
Pages (from-to)372-380
Number of pages9
JournalCatalysis, Science & technology
Issue number2
Early online date01 Nov 2022
Publication statusPublished - 23 Jan 2023


  • Catalysis


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