Post-Transition-State Dynamic Effects in the Transmetalation of Pd(II)-F to Pd(II)-CF₃

The observation of post-transition-state dynamic effects in the context of metal-based transformation is rare. To date, there has been no reported case of a dynamic effect for the widely employed class of palladium-mediated coupling reactions. We performed an experimental and computational study of the trifluoromethylation of Pd^(II)F, which is a key step in the Pd⁽⁰⁾/Pd^(II)-catalyzed trifluoromethylation of aryl halides or acid fluorides. Our experiments show that the cis/trans speciation of the formed Pd^(II)CF₃ is highly solvent- and transmetalation reagent-dependent. We employed GFN2-xTB- and B3LYP-D3-based molecular dynamics trajectory calculations (with and without explicit solvation) along with high-level QM calculations and found that depending on the medium, different transmetalation mechanisms appear to be operative. A statistically representative number of Born-Oppenheimer molecular dynamics (MD) simulations suggest that in benzene, a difluorocarbene is generated in the transmetalation with R₃SiCF₃, which subsequently recombines with the Pd via two distinct pathways, leading to either the cis- or trans-Pd^(II)CF₃. Conversely, GFN2-xTB simulations in MeCN suggest that in polar/coordinating solvents an ion-pair mechanism is dominant. A CF₃ anion is initially liberated and then rebinds with the Pd^(II) cation to give a cis- or trans-Pd^(II). In both scenarios, a single transmetalation transition state gives rise to both cis- and trans-species directly, owing to bifurcation after the transition state. The potential subsequent cis- to trans isomerization of the Pd^(II)CF₃ was also studied and found to be strongly inhibited by free phosphine, which in turn was experimentally identified to be liberated through displacement by a polar/coordinating solvent from the cis-Pd^(II)CF₃ complex. The simulations also revealed how the variation of the Pd-coordination sphere results in divergent product selectivities.