Abstract
The manifold of reaction pathways for the oxidative addition of phenyl bromide and phenyl chloride substrates to phosphine-modified palladium(0) complexes has been investigated with dispersion-corrected density functional theory (B3LYP-D2) for a range of synthetically relevant ligands, permitting the evaluation of ligand, substrate and method effects on calculated predictions. Bulky and electron-rich ligands P(t)Bu3 and SPhos can access low-coordinate complexes more easily, facilitating formation of the catalytically active species throughout the cycle. While the bisphosphine oxidative addition step is reasonably facile for the smaller PCy3 and PPh3 ligands, the dissociation of these ligands to generate reactive palladium complexes becomes more important and the catalyst is more likely to become trapped in unreactive intermediates. This study demonstrates the feasibility of exploring the catalytic manifold for synthetically relevant ligands with computational chemistry, but also highlights the remaining challenges.
Highlights
Palladium-catalyzed cross-coupling reactions have been developed to accommodate a variety of substrates,[1] permitting the formation of new C–C or C–Y bonds, where Y is a heteroatom
Accurate computational studies of catalytic cycles, especially where a manifold of competing reaction pathways exists, are an important component of this methodology and we have evaluated the impact of computational method effects to establish and validate a theoretical approach suitable for the study of the key oxidative addition step for synthetically relevant organometallic catalysts.[25]
We deliberately focused on the PtBu3 ligand because its large steric bulk restricts the number of accessible reaction pathways in the mechanistic manifold and limits the number of complexes and conformers which need to be considered
Summary
Palladium-catalyzed cross-coupling reactions have been developed to accommodate a variety of substrates,[1] permitting the formation of new C–C or C–Y bonds, where Y is a heteroatom. In the dissociative pathway (Scheme 3, shown in pale grey outline), ligand loss would occur before coordination of the aryl halide substrate to form the [PdL(ArX)] adduct 3, and undergo monoligated oxidative addition via [4]‡. In the first associative bisphosphine pathway (Path B), associative displacement of one ligand by the aryl halide substrate via [6]‡ can generate the [PdL(ArX)] adduct 3 At this stage the pathway merges with Path A and oxidative addition occurs to the monoligated metal center via TS [4]‡ (associative displacement pathway (Path B, connection to Path A shown in green in Scheme 3)). Based on a computational study by Lledós, Espinet and co-workers, albeit without consideration of dispersion corrections, the observed higher activity of bulky ligands may be related to avoiding the formation of side products and reservoir species such as 9 and 10.40
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