Significance of Conformational Analysis in the Computational Studies of the Reactions in a Flexible Substrate: Tandem C–C Coupling and C–H Activation Reaction of a Diene

We carried out an extensive computational study on the Pd-catalyzed intramolecular Heck reaction and C–H activation of a brominated diene, resulting in a fused cyclopentane. As the substrate is flexible, we have used conformational search, clustering analysis, and modeling to select eight conformations to study the catalytic cycle. Coordination of the catalyst (PdPPh₃) on the re and si faces of the substrate gave rise to 16 complexes. The bidentate coordination from both the double bonds of the substrate is found to be more stable than the monodentate coordination. Migratory insertion is the regioselective (5-exo versus 6-endo cyclization) step. The selectivity is correlated with the unique geometric features of the intermediates; in the twisted orientation, Pd–C1 and C5–C6 bonds are perpendicular to each other and can facilitate 5-exo and 6-endo cyclizations, while the eclipsed orientation where these bonds are parallel can only undergo 5-exo cyclization. The 5-exo routes from eclipsed orientations have much lower activation free energies, in agreement with the experiments. Many pathways proposed for the C–H activations in similar tandem reactions were analyzed. The next step in 5-exo pathways is the C–H activation where ortho-H of the phenyl group moves to Pd, either directly or after the exchange of Br– with HCO₃–. For the next important step, the second C–C bond formation, we analyzed three pathways different in the oxidation state and coordination at the Pd center. In summary, various conformations of a flexible substrate have different characteristic reaction profiles, which makes it difficult to conclude on the choice of pathways without taking care of the conformational flexibility.