Effect of α-Substitution on the Reactivity of C(sp)-H Bonds in Pd-Catalyzed C-H Arylation.

We report mechanistic studies on the reactivity of different α-substituted C(sp)-H bonds, -CHR (R = H, Me, COMe, CONMe, OMe, and Ph, as well as the cyclopropyl and isopropyl derivatives -CH(CH) and -CHMe) in the context of Pd-catalyzed C(sp)-H arylation. Primary kinetic isotope effects, /, were determined experimentally for R = H (3.2) and Me (3.5), and these, along with the determination of reaction orders and computational studies, indicate rate-limiting C-H activation for all substituents except when R = COMe. This last result was confirmed experimentally (/ ∼ 1). A reactivity scale for C(sp)-H activation was then determined: CCOMe > C(CH) ≥ CCONMe > C ≫ CPh > CMe > COMe ≫ CMe. C-H activation involves AMLA/CMD transition states featuring intramolecular O → H-C H-bonding assisted by C-H → Pd agostic bonding. The "AMLA coefficient", χ, is introduced to quantify the energies associated with these interactions via natural bond orbital 2nd order perturbation theory analysis. Higher barriers correlate with lower χ values, which in turn signal a greater agostic interaction in the transition state. We believe that this reactivity scale and the underlying factors that determine this will be of use for future studies in transition-metal-catalyzed C(sp)-H activation proceeding via the AMLA/CMD mechanism.