Effect of α-Substitution on the Reactivity of C(sp³)-H Bonds in Pd⁰-Catalyzed C-H Arylation

We report mechanistic studies on the reactivity of different α-substituted C(sp³)-H bonds, -CH_nR (R = H, Me, CO₂Me, CONMe₂, OMe, and Ph, as well as the cyclopropyl and isopropyl derivatives -CH(CH₂)₂ and -CHMe₂) in the context of Pd⁰-catalyzed C(sp³)-H arylation. Primary kinetic isotope effects, k_H/k_D, 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 = CO₂Me. This last result was confirmed experimentally (k_H/k_D ∼ 1). A reactivity scale for C(sp³)-H activation was then determined: CH₂CO₂Me > CH(CH₂)₂ ≥ CH₂CONMe₂ > CH₃ ≫ CH₂Ph > CH₂Me > CH₂OMe ≫ CHMe₂. 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(sp³)-H activation proceeding via the AMLA/CMD mechanism.