Effect of α-Substitution on the Reactivity of C(sp(3))–H Bonds in Pd(0)-Catalyzed C–H Arylation

[Image: see text] We report mechanistic studies on the reactivity of different α-substituted C(sp(3))–H bonds, −CH(n)R (R = H, Me, CO(2)Me, CONMe(2), OMe, and Ph, as well as the cyclopropyl and isopropyl derivatives −CH(CH(2))(2) and −CHMe(2)) in the context of Pd(0)-catalyzed C(sp(3))–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 = CO(2)Me. This last result was confirmed experimentally (k(H)/k(D) ∼ 1). A reactivity scale for C(sp(3))–H activation was then determined: CH(2)CO(2)Me > CH(CH(2))(2) ≥ CH(2)CONMe(2) > CH(3) ≫ CH(2)Ph > CH(2)Me > CH(2)OMe ≫ CHMe(2). 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(3))–H activation proceeding via the AMLA/CMD mechanism.