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, −CHnR (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, kH/kD, 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 (kH/kD ∼ 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.