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

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: C H 2 CO 2 Me > C H (CH 2 ) 2 ≥ C H 2 CONMe 2 > C H 3 ≫ C H 2 Ph > C H 2 Me > C H 2 OMe ≫ C H Me 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.