Effect of α-Substitution on the Reactivity of C(sp<sup>3</sup>)–H Bonds in Pd<sup>0</sup>-Catalyzed C–H Arylation
Matthew Wheatley, Marco Zuccarello, Μαρία Τσιτοπούλου, Stuart A. Macgregor, Olivier Baudoin
Abstract
High Resolution Image Download MS PowerPoint Slide 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.