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

• Published in: ACS catalysis Vol. 13; no. 19; pp. 12563 - 12570
• Main Authors: Wheatley, Matthew, Zuccarello, Marco, Tsitopoulou, Maria, Macgregor, Stuart A., Baudoin, Olivier
• Format: Journal Article
• Language: English
• Published: American Chemical Society 06.10.2023
• Subjects: DFT; reaction mechanism; relative rates; palladium; C−H activation; kinetics; reactivity series
• ISSN: 2155-5435; 2155-5435
• DOI: 10.1021/acscatal.3c03806

We report mechanistic studies on the reactivity of different α-substituted C­(sp3)–H bonds, −CH n R (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: CH 2CO2Me > CH(CH2)2 ≥ CH 2CONMe2 > CH 3 ≫ CH 2Ph > CH 2Me > CH 2OMe ≫ 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.