Understanding the Reactivity of Pd0/PR3-Catalyzed Intermolecular C(sp3)-H Bond Arylation

Mechanistic details pertaining to the Pd-0/PCy3-catalyzed intermolecular arylation of a terminal beta-C(sp(3))-H bond aryl amide substrate (SM = EtCONH-Ar, where Ar = C6H5, C6F5 and CONH-Ar is a directing group (DG)) in the Presence of CsF base were elucidated. Key mechanistic features of this reaction are (1) oxidative addition of the aryl halide PhI to Pd-0/PCy3, (2) deprotonation of SM by CsF to form DG' = [EtCON-Ar]Cs+ for subsequent coordination to intermediate I-Pd-II(PCy3)Ph (the substantially lower pK(a) of the EtCONHC6F5 in comparison,to EtCONHC6H5 is instrumental for the presence of a larger population of the reactive deprotonated amides for Ar C6F5), (3) Cs-2-I-F cluster formation upon external (the second) CsF molecule approach to the active site of the I-Pd-II(PCy3)Ph(DG') intermediate, (4) Cs-2-I-F cluster assisted beta-C(sp(3))- H bond activation via a concerted metalation deprotonation (CMD) mechanism, and (5) reprotonation of the amide directing group to facilitate the C(sp(3))-Ph reductive elimination. The energy barriers, Delta G(double dagger) (Delta G(disp)(double dagger)), associated with the Cs-2- I F cluster mediated P-C(sp(3))-H bond activation transition state are 6.5 (8.7) and 10.2 (12.9) kcal/mol when DG = CONFIC6H5, CONHC6F5, respectively. It was shown that (a) the PCy3 ligand only semidissociates upon beta-C(sp(3)) H bond cleavage and (b) the I-to-F substitution in I-[Pd-II](Ph)(PCy3)(DG') is a facile process that makes the direct-halide assisted beta-C(sp(3)) H bond activation relatively less energy demanding and opens the possibility for a competing Ph F bond formation reaction. It was shown that the direct-I assisted C H bond activation TS, which associates with a relatively large energy barrier, is an H-atom insertion transition state into the Pd I bond, while the direct-F assisted C-H bond activation TS, which occurs with a relatively low energy barrier (but still is much larger than that required for the Cs-2-I-F cluster assisted pathway), is a direct proton abstraction transition state.