Factors Impacting the Mechanism of the Mono-N-Protected Amino Acid Ligand-Assisted and Directing-Group-Mediated C-H Activation Catalyzed by Pd(II) Complex

We computationally studied the roles of the (a) protecting group (PG), (b) side chain (R), and (c) length of amino acid backbone of the mono-N-protected amino acid (MPAA) ligand as well as (d) the nature of the substrate (DG-SUB) and directing group (DG) on the following elementary steps of the "N-H bond cleavage and subsequent C-H bond activation" mechanism for [MPAA] Pd(10-catalyzed C-H activation: (i) formation of the prereaction complex, [MPAA] Pd(11) [DG-SUB], with a weakly coordinated monoanionic amino acid ligand; (ii) N-H bond cleavage and formation of the catalytically active intermediate, [MPAA1 Pd(11) [DG-SUB], with a bidentately coordinated dianionic amino acid ligand, and (iii) C-H bond activation in [MPAA1 Pd(II) [DG-SUB] occurring via the concerted metalation/deprotonation pathways A (outer-sphere) and B (inner-sphere). For the prereaction complex, we find that weak coordination of the MPAA ligand to Pd(11) is affected by (a) the strong electron-withdrawing ability of the PG, (b) longer amino acid backbone, and (c) a strong Pd-DG interaction. For the N-H bond-cleavage step, we find that facile N-H cleavage is affected by (a) the strong electron-withdrawing ability of the PG, (b) the existence of stabilizing noncovalent interactions, and (c) a weak Pd DG interaction. For the C-H activation step, we report that (a) the increase in the electron-withdrawing ability of the PG stabilizes both pathways A and B, whereas proton affinity of the PG impacts only pathway B; (b) the geometrical features of the substrate ligand motif in [MPAA1 Pd(II) [DG-SUB] and the existence of stabilizing noncovalent interactions can alter the reaction mechanism; and (c) the enantioselectivity of the reaction is reported to be controlled by either steric congestion around the substrate (in pathway A) or cooperative ligand-substrate geometrical constraints (in pathway B).