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

Abstract

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(II)-catalyzed C−H activation: (i) formation of the prereaction complex, [MPAA]−Pd(II)−[DG-SUB], with a weakly coordinated monoanionic amino acid ligand; (ii) N−H bond cleavage and formation of the catalytically active intermediate, [MPAA′]−Pd(II)−[DG-SUB], with a bidentately coordinated dianionic amino acid ligand, and (iii) C− H bond activation in [MPAA′]−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(II) 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 [MPAA′]−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).

Mono-N-protected amino acid ligands stabilize dimeric palladium(ii) complexes of importance to C–H functionalization

“…Several computational studies have established cyclopalladation pathways for monomeric Pd( ii )MPAA complexes, 19 – 25 and we previously studied the effect of acetate-bridged dimeric Pd( ii ) complexes on cyclopalladation, 44 but a similar study on dimeric MPAA-bridged Pd( ii ) complexes has not yet been reported. Here, we investigate the mechanisms of cyclopalladation of [Pd( ii ) (κ- N –F 3 C-dmba) (κ-OAc) (μ-NAc-Gly)] 2 ( 18-D ) 69 and its monomer ( 21-M ) complex (where - D and - M signify dimeric and monomeric species, respectively).…”

“…Notably, previous DFT studies of MPAA promoted C–H cleavage have evaluated energies of monomeric transitions states relative to monomeric MPAA reactants without commenting on possible dimeric pathways to C–H cleavage. 19 – 25 When the full potential energy surface is analyzed, as in Fig. 6 , it is apparent that assessing only the intrinsic barrier to C–H cleavage ( i.e.…”

“…Numerous approaches, including DFT calculations, 19 – 23 mass spectrometry, 24 , 25 and steady state kinetics 10 , 26 have been used to investigate the mechanism(s) by which MPAA ligands affect Pd( ii )-catalyzed C–H functionalization. These studies have concluded that MPAA-promoted, Pd( ii )-catalyzed C–H bond functionalization proceeds via a N–H cleavage and subsequent C–H activation mechanism.…”

“… 21 The proposed active catalyst is generated by κ 2 -( N , O ) coordination of MPAA to Pd( ii ) ( Chart 1 ) followed by deprotonation of the N -protected amide. Concerted metallation-deprotonation (CMD) 27 – 31 of the substrate C–H bond by either the N -protecting group 25 of the MPAA ligand or an external base 19 could then occur. κ 2 -( N , O ) binding of the MPAA ligand is thought to enforce a rigid structure capable of relaying chirality from the MPAA to a prochiral substrate in the CMD transition state.…”

Di-Palladium Complexes are Active Catalysts for Mono-N-Protected Amino Acid Accelerated Enantioselective C-H Functionalization

“…Given the general structural ambiguity surrounding Pd-MPAA catalysis, mechanistic models generally defer to the widely-held notion that MPAA ligands coordinate mono-palladium species by di-or mono-anionic chelation (Figure 2A and B, respectively). 1,[29][30][31][32][33] Figure 1: (A) MPAA induced, enantioselective cyclopalladation. 12 (B) Pd-MPAA catalyzed enantioselective C-H functionalization.…”