Computational Studies on the Mechanism and Origin of the Different Regioselectivities of Manganese Porphyrin-Catalyzed C–H Bond Hydroxylation and Amidation of Equilenin Acetate

Abstract

The manganese porphyrin-catalyzed C−H bond hydroxylation and amidation of equilenin acetate developed by Breslow and his co-worker have been investigated with density functional theory (DFT) calculations. The hydroxylation of C(sp 2 )−H bond of equilenin acetate leading to the 6-hydroxylated product is more favorable than the hydroxylation of C(sp 3 )−H bond of equilenin acetate, leading to the 11β-hydroxylation product. The computational results suggest that the C(sp 2 )−H bond hydroxylation of equilenin acetate undergoes an oxygenatom-transfer mechanism, which is more favorable than the C(sp 3 )−H bond hydroxylation undergoing the hydrogen-atomabstraction/oxygen-rebound (HAA/OR) mechanism by 1.6 kcal/ mol. That is why, the 6-hydroxylated product is the major product and the 11β-hydroxylated product is the minor product. In contrast, the 11β-amidated product is the only observed product in manganese porphyrin-catalyzed amidation reaction. The benzylic amidation undergoes a hydrogen-atom-abstraction/nitrogen-rebound (HAA/NR) mechanism, in which hydrogen atom abstraction is followed by nitrogen rebound, leading to the 11β-amidated product. The benzylic C(sp 3 )−H bond amidation at the C-11 position is more favorable than aromatic amidation at the C-6 position by 4.9 kcal/mol. Therefore, the DFT computational results are consistent with the experiments that manganese porphyrin-catalyzed C−H bond hydroxylation and amidation of equilenin acetate have different regioselectivities.

Biocatalytic Intramolecular C−H aminations via Engineered Heme Proteins: Full Reaction Pathways and Axial Ligand Effects

“…As shown in Figure 1 , the basic reaction pathway is similar to previous work of metalloporphyrin‐catalyzed C−H aminations,[ 6a , 11b , 11c , 12a ] having first nitrene formation and then nitrene transfer (C−H amination) steps. It should be noted that the general reaction pathway feature described here is the same no matter there is no ligand, negatively charged ligands with different coordination atoms, or neutral ligand.…”

Computational Mechanistic Investigations of Biocatalytic Nitrenoid C−H Functionalizations via Engineered Heme Proteins

“…As shown in Figure 2, the general reaction pathway is similar to metalloporphyrin‐catalyzed C−H aminations [11e,15a,c,16a] and biocatalytic intermolecular C−H aminations [15b–d] . Clearly, the nitrene formation step with transition state TS1 is the overall RDS in the whole reaction pathway, consistent with experiment [1k] .…”

Theoretical Insight into the Mechanism and Selectivity in Manganese-Catalyzed Oxidative C(sp3)–H Methylation

“…Geometries of intermediates and transition states were optimized at the (U)­B3LYP-D3­(BJ)/BSI level in the acetonitrile/dichloromethane solvent with the SMD continuum solvation model, where BSI denotes the mixed basis set of LanL2DZ for the Mn atom and 6–31G­(d,p) for other atoms. In previous reports, it has been confirmed that the B3LYP functional shows a satisfactory performance for describing manganese/iron-based catalytic systems. ,,− Harmonic vibrational frequency calculations were performed for all optimized geometries at the same level to confirm whether they are local minima or transition states and to obtain thermochemical corrections and Gibbs free energy. Intrinsic reaction coordinate (IRC) calculations were performed to determine that all transition states connect to their precursors and products.…”