DFT Study on the Mechanistic Origin of the Distinct Reactivities of Three Iodine(III) Reagents in MIA‐Directed Pd‐Catalyzed C(sp3)–H Alkoxylation

Abstract

Hypervalent iodine(III) reagents are widely used in Pd‐catalyzed C─H functionalization, yet their efficacy varies dramatically with the acyloxy group. This DFT study elucidates the mechanistic origins of the reactivity differences among PhI(OAc)₂, PhI(OCOCF₃)₂, and PhI(OPiv)₂ in a C(sp³)–H alkoxylation. All three systems are found to follow a unified pathway involving the oxidative addition of an acyloxy radical to a Pd(II) center, followed by concerted metalation‐deprotonation (CMD) for C─H cleavage and a final S_N2‐type reductive elimination. PhI(OAc)₂ delivers the highest yield due to an optimal radical dissociation energy (17.9 kcal/mol) and the lowest CMD activation barrier (19.7 kcal/mol). In contrast, the strong electron‐withdrawing nature of the trifluoroacetoxy groups significantly elevates the radical dissociation energy of PhI(OCOCF₃)₂ to 38.1 kcal/mol, rendering oxidant activation the rate‐determining step. For PhI(OPiv)₂, the pivalate group's weak trans effect destabilizes the CMD step (21.2 kcal/mol). These findings provide a mechanistically grounded electronic rationale for acyloxy‐group effects in this MIA (2‐Methoxyiminoacyl)‐directed model alkoxylation system and may offer qualitative guidance for related Pd‐catalyzed C(sp³)–H alkoxylation reactions.