Theoretical Study on the Ortho–Para Reactivity Difference in Ru-Catalyzed Amination of Aminopyridines via η6-Coordination: Role of Meisenheimer Intermediate Coordination Ability

η6-Coordination catalysis has emerged as an effective strategy for activating electron-rich (hetero)arenes toward nucleophilic substitution. Recent experimental studies on Ru(II)-catalyzed amination of aminopyridines revealed a striking ortho–para reactivity difference, with ortho-substituted substrates undergoing efficient amination while para analogs are unreactive under identical conditions. Herein, we present a density functional theory investigation to elucidate the origin of this divergence. Computed free-energy profiles show that both substitution patterns follow a similar stepwise mechanism involving Ru-bound Meisenheimer intermediates and a proton-transfer relay, with C–N bond cleavage/rearomatization as the rate-determining step. However, the para pathway suffers from a substantially higher overall barrier, originating from the intrinsically less stable Meisenheimer intermediates. Energy decomposition analysis indicates that the decisive factor is weaker orbital interaction between the CpRu(II) fragment and the para-substituted Meisenheimer intermediate, whereas electrostatics and dispersion play negligible roles. These findings highlight the key role of metal–substrate orbital interactions in stabilizing dearomatized intermediates, offering mechanistic insights for rational design of η6-coordination catalysis with enhanced reactivity and selectivity.