Meta‐Selective C–H Alkylation of 2‐Phenylpyridine Catalyzed by Ruthenium: DFT Study on the Mechanism and Regioselectivity

Density functional theory calculations have been performed to quantitatively characterize ruthenium‐catalyzed meta ‐selective C–H functionalizations of 2‐phenylpyridine. The reaction with tert ‐butyl bromide was used as a model, and the proposed catalytic cycle is comprised of three successive steps: C–H activation, alkylation of the ruthenacycle, and demetalation, and separation of the product, among which C–H activation is the rate‐determining step having a free‐energy barrier of 29.2 kcal mol –1 . Alkylation of the ruthenacycle is predicted to be the selectivity‐determining step. The plausible reaction mechanism of the alkylation of the ruthenacycle depends on the nature of alkylating reagents, because use of simple alkyl halides would favor the electrophilic aromatic substitution mechanism over the radical mechanism, while the radical mechanism might become more competitive if a tertiary α‐bromo ester serves as an alkylating source. To address the regioselectivity issue, the kinetic parameters for the formation of different regioisomeric products have been calculated, which are consistent with the experimental findings and can provide additional insights.