Ruthenium-catalyzed C─H alkenylation of trypanocidal naphthoquinones: a mechanistic benchmarking study

Quinones are privileged scaffolds in biological redox chemistry and drug discovery, but methods to install versatile click handles onto their cores remain scarce. This work presents a comprehensive computational study of the Ru(II)‐catalyzed C H alkenylation of menadione with ethenesulfonyl fluoride, a transformation that introduces sulfonyl‐fluoride groups for subsequent SuFEx chemistry. Nine density functionals—from GGAs to double hybrids—are first benchmarked against DLPNO‐CCSD(T) reference energies for all key on‐cycle intermediates and transition states along the cationic [Ru(OAc)(p‐cymene)]+ pathway. Among them, ωB2PLYP best matches the coupled‐cluster reference and is the only method to achieve root‐mean‐square deviations of ≈1 kcal mol−1. Given that the computed on‐cycle barriers are modest, the results indirectly support that the overall rate is dictated by off‐cycle formation of the active cationic species via ligand exchange/speciation. Within the catalytic cycle, C H activation presents the highest global barrier, although migratory insertion can display a higher local barrier (relative to its immediate precursor) for specific ring substitutions. Finally, it is shown that the r2SCAN‐3c composite method offers a computationally efficient route for probing analogous catalytic cycles. These results deliver a robust protocol for designing naphthoquinone derivatives as next‐generation therapeutic agents against Trypanosoma cruzi and related parasites.