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.