Deciphering reactivity and selectivity patterns in aliphatic C−H bond oxygenation of cyclopentane and cyclohexane derivatives

A kinetic, product, and computational study on the reactions of the cumyloxyl radical with monosubstituted cyclopentanes and cyclohexanes has been carried out. HAT rates, site selectivities for C−H bond oxidation, and DFT computations provide quantitative information and theoretical models to explain the observed patterns. Cyclopentanes functionalize predominantly at C-1, and tertiary C−H bond activation barriers decrease on going from methyl- and tert-butylcyclopentane to phenylcyclopentane, in line with the computed C−H BDEs. With cyclohexanes, the relative importance of HAT from C-1 decreases on going from methyl- and phenylcyclohexane to ethyl-, isopropyl-, and tertbutylcyclohexane. Deactivation is also observed at C-2 with site selectivity that progressively shifts to C-3 and C-4 with increasing substituent steric bulk. The site-selectivities observed in the corresponding oxidations promoted by ethyl(trifluoromethyl)dioxirane support this mechanistic picture. Comparison of these results with those obtained previously for C−H bond azidation and functionalizations promoted by the PINO radical of phenyl and tert-butylcyclohexane, together with new calculations, provides a mechanistic framework for understanding C−H bond functionalization of cycloalkanes. The nature of the HAT reagent, C−H bond strengths, and torsional effects are important determinants of site-selectivity, with the latter effects that play a major role in the reactions of oxygen-centered HAT reagents with monosubstituted cyclohexanes.