Monosubstituted cycloalkanes undergo regio- and enantioselective aliphatic C–H oxidation with H2O2 catalyzed by biologically inspired manganese catalysts. The reaction furnishes the corresponding ketones resulting from oxidation at C3 and C4 methylenic sites (K3 and K4, respectively) leading to a chiral desymmetrization that proceeds with remarkable enantioselectivity (64% ee) but modest regioselectivity at C3 (K3/K4 ≈ 2) for tert-butylcyclohexane, and with up to 96% ee and exquisite regioselectity toward C3 (up to K3/K4 > 99) when N-cyclohexylalkanamides are employed as substrates. Efficient H2O2 activation, high yield, and highly enantioselective C–H oxidation rely on the synergistic cooperation of a sterically bulky manganese catalyst and an oxidatively robust alkanoic acid. This represents the first example of nonenzymatic highly enantioselective oxidation of nonactivated methylenic sites. Furthermore, the principles of catalyst design disclosed in this work constitute a unique platform for further development of stereoselective C–H oxidation reactions.

Methods for selective oxidation of aliphatic C–H bonds are called on to revolutionize organic synthesis by providing novel and more efficient paths. Realization of this goal requires the discovery of mechanisms that can alter in a predictable manner the innate reactivity of these bonds. Ideally, these mechanisms need to make oxidation of aliphatic C–H bonds, which are recognized as relatively inert, compatible with the presence of electron rich functional groups that are highly susceptible to oxidation. Furthermore, predictable modification of the relative reactivity of different C–H bonds within a molecule would enable rapid diversification of the resulting oxidation products. Herein we show that by engaging in hydrogen bonding, fluorinated alcohols exert a polarity reversal on electron rich functional groups, directing iron and manganese catalyzed oxidation toward a priori stronger and unactivated C–H bonds. As a result, selective hydroxylation of methylenic sites in hydrocarbons and remote aliphatic C–H oxidation of otherwise sensitive alcohol, ether, amide, and amine substrates is achieved employing aqueous hydrogen peroxide as oxidant. Oxidations occur in a predictable manner, with outstanding levels of product chemoselectivity, preserving the first-formed hydroxylation product, thus representing an extremely valuable tool for synthetic planning and development.

Bulky iron complexes are described that catalyze the site-selective oxidation of alkyl C-H bonds with hydrogen peroxide under mild conditions. Steric bulk at the iron center is introduced by appending trialkylsilyl groups at the meta-position of the pyridines in tetradentate aminopyridine ligands, and this effect translates into high product yields, an enhanced preferential oxidation of secondary over tertiary C-H bonds, and the ability to perform site-selective oxidation of methylenic sites in terpenoid and steroidal substrates. Unprecedented site selective oxidation at C6 and C12 methylenic sites in steroidal substrates is shown to be governed by the chirality of the catalysts.

Aliphatic C-H bond functionalization is at the frontline of research because it can provide straightforward access to simplified and cost-effective synthetic procedures. A number of these methodologies are based on hydrogen atom transfer (HAT), which, as a consequence of the inert character of C-H bonds, often represents the most challenging step of the overall process. Because the majority of organic molecules contain multiple nonequivalent C-H bonds that display similar chemical properties, differentiating between these bonds with high levels of selectivity represents one of the most challenging issues. Clarification of the factors that govern the relative reactivity of C-H bonds toward HAT reagents is thus of primary importance in order to develop selective functionalization procedures. In this Account we describe, through the combination of kinetic studies employing a genuine HAT reagent such as the cumyloxyl radical, along with oxidations performed with HO and iron or manganese catalysts, our contribution toward the development of selective C-H functionalization methodologies. Despite the different nature of these reagents, an oxygen-centered radical and a metal-oxo species, congruent reactivity and selectivity patterns have emerged, providing strong evidence that both reactions proceed via HAT. Consequently, selectivity in this class of metal catalyzed C-H oxidations can be reasonably predicted and synthetically exploited. Amides have been identified as preferential functional groups for governing selectivity on the basis of electronic, steric, and stereoelectronic effects. Torsional effects have proven moreover to be particularly important C-H directing factors in the oxidation of cyclohexane scaffolds where a delicate balance of these effects, in synergistic combination with catalyst design, enables highly chemoselective and enantioselective oxidations. Medium effects have been also shown to govern the relative HAT reactivity of C-H bonds in proximity to polar, hydrogen bond acceptor (HBA) functional groups. By engaging in hydrogen bonding with these groups, fluorinated alcohols strongly deactivate proximal C-H bonds toward HAT-based oxidation. As a result, alcohols, ethers, amines, and amides, which are electron rich and effective proximal C-H activating groups toward HAT reagents in conventional solvents, become oxidatively robust deactivating functionalities that direct C-H oxidation toward remote positions. These deactivating effects enable moreover the accomplishment of product chemoselective methylenic hydroxylations. Overall, clarification of the factors that govern HAT-based reactions has served to provide unique examples of catalytic methodologies for chemoselective and enantioselective oxidation of nonactivated aliphatic C-H bonds of potential utility in organic synthesis.

A time-resolved kinetic study in acetonitrile and a theoretical investigation of hydrogen abstraction reactions from N,N-dimethylformamide (DMF) and N,N-dimethylacetamide (DMA) by the cumyloxyl (CumO(•)) and benzyloxyl (BnO(•)) radicals was carried out. CumO(•) reacts with both substrates by direct hydrogen abstraction. With DMF, abstraction occurs from the formyl and N-methyl C-H bonds, with the formyl being the preferred abstraction site, as indicated by the measured kH/kD ratios and by theory. With DMA, abstraction preferentially occurs from the N-methyl groups, whereas abstraction from the acetyl group represents a minor pathway, in line with the computed C-H BDEs and the kH/kD ratios. The reactions of BnO(•) with both substrates were best described by the rate-limiting formation of hydrogen-bonded prereaction complexes between the BnO(•) α-C-H and the amide oxygen, followed by intramolecular hydrogen abstraction. This mechanism is consistent with the very large increases in reactivity measured on going from CumO(•) to BnO(•) and with the observation of kH/kD ratios close to unity in the reactions of BnO(•). Our modeling supports the different mechanisms proposed for the reactions of CumO(•) and BnO(•) and the importance of specific substrate/radical hydrogen bond interactions, moreover providing information on the hydrogen abstraction selectivity.