The development of catalytic systems capable of oxygenating unactivated C–H bonds with excellent site-selectivity and functional group tolerance under mild conditions remains a challenge. Inspired by the secondary coordination sphere (SCS) hydrogen bonding in metallooxygenases, reported herein is an SCS solvent hydrogen bonding strategy that employs 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) as a strong hydrogen bond donor solvent to enable remote C–H hydroxylation in the presence of basic aza-heteroaromatic rings with a low loading of a readily available and inexpensive manganese complex as a catalyst and hydrogen peroxide as a terminal oxidant. We demonstrate that this strategy represents a promising compliment to the current state-of-the-art protection approaches that rely on precomplexation with strong Lewis and/or Brønsted acids. Mechanistic studies with experimental and theoretical approaches reveal the existence of a strong hydrogen bonding between the nitrogen-containing substrate and HFIP, which prevents the catalyst deactivation by nitrogen binding and deactivates the basic nitrogen atom toward oxygen atom transfer and the α-C–H bonds adjacent to the nitrogen center toward H-atom abstraction. Moreover, the hydrogen bonding exerted by HFIP has also been demonstrated not only to facilitate the O–O bond heterolytic cleavage of a putative MnIII–OOH precursor to generate MnV(O)­(OC­(O)­CH2Br) as an active oxidant but also to affect the stability and the activity of MnV(O)­(OC­(O)­CH2Br).

Biomimetic iron and manganese complexes have emerged as important catalysts in chemo-, regio-, and stereoselective oxidation reactions. In this study, we describe a remote hydroxylation of undirected C(sp 3 )−H bonds utilizing a simple manganese complex as a catalyst and hydrogen peroxide (H 2 O 2 ) as a terminal oxidant in the presence of bromoacetic acid (BrCH 2 CO 2 H) as an additive. Crucial features of this catalytic system are the excellent catalytic activity of an easily preparable manganese catalyst, [Mn(R,R-BPMCN)] 2+ (1), a low catalyst loading, a short reaction time, a broad substrate scope, and an easy scaleup. Mechanistic studies were also performed to elucidate the role of BrCH 2 CO 2 H and the nature of the hydroxylating intermediate, revealing that the BrCH 2 CO 2 H additive facilitates the generation of a highly electrophilic Mn(V)−oxo bromoacetate intermediate as a responsible oxidant via a heterolytic O−O bond cleavage of a postulated Mn(III)−OOH precursor. One notable observation in the mechanistic studies was that a significant amount of 18 O was incorporated from H 2 18 O into the alcohol product in these catalytic oxidation reactions. On the basis of the above experimental observations and from the support of density functional theory (DFT) calculations, we conclude that a highly electrophilic Mn(V)−oxo bromoacetate complex was generated as a responsible oxidant that effects the undirected C(sp 3 )−H hydroxylation via an oxygen-rebound mechanism, thus mimicking both the structure and the function of the active intermediate of iron(IV)−oxo succinate for α-ketoglutarate (αKG)dependent nonheme iron oxygenases.