Beyond ferryl-mediated hydroxylation: 40 years of the rebound mechanism and C-H activation

Abstract

Since our initial report in 1976, the oxygen rebound mechanism has become the consensus mechanistic feature for an expanding variety of enzymatic C-H functionalization reactions and small molecule biomimetic catalysts. For both the biotransformations and models, an initial hydrogen atom abstraction from the substrate (R-H) by high-valent iron-oxo species (Feⁿ=O) generates a substrate radical and a reduced iron hydroxide, [Fe^n-1-OH ·R]. This caged radical pair then evolves on a complicated energy landscape through a number of reaction pathways, such as oxygen rebound to form R-OH, rebound to a non-oxygen atom affording R-X, electron transfer of the incipient radical to yield a carbocation, R⁺, desaturation to form olefins, and radical cage escape. These various flavors of the rebound process, often in competition with each other, give rise to the wide range of C-H functionalization reactions performed by iron-containing oxygenases. In this review, we first recount the history of radical rebound mechanisms, their general features, and key intermediates involved. We will discuss in detail the factors that affect the behavior of the initial caged radical pair and the lifetimes of the incipient substrate radicals. Several representative examples of enzymatic C-H transformations are selected to illustrate how the behaviors of the radical pair [Fe^n-1-OH ·R] determine the eventual reaction outcome. Finally, we discuss the powerful potential of "radical rebound" processes as a general paradigm for developing novel C-H functionalization reactions with synthetic, biomimetic catalysts. We envision that new chemistry will continue to arise by bridging enzymatic "radical rebound" with synthetic organic chemistry.

Keywords: C–H activation; Iron; Metal oxo; Oxygenase; Radical; Rebound.

Fig. 1

A variety of biotransformations catalyzed by iron-containing oxygenases and their mechanistic features

Fig. 2

Mechanism of aliphatic C–H hydroxylation catalyzed by cytochrome P450 (the oxygen rebound mechanism)

Fig. 3

a Hydroxylation of cyclohexanol by Fenton’s reagent. b Directive effect in cyclohexanol hydroxylation by Fenton’s reagent suggests a coordinated Fe^IV=O intermediate

Fig. 4

a Oxidation of tetradeuteronorbornane catalyzed by P450_LM2. b Oxidation of 3,3,6,6-tetradeuterocyclohexene catalyzed by P450s and synthetic iron porphyrins

Fig. 5

(TMP^+·)Fe^IV=O, the first model compound I: a structure of oxoiron(IV)TMP radical cation; b depiction of (TMP^+·)Fe^IV=O from reference 56 and its Mössbauer spectrum, which indicates high-valent iron

Fig. 6

A highly reactive model ferryl porphyrin cation radical of an electron-withdrawing iron porphyrin, ref 64

Fig. 7

Equation 1 shows the Bordwell equation that relates the newly formed FeO–H bond energy to its pK _a and redox potential via a Hess cycle. C is a constant depending on the solvent and the electrode. For aqueous solution and normal hydrogen electrode, the value of C is 57.6 kcal/mol. Figure 2a–d shows the active site structures and pK _as of compound II for common heme-containing proteins. Active site structures were rendered using following structures: a myoglobin (PDB: 2V1H); b aromatic peroxygenase from Agrocybe aegerita (AaeAPO, PDB: 2YOR); c chloroperoxidase (CPO, PDB: 2J19); d cytochrome P450 (CYP119, PDB: 1IO7). Colors: iron (dark pink), nitrogen (blue), oxygen (red), carbon (silver), sulfur (yellow)

Fig. 8

a Active site structure of a typical αKG dependent non-heme iron(II) dioxygenase, TauD, (PDB: 1OS7) and the mechanism of taurine hydroxylation catalyzed by TauD. b Active site structure of a representative non-heme diiron hydroxylase, soluble methane monooxygenase (sMMO) in reduced state (PDB: 1FYZ) and the typical mechanism of C–H hydroxylation catalyzed by non-heme diiron hydroxylase. Colors: iron (orange), oxygen (red), nitrogen (blue), sulfur (yellow)

Fig. 9

a Mechanisms of rearrangement of the 2-norcaranyl radical and cation intermediates. b Oxidation of bicyclopentane catalyzed by liver microsomal P450. c A representative cyclopropane-based radical clock probe and radical lifetimes of common cytochrome P450s

Fig. 10

Energy profile and reaction coordinate for the methane hydroxylation by a ferryl-porphyrin cation radical. The figure is adapted from Ogliaro et al. [120]

Fig. 11

a Oxidation of radical clock probes with different rearrangement rate constants by non-heme diiron hydroxylase AlkB. b Schematic illustration of geminate recombination and cage escape. The scheme is adapted from Austin et al. [107]

Fig. 12

Catalytic cycle of metMb-catalyzed peroxynitrite decomposition

Fig. 13

Generation of the radical pair via hydrogen atom abstraction and the various reaction outcomes depending on the behavior of the radical pair

Fig. 14

Oxidative decarboxylation catalyzed by OleT_JE

Fig. 15

a Mechanism of the C–C scission of DHC catalyzed by P450_SCC. b Proposed mechanism of the aromatization step in the conversion of androgens to estrogens catalyzed by CYP19A1

Fig. 16

Mechanism of IPNS-catalyzed formation of isopenicillin from ACV

Fig. 17

Mechanism of C–H chlorination catalyzed by SyrB2 (PDB: 2FCT). Colors: iron (magenta), oxygen (red), nitrogen (blue), chlorine (green)

Fig. 18

a C–H Chlorination of 12-epi-fischerindole U catalyzed by the halogenase WelO5. b Relocation of the iron-oxo unit in the formation of oxoiron(IV) intermediate. c Active site structure of WelO5 (PDB: 5IQT). Colors: iron (orange), oxygen (red), nitrogen (blue), chlorine (green)

Fig. 19

a Synthesis of HMP and MPn from 2-HEP catalyzed by HEPD and MPnS respectively. b Synthesis of fosfomycin from 2S-HPP catalyzed by HppE

Fig. 20

Comparison between common radical C–H functionalizations (a) and those mediated by iron oxygenases and their model compounds (b)

Fig. 21

a Detection of the chlorination product in alkane hydroxylation catalyzed by a manganese porphyrin. b Halogenation reactivity of several non-heme iron model compounds

Fig. 22

Aliphatic C–H chlorination catalyzed by manganese porphyrins

Fig. 23

Effect of axial ligands on the oxygen rebound step

Fig. 24

The concept of heteroatom rebound catalysis (HRC) for developing C–H functionalization reactions

Fig. 25

Trapping of alkyl radicals by trans-Mn^IV(TMP)F₂ via fluorine atom transfer. X-ray crystal structure of trans-Mn^IV(TMP)F₂ drawn at 50% probability of the electron density with following atom colors: F (yellow), Mn (magenta), N (blue), C (cyan) (H atoms are omitted for clarity)

Fig. 26

a Aliphatic C–H fluorination catalyzed by manganese porphyrins. b Benzylic C–H fluorination catalyzed by magnanese salens

Fig. 27

Aliphatic C–H ¹⁸F labeling mediated by manganese salen catalysts

Fig. 28

Manganese-catalyzed late-stage aliphatic C–H azidation

Fig. 29

Comparison of the enantioselectivity between Mn-catalyzed C–H azidation and fluorination

Fig. 30

Mn-catalyzed decarboxylative fluorination

Fig. 31

Fe-catalyzed aliphatic C–H azidation