As a result of the adaptation of life to an aerobic environment, nature has evolved a panoply of metalloproteins for oxidative metabolism and protection against reactive oxygen species. Despite the ...diverse structures and functions of these proteins, they share common mechanistic grounds. An open-shell transition metal like iron or copper is employed to interact with O2 and its derived intermediates such as hydrogen peroxide to afford a variety of metal–oxygen intermediates. These reactive intermediates, including metal-superoxo, -(hydro)peroxo, and high-valent metal–oxo species, are the basis for the various biological functions of O2-utilizing metalloproteins. Collectively, these processes are called oxygen activation. Much of our understanding of the reactivity of these reactive intermediates has come from the study of heme-containing proteins and related metalloporphyrin compounds. These studies not only have deepened our understanding of various functions of heme proteins, such as O2 storage and transport, degradation of reactive oxygen species, redox signaling, and biological oxygenation, etc., but also have driven the development of bioinorganic chemistry and biomimetic catalysis. In this review, we survey the range of O2 activation processes mediated by heme proteins and model compounds with a focus on recent progress in the characterization and reactivity of important iron–oxygen intermediates. Representative reactions initiated by these reactive intermediates as well as some context from prior decades will also be presented. We will discuss the fundamental mechanistic features of these transformations and delineate the underlying structural and electronic factors that contribute to the spectrum of reactivities that has been observed in nature as well as those that have been invented using these paradigms. Given the recent developments in biocatalysis for non-natural chemistries and the renaissance of radical chemistry in organic synthesis, we envision that new enzymatic and synthetic transformations will emerge based on the radical processes mediated by metalloproteins and their synthetic analogs.
The remarkable aliphatic C–H hydroxylations catalyzed by the heme-containing enzyme, cytochrome P450, have attracted sustained attention for more than four decades. The effectiveness of P450 enzymes ...as highly selective biocatalysts for a wide range of oxygenation reactions of complex substrates has driven chemists to develop synthetic metalloporphyrin model compounds that mimic P450 reactivity. Among various known metalloporphyrins, manganese derivatives have received considerable attention since they have been shown to be versatile and powerful mediators for alkane hydroxylation and olefin epoxidation. Mechanistic studies have shown that the key intermediates of the manganese porphyrin-catalyzed oxygenation reactions include oxo- and dioxomanganese(V) species that transfer an oxygen atom to the substrate through a hydrogen abstraction/oxygen recombination pathway known as the oxygen rebound mechanism. Application of manganese porphyrins has been largely restricted to catalysis of oxygenation reactions until recently, however, due to ultrafast oxygen transfer rates. In this Account, we discuss recently developed carbon–halogen bond formation, including fluorination reactions catalyzed by manganese porphyrins and related salen species. We found that biphasic sodium hypochlorite/manganese porphyrin systems can efficiently and selectively convert even unactivated aliphatic C–H bonds to C–Cl bonds. An understanding of this novel reactivity derived from results obtained for the oxidation of the mechanistically diagnostic substrate and radical clock, norcarane. Significantly, the oxygen rebound rate in Mn-mediated hydroxylation is highly correlated with the nature of the trans-axial ligands bound to the manganese center (L–MnVO). Based on the ability of fluoride ion to decelerate the oxygen rebound step, we envisaged that a relatively long-lived substrate radical could be trapped by a Mn–F fluorine source, effecting carbon–fluorine bond formation. Indeed, this idea led to the discovery of the first Mn-catalyzed direct aliphatic C–H fluorination reactions utilizing simple, nucleophilic fluoride salts. Mechanistic studies and DFT calculations have revealed a trans-difluoromanganese(IV) species as the key fluorine transfer intermediate. In addition to catalyzing normal 19F-fluorination reactions, manganese salen complexes were found to enable the incorporation of radioactive 18F fluorine via C–H activation. This advance represented the first direct Csp3 –H bond 18F labeling with no-carrier-added 18Ffluoride and facilitated the late-stage labeling of drug molecules for PET imaging. Given the high reactivity and enzymatic-like selectively of metalloporphyrins, we envision that this new Heteroatom-Rebound Catalysis (HRC) strategy will find widespread application in the C–H functionalization arena and serve as an effective tool for forming new carbon–heteroatom bonds at otherwise inaccessible sites in target molecules.
A series of cationic cobalt porphyrins was found to catalyze electrochemical water oxidation to O ₂ efficiently at room temperature in neutral aqueous solution. ...Co–5,10,15,20-tetrakis-(1,3-dimethylimidazolium-2-yl)porphyrin, with a highly electron-deficient meso -dimethylimidazolium porphyrin, was the most effective catalyst. The O ₂ formation rate was 170 nmol⋅cm ⁻²⋅min ⁻¹ (k ₒbₛ = 1.4 × 10 ³ s ⁻¹) with a Faradaic efficiency near 90%. Mechanistic investigations indicate the generation of a Co ᴵⱽ-O porphyrin cation radical as the reactive oxidant, which has accumulated two oxidizing equivalents above the Co ᴵᴵᴵ resting state of the catalyst. The buffer base in solution was shown to play several critical roles during the catalysis by facilitating both redox-coupled proton transfer processes leading to the reactive oxidant and subsequent O–O bond formation. More basic buffer anions led to lower catalytic onset potentials, extending below 1 V. This homogeneous cobalt-porphyrin system was shown to be robust under active catalytic conditions, showing negligible decomposition over hours of operation. Added EDTA or ion exchange resin caused no catalyst poisoning, indicating that cobalt ions were not released from the porphyrin macrocycle during catalysis. Likewise, surface analysis by energy dispersive X-ray spectroscopy of the working electrodes showed no deposition of heterogeneous cobalt films. Taken together, the results indicate that Co–5,10,15,20-tetrakis-(1,3-dimethylimidazolium-2-yl)porphyrin is an efficient, homogeneous, single-site water oxidation catalyst.
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 (Fe
n
=O) generates a substrate radical and a reduced iron hydroxide, Fe
n−1
–O
H ·
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
–O
H ·
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.
Cytochrome P450 enzymes are able to oxidize substrates that are more inert than their own surrounding protein framework. Now, a quantitative understanding has emerged as to how the enzymes accomplish ...this remarkable feat.
An efficient protocol for the selective fluorination of benzylic CH bonds is described. The process is catalyzed by manganese salen complexes and uses nucleophilic fluorine sources, such as ...triethylamine trihydrofluoride and KF. Reaction rates are sufficiently high (30 min) to allow adoption for the incorporation of 18F fluoride sources for PET imaging applications.
Reactions that directly transform aliphatic C–H bonds into alkyl azides are noticeably lacking in the repertoire of synthetic reactions, despite the importance of molecules containing C–N3 bonds in ...organic synthesis, chemical biology, and drug discovery. Harnessing the ubiquity of C–H bonds in organic molecules and the versatility of the azide functional group, such transformations could have broad applications in various disciplines. Radical C–H activation represents an appealing strategy to achieve aliphatic C–H azidation, as it overcomes many drawbacks of conventional organometallic approaches in activating inert aliphatic C–H bonds. Novel C–H azidation methodologies could be realized by combining radical C–H activation via hydrogen atom abstraction with suitable azide-transfer reagents. In this perspective, we survey the history of radical C–H azidation and summarize several significant recent advances in the field. All radical C–H azidations to date follow a general approach comprising an initial radical C–H abstraction step and a subsequent azide transfer to the incipient carbon-centered radicals. A particular focus of this perspective is on the beneficial effects of using transition-metal catalysts in C–H azidation reactions, which have “tamed” azide radicals and led to reactions that proceed efficiently under much milder conditions and provide broader substrate scope and higher regioselectivities and stereoselectivities, compared to previous approaches.
We report a manganese porphyrin mediated aliphatic C−H bond chlorination using sodium hypochlorite as the chlorine source. In the presence of catalytic amounts of phase transfer catalyst and ...manganese porphyrin Mn(TPP)Cl 1, reaction of sodium hypochlorite with different unactivated alkanes afforded alkyl chlorides as the major products with only trace amounts of oxygenation products. Substrates with strong C−H bonds, such as neopentane (BDE =∼100 kcal/mol) can be also chlorinated with moderate yield. Chlorination of a diagnostic substrate, norcarane, afforded rearranged products indicating a long-lived carbon radical intermediate. Moreover, regioselective chlorination was achieved by using a hindered catalyst, Mn(TMP)Cl, 2. Chlorination of trans-decalin with 2 provided 95% selectivity for methylene-chlorinated products as well as a preference for the C2 position. This novel chlorination system was also applied to complex substrates. With 5α-cholestane as the substrate, we observed chlorination only at the C2 and C3 positions in a net 55% yield, corresponding to the least sterically hindered methylene positions in the A-ring. Similarly, chlorination of sclareolide afforded the equatorial C2 chloride in a 42% isolated yield. Regarding the mechanism, reaction of sodium hypochlorite with the MnIII porphyrin is expected to afford a reactive MnVO complex that abstracts a hydrogen atom from the substrate, resulting in a free alkyl radical and a MnIVOH complex. We suggest that this carbon radical then reacts with a MnIVOCl species, providing the alkyl chloride and regenerating the reactive MnVO complex. The regioselectivity and the preference for CH2 groups can be attributed to nonbonded interactions between the alkyl groups on the substrates and the aryl groups of the manganese porphyrin. The results are indicative of a bent MnvO---H---C geometry due to the CH approach to the MnvO (dπ−pπ)* frontier orbital.
We report a manganese-catalyzed aliphatic C–H azidation reaction that can efficiently convert secondary, tertiary, and benzylic C–H bonds to the corresponding azides. The method utilizes aqueous ...sodium azide solution as the azide source and can be performed under air. Besides its operational simplicity, the potential of this method for late-stage functionalization has been demonstrated by successful azidation of various bioactive molecules with yields up to 74%, including the important drugs pregabalin, memantine, and the antimalarial artemisinin. Azidation of celestolide with a chiral manganese salen catalyst afforded the azide product in 70% ee, representing a Mn-catalyzed enantioselective aliphatic C–H azidation reaction. Considering the versatile roles of organic azides in modern chemistry and the ubiquity of aliphatic C–H bonds in organic molecules, we envision that this Mn-azidation method will find wide application in organic synthesis, drug discovery, and chemical biology.
For cancer cells to survive and proliferate, they must escape normal immune destruction. One mechanism by which this is accomplished is through immune suppression effected by up-regulation of ...indoleamine 2,3-dioxygenase (IDO1), a heme enzyme that catalyzes the oxidation of tryptophan to N-formylkynurenine. On deformylation, kynurenine and downstream metabolites suppress T cell function. The importance of this immunosuppressive mechanism has spurred intense interest in the development of clinical IDO1 inhibitors. Herein, we describe the mechanism by which a class of compounds effectively and specifically inhibits IDO1 by targeting its apo-form. We show that the in vitro kinetics of inhibition coincide with an unusually high rate of intrinsic enzyme–heme dissociation, especially in the ferric form. X-ray crystal structures of the inhibitor–enzyme complexes show that heme is displaced from the enzyme and blocked from rebinding by these compounds. The results reveal that apo-IDO1 serves as a unique target for inhibition and that heme lability plays an important role in posttranslational regulation.
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