Mononuclear Nonheme High‐Spin (S=2) versus Intermediate‐Spin (S=1) Iron(IV)–Oxo Complexes in Oxidation Reactions

Mononuclear nonheme high‐spin (S=2) iron(IV)–oxo species have been identified as the key intermediates responsible for the C?H bond activation of organic substrates in nonheme iron enzymatic reactions. Herein we report that the C?H bond activation of hydrocarbons by a synthetic mononuclear nonheme high‐spin (S=2) iron(IV)–oxo complex occurs through an oxygen non‐rebound mechanism, as previously demonstrated in the C?H bond activation by nonheme intermediate (S=1) iron(IV)–oxo complexes. We also report that C?H bond activation is preferred over C=C epoxidation in the oxidation of cyclohexene by the nonheme high‐spin (HS) and intermediate‐spin (IS) iron(IV)–oxo complexes, whereas the C=C double bond epoxidation becomes a preferred pathway in the oxidation of deuterated cyclohexene by the nonheme HS and IS iron(IV)–oxo complexes. In the epoxidation of styrene derivatives, the HS and IS iron(IV) oxo complexes are found to have similar electrophilic characters.     

Olefin cis‐Dihydroxylation and Aliphatic C?H Bond Oxygenation by a Dioxygen‐Derived Electrophilic Iron–Oxygen Oxidant

Many iron‐containing enzymes involve metal–oxygen oxidants to carry out O₂‐dependent transformation reactions. However, the selective oxidation of C H and CC bonds by biomimetic complexes using O₂ remains a major challenge in bioinspired catalysis. The reactivity of iron–oxygen oxidants generated from an Fe^II–benzilate complex of a facial N₃ ligand were thus investigated. The complex reacted with O₂ to form a nucleophilic oxidant, whereas an electrophilic oxidant, intercepted by external substrates, was generated in the presence of a Lewis acid. Based on the mechanistic studies, a nucleophilic Fe^II–hydroperoxo species is proposed to form from the benzilate complex, which undergoes heterolytic O O bond cleavage in the presence of a Lewis acid to generate an Fe^IV–oxo–hydroxo oxidant. The electrophilic iron–oxygen oxidant selectively oxidizes sulfides to sulfoxides, alkenes to cis‐diols, and it hydroxylates the C H bonds of alkanes, including that of cyclohexane.     

Olefin cis‐Dihydroxylation and Aliphatic CH Bond Oxygenation by a Dioxygen‐Derived Electrophilic Iron–Oxygen Oxidant

Many iron‐containing enzymes involve metal–oxygen oxidants to carry out O₂‐dependent transformation reactions. However, the selective oxidation of C? H and C?C bonds by biomimetic complexes using O₂ remains a major challenge in bioinspired catalysis. The reactivity of iron–oxygen oxidants generated from an Fe^II–benzilate complex of a facial N₃ ligand were thus investigated. The complex reacted with O₂ to form a nucleophilic oxidant, whereas an electrophilic oxidant, intercepted by external substrates, was generated in the presence of a Lewis acid. Based on the mechanistic studies, a nucleophilic Fe^II–hydroperoxo species is proposed to form from the benzilate complex, which undergoes heterolytic O? O bond cleavage in the presence of a Lewis acid to generate an Fe^IV–oxo–hydroxo oxidant. The electrophilic iron–oxygen oxidant selectively oxidizes sulfides to sulfoxides, alkenes to cis‐diols, and it hydroxylates the C? H bonds of alkanes, including that of cyclohexane.     

Does Hydrogen‐Bonding Donation to Manganese(IV)–Oxo and Iron(IV)–Oxo Oxidants Affect the Oxygen‐Atom Transfer Ability? A Computational Study

Iron(IV)–oxo intermediates are involved in oxidations catalyzed by heme and nonheme iron enzymes, including the cytochromes P450. At the distal site of the heme in P450 Compound I (Fe^IV–oxo bound to porphyrin radical), the oxo group is involved in several hydrogen‐bonding interactions with the protein, but their role in catalysis is currently unknown. In this work, we investigate the effects of hydrogen bonding on the reactivity of high‐valent metal–oxo moiety in a nonheme iron biomimetic model complex with trigonal bipyramidal symmetry that has three hydrogen‐bond donors directed toward a metal(IV)–oxo group. We show these interactions lower the oxidative power of the oxidant in reactions with dehydroanthracene and cyclohexadiene dramatically as they decrease the strength of the O? H bond (BDE_OH) in the resulting metal(III)–hydroxo complex. Furthermore, the distal hydrogen‐bonding effects cause stereochemical repulsions with the approaching substrate and force a sideways attack rather than a more favorable attack from the top. The calculations, therefore, give important new insights into distal hydrogen bonding, and show that in biomimetic, and, by extension, enzymatic systems, the hydrogen bond may be important for proton‐relay mechanisms involved in the formation of the metal–oxo intermediates, but the enzyme pays the price for this by reduced hydrogen atom abstraction ability of the intermediate. Indeed, in nonheme iron enzymes, where no proton relay takes place, there generally is no donating hydrogen bond to the iron(IV)–oxo moiety.     

Fine Control of the Redox Reactivity of a Nonheme Iron(III)–Peroxo Complex by Binding Redox‐Inactive Metal Ions

Redox‐inactive metal ions are one of the most important co‐factors involved in dioxygen activation and formation reactions by metalloenzymes. In this study, we have shown that the logarithm of the rate constants of electron‐transfer and C−H bond activation reactions by nonheme iron(III)–peroxo complexes binding redox‐inactive metal ions, [(TMC)Fe^III(O₂)]⁺‐M^{n +} (M^{n +}=Sc³⁺, Y³⁺, Lu³⁺, and La³⁺), increases linearly with the increase of the Lewis acidity of the redox‐inactive metal ions (ΔE ), which is determined from the g_zz values of EPR spectra of O₂^.−‐M^{n +} complexes. In contrast, the logarithm of the rate constants of the [(TMC)Fe^III(O₂)]⁺‐M^{n +} complexes in nucleophilic reactions with aldehydes decreases linearly as the ΔE value increases. Thus, the Lewis acidity of the redox‐inactive metal ions bound to the mononuclear nonheme iron(III)–peroxo complex modulates the reactivity of the [(TMC)Fe^III(O₂)]⁺‐M^{n +} complexes in electron‐transfer, electrophilic, and nucleophilic reactions.     

Differences and Comparisons of the Properties and Reactivities of Iron(III)–hydroperoxo Complexes with Saturated Coordination Sphere

Heme and nonheme monoxygenases and dioxygenases catalyze important oxygen atom transfer reactions to substrates in the body. It is now well established that the cytochrome P450 enzymes react through the formation of a high‐valent iron(IV)–oxo heme cation radical. Its precursor in the catalytic cycle, the iron(III)–hydroperoxo complex, was tested for catalytic activity and found to be a sluggish oxidant of hydroxylation, epoxidation and sulfoxidation reactions. In a recent twist of events, evidence has emerged of several nonheme iron(III)–hydroperoxo complexes that appear to react with substrates via oxygen atom transfer processes. Although it was not clear from these studies whether the iron(III)–hydroperoxo reacted directly with substrates or that an initial O?O bond cleavage preceded the reaction. Clearly, the catalytic activity of heme and nonheme iron(III)–hydroperoxo complexes is substantially different, but the origins of this are still poorly understood and warrant a detailed analysis. In this work, an extensive computational analysis of aromatic hydroxylation by biomimetic nonheme and heme iron systems is presented, starting from an iron(III)–hydroperoxo complex with pentadentate ligand system (L₅²). Direct C?O bond formation by an iron(III)–hydroperoxo complex is investigated, as well as the initial heterolytic and homolytic bond cleavage of the hydroperoxo group. The calculations show that [(L₅²)Fe^III(OOH)]²⁺ should be able to initiate an aromatic hydroxylation process, although a low‐energy homolytic cleavage pathway is only slightly higher in energy. A detailed valence bond and thermochemical analysis rationalizes the differences in chemical reactivity of heme and nonheme iron(III)–hydroperoxo and show that the main reason for this particular nonheme complex to be reactive comes from the fact that they homolytically split the O?O bond, whereas a heterolytic O?O bond breaking in heme iron(III)–hydroperoxo is found.     

Lewis Acid Coupled Electron Transfer of Metal–Oxygen Intermediates

Redox‐inactive metal ions and Brønsted acids that function as Lewis acids play pivotal roles in modulating the redox reactivity of metal–oxygen intermediates, such as metal–oxo and metal–peroxo complexes. The mechanisms of the oxidative C?H bond cleavage of toluene derivatives, sulfoxidation of thioanisole derivatives, and epoxidation of styrene derivatives by mononuclear nonheme iron(IV)–oxo complexes in the presence of triflic acid (HOTf) and Sc(OTf)₃ have been unified as rate‐determining electron transfer coupled with binding of Lewis acids (HOTf and Sc(OTf)₃) by iron(III)–oxo complexes. All logarithms of the observed second‐order rate constants of Lewis acid‐promoted oxidative C?H bond cleavage, sulfoxidation, and epoxidation reactions of iron(IV)–oxo complexes exhibit remarkably unified correlations with the driving forces of proton‐coupled electron transfer (PCET) and metal ion‐coupled electron transfer (MCET) in light of the Marcus theory of electron transfer when the differences in the formation constants of precursor complexes were taken into account. The binding of HOTf and Sc(OTf)₃ to the metal–oxo moiety has been confirmed for Mn^IV–oxo complexes. The enhancement of the electron‐transfer reactivity of metal–oxo complexes by binding of Lewis acids increases with increasing the Lewis acidity of redox‐inactive metal ions. Metal ions can also bind to mononuclear nonheme iron(III)–peroxo complexes, resulting in acceleration of the electron‐transfer reduction but deceleration of the electron‐transfer oxidation. Such a control on the reactivity of metal–oxygen intermediates by binding of Lewis acids provides valuable insight into the role of Ca²⁺ in the oxidation of water to dioxygen by the oxygen‐evolving complex in photosystem II.     

Electrophilic Iron Catalyst Paired with a Lithium Cation Enables Selective Functionalization of Non‐Activated Aliphatic C−H Bonds via Metallocarbene Intermediates

Combining an electrophilic iron complex [Fe(^Fpda)(THF)]₂ ( 3 ) [^Fpda=N,N′‐bis(pentafluorophenyl)‐o‐phenylenediamide] with the pre‐activation of α‐alkyl‐substituted α‐diazoesters reagents by LiAl(OR^F)₄ [OR^F=(OC(CF₃)₃] provides unprecedented access to selective iron‐catalyzed intramolecular functionalization of strong alkyl C(sp³)?H bonds. Reactions occur at 25 °C via α‐alkyl‐metallocarbene intermediates, and with activity/selectivity levels similar to those of rhodium carboxylate catalysts. Mechanistic investigations reveal a crucial role of the lithium cation in the rate‐determining formation of the electrophilic iron‐carbene intermediate, which then proceeds by concerted insertion into the C?H bond.     

Mechanism of Oxidative Amidation of Nitroalkanes with Oxygen and Amine Nucleophiles by Using Electrophilic Iodine

Recently, we developed a direct method to oxidatively convert primary nitroalkanes into amides that entailed mixing an iodonium source with an amine, base, and oxygen. Herein, we systematically investigated the mechanism and likely intermediates of such methods. We conclude that an amine–iodonium complex first forms through N?halogen bonding. This complex reacts with aci‐nitronates to give both α‐iodo‐ and α,α‐diiodonitroalkanes, which can act as alternative sources of electrophilic iodine and also generate an extra equimolar amount of I⁺ under O₂. In particular, evidence supports α,α‐diiodonitroalkane intermediates reacting with molecular oxygen to form a peroxy adduct; alternatively, these tetrahedral intermediates rearrange anaerobically to form a cleavable nitrite ester. In either case, activated esters are proposed to form that eventually reacts with nucleophilic amines in a traditional fashion.     

Highly Reactive Nonheme Iron(III) Iodosylarene Complexes in Alkane Hydroxylation and Sulfoxidation Reactions

High‐spin iron(III) iodosylarene complexes bearing an N‐methylated cyclam ligand are synthesized and characterized using various spectroscopic methods. The nonheme high‐spin iron(III) iodosylarene intermediates are highly reactive oxidants capable of activating strong C? H bonds of alkanes; the reactivity of the iron(III) iodosylarene intermediates is much greater than that of the corresponding iron(IV) oxo complex. The electrophilic character of the iron(III) iodosylarene complexes is demonstrated in sulfoxidation reactions.     

Fine Control of the Redox Reactivity of a Nonheme Iron(III)–Peroxo Complex by Binding Redox-Inactive Metal Ions

Redox-inactive metal ions are one of the most important co-factors involved in dioxygen activation and formation reactions by metalloenzymes. In this study, we have shown that the logarithm of the rate constants of electron-transfer and C−H bond activation reactions by nonheme iron(III)–peroxo complexes binding redox-inactive metal ions, [(TMC)Fe^III(O₂)]⁺-Mⁿ⁺ (Mⁿ⁺=Sc³⁺, Y³⁺, Lu³⁺, and La³⁺), increases linearly with the increase of the Lewis acidity of the redox-inactive metal ions (ΔE), which is determined from the g_zz values of EPR spectra of O₂^.−-Mⁿ⁺ complexes. In contrast, the logarithm of the rate constants of the [(TMC)Fe^III(O₂)]⁺-Mⁿ⁺ complexes in nucleophilic reactions with aldehydes decreases linearly as the ΔE value increases. Thus, the Lewis acidity of the redox-inactive metal ions bound to the mononuclear nonheme iron(III)–peroxo complex modulates the reactivity of the [(TMC)Fe^III(O₂)]⁺-Mⁿ⁺ complexes in electron-transfer, electrophilic, and nucleophilic reactions.     

Formation of the iron-oxo hydroxylating species in the catalytic cycle of aromatic amino acid hydroxylases

The first part of the catalytic cycle of the pterin‐dependent, dioxygen‐using nonheme‐iron aromatic amino acid hydroxylases, leading to the Fe^IV?O hydroxylating intermediate, has been investigated by means of density functional theory. The starting structure in the present investigation is the water‐free Fe? O₂ complex cluster model that represents the catalytically competent form of the enzymes. A model for this structure was obtained in a previous study of water‐ligand dissociation from the hexacoordinate model complex of the X‐ray crystal structure of the catalytic domain of phenylalanine hydroxylase in complex with the cofactor (6R)‐L ‐erythro‐5,6,7,8‐tetrahydrobiopterin (BH₄) (PAH‐Fe^II‐BH₄). The O? O bond rupture and two‐electron oxidation of the cofactor are found to take place via a Fe‐O‐O‐BH₄ bridge structure that is formed in consecutive radical reactions involving a superoxide ion, O₂^?. The overall effective free‐energy barrier to formation of the Fe^IV?O species is calculated to be 13.9 kcal mol^?1, less than 2 kcal mol^?1 lower than that derived from experiment. The rate‐limiting step is associated with a one‐electron transfer from the cofactor to dioxygen, whereas the spin inversion needed to arrive at the quintet state in which the O? O bond cleavage is finalized, essentially proceeds without activation.     

Mononuclear Manganese–Peroxo and Bis(μ‐oxo)dimanganese Complexes Bearing a Common N‐Methylated Macrocyclic Ligand

Mononuclear Mn^III–peroxo and dinuclear bis(μ‐oxo)Mn^III₂ complexes that bear a common macrocyclic ligand were synthesized by controlling the concentration of the starting Mn^II complex in the reaction of H₂O₂ (i.e., a Mn^III–peroxo complex at a low concentration (≤1 mM ) and a bis(μ‐oxo)Mn^III₂ complex at a high concentration (≥30 mM )). These intermediates were successfully characterized by various physicochemical methods such as UV–visible spectroscopy, ESI‐MS, resonance Raman, and X‐ray analysis. The structural and spectroscopic characterization combined with density functional theory (DFT) calculations demonstrated unambiguously that the peroxo ligand is bound in a side‐on fashion in the Mn^III–peroxo complex and the Mn₂O₂ diamond core is in the bis(μ‐oxo)Mn^III₂ complex. The reactivity of these intermediates was investigated in electrophilic and nucleophilic reactions, in which only the Mn^III–peroxo complex showed a nucleophilic reactivity in the deformylation of aldehydes.     

Effect of Ligand Fields on the Reactivity of O2‐Activating Iron(II)‐Benzilate Complexes of Neutral N5 Donor Ligands

Three new iron(II)‐benzilate complexes [(N4Py)Fe^II(benzilate)]ClO₄ ( 1 ), [(N4Py^Me2)Fe^II(benzilate)]ClO₄ ( 2 ) and [(N4Py^Me4)Fe^II(benzilate)]ClO₄ ( 3 ) of neutral pentadentate nitrogen donor ligands have been isolated and characterized to study their dioxygen reactivity. Single‐crystal X‐ray structures reveal a mononuclear six‐coordinate iron(II) center in each case, where benzilate binds to the iron center in monodentate mode via one carboxylate oxygen. Introduction of methyl groups in the 6‐positions of the pyridine rings makes the N4Py^Me2 and N4Py^Me4 ligand fields weaker compared to that of the parent N4Py ligand. All the complexes ( 1 – 3 ) react with dioxygen to decarboxylate the coordinated benzilate to benzophenone quantitatively. The decarboxylation is faster for the complex of the more sterically hindered ligand and follows the order 3 > 2 > 1 . The complexes display oxygen atom transfer reactivity to thioanisole and also exhibit hydrogen atom transfer reactions with substrates containing weak C?H bonds. Based on interception studies with external substrates, labelling experiments and Hammett analysis, a nucleophilic iron(II)‐hydroperoxo species is proposed to form upon two‐electron reductive activation of dioxygen by each iron(II)‐benzilate complex. The nucleophilic oxidants are converted to the corresponding electrophilic iron(IV)‐oxo oxidant upon treatment with a protic acid. The high‐spin iron(II)‐benzilate complex with the weakest ligand field results in the formation of a more reactive iron‐oxygen oxidant.     

Tuning the Redox Properties of a Nonheme Iron(III)–Peroxo Complex Binding Redox‐Inactive Zinc Ions by Water Molecules

Redox‐inactive metal ions play important roles in tuning chemical properties of metal–oxygen intermediates. Herein we report the effect of water molecules on the redox properties of a nonheme iron(III)–peroxo complex binding redox‐inactive metal ions. The coordination of two water molecules to a Zn²⁺ ion in (TMC)Fe^III‐(O₂)‐Zn(CF₃SO₃)₂ ( 1 ‐Zn²⁺) decreases the Lewis acidity of the Zn²⁺ ion, resulting in the decrease of the one‐electron oxidation and reduction potentials of 1 ‐Zn²⁺. This further changes the reactivities of 1 ‐Zn²⁺ in oxidation and reduction reactions; no reaction occurred upon addition of an oxidant (e.g., cerium(IV) ammonium nitrate (CAN)) to 1 ‐Zn²⁺, whereas 1 ‐Zn²⁺ coordinating two water molecules, (TMC)Fe^III‐(O₂)‐Zn(CF₃SO₃)₂‐(OH₂)₂ [ 1 ‐Zn²⁺‐(OH₂)₂], releases the O₂ unit in the oxidation reaction. In the reduction reactions, 1 ‐Zn²⁺ was converted to its corresponding iron(IV)–oxo species upon addition of a reductant (e.g., a ferrocene derivative), whereas such a reaction occurred at a much slower rate in the case of 1 ‐Zn²⁺‐(OH₂)₂. The present results provide the first biomimetic example showing that water molecules at the active sites of metalloenzymes may participate in tuning the redox properties of metal–oxygen intermediates.     

Regioselectivity of aliphatic versus aromatic hydroxylation by a nonheme iron(II)-superoxo complex

Many enzymes in nature utilize molecular oxygen on an iron center for the catalysis of substrate hydroxylation. In recent years, great progress has been made in understanding the function and properties of iron(IV)-oxo complexes; however, little is known about the reactivity of iron(II)-superoxo intermediates in substrate activation. It has been proposed recently that iron(II)-superoxo intermediates take part as hydrogen abstraction species in the catalytic cycles of nonheme iron enzymes. To gain insight into oxygen atom transfer reactions by the nonheme iron(II)-superoxo species, we performed a density functional theory study on the aliphatic and aromatic hydroxylation reactions using a biomimetic model complex. The calculations show that nonheme iron(II)-superoxo complexes can be considered as effective oxidants in hydrogen atom abstraction reactions, for which we find a low barrier of 14.7 kcal mol(-1) on the sextet spin state surface. On the other hand, electrophilic reactions, such as aromatic hydroxylation, encounter much higher (>20 kcal mol(-1)) barrier heights and therefore are unlikely to proceed. A thermodynamic analysis puts our barrier heights into a larger context of previous studies using nonheme iron(IV)-oxo oxidants and predicts the activity of enzymatic iron(II)-superoxo intermediates.     

Palladium‐Catalyzed C?H Activation of N‐Allyl Imines: Regioselective Allylic Alkylations to Deliver Substituted Aza‐1,3‐Dienes

A new mode of activation of an imine via a rare aza‐substituted π‐allyl complex is described. Palladium‐catalyzed C(sp³) H activation of the N‐allyl imine and the subsequent nucleophilic attack by the α‐alkyl cyanoester produced the 1‐aza‐1,3‐diene as the sole regioisomer. In contrast, nucleophilic attack by the α‐aryl cyanoester exclusively delivered the 2‐aza‐1,3‐diene, which was employed in an inverse‐electron‐demand Diels–Alder reaction for heterobiaryl synthesis.     

Long‐Lived Trifluoromethanide Anion: A Key Intermediate in Nucleophilic Trifluoromethylations

The trifluoromethanide anion is the postulated key intermediate in nucleophilic trifluoromethylation reactions. However, for more than six decades, the trifluoromethanide anion was widely believed to exist only as a short‐lived transient species in the condensed phase. It has now been prepared in bulk for the first time in THF solution. The trifluoromethanide anion with the [K(18‐crown‐6)]⁺ cation was unequivocally characterized by low‐temperature ¹⁹F and ¹³C NMR spectroscopy. Its intermediacy in nucleophilic trifluoromethylation reactions was directly evident by its reaction chemistry with various electrophilic substrates. Variable‐temperature NMR spectroscopy, along with quantum mechanical calculations, support the persistence of the trifluoromethanide anion.     

Structure and Unprecedented Reactivity of a Mononuclear Nonheme Cobalt(III) Iodosylbenzene Complex

A mononuclear nonheme cobalt(III) iodosylbenzene complex, [Co^III(TQA)(OIPh)(OH)]²⁺ ( 1 ), is synthesized and characterized structurally and spectroscopically. While 1 is a sluggish oxidant in oxidation reactions, it becomes a competent oxidant in oxygen atom transfer reactions, such as olefin epoxidation, in the presence of a small amount of proton. More interestingly, 1 shows a nucleophilic reactivity in aldehyde deformylation reaction, demonstrating that 1 has an amphoteric reactivity. Another interesting observation is that 1 can be used as an oxygen atom donor in the generation of high‐valent metal‐oxo complexes. To our knowledge, we present the first crystal structure of a Co^III iodosylbenzene complex and the unprecedented reactivity of metal‐iodosylarene adduct.     

Palladium‐Catalyzed CH Activation of N‐Allyl Imines: Regioselective Allylic Alkylations to Deliver Substituted Aza‐1,3‐Dienes

A new mode of activation of an imine via a rare aza‐substituted π‐allyl complex is described. Palladium‐catalyzed C(sp³)? H activation of the N‐allyl imine and the subsequent nucleophilic attack by the α‐alkyl cyanoester produced the 1‐aza‐1,3‐diene as the sole regioisomer. In contrast, nucleophilic attack by the α‐aryl cyanoester exclusively delivered the 2‐aza‐1,3‐diene, which was employed in an inverse‐electron‐demand Diels–Alder reaction for heterobiaryl synthesis.