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Published 6 Mar 2012 | DOI: 10.1038/ncomms1718

Selective functionalization of unactivated CH bonds and ammonia production are extremely important industrial processes. A range of metalloenyzmes achieve these challenging tasks in biology by activating dioxygen and dinitrogen using cheap and abundant transition metals, such as iron, copper and manganese. High-valent ironoxo and nitrido complexes act as active intermediates in many of these processes. The generation of well-described model compounds can provide vital insights into the mechanism of such enzymatic reactions. Advances in the chemistry of model high-valent ironoxo and nitrido systems can be related to our understanding of the biological systems.

High-valent oxoiron(IV) and formally oxoiron(V) species have been spectroscopically identied as active intermediates in the catalytic cycles of a number of enzymatic systems110. Haem and non-haem proteins use these reactive intermediates to couple the activation of

dioxygen to the oxidation of their substrates. In most cases, an oxygen atom is inserted into an unactivated CH bond of the substrate; for example, in hydroxylation reactions110. However, many other reactions, including halogenation, desaturation, cyclization, epoxidation and decarboxylation, are also known to involve oxoiron species1,3. Superoxidized iron complexes with (valence) isoelectronic imido and nitrido ligands, as well as surface nitrides, have also been implicated as key intermediates in the nitrogen atom transfer reactions11, the biological synthesis of ammonia by the nitrogenase enzyme1216 and the industrial Haber-Bosch process17.

The generation of well-described model compounds can provide vital insights into the mechanism of such enzymatic reactions. Consequently, considerable eort has been made by synthetic chemists to prepare viable models for the putative reaction intermediates in the catalytic cycles of O2 and N2 activating enzymes. In this review, we provide an overview of all high-valent oxoiron and nitridoiron species that have been either identied or proposed as reactive intermediates in biology.

Subsequently, we summarize some of the recent advances in bioinorganic chemistry that have led to the identication and isolation of iron complexes in unusually high formal oxidation states, containing ironoxygen or ironnitrogen multiple bonds. The spectroscopic characterization and the reactivity studies of these model complexes provide vital insights into the mechanism that nature uses to induce the reductive cleavage of dioxygen or dinitrogen in carrying out a number of important biochemical oxidative transformations. Moreover, the comparative review of the electronic structures of the isoelectronic oxoiron and nitridoiron functionalities reveals that the FeN bonds are intrinsically more covalent than the FeO bonds.

1 Department of Chemistry and Pharmacy, Inorganic Chemistry, Friedrich-Alexander-University Erlangen Nuremberg, Egerlandstr. 1, Erlangen 91058, Germany. 2 Department of Chemistry, Humboldt-Universitt zu Berlin, Brook-Taylor Str. 2, Berlin 12489, Germany. Correspondence should be addressed to K.R. (email: [email protected]) or to K.M. (email: [email protected]).

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The biology and chemistry of high-valent ironoxo and ironnitrido complexes

Johannes Hohenberger1, Kallol Ray2 & Karsten Meyer1

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Ironoxo complexesIronoxo intermediates in biology. Heme and non-heme proteins

activate dioxygen or hydrogen peroxide to generate high-valent oxoiron reactive intermediates, which are used to carry out a diverse set of biological tasks110. Important processes such as catabolism, angiogenesis, respiration, and apoptosis rely on oxidation reactions driven by these reactive intermediates13. The coordination environment of the oxoiron unit is, however, found to be dierent in dierent enzymes. Three types of high-valent ironoxo active sites have been identied in haem and non-haem enzymes (Fig. 1). The haem- containing peroxidases, oxygenases and catalases comprise mononu-clear iron-protophyrin IX active sites coordinated to either a cysteine, histidine or tyrosine residue3,18. The second type involves mononu-clear iron centres that are coordinated to two histidines and a carboxylate group, thereby forming a characteristic 2-His-1-carboxylate facial triad, which has been recognized as a common structural motif for many mononuclear non-haem iron enzymes13. The third type of active sites is characterized by diiron centres with two histidines and four carboxylates and are associated with methane and toluene monooxygenases, fatty acid desaturases and ribonucleotidereductase5,10. Most of these enzymes activate dioxygen in the iron(II) state and carry out a variety of two-electron oxidation processes (Fig. 2); the remaining two reducing equivalents required for the four-electron reduction of dioxygen are oen provided by a cosubstrate (Fig. 1). One specic group of non-haem enzymes utilizes 2-oxoacids or tetrahydrobiopterin as the cosubstrate, delivering two electrons simultaneously to the active site to aord peroxoiron(II) and oxoiron(IV) species in the proposed reaction mechanism1. Enzymes, such as cytochrome-P450 (P450), soluble methane monooxygenase (sMMO) or Rieske dioxygenases, on the other hand, use NADH as the electron donor to form peroxoiron(III) and formally oxoiron(V) species (Fig. 1); all the redox equivalents of the formal oxoiron(V) species are stored either at the metal centre(s) in non-haem enzymes (for example, Fe2IV(-O)2 intermediate Q in sMMO5,10 and (OH)FeV = O intermediate4 in Rieske dioxygenase) or distributed over the ligand in haem enzymes (for example, Compound-I (Cpd-I), which is an oxoiron(IV) porphyrin -cation radical species)3,6,7,9. In addition to dioxygen, hydrogen

peroxide can also act as an oxygen-atom source by reacting directly with the iron(III) state of the enzyme3,6,9, to generate the active oxidant (no reductase components are required in this case).

These high-valent ironoxo intermediates in biology have been primarily characterized by 57Fe Mssbauer spectroscopy19, as it serves as a local probe of the iron centre. Mssbauer isomer shis () are directly related to the electron density at the iron nucleus and, therefore, are oen used as a probe of the oxidation state of the metal. The quadrupole splitting (EQ) values, on the other hand, are a measure of the electric eld gradient at the iron nucleus and can be strongly correlated to electronic spin ground state and molecular geometry. Nuclear hyperne tensors (A) depend strongly on the nature of the orbitals in which unpaired electrons reside and may be used as a tool to understand the electronic structure of paramagnetic species. Whereas and EQ values (Table 1) obtained from zero-eld Mssbauer studies of the active oxidants in both haem and non-haem oxygenases are consistent with an iron(IV) oxidation state, the analysis of the Mssbauer spectra in an applied magnetic eld reveals dierent spin states in the two cases. For haem enzymes the A tensor shows a qualitative trend of two large negative values, one small negative value20,21, thereby reecting an intermediate spin, S = 1 spin state for the iron(IV) centre. In CPd-I intermediates, this S = 1 spin state is coupled ferromagnetically or antiferromagnetically to the porphyrin radical cation, giving an overall quartet or doublet state, respectively3,6,7,9. In contrast, for the non-haem case, a high-spin S = 2 state is demonstrated by three large negative A tensors1,19. The high-spin conguration is possibly due to the weak ligand eld exerted by the combination of histidine and carboxylate ligands or the proposed pseudo-trigonal symmetry22, which renders the d(x2 y2) and d(xy) orbitals nearly degenerate in energy (Fig. 3 (refs 23 and 24)).

In spite of the spin state dierence in the mononuclear high-valent oxoiron(IV) intermediates of the haem and non-haem enzymes, the FeO bond strengths for the S = 1 and S = 2 states are comparable. The Fe = O bond distances (1.641.68 ), obtained from extended X-ray absorption ne structure (EXAFS) or X-ray diraction studies, and the FeO stretching frequencies (776843 cm 1),

O O O

Hisdist

H2O

H2O2

FeII FeIII OO

FeII OOC(O)R

FeIV O

FeIII OOH

FeV O

FeIII

H O

1e from NADH

H+

CO2 R

His

Glu

Fe Fe

HO FeV

O Asp

IV IV

His

OO O N

N H

His

N H

Glu

His

Rieske dioxygenase

OOC

O COO

N N N

FeIV

Cpd-I

X= cysteine, tyrosine or histidine

H+

H2O

Asp

N NH

His

FeIV

His

TauD-J

Figure 1 | Mechanisms of dioxygen and hydrogen peroxide activation by iron containing haem and non-haem oxygenases. The structures in the boxes depict high-valent intermediates of the enzymatic reactions; TauD-J: intermediate J of taurine dioxygenase, Q: intermediate Q of soluble methane monooxygenase, Cpd-I: Compound-I intermediates of iron containing haem enzymes, like catalase, peroxidase or cytochrome-P450; His: histidine; Hisdist: distal histidine; Asp: asparagine; Glu: glutamic acid.

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Hydroxylase (CPO-I and P450-I)

Peroxidase (HRP-I)

Catalase

Hydroxylase

Halogenase

Desaturase

cis-Dihydroxylation

R-H

FeIII

S Cys

+ R-OH

R FeIII

R-OH

FeIV

FeII

Cys Cys

Cpd-I Cpd-II (protonated)

Cpd-I Cpd-II

Cpd-I

H AH

R-H FeIV

R FeIII

AH A

N His

X X

FeII +R-X

FeIV

FeIII

N His

+ H2O

H2O2 H2O + O2

R R

H OH2

O Tyr

FeIV

FeIII

O Tyr

R R

H R R

FeIV

FeIII

FeII +

Methane monooxygenase (Q)

CH3-H

CH3

FeIII

FeIV O

FeIII

HO CH3OHH2O

FeIII

FeIV O

FeIII

2H+

H H

H+ H

Ring opening

FeV

FeIII

O FeIV

CH3

FeIII O

FeIV

CH3OH H2O

CH3-H

FeIII FeIII

2H+

Figure 2 | Reactions catalysed by high-valent oxo intermediates of iron-containing enzymes. Enzyme reactions: (a) haem enzymes, (b) a non-haem diiron enzyme and (c) non-haem monoiron enzymes. Cpd-I, compound-I of iron containing haem enzymes; Cpd-II, compound-II of iron containing haem enzymes; CPO-I, compound-I of chloroperoxidase; P450-I, compound-I of cytochrome-P450; HRP-I, compound-I of horse-radish peroxidase; AH, reducing substrate for peroxidase (in case of glutathione peroxidase AH is monomeric glutathione); Cys, cysteine; Tyr, tyrosine.

obtained from resonance Raman studies, are found to be similar in both cases13,57,9,10,18. This similarity is expected based on the molecular orbital diagram shown in Fig. 3. For both the S = 1 and S = 2 congurations the FeO antibonding *{(d(xz),d(yz)} levels contain two electrons. A signicantly larger FeO distance (1.81 ) and lower FeO stretching frequency (565 cm 1), however, are observed for the one-electron reduced form of Cpd-I of the thiolateligated haem enzymes, where the oxoiron(IV) unit is protonated (Fig. 2)2528. A protonated oxoiron(IV) centre is also reected in the Mssbauer data as the variation of the Fe d(xz)/d(yz) spin populations, owing to the protonation of the oxoiron(IV) unit, provides unique EQ values signicantly larger ( > 2 mm s 1) than those in the deprotonated form ( < 1.6 mm s 1)2528.

Ironoxo model complexes. The rst high-valent oxoiron complex was synthesized in 1981 by Groves et al.7,8 via oxidation of [(TMP)FeIII(Cl)] (TMP = meso-tetramesityl porphinate anion) with meta-chloroperbenzoic acid in a dichloromethane-methanol mixture at 78 C. On the basis of its absorption spectra, the electronic structure of the resultant green compound was best described as an oxoiron(IV) porphyrin -radical cation (d4) species [(TMP + )FeIV(O)(CH3OH)] + , which showed the characteristic features of Cpd-I intermediates; namely, a weak and broad Soret band at 405 nm and a Q-band at 605 nm6,9. On the basis of electron paramagnetic resonance (EPR) and applied-eld Mssbauer spectroscopy (Table 1), an overall quartet (St = 3/2) ground state was deduced, arising from a ferromagnetic coupling of the S = 1 iron(IV) centre with a porphyrin -cation radical (S = 1/2). The structural analysis of the intermediate by EXAFS revealed a short FeO bond distance of 1.60 , indicating

that Fe = O possesses double-bond character. The oxoiron(IV) double-bond character is further supported by a resonance Raman vibrational band centred at = 828 cm 1 in dichloromethane methanol, which was assigned to the (FeO) stretching vibration based on its shi to 792 cm 1 on 18O labelling. In the absence of methanol, the (FeO) stretching vibration was observed at 801 cm 1 due to the binding of the chloride anion as an axial ligand trans to the oxo unit. Thus, as also suggested from theoretical studies29, the axial ligand competes with the oxo-group in binding to the iron-centre, therefore decreasing the strength of the FeO bond.

The [(TMP + )FeIV(O)(CH3OH)] + complex was found to be a competent oxidant in olen epoxidation and alkane hydroxylations6,7. Since then, a number of oxoiron(IV) porphyrin -radicals bearing electron-rich and -decient porphyrins (Fig. 4) have been prepared in an eort to understand the electronic eects of the porphyrins on the chemical properties of the oxoiron(IV) intermediates3. The results of these studies, which are summarized in some recent review articles3,6,7, indicate that the electronic nature of porphyrin ligands controls the oxidizing power of oxoiron porphyrins, and that oxoiron species with electron-decient porphyrins are more powerful oxidants in the oxygenation of organic substrates. The axial ligands bound trans to the ironoxo moiety also markedly inuence the reactivities of oxoiron(IV) porphyrin -cation radicals. For example, a recent study by Kang et al.30, which investigated a series of complexes [(TMP + )FeIV(O)(p-Y-pyO)] + (Y = OCH3,

CH3, H, Cl) and [(TMP + )FeIV(O)(X)] (X = CF3SO3 , Cl , AcO , OH ) in H-atom abstraction and O-transfer reactions by experimental (Fig. 5a) and theoretical methods, showed that rates of both the O-transfer and H-atom abstraction reactions of the porphyrin

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Table 1 | Structural and spectroscopic properties of high-valent ironoxo and nitrido units in chemistry and biology.

Species Fe-spin (oxidation) state

Mssbauer spectroscopy (Fe-X) (cm 1)

Fe-X distance ()

EPR-Data

(mm s 1)

EQ (mm s 1)

A (Ax, Ay, Az) (T)

g(gx, gy, gz)- values

Haem systemsP450-I (ref. 48) S=1 (IV) 0.11 0.90 ( 20, 23, 3) (1.96, 1.86, 2.00) CPO-I (ref. 48) S=1 (IV) 0.13 0.96 ( 24, 22, 1) (1.72, 1.61, 2.00) HRP-I (ref. 9 and refs therein) S=1 (IV) 0.08 1.25 ( 19.3, 19.3, 6) 790 1.641.67 geff=2 [FeIV=O(TMP)] + (refs 8,9

and refs therein)

S=1 (IV) 0.08 1.62 ( 25, 25, 6) 828 (CH2 Cl2-CH3OH)

1.641.65

801 (CH2Cl2)

P450-II (ref. 28) S=1 (IV) 0.14 2.06 ( 19, 19, 7) 1.82 CPO-II (ref. 27) S=1 (IV) 0.10 2.06 ( 20, 20, 7) 565 1.82 HRP-II (ref. 20) S=1 (IV) 0.03 1.61 ( 19.3, 19.3, 6.5) 776790 1.601.93

Mononuclear non-haem systemsTauD-J (refs 1,19) S=2 (IV) 0.30 0.9 ( 18.4, 17.6, 31) 821 1.62 [(H2O)5FeIVO]2 + (ref. 58) S=2 (IV) 0.38 0.33 ( 20.3, 20.3, ND)

[(TMG3tren)FeIVO]2 + (refs 59,60) S=2 (IV) 0.09 0.29 ( 15.5, 14.8, 28) 843 1.661(2) [(H3buea)FeIVO] (ref. 54) S=2 (IV) 0.02 0.43 ND 798 1.680(1) gx=8.19 (sharp);

g=4.06 (broad)

[(Me4cy)FeIVO (NCCH3)]2 + (ref. 41)

S=1 (IV) 0.17 1.24 ( 22.6, 18.3, 2.9) 834 1.646(3)

[(Me4cyS)FeIVO ] + (ref. 47) S=1 (IV) 0.19 0.22 ( 23, 22, 5) ND 1.70 [(Me3NTB)FeIVO]2 + (ref. 64) S=1 (IV) 0.02 1.53 ( 19, 19, 0)

[(TAML)FeVO] (ref. 32) S=1/2 (V) 0.42 4.25 ( 49.3, 1.5, 16.3) 1.58 (1.99, 1.97, 1.74)

Diiron non-haem systemsMMOH intermediate Q (ref. 70) S=2 (IV) 0.17 0.53 1.77 Ribonucleotide reductase intermediate X (refs 5,19)

S=2 (IV) 0.26 0.6 ( 20, 20, 15) 1.80

[{(Me2(OMe)TPA) FeIV}2 (-O)2]4 + (ref. 71)

S=1 (IV) 0.04 2.09 674 1.78

[(Me2(OMe)TPA)2FeIV (OH)FeIV(O)]4 + (ref. 73)

S=1 (FeIV(O)) 0.03 0.92 1.68

S=1(FeIV(OH)) 0.0 1.96 1.76

-Nitrido diiron complexes

[(Me3tacn)(Cl4cat)FeIII(-N) FeIV(Cl4cat) (Me3tacn)] (refs 93,95)

S=5/2(III) 0.52 1.67 22.0 (Isotropic) 911 (14N) 1.495(7) (3.99, 4.14, 2.0)

S=1(IV) 0.09 0.81 + 5.5 (Isotropic) 884 (15N) 1.976(7) [(Me3tacn)(Cl4cat)FeIV(-N)FeIV

(Cl4cat) (Me3tacn)] (ref. 93)

S=1 (IV) 0.04 1.55 ND 407 1.703(1)

[(Me3tacn)(Ph2acac)FeIII(-N) FeIV(Cl4cat) (Me3tacn)] (ref. 95)

S=5/2(III) 0.60 2.00 ( 23.0, 23.0, 9.0) 1.785(7) (3.96, 4.07, 1.98)

S=1 (IV) 0.04 1.13 (6.0, 6.0, 1.6) 1.695(7) [{Trans-(cy)FeIII(N3)}(-N)

{trans-(cy)FeIV(N3)}]2 + (ref. 81)

S=3/2(III) 0.20 2.09 ( 2.8, 7.8, 19.7) (2.04, 2.06, 2.20)

S=1 (IV) 0.11 0.97 ( 13.6, 10.1, 1.1) [{Cis-(cy)FeIII(N3)}(-N)

{trans-(cy)FeIV(N3)}]2 + (ref. 81)

S=5/2(III) 0.47 1.89 ( 13.5, 14.5, 22.7) (2.04, 2.06, 2.20)

S=1 (IV) 0.14 0.79 ( 10.0, 10.5, 1.2)

Mononuclear ironnitrido complexes

[(TPP)FeV(N)] (ref. 80) S=3/2(V) ND 876 Trans-[(N3)(cy)FeV(N)] + (ref. 81) S=1/2(V) 0.04 1.90 ( 13.3, 10.6, 2.5) 2.0 (xed to isotopic value)

[(cy-ac)FeV(N)] + (refs 40,82,83) S=1/2(V) 0.04 1.67 ( 12.8, 11.4, 1.9) 864 2.0 (xed to isotopic value)

[(Me3cy-ac)FeVI(N)]2 + (ref. 84) S=0(VI) 0.29 1.532 ND 1064 (calc) 1.57 [(PhBPiPr3)FeIV(N)] (refs 85,86

and refs therein)

S=0(IV) 0.34(1) 6.01(1) ND 1034 (14N) 1.511.55

(4 K, 45 mT) 1007 (15N)[(TIMENmesFeIV(N)] + (ref. 87) S=0(IV) 0.27 6.04 ND 1008 (14N) 1.526(2)

982 (15N)

[(PhB(tBuIm)3)FeIV(N)] (ref. 92) S=0(IV) 0.28 6.23 ND 1.512(1) [(PhB(tBuIm)3)FeV(N)] + (ref. 92) S=1/2(V) 0.45 (78 K) 4.78 ND 1.506(2)(35 K) (2.30, 2.30,1.97)

0.49 (200 K) 4.73 1.502(2)(100 K)

Abbreviations: ND, not-determined; P450-I, cytochrome-P450 compound-I; P450-II, cytochrome-P450 compound-II; CPO-I and CPO-II, chloroperoxidase compound-I and II, respectively; HRP-I and HRP-II, horse-radish peroxidase compound I and II, respectively; TMP, meso-tetramesityl porphyrin; Me4cy, 1,4,8,11-tetramethylcyclam; TMG3tren, tris[2-(N-tetramethylguanidyl)ethyl]amine;

Me3NTB, tris((N-methylbenzimidazol-2-yl)methyl)amine), H3buea, tris(tert-butylureaylethylene)aminato, Me2(OMe)TPA, tris((4-methoxy-3,5-dimethylpyridin-2-yl)-methyl)amine; TPA, tris(2-pyridylmethyl)amine; TAML, tetraamido macrocyclic ligand.

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Threefold symmetry

Fourfold symmetry

FeIV

FeVI

z2 z2

Anti bonding

Non bonding

xz, yz

x2y2 x2y2

xz, yz

x2y2, xy x2y2, xy

xy xy

Figure 3 | Tetragonal and trigonal ligand elds of high-valent transition metal complexes with strong -donor oxo and nitrido ligands23,24. In threefold

symmetry, a non-bonding, doubly degenerate set of (x2y2, xy) orbitals allows for the stabilization and isolation of nitridoiron(IV) and (V) complexes and enables the spin state S = 2 for oxoiron(IV) species. In tetragonal ligand elds, oxo complexes exhibit the classical 1 + 2 + 1 + 1 d-orbital energy scheme (ref. 49). According to Bendix et al. (ref. 23), complexes with the more covalent nitrido and weak equatorial ligands deviate from this and approach a1 + 3 + 1 splitting diagram, in which the x2 y2 orbital can even be lower in energy than the (xz, yz) set.

complexes increase with increasing electron donation from the axial ligand. Their results have been extended to correlate the strong oxidizing power of the thiolate-ligated P450 enzyme to the strong electron donation from the axial thiolate ligand31.

In contrast to the haem-based systems, which mainly stabilize an oxoiron(IV) -cation radical unit, an iron(V) oxidation state can be stabilized with redox-innocent, non-haem ligand systems. Accordingly, Tiago de Oliveira et al.32 reported the synthesis of an oxoiron(V) (d3) complex by using their signature tetraamido macrocyclic ligand (TAML). The reaction of [(TAML)FeIII(H2O)]

with meta-chloroperbenzoic acid in n-butyronitrile at 60 C, in presence of small amounts of water, pyridine or benzoic acid, yielded a deep green complex, which has been characterized as [(TAML)FeV(O)] , based on a combined Mssbauer, EPR and EXAFS study. The iron(V) oxidation state was conrmed on the basis of its characteristic Mssbauer spectrum with an unusually low, negative isomer shi of 0.42 mm s 1 and large quadrupole splitting of 4.25 mm s 1 at 4.2 K (Table 1). The EPR spectrum revealed an S = 1/2 ground state, and EXAFS provided evidence of a short FeO distance of 1.58 consistent with the [(TAML)FeV(O)] assignment for the complex.

An FeV(O)(OH) species has been implicated as the active oxidant responsible for the cis-dihydroxylation of C = C double bonds2,4,33 and the oxidation of water34 in a number of iron- containing non-haem natural and model systems, but with only indirect proof of its existence3537. However, the spectroscopically characterized [(TAML)FeV(O)] anion, which is the only known isolable oxoiron(V) species in the literature, was found to be a sluggish oxidant32; reacting with the weak CH bonds of dihydroanthracene only. Moreover, no [(TAML)FeV(O)] mediated cis-dihydroxylation reaction have thus far been reported. Additionally, no [(TAML)FeV(O)] intermediate could be identied during the [(TAML)FeIII] mediated water oxidation reaction38. Therefore, the involvement of FeV(O)(OH) intermediates in oxygenation reactions remained doubtful until very recently39. Using variable-temperature mass spectrometry, Prat et al.39 provided evidence for such a reactive intermediate in a synthetic system.

While the rst paper on the synthesis and characterization of an oxoiron(IV) porphyrin species appeared in 1981 (ref. 8), the original report of a non-haem oxoiron(IV) complex appeared almost two decades later in 2000 (ref. 40). The biggest impediment to progress in identifying and trapping a non-haem oxoiron(IV) species was the lack of a convenient spectroscopic signature that would readily signal its presence in a reaction mixture. Although oxoiron(IV) porphyrin complexes had been well characterized for some time, their

ultravioletvisible spectra were dominated by intense porphyrin ligand transitions that obscured weaker bands that may be associated with the FeIV = O unit. Thus, design of suitable ligand systems to stabilize oxoiron(IV) units in non-haem ligand environment was warranted so as to obtain deeper insights into their electronic structure.

Grapperhaus et al.40 were the rst to obtain a major breakthrough in this regard. They generated a terminal non-haem oxoiron(IV) species by the ozonolysis of [(cy-ac)FeIII(CF3SO3)] +

(cy-ac = 1,4,8,11-tetraazacyclotetradecane-1-acetate) in a mixture of acetone/water at 80 C. The eeting intermediate was characterized to be a low-spin (S = 1) iron(IV) species based on Mssbauer studies ( = 0.1 mm s 1 and EQ = 1.39 mm s 1)40. The instability of the compound, however, prevented its further spectroscopic characterization. Subsequently, Rohde et al.41 reported the rst X-ray crystal structure of a mononuclear S = 1 oxoiron(IV) complex that was generated in the reaction of [(Me4cy)FeII(CH3CN)]2 +

(Me4cy = 1,4,8,11-tetramethylcyclam) and iodosobenzene (PhIO) in CH3CN at 25 C. The molecular structure of the [(Me4cy)FeIV(O)

(CH3CN)]2 + complex features a short Fe = O distance of 1.646(3) with an acetonitrile ligand bound trans to the oxo group (Fig. 5b).

The macrocyclic Me4cy ligand adopts a trans-I conguration42 such that all four methyl groups are oriented anti to the oxo atom. A syn

orientation of the oxo group has also been recently demonstrated in the crystal structure of the [(Me4cy)FeIV(O)Sc(OSO2CF3)4OH]

complex, formed by the reaction of [(Me4cy)FeIV(O)(CH3CN)]2 + with Sc(CF3SO3)343. In addition to the oxo-ligand inversion, the strong binding of Sc3 + to the Fe = O moiety of the [(Me4cy)FeIV(O)

(CH3CN)]2 + complex induces a pentacoordinated square-pyramidal coordination at the iron centre and an elongated FeO distance of 1.754(3) .

Since the report of the [(Me4cy)FeIV(O)(CH3CN)]2 + complex in 2003, a handful of non-haem S = 1 oxoiron(IV) complexes have been synthesized in the past 8 years, using various tetradentate and pentadentate ligand systems (Fig. 4), containing pyridine and amine nitrogen donors33,44. The structural analysis of the intermediates by X-ray crystallography for [(Me4cy)FeIV(O)(CH3CN)]2 + , [(Me3cypy)FeIV(O)]2 + (Me3cy-py = 1-(2-pyridylmethyl)-4,8,11-trimethyl-1,4,8,11-tetraazacyclotetradecane)45 and [(N4Py)FeIV(O)]2 +

(N4Py = N,N-bis(2-pyridylmethyl)-bis(2-pyridyl)methylamine), or EXAFS for others, revealed a short FeO distance of ~1.64 , which is comparable with those of oxoiron(IV) porphyrin intermediates6,7,9,18 and signicantly dierent from the 1.81 distance of Boroviks oxoiron(III)46, 1.75 of Nams43 [(Me4cy)FeIV(O)

Sc(OSO2CF3)4OH] and the 1.58 distance of Collins oxoiron(V)

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F F

R =

N N

TPP TMP TDCPP TDFPP TPFPP

Me3cy-py: R = Me, R' = CH2Py Me4cy: R = R' = Mecy: R = R' =H

cy-ac: R = H, R' = CH2COO Me3cy-ac: R = Me, R' = CH2COO

Me3cyS: R = Me, R' = CH2CH2S

NH HN

O O

R R

tacn: R = H Me3tacn: R = Me

PhBPiPr3

TAML

N N N

N N

H N

OMe

H3buea

TMG3tren

Me2(OMe)TPA

Me3NTB

Py Py

N4Py

B N N

B P(iPr)2

N N

PhB(tBuIm)3

TIMENmes

BnTPEN

Figure 4 | Macrocyclic and chelating ligands for the stabilization of high-valent oxo and nitridoiron complexes. Structures in the rst line depict porphyrin-based ligands; in the second line macrocyclic ligands, involving amine or amide nitrogen donors; in the third and fourth line, nitrogen- and boron-anchored tri- and tetrapodal chelates. Py, 2-pyridyl group; Ph, phenyl group; iPr, iso-propyl group.

complexes32. Another relatively long FeO distance of 1.70 has been obtained for the thiolate-ligated [(Me4cyS)FeIV(O)] +

(Me4cyS = monoanion of 1-(mercaptoethyl)-4,8,11-trimethyl-1,4,8, 11-tetraazacyclotetradecane) complex47, which acts as the model complex for the recently characterized48 thiolate-ligated Cpd-I intermediate in the catalytic cycle of P450. All these compounds feature a near-infrared absorption band of moderate intensity44, which, on the basis of magnetic circular dichroism, has been attributed to three of the ve ligand-eld transitions expected for an S = 1 Fe(IV) centre in C4V symmetry49.

The general method of synthesizing the non-haem oxoiron(IV) complexes involves the reaction of the iron(II) precursor with an oxygen atom donor, like PhIO or peracids (Fig. 6)44. In rare cases, they have been generated electrochemically50 or photochemically51, using water as the oxygen source and also by using hydrogen peroxide in presence of a base52. Only recently, dioxygen has been used as an oxidant, which has helped to improve our understanding of the mechanism of dioxygen activation at a mononuclear iron active site45,5355. Most of the intermediates shown in Fig. 1 have been independently identied and have established the credibility of the proposed mechanism of dioxygen activation. The formation of the high-valent iron oxidant via a reductive OO bond cleavage step requires two electrons and protons. Thibon et al.45 used BPh4 (electron donor) and HClO4 (proton donor) to demonstrate the formation of a high-valent S = 1 iron(IV) species in [(Me3cypy)FeIV(O)]2 + from [(Me3cy-py)FeII]2 + and dioxygen. Lee et al.55, on the other hand, were able to generate S = 1 [(Me4cy)FeIV(O)

(CH3CN)]2 + from [(Me4cy)FeII(CH3CN)]2 + and O2, using olens containing allylic CH bonds as H-atom (H + + e ) donors. In both studies, no intermediates could be trapped during oxoiron(IV)

formation. Hong et al.53 also reported the synthesis of the known [(N4Py)FeIII-OOH]2 + or [(BnTPEN)FeIII-OOH]2 + (BnTPEN = N-benzyl-N,N,N-tris(2-pyridylmethyl)-1,2-diaminoethane) complexes in near-quantitative yield, by activating dioxygen in the presence of acid and 1-benzyl-1,4-dihydronicotinamide, an NADH analogue. However, no oxoiron(IV) complex could be identied in these reactions as well. The missing link connecting the mechanistic steps of the above studies was the experimental demonstration of OO bond cleavage in a hydroperoxoiron(III) complex to yield the corresponding high-valent ironoxo species. This link has recently been identied independently by the groups of Li et al.56 and Cho et al., who generated a high-spin FeIII-OOH complex supported by the Me4cy ligand via protonation of the side-on peroxoiron(III)

conjugate base56,57. This hydroperoxo complex was shown to convert quantitatively to the corresponding S = 1 oxoiron(IV) complex either through acid-mediated OO bond heterolysis, followed by the reduction of the transient oxoiron(V) intermediate56 or directly by OO bond homolysis57.

The [(H3buea)FeII] complex of the tris(ureaylato) ligand, used by MacBeth et al.46, also reacts with O2 to yield an oxoiron(III) intermediate, which is proposed to derive from the reduction of an initially formed oxoiron(IV) species. Although the oxoiron(IV) species on the way to the generation of the oxoiron(III) complex could not be trapped, it has recently been synthesized by the one-electron oxidation of the preformed [(H3buea)FeIII(O)]2 (ref. 54). Interestingly, an S = 2 state has been determined for [(H3buea)FeIV(O)] on the basis of a sharp resonance at g = 8.19 in the parallel mode EPR spectra, which is indicative of a transition from the | 2 > doublet of an S = 2 spin manifold. Anionic [(H3buea)FeIV(O)] represents the only example of an

S = 2 oxoiron(IV) complex generated by O2 activation. Two examples

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H2O

[LFe(n+2)(O)]+

[LFen ]+ 2e ; 2H+

Reactivity

[LFen ]+

H2O

Electron rich

H2O2; Base

H2O

[LFen ]+ h or N2

[LFe(n+2)(N)] + [LFe(n1)]

O2; 2H

N N

FeIV N

N N

FeIV

[O]

[LFen ]+

[LFe(n+2)(N)]

(OTf)2

Figure 6 | Synthetic routes for high-valent oxo and nitridoiron complexes. Common synthetic routes for ironoxo complexes include oxidation of the iron centre with water as an oxygen source50,51 or the

oxidation of the complex with hydrogen peroxide52,5557, elemental

oxygen45,54 or other oxygen-atom donors44,47. A number of transition metal nitrido complexes have been synthesized via deoxygenation of NO, reductive decarbonylation of isocyanate, NN bond cleavage in N2O reduction, inter-metal N-atom transfer from nitrido complexes, and metathesis of nitrile from metal alkylidyne and a MM multiple bonded complex. In contrast, fewer synthetic routes are known for ironnitrido complexes: the photo- and thermolysis of azide precursors80,81, N-atom

transfer via strain release by anthracene elimination from 2,3:5,6-dibenzo-7-azabicyclo[2.2.1]hepta-2,5-diene85, and, only recently, with elemental dinitrogen (synthesis not depicted)100. [O] represents oxygen-atom donors, like iodosobenzene or peracids.

N N

+Sc(OTf)3 +H2O

FeIV N

N N

NCCH3

FeIV N

TfOH CH3CN

TfO

OTf

OTf OH

3+ 2+

LFeIII

LFeIV LFeIV

FeIVL

H+

H2O

LFeIII

HO O

Low-spin

Low-spin Low-spin

High-spin

FeIVL FeIVL

OMe

L = N

Figure 5 | Reactivity of high-valent mono- and diiron-oxo model complexes. (a) Axial ligand effects on the oxo-transfer (dotted line) and H-atom abstraction (bold line) reactivity of the complexes [(Me4cy)FeIV

(O)X]+(X = NCCH3, O2CCF3, N3, or SR)65 and [(TMP) + FeIV(O)X](X = CF3SO3, Cl, AcO, OH)30; (b) Structural changes of the oxoiron(IV)

unit of the model complex as a result of binding to a Sc3 + ion43; OTf, triate. (c) Interconversions among high-valent diiron complexes71,73,74.

of synthetic high-spin oxoiron(IV) species have been described before the report of MacBeth et al. (ref. 46): one from Pestovsky et al.58, using [FeII(H2O)6]2 + and ozone in water and the other from England

et al.59,60, using [FeII(TMG3tren)(OTf)] + and iodosylbenzene. The S = 2 ground state in [(TMG3tren)FeIV(O)]2 + and [(H2O)5FeIV(O)]2 +

has been determined by applied-eld Mssbauer studies, which, similar to the oxoiron(IV) intermediates observed in the catalytic cycle of nonhaem oxygenases, are characterized by a large and negative hyperne splitting component in z-direction and by a small and negative quadrupole splitting (EQ) parameter (Table 1). The molecular structures of [(TMG3tren)FeIV(O)]2 + and [(H3buea)FeIV(O)] , as determined by X-ray crystallography, reveal a trigonal bipyramidal geometry at the metal centre, with Fe = O distances of 1.661(2)60 and 1.680(1) 54, respectively. The S = 2 ground state in [(TMG3tren)FeIV(O)]2 + and [(H3buea)FeIV(O)] is attributed to their threefold symmetry with degenerate sets of d(xy) and d(x2 y2) orbitals (Fig. 3)23,24.

The reactivity of non-haem oxoiron(IV) complexes in CH hydroxylation and oxo-transfer reactions has been considered in depth by theoretical6163 and experimental methods44,64,65. So far, all theoretical studies have led to the common conclusion that the ferryl species are better oxidants on the quintet-state than the corresponding triplet-state. There is a long-term debate, however, on how to rationalize the higher reactivity of the quintate state6669. Moreover, direct experimental evidence for the higher reactivity of the S = 2 state is lacking in the literature. Presumably, because the oxoiron(IV) core is protected by the sterically bulky chelator in the recently reported S = 2 [(TMG3tren)FeIV(O)]2 + complex59,60,67, its reactivity towards CH bond cleavage is only comparable with triplet ferryl analogues. Indirect evidence of the higher reactivity of the quintate state is, however, provided by Seo et al.64 in their report of a highly reactive mononuclear oxoiron(IV) complex, [(Me3NTB)

FeIV(O)(CH3CN)]2 + (with Me3NTB = tris((N-methyl-benzimidazol- 2-yl)methyl)amine), that attacks the strong CH bonds of cyclohexane at 40 C. This complex is the most reactive species among oxoiron(IV) complexes reported so far. Although an S = 1 ground state has been obtained for the complex from applied-eld Mss-bauer spectroscopy at 4.2 K, densityfunctional theory (DFT) calculations explain the unprecedented high reactivity of [(Me3NTB)

FeIV(O)(CH3CN)]2 + on the basis of the easily accessible extremely low-lying excited S = 2 state that mediates the reactivity. The two-state reactivity, proposed for [(Me3NTB)FeIV(O)(CH3CN)]2 + , has also been used to explain the reactivity pattern of a series of [(Me4cy)FeIV(O)(X)]+ complexes (X = NCCH3, O2CCF3, N3

or SR)65. In this series, the reactivity rates of O-transfer to PPh3 were found to decrease in the order NCCH3 > O2CCF3 > N3 >

SR consistent with the decreasing electrophilicity of the Fe = O unit. The rates of H-atom abstraction from dihydroanthracene, however, increased with the introduction of a more electron donating axial ligand (Fig. 5a). The latter counter-intuitive trend has been rationalized by the decrease in calculated energy gap between the triplet ground state and the quintet excited state as the axial ligand becomes more electron donating, thereby lowering the activation barrier for

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H-atom abstraction. This is in contrast to the Cpd-I model compounds (formally oxoiron(V) species), where the determined rates of O-transfer and CH abstraction reactions increase with increasing donation from the axial ligands (Fig. 5a).

Dinuclear bis(-oxo)diiron(IV) model complexes. Intermediate Q is considered as the key oxidizing species in the catalytic cycle of sMMO, performing the chemically exceedingly challenging conversion of methane to methanol. A detailed analysis of EXAFS and Mssbauer spectroscopic data revealed that Q is best described as a strongly exchange-coupled S = 2 diiron(IV) species with an FeFe distance of 2.46 and pairs of short and long FeO bonds of 1.77 and 2.05 , respectively, consistent with an Fe2IV(-O)2-diamond core structure70. Xue et al.71 succeeded in preparing the rst and only example of a synthetic complex possessing a Fe2IV(-O)2 core by electrochemical oxidation of the previously reported precursor [(Me2(OMe)TPA)2FeIII/IV(-

O)2](ClO4)3 (with Me2(OMe)TPA = tris(3,5-dimethyl-4-methoxypyridyl-2-methyl)amine)72. Combined Mssbauer and EXAFS data revealed that in [{(Me2(OMe)TPA)FeIV}2(-O)2]4 + two low-spin (S = 1) Fe(IV)-centres are antiferromagnetically coupled and exhibit

FeO and FeFe distances of 1.78 and 2.73 , respectively. Cationic [{(Me2(OMe)TPA)FeIV}2(-O)2]4 + could also be generated chemically, via the intermediate formation of an open-core [(O)FeIV-O

FeIV(OH)]3 + complex cation, containing two S = 1 FeIV centres, by reacting the (-oxo)-diiron(III) precursor with H2O2 in the presence of an acid73. Additionally, a new product with high-spin FeIV S = 2 and high-spin FeIII S = 5/2 centres in a valence-localized [(O)FeIVO-FeIII(OH)]2 + core was obtained by treating [(Me2(OMe)TPA)2

FeIIIFeIV(-O)2](ClO4)3 with hydroxide74. A comparative reactivity study of [{(Me2(OMe)TPA)FeIV}2(-O)2]4 + , [(O)FeIV-O

FeIV(OH)]3 + , [(O)FeIV-O-FeIII(OH)]2 + and the previously reported72 S = 1 [FeIV = O]2 + cations (Fig. 5c) showed that the terminal iron(IV) oxo units are at least three orders of magnitude more reactive than the ones with diamond cores74. The most potent CH activator is the complex with an S = 2 quintet ground state of the Fe = O moiety. Hence, for the rst time, an experimental demonstration of increased reactivity of quintet oxoiron(IV) species over the corresponding triplet species was provided.

Ironnitrido complexesIronnitrido intermediates in biology. Iron-nitrido complexes, which are isoelectronic to ironoxo complexes, are also considered as key intermediates in a number of important biological transformations. However, while a number of transient high-valent ironoxo intermediates in the catalytic cycle of haem and non-haem enzymes have been identied and spectroscopically characterized13,57,9,10,18, direct evidence for the involvement of ironnitrido intermediates in biology is lacking. Ironnitride-mediated mechanistic postulates have nevertheless been motivated on the basis of indirect evidences that are obtained from various biochemical experiments1316. For example, in the FeMo cofactor of the nitrogenase enzyme, the structure of which features seven iron centres and a single molybdenum centre held together by nine bridging sulphides and a carbide atom (Fig. 7)12,75, dinitrogen reduction is proposed to occur at a single iron site76. Dinitrogen binds and is heterolytically cleaved at this iron site, which results in the release of ammonia and generation of FeIVN. However, alternative mechanisms involving molybdenum or polynuclear iron reactive sites have also been proposed in the literature1316. Moreover, a related imidoiron(IV) porphyrin (Fig. 7) species is postulated to be the reactive intermediate for cytochrome-P450-LM-3,4 catalysed N-atom transfer reactions11.

Ironnitrido model complexes. To probe the possibility of the involvement of ironnitrido intermediates in biological dinitrogen- reduction and atom-transfer reactions, bioinorganic chemists

became interested in the synthesis and reactivity of model compounds involving high-valent nitridoiron moieties. Here we summarize the recent advances in this eld with a focus on monoand dinuclear complexes; thus, omitting the few rare examples of polynuclear ironnitrido complexes7779.

The rst high-valent nitridoiron complex was characterized in 1989, when Wagner and Nakamoto80 photolysed a porphyrin-ligated FeIII azide complex [(TPP)FeIII(N3)] (TPP, tetraphenylporphinate anion) in a frozen matrix of dichloromethane at 30 K. The resulting matrix-stabilized nitrido complex [(TPP)FeV(N)] exhibits a resonance Raman vibrational band centred at = 876 cm 1, which was assigned to the (FeN) stretching vibration (Table 1). Labelling experiments with 57Fe as well as 15N allowed for the unambiguous assignment of this (FeN) band. Although no further spectroscopic characterization of the FeV = N species was performed, the authors proposedbased on the relatively small force constant in comparison with the isoelectronic [(TPP)Mn(O)]a d3 high-spin (S = 3/2) rather than a low-spin S = 1/2 electronic ground state for the nitridoiron(V) species80. The stabilization of the unusually high FeV oxidation state in [(TPP)FeV(N)] reects the higher -donating property of the nitrido ligand that stabilizes higher metal oxidation states; the isoelectronic [(TMP + )FeIV(O)] + complex7,8 could only be stabilized as a d4 oxoiron(IV) -cation radical species. The higher -donation from the nitrido ligand arises from the smaller eective nuclear charge (Z*) of nitrogen compared to oxygen29, which causes the N p orbitals to be better energetically matched with the valence d orbitals on Fe.

Meyer et al.81 reported the rst high-yield synthesis of a nitridoiron(V) species by photolysis of trans-[(cy)FeIII(N3)2] + in frozen CH3CN; the reaction produced two species, which have been identied as the photo-reduced ve-coordinate ferrous species, trans-[(cy)FeII(N3)] + , formed via homolytic FeN3 bond cleavage, and the photo-oxidized trans-[(N3)(cy)FeV(N)] + , formed via homolytic NN bond cleavage and N2 evolution81. The high-valent FeV species was identied unequivocally by its characteristic

Mssbauer spectrum, with an isomer shi of 0.04 mms 1 and a quadrupole splitting EQ of 1.90 mms 1 at 80 K (Table 1)81.

The FeII complex was actually shown to be the major product of photolysis of the corresponding [(cy-ac)FeIII(N3)] + complex in solution (CH3CN at 35 C)40, while the formation of the photo-oxidized FeV complex [(cy-ac)FeV(N)] + prevailed in a frozen matrix. Interestingly, the Mssbauer isomer shi of 0.04 mms 1 reported40,81 for the pentavalent Fe ion in [(cy-ac)FeV(N)] + and trans-[(N3)(cy)FeV(N)] + is found to be similar to that of 0.01 mms 1

reported40 for tetravalent Fe in [(cy-ac)FeIV(O)] + and signicantly more positive than the value reported for Collins [(TAML)FeV(O)] complex ( 0.46 mms 1)32. This trend of higher isomer shis in nitrido as compared with the corresponding oxo complexes has been explained29 on the basis of higher covalency of the ironnitrido bond (compared with the ironoxo). The nitridoiron(V) species trans-[(N3)(cy)FeV(N)] + and [(cy-ac)FeV(N)] + have initially been reported to possess a high-spin d3, S = 3/2, electronic ground state.

However, in a subsequent in-depth spectroscopic and theoretical work, Aliaga-Alcalde et al.82 concluded that [(cy-ac)FeV(N)] + has an unusual orbitally degenerate S = 1/2 ground state. Initially, the FeN stretch in [(cy-ac)FeV(N)] + could not be identied in the infrared vibrational spectrum. However, by using synchrotron-based nuclear-resonant-vibrational-spectroscopy coupled to DFT, Petrenko et al.83 identied the (FeN) band unambiguously at 864 cm 1. Furthermore, the (photochemically inactive) ferric azide of the corresponding methylated cyclam ligand can be oxidized to yield [(Me3cy-ac)FeIV(N3)]2 + , which, in turn, is photochemically active. Accordingly, photolysis at 650 nm in frozen matrix yields another, yellow product, [(Me3cy-ac)FeVI(N)]2 + with one major component (73%) at = 0.29 mms 1 and EQ = 1.53 mms 1 in the Mssbauer spectrum84. This unusually low, negative isomer shi is consistent with a hexavalent FeVIN species. The assignment

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SO2C7H7

OOC

COO

N N N

FeV

Cys

Mo S(Cys275)

(His442)N

S S

Fe Fe

FeI N N FeII N NH FeIII N NH2

FeIV N

+H+

NH +N2

3 NH3

+H+

FeI NH3

+H+

FeII NH2

+H+

FeIII NH

Figure 7 | Proposed structures of biological intermediates with iron nitrogen multiple bonds. The proposed structures have inspired studies on model ironnitrido and imido complexes. (a) Structure of the iron(IV) imido porphyrin intermediate that has been invoked for cytochrome-P450 catalysed nitrogen group transfer reactions11. (b) The iron molybdenum cofactor of the nitrogenase enzyme with a central carbide (C)12,75, and the

proposed intermediates (scheme in the box) of the dinitrogen activation process occurring at a single iron site76.

is further supported by a short FeN distance of 1.57 (determined by EXAFS), a complementary computational analysis, and a linear relationship between the isomer shis and oxidation states in a series of complexes with similar iron complex core structures and varying formal oxidation states, ranging from + II to + VI (ref. 84). This is the rst FeVI coordination complex ever reported, with the ferrate anion FeO42 being the only other known example of an

FeVI ion. However, just like all previous nitridoiron species, complex [(Me3cy-ac)FeVI(N)]2 + is only stable in cryogenic matrices and decomposes to a high-spin FeIII species on warming.

In 2004, Betley and Peters85 synthesized the rst terminal FeIVN complex that is stable in solution at room temperature. By using a phenyl-tris-diisopropylphosphinoborate (PhBPiPr3 ) as the stabilizing tripodal chelate and lithium amide 2,3,5,6-dibenzo-7-azabicyclo[2.2.1]hepta-2,5-diene (dbabh) as the N-atom transfer reagent, the four-coordinate [(PhBPiPr3)FeIV(N)] could be obtained and thoroughly characterized by 1H-, 31P- and 15N-NMR,

Mssbauer and infrared spectroscopy in solution (Table 1)85. An EXAFS analysis provided further insight into the molecular structure of [(PhBPiPr3)FeIV(N)] and revealed the unusually short FeN bond distance of 1.511.55 86. An X-ray diraction analysis of the crystallized product remained elusive due to dimerization to a dinitrogen bridged FeI/FeI-dinuclear species on concentration change during solvent evaporation. This dimerization, a six-electron reaction mediated by two iron centres, is by itself a remarkable reaction. The observation of signicant amounts of ammonia on treatment of [(PhBPiPr3)FeIV(N)] with protons and electrons is even more

signicant and lend credence to the involvement of similar intermediates during biological dinitrogen reduction.

The structural characterization of FeIVN complexes by single-crystal X-ray diraction was rst accomplished in 2008. Photolysis of an N-anchored tris(carbene)-ligated azide complex [(TIMENmes)FeII(N3)] + (TIMENmes = tris[2-(3-mesitylimidazol-2-ylidene)ethyl]amine) yielded the four-coordinate tetravalent [(TIMENmes)FeIV(N)] + as a purple crystalline material87. The spectroscopic ngerprint (infrared, 15N NMR and Mssbauer spectroscopy) of [(TIMENmes)FeIV(N)] + is very similar to Peters complex [(PhBPiPr3)FeIV(N)] (Table 1). Even the crystallographically determined FeN distance of 1.526 in [(TIMENmes)FeIV(N)] + is (within the experimental error) identical to that of EXAFS-spectroscopically determined one in [(PhBPiPr3)FeIV(N)]. However, the geometries in these two nitrido complexes are markedly dierent.

While the coordination polyhedron in the tris(phosphino)borate nitridoiron(IV) is best described as tetrahedral, the four-coordinate amine-anchored tris(carbene) nitride is trigonal pyramidal with the iron centre located approximately 0.4 above the plane of the carbene carbons. Also, while the axial nitride in [(PhBPiPr3)FeIV(N)]

is relatively unprotected, the functionalization of the imidazole N3 nitrogens in the tris(carbene) of [(TIMENmes)FeIV(N)] + with sterically encumbering xylene and mesitylene groups places these substituents perpendicular to the tris(carbene)iron plane; thus, creating a narrow cylindrical cavity, and eectively preventing bimolecular decomposition pathways. Moreover, the nitrido 15N resonance in cationic [(TIMENmes)FeIV(N)] + ( = 741 p.p.m. rel. to CH3NO2) is considerably down-eld shied compared with the neutral [(PhBPiPr3)FeIV(N)] ( = 572 p.p.m.) and, hence, is more similar to the nitrido ligand in trans-[(CF3COO)(cy)MnV(N)] +

(MnV, d2, S = 0)88. DFT calculations predict a diamagnetic {(x2 y2)2(xy)2}{(z2)0(xz)0(yz)0} electronic ground state, which is in agreement with the diamagnetic 1H NMR spectra of these FeIVN complexes. The {(x2 y2)2(xy)2}{(z2)0(xz)0(yz)0} conguration also leads to an extreme asymmetric electron distribution around the Fe ion, which results in the largest quadrupole splitting parameters ever observed with EQ values of more than 6 mms 1 (Table 1,

Fig. 3). The S = 0 ground state85,87 of [(TIMENmes)FeIV(N)] + and [(PhBPiPr3)FeIV(N)] is, however, in stark contrast to the S = 2 ground state of the [(TMG3tren)FeIV(O)]2 + complex59,60 with an {(x2 y2)

1(xy)1(xz)1(yz)1(z2)0} electronic conguration (Fig. 3). Although all three complexes possess a threefold symmetry, the strong antibonding character of the *(xz, yz) orbitals in [(TIMENmes)FeIV(N)] + and [(PhBPiPr3)FeIV(N)], which results in the inversion of the (z2)

and (xz), (yz) levels, is likely due to dierences in Z* between N and O that allow for better -overlap to occur for Fe N multiple bond29.

Scepaniak et al.90 combined the ligand systems of Vogel et al.87 and Betley and Peters85 by using the phenyl-tris(1-tert-butylimidazol- 2ylidene)borate (PhB(tBuIm)3 ), a boron-anchored tripodal tris

(carbene) ligand system originally introduced by Frnkel et al.89 Photolysis of [(PhB(tBuIm)3)FeII(N3)] also yielded the corresponding diamagnetic FeIVN species, the complex [(PhB(tBuIm)3)FeIV(N)], which was characterized by 1H and 15N NMR spectroscopy as well as electronic absorption spectroscopy, resonance Raman spectroscopy and single-crystal diraction studies90. Similar to [(PhBPiPr3)FeIV(N)], this nitridoiron(IV) species possesses a pseudo-tetrahedral geometry with an S = 0 electronic ground state. The reactivity of [(PhB(tBuIm)3)FeIV(N)], however, is surprisingly dierent to that of [(PhBPiPr3)FeIV(N)]. While [(PhB(tBuIm)3)FeIV(N)] reportedly does not react with protons and electrons, the carbene-based nitride engages in electrophilic reactions with phosphines, like Ph3P, yielding the phosphiniminato complex [PhB(tBuIm)3FeII(NPPh3)], a rare example of a four-coordinate FeII complex with a sharp S = 2

S = 0 spin-crossover transition at 78 K91.

Most interestingly, the iron(IV) complex [(PhB(tBuIm)3)FeIV(N)] could be oxidized with [Fe(Cp)2]BArF (with BArF = tetrakis(3,5-bis(triuoromethyl)phenyl)borate) to yield the corresponding

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pentavalent FeVN complex [(PhB(tBuIm)3)FeV(N)] + , which is the rst example of an FeVN that could be isolated and thoroughly characterized in solution and in solid state92. An X-ray diraction study revealed overall similar bond metrics to its tetravalent precursor, with the most remarkable feature being the very short FeN bond distance of 1.502 in crystals of [(PhB(tBuIm)3)FeV

(N)]BArF (Table 1). The complex was further investigated by EPR and Mssbauer spectroscopy, supplemented by DFT calculations (Table 1), thereby conrming the doublet ground state. Like Peters FeIV nitride [(PhBPiPr3)FeIV(N)], but not its FeIV precursor, [(PhB(tBuIm)3)FeIV(N)], the nitridoiron(V) complex reacts with protons (from water) under reductive conditions at 78 C in

tetrahydrofuran and evolves almost quantitative yields of NH3 with concomitant formation of an FeII species.

Dinuclear model complexes. As mentioned in the previous section, photolysis of FeIII azide complexes leads to the generation of a photo-oxidized FeV terminal nitride species and a photo- reduced FeII species. At ambient temperature, the FeII and FeV species react with each other to yield -nitrido-bridged FeIII/ FeIV complexes. Thus, via photolysis of [(Me3tacn)(Cl4cat)FeIII

(N3)] (Me3tacn, 1,4,7-trimethyl-1,4,7-triazacyclononane; Cl4cat2 , tetrachlorocatecholate) in solution at ambient temperature, Justel

et al.93 synthesized the nitrido-bridged dinuclear complex [(Me3tacn)(Cl4cat)FeIII(-N)FeIV(Cl4cat)(Me3tacn)]. This mixed-valent diiron compound has two iron centres with distinct oxidation states of + III and + IV, which could be oxidized with bromine to yield the symmetrical FeIV = N = FeIV complex. Both species have been crystallographically characterized, but only the FeIV/FeIV species allowed for the unambiguous determination of the FeIVN bond distance of 1.703(1) within the FeIV = N = FeIV moiety. The total and residual electron densities of [(Me3tacn)(Cl4cat)FeIII(-

N)FeIV(Cl4cat)(Me3tacn)] were modelled with two disordered positions for the bridging nitrogen, implying that the core unit is not symmetrical and has two dierent FeN bond distances. In accordance with this model, the Mssbauer spectra of mixed-valent [(Me3tacn)(Cl4cat)FeIII(-N)FeIV(Cl4cat)(Me3tacn)] showed two distinct Mssbauer doublets with isomer shis at = 0.52 and 0.09 mms 1, characteristic for octahedral high-spin FeIII and low-spin FeIV ions, respectively (Table 1). These results provide strong evidence for localized valencies at the iron centres of [(Me3tacn)

(Cl4cat)FeIII(-N)FeIV(Cl4cat)(Me3tacn)], in contrast to those of the nitrido-bridged diiron complex [(TPP)Fe3.5(-N)Fe3.5(TPP)], reported in 1976, where the excess electron is fully delocalized, resulting in formal oxidation states of 3.5 at both iron centres94. Remarkably, replacing one of the bidentate catecholate ligands in [(Me3tacn)(Cl4cat)FeIII(N3)] with the acetylacetonate derivative 1,3-diphenylpropane-1,3-dionate (Ph2acac ), and photolysing a 1:1 mixture of [(Me3tacn)(Cl4cat)FeIII(N3)] and [(Me3tacn)(Ph2acac)

FeIII(N3)], yields the asymmetric binuclear complex [(Me3tacn) (Ph2acac)FeIII(-N)FeIV(Cl4cat)(Me3tacn)] without a crystallo-graphically imposed inversion centre. Consequently, the mixed-

valent complex [(Me3tacn)(Ph2acac)FeIII(-N)FeIV(Cl4cat)(Me3tacn)] allows for the unambiguous determination of the FeN bond distances within the FeIIIN = FeIV moiety at 1.785(7) and 1.695(7) , respectively. However, the dierence in bond lengths is not as large as expected and is merely attributed to the varying radii of the iron ions in the dierent oxidation states. The Mssbauer spectrum of [(Me3tacn)(Ph2acac)FeIII(-N)FeIV(Cl4cat)(Me3tacn)] is very similar to that of [(Me3tacn)(Cl4cat)FeIII(-N)FeIV(Cl4cat)(Me3tacn)]

( = 0.60 and 0.04 mms 1; Table 1), showing localized valencies in the asymmetric mixed-valent complex95.

In 1999, Meyer et al.81 continued the investigation of high-valent nitrido species formation via photolysis of the corresponding azido complexes. Photolysis of trans-[(cy)FeIII(N3)2] + and cis-[(cy)FeIII(N3)2] + in solution at ambient temperatures resulted

in the formation of binuclear -nitrido-bridged complexes [{trans-(cy)FeIII(N3)}(-N){trans-(cy)FeIV(N3)}]2 + and [{cis-(cy)FeIII(N3)}(-N){trans-(cy)FeIV(N3)}]2 + , respectively81. On the basis of EPR and applied-eld Mssbauer spectroscopy (Table 1), the total spin state (St) in these mixed-valent complexes, St = 1/2 for trans/trans and St = 3/2 for trans/cis-isomer, was explained based on the assumption of strong antiferromagnetic coupling of an intermediate-spin FeIII (S = 3/2 in trans/trans), or a high-spin FeIII (S = 5/2 in trans/cis) with a low-spin FeIV (S = 1) metal centre and localized valencies in the [FeIV = NFeIII]4 + core93.

Conclusion and future challenges

Employing reactive complexes of abundant metals for synthesis, catalysis and energy supply is of great current interest. Selective functionalization of unactivated CH bonds in organic compounds, for example, is a highly attractive strategy in organic synthesis, and the oxidation of methane and water are considered holy grails in synthetic chemistry96. Similarly, energy-efficient production of ammonia is extremely important, as fertilizers generated from ammonia are responsible for sustaining one-third of Earths population. A range of metalloenyzmes achieve these challenging tasks in biology by activating dioxygen and dinitrogen and using cheap and abundant rst-row transition metals, like iron and manganese. Such reactions are carried out under ambient conditions with high efficiency and high stereospecicity. The recent results presented here from the bioinorganic chemistry community lend credence to the participation of high-valent oxoion and nitridoiron complexes in the above-mentioned processes. Oxo and nitridoiron model complexes have now been synthesized using dioxygen or dinitrogen as the oxidant, via mechanisms reminiscent of the O2 and N2 activation process proposed in biology. Many of these complexes show intriguing reactivities, which in turn have provided vital insights into the modelled enzymatic reactions. Among the most signicant conclusion of these studies is the observed activation of the model ferryl unit on axial ligand coordination trans to the oxo group. This has been attributed to strong electron donation from the axial thiolate ligand and explains the high reactivity of the natural thiolate-bound P450-I. Another important nding is the recently demonstrated73,74 increased reactivity of the linear [(O)FeIV-O-FeIII(OH2)]2 + model complex, as compared with the ring-like [FeIV2(-O)2]2 + core, that provides evidence for a comparable, more ring-opened form of Q with a terminal FeIV = O unit as the active species in the reactivity of MMO. Additionally, although direct evidence for the involvement of oxoiron(V) intermediates in water oxidation is lacking in the literature, Kundu et al.97, has recently demonstrated a OO bond formation reaction mediated by polynuclear oxoiron(IV) intermediates. Such a metal-mediated OO bond formation step is considered to be the most critical part of dioxygen evolution in photosystem-II98. In N2 activation and transformation chemistry, Lee et al. (ref. 99) have shown that many important intermediates in a variety of oxidation

states of a hypothetical N2 to NH3 conversion cycle can be accommodated at a mononuclear iron site. More recently, Rodriguez

et al.100 have demonstrated the potassium-assisted cooperativity of three iron centres in the activation and cleavage of dinitrogen and subsequent generation of ammonia on reaction of the nitride species with dihydrogen.

Unfortunately, the reactions exhibited by the model complexes are found to be non-catalytic, with activities falling far short of the activity of the biological catalysts. The low reactivity of the model complexes can be explained by the inability of synthetic chemists to exactly reproduce the biological ligand and protein environment. For example, even the ligand set of two histidines and one carboxylate, as observed in the rst coordination sphere of non-haem oxygenases, is extremely difficult to synthesize and manipulate. Similarly, it has not yet been possible to generate an oxoiron(IV) porphyrin -cation radical model complex with an axial thiolate

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ligand trans to the ironoxo unit, as observed in Cpd-I of cytochrome-P450. Additionally, no iron-based model complexes mimicking the FeMo cofactor activity of the nitrogenase enzyme are known in the literature, and, as a result, the role of the postulated carbide ligand in dinitrogen activation is far from understood. Thus, new and innovative synthetic strategies are needed to generate superoxidized iron centres in ligand environments that better resemble the active site of the metalloenzymes. This goal may eventually lead to the development of iron-catalysed selective functionalization of organic compounds or ammonia synthesis by using cheap and accessible sources of dioxygen or dinitrogen under ambient conditions.

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NATURE COMMUNICATIONS | DOI: 10.1038/ncomms1718

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How to cite this article: Hohenberger, J. et al. The biology and chemistry of high-valent

ironoxo and ironnitrido complexes. Nat. Commun. 3:720 doi: 10.1038/ncomms1718

(2012).

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Selective functionalization of unactivated C-H bonds and ammonia production are extremely important industrial processes. A range of metalloenyzmes achieve these challenging tasks in biology by activating dioxygen and dinitrogen using cheap and abundant transition metals, such as iron, copper and manganese. High-valent iron-oxo and -nitrido complexes act as active intermediates in many of these processes. The generation of well-described model compounds can provide vital insights into the mechanism of such enzymatic reactions. Advances in the chemistry of model high-valent iron-oxo and -nitrido systems can be related to our understanding of the biological systems.

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Title

The biology and chemistry of high-valent iron-oxo and iron-nitrido complexes

Author

Hohenberger, Johannes; Ray, Kallol; Meyer, Karsten

Pages

720

Publication year

2012

Publication date

Mar 2012

Publisher

Nature Publishing Group

e-ISSN

20411723

Source type

Scholarly Journal

Language of publication

English

DOI

https://doi.org/10.1038/ncomms1718

ProQuest document ID

950005200

The biology and chemistry of high-valent iron-oxo and iron-nitrido complexes

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