REVIEW Published 6 Mar 2012 | DOI: 10.

1038/ncomms1718

The biology and chemistry of high-valent iron–oxo

and iron–nitrido complexes
Johannes Hohenberger1, Kallol Ray2 & Karsten Meyer1

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.

H
igh-valent oxoiron(IV) and formally oxoiron(V) species have been spectroscopically identi-
fied as active intermediates in the catalytic cycles of a number of enzymatic systems1–10.
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 unac-
tivated C–H bond of the substrate; for example, in hydroxylation reactions1–10. 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
enzyme12–16 and the industrial Haber-Bosch process17.
The generation of well-described model compounds can provide vital insights into the mecha-
nism of such enzymatic reactions. Consequently, considerable effort 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 identified or proposed as reactive intermediates in biology.
Subsequently, we summarize some of the recent advances in bioinorganic chemistry that have led to
the identification and isolation of iron complexes in unusually high formal oxidation states, contain-
ing iron–oxygen or iron–nitrogen multiple bonds. The spectroscopic characterization and the reac-
tivity 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 bio-
chemical oxidative transformations. Moreover, the comparative review of the electronic structures of
the isoelectronic oxoiron and nitridoiron functionalities reveals that the Fe–N bonds are intrinsically
more covalent than the Fe–O bonds.

1 Department of Chemistry and Pharmacy, Inorganic Chemistry, Friedrich-Alexander-University Erlangen – Nuremberg, Egerlandstr. 1, Erlangen 91058,
Germany. 2 Department of Chemistry, Humboldt-Universität 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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REVIEW nature communications | DOI: 10.1038/ncomms1718

Iron–oxo complexes peroxide can also act as an oxygen-atom source by reacting directly
Iron–oxo intermediates in biology. Heme and non-heme proteins with the iron(III) state of the enzyme3,6,9, to generate the active
activate dioxygen or hydrogen peroxide to generate high-valent oxoi­ oxidant (no reductase components are required in this case).
ron reactive intermediates, which are used to carry out a diverse These high-valent iron–oxo intermediates in biology have been
set of biological tasks1–10. Important processes such as catabolism, primarily characterized by 57Fe Mössbauer spectroscopy19, as it
angiogenesis, respiration, and apoptosis rely on oxidation reactions serves as a local probe of the iron centre. Mössbauer isomer shifts
driven by these reactive intermediates1–3. The coordination environ- (δ) are directly related to the electron density at the iron nucleus
ment of the oxoiron unit is, however, found to be different in differ- and, therefore, are often used as a probe of the ‘oxidation state’ of the
ent enzymes. Three types of high-valent iron–oxo active sites have metal. The quadrupole splitting (∆EQ) values, on the other hand, are
been identified in haem and non-haem enzymes (Fig. 1). The haem- a measure of the electric field gradient at the iron nucleus and can
containing peroxidases, oxygenases and catalases comprise mononu- be strongly correlated to electronic spin ground state and molecu-
clear iron-protophyrin IX active sites coordinated to either a cysteine, lar geometry. Nuclear hyperfine tensors (A) depend strongly on the
histidine or tyrosine residue3,18. The second type involves mononu- nature of the orbitals in which unpaired electrons reside and may
clear iron centres that are coordinated to two histidines and a car- be used as a tool to understand the electronic structure of paramag-
boxylate group, thereby forming a characteristic 2-His-1-carboxylate netic species. Whereas δ and ∆EQ values (Table 1) obtained from
facial triad, which has been recognized as a common structural motif zero-field Mössbauer studies of the active oxidants in both haem
for many mononuclear non-haem iron enzymes1–3. The third type of and non-haem oxygenases are consistent with an iron(IV) oxidation
active sites is characterized by diiron centres with two histidines and state, the analysis of the Mössbauer spectra in an applied magnetic
four carboxylates and are associated with methane and toluene mono­ field reveals different spin states in the two cases. For haem enzymes
oxygenases, fatty acid desaturases and ribonucleotidereductase5,10. the A tensor shows a qualitative trend of ‘two large negative values,
Most of these enzymes activate dioxygen in the iron(II) state and carry one small negative value’20,21, thereby reflecting an intermediate
out a variety of two-electron oxidation processes (Fig. 2); the remain- spin, S = 1 spin state for the iron(IV) centre. In CPd-I intermediates,
ing two reducing equivalents required for the four-electron reduction this S = 1 spin state is coupled ferromagnetically or antiferromag-
of dioxygen are often provided by a cosubstrate (Fig. 1). One specific netically to the porphyrin radical cation, giving an overall quartet
group of non-haem enzymes utilizes 2-oxoacids or tetrahydrobiopt- or doublet state, respectively3,6,7,9. In contrast, for the non-haem
erin as the cosubstrate, delivering two electrons simultaneously to case, a high-spin S = 2 state is demonstrated by ‘three large nega-
the active site to afford peroxoiron(II) and oxoiron(IV) species in the tive’ A tensors1,19. The high-spin configuration is possibly due to
proposed reaction mechanism1. Enzymes, such as cytochrome-P450 the weak ligand field exerted by the combination of histidine and
(P450), soluble methane monooxygenase (sMMO) or Rieske dioxy- carboxylate ligands or the proposed pseudo-trigonal symmetry22,
genases, on the other hand, use NADH as the electron donor to form which renders the d(x2 − y2) and d(xy) orbitals nearly degenerate in
peroxoiron(III) and formally oxoiron(V) species (Fig. 1); all the redox energy (Fig. 3 (refs 23 and 24)).
equivalents of the formal oxoiron(V) species are stored either at the In spite of the spin state difference in the mononuclear high-
metal centre(s) in non-haem enzymes (for example, Fe2IV(µ-O)2 inter­ valent oxoiron(IV) intermediates of the haem and non-haem
mediate Q in sMMO5,10 and (OH)FeV = O intermediate4 in Rieske enzymes, the Fe–O bond strengths for the S = 1 and S = 2 states are
dioxygenase) or distributed over the ligand in haem enzymes (for comparable. The Fe = O bond distances (1.64–1.68 Å), obtained from
example, Compound-I (Cpd-I), which is an oxoiron(IV) porphyrin extended X-ray absorption fine structure (EXAFS) or X-ray diffrac-
π-cation radical species)3,6,7,9. In addition to dioxygen, hydrogen tion studies, and the Fe–O stretching frequencies (776–843 cm − 1),

Hisdist Hisdist
O2 H H H H H2O2
–H2O
Fe II
FeIII OO O O O O FeIII

O O FeIII FeIII
1e from H+
–CO2
NADH
R O

FeII OOC(O)R FeIII OOH

O His
H+ Glu
H O
O O O HO
H2O IV O IV Glu FeV N NH
Glu O Fe Fe O O
O O O N
FeIV O FeV O His O O Asp
N N His NH
Glu
N N
H H His

OH Q Rieske dioxygenase
O
O Asp
R O FeIV OOC O COO
N
NH N
O N N
FeIV
N N
N His
His H
X Cpd-I
TauD-J
X= cysteine, tyrosine or histidine

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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nature communications | DOI: 10.1038/ncomms1718 REVIEW

Hydroxylase (CPO-I and P450-I)

• Hydroxylase
R •
O OH R
O R-OH
R-H III
R-H OH
• Fe IV IV Fe + R-OH
Fe
Fe IV
FeIII FeII
S S S
Cys Cys Cys

Cpd-I Cpd-II (protonated)

Halogenase •
Peroxidase (HRP-I) R
+ O R-H OH OH
H •
O AH •
A O AH A IV + R-X
X Fe X FeIII FeII
• FeIV FeIV FeIII + H2O
N N N
His His His
Cpd-I Cpd-II

Catalase Desaturase
O H2O2 H2O + O2
R R R R
• FeIV FeIII
O H H OH H OH2
O O + R R
Tyr Tyr FeIV FeIII FeII
Cpd-I

Methane monooxygenase (Q) cis-Dihydroxylation

CH3•
CH3OH
O• CH3-H HO
FeIII FeIV FeIII FeIV FeIII FeIII
O O
2H+ H2O H H –H+ H H
HO O O O
III
Ring opening FeV Fe
CH3•
H CH3OH
O CH3-H O
FeIV FeIV FeIV FeIII FeIII FeIII
O O 2H+ H2O

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 that Fe = O possesses double-bond character. The oxoiron(IV)
in both cases1–3,5–7,9,10,18. This similarity is expected based on the double-bond character is further supported by a resonance Raman
molecular orbital diagram shown in Fig. 3. For both the S = 1 and vibrational band centred at ν = 828 cm − 1 in dichloromethane meth-
S = 2 configurations the Fe–O antibonding π*{(d(xz),d(yz)} levels anol, which was assigned to the ν(Fe–O) stretching vibration based
contain two electrons. A significantly larger Fe–O distance (1.81 Å) on its shift to 792 cm − 1 on 18O labelling. In the absence of metha-
and lower Fe–O stretching frequency (565 cm − 1), however, are nol, the ν(Fe–O) stretching vibration was observed at 801 cm − 1 due
observed for the one-electron reduced form of Cpd-I of the thiolate- to the binding of the chloride anion as an axial ligand trans to the
ligated haem enzymes, where the oxoiron(IV) unit is protonated oxo unit. Thus, as also suggested from theoretical studies29, the axial
(Fig. 2)25–28. A protonated oxoiron(IV) centre is also reflected in ligand competes with the oxo-group in binding to the iron-centre,
the Mössbauer data as the variation of the Fe d(xz)/d(yz) spin popu- therefore decreasing the strength of the Fe–O bond.
lations, owing to the protonation of the oxoiron(IV) unit, provides The [(TMP + •)FeIV(O)(CH3OH)] + complex was found to be
unique ∆EQ values significantly larger ( > 2 mm s − 1) than those in a competent oxidant in olefin epoxidation and alkane hydroxyla-
the deprotonated form ( < 1.6 mm s − 1)25–28. tions6,7. Since then, a number of oxoiron(IV) porphyrin π-radicals
bearing electron-rich and -deficient porphyrins (Fig. 4) have been
Iron–oxo model complexes. The first high-valent oxoiron com- prepared in an effort to understand the electronic effects of the
plex was synthesized in 1981 by Groves et al.7,8 via oxidation of porphyrins on the chemical properties of the oxoiron(IV) inter-
[(TMP)FeIII(Cl)] (TMP = meso-tetramesityl porphinate anion) with mediates3. The results of these studies, which are summarized in
meta-chloroperbenzoic acid in a dichloromethane-methanol mix- some recent review articles3,6,7, indicate that the electronic nature of
ture at − 78 °C. On the basis of its absorption spectra, the electronic porphyrin ligands controls the oxidizing power of oxoiron porphy-
structure of the resultant green compound was best described as an rins, and that oxoiron species with electron-deficient porphyrins are
oxoiron(IV) porphyrin π-radical cation (d4) species [(TMP + •)FeIV more powerful oxidants in the oxygenation of organic substrates.
(O)(CH3OH)] + , which showed the characteristic features of Cpd-I The axial ligands bound trans to the iron–oxo moiety also markedly
intermediates; namely, a weak and broad Soret band at 405 nm and influence the reactivities of oxoiron(IV) porphyrin π-cation radi-
a Q-band at 605 nm6,9. On the basis of electron paramagnetic reso- cals. For example, a recent study by Kang et al.30, which investigated
nance (EPR) and applied-field Mössbauer spectroscopy (Table 1), an a series of complexes [(TMP + •)FeIV(O)(p-Y-pyO)] + (Y = OCH3,
overall quartet (St = 3/2) ground state was deduced, arising from a CH3, H, Cl) and [(TMP + •)FeIV(O)(X)] (X = CF3SO3 − , Cl − , AcO − ,
ferromagnetic coupling of the S = 1 iron(IV) centre with a porphyrin OH − ) in H-atom abstraction and O-transfer reactions by experi-
π-cation radical (S = 1/2). The structural analysis of the intermediate mental (Fig. 5a) and theoretical methods, showed that rates of both
by EXAFS revealed a short Fe–O bond distance of 1.60 Å, indicating the O-transfer and H-atom abstraction reactions of the porphyrin

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REVIEW nature communications | DOI: 10.1038/ncomms1718

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

Species Fe-spin Mössbauer spectroscopy ν (Fe-X) Fe-X EPR-Data

(oxidation) (cm − 1) distance (Å)
state
δ ∆EQ A (Ax, Ay, Az) g(gx, gy, gz)-
(mm s − 1) (mm s − 1) (T) values
Haem systems
P450-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 1.64–1.67 geff=2
[FeIV=O(TMP·)] + (refs 8,9 S=1 (IV) 0.08 1.62 ( − 25, − 25, − 6) 828 (CH2 1.64–1.65 —
and refs therein) Cl2-CH3OH)
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) 776–790 1.60–1.93 —

Mononuclear non-haem systems

 TauD-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 + S=1 (IV) 0.17 1.24 ( − 22.6, − 18.3, − 2.9) 834 1.646(3) —
(ref. 41)
[(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 systems

 MMOH intermediate Q (ref. 70) S=2 (IV) 0.17 0.53 — 1.77
 Ribonucleotide reductase S=2 (IV) 0.26 − 0.6 ( − 20, − 20, − 15) — 1.80 —
intermediate X (refs 5,19)
[{(Me2(OMe)TPA) FeIV}2 S=1 (IV) − 0.04 2.09 674 1.78 —
(µ-O)2]4 + (ref. 71)
[(Me2(OMe)TPA)2FeIV S=1 (FeIV(O)) − 0.03 0.92 — 1.68 —
(OH)FeIV(O)]4 + (ref. 73)
S=1(FeIV(OH)) 0.0 1.96 — 1.76

µ-Nitrido diiron complexes

[(Me3tacn)(Cl4cat)FeIII(µ-N) S=5/2(III) 0.52 1.67 − 22.0 (Isotropic) 911 (14N) 1.495(7) (3.99, 4.14, 2.0)
FeIV(Cl4cat) (Me3tacn)] (refs 93,95)
S=1(IV) 0.09 0.81 + 5.5 (Isotropic) 884 (15N) 1.976(7)
[(Me3tacn)(Cl4cat)FeIV(µ-N)FeIV S=1 (IV) 0.04 1.55 ND 407 1.703(1) —
(Cl4cat) (Me3tacn)] (ref. 93)
[(Me3tacn)(Ph2acac)FeIII(µ-N) S=5/2(III) 0.60 2.00 ( − 23.0, − 23.0, − 9.0) — 1.785(7) (3.96, 4.07, 1.98)
FeIV(Cl4cat) (Me3tacn)] (ref. 95)
S=1 (IV) 0.04 1.13 (6.0, 6.0, 1.6) 1.695(7)
[{Trans-(cy)FeIII(N3)}(µ-N) S=3/2(III) 0.20 2.09 ( − 2.8, − 7.8, − 19.7) — — (2.04, 2.06,
{trans-(cy)FeIV(N3)}]2 + (ref. 81) 2.20)
S=1 (IV) 0.11 0.97 ( − 13.6, − 10.1, − 1.1) —
[{Cis-(cy)FeIII(N3)}(µ-N) S=5/2(III) 0.47 1.89 ( − 13.5, − 14.5, − 22.7) — — (2.04, 2.06,
{trans-(cy)FeIV(N3)}]2 + (ref. 81) 2.20)
S=1 (IV) 0.14 0.79 ( − 10.0, − 10.5, − 1.2) —

Mononuclear iron–nitrido 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 (fixed 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 (fixed 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 S=0(IV) − 0.34(1) 6.01(1) ND 1034 (14N) 1.51–1.55 —
and refs therein)
(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 Fourfold
symmetry symmetry
z
y O
N O N
IV VI
Fe IV Fe
IV Fe Fe
x

σ∗ z
2
σ∗ z
2
σ∗ z
2
π∗ xz, yz Anti 2 2
σ∗ z
2
π∗ xz, yz bonding σ∗ 2
x –y
2 σ∗ x –y
π∗ xz, yz
π∗ xz, yz

2 2 2 2 Non xy xy
x −y , xy x −y , xy
bonding

Figure 3 | Tetragonal and trigonal ligand fields of high-valent transition metal complexes with strong -donor oxo and nitrido ligands23,24. In threefold
symmetry, a non-bonding, doubly degenerate set of (x2–y2, 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 fields, 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 a
1 + 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 ultraviolet–visible spectra were dominated by intense porphyrin
axial ligand. Their results have been extended to correlate the strong ligand transitions that obscured weaker bands that may be associ-
oxidizing power of the thiolate-ligated P450 enzyme to the strong ated with the FeIV = O unit. Thus, design of suitable ligand systems
electron donation from the axial thiolate ligand31. to stabilize oxoiron(IV) units in non-haem ligand environment
In contrast to the haem-based systems, which mainly stabilize was warranted so as to obtain deeper insights into their electronic
an oxoiron(IV) π-cation radical unit, an iron(V) oxidation state structure.
can be stabilized with redox-innocent, non-haem ligand systems. Grapperhaus et al.40 were the first to obtain a major break-
Accordingly, Tiago de Oliveira et al.32 reported the synthesis of an through in this regard. They generated a terminal non-haem
oxoiron(V) (d3) complex by using their signature tetraamido mac- oxoiron(IV) species by the ozonolysis of [(cy-ac)FeIII(CF3SO3)] +
rocyclic ligand (TAML). The reaction of [(TAML)FeIII(H2O)] − (cy-ac = 1,4,8,11-tetraazacyclotetradecane-1-acetate) in a mixture
with meta-chloroperbenzoic acid in n-butyronitrile at − 60 °C, of acetone/water at − 80 °C. The fleeting intermediate was charac-
in presence of small amounts of water, pyridine or benzoic acid, terized to be a low-spin (S = 1) iron(IV) species based on Mössbauer
yielded a deep green complex, which has been characterized as studies (δ = 0.1 mm s − 1 and ∆EQ = 1.39 mm s − 1)40. The instabil-
[(TAML)FeV(O)] − , based on a combined Mössbauer, EPR and ity of the compound, however, prevented its further spectroscopic
EXAFS study. The iron(V) oxidation state was confirmed on the characterization. Subsequently, Rohde et al.41 reported the first
basis of its characteristic Mössbauer spectrum with an unusually X-ray crystal structure of a mononuclear S = 1 oxoiron(IV) com-
low, negative isomer shift of − 0.42 mm s − 1 and large quadrupole plex that was generated in the reaction of [(Me4cy)FeII(CH3CN)]2 +
splitting of 4.25 mm s − 1 at 4.2 K (Table 1). The EPR spectrum (Me4cy = 1,4,8,11-tetramethylcyclam) and iodosobenzene (PhIO)
revealed an S = 1/2 ground state, and EXAFS provided evidence of a in CH3CN at 25 °C. The molecular structure of the [(Me4cy)FeIV(O)
short Fe–O distance of 1.58 Å consistent with the [(TAML)FeV(O)] − (CH3CN)]2 + complex features a short Fe = O distance of 1.646(3) Å
assignment for the complex. with an acetonitrile ligand bound trans to the oxo group (Fig. 5b).
An FeV(O)(OH) species has been implicated as the active The macrocyclic Me4cy ligand adopts a trans-I configuration42 such
oxidant responsible for the cis-dihydroxylation of C = C dou- that all four methyl groups are oriented anti to the oxo atom. A syn
ble bonds2,4,33 and the oxidation of water34 in a number of iron- orientation of the oxo group has also been recently demonstrated
containing non-haem natural and model systems, but with only in the crystal structure of the [(Me4cy)FeIV(O)Sc(OSO2CF3)4OH]
indirect proof of its existence35–37. However, the spectroscopically complex, formed by the reaction of [(Me4cy)FeIV(O)(CH3CN)]2 +
characterized [(TAML)FeV(O)] − anion, which is the only known with Sc(CF3SO3)343. In addition to the oxo-ligand inversion, the
isolable oxoiron(V) species in the literature, was found to be a strong binding of Sc3 + to the Fe = O moiety of the [(Me4cy)FeIV(O)
sluggish oxidant32; reacting with the weak C–H bonds of dihy- (CH3CN)]2 + complex induces a pentacoordinated square-pyrami-
droanthracene only. Moreover, no [(TAML)FeV(O)] − mediated dal coordination at the iron centre and an elongated Fe–O distance
cis-dihydroxylation reaction have thus far been reported. Addition- of 1.754(3) Å.
ally, no [(TAML)FeV(O)] − intermediate could be identified during Since the report of the [(Me4cy)FeIV(O)(CH3CN)]2 + complex
the [(TAML)FeIII] − mediated water oxidation reaction38. There- in 2003, a handful of non-haem S = 1 oxoiron(IV) complexes have
fore, the involvement of FeV(O)(OH) intermediates in oxygenation been synthesized in the past 8 years, using various tetradentate and
reactions remained doubtful until very recently39. Using variable- pentadentate ligand systems (Fig. 4), containing pyridine and amine
temperature mass spectrometry, Prat et al.39 provided evidence for nitrogen donors33,44. The structural analysis of the intermediates by
such a reactive intermediate in a synthetic system. X-ray crystallography for [(Me4cy)FeIV(O)(CH3CN)]2 + , [(Me3cy-
While the first paper on the synthesis and characterization of an py)FeIV(O)]2 + (Me3cy-py = 1-(2′-pyridylmethyl)-4,8,11-trime-
oxoiron(IV) porphyrin species appeared in 1981 (ref. 8), the origi- thyl-1,4,8,11-tetraazacyclotetradecane)45 and [(N4Py)FeIV(O)]2 +
nal report of a non-haem oxoiron(IV) complex appeared almost two (N4Py = N,N-bis(2-pyridylmethyl)-bis(2-pyridyl)methylamine),
decades later in 2000 (ref. 40). The biggest impediment to progress or EXAFS for others, revealed a short Fe–O distance of ~1.64 Å,
in identifying and trapping a non-haem oxoiron(IV) species was which is comparable with those of oxoiron(IV) porphyrin inter-
the lack of a convenient spectroscopic signature that would readily mediates6,7,9,18 and significantly different from the 1.81 Å distance
signal its presence in a reaction mixture. Although oxoiron(IV) por- of Borovik’s oxoiron(III)46, 1.75 Å of Nam’s43 [(Me4cy)FeIV(O)
phyrin complexes had been well characterized for some time, their Sc(OSO2CF3)4OH] and the 1.58 Å distance of Collins’ oxoiron(V)

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REVIEW nature communications | DOI: 10.1038/ncomms1718

R
Cl F F F

–
N N R= F
R R
N – Cl F F F
N
TPP TMP TDCPP TDFPP TPFPP

R
Me3cy-py: R = Me, R' = CH2Py N
R R' O NH HN O
N N Me4cy: R = R' = Me
cy: R = R' =H N N
R R
cy-ac: R = H, R' = CH2COO – NH HN
N N Me3cy-ac: R = Me, R' = CH2COO –
R R Me3cyS: R = Me, R' = CH2CH2S – O O tacn: R = H
Me3tacn: R = Me

TAML

H
N N OMe N N– N
N N N
N N N N O
3
3 3 3
H3buea
TMG3tren Me2(OMe)TPA
Me3NTB

Py Ph
Py Py
N B–
N N N B– P(iPr)2
N N
N 3
3
N
Py Py 3 PhB(tBuIm)3– PhBPiPr3–
Py Py mes
N4Py TIMEN

BnTPEN

Figure 4 | Macrocyclic and chelating ligands for the stabilization of high-valent oxo– and nitrido–iron complexes. Structures in the first 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 Fe–O distance of 1.70 Å formation. Hong et al.53 also reported the synthesis of the known
has been obtained for the thiolate-ligated [(Me4cyS)FeIV(O)] + [(N4Py)FeIII-OOH]2 + or [(BnTPEN)FeIII-OOH]2 + (BnTPEN =
(Me4cyS = monoanion of 1-(mercaptoethyl)-4,8,11-trimethyl-1,4,8, N-benzyl-N,N’,N’-tris(2-pyridylmethyl)-1,2-diaminoethane) com-
11-tetraazacyclotetradecane) complex47, which acts as the model plexes in near-quantitative yield, by activating dioxygen in the
complex for the recently characterized48 thiolate-ligated Cpd-I presence of acid and 1-benzyl-1,4-dihydronicotinamide, an NADH
intermediate in the catalytic cycle of P450. All these compounds analogue. However, no oxoiron(IV) complex could be identified in
feature a near-infrared absorption band of moderate intensity44, these reactions as well. The missing link connecting the mechanistic
which, on the basis of magnetic circular dichroism, has been attrib- steps of the above studies was the experimental demonstration of
uted to three of the five ligand-field transitions expected for an S = 1 O–O bond cleavage in a hydroperoxoiron(III) complex to yield the
Fe(IV) centre in C4V symmetry49. corresponding high-valent iron–oxo species. This link has recently
The general method of synthesizing the non-haem oxoiron(IV) been identified independently by the groups of Li et al.56 and Cho
complexes involves the reaction of the iron(II) precursor with an et al., who generated a high-spin FeIII-OOH complex supported
oxygen atom donor, like PhIO or peracids (Fig. 6)44. In rare cases, by the Me4cy ligand via protonation of the side-on peroxoiron(III)
they have been generated electrochemically50 or photochemically51, conjugate base56,57. This hydroperoxo complex was shown to con-
using water as the oxygen source and also by using hydrogen per- vert quantitatively to the corresponding S = 1 oxoiron(IV) complex
oxide in presence of a base52. Only recently, dioxygen has been either through acid-mediated O–O bond heterolysis, followed by
used as an oxidant, which has helped to improve our understand- the reduction of the transient oxoiron(V) intermediate56 or directly
ing of the mechanism of dioxygen activation at a mononuclear iron by O–O bond homolysis57.
active site45,53–55. Most of the intermediates shown in Fig. 1 have The [(H3buea)FeII] − complex of the tris(ureaylato) ligand, used by
been independently identified and have established the credibility MacBeth et al.46, also reacts with O2 to yield an oxoiron(III) interme-
of the proposed mechanism of dioxygen activation. The formation diate, which is proposed to derive from the reduction of an initially
of the high-valent iron oxidant via a reductive O–O bond cleav- formed oxoiron(IV) species. Although the oxoiron(IV) species on
age step requires two electrons and protons. Thibon et al.45 used the way to the generation of the oxoiron(III) complex could not be
BPh4 − (electron donor) and HClO4 (proton donor) to demonstrate trapped, it has recently been synthesized by the one-electron oxidation
the formation of a high-valent S = 1 iron(IV) species in [(Me3cy- of the preformed [(H3buea)FeIII(O)]2 − (ref. 54). Interestingly, an S = 2
py)FeIV(O)]2 + from [(Me3cy-py)FeII]2 + and dioxygen. Lee et al.55, state has been determined for [(H3buea)FeIV(O)] − on the basis of a
on the other hand, were able to generate S = 1 [(Me4cy)FeIV(O) sharp resonance at g = 8.19 in the parallel mode EPR spectra, which is
(CH3CN)]2 + from [(Me4cy)FeII(CH3CN)]2 + and O2, using olefins indicative of a transition from the | ± 2 > doublet of an S = 2 spin mani-
containing allylic C–H bonds as H-atom (H + + e − ) donors. In fold. Anionic [(H3buea)FeIV(O)] − represents the only example of an
both studies, no intermediates could be trapped during oxoiron(IV) S = 2 oxoiron(IV) complex generated by O2 activation. Two examples

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nature communications | DOI: 10.1038/ncomms1718 REVIEW

H2O
[LFe(n+2)(O)]+ [LFen ]+
–2e– ; –2H+

Reactivity
Reactivity
H2O2; Base
[LFe(n+2)(O)]+ [LFen ]+
–H2O
Electron rich Electron rich
O2; 2H• N3– hν or ∆
O [LFe(n+2)(O)]+ [LFen ]+ [LFe(n+2)(N)]
O –H2O –N2 + [LFe(n–1)]
N N N
N FeIV •
FeIV N N N N–
N
[O]
X [LFe(n+2)(O)]+ ∆
X [LFen ]+ [LFe(n+2)(N)]
–
(OTf)2

O
Figure 6 | Synthetic routes for high-valent oxo– and nitrido–iron
N N
+Sc(OTf)3 FeIV complexes. Common synthetic routes for iron–oxo complexes include
N N N N
FeIV
+H2O oxidation of the iron centre with water as an oxygen source50,51 or the
N N
–TfOH O oxidation of the complex with hydrogen peroxide52,55–57, elemental
NCCH3
–CH3CN TfO OTf oxygen45,54 or other oxygen-atom donors44,47. A number of transition
Sc
TfO OTf metal nitrido complexes have been synthesized via deoxygenation of
OH NO, reductive decarbonylation of isocyanate, N–N bond cleavage in
N2O reduction, inter-metal N-atom transfer from nitrido complexes, and
3+ 2+ metathesis of nitrile from metal alkylidyne and a M–M multiple bonded
O O
LFeIII FeIVL OH– III IV
complex. In contrast, fewer synthetic routes are known for iron–nitrido
LFe Fe L
O complexes: the photo- and thermolysis of azide precursors80,81, N-atom
HO O transfer via strain release by anthracene elimination from 2,3:5,6-dibenzo-
Low-spin High-spin 7-azabicyclo[2.2.1]hepta-2,5-diene85, and, only recently, with elemental
dinitrogen (synthesis not depicted)100. [O] represents oxygen-atom
+e– –e– +e– donors, like iodosobenzene or peracids.

4+ 3+
O O
LFeIV FeIVL H+ LFeIV FeIVL The reactivity of non-haem oxoiron(IV) complexes in C–H
O hydroxylation and oxo-transfer reactions has been considered in
HO O
depth by theoretical61–63 and experimental methods44,64,65. So far,
Low-spin H2O Low-spin all theoretical studies have led to the common conclusion that the
ferryl species are better oxidants on the quintet-state than the cor-
responding triplet-state. There is a long-term debate, however, on
OMe
how to rationalize the higher reactivity of the quintate state66–69.
L= N Moreover, direct experimental evidence for the higher reactivity of
N the S = 2 state is lacking in the literature. Presumably, because the
oxoiron(IV) core is protected by the sterically bulky chelator in the
3
recently reported S = 2 [(TMG3tren)FeIV(O)]2 + complex59,60,67, its
reactivity towards C–H bond cleavage is only comparable with tri-
Figure 5 | Reactivity of high-valent mono- and diiron-oxo model
plet ferryl analogues. Indirect evidence of the higher reactivity of
complexes. (a) Axial ligand effects on the oxo-transfer (dotted line) and
the quintate state is, however, provided by Seo et al.64 in their report
H-atom abstraction (bold line) reactivity of the complexes [(Me4cy)FeIV
of a highly reactive mononuclear oxoiron(IV) complex, [(Me3NTB)
(O)X]+(X = NCCH3, −O2CCF3, −N3, or −SR)65 and [(TMP) + •FeIV(O)X]
FeIV(O)(CH3CN)]2 + (with Me3NTB = tris((N-methyl-benzimidazol-
(X = CF3SO3−, Cl−, AcO−, OH−)30; (b) Structural changes of the oxoiron(IV)
2-yl)methyl)amine), that attacks the strong C–H bonds of cyclohex-
unit of the model complex as a result of binding to a Sc3 + ion43; OTf,
ane at − 40 °C. This complex is the most reactive species among
triflate. (c) Interconversions among high-valent diiron complexes71,73,74.
oxoiron(IV) complexes reported so far. Although an S = 1 ground
state has been obtained for the complex from applied-field Möss-
of synthetic high-spin oxoiron(IV) species have been described before bauer spectroscopy at 4.2 K, density–functional theory (DFT) cal-
the report of MacBeth et al. (ref. 46): one from Pestovsky et al.58, culations explain the unprecedented high reactivity of [(Me3NTB)
using [FeII(H2O)6]2 + and ozone in water and the other from England FeIV(O)(CH3CN)]2 + on the basis of the easily accessible extremely
et al.59,60, using [FeII(TMG3tren)(OTf)] + and iodosylbenzene. The low-lying excited S = 2 state that mediates the reactivity. The two-
S = 2 ground state in [(TMG3tren)FeIV(O)]2 + and [(H2O)5FeIV(O)]2 + state reactivity, proposed for [(Me3NTB)FeIV(O)(CH3CN)]2 + ,
has been determined by applied-field Mössbauer studies, which, similar has also been used to explain the reactivity pattern of a series of
to the oxoiron(IV) intermediates observed in the catalytic cycle of non- [(Me4cy)FeIV(O)(X)]+ complexes (X = NCCH3, − O2CCF3, − N3
haem oxygenases, are characterized by a large and negative hyperfine or − SR)65. In this series, the reactivity rates of O-transfer to PPh3
splitting component in z-direction and by a small and negative quad- were found to decrease in the order NCCH3 > − O2CCF3 > − N3 >
rupole splitting (∆EQ) parameter (Table 1). The molecular structures − SR consistent with the decreasing electrophilicity of the Fe = O unit.
of [(TMG3tren)FeIV(O)]2 + and [(H3buea)FeIV(O)] − , as determined The rates of H-atom abstraction from dihydroanthracene, however,
by X-ray crystallography, reveal a trigonal bipyramidal geometry at increased with the introduction of a more electron donating axial
the metal centre, with Fe = O distances of 1.661(2)60 and 1.680(1) Å54, ligand (Fig. 5a). The latter counter-intuitive trend has been ration-
respectively. The S = 2 ground state in [(TMG3tren)FeIV(O)]2 + and alized by the decrease in calculated energy gap between the triplet
[(H3buea)FeIV(O)] − is attributed to their threefold symmetry with ground state and the quintet excited state as the axial ligand becomes
degenerate sets of d(xy) and d(x2 − y2) orbitals (Fig. 3)23,24. more electron donating, thereby lowering the activation barrier for

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REVIEW nature communications | DOI: 10.1038/ncomms1718

H-atom abstraction. This is in contrast to the Cpd-I model com- became interested in the synthesis and reactivity of model
pounds (formally oxoiron(V) species), where the determined rates compounds involving high-valent nitridoiron moieties. Here we
of O-transfer and C–H abstraction reactions increase with increas- summarize the recent advances in this field with a focus on mono-
ing donation from the axial ligands (Fig. 5a). and dinuclear complexes; thus, omitting the few rare examples of
polynuclear iron–nitrido complexes77–79.
Dinuclear bis(µ-oxo)diiron(IV) model complexes. Intermedi- The first high-valent nitridoiron complex was characterized in
ate Q is considered as the key oxidizing species in the catalytic 1989, when Wagner and Nakamoto80 photolysed a porphyrin-ligated
cycle of sMMO, performing the chemically exceedingly challeng- FeIII azide complex [(TPP)FeIII(N3)] (TPP, tetraphenylporphinate
ing conversion of methane to methanol. A detailed analysis of anion) in a frozen matrix of dichloromethane at 30 K. The resulting
EXAFS and Mössbauer spectroscopic data revealed that Q is best matrix-stabilized nitrido complex [(TPP)FeV(N)] exhibits a reso-
described as a strongly exchange-coupled S = 2 diiron(IV) spe- nance Raman vibrational band centred at ν = 876 cm − 1, which was
cies with an Fe–Fe distance of 2.46 Å and pairs of short and long assigned to the ν(Fe–N) stretching vibration (Table 1). Labelling
Fe–O bonds of 1.77 and 2.05 Å, respectively, consistent with an experiments with 57Fe as well as 15N allowed for the unambiguous
Fe2IV(µ-O)2-diamond core structure70. Xue et al.71 succeeded assignment of this ν(Fe–N) band. Although no further spectroscopic
in preparing the first and only example of a synthetic complex characterization of the FeV = N species was performed, the authors
possessing a Fe2IV(µ-O)2 core by electrochemical oxidation of proposed—based on the relatively small force constant in comparison
the previously reported precursor [(Me2(OMe)TPA)2FeIII/IV(µ- with the isoelectronic [(TPP)Mn(O)]—a d3 high-spin (S = 3/2) rather
O)2](ClO4)3 (with Me2(OMe)TPA = tris(3,5-dimethyl-4-methoxypy- than a low-spin S = 1/2 electronic ground state for the nitridoiron(V)
ridyl-2-methyl)amine)72. Combined Mössbauer and EXAFS data species80. The stabilization of the unusually high FeV oxidation state
revealed that in [{(Me2(OMe)TPA)FeIV}2(µ-O)2]4 + two low-spin in [(TPP)FeV(N)] reflects the higher π-donating property of the
(S = 1) Fe(IV)-centres are antiferromagnetically coupled and exhibit nitrido ligand that stabilizes higher metal oxidation states; the isoelec-
Fe–O and Fe–Fe distances of 1.78 and 2.73 Å, respectively. Cationic tronic [(TMP + •)FeIV(O)] + complex7,8 could only be stabilized as a d4
[{(Me2(OMe)TPA)FeIV}2(µ-O)2]4 + could also be generated chemi- oxoiron(IV) π-cation radical species. The higher π-donation from the
cally, via the intermediate formation of an open-core [(O)FeIV-O- nitrido ligand arises from the smaller effective nuclear charge (Z*) of
FeIV(OH)]3 + complex cation, containing two S = 1 FeIV centres, by nitrogen compared to oxygen29, which causes the N p orbitals to be
reacting the (µ-oxo)-diiron(III) precursor with H2O2 in the presence better energetically matched with the valence d orbitals on Fe.
of an acid73. Additionally, a new product with high-spin FeIV S = 2 Meyer et al.81 reported the first high-yield synthesis of a
and high-spin FeIII S = 5/2 centres in a valence-localized [(O)FeIV- nitridoiron(V) species by photolysis of trans-[(cy)FeIII(N3)2] + in
O-FeIII(OH)]2 + core was obtained by treating [(Me2(OMe)TPA)2 frozen CH3CN; the reaction produced two species, which have
FeIIIFeIV(µ-O)2](ClO4)3 with hydroxide74. A comparative reac- been identified as the photo-reduced five-coordinate ferrous spe-
tivity study of [{(Me2(OMe)TPA)FeIV}2(µ-O)2]4 + , [(O)FeIV-O- cies, trans-[(cy)FeII(N3)] + , formed via homolytic Fe–N3 bond
FeIV(OH)]3 + , [(O)FeIV-O-FeIII(OH)]2 + and the previously report- cleavage, and the photo-oxidized trans-[(N3)(cy)FeV(N)] + , formed
ed72 S = 1 [FeIV = O]2 + cations (Fig. 5c) showed that the terminal via homolytic N–N bond cleavage and N2 evolution81. The high-
iron(IV) oxo units are at least three orders of magnitude more re- valent FeV species was identified unequivocally by its characteristic
active than the ones with diamond cores74. The most potent C–H Mössbauer spectrum, with an isomer shift δ of − 0.04 mms − 1 and
activator is the complex with an S = 2 quintet ground state of the a quadrupole splitting ∆EQ of − 1.90 mms − 1 at 80 K (Table 1)81.
Fe = O moiety. Hence, for the first time, an experimental demonstra- The FeII complex was actually shown to be the major product of
tion of increased reactivity of quintet oxoiron(IV) species over the photolysis of the corresponding [(cy-ac)FeIII(N3)] + complex in
corresponding triplet species was provided. solution (CH3CN at − 35 °C)40, while the formation of the photo-
oxidized FeV complex [(cy-ac)FeV(N)] + prevailed in a frozen
Iron–nitrido complexes matrix. Interestingly, the Mössbauer isomer shift δ of − 0.04 mms − 1
Iron–nitrido intermediates in biology. Iron-nitrido complexes, reported40,81 for the pentavalent Fe ion in [(cy-ac)FeV(N)] + and
which are isoelectronic to iron–oxo complexes, are also considered trans-[(N3)(cy)FeV(N)] + is found to be similar to that of 0.01 mms − 1
as key intermediates in a number of important biological transfor- reported40 for tetravalent Fe in [(cy-ac)FeIV(O)] + and significantly
mations. However, while a number of transient high-valent iron–oxo more positive than the value reported for Collins’ [(TAML)FeV(O)]
intermediates in the catalytic cycle of haem and non-haem enzymes complex ( − 0.46 mms − 1)32. This trend of higher isomer shifts in
have been identified and spectroscopically characterized1–3,5–7,9,10,18, nitrido as compared with the corresponding oxo complexes has
direct evidence for the involvement of iron–nitrido intermediates in been explained29 on the basis of higher covalency of the iron–nitrido
biology is lacking. Iron–nitride-mediated mechanistic postulates bond (compared with the iron–oxo). The nitridoiron(V) species
have nevertheless been motivated on the basis of indirect evidences trans-[(N3)(cy)FeV(N)] + and [(cy-ac)FeV(N)] + have initially been
that are obtained from various biochemical experiments13–16. For reported to possess a high-spin d3, S = 3/2, electronic ground state.
example, in the FeMo cofactor of the nitrogenase enzyme, the struc- However, in a subsequent in-depth spectroscopic and theoretical
ture of which features seven iron centres and a single molybdenum work, Aliaga-Alcalde et al.82 concluded that [(cy-ac)FeV(N)] + has
centre held together by nine bridging sulphides and a carbide atom an unusual orbitally degenerate S = 1/2 ground state. Initially, the
(Fig. 7)12,75, dinitrogen reduction is proposed to occur at a single Fe–N stretch in [(cy-ac)FeV(N)] + could not be identified in the
iron site76. Dinitrogen binds and is heterolytically cleaved at this infrared vibrational spectrum. However, by using synchrotron-
iron site, which results in the release of ammonia and generation of based nuclear-resonant-vibrational-spectroscopy coupled to DFT,
FeIV≡N. However, alternative mechanisms involving molybdenum Petrenko et al.83 identified the ν(Fe–N) band unambiguously at
or polynuclear iron reactive sites have also been proposed in the lit- 864 cm − 1. Furthermore, the (photochemically inactive) ferric azide
erature13–16. Moreover, a related imidoiron(IV) porphyrin (Fig. 7) of the corresponding methylated cyclam ligand can be oxidized to
species is postulated to be the reactive intermediate for cytochrome- yield [(Me3cy-ac)FeIV(N3)]2 + , which, in turn, is photochemically
P450-LM-3,4 catalysed N-atom transfer reactions11. active. Accordingly, photolysis at 650 nm in frozen matrix yields
another, yellow product, [(Me3cy-ac)FeVI(N)]2 + with one major
Iron–nitrido model complexes. To probe the possibility of the component (73%) at δ =  − 0.29 mms − 1 and ∆EQ = 1.53 mms − 1 in
involvement of iron–nitrido intermediates in biological dinitrogen- the Mössbauer spectrum84. This unusually low, negative isomer
reduction and atom-transfer reactions, bioinorganic chemists shift is consistent with a hexavalent FeVI≡N species. The assignment

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© 2012 Macmillan Publishers Limited. All rights reserved.
nature communications | DOI: 10.1038/ncomms1718 REVIEW

SO2C7H7 The structural characterization of FeIV≡N complexes by sin-

–
OOC
N gle-crystal X-ray diffraction was first accomplished in 2008. Pho-
COO–
tolysis of an N-anchored tris(carbene)-ligated azide complex
N
FeV
N [(TIMENmes)FeII(N3)] + (TIMENmes = tris[2-(3-mesitylimidazol-
N N 2-ylidene)ethyl]amine) yielded the four-coordinate tetravalent
[(TIMENmes)FeIV(N)] + as a purple crystalline material87. The
S spectroscopic fingerprint (infrared, 15N NMR and Mössbauer spec-
Cys
troscopy) of [(TIMENmes)FeIV(N)] + is very similar to Peters’ com-
O
plex [(PhBPiPr3)FeIV(N)] (Table 1). Even the crystallographically
S
Fe Fe determined Fe–N distance of 1.526 Å in [(TIMENmes)FeIV(N)] + is
O S S
R (within the experimental error) identical to that of EXAFS-spec-
R'
O Mo S
Fe
C
Fe
S Fe S(Cys275) troscopically determined one in [(PhBPiPr3)FeIV(N)]. However, the
S S geometries in these two nitrido complexes are markedly different.
(His442)N Fe Fe S
While the coordination polyhedron in the tris(phosphino)borate
S nitridoiron(IV) is best described as tetrahedral, the four-coordinate
amine-anchored tris(carbene) nitride is trigonal pyramidal with
N2 the iron centre located approximately 0.4 Å 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
+H+ +H+ sterically encumbering xylene and mesitylene groups places these
FeI N N FeII N NH FeIII N NH2
+e– +e– substituents perpendicular to the tris(carbene)—iron plane; thus,
+
+H
–NH3 creating a narrow cylindrical cavity, and effectively preventing
–NH3 +N2 +e– bimolecular decomposition pathways. Moreover, the nitrido 15N
resonance in cationic [(TIMENmes)FeIV(N)] + (δ = 741 p.p.m. rel.
+H+ +H+ +H+
FeI NH3 FeII NH2 FeIII NH FeIV N to CH3NO2) is considerably down-field shifted compared with the
+e– +e– +e–
neutral [(PhBPiPr3)FeIV(N)] (δ = 572 p.p.m.) and, hence, is more
similar to the nitrido ligand in trans-[(CF3COO)(cy)MnV(N)] +
Figure 7 | Proposed structures of biological intermediates with iron–
(MnV, d2, S = 0)88. DFT calculations predict a diamagnetic {(x2
nitrogen multiple bonds. The proposed structures have inspired studies
− y2)2(xy)2}{(z2)0(xz)0(yz)0} electronic ground state, which is in
on model iron–nitrido and imido complexes. (a) Structure of the iron(IV)
agreement with the diamagnetic 1H NMR spectra of these FeIV≡N
imido porphyrin intermediate that has been invoked for cytochrome-P450
complexes. The {(x2 − y2)2(xy)2}{(z2)0(xz)0(yz)0} configuration also
catalysed nitrogen group transfer reactions11. (b) The iron molybdenum
leads to an extreme asymmetric electron distribution around the
cofactor of the nitrogenase enzyme with a central carbide (C)12,75, and the
Fe ion, which results in the largest quadrupole splitting parameters
proposed intermediates (scheme in the box) of the dinitrogen activation
ever observed with ∆EQ values of more than 6 mms − 1 (Table 1,
process occurring at a single iron site76.
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
is further supported by a short Fe–N distance of 1.57 Å (determined state of the [(TMG3tren)FeIV(O)]2 + complex59,60 with an {(x2 − y2)
by EXAFS), a complementary computational analysis, and a linear 1(xy)1(xz)1(yz)1(z2)0} electronic configuration (Fig. 3). Although all
relationship between the isomer shifts and oxidation states in a three complexes possess a threefold symmetry, the strong antibond-
series of complexes with similar iron complex core structures and ing character of the π*(xz, yz) orbitals in [(TIMENmes)FeIV(N)] +
varying formal oxidation states, ranging from + II to + VI (ref. 84). and [(PhBPiPr3)FeIV(N)], which results in the inversion of the (z2)
This is the first FeVI coordination complex ever reported, with the and (xz), (yz) levels, is likely due to differences in Z* between N
ferrate anion FeO42 − being the only other known example of an and O that allow for better π-overlap to occur for Fe ≡ N multiple
FeVI ion. However, just like all previous nitridoiron species, com- bond29.
plex [(Me3cy-ac)FeVI(N)]2 + is only stable in cryogenic matrices Scepaniak et al.90 combined the ligand systems of Vogel et al.87 and
and decomposes to a high-spin FeIII species on warming. Betley and Peters85 by using the phenyl-tris(1-tert-butylimidazol-
In 2004, Betley and Peters85 synthesized the first terminal 2ylidene)borate (PhB(tBuIm)3 − ), a boron-anchored tripodal tris
IV
Fe ≡N complex that is stable in solution at room temperature. (carbene) ligand system originally introduced by Fränkel et al.89
By using a phenyl-tris-diisopropylphosphinoborate (PhBPiPr3− ) as Photolysis of [(PhB(tBuIm)3)FeII(N3)] also yielded the corresponding
the stabilizing tripodal chelate and lithium amide 2,3,5,6-dibenzo- diamagnetic FeIV≡N species, the complex [(PhB(tBuIm)3)FeIV(N)],
7-azabicyclo[2.2.1]hepta-2,5-diene (dbabh) as the N-atom trans- which was characterized by 1H and 15N NMR spectroscopy as
fer reagent, the four-coordinate [(PhBPiPr3)FeIV(N)] could be well as electronic absorption spectroscopy, resonance Raman
obtained and thoroughly characterized by 1H-, 31P- and 15N-NMR, spectroscopy and single-crystal diffraction studies90. Similar to
Mössbauer and infrared spectroscopy in solution (Table 1)85. An [(PhBPiPr3)FeIV(N)], this nitridoiron(IV) species possesses a pseudo-
EXAFS analysis provided further insight into the molecular struc- tetrahedral geometry with an S = 0 electronic ground state. The reac-
ture of [(PhBPiPr3)FeIV(N)] and revealed the unusually short Fe–N tivity of [(PhB(tBuIm)3)FeIV(N)], however, is surprisingly different to
bond distance of 1.51–1.55 Å86. An X-ray diffraction analysis of the that of [(PhBPiPr3)FeIV(N)]. While [(PhB(tBuIm)3)FeIV(N)] report-
crystallized product remained elusive due to dimerization to a dini- edly does not react with protons and electrons, the carbene-based
trogen bridged FeI/FeI-dinuclear species on concentration change nitride engages in electrophilic reactions with phosphines, like Ph3P,
during solvent evaporation. This dimerization, a six-electron reac- yielding the phosphiniminato complex [PhB(tBuIm)3FeII(NPPh3)],
tion mediated by two iron centres, is by itself a remarkable reaction. a rare example of a four-coordinate FeII complex with a sharp S = 2↔
The observation of significant amounts of ammonia on treatment S = 0 spin-crossover transition at 78 K91.
of [(PhBPiPr3)FeIV(N)] with protons and electrons is even more Most interestingly, the iron(IV) complex [(PhB(tBuIm)3)FeIV(N)]
significant and lend credence to the involvement of similar interme- could be oxidized with [Fe(Cp)2]BArF (with BArF = tetrakis(3,5-
diates during biological dinitrogen reduction. bis(trifluoromethyl)phenyl)borate) to yield the corresponding

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REVIEW nature communications | DOI: 10.1038/ncomms1718

pentavalent FeV≡N complex [(PhB(tBuIm)3)FeV(N)] + , which is the in the formation of binuclear µ-nitrido-bridged complexes
first example of an FeV≡N that could be isolated and thoroughly [{trans-(cy)FeIII(N3)}(µ-N){trans-(cy)FeIV(N3)}]2 + and [{cis-
characterized in solution and in solid state92. An X-ray diffrac- (cy)FeIII(N3)}(µ-N){trans-(cy)FeIV(N3)}]2 + , respectively81. On the
tion study revealed overall similar bond metrics to its tetravalent basis of EPR and applied-field Mössbauer spectroscopy (Table 1),
precursor, with the most remarkable feature being the very short the total spin state (St) in these mixed-valent complexes, St = 1/2 for
Fe–N bond distance of 1.502 Å in crystals of [(PhB(tBuIm)3)FeV trans/trans and St = 3/2 for trans/cis-isomer, was explained based on
(N)]BArF (Table 1). The complex was further investigated by EPR the assumption of strong antiferromagnetic coupling of an interme-
and Mössbauer spectroscopy, supplemented by DFT calcula- diate-spin FeIII (S = 3/2 in trans/trans), or a high-spin FeIII (S = 5/2
tions (Table 1), thereby confirming the doublet ground state. Like in trans/cis) with a low-spin FeIV (S = 1) metal centre and localized
Peters’ FeIV nitride [(PhBPiPr3)FeIV(N)], but not its FeIV precur- valencies in the [FeIV = N–FeIII]4 + core93.
sor, [(PhB(tBuIm)3)FeIV(N)], the nitridoiron(V) complex reacts
with protons (from water) under reductive conditions at − 78 °C in Conclusion and future challenges
tetrahydrofuran and evolves almost quantitative yields of NH3 with Employing reactive complexes of abundant metals for synthesis,
concomitant formation of an FeII species. catalysis and energy supply is of great current interest. Selective
functionalization of unactivated C–H bonds in organic compounds,
Dinuclear model complexes. As mentioned in the previous sec- for example, is a highly attractive strategy in organic synthesis, and
tion, photolysis of FeIII azide complexes leads to the generation the oxidation of methane and water are considered ‘holy grails’
of a photo-oxidized FeV terminal nitride species and a photo- in synthetic chemistry96. Similarly, energy-efficient production
reduced FeII species. At ambient temperature, the FeII and FeV of ammonia is extremely important, as fertilizers generated from
species react with each other to yield µ-nitrido-bridged FeIII/ ammonia are responsible for sustaining one-third of Earth’s popula-
FeIV complexes. Thus, via photolysis of [(Me3tacn)(Cl4cat)FeIII tion. A range of metalloenyzmes achieve these challenging tasks in
(N3)] (Me3tacn, 1,4,7-trimethyl-1,4,7-triazacyclononane; Cl4cat2 − , biology by activating dioxygen and dinitrogen and using cheap and
tetrachlorocatecholate) in solution at ambient temperature, Justel abundant first-row transition metals, like iron and manganese. Such
et al.93 synthesized the nitrido-bridged dinuclear complex reactions are carried out under ambient conditions with high effi-
[(Me3tacn)(Cl4cat)FeIII(µ-N)FeIV(Cl4cat)(Me3tacn)]. This mixed- ciency and high stereospecificity. The recent results presented here
valent diiron compound has two iron centres with distinct oxida- from the bioinorganic chemistry community lend credence to the
tion states of + III and + IV, which could be oxidized with bromine participation of high-valent oxo–ion and nitrido–iron complexes in
to yield the symmetrical FeIV = N = FeIV complex. Both species have the above-mentioned processes. Oxo and nitridoiron model com-
been crystallographically characterized, but only the FeIV/FeIV spe- plexes have now been synthesized using dioxygen or dinitrogen as
cies allowed for the unambiguous determination of the FeIV–N the oxidant, via mechanisms reminiscent of the O2 and N2 activation
bond distance of 1.703(1) Å within the FeIV = N = FeIV moiety. The process proposed in biology. Many of these complexes show intrigu-
total and residual electron densities of [(Me3tacn)(Cl4cat)FeIII(µ- ing reactivities, which in turn have provided vital insights into the
N)FeIV(Cl4cat)(Me3tacn)] were modelled with two disordered po- modelled enzymatic reactions. Among the most significant conclu-
sitions for the bridging nitrogen, implying that the core unit is not sion of these studies is the observed activation of the model ferryl
symmetrical and has two different Fe–N bond distances. In ac- unit on axial ligand coordination trans to the oxo group. This has
cordance with this model, the Mössbauer spectra of mixed-valent been attributed to strong electron donation from the axial thiolate
[(Me3tacn)(Cl4cat)FeIII(µ-N)FeIV(Cl4cat)(Me3tacn)] showed two ligand and explains the high reactivity of the natural thiolate-bound
distinct Mössbauer doublets with isomer shifts at δ = 0.52 and P450-I. Another important finding is the recently demonstrated73,74
0.09 mms − 1, characteristic for octahedral high-spin FeIII and low- increased reactivity of the linear [(O)FeIV-O-FeIII(OH2)]2 + model
spin FeIV ions, respectively (Table 1). These results provide strong complex, as compared with the ring-like [FeIV2(µ-O)2]2 + core, that
evidence for localized valencies at the iron centres of [(Me3tacn) provides evidence for a comparable, more ring-opened form of Q
(Cl4cat)FeIII(µ-N)FeIV(Cl4cat)(Me3tacn)], in contrast to those of with a terminal FeIV = O unit as the active species in the reactivity of
the nitrido-bridged diiron complex [(TPP)Fe3.5(µ-N)Fe3.5(TPP)], MMO. Additionally, although direct evidence for the involvement of
reported in 1976, where the excess electron is fully delocalized, oxoiron(V) intermediates in water oxidation is lacking in the litera-
resulting in formal oxidation states of 3.5 at both iron centres94. ture, Kundu et al.97, has recently demonstrated a O–O bond forma-
Remarkably, replacing one of the bidentate catecholate ligands in tion reaction mediated by polynuclear oxoiron(IV) intermediates.
[(Me3tacn)(Cl4cat)FeIII(N3)] with the acetylacetonate derivative Such a metal-mediated O–O bond formation step is considered to be
1,3-diphenylpropane-1,3-dionate (Ph2acac − ), and photolysing a 1:1 the most critical part of dioxygen evolution in photosystem-II98. In
mixture of [(Me3tacn)(Cl4cat)FeIII(N3)] and [(Me3tacn)(Ph2acac) N2 activation and transformation chemistry, Lee et al. (ref. 99) have
FeIII(N3)], yields the asymmetric binuclear complex [(Me3tacn) shown that many important intermediates in a variety of oxidation
(Ph2acac)FeIII(µ-N)FeIV(Cl4cat)(Me3tacn)] without a crystallo- states of a hypothetical N2 to NH3 conversion cycle can be accom-
graphically imposed inversion centre. Consequently, the mixed- modated at a mononuclear iron site. More recently, Rodriguez
valent complex [(Me3tacn)(Ph2acac)FeIII(µ-N)FeIV(Cl4cat)(Me3tacn)] et al.100 have demonstrated the potassium-assisted cooperativity
allows for the unambiguous determination of the Fe–N bond dis- of three iron centres in the activation and cleavage of dinitrogen
tances within the FeIII–N = FeIV moiety at 1.785(7) Å and 1.695(7) Å, and subsequent generation of ammonia on reaction of the nitride
respectively. However, the difference in bond lengths is not as large species with dihydrogen.
as expected and is merely attributed to the varying radii of the iron Unfortunately, the reactions exhibited by the model complexes
ions in the different oxidation states. The Mössbauer spectrum of are found to be non-catalytic, with activities falling far short of the
[(Me3tacn)(Ph2acac)FeIII(µ-N)FeIV(Cl4cat)(Me3tacn)] is very sim- activity of the biological catalysts. The low reactivity of the model
ilar to that of [(Me3tacn)(Cl4cat)FeIII(µ-N)FeIV(Cl4cat)(Me3tacn)] complexes can be explained by the inability of synthetic chemists
(δ = 0.60 and 0.04 mms − 1; Table 1), showing localized valencies in to exactly reproduce the biological ligand and protein environment.
the asymmetric mixed-valent complex95. For example, even the ligand set of two histidines and one car-
In 1999, Meyer et al.81 continued the investigation of high- boxylate, as observed in the first coordination sphere of non-haem
valent nitrido species formation via photolysis of the correspond- oxygenases, is extremely difficult to synthesize and manipulate.
ing azido complexes. Photolysis of trans-[(cy)FeIII(N3)2] + and Similarly, it has not yet been possible to generate an oxoiron(IV)
cis-[(cy)FeIII(N3)2] + in solution at ambient temperatures resulted porphyrin π-cation radical model complex with an axial thiolate

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nature communications | DOI: 10.1038/ncomms1718 REVIEW

ligand trans to the iron–oxo unit, as observed in Cpd-I of cytochrome- 22. Sinnecker, S. et al. Spectroscopic and computational evaluation of the structure
P450. Additionally, no iron-based model complexes mimicking the of the high-spin Fe(IV)-Oxo intermediates in taurine: α-Ketoglutarate dioxy-
genase from Escherichia coli and Its His99Ala ligand variant. J. Am. Chem. Soc.
FeMo cofactor activity of the nitrogenase enzyme are known in the 129, 6168–6179 (2007).
literature, and, as a result, the role of the postulated carbide ligand in 23. Birk, T. & Bendix, J. Atom transfer as a preparative tool in coordination chem-
dinitrogen activation is far from understood. Thus, new and innova- istry. Synthesis and characterization of Cr(V) nitrido complexes of bidentate
tive synthetic strategies are needed to generate superoxidized iron ligands. Inorg. Chem. 42, 7608–7615 (2003).
centres in ligand environments that better resemble the active site of 24. Mehn, M. P. & Peters, J. C. Mid- to high-valent imido and nitrido complexes of
iron. J. Inorg. Biochem. 100, 634–643 (2006).
the metalloenzymes. This goal may eventually lead to the develop- 25. Behan, R. K. & Green, M. T. On the status of ferryl protonation. J. Inorg. Bio-
ment of iron-catalysed selective functionalization of organic com- chem. 100, 448–459 (2006).
pounds or ammonia synthesis by using cheap and accessible sources 26. Stone, K. L., Behan, R. K. & Green, M. T. Resonance Raman spectroscopy of
of dioxygen or dinitrogen under ambient conditions. chloroperoxidase compound II provides direct evidence for the existence of an
iron(IV)-hydroxide. Proc. Natl Acad. Sci. USA 103, 12307–12310 (2006).
27. Stone, K. L., Hoffart, L. M., Behan, R. K., Krebs, C. & Green, M. T. Evidence for
References two Ferryl species in chloroperoxidase compound II. J. Am. Chem. Soc. 128,
1. Krebs, C., Fujimori, D. G., Walsh, C. T. & Bollinger, J. M. Jr. Non-heme Fe(IV)- 6147–6153 (2006).
Oxo intermediates. Acc. Chem. Res. 40, 484–492 (2007). 28. Behan, R. K., Hoffart, L. M., Stone, K. L., Krebs, C. & Green, M. T. Evidence
2. Costas, M., Mehn, M. P., Jensen, M. P. & Que, L. Dioxygen activation at mono- for basic Ferryls in Cytochromes P450. J. Am. Chem. Soc. 128, 11471–11474
nuclear nonheme iron active sites: enzymes, models, and intermediates. Chem. (2006).
Rev. 104, 939–986 (2004). 29. Berry, J. F., DeBeer George, S. & Neese, F. Electronic structure and spectroscopy
3. Nam, W. Guest editorial: dioxygen activation by metalloenzymes and models. of ‘superoxidized’ iron centers in model systems: theoretical and experimental
Acc. Chem. Res. 40, 465 (2007). trends. Phys. Chem. Chem. Phys. 10, 4361–4374 (2008).
4. Chakrabarty, S., Austin, R. N., Deng, D., Groves, J. T. & Lipscomb, J. D. Radi- 30. Kang, Y. et al. Enhanced reactivities of iron(IV)-oxo porphyrin π-cation radi-
cal intermediates in monooxygenase reactions of rieske dioxygenases. J. Am. cals in oxygenation reactions by electron-donating axial ligands. Chemistry—A
Chem. Soc. 129, 3514–3515 (2007). European J. 15, 10039–10046 (2009).
5. Friedle, S., Reisner, E. & Lippard, S. J. Current challenges of modeling diiron 31. Shaik, S. et al. P 450 enzymes: their structure, reactivity, and selectivity—mod-
enzyme active sites for dioxygen activation by biomimetic synthetic complexes. eled by QM/MM calculations. Chem. Rev. 110, 949–1017 (2010).
Chem. Soc. Rev. 39, 2768–2779 (2010). 32. Tiago de Oliveira, F. et al. Chemical and spectroscopic evidence for an FeV-Oxo
6. Fujii, H. Electronic structure and reactivity of high-valent oxo iron porphyrins. complex. Science 315, 835–838 (2007).
Coord. Chem. Rev. 226, 51–60 (2002). This paper reports the synthesis, structure, and reactivity of the first and
7. Groves, J. T. High-valent iron in chemical and biological oxidations. J. Inorg. only known example of an isolable oxoiron(V) complex supported by a
Biochem. 100, 434–447 (2006). tetraamido macrocyclic ligand.
8. Groves, J. T., Haushalter, R. C., Nakamura, M., Nemo, T. E. & Evans, B. J. High- 33. Shan, X. & Que , L. Jr. High-valent nonheme iron-oxo species in biomimetic
valent iron-porphyrin complexes related to peroxidase and cytochrome P-450. oxidations. J. Inorg. Biochem. 100, 421–433 (2006).
J. Am. Chem. Soc. 103, 2884–2886 (1981). 34. Fillol, J. L. et al. Efficient water oxidation catalysts based on readily available
9. Jung, C. The mystery of cytochrome P450 Compound I: a mini-review dedi- iron coordination complexes. Nat. Chem. 3, 807–813 (2011).
cated to Klaus Ruckpaul. Biochimica et Biophysica Acta (BBA) 1814, 46–57 This paper reports the use of iron—a rich, cheap and non-toxic metal—as a
(2011). catalyst to generate oxygen from water.
10. Tinberg, C. E. & Lippard, S. J. Dioxygen activation in soluble methane mo- 35. Lyakin, O. Y., Bryliakov, K. P., Britovsek, G. J. P. & Talsi, E. P. EPR spectroscopic
nooxygenase. Acc. Chem. Res. 44, 280–288 (2011). trapping of the active species of nonheme iron-catalyzed oxidation. J. Am.
11. Svastits, E. W., Dawson, J. H., Breslow, R. & Gellman, S. H. Functionalized Chem. Soc. 131, 10798–10799 (2009).
nitrogen atom transfer catalyzed by cytochrome P-450. J. Am. Chem. Soc. 107, 36. Yoon, J. et al. Reactive intermediates in oxygenation reactions with mononu-
6427–6428 (1985). clear nonheme iron catalysts. Angew. Chem. Int. Ed. 48, 1257–1260 (2009).
12. Lancaster, K. M. et al. X-ray emission spectroscopy evidences a central carbon 37. Comba, P. & Wunderlich, S. Iron-catalyzed halogenation of alkanes: modeling
in the nitrogenase iron-molybdenum cofactor. Science 334, 974–977 (2011). of nonheme halogenases by experiment and DFT calculations. Chemistry—A
13. Thorneley, R. N. F. & Lowe, D. J. The mechanism of Klebsiella pneumoniae ni- Eur. J. 16, 7293–7299 (2010).
trogenase action. Simulation of the dependences of hydrogen evolution rate on 38. Ellis, W. C., McDaniel, N. D., Bernhard, S. & Collins, T. J. Fast water oxidation
component-protein concentration and ratio and sodium dithionite concentra- using iron. J. Am. Chem. Soc. 132, 10990–10991 (2010).
tion. Biochem. J. 224, 903–909 (1984). 39. Prat, I. et al. Observation of Fe(V)=O using variable-temperature mass spec-
14. Thorneley, R. N. F. & Lowe, D. J. The mechanism of Klebsiella pneumoniae trometry and its enzyme-like C–H and C=C oxidation reactions. Nat. Chem. 3,
nitrogenase action. Pre-steady-state kinetics of an enzyme-bound intermediate 788–793 (2011).
in nitrogen reduction and of ammonia formation. Biochem. J. 224, 887–894 40. Grapperhaus, C. A., Mienert, B., Bill, E., Weyhermueller, T. & Wieghardt,
(1984). K. Mononuclear (Nitrido)iron(V) and (Oxo)iron(IV) complexes via
15. Lowe, D. J. & Thorneley, R. N. F. The mechanism of Klebsiella pneumoniae photolysis of [(cyclam-acetato)FeIII(N3)]+ and ozonolysis of [(cyclam-
nitrogenase action. Pre-steady-state kinetics of hydrogen formation. Biochem. J. acetato)FeIII(O3SCF3)]+ in water/acetone mixtures. Inorg. Chem. 39,
224, 877–886 (1984). 5306–5317 (2000).
16. Lowe, D. J. & Thorneley, R. N. F. The mechanism of Klebsiella pneumoniae In this paper, a non-heme oxoiron(IV) complex has been generated for the
nitrogenase action. The determination of rate constants required for the simu- first time as a model for the oxoiron(IV) intermediates found in the cata-
lation of the kinetics of nitrogen reduction and hydrogen evolution. Biochem. J. lytic cycle of a number of iron containing non-heme dioxygenases.
224, 895–901 (1984). 41. Rohde, J.- U. et al. Crystallographic and spectroscopic characterization of a
17. Ertl, G. Elementary steps in heterogeneous catalysis. Angew. Chem. Int. Ed. 29, nonheme Fe(IV)=O complex. Science 299, 1037–1039 (2003).
1219–1227 (1990). 42. Bosnich, B., Poon, C. K. & Tobe, M. L. Complexes of Cobalt(III) with a cyclic
This paper offers a comprehensive overview of and detailed insights into tetradentate secondary amine. Inorg. Chem. 4, 1102–1108 (1965).
the mechanistics of heterogenous catalysis with an emphasis on ammonia 43. Fukuzumi, S. et al. Crystal structure of a metal ion-bound oxoiron(IV) complex
synthesis based on ‘surface nitride’ species. and implications for biological electron transfer. Nat. Chem. 2, 756–759 (2010).
18. Hersleth, H.- P., Ryde, U., Rydberg, P., Görbitz, C. H. & Andersson, K. K. Struc-
44. Que, L. Jr. The road to non-heme oxoferryls and beyond. Acc. Chem. Res. 40,
tures of the high-valent metal-ion haem-oxygen intermediates in peroxidases,
493–500 (2007).
oxygenases and catalases. J. Inorg. Biochem. 100, 460–476 (2006).
45. Thibon, A. et al. Proton- and reductant-assisted dioxygen activation by a non-
19. Krebs, C. et al. Rapid Freeze-Quench 57Fe Mössbauer spectroscopy: monitor-
heme iron(II) complex to form an oxoiron(IV) intermediate. Angew. Chem. Int.
ing changes of an iron-containing active site during a biochemical reaction.
Ed. 47, 7064–7067 (2008).
Inorg. Chem. 44, 742–757 (2005).
46. MacBeth, C. E. et al. O2 activation by nonheme iron complexes: a monomeric
This paper demonstrates the applicability of Mössbauer spectroscopy in
establishing the mechanism of dioxygen activation by iron-containing non- Fe(III)-oxo complex derived from O2. Science 289, 938–941 (2000).
heme dioxygenases. 47. Bukowski, M. R. et al. A thiolate-ligated nonheme oxoiron(IV) complex rel-
20. Schulz, C. E., Rutter, R., Sage, J. T., Debrunner, P. G. & Hager, L. P. Mössbauer evant to Cytochrome P450. Science 310, 1000–1002 (2005).
and electron paramagnetic resonance studies of horseradish peroxidase and its This paper demonstrates the possibility of stabilizing a thiolate ligand
catalytic intermediates. Biochemistry 23, 4743–4754 (1984). in an oxidizing atmosphere by synthesizing a thiolate-ligated non-heme
21. Jayaraj, K. et al. Compound I and II analogs of a chlorin. J. Am. Chem. Soc. 117, oxoiron(IV) complex as a model for the compound-I intermediate found in
9079–9080 (1995). cytochrome P450.

nature communications | 3:720 | DOI: 10.1038/ncomms1718 | www.nature.com/naturecommunications 11

© 2012 Macmillan Publishers Limited. All rights reserved.
REVIEW nature communications | DOI: 10.1038/ncomms1718

48. Rittle, J. & Green, M. T. Cytochrome P450 compound I: capture, characteriza- 72. Dong, Y. et al. A high-valent nonheme iron intermediate. Structure and proper-
tion, and C-H bond activation kinetics. Science 330, 933–937 (2010). ties of [Fe2(µ-O)2(5-Me-TPA)2](ClO4)3. J. Am. Chem. Soc. 117, 2778–2792
This paper reports the spectroscopic and kinetic-characterization of the (1995).
long-sought principal compound-I intermediate involved in the catalytic 73. Xue, G., Fiedler, A. T., Martinho, M., Münck, E. & Que, L. Insights into the
cycle of cytochrome P450. P-to-Q conversion in the catalytic cycle of methane monooxygenase from a
49. Decker, A., Rohde, J.- U., Que, L. Jr. & Solomon, E. I. Spectroscopic and synthetic model system. Proc. Natl Acad. Sci. USA 105, 20615–20620 (2008).
quantum chemical characterization of the electronic structure and bonding in a 74. Xue, G., De Hont, R., Muenck, E. & Que, L. Jr. Million-fold activation of the
non-Heme FeIVO complex. J. Am. Chem. Soc. 126, 5378–5379 (2004). [Fe2(µ-O)2] diamond core for C-H bond cleavage. Nat. Chem. 2, 400–405
50. Collins, M. J., Ray, K. & Que, L. Jr. Electrochemical generation of a nonheme (2010).
oxoiron(IV) complex. Inorg. Chem. 45, 8009–8011 (2006). This paper reports the surprising observation that the [Fe2IV(µ-O)2] dia-
51. Kotani, H., Suenobu, T., Lee, Y.- M., Nam, W. & Fukuzumi, S. Photocatalytic mond core of a model complex opens up to achieve a million-fold increase
generation of a non-heme oxoiron(IV) complex with water as an oxygen in its reactivity with C-H bonds; thereby, supporting the possibility of
source. J. Am. Chem. Soc. 133, 3249–3251 (2011). a similar ring-opened form of Q as the active species in the reactivity of
52. Li, F., England, J. & Que, L. Near-stoichiometric conversion of H2O2 to FeIV=O MMO.
at a nonheme iron(II) center. Insights into the O–O bond cleavage step. J. Am. 75. Einsle, O. et al. Nitrogenase MoFe-protein at 1.16.Å. resolution: a central ligand
Chem. Soc. 132, 2134–2135 (2010). in the FeMo-cofactor. Science 297, 1696–1700 (2002).
53. Hong, S., Lee, Y.- M., Shin, W., Fukuzumi, S. & Nam, W. Dioxygen activation 76. Peters, J. & Mehn, M. P. In Activation of Small Molecules (ed. Tolman, W.B.)
by mononuclear nonheme Iron(II) complexes generates ironoxygen intermedi- 81–119 (Wiley-VCH, 2006).
ates in the presence of an NADH analogue and proton. J. Am. Chem. Soc. 131, 77. Bennett, M. V. & Holm, R. H. Self-assembly of a tetradecanuclear iron nitride
13910–13911 (2009). cluster. Angew. Chem. Int. Ed. 45, 5613–5616 (2006).
-
54. Lacy, D. C. et al. Formation, structure, and EPR detection of a high spin FeIV 78. Powers, T. M., Fout, A. R., Zheng, S.- L. & Betley, T. A. Oxidative group transfer
- -
Oxo species derived from either an FeIII Oxo or FeIII OH complex. J. Am. to a triiron complex to form a nucleophilic µ3-nitride, [Fe3(µ3-N)]. J. Am.
Chem. Soc. 132, 12188–12190 (2010). Chem. Soc. 133, 3336–3338 (2011).
This paper represents the only example in the literature where a high-spin 79. King, E. R., Hennessy, E. T. & Betley, T. A. Catalytic C-H bond amination from
oxoiron(IV) complex has been generated by dioxygen activation via a mech- high-spin iron imido complexes. J. Am. Chem. Soc. 133, 4917–4923 (2011).
anism reminiscent of the dioxygen activation process proposed in biology. 80. Wagner, W. D. & Nakamoto, K. Resonance Raman spectra of nitridoiron(V)
55. Lee, Y.- M. et al. Dioxygen activation by a non-heme iron(II) complex: porphyrin intermediates produced by laser photolysis. J. Am. Chem. Soc. 111,
formation of an iron(IV)oxo complex via C-H activation by a putative 1590–1598 (1989).
iron(III)superoxo species. J. Am. Chem. Soc. 132, 10668–10670 (2010). 81. Meyer, K., Bill, E., Mienert, B., Weyhermueller, T. & Wieghardt, K. Photolysis of
56. Li, F. et al. Characterization of a high-spin non-Heme FeIII–OOH intermediate cis- and trans-[FeIII(cyclam)(N3)2]+ complexes: spectroscopic characterization
and its quantitative conversion to an FeIVO Complex. J. Am. Chem. Soc. 133, of a Nitridoiron(V) species. J. Am. Chem. Soc. 121, 4859–4876 (1999).
7256–7259 (2011). 82. Aliaga-Alcalde, N. et al. The geometric and electronic structure of [(cyclam-
57. Cho, J. et al. Structure and reactivity of a mononuclear non-haem iron(III)– acetato)Fe(N)]+: a genuine iron(V) species with a ground-state Spin S=1/2.
peroxo complex. Nature 478, 502–505 (2011). Angew. Chem. Int. Ed. 44, 2908–2912 (2005).
58. Pestovsky, O. et al. Aqueous FeIV=O: spectroscopic identification and oxo- 83. Petrenko, T. et al. Characterization of a genuine iron(V)nitrido species by
group exchange. Angew. Chem. Int. Ed. 44, 6871–6874 (2005). nuclear resonant vibrational spectroscopy coupled to density functional calcu-
59. England, J. et al. A synthetic high-spin Oxoiron(IV) complex: generation, spec- lations. J. Am. Chem. Soc. 129, 11053–11060 (2007).
troscopic characterization, and reactivity. Angew. Chem. Int. Ed. 48, 3622–3626 84. Berry, J. F. et al. An octahedral coordination complex of Iron(VI). Science 312,
(2009). 1937–1941 (2006).
60. England, J. et al. The crystal structure of a high-spin Oxoiron(IV) complex and This paper presents the spectroscopic characterization of the first example
characterization of its self-decay pathway. J. Am. Chem. Soc. 132, 8635–8644 of an FeVI coordination complex generated via photolysis of the parent FeIV
(2010). azide in a frozen matrix at 77 K.
61. Shaik, S., Hirao, H. & Kumar, D. Reactivity of high-valent iron–oxo species 85. Betley, T. A. & Peters, J. C. A tetrahedrally coordinated L3Fe-Nx platform that
in enzymes and synthetic reagents: a tale of many states. Acc. Chem. Res. 40, accommodates terminal nitride (FeIV≡N) and dinitrogen (FeI-N2-FeI) ligands.
532–542 (2007). J. Am. Chem. Soc. 126, 6252–6254 (2004).
62. Cho, K.- B., Shaik, S. & Nam, W. Theoretical predictions of a highly reactive This paper reports spectroscopic evidence for the formation of the first
non-heme FeIV=O complex with a high-spin ground state. Chem. Commun. 46, nitridoiron(IV) complex at room temperature through N-atom transfer
4511–4513 (2010). via strain release by anthracene elimination from 2,3:5,6-dibenzo-7-
63. Ye, S. & Neese, F. Nonheme oxo-iron(IV) intermediates form an oxyl radical azabicyclo[2.2.1]hepta-2,5-diene.
upon approaching the C–H bond activation transition state. Proc. Natl Acad. 86. Rohde, J.- U. et al. XAS characterization of a nitridoiron(IV) complex with a
Sci. USA 108, 1228–1233 (2011). very short Fe-N bond. Inorg. Chem. 46, 5720–5726 (2007).
64. Seo, M. S. et al. A mononuclear nonheme iron(IV)-oxo complex which is more 87. Vogel, C., Heinemann, F. W., Sutter, J., Anthon, C. & Meyer, K. An iron nitride
reactive than cytochrome P450 model compound I. Chem. Sci. 2, 1039–1045 complex. Angew. Chem. Int. Ed. 47, 2681–2684 (2008).
(2011). 88. Meyer, K., Bendix, J., Metzler-Nolte, N., Weyhermüller, T. & Wieghardt, K.
65. Sastri, C. V. et al. Axial ligand tuning of a nonheme iron(IV)-oxo unit for hy- Nitridomanganese(V) and -(VI) complexes containing macrocyclic amine
drogen atom abstraction. Proc. Natl Acad. Sci. USA 104, 19181–19186 (2007). ligands. J. Am. Chem. Soc. 120, 7260–7270 (1998).
66. de Visser, S. P. Propene activation by the Oxo-iron active species of Taurine/α- 89. Fränkel, R. et al. Homoleptic carbene complexes: Part IX. Bis(imidazolin-
Ketoglutarate Dioxygenase (TauD) enzyme. How does the catalysis compare to 2-ylidene-1-yl)borate complexes of palladium(II), platinum(II) and gold(I).
heme-enzymes? J. Am. Chem. Soc. 128, 9813–9824 (2006). Inorg. Chim. Acta 312, 23–39 (2001).
67. Janardanan, D., Wang, Y., Schyman, P., Que, L. Jr. & Shaik, S. The fundamental 90. Scepaniak, J. J. et al. Structural and spectroscopic characterization of an
role of exchange-enhanced reactivity in C-H activation by S=2 oxo iron(IV) electrophilic iron nitrido complex. J. Am. Chem. Soc. 130, 10515–10517
complexes. Angew. Chem. Int. Ed. 49, 3342–3345 (2010). (2008).
68. Michel, C. & Baerends, E. J. What singles out the FeO2+ Moiety? A density- 91. Scepaniak, J. J. et al. Spin crossover in a four-coordinate iron(II) complex.
functional theory study of the methane-to-methanol reaction catalyzed by J. Am. Chem. Soc. 133, 3824–3827 (2011).
the first row transition-metal oxide dications MO(H2O)p2+, M=V-Cu. Inorg. 92. Scepaniak, J. J. et al. Synthesis, structure, and reactivity of an Iron(V) nitride.
Chem. 48, 3628–3638 (2009). Science 331, 1049–1052 (2011).
69. Solomon, E. I., Wong, S. D., Liu, L. V., Decker, A. & Chow, M. S. Peroxo and This paper presents the first structural and spectroscopic characterization of
oxo intermediates in mononuclear nonheme iron enzymes and related active a nitridoiron(V) complex that reacts with water under reductive conditions
sites. Curr. Opin. Chem. Biol. 13, 99–113 (2009). to yield ammonia in almost quantitative yield.
70. Shu, L. et al. An Fe2IVO2 diamond core structure for the key intermediate Q of 93. Justel, T. et al. µ-nitridodiiron complexes with asymmetric [FeIV≡N-FeIII]4+
methane monooxygenase. Science 275, 515–518 (1997). and symmetric [FeIV=N=FeIV]5+ structural elements. Angew. Chem. Int. Ed.
71. Xue, G. et al. A synthetic precedent for the [FeIV2(µ-O)2] diamond core pro- 34, 669–672 (1995).
posed for methane monooxygenase intermediate Q. Proc. Natl Acad. Sci. USA 94. Summerville, D. A. & Cohen, I. A. Metal-metal interactions involving metal-
104, 20713–20718 (2007). loporphyrins. III. Conversion of tetraphenylporphinatoiron(III) azide to an
This paper reports a high-valent synthetic iron-oxo complex with a N-bridged hemin dimer. J. Am. Chem. Soc. 98, 1747–1752 (1976).
‘diamond core’ Fe(-O)2Fe structure that mimics the structure of a key 95. Justel, T. et al. The molecular and electronic structure of symmetrically and
intermediate in the catalytic cycle of methane monooxygenase; hence, it
asymmetrically coordinated, non-heme iron complexes containing [FeIII(µ-N)
provides a suitable basis for the pursuit of a number of different research
FeIV]4+ (S=3/2) and [FeIV(µ-N)FeIV]5+ (S=0) cores. Chemistry—A European J.
avenues pertaining to the mechanism of dioxygen activation and substrate
oxidation by diiron centers. 5, 793–810 (1999).

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© 2012 Macmillan Publishers Limited. All rights reserved.
nature communications | DOI: 10.1038/ncomms1718 REVIEW
96. Arndtsen, B. A., Bergman, R. G., Mobley, T. A. & Peterson, T. H. 100. Rodriguez, M. M., Bill, E., Brennessel, W. W. & Holland, P. L. N2 reduction
Selective intermolecular carbon-hydrogen bond activation by synthetic and hydrogenation to ammonia by a molecular iron-potassium complex.
metal complexes in homogeneous solution. Acc. Chem. Res. 28, 154–162 Science 334, 780–783 (2011).
(1995). This paper presents the first example of a multi-metallic polynuclear
97. Kundu, S. et al. O–O Bond formation mediated by a hexanuclear iron complex iron complex that binds N2, cleaves the N–N-bond, and releases NH3 on
supported on a Stannoxane core. Chemistry—A European J., doi:10.1002/ treatment with H2.
chem.201102326 (2012).
98. Siegbahn, P. E. M. Theoretical studies of O–O bond formation in photosystem Additional information
II. Inorg. Chem. 47, 1779–1786 (2008). Competing financial interests: The authors declare no competing financial interests.
99. Lee, Y., Mankad, N. P. & Peters, J. C. Triggering N2 uptake via redox-induced
expulsion of coordinated NH3 and N2 silylation at trigonal bipyramidal iron. Reprints and permission information is available online at http://npg.nature.com/
Nat. Chem. 2, 558–565 (2010). reprintsandpermissions/
This paper presents the first structural and spectroscopic characterization of How to cite this article: Hohenberger, J. et al. The biology and chemistry of high-valent
a nitridoiron(V) complex that reacts with water under reductive conditions iron–oxo and iron–nitrido complexes. Nat. Commun. 3:720 doi: 10.1038/ncomms1718
to yield ammonia in almost quantitative yield. (2012).

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