R

Ic

Sa

Ub

c

d

C

a

ARRAA

Dt

KMBOIIM

0h

Coordination Chemistry Reviews 257 (2013) 381– 393

Contents lists available at SciVerse ScienceDirect

Coordination Chemistry Reviews

jo ur n al homepage: www.elsev ier .com/ locate /ccr

eview

ntrinsic properties and reactivities of mononuclear nonheme iron–oxygenomplexes bearing the tetramethylcyclam ligand

am P. de Vissera,∗, Jan-Uwe Rohdeb,∗, Yong-Min Leec,d, Jaeheung Choc,d, Wonwoo Namc,d,∗∗

Manchester Interdisciplinary Biocenter and School of Chemical Engineering and Analytical Science, University of Manchester, 131 Princess Street, Manchester M1 7DN,nited KingdomDepartment of Chemistry, The University of Iowa, Iowa City, IA 52242, United StatesDepartment of Bioinspired Chemistry, Ewha Womans University, Seoul 120-750, South KoreaDepartment of Chemistry and Nano Science, Ewha Womans University, Seoul 120-750, South Korea

ontents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3822. Iron(IV)-oxo complexes of TMC and related macrocyclic ligands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 383

2.1. Synthesis and characterization of mononuclear nonheme iron(IV)-oxo complexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3832.2. Trans-Influences in [FeIV(O)(TMC)(X)]n+ complexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3862.3. Reactivities of [FeIV(O)(TMC)(X)]n+ complexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3862.4. DFT calculations on iron(IV)-oxo complexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387

2.4.1. [FeIV(O)(TMC)(X)]n+ complexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3872.4.2. A complex of a thiolate-appended TMC ligand, [FeIV(O)(TMCS)]+ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 389

3. Iron(III)-superoxo species, [FeIII(O2)(TMC)]2+ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3894. Iron(III)-peroxo and -hydroperoxo complexes, [FeIII(O2)(TMC)]+ and [FeIII(O2H)(TMC)]2+ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 390

4.1. Synthesis, characterization, and interconversion of iron–oxygen intermediates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3904.2. Reactivity comparison . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 391

5. Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 391Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 392References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 392

r t i c l e i n f o

rticle history:eceived 17 April 2012eceived in revised form 5 June 2012ccepted 8 June 2012vailable online 7 July 2012

edicated to Prof. Edward I. Solomon onhe occasion of his 65th birthday.

eywords:etalloenzymes

iomimeticsxygen activation

a b s t r a c t

Iron–oxygen species, such as iron(IV)-oxo, iron(III)-superoxo, iron(III)-peroxo, and iron(III)-hydroperoxocomplexes, are key intermediates often detected in the catalytic cycles of dioxygen activation byheme and nonheme iron enzymes. Our understanding of the chemistry of these key intermediateshas improved greatly by studies of the structural and spectroscopic properties and reactivities oftheir synthetic analogues. One class of biomimetic coordination complexes that has proven to be par-ticularly versatile in studying dioxygen activation by metal complexes is comprised of FeIV O andFeIII O2(H) complexes of the macrocyclic tetramethylcyclam ligand (TMC, 1,4,8,11-tetramethyl-1,4,8,11-tetraazacyclotetradecane). Several recent advances have been made in the synthesis and isolation of newiron–oxygen complexes of this ligand, their structural and spectroscopic characterization, and elucida-tion of their reactivities in various oxidation reactions. In this review, we summarize the chemistry ofthe first structurally characterized mononuclear nonheme iron(IV)-oxo complex, in which the FeIV O

IV n+

ron-oxontermediates

acrocyclic ligands

group was stabilized by the TMC ligand. Complexes with different axial ligands, [Fe (O)(TMC)(X)] ,and complexes of other cyclam ligands are discussed as well. Very recently, significant progress has alsobeen reported in the area of other iron–oxygen intermediates, such as iron(III)-superoxo, iron(III)-peroxo,and iron(III)-hydroperoxo complexes bearing the TMC ligand. The present results demonstrate how syn-thetic and mechanistic developments in biomimetic research can advance our understanding of dioxygenactivation occurring in monon

∗ Corresponding authors.∗∗ Corresponding author at: Ewha Womans University. Tel.: +82 2 3277 2392; Fax: +82

E-mail addresses: sam.devisser@manchester.ac.uk (S.P. de Visser), jan-uwe-rohde@uio

010-8545/$ – see front matter © 2012 Elsevier B.V. All rights reserved.ttp://dx.doi.org/10.1016/j.ccr.2012.06.002

uclear nonheme iron enzymes.© 2012 Elsevier B.V. All rights reserved.

2 3277 4441.wa.edu (J.-U. Rohde), wwnam@ewha.ac.kr (W. Nam).

3 Chemi

1

biiltiTtT(ptrfpdps�eraaaii[sisdsCl4dsob

ka

82 S.P. de Visser et al. / Coordination

. Introduction

The cytochromes P450 (CYP 450) are a versatile group of heme-ased monooxygenases with vital functions for human health,

ncluding the biodegradation and metabolism of toxic compoundsn the body as well as the biosynthesis of hormones [1–7]. They uti-ize molecular oxygen at a heme center and react via oxygen atomransfer to substrates, leading to C H hydroxylation, C C epox-dation, aromatic hydroxylation, and heteroatom oxidation [8,9].he CYP 450s contain a central heme active site that is linked tohe protein via a thiolate bridge from a cysteinate residue [10,11].he catalytic cycle of the CYP 450s starts from the resting stateFig. 1A) [12–14], where a water molecule fills the sixth bindingosition of the metal. Upon substrate binding into the active site,he water molecule is released and a five-coordinate high-spin fer-ic species with a vacant coordination site for dioxygen binding isormed (Fig. 1B). After the reduction of the ferric heme by reducedutidaredoxin to a five-coordinate high-spin ferrous heme (Fig. 1C),ioxygen binds to the heme in a ferric-superoxo form (Fig. 1D) andicks up another electron and proton to form a ferric-hydroperoxopecies (Fig. 1E) that is protonated to give an iron(IV)-oxo heme-cation radical oxidant (Fig. 1F), which is the active species of thenzyme and also known as Compound I (Cpd I). Due to the higheactivity and short lifetime of Cpd I, it has been difficult to trapnd characterize it with spectroscopic methods, but recently Rittlend Green collected the first pieces of evidence from Mössbauernd UV–vis spectroscopic experiments [15]. However, its partic-pation as active oxidant in the catalytic cycle was inferred fromndirect evidence [16,17] and high-level computational studies18–22] for a long time. Until recently, therefore, there was con-iderable discussion in the literature regarding the active oxidantn CYP 450 enzymes, where some site-directed mutation studieseemed to implicate the ferric-hydroperoxo species as active oxi-ant [23]. A series of computational and experimental biomimetictudies, however, contradicted this conclusion and reasoned thatpd I is a superior oxidant over the ferric-hydroperoxo species at

east in heme enzymes and iron porphyrin models [24–27]. In CYP50 enzymes, the second reduction step is rate-determining andioxygen-bound intermediates are short-lived (see Fig. 1). As a con-equence, biochemical studies into the mechanism and reactivityf Cpd I have been hampered by its short lifetime, and research has

een redirected to biomimetic model complexes instead.

A mononuclear FeIV O species is also believed to be theey oxidant of nonheme iron enzymes that activate dioxygent a mononuclear FeII site. These enzymes carry out substrate

FeIII

S

H2O

Cys

FeIII

SCysH2O

e–

FeIV

S

O

Cys

+.H

H2O

H2O

R-H

R-H

R-HR-OH

A

B

F

Fig. 1. Proposed catalytic cycle of

stry Reviews 257 (2013) 381– 393

hydroxylation, halogenation, and other reactions involving C Hbond activation for a variety of purposes, including biosyn-thetic functions, DNA repair, and cellular oxygen sensing. Manyof these enzymes, including several ˛-ketoglutarate- (˛KG)and pterin-dependent oxygenases for which such a high-valentFe intermediate has been trapped in recent years, contain a2His/1carboxylate ligand motif that links the metal to the protein.The catalytic cycle of one representative enzyme, taurine:˛-ketoglutarate dioxygenase (TauD) [7,28–34], is shown in Fig. 2 andstarts from a resting state where the three remaining Fe coordina-tion sites are occupied by water molecules, and upon co-substratebinding, namely �KG, two water molecules are replaced and thethird water molecule is released when substrate (taurine) entersthe binding site (Fig. 2A′). Subsequently, molecular oxygen bindsthe metal in the ferric-superoxo form (Fig. 2B′), which is an elusiveintermediate that has been proposed by computational modeling toattack the �-keto position of �KG to form a bicyclic ring-structure(Fig. 2C′) [35,36]. Decarboxylation then leads to a high-valentiron(IV)-oxo species with succinate bound (Fig. 2D′), which reactswith substrate via hydrogen atom (H-atom) abstraction from thesubstrate to give a ferric-hydroxo complex (Fig. 2E′). Rebound of thehydroxyl group finally leads to the alcohol product (Fig. 2F′). Theiron(IV)-oxo species, in contrast to Cpd I of the CYP 450s, appearsto have a lifetime that is long enough to enable spectroscopic char-acterization, and work by Hausinger, Krebs, and Bollinger providedcompelling evidence of its spectroscopic and catalytic properties[37–39]. In particular, D′ was characterized by spectroscopic tech-niques as a high-spin FeIV O species, and its kinetics were followedspectroscopically. Further studies with deuterated substrate gaveevidence of an elevated kinetic isotope effect for the reaction andimplicated a rate determining H-atom abstraction reaction in theprocess. To gain further insights into nonheme iron(IV)-oxo species,a range of biomimetic model complexes was studied and character-ized, which revealed considerable differences in activity betweennonheme iron and heme complexes.

One of the first biomimetic model systems where an iron(IV)-oxo species was trapped and characterized structurally was amononuclear nonheme iron(IV)-oxo complex of the tetraaza-macrocyclic TMC ligand (TMC, 1,4,8,11-tetramethyl-1,4,8,11-tetraazacyclotetradecane) [40]. This iron complex has since beenintensely studied, and valuable insights into its physical properties,

axial ligand influences, and reactivities with substrates have beengained from this work. Furthermore, reactivity studies of several[FeIV(O)(TMC)(X)]n+ complexes (X = a neutral or anionic ligand),[FeIII(O2)(TMC)]+, and [FeIII(O2H)(TMC)]2+ have unveiled consid-

FeIII

S

O2–

Cys

FeII

SCys

O2

FeIII

S

O

Cys

O H+

R-H

R-H

R-He–, H +

C

D

E

cytochrome P450 enzymes.

S.P. de Visser et al. / Coordination Chemistry Reviews 257 (2013) 381– 393 383

α-KGtaur ine

FeII

His

OHisOAsp R

NH3+

-O3S+O2

FeIII

His

OHisOAsp R

NH3+

-O3S O

FeIV

His

OHisOAsp R

NH3+

-O3S O

O O O

O

FeIVHis

Asp

NH3+

-O3S O

O R

O

FeIII

is

HisAsp

NH3+

-O3S OH

O R

O

FeIIHis

Asp

NH3+

-O3S

O R

O

OH

produ cts CO2

'C'B'A

O

f tauri

ecuoc

2l

ttteAmr

2i

a((i

[

Swr1abF[ira

lar dichroism (VT MCD) spectroscopic studies. From group theory,five d–d ligand-field transitions are expected for an axially distortedS = 1 FeIV O complex (C4v, d4; Fig. 4). Three bands were observed

HHis E'F'

Fig. 2. Proposed catalytic cycle o

rable differences with respect to analogous intermediates in theatalytic cycle of CYP 450 enzymes. In this review, we will give anp-to-date overview of experimental and computational studiesf [FeIV(O)(TMC)(X)]n+, [FeIII(O2)(TMC)]+, and [FeIII(O2H)(TMC)]2+

omplexes and their comparison to CYP 450 intermediates.

. Iron(IV)-oxo complexes of TMC and related macrocyclicigands

Among the Fe Ox intermediates supported by the TMC ligand,he iron(IV)-oxo complex [FeIV(O)(TMC)(NCCH3)]2+ was the firsto be identified and isolated. Extensive spectroscopic and struc-ural studies of this complex provided detailed insights into itslectronic structure and the intrinsic properties of the FeIV O unit.lso described in this section are iron(IV)-oxo complexes of otheracrocyclic ligands that are closely related to TMC and complexes

esulting from axial ligand substitution.

.1. Synthesis and characterization of mononuclear nonhemeron(IV)-oxo complexes

The [FeIV(O)(TMC)(NCCH3)]2+ complex was first prepared incetonitrile solution by oxygen atom transfer from iodosylbenzenePhIO) to the corresponding iron(II) complex, [FeII(TMC)(NCCH3)]2+

Eq. (1)). It was readily identified as a new intermediate by a bandn the near-IR region of its absorption spectrum (�max = 824 nm).

FeII(TMC)(NCCH3)]2+ + PhIO −→

CH3CN[FeIV(O)(TMC)(NCCH3)]

2+ + PhI

(1)

ingle crystals of the triflate salt of this highly oxidized complexere obtained at −40 ◦C, and its structure was established by X-

ay crystallography (Fig. 3a), which revealed an Fe O distance of.646(3) A [40]. This very short distance is consistent with strong �nd � bonding between the Fe center and the O atom and a formal

ond order of 2 (Fig. 3b). Notably, it is significantly shorter than thee O distances in diiron(III) complexes with bridging oxo ligands41,42]. The crystal structure also showed that the FeIV O groups sterically shielded by the macrocyclic TMC ligand, providing aationale for the remarkable stability of this compound (t1/2 ≈ 10 ht 25 ◦C) [43].

HisD'

ne:˛-ketoglutarate dioxygenase.

The complex was further characterized by peaks in itselectrospray ionization mass spectrum (ESI MS) attributableto [FeIV(O)(TMC)(NCCH3)]2+ and [FeIV(O)(TMC)(OTf)]+

(OTf− = CF3SO3−), by a 57Fe Mössbauer quadrupole doublet

having a low isomer shift (ı) of 0.17 mm s−1, and by an FeO stretch-ing vibration (�FeO) at 835 cm−1. The value for �FeO represents theaverage of data obtained by three different vibrational techniques(i.e., 834 cm−1 by IR, 839 cm−1 by resonance Raman (rRaman), and831 cm−1 by nuclear resonance vibrational spectroscopy (NRVS)),which exhibit 18O-isotope shifts of ca. 35 cm−1 as expected fora diatomic �FeO mode. In addition, NRVS-active FeNeq and FeNax

stretching and OFeNax bending modes were identified in the rangeof ca. 300–650 cm−1 [44].

To shed some light on the origin of the unique near-IRabsorption band of [FeIV(O)(TMC)(NCCH3)]2+, Decker and Solomon[45–47] carried out detailed variable-temperature magnetic circu-

Fig. 3. Molecular structures of iron(IV)-oxo complexes of the TMC ligand.(a) Crystallographically determined structure and (b) schematic drawing of[FeIV(O)(TMC)(NCCH3)]2+ and (c) crystallographically determined structure of aSc3+-bound FeIV(O)(TMC) complex, [(TMC)FeIV(�-O)Sc(OH)(OTf)4]. Hydrogen atomshave been omitted. Carbon, gray; nitrogen, blue; oxygen, red; iron, scarlet; scan-dium, orange; sulfur, yellow; fluorine, green.

384 S.P. de Visser et al. / Coordination Chemistry Reviews 257 (2013) 381– 393

dz2

dx2–y2

dxz/dyzdxy

Ene

rgy

Band VBand I

Band IVBand II IBand II

dz2

dx2–y2

dxz/dyzdxy

Ene

rgy

Band VBand I

Band IVBand II IBand II

Fig. 4. Ligand-field splitting diagram and spin- and electric-dipole-allowed d–dtc

iaItbpa(btissditc

scstTa[awhtgc(t[e1t

F[

NN

NNR

R

R

R

TMC, R = MeTBC, R = Bn

TAPH, R = HTAPM, R = Me

N N

NN

RR

RR

NN

NNH

H

H

cycla m-acHCO2H

NN

NN

TMCSH, R = CH2SHR

ransitions for an S = 1 FeIV O complex (C4v) with assignments of the spectroscopi-ally observed bands.

n the low-energy region of the MCD spectra (<16 000 cm−1) andssigned to the following three transitions: 3dxy → 3dx2−y2 (band), 3dxy → 3dxz/yz (band II), and 3dxz/yz → 3dx2−y2 (band III), wherehe z axis is defined by the Fe O bond. In support of this assignment,and II displays a fine structure that could be attributed to a vibronicrogression in the FeO stretching mode, because the excitation ofn electron from a nonbonding orbital (3dxy) into Fe O �* orbitals3dxz/yz) causes a weakening of the Fe O � bond. Two additionalands associated with 3dxz/yz → 3dz2 (band IV) and 3dxy → 3dz2

ransitions (band V) were found at higher energies. By correlat-ng the energies of the bands observed in the MCD and absorptionpectra, the broad feature in the near-IR region of the absorptionpectrum was revealed to be a composite of the three low-energy–d transitions (bands I, II, and III), with band III being the most

ntense (Fig. 5). On the basis of this analysis, the near-IR absorp-ion band can be viewed as a fingerprint signature of S = 1 FeIV Oomplexes.

Several other macrocyclic ligands related to TMC wereuccessfully used for the generation of mononuclear FeIV Oomplexes, including tetradentate ligands with differentubstituents and ring sizes (e.g., 14-membered TBC (1,4,8,11-etrabenzyl-1,4,8,11-tetraazacyclotetradecane), 15-memberedAPM (1,4,8,12-tetramethyl-1,4,8,12-tetraazacyclopentadecane),nd 15-membered TAPH (1,4,8,12-tetraazacyclopentadecane)48,49]) as well as pentadentate ligands with neutral andnionic donor groups (Chart 1; Table 1). One early example,hich actually pre-dates all of the other complexes reviewedere, is the [FeIV(O)(cyclam-ac)]+ (cyclam-acH = 1,4,8,11-etraazacyclotetradecane-1-acetic acid) complex from Wieghardt’sroup [50] having a carboxylate group appended to theyclam scaffold. Noteworthy are also [FeIV(O)(TMC-py)]2+

TMC-py = 4,8,11-trimethyl-1-(2-pyridylmethyl)-1,4,8,11-etraazacyclotetradecane) reported by Banse and coworkers51], which represents another crystallographically characterized

xample, and [FeIV(O)(TMCS)]+ (TMCSH = 4,8,11-trimethyl-,4,8,11-tetraazacyclotetradecane-1-ethanethiol) with a pendanthiolate donor (see Section 2.4.2) [52,53].

0

200

400

1000800600400Wavelength (nm)

Ext

inct

ion

Coe

ffici

ent

(M–1

cm–1

)

Band s I, II & II I

Band IV

Band V

ig. 5. Electronic absorption spectra of [FeIV(O)(TMC)(NCCH3)]2+ (black) andFeIV(O)(TMC){OC(O)CF3}]+ (red) in CH3CN.

TMC-py, R = C5H4N

Chart 1. Structures of TMC and related macrocyclic ligands.

While PhIO has often been the oxidant of choice for the prepa-ration of iron(IV)-oxo complexes, H2O2 [40,54], O3 [50], andperoxycarboxylic acids [53,55] have also been employed. How-ever, H2O2 may have limited utility, because it also can functionas a reductant toward nonheme iron(IV)-oxo complexes as wasshown very recently [56]. The biologically relevant oxidant (i.e.,O2) has now increasingly been used to access iron(IV)-oxo com-plexes. In one case, [FeII(TMC)(NCCH3)]2+ was found to react withO2 in the presence of alcohols or ethers, where the FeII com-plex has lower redox potentials than in acetonitrile only [57].The complex-to-dioxygen stoichiometry of 2:1 was suggestive ofa dinuclear O2 activation pathway proceeding through a (�-1,2-peroxo)diiron(III) species and subsequent homolytic O–O bondcleavage to afford two equivalents of the iron(IV)-oxo complex.Alternatively, [FeII(TMC)(NCCH3)]2+ could react with O2 in acetoni-trile to give [FeIV(O)(TMC)(NCCH3)]2+ when both a reductant, suchas BPh4

− [51] and NADH (dihydronicotinamide adenine dinucle-otide) analogues (e.g., BNAH (1-benzyl-1,4-dihydronicotinamide)and AcrH2 (10-methyl-9,10-dihydroacridine) derivatives) [58], andan acid, such as HClO4, were present. These results indicated thatboth an electron and a proton were required for O2 activation (Sec-tion 3). Interestingly, [FeIV(O)(TMC)(NCCH3)]2+ was also generatedfrom [FeII(TMC)(NCCH3)]2+ and O2 in the presence of substrateswith weak C H bonds, suggestive of the involvement of hydrogenatom transfer from the substrate to an iron–oxygen species (Section3) [59].

Relevant properties of the iron(IV)-oxo complexes reviewedhere, including the [FeIV(O)(TMC)(X)]+ complexes (Section 2.2),are summarized in Table 1. They generally exhibit (i) charac-teristic low-intensity bands in the near-IR region with absorp-tion maximum wavelengths ranging from 750 to 900 nm (ε,100–400 M−1 cm−1), (ii) FeO stretching vibrations in the rangeof 810–860 cm−1, and (iii) low 57Fe Mössbauer isomer shifts (ı)[60,61]. The large and positive zero-field splittings (D, 20–35 cm−1)are consistent with an S = 1 ground state [62,63]. Because the life-times of many of these complexes are too short to allow thegrowth of single crystals, their metal–ligand distances have beendetermined by Fe K-edge EXAFS (extended X-ray absorption finestructure) analysis, with Fe O distances falling in the range of1.64(2)–1.70(2) A. In the pre-edge region of the Fe K-edge X-rayabsorption spectra, the iron(IV)-oxo complexes display relativelyintense peaks associated with 1s → 3d transitions, whose energies

and intensities are sensitive to the oxidation state and coordina-tion geometry, respectively, of the Fe center. The peak energies(ca. 7114–7115 eV) usually are about 0.5–1 eV higher than those ofrelated FeIII complexes and about 1–1.5 eV higher than those of the

S.P. de

Visser

et al.

/ Coordination

Chemistry

Review

s 257 (2013) 381– 393

385

Table 1Properties of iron(IV)-oxo complexes of TMC and related macrocyclic ligands.a

Complex Fe O (Å)b Fe N/O (Å)b,c Epre-edge (eV)d XAS pre-edge aread �FeO (cm−1)e ��FeO (cm−1)e ı (mm s−1) �EQ (mm s−1) D (cm−1) �max (nm) Refs.

Neutral donor set, [FeIVOL5]2+

[FeO(TAPH)(NCCH3)]2+ 841 35 750 [49][FeO(TMC)(NCCH3)]2+ 1.646 2.091cis

2.058trans7114.1 26 835f 35f 0.17 1.24 26.95g 824 [40]

[FeO(TMC)(NCCH3)]2+ h 1.64 2.08 0.14 0.78 27.5 806, 1026 [70][FeO(TMC-py)]2+ 1.667 2.083cis

2.118trans826 34 0.18 1.08 29 834 [51]

Metal-ion bound, [L4FeIV(�-O)MIIIX5][(TMC)Fe(�-O)Sc(OH)(OTf)4]h 1.754 2.175cis [66]Monoanionic donor set, trans-[FeIVOL4X]+

[FeO(TMC){OC(O)CF3}]+ 1.64 2.08 7114.2 31 854 37 0.20 1.39 31 836, 940, 990 [43,73][FeO(TMC)(NCO)]+ 1.67 2.07 7114.7 26 822 30 0.16 0.42 31 350, 845, 1010 [73][FeO(TMC)(NCS)]+ 1.65 2.07 7114.3 24 820 34 0.16 0.60 30 387, 850, 1010 [72,73][FeO(TMC)(NCS)]+ h 0.14 0.61 31 415, 812, 1015 [70][FeO(TMC)(N3)]+ 1.66 2.08 7114.4 24 814 34 0.17 0.70 29 407, 850, 1050 [72,73][FeO(TMC)(CN)]+ 1.66 2.08 7114.1 21 823 34 0.15 0.25 31 858 [73][FeO(TMC)(OH)]+ i 1.68 2.10 7115.1 20 0.15 0.16 31 830, 1060 [73][FeO(cyclam-ac)]+ 0.01 1.37 23 676 [50][FeO(TMCS)]+ j 1.70 2.09 7114.3 18 0.19 –0.22 35 460, 570, 860 [52,53][FeO(TMCSO2)]+ 1.64 2.06 7114.1 25 831 0.19 1.28 330, 830, 990 [53]

a Structures of ligands are shown in Chart 1.b Distances from EXAFS are given with three significant figures and distances from X-ray crystallography with four significant figures.c For crystallographically determined Fe N distances, the position of the N atom with respect to the oxo ligand is indicated (cis or trans); average values are given for equatorial Fe N distances.d Fe K-edge XAS pre-edge peak energies, Epre-edge (referenced to an Fe foil calibration point of 7112.0 eV), and intensities (observed peak areas).e From resonance Raman spectroscopy, unless noted otherwise; 18O-isotope shifts, ��FeO = �(Fe16O) − �(Fe18O).f Average from IR, resonance Raman, and NRV spectroscopy [40,44,73].g From EPR spectroscopy [63].h Isomer where oxo ligand is oriented syn with the four TMC N-methyl substituents.i Fe OH = 1.94 A.j Fe S = 2.33 A.

3 Chemistry Reviews 257 (2013) 381– 393

csco

sooOct(fwtt[gds

2

tfpwpb[

rls[sitvdtbb[Mi(giFpatac

t[i�oisw

O

C H

C OH

RR

OH

P

P-O NN

NH3C

+ HCHOH

N-dea lkylat ionP-oxidati on

S-oxidati on

Aliphat ic hydroxylati on

Alkene epoxida tion

Aromatic hydroxylation Alkylaromat ic oxidati on

C OHH

C O

Alcoh ol oxid atio n

S

SO

N

NFe

N

N

X

86 S.P. de Visser et al. / Coordination

orresponding FeII complexes [64,65]. The increased peak inten-ities (ca. 20–30 area units) are a consequence of the strong andovalent Fe O bonding interaction, which results in axial distortionf the Fe coordination geometry and 3dz2 –4pz mixing.

The structure and reactivity of one FeIV O complex was sub-tantially altered by coordination to a strong Lewis acid. Reactionf [FeIV(O)(TMC)(NCCH3)]2+ with Sc(OTf)3 led to the isolationf the metal-ion bound iron(IV)-oxo complex [(TMC)FeIV(�-)Sc(OH)(OTf)4] [66]. The crystal structure revealed that the Feenter is five-coordinate and the oxo ligand occupies the coordina-ion site syn with the four N-methyl substituents of the TMC ligandFig. 3c). The Fe O distance is with 1.754 A significantly longer thanor the other two crystallographically characterized complexes,hich was attributed to a weakening of the Fe O bond due to

he coordination of the Lewis-acidic ScIII center. Although this dis-ance would also be consistent with an oxo-bridged FeIII complex41,42], it is still shorter than the 1.82 A distance of the FeIV OHroup reported for the protonated compounds II of chloroperoxi-ase [67,68] and cytochrome P450 119 [69]. Another example of ayn isomer was characterized spectroscopically [70].

.2. Trans-Influences in [FeIV(O)(TMC)(X)]n+ complexes

Systematic investigations of the influence of anionic ligands onhe spectroscopic properties of FeIV O complexes were reportedor two series of complexes, [FeIV(O)(TPA)(X)]+ (TPA = tris(2-yridylmethyl)amine) [71] and [FeIV(O)(TMC)(X)]+ [43,72,73],here the X ligand is coordinated to the FeIV center in cis or transosition relative to the oxo ligand. These complexes were accessedy exchange of the neutral solvent ligands in the parent complexes,FeIV(O)(TPA)(NCCH3)]2+ and [FeIV(O)(TMC)(NCCH3)]2+.

For the [FeIV(O)(TPA)(X)]n+ complexes with different equato-ial ligands, the ligand-field band in the near-IR region shifts toower energies (�max = 724–800 nm) with decreasing ligand-fieldtrength of the X ligand according to the spectrochemical series71]. On the other hand, the spectral changes caused by axial ligandubstitution in [FeIV(O)(TMC)(NCCH3)]2+ are more complex as theynvolve not only an energy shift but also a redistribution of absorp-ion intensities (Fig. 5). Thus, [FeIV(O)(TMC)(X)]+ complexes witharious carboxylate (X− = CF3CO2

− and CH3CO2− [43,74]) and pseu-

ohalide ligands (X− = NCO−, NCS−, N3−, CN−, and OH− [70,72,73])

rans to the oxo ligand exhibit �max values of 800–860 nm androader absorption envelopes with additional peaks that extendeyond 1000 cm−1 (Table 1). For [FeIV(O)(TMC)(NCCH3)]2+ andFeIV(O)(TMC){OC(O)CF3}]+, the perturbations were analyzed by

CD spectroscopy and attributed to variations in energies andntensities of two of the five d–d transitions, i.e., 3dxy → 3dxz/yzband II) and 3dxz/yz → 3dx2−y2 (band III), which in turn sug-est that the 3dxz/yz orbitals are destabilized by Fe OC(O)CF3 �nteractions [46]. Aside from the pronounced modulation of theeIV O near-IR signature, some of the [FeIV(O)(TMC)(X)]+ com-lexes (X− = NCO−, NCS− and N3

−) as well as [FeIV(O)(TMCS)]+

nd [FeIV(O)(TMCSO2)]+ (TMCSO2H = 4,8,11-trimethyl-1,4,8,11-etraazacyclotetradecane-1-ethanesulfinic acid) possess distinctbsorption peaks in the UV–vis region that are associated withharge transfer transitions [53,72,73].

In contrast to the electronic modulation, the Fe O dis-ance was rather insensitive to the identity of the trans ligandd(Fe O) = 1.64–1.68 A for [FeIV(O)(TMC)(X)]n+]. The FeO stretch-ng mode proved to be a more sensitive reporter. The values ofFeO span a range of 40 cm−1 and decrease with increasing basicity

f the axial ligand (CF3CO2

− < CH3CN < CN− ≈ NCO− ≈ NCS− < N3−),

ndicating that a stronger trans donor weakens the Fe O bond. Aimilar relationship between �FeO and donor strength of axial ligandas reported for iron(IV)-oxo porphyrin complexes [75–77]. The

Fig. 6. Oxidation reactions mediated by [FeIV(O)(TMC)(X)]n+ and related nonhemeiron(IV)-oxo complexes.

changes in the �FeO value could also be used to estimate changesin the Fe O distance. Green [78] had previously demonstrated thatBadger’s rule, an empirical relationship between bond length (re)and stretching frequency (�e), can be applied to the Fe O bonds ofheme and nonheme iron complexes (Eq. (2), where Cij and dij referto theoretically derived constants). Based on this relationship, the40 cm−1 range found for �FeO in [FeIV(O)(TMC)(X)]n+ complexes iscorrelated with a distance range of 0.02 A, which is in agreementwith the distances experimentally observed by X-ray crystallogra-phy and EXAFS analysis [73].

re = Cij

(�e)2/3+ dij (2)

The 57Fe Mössbauer isomer shifts and XAS (X-ray absorptionspectroscopy) pre-edge peak energies of the [FeIV(O)(TMC)(X)]n+

complexes remain fairly constant and substantiate the FeIV oxi-dation state assignment. But the quadrupole splittings (�EQ) andXAS pre-edge peak areas vary with the X ligand, presumably dueto varying extent of axial distortion [73].

2.3. Reactivities of [FeIV(O)(TMC)(X)]n+ complexes

Since [FeIV(O)(TMC)(NCCH3)]2+ was the first synthetic iron(IV)-oxo species to be stabilized and characterized, it led to a variety ofreactivity studies with different substrates. Summarized in Fig. 6are chemical reactions investigated with [FeIV(O)(TMC)(X)]n+ com-plexes. Initially, the oxidation of PPh3 by [FeIV(O)(TMC)(NCCH3)]2+

was studied [40], because it is a facile reaction requiring a smallactivation energy. Subsequent studies utilized thioanisole, and itssulfoxidation by the iron(IV)-oxo complex [26,72,79,80] was inves-tigated giving evidence of a direct oxygen atom transfer mechanismin line with what was proposed for CYP 450 enzymes [81,82].Using a selection of para-substituted sulfides, reactivity trendswere determined and the measured rate constants were plottedas a function of the Hammett parameters, which gave Hammett �values between −1.4 and −2.5 [26,80]. These highly negative Ham-mett � values implicate electrophilic character of the Fe O group,as concluded before for sulfoxidation reactions by other metal-oxospecies [83–85].

Many studies addressed the enzymatically relevant and

mechanistically important reaction of aliphatic C H abstrac-tion by nonheme iron(IV)-oxo complexes. Typical substratesused in the reactions include alkylaromatic compounds withweak C H bonds, such as xanthene (BDEC H = 75.5 kcal mol−1),

S.P. de Visser et al. / Coordination Chemistry Reviews 257 (2013) 381– 393 387

N

NFe

N

N

XIV 16 n+

N

NFe

N

N

XIV 18 n+

H218O H2

16O16O 18O

91(ocev[rlsBt>irtm[[

[oiabNtcti[bwf[apam�a

dm1

tdtefiegaa

[Fe ( O)(TMC)(X)] [Fe ( O)(TMC)(X)]

Scheme 1.

,10-dihydroanthracene (DHA, BDEC H = 77 kcal mol−1),,4-cyclohexadiene (BDEC H = 78 kcal mol−1), and fluoreneBDEC H = 80 kcal mol−1) [86–88]. Due to the relatively lowxidizing power of many biomimetic nonheme iron(IV)-oxoomplexes, these alkylaromatic compounds turned out to bexcellent substrates for mechanistic studies on C H bond acti-ation reactions [83,89–91]. Studies on the axial ligand effect ofFeIV(O)(TMC)(X)]n+ in C H abstraction and oxygen atom transfereactions highlighted the fact that electron-donating anionicigands enhance the H-atom abstraction ability of the iron-oxopecies [92]. A plot of the second-order rate constants against theDEC H values of the substrates gave a linear correlation. Moreover,he reactions proceeded with a high kinetic isotope effect (KIE) of10 for hydrogen atom abstraction from xanthene and DHA. Thedentity of the axial ligand in [FeIV(O)(TMC)(X)]n+ also affectededuction potentials and reorganization energies in electronransfer processes, as different reduction potentials were deter-

ined for [FeIV(O)(TMC)(NCCH3)]2+ (Ered = 0.39 V and � = 2.37 eV),FeIV(O)(TMC){OC(O)CF3}]+ (Ered = 0.13 V and � = 2.12 eV), andFeIV(O)(TMC)(N3)]+ (Ered = –0.05 V and � = 1.97 eV) [93].

As shown in Fig. 6, nonheme iron(IV)-oxo complexes, includingFeIV(O)(TMC)(X)]n+, mediate alcohol oxidation, N-dealkylation,lefin oxidation, and aromatic hydroxylation reactions. Theron(IV)-oxo complexes activate alcohols exclusively by H-atombstraction from the �-CH bonds of the alcohols, and the C Hond cleavage is the rate-determining step [94,95]. The oxidative-dealkylation reaction was proposed to occur via an electron

ransfer-proton transfer (ET-PT) mechanism [96,97] that pro-eeds with an initial electron transfer followed by a protonransfer to give an overall hydrogen atom abstraction. Althought has been shown that the nonheme iron(IV)-oxo complexes,FeIV(O)(TPA)(NCCH3)]2+ and [FeIV(O)(Bn-TPEN)]2+ (Bn-TPEN = N-enzyl-N,N′,N′-tris(2-pyridylmethyl)ethane-1,2-diamine), reactith olefins to give the corresponding epoxide products (e.g., the

ormation of cyclooctene oxide in the oxidation of cyclooctene)49,55,98], the mechanism of the reaction remains elusive. Inromatic hydroxylation reactions, Nam and co-workers have pro-osed that the aromatic ring oxidation by [FeIV(O)(TPA)(NCCH3)]2+

nd [FeIV(O)(Bn-TPEN)]2+ does not occur via a H-atom abstractionechanism but involves an initial electrophilic attack on the-system of the aromatic ring to produce a tetrahedral radical or

cationic �-complex [99,100].The [FeIV(O)(TMC)(NCCH3)]2+ complex was also used in eluci-

ating the mechanism of oxygen exchange between high-valentetal-oxo species and labeled water (Scheme 1) [101], because

8O-labeled water experiments have frequently been carried outo obtain indirect insight into the nature of the reactive interme-iates involved in catalytic oxygenation reactions [102–105]. Inhis study, direct evidence that nonheme iron(IV)-oxo complexesxchange their oxygen atom with H2

18O was obtained for therst time by monitoring changes of the iron(IV)-oxo species by

lectrospray ionization mass spectrometry. The degree of the oxy-en exchange depended markedly on the concentration of H2

18Ond the reaction temperature but not on the presence of a transxial ligand. Thus, a mechanism for the oxygen-atom exchange in

Fig. 7. Molecular orbitals of [FeIV(O)(TMC)(Cl)]+.

nonheme iron(IV)-oxo models was proposed that does not pro-ceed via the trans oxo-hydroxo tautomerism pathway proposed forhigh-valent metal-oxo porphyrins [106] but by a variant involvinga cis-dihydroxoiron(IV) transition state.

2.4. DFT calculations on iron(IV)-oxo complexes

2.4.1. [FeIV(O)(TMC)(X)]n+ complexesTo understand the reactivity patterns of the [FeIV(O)(TMC)(X)]n+

complexes and in particular the effect of the axial ligand on the reac-tion rates and mechanisms, a series of detailed density functionaltheory (DFT) calculations were done and established two-state-reactivity type mechanisms [107–109]. High-lying occupied andlow-lying virtual orbitals of [FeIV(O)(TMC)(Cl)]+ are shown in Fig. 7.The lowest metal 3d orbital is the �*xy orbital that is located in theplane of the nitrogen atoms of the TMC ring and is nonbonding anddoubly occupied. Slightly higher in energy are a pair of degener-ate �*FeO orbitals for the antibonding interactions of 3dxz/yz on ironwith 2px/y on the oxygen atom. With a halide as an axial ligand,these two orbitals also mix with 3px/y atomic orbitals on the halide,which is absent with neutral ligands such as acetonitrile. Higherlying and virtual are the �∗

z2 orbital for the antibonding interactionsalong the Fe O bond and the �∗

x2−y2 orbital for the antibonding

interaction of the metal with the nitrogen atoms of the TMC group.Experimental studies characterized all [FeIV(O)(TMC)(X)]n+ inter-mediates irrespective of the axial ligand as triplet spin states with�∗2

xy�∗1xz �∗1

yz orbital occupation. Higher in energy is a quintet spin

state with �∗2xy�∗1

xz �∗1yz �∗1

x2−y2 configuration, which is the ground

state in enzymatic nonheme iron(IV)-oxo complexes [110]. DFT cal-culations generally give the triplet and quintet spin state close inenergy and environmental perturbations and/or solvent effect canchange their ordering and relative energies slightly.

Subsequently, the H-atom abstraction ability of the[FeIV(O)(TMC)(X)]n+ complexes was calculated with DFT methodsusing a range of model substrates [107–109], and Fig. 8 displaysthe aliphatic hydroxylation mechanism of the benzyl position ofethylbenzene by [FeIV(O)(TMC)(X)]n+ (X = NCCH3 or Cl−) with datataken from ref 109. The reaction starts from a reactant complex(R) between iron(IV)-oxo species and substrate and proceeds

with a H-atom abstraction via a transition state (TSHA) leadingto an iron(III)-hydroxo with a nearby radical (A). Rebound of thehydroxo group to the ethylbenzene radical restgroup is barrierlessand leads to alcohol products (PA). The overall exothermicity

388 S.P. de Visser et al. / Coordination Chemistry Reviews 257 (2013) 381– 393

F thylbek ngths

i

itwttttcToarNft

Hoiti

Frw

ig. 8. Free energy profile for aliphatic hydroxylation of the benzyl position in ecal mol−1 relative to a reactant complex in the quintet spin state, whereas bond len wavenumbers.

s large for the oxidant with X = NCCH3 but considerably lesshan that for X = Cl−. This affects the complete reaction pathway,hereby all barriers and intermediates are lower in energy for

he reaction starting with [FeIV(O)(TMC)(NCCH3)]2+ as comparedo those starting with [FeIV(O)(TMC)(Cl)]+. Note that although theriplet spin reactants are the ground state, actually the mechanismakes place on the quintet spin state, which implies a spin staterossing from triplet to quintet prior to the H-atom abstraction.hus, in the triplet spin state the electron transfer fills a �*rbital with a second electron, whereas in the quintet spin state

complete exchange stabilized metal 3d-system is formed thatesults in favorable high-spin over intermediate-spin reactivity.evertheless, the DFT calculations confirm the conclusions derived

rom experiment that [FeIV(O)(TMC)(NCCH3)]2+ is a better oxidanthan [FeIV(O)(TMC)(Cl)]+ in H-atom abstraction reactions.

Optimized geometries are typical for structures calculated for-abstraction barriers for a range of substrates and iron(IV)-

xo oxidants [111–119] and show that the substrate attacks theron(IV)-oxo group from the top. This follows from the electronransfer processes, whereby an electron is shuttled from substratento the �∗

z2 orbital along the Fe O bond [120]. The imaginary

ig. 9. Free energy profile for aromatic hydroxylation of the para-position of ethylbenzene

elative to a reactant complex in the quintet spin state, whereas bond lengths are in

avenumbers.

nzene by [FeIV(O)(TMC)(NCCH3)]2+ and [FeIV(O)(TMC)(Cl)]+. Free energies are inare in angstroms, angles in degrees and the imaginary mode in the transition state

frequencies in the transition state are large (>i900 cm−1), whichimplicates that the reaction will proceed with a considerablekinetic isotope effect and tunneling [114,115,121]. Despite thefact that both rate determining transition states 5TSHA,NCCH3

and5TSHA,Cl refer to a H-atom abstraction barrier with significant radi-cal character on the substrate, the intermediates show considerabledifferences in electron occupation. Thus, 5ACl is a radical intermedi-ate with �∗1

xy �∗1xz �∗1

yz ∗1

x2−y2 ∗1

z2 �1sub configuration with an S = 2 on the

metal antiferromagnetically coupled to a substrate radical. On theother hand, 5ANCCH3 represents a cationic intermediate that is theresult of a formal hydride transfer from substrate to oxo group with�∗2

xy �∗1xz �∗1

yz ∗1

x2−y2 ∗1

z2 �0sub configuration. Note that the second elec-

tron transfer that is part of the hydride transfer is only transferredafter the transition state and en route to the intermediate.

Another process studied in detail relates to the aromatic hydrox-ylation of arenes by [FeIV(O)(TMC)(X)]n+ complexes. An example

of two calculated energy profiles of ethylbenzene hydroxylationby [FeIV(O)(TMC)(NCCH3)]2+ and [FeIV(O)(TMC)(Cl)]+ are shown inFig. 9. The mechanisms are the same irrespective of the axial lig-and and follow a mechanism devised for Cpd I of CYP 450 [100,122]

by [FeIV(O)(TMC)(NCCH3)]2+ and [FeIV(O)(TMC)(Cl)]+. Free energies are in kcal mol−1

angstroms, angles in degrees and the imaginary mode in the transition state in

Chemistry Reviews 257 (2013) 381– 393 389

wsotpaTsak

[trdeilsfveaqhlot

[atsiastr

2[

olChStNswdtaditloue

tmls

[FeII(TMC )(NCCH3)]2+ + O2

[FeIII(O2)(TMC)]2+ [FeIII(O2H)(TMC )]2+

e–, H+

R-H R

AB

iron(III )-sup eroxo iron (III)-hydr ope rox o

C

S.P. de Visser et al. / Coordination

ith an electrophilic addition leading to a �-complex (B) via a tran-ition state TSarom. Thereafter, the ipso-proton is reshuttled to onef the nitrogen atoms of the TMC ring to form a phenolate boundo iron(III) with a protonated TMC ligand. Rebound of the proton tohenolate gives phenol products (PB). The latter steps proceed fastnd with virtually no barrier heights, so that the initial barrier viaSarom is rate determining. The imaginary frequencies in the tran-ition states are considerably lower than those found for hydrogentom abstraction reactions and lead to almost no or slightly inverseinetic isotope effects.

Although the mechanistic features of the reactions starting withFeIV(O)(TMC)(NCCH3)]2+ and [FeIV(O)(TMC)(Cl)]+ are the same,here are considerable differences in electronic properties along theeaction mechanism. Thus, in analogy to the H-abstraction barriersiscussed above, the initial electrophilic addition leads to a singlelectron transfer from the arene to the metal and gives partial rad-cal character of the arene in the transition state. With Cl− as axialigand, this state relaxes to a radical intermediate (5BCl), whereas aecond electron transfer takes place en route from 5TSarom,NCCH3 toorm a cationic intermediate 5BNCCH3 . These differences in radicalersus cationic pathways were allocated to differences in orbitalnergy level of the �*xy orbital, which is higher in energy for RClnd thereby affects the electron affinity of the oxidant and conse-uently the electron transfer processes. Therefore, the axial ligandas a profound effect on the orbital energy levels and in particu-

ar the one involving metal 3d-interactions. It affects the spin staterdering and energies as well as the electron abstraction ability ofhe oxidant. As such, it has a dominant effect on reactivity patterns.

Further studies on the relative reactivities ofFeIV(O)(TMC)(X)]n+ complexes in H-atom abstraction and oxygentom transfer reactions found computational trends accordingo the electrophilicity of the oxidant [123]. At first glance, thesetudies seemed to contradict experiment; however, when blend-ng of rate constants for triplet and quintet states was taken intoccount, the correct trends were observed. This implies that fullpin equilibration occurs and that the spin orbit coupling betweenhe triplet and quintet spin states may affect rate constants andeactivity patterns.

.4.2. A complex of a thiolate-appended TMC ligand,FeIV(O)(TMCS)]+

Comparative studies by Dawson and co-workers [124] on per-xidase and CYP 450 enzymes highlighted differences in the axialigand bound to the heme, whereby the axial thiolate ligand in theYP 450 s was proposed to induce a ‘push-effect’, but the axialistidine ligand in peroxidases gives a ‘pull-effect’ of electrons.ince then many studies on iron porphyrins have tried to quan-ify the axial ligand effect [66,125–127]. In particular, Gross andimri [125] found a trans-influence of the axial ligand that affected

pectroscopic parameters including FeO stretching frequencies asell as a trans-effect on the rate constants of styrene epoxi-ation. Subsequently, Nam and co-workers have demonstratedhat iron(IV)-oxo porphyrin �-cation radicals, [FeIV(O)(Porp+•)(Cl)]nd [FeIV(O)(Porp+•)(NCCH3)]+, exhibit different reactivity patternsepending on the identity of the axial ligand, as shown, for example,

n the selectivity for cis- versus trans-olefins in olefin epoxidation,he oxidizing power in alkane C H bond activation, and the regiose-ectivity of aromatic ring versus aliphatic C H hydroxylation in thexidation of ethylbenzene [128–131]. These results demonstratenambiguously that iron(IV)-oxo porphyrin �-cation radicals canxhibit diverse reactivity patterns under different circumstances.

To understand the ligand binding in CYP 450 enzymes and

o mimic this in synthetic analogs, many attempts have been

ade to create biomimetic model complexes with axial thiolateigation. One of the first successfully characterized iron(IV)-oxopecies with axially ligated thiolate was the [FeIV(O)(TMCS)]+

[FeIV(O)(TMC) (NCC H3)]2+ + HO

Scheme 2.

complex [52]. Subsequently, this led to a series of exper-imental and computational studies into the reactivities of[FeIV(O)(TMCS)]+.

Computational modeling established the electronic propertiesof [FeIV(O)(TMCS)]+ and studied C H abstraction and double bondepoxidation with propene as a model substrate [120]. In contrastto the [FeIV(O)(TMC)(X)]n+ models described above, calculationson [FeIV(O)(TMCS)]+ identified it as a high-spin (quintet) groundstate slightly below the experimentally assigned triplet spin groundstate. Thus, the triplet-quintet energy gap is determined by therelative energies of the �*xy and �∗

x2−y2 molecular orbitals and

when the energy gap narrows the quintet spin state drops belowthe triplet in energy [123]. In particular, in five-coordinate com-plexes including the enzymatic nonheme iron(IV)-oxo species, the�∗

xy/�∗x2−y2 energy gap is small and a high-spin state is found as the

ground state. Another facet of this spin state ordering is the fact that[FeIV(O)(TMCS)]+ reacts via single-state-reactivity on a quintet spinstate surface only.

Thereafter, a comparative study on the regioselectivity ofaliphatic hydroxylation versus epoxidation by [FeIV(O)(TMCS)]+

and [FeIV(O)(Porp+•)(SH)] was performed. Gas-phase epoxidationbarriers were a few kcal mol−1 lower in energy than H-atomabstraction barriers from propene by [FeIV(O)(Porp+•)(SH)]. On theother hand, reactivity of propene with [FeIV(O)(TMCS)]+ gave domi-nant H-atom abstraction reaction instead. This was explained fromstereochemical interactions of hydrogen atoms of the TMCS ringwith the approaching substrate, whereby the substrate is closer inthe epoxidation transition states than in the H-atom abstractiontransition states.

3. Iron(III)-superoxo species, [FeIII(O2)(TMC)]2+

Dioxygen activation by a high-spin iron(II) complex in the pres-ence of electron and proton sources in CH3CN was reported by Namand co-workers [58]. In this reaction, [FeIV(O)(TMC)(NCCH3)]2+

was generated from [FeII(TMC)(NCCH3)]2+ and O2 in the presenceof NADH analogues, such as BNAH and AcrH2 derivatives, as anelectron source and HClO4 as a proton source in CH3CN. The mech-anism proposed for O2 activation is as follows: The reaction isinitiated by binding of O2 to the high-spin iron(II) complex, produc-ing an iron(III)-superoxo species. Subsequently, iron(III)-peroxoand iron(III)-hydroperoxo species are generated by consecutiveelectron- and proton-transfer reactions (Scheme 2, pathway A).Finally, homolytic O O bond cleavage affords the iron(IV)-oxospecies (Scheme 2, pathway C) [91]. It was also reported by Namand co-workers that [FeIV(O)(TMC)(NCCH3)]2+ could be generatedin the reaction of [FeII(TMC)(NCCH3)]2+ and O2 in the presenceof substrates with weak C H bonds (e.g., olefins, such as cyclo-hexene and cyclooctene, and alkylaromatic compounds, such as

xanthene and 9,10-dihydroanthracene) [59]. In this reaction, aniron(III)-superoxo intermediate was proposed as an active oxidantthat abstracts a H-atom from the substrate (Scheme 2, pathwayB). Especially, when the substrates were olefins (e.g., cyclohexene

3 Chemistry Reviews 257 (2013) 381– 393

aytfg(1k[cC[[

t[atmcTwei

tarprafhw[

4[

4i

btf[uisTuisccaTcwstais

Fig. 10. Molecular structures of iron–oxygen complexes of the TMC ligand. (a)Crystallographically determined structure of the ‘side-on’ iron(III)-peroxo complex,[FeIII(O2)(TMC)]+, and (b) DFT optimized structure of the ‘end-on’ iron(III)-hydroperoxo complex, [FeIII(O2H)(TMC)]2+. Hydrogen atoms have been omitted

90 S.P. de Visser et al. / Coordination

nd cyclooctene), [FeIV(O)(TMC)(NCCH3)]2+ was formed in a highield because of its low reactivity toward these olefins. Inhese reactions, the formation of [FeIV(O)(TMC)(NCCH3)]2+ wasaster with olefins having lower C H bond dissociation ener-ies [132]; the second-order rate constants for cyclohexeneBDE = 81 kcal mol−1) and cyclooctene (BDE = 85 kcal mol−1) were.2 M−1 s−1 and 2.9 × 10−1 M−1 s−1, respectively. Furthermore, ainetic isotope effect (KIE) value of 6.3(3) in the formation ofFeIV(O)(TMC)(NCCH3)]2+ was obtained using cyclohexene andyclohexene-d10 as substrates. These results indicated that the

H bond activation of the olefin by an iron(III)-superoxo species,FeIII(O2)(TMC)]2+, is the rate-determining step in the formation ofFeIV(O)(TMC)(NCCH3)]2+ (Scheme 2, pathway B) [59].

DFT calculations were performed on the H-atom abstrac-ion from cyclohexadiene by [FeIV(O)(TMC)(NCCH3)]2+ andFeIII(O2)(TMC)]2+ [133]. For [FeIV(O)(TMC)(NCCH3)]2+, H-bstraction barriers of 19.7 and 10.6 kcal mol−1 were found for theriplet and quintet spin states, respectively. In contrast to experi-

ental results, however, the barrier heights for H-abstraction fromyclohexadiene by [FeIII(O2)(TMC)]2+ are well higher in energy.his was explained by differences in spin-inversion-probability,hereby the iron(IV)-oxo intermediate stays on the more

ndothermic triplet spin state, whereas the iron(III)-superoxontermediate can relax to a more reactive spin state surface.

Apart from studies on iron(III)-superoxo intermediates, calcula-ions also were performed on iron(II)-superoxo, [FeII(O2)(TMC)]+,nd nickel(II)-superoxo, [NiII(O2)(TMC)]+, intermediates and theireactivities with substrates [134,135]. The iron(II)-superoxo com-lex was found to be a sluggish oxidant in aromatic hydroxylationeactions but capable of reacting with aliphatic C H substrates on

sextet spin state surface with low barriers [135]. Barrier heightsor analogous processes catalyzed by [NiII(O2)(TMC)]+ were evenigher and it was only found to be a suitable oxidant for substratesith weak C H bonds (e.g., xanthene or cyclohexadiene) and PPh3

134].

. Iron(III)-peroxo and -hydroperoxo complexes,FeIII(O2)(TMC)]+ and [FeIII(O2H)(TMC)]2+

.1. Synthesis, characterization, and interconversion ofron–oxygen intermediates

An iron(III)-peroxo complex, [FeIII(O2)(TMC)]+, was preparedy reacting the corresponding iron(II) complex with H2O2 inhe presence of base [91,136]. The blue intermediate persistedor several hours at 0 ◦C, and the greater thermal stability ofFeIII(O2)(TMC)]+ allowed for the isolation of crystals, which weresed for a structure determination and spectroscopic and reactiv-

ty studies. The electronic absorption spectrum of [FeIII(O2)(TMC)]+

hows a distinct absorption band at 750 nm (ε = 600 M−1 cm−1).he rRaman spectrum of the iron(III)-peroxo complex, obtainedpon 778-nm excitation in acetone-d6 at 77 K, exhibits two 18O-

sotope-sensitive bands at 825 and 487 cm−1. The X-ray crystaltructure of [FeIII(O2)(TMC)]ClO4 revealed a mononuclear ironomplex with a side-on bound O2

2− ligand. The iron center isoordinated in a distorted octahedral geometry arising from the tri-ngular FeOO moiety with a small bite angle of 45.03(17)◦ (Fig. 10a).he FeOO geometry is similar to that of the crystallographicallyharacterized 1:1 Fe/O2 adduct of naphthalene dioxygenase (NDO),here dioxygen binds side-on to the iron center in the active

ite (1.75 A resolution, rO O ≈ 1.45 A) [137]. Furthermore, the struc-

urally determined O O distance of 1.463(6) A and the rRaman datare indicative of peroxo character of the OO group [138–140]. Its worth noting that all four N-methyl groups point to the sameide of the FeN4 plane as the peroxo moiety, as observed in other

except for that of the hydroperoxo group. Carbon, gray; nitrogen, blue; oxygen, red;hydrogen, cyan; iron, scarlet.

metal(III)-peroxo complexes [141–143]. In the case of the Sc3+-bound iron(IV)-oxo complex, [(TMC)FeIV(�-O)Sc(OH)(OTf)4], theN-methyl groups are also syn with the oxo ligand (Fig. 3c) [66],whereas those in [FeIV(O)(TMC)(NCCH3)]2+ are anti to the oxo lig-and (Fig. 3a) [40]. In addition, no axial ligand binds to the Feion trans to the peroxo ligand in [FeIII(O2)(TMC)]+, which is sim-ilar to other metal(III)-peroxo complexes [141–143] as well asthe Sc3+-bound FeIV(O)(TMC) complex [66], but different from the[FeIV(O)(TMC)(NCCH3)]2+ complex [40].

Addition of a slight excess amount of HClO4 to a solution of[FeIII(O2)(TMC)]+ in acetone/CF3CH2OH (3:1) at −40 ◦C imme-diately produced a violet intermediate, [FeIII(O2H)(TMC)]2+

(Fig. 10b). Subsequently, this iron(III)-hydroperoxo specieswas converted to the corresponding iron(IV)-oxo complex,[FeIV(O)(TMC)]2+ (Scheme 3). The iron(III)-hydroperoxide complex,[FeIII(O2H)(TMC)]2+, was characterized using a variety of spectro-scopic methods; the EPR spectrum of a frozen acetone/CF3CH2OH(3:1) solution of the complex measured at 10 K shows signalsat g = 6.8, 5.2, and 1.96, which is consistent with a high-spin(S = 5/2) FeIII species [144,145]. The rRaman spectrum of the[FeIII(O2H)(TMC)]2+ complex exhibits two 18O-isotope-sensitivebands at 658 and 868 cm−1 for the FeO and OO stretching vibra-tions, respectively [91]. The structural information obtained byXAS/EXAFS and DFT calculations indicates that an end-on, high-spin [FeIII(O2H)(TMC)]2+ complex with syn orientation of OOH−

and N-methyl groups does not bind a solvent ligand trans to theOOH− ligand [91].

Concerning the conversion of [FeIII(O2H)(TMC)]2+ into[FeIV(O)(TMC)]2+, two plausible mechanisms are consideredfor hydroperoxide O O bond cleavage in [FeIII(O2H)(TMC)]2+:One involves heterolytic O O bond cleavage to generate anFeV O species, followed by one-electron reduction to give theFeIV O complex (Scheme 4, pathways A and B). The secondpossible mechanism involves homolytic O O bond cleavage in[FeIII(O2H)(TMC)]2+ to afford [FeIV(O)(TMC)]2+ and a hydroxylradical (Scheme 4, pathway C). Que and co-workers have proposedthe former mechanism based on the observation that the formationrate of [FeIV(O)(TMC)]2+ from [FeIII(O2H)(TMC)]2+ in CH3CN solu-tion was accelerated with increasing proton concentration [146]. Incontrast, Nam and co-workers have proposed the homolytic O Obond cleavage mechanism based on the observation that the rate ofhydroperoxo O O bond cleavage in [FeIII(O2H)(TMC)]2+ was inde-pendent of the proton concentration for the acetone/CF3CH2OHsolvent system [91]. Additional evidence in support of the O Obond homolysis mechanism was obtained by carrying out reac-

tions in the presence and absence of substrates; the yields of the[FeIV(O)(TMC)]2+ product formed in the presence and absenceof substrates were the same (Scheme 4, pathways A and D),

S.P. de Visser et al. / Coordination Chemistry Reviews 257 (2013) 381– 393 391

N N

N NFeIII

N N

N NFeIII

OOH

N N

N NFeIV

O

nucleo philic • nucleop hil ic • electrophi lic ox

elect rophi lic

+O O 2+ 2+

Iron (III )-per oxo Iron (III )-hydroperox o Iron(I V)-oxo

+H+ –HO•

eme 3

sg

4

crct[lsp[w[[iscthtaait1t

htspuii

deformylation deformylat ion

Sch

uggesting that a highly reactive iron(V)-oxo species was notenerated in the O O bond cleavage of [FeIII(O2H)(TMC)]2+ [91].

.2. Reactivity comparison

The reactivities of the iron(III)-peroxo and iron(III)-hydroperoxoomplexes were examined in both nucleophilic and electrophiliceactions and then compared to those of the iron(IV)-oxoomplex (Scheme 3). When the nucleophilic character of thehree intermediates, [FeIII(O2)(TMC)]+, [FeIII(O2H)(TMC)]2+, andFeIV(O)(TMC)(NCCH3)]2+, was tested in aldehyde deformy-ation reactions [147], the iron(III)-hydroperoxo specieshowed the greatest reactivity in the deformylation of 2-henylpropionaldehyde (2-PPA), and the reactivity order ofFeIII(O2H)(TMC)]2+ > [FeIII(O2)(TMC)]+ > [FeIV(O)(TMC)(NCCH3)]2+

as observed [91]. Interestingly, formation ofFeIV(O)(TMC)(NCCH3)]2+ was observed in the reaction ofFeIII(O2H)(TMC)]2+ and 2-PPA, proposing that the reaction isnitiated via the nucleophilic attack of the iron(III)-hydroperoxopecies on the carbonyl carbon of 2-PPA, followed by O O bondleavage of the peroxohemiacetal leading to the formation ofhe iron(IV)-oxo species [91]. The high reactivity of the iron(III)-ydroperoxo species in nucleophilic reactions, compared tohe side-on iron(III)-peroxo species (i.e., [FeIII(O2)(TMC)]+), wasscribed to the end-on binding mode of the hydroperoxo lig-nd [147,148]. The reactivity of [FeIII(O2H)(TMC)]2+ was furthernvestigated using primary (1◦-CHO), secondary (2◦-CHO), andertiary (3◦-CHO) aldehydes, and the observed reactivity order of◦-CHO > 2◦-CHO > 3◦-CHO supports the nucleophilic character ofhe iron(III)-hydroperoxo species.

The electrophilic character of the iron(III)-peroxo, iron(III)-ydroperoxo, and iron(IV)-oxo complexes was also investigated inhe oxidation of alkylaromatic compounds with weak C H bonds,uch as xanthene and 9,10-dihydroanthracene. While the iron(III)-

eroxo complex did not show any significant spectral changespon addition of the substrates, the iron(III)-hydroperoxo and

ron(IV)-oxo complexes reacted with DHA, showing that theseron–oxygen intermediates are capable of abstracting an H-atom

FeIII

2+

FeIV

2+

FeV

3+

OH

OHŠ

eŠABC

Sub

Prod -[O]

FeIII 3+

D

[FeIV(O)(T MC)]2+

[FeIII(O2H)(TMC)]2+

[FeV(O)(TMC)]3+

O OH

O

O

Scheme 4.

idatio n oxidatio n

.

from DHA with similar reactivity in this C H bond activationreaction. Thus, as summarized in Scheme 3, the iron(III)-peroxoand iron(IV)-oxo complexes show reactivities in nucleophilic andelectrophilic reactions, respectively. Interestingly, the high-spiniron(III)-hydroperoxo complex is an active oxidant in both nucle-ophilic and electrophilic reactions.

Recent comparative studies on the reactivity of nonhemeiron(III)-hydroperoxo and iron(IV)-oxo with an N4Py (N,N-bis(2-pyridylmethyl)-N-[bis(2-pyridyl)methyl]amine or Bn-TPEN ligandsystem in substrate halogenation reactions showed higher activityfor the nonheme iron(III)-hydroperoxo than for the iron(IV)-oxo complexes [149]. Thus, the reaction of tetrabutylammoniumbromide with iron(III)-hydroperoxo complexes resulted in the for-mation of OBr− with rate constants that were three orders ofmagnitude higher than those for reactions with the correspond-ing iron(IV)-oxo complexes. DFT studies confirmed the reactionprocesses and showed that the nonheme iron(III)-hydroperoxospecies is a potential oxidant. The origin of the reactivity differencesbetween heme and nonheme iron(III)-hydroperoxo was assignedto differences in spin states, whereby the nonheme iron(III)-hydroperoxo complex has a high-spin ground state, whereas itis low-spin for the heme-based iron(III)-hydroperoxo complex,thereby making the former species more reactive. These stud-ies have thus highlighted critical differences between heme andnonheme iron(III)-hydroperoxo versus iron(IV)-oxo intermediates,where the heme iron(III)-hydroperoxo species was found to be asluggish oxidant [24–27].

5. Conclusion

In recent years, considerable new insights into the intrin-sic properties of nonheme metal–oxygen complexes have beengained through a combination of experimental and computa-tional techniques. Thus, short-lived catalytic cycle intermediates,such as the iron(IV)-oxo, iron(III)-superoxo, iron(III)-peroxo, andiron(III)-hydroperoxo species, were synthesized and spectroscopi-cally characterized using biomimetic nonheme ligand systems. Themost successful set of data to date has come from the nonhemeiron system with the TMC ligand [9,150–152]. A range of differentstructures were stabilized and characterized and detailed reactiv-ity patterns with a selection of substrate types were investigated.A clear picture is now starting to emerge surrounding the activityof enzymatic catalytic cycle intermediates and the potency of oxi-dants. The TMC ligand system with its tetradentate coordinationalso enabled studies of the influences/effects of axial ligands on thespectroscopic properties and reactivity of FeIV O intermediates.

Furthermore, comparisons between heme and nonheme ironsystems have been made and remarkable differences have been

discovered. In particular, studies of biomimetic porphyrin com-plexes, where Cpd I was found to be the only viable oxidant inoxygen atom transfer reactions, have suggested the existence ofa single active oxidant in heme enzymes, such as the cytochromes

3 Chemi

Poaocfai

A

K2

R

92 S.P. de Visser et al. / Coordination

450. By contrast, recent evidence from nonheme iron based super-xo and hydroperoxo complexes revealed reactivity patterns thatre considerably different from those of their heme analogues withccasionally higher reactivities for these intermediates than for theorresponding iron(IV)-oxo complexes. Future studies into the dif-erences and comparisons of heme and nonheme iron oxygenasesre expected to give further insights into the chemistry of thesemportant enzymes.

cknowledgments

WN acknowledges the financial support from NRF/MEST oforea through the CRI (W.N.), GRL (2010-00353), and WCU (R31-008-000-10010-0) programs.

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