This journal is c The Royal Society of Chemistry 2012 Chem. Commun., 2012, 48, 2189–2191 2189

Cite this: Chem. Commun., 2012, 48, 2189–2191

Nonheme iron-oxo and -superoxo reactivities: O2 binding and spininversion probability matterw

Kyung-Bin Cho,a Hui Chen,b Deepa Janardanan,c Sam P. de Visser,d Sason Shaik*c andWonwoo Nam*a

Received 6th December 2011, Accepted 20th December 2011

DOI: 10.1039/c2cc17610f

DFT calculated barriers for C–H activation of 1,4-cyclohexadiene

by nonheme iron(IV)-oxo and iron(III)-superoxo species show that

the experimental trends can be explained if the spin inversion

probability of the TMC iron(IV)-oxo is assumed to be poor. Also,

the TMC iron(III)-superoxo reaction proceeds with an endothermic

O2-binding energy followed by an intrinsically reactive quintet state.

Iron-oxo (FeIVO) and -superoxo (FeIIIO2��) species are biologically

important complexes, where the former is considered to be the

ultimate oxidant in enzymatic reactions, whereas the latter is

often invoked as its precursor.1 As such, there is an interest in

establishing the relative oxidising abilities of the two species in

biomimetic systems. In a recent work,2 it was demonstrated

that the ferrous complex [(TMC)FeII]2+ oxidises cyclohexene

in concert with formation of [(TMC)FeIVO]2+ in the presence

of air. This result implies that the reactive species in the

reaction was [(TMC)FeIIIO2]2+, although the FeIIIO2

�� species

was not directly observed. If verified, this species would be more

reactive than the corresponding [(TMC)FeIVO]2+, which is

inert towards cyclohexene.2 This is a counter-intuitive result,

contrary to recent computations on related heme and nonheme

FeIVO and FeIIIO2�� species, whereby the former oxidant was

found to be superior under most circumstances.3 Here, we

address this puzzle by use of density functional theory (DFT)

to investigate the C–H activation reaction of 1,4-cyclohexadiene

(CHD) by four iron-(super)oxo species with neutral ligands;

[(N4Py)FeIVO]2+ (1), [(N4Py)FeIIIO2]2+ (2), [(TMC)FeIVO]2+ (3)

and [(TMC)FeIIIO2]2+ (4) (see Scheme 1 for ligand structures).

The C–H activation barriers with FeIVO have been previously

calculated;4 however, in order to make meaningful comparisons

to the FeIIIO2�� cases, the barriers are re-examined here within

a uniform computational protocol. The energies discussed here

are relative electronic energies (DE) only, calculated at theB3LYP/LACV3P*+//LACVP level including solvent effects

(acetonitrile, via the CPCM model including optimization;

see ESIw for details about the choice of this level). This levelof energy should typically be a few kcal mol�1 lower than

corresponding experimental free energies (DGzexp).Valence electron orbitals: in the FeIVO case, the electron

configuration and its changes during the C–H activation have

been extensively discussed before5 and are shown in Fig. 1. The

relevant spin states here are triplet and quintet states. In the

FeIIIO2�� case, however, the iron d-orbitals are more localized,

albeit having somemixing with the OOp�xz andOOp�xy orbitals of O2.

As such, the number of possibly relevant electron configura-

tions increases dramatically. For instance, with 4, we found no

less than 12 different configurations ranging from singlet to

septet. A full and in-depth description of these states using DFT

and ab initio methods is presented separately.6 Here, we focus

only on a few of these ferric-superoxo states that are likely to be

relevant for the observed reactivity.

Scheme 1 The two ligand systems used in this study.

Fig. 1 Valence electron orbitals in FeIVO and FeIIIO2��. For FeIVO, the

low-spin configuration is shown as black + red and the high-spin

configuration as black+ blue. During the low-spin reaction, one b-electronfrom the substrate is transferred to a p* orbital, while in the high-spin case,an a-electron goes to the s�

z2orbital. For FeIIIO2

��, numerous different

configurations are possible, and only the high-spin S = 3 state is shown.

aDept of Bioinspired Chemistry, Ewha Womans University,Seoul 120-750, Korea. E-mail: wwnam@ewha.ac.kr;Fax: +82-2-3277-4441; Tel: +82-2-3277-2392

bCAS Key Laboratory of Photochemistry, Institute of Chemistry,Chinese Academy of Sciences, Beijing, China.E-mail: chenh@iccas.ac.cn

c Institute of Chemistry and The Lise Meitner-Minerva Center forComputational Quantum Chemistry, The Hebrew University ofJerusalem, 91904 Jerusalem, Israel.E-mail: sason@yfaat.ch.huji.ac.il; Fax: +972-2-6584680;Tel: +972-2-6585909

dManchester Interdisciplinary Biocenter and School of ChemicalEngineering and Analytical Science, The University of Manchester,Manchester, UK. E-mail: sam.devisser@manchester.ac.uk

w Electronic supplementary information (ESI) available: Computa-tional details, energies, Mulliken spin density distributions, geometriesand in-depth discussions. See DOI: 10.1039/c2cc17610f

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2190 Chem. Commun., 2012, 48, 2189–2191 This journal is c The Royal Society of Chemistry 2012

Reactivity of N4Py complexes: the N4Py ligand, with its five-

coordination to the iron, provides one site for binding the O2 or

the O ligand, and the calculations are relatively straightforward.

A calculated barrier (DEz) of 13.4/12.3 kcal mol�1 for 31/51,respectively (Table 1 and Fig. 2), shows that the 51 state would

presumably mediate the reaction. Our 5DEz barrier is close to thevalue reported in an earlier study (10.8 kcal mol�1),4b with a

different computational protocol. This 5DEz value is reasonablyclose to the experimental DGzexp value of 14 kcal mol

�1.7 Addition

of counter ions to remove potential artificial effects4c gives minor

differences in barrier heights, 3/5DEz = 13.8/13.6 kcal mol�1.For 2, we found a multitude (9) of possible electronic states

(see ESIw, Table SIII-2). [(N4Py)FeII]2+ binds O2 exothermically(�1.7 kcal mol�1) to form 2 as a side-on complex in a septet spinground state (72s). 2 performs C–H activation via a few closely

lying transition states (TS), the lowest of which was found to

be in the singlet state, 14.3 kcal mol�1 above 72s. Here too,

counter ion effects on the barrier are marginal (14.5 kcal mol�1). It

appears, therefore, that 1 and 2 give similar H-atom abstraction

barriers and could be competitive oxidants; however, experimental

verification is pending on this issue.

Reactivity of TMC complexes: for the TMC ligand there are

at least 336 structures (see ESIw), corresponding to stereo-isomers and spin states. It is therefore evident that we must

make some intelligent selections. Here, we chose the stereo-

isomer of 3 corresponding to its crystal structure,8 and for 4

corresponding to the crystal structure for the iron-peroxo

[(TMC)FeIIIO2]+ species9 (see ESIw for further justifications).

The DEz for 33/53 was calculated to be 19.7/10.6 kcal mol�1,respectively; hence, 5DEz would be the actual reaction barrier.Also, the counter ion effects can be disregarded here as well

(3/5DEz= 20.2/10.9 kcal mol�1). At first glance, the result seemsto contradict experimental observation, since the calculated

H-abstraction barrier for 53 (10.6 kcal mol�1) is found to be

lower than that for 51 (12.3 kcal mol�1). Experimental data

showed a rate enhancement of 100 times for 1 over 3 at�30 1C,7with a measured DGzexp of 16.1 kcal mol

�1 for the reaction of

3 with CHD (note the difference of 2.1 kcal mol�1 from 1).

We have ruled out procedural errors as the source of this

discrepancy by reproducing the results using a different compu-

tational protocol (see ESIw). Furthermore, the lower computedbarrier for 3 is reasonable since it has a lower quintet–triplet

energy gap due to a weaker strength of the TMC ligand field.

Therefore, as was argued before,4a,b one can conclude that spin-

inversion probability (SIP) is low during H-abstraction reactions

by 3 so that the majority of the reactions will take place on the

triplet spin state surface. Thus, at the extreme point of SIP = 0,

the reaction would occur only in the triplet surface with 3DEz at19.7 kcal mol�1. However, in practice, SIP has some finite value,

1 Z SIP Z 0, which will be sufficiently small to slow down thereaction and raise the effective barrier for 3 by B2.1 kcal mol�1

above that for 51. A more realistic value based on SIP would,

therefore, be Z 14.4 kcal mol�1 (5DEz(1) + 2.1). As such,accepting the validity of the relative DFT barriers for 1 vs. 3

requires a scenario wherein 3 is protected by a poorer SIP.

Turning our attention to 4, we find that the H-abstraction

reaction from CHD involves the following three parts:

(i) O2-binding to FeII, (ii) spin state equilibrium, and (iii) the

C–H activation itself.

O2 binding to FeII: B3LYP calculations show that the

O2-unbound structure has a septet ground state (74u). Upon

binding O2, the energetically lowest structure is still a septet of

a side-on type (74s). The valence electronic configuration has

five a-electrons on the iron and one in OOp�xy (Table 1). TheB3LYP O2-binding energy is endothermic by 9.2 kcal mol

�1;

hence, this value should be added to the DEz barrier value.Spin state change: the second lowest state, which is a quintet

end-on bound state (54e), is 4.0 kcal mol�1 above 74s having

the same electron configuration as in 74s, but with one

b-electron in OOp�xy instead. The corresponding side-on quintetstate with the same electron configuration (54s) is 4.5 kcal mol

�1

above 74s, which makes54s the third lowest state. It is this

state that correlates to the lowest TS of the H-abstraction

reaction (see below); hence, a spin pre-equilibrium 74s -54s is

necessary for the reaction. It should be noted here that the74s -

54s transition can be assisted by spin–orbit coupling on

the superoxomoiety ðhOOp�xyjHSOjOOp�xziÞ which has been shownto be effective,10 and hence the SIP may be close to 1.

Table 1 Important species found in this study

Species DE/kcal mol�1 Valence orbitals

31TS 13.43 "p�yzð#sCH ! #p�xzÞ51TS 12.34 "d"p�yz

"p�xz"s�xyð"sCH ! "s�z2 Þ

33TS 19.66 "p�yzð#sCH ! #p�xzÞ53TS 10.60 "d"p�yz

"p�xz"s�xyð"sCH ! "s�z2 Þ

72ua 1.68 "dx2�y2

"dyz"dxy

"dz2"OOp�xy

"OOp�xz72s 0.00 "dx2�y2

"dxz"dyz

"dxy"dz2

"OOp�xy12e 0.57 "dyz

#OOp�xy12TS 14.26 "dyzð"sCH ! "OOp�xyÞ74u �9.16 "dx2�y2 "dyz"dxy"dz2 "OOp�xy"OOp�xz74s 0.00 "dx2�y2

"dxz"dyz

"dxy"dz2

"OOp�xy54s 4.48 "dx2�y2

"dxz"dyz

"dxy"dz2

#OOp�xy54TS 10.53 "dx2�y2

"dxz"dyz

"dxy"dz2 ð"sCH ! "OOp�xyÞ

a O2 placed about 20 Å away from the metal center.

Fig. 2 Reaction energy profile overlaid for the species 1–4. All the

species undergo spin state change in order to switch to the spin state

surface with the lowest barrier. However, the fact that the barrier for 3 is

lower than that for 1 indicates that SIPa 1 and thus the real barrier for 3should be higher. At the same time, shortcomings with B3LYPmay cause

too high O2-binding energy; hence, the real barrier for 4 should be lower.

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This journal is c The Royal Society of Chemistry 2012 Chem. Commun., 2012, 48, 2189–2191 2191

C–H activation: the lowest 5TS (54TS) has an electronic configu-

ration corresponding to 54s and is 6.1 kcal mol�1 higher than 54s.

Subsequent calculations on this TS with counter ions included

yielded a value of 7.3 kcal mol�1. This value becomes 6.4 kcal mol�1

when using B2PLYP-D/LACV3P*+//B3LYP/LACVP. It is of

interest to note that the inherent reactivity of the ferric-superoxo54s species is significantly higher than that of the corresponding

iron-oxo, 3. The same is true for the N4Py case (1 vs. 52, see ESIw,Table SIII-5), but due to a stronger ligand field placing the dx2�y2

orbital higher up in energy, 1/32 states are lower at the reactant

stage and moreover, exchange enhanced reactivity11 is reduced.

Implications: the barriers for H-abstraction from CHD by the

four species discussed above are shown in Fig. 2. It is seen that in

contrast to N4Py, where O2-binding is more or less thermoneutral,

the same process is highly endothermic for TMC. Inspecting the

structures, one can see that in 4, the direction of the bound O–O is

generally parallel and/or perpendicular to the Fe–N axes, while it

is bisecting both the Fe–N axes in 2. These binding modes

minimize the steric hindrance between O2 and the respective

ligands. Despite this, the steric repulsion between the TMCmethyl

groups and O2�� is sufficiently significant to prevent O2 to bind to

[(TMC)FeII]2+ as strong as in 2 (calculations with and without

the methyl groups reveal that the binding is obstructed by

3.4 kcal mol�1). As a result, the total DEz for 4 is 19.7 kcal mol�1.This is lower than the experimentally determined rate constant2 for

the reaction of 4with the much stronger C–H bond of cyclohexene

that translates to a DGzexp of 17.3 kcal mol�1. Clearly, the

computed barrier is overestimated, and the culprit seems to be

the overestimated endothermicity of O2-binding. There are indeed

reasons to question this value, as B3LYP is known to in general

underestimate the Fe–O2 bond strength in heme systems.12 Using a

test set of different functionals confirms that B3LYP along with

OLYP are the ones that underestimate the O2-binding energy

mostly in the set (see ESIw, Fig. S1). M06 and BP86 give anexothermic O2-binding energy, while BLYP, B3LYP-D, B3LYP*

and the CPU-demanding double-hybrid B2PLYP with dispersion

included (B2PLYP-D) give an endothermicity that is half or less

than that of B3LYP. In addition to this, our own CCSD(T)

calculations indicate that this O2-bonding is indeed underestimated

by 2.9 kcal mol�1 in the gas phase.6 The fact that [(TMC)FeII]2+ is

stable in solution in the presence of O2 and that 4 has not been

observed even in the absence of the substrate2 further supports the

notion of endothermicity for the O2-binding; however, it is probably

not as endothermic as B3LYP indicates.13 Also, if B3LYP

overestimates the septet stability relative to the quintet, this will

also aggravate the overestimation of DEz for the reaction of 4.If we accept the experimental results,2 the only way that the

computational and experimental results can be made compa-

tible is protection of 3 by poor SIP, while the binding of O2 is

slightly less endothermic than the B3LYP datum. Thus, as

argued above, DEz for 3 should be closer to 14.4 kcal mol�1

due to SIP. As such, for 4 to react faster than 3, the O2-binding

to form 54s must be maximally endothermic by 14.4 � 6.1 =8.3 kcal mol�1, which is lower than 9.2+ 4.5= 13.7 kcal mol�1

as given by B3LYP. Hence, if the (negative) B3LYP O2-binding

energy and spin pre-equilibrium to 54 combined is overestimated

by 5.4 kcal mol�1, then 4 would be as reactive as 3. While we

have provided arguments for such a case, it cannot be ruled

out that the reaction may actually follow other reaction

mechanisms than what is experimentally proposed,2 as the

experiments themselves are not conclusive. This poses a double

challenge for both experiment and theory, to be addressed in

the future.

The recent intriguing suggestion that FeIIIO2�� is more

reactive than FeIVO for TMC is addressed in this study. We

find that (i) O2-binding adds to the reaction barrier in 4, (ii) the

reactivities are close for FeIVO and FeIIIO2�� (1 vs. 2 and 3 vs. 4

after corrections), (iii) both 2 and 4 undergo spin state changes

during the reaction (to singlet and quintet, respectively), (iv) 3 is

protected by poor SIP, and (v) 4 will be more reactive than

3 only if the 74u -54s transition is less than 8.3 kcal mol

�1. The

fact that [(TMC)FeII]2+ and not [(TMC)FeIVO]2+ reacts with

cyclohexene2 in presence of O2 gives some credence to the last

scenario. Note that the differences of N4Py complexes are most

likely due to the lack of steric hindrance in O2-binding, and a

different driving force may also be a factor.

This work was supported by ISF Grant 53/09 (S.S.),

NRF/MEST of Korea through CRI and WCU R31-2008-

000-10010-0 (W.N.), CAS (H.C.) and an RSC Journal Grant

(S.dV.).

Notes and references

1 (a) W. A. van der Donk, C. Krebs and J. M. Bollinger Jr, Curr.Opin. Struct. Biol., 2010, 20, 673–683; (b) P. C. A. Bruijnincx,G. van Koten and R. J. M. K. Gebbink, Chem. Soc. Rev., 2008, 37,2716–2744; (c) J. M. Bollinger Jr. and C. Krebs, Curr. Opin. Chem.Biol., 2007, 11, 151–158; (d) W. Nam, Acc. Chem. Res., 2007,40, 465, and references therein.

2 Y.-M. Lee, S. Hong, Y. Morimoto, W. Shin, S. Fukuzumi andW. Nam, J. Am. Chem. Soc., 2010, 132, 10668–10670.

3 (a) W. Lai and S. Shaik, J. Am. Chem. Soc., 2011, 133, 5444–5452;(b) L. W. Chung, X. Li, H. Hirao and K. Morokuma, J. Am.Chem. Soc., 2011, 133, 20076–20079.

4 (a) H. Hirao, L. Que Jr., W. Nam and S. Shaik, Chem.–Eur. J.,2008, 14, 1740–1756; (b) D. Janardanan, Y. Wang, P. Schyman,L. Que Jr. and S. Shaik, Angew. Chem., Int. Ed., 2010, 49,3342–3345; (c) D. Janardanan, D. Usharani, H. Chen andS. Shaik, J. Phys. Chem. Lett., 2011, 2, 2610–2617.

5 (a) A. S. Borovik, Chem. Soc. Rev., 2011, 40, 1870–1874;(b) S. Shaik, S. Cohen, Y. Wang, H. Chen, D. Kumar andW. Thiel, Chem. Rev., 2010, 110, 949–1017; (c) C. Krebs,D. G. Fujimori, C. T. Walsh and J. M. Bollinger, Acc. Chem.Res., 2007, 40, 484–492; (d) L. Que Jr., Acc. Chem. Res., 2007, 40,493–500; (e) W. Nam, Acc. Chem. Res., 2007, 40, 522–531;(f) S. Shaik, H. Hirao and D. Kumar, Acc. Chem. Res., 2007, 40,532–542; (g) P. Comba, M. Maurer and P. Vadivelu, Inorg. Chem.,2009, 48, 10389–10396; (h) C. Geng, S. Ye and F. Neese,Angew. Chem., Int. Ed., 2010, 49, 5717–5720.

6 H. Chen, K.-B. Cho, W. Lai, W. Nam and S. Shaik, J. Am. Chem.Soc., 2012, submitted.

7 J. England, M. Martinho, E. R. Farquhar, J. R. Frisch,E. L. Bominaar, E. Münck and L. Que Jr., Angew. Chem., Int. Ed.,2009, 48, 3622–3626.

8 J.-U. Rohde, J.-H. In, M. H. Lim, W. W. Brennessel,M. R. Bukowski, A. Stubna, E. Münck, W. Nam and L. QueJr., Science, 2003, 299, 1037–1039.

9 J. Cho, S. Jeon, S. A. Wilson, L. V. Liu, E. A. Kang, J. J. Braymer,M. H. Lim, B. Hedman, K. O. Hodgson, J. S. Valentine,E. I. Solomon and W. Nam, Nature, 2011, 478, 502–505.

10 R. Prabhakar, P. E. M. Siegbahn, B. F. Minaev and H. Ågren,J. Phys. Chem. B, 2002, 106, 3742–3750.

11 S. Shaik, H. Chen and D. Janardanan, Nat. Chem., 2011, 3, 19–27.12 M. Radoń and K. Pierloot, J. Phys. Chem. A, 2008, 112,

11824–11832.13 P. E. M. Siegbahn, Faraday Discuss., 2003, 124, 289–296.

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