REPRINT - Ewha Womans Universitycbs.ewha.ac.kr/pub/data/2011_04.pdflectivity of cis- versus...

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REPRINT

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REPRINTBiomimetic Complexes

The Axial Ligand Effect on Aliphatic andAromatic Hydroxylation by Non-hemeIron(IV)–oxo Biomimetic Complexes

Out of orbit : A series of density func-tional theory (DFT) calculations onaliphatic and aromatic hydroxylationreactions have been performed byusing [FeIV=OACHTUNGTRENNUNG(TMC)(L)]n+ . Thesestudies predict regioselective aliphatichydroxylation over aromatic hydroxy-lation (see scheme). The observedtrends and product distributions havebeen rationalized by using thermody-namic cycles and orbital assignments,and explain the reasons for the regio-selectivity preference. (TMC=1,4,8,11-tetramethyl-1,4,8,11-tetraazacyclotetra-decane, and L=CNCH3 or Cl

�).

S. P. d. Visser,* R. Latifi, L. Tahsini,W. Nam* 493 – 504

Keywords: biomimetics ·heme proteins · hydroxylation · iron ·theoretical chemistry

2011 – 2 / 6

DOI: 10.1002/asia.201000586

The Axial Ligand Effect on Aliphatic and Aromatic Hydroxylation byNon-heme Iron(IV)–oxo Biomimetic Complexes

Sam P. de Visser,*[a] Reza Latifi,[a, b] Laleh Tahsini,[a, b] and Wonwoo Nam*[b]

Dedicated to Professor Eiichi Nakamura on the occasion of his 60th birthday

Introduction

Cytochrome P450 enzymes (cyt P450) are heme-based mon-oxygenases that are highly versatile and are found in manybiosystems, including the human body.[1] These enzymes,generally, function as monoxygenases where they bind andutilize molecular oxygen on a heme center and transfer oneoxygen atom of O2 to a substrate, while the other oxygen

atom leaves the process as a water molecule. An extract ofthe active site of cyt P450 enzymes is given in Figure 1, astaken from the 3L63 protein databank (pdb) file.[2] Thus, theenzyme contains a central heme group that is bound to theprotein backbone through an iron–thiolate linkage of a cys-teinate residue. It is believed that this cysteinate residue en-tices a “push-effect” on the heme, whereby electron density

Abstract: Iron(IV)-oxo heme cationradicals are active species in enzymesand biomimetic model complexes.They are potent oxidants in oxygenatom transfer reactions, but the reactiv-ity is strongly dependent on the ligandsystem of the iron(IV)–oxo group andin particular the nature of the ligandtrans to the oxo group (the axialligand). To find out what effect theaxial ligand has on the reactivity ofnon-heme iron(IV)–oxo species, wehave performed a series of densityfunctional theory (DFT) calculations

on aliphatic and aromatic hydroxyl-ation reactions by using [FeIV=O-(TMC)(L)]n (TMC=1,4,8,11-tetra-methyl-1,4,8,11-tetraazacyclotetrade-cane, and L= acetonitrile or chloride).The studies show that the regioselectiv-ity of aliphatic over aromatic hydroxyl-ation is preferred. The studies are ingood agreement with experimental

product distributions. Moreover, thesystem with the acetonitrile axialligand is orders of magnitude more re-active than that with a chloride axialligand. We have analyzed our resultsand we have shown that the metal–ligand interactions influence the orbitalenergies and as a consequence also theelectron affinities and hydrogen atomabstraction abilities. Thermodynamiccycles explain the regioselectivity pref-erences.

Keywords: biomimetics · hemeproteins · hydroxylation · iron ·theoretical chemistry

[a] Dr. S. P. d. Visser, Dr. R. Latifi, Dr. L. TahsiniThe Manchester Interdisciplinary Biocentreand the School of Chemical Engineering and Analytical ScienceThe University of Manchester131 Princess Street, Manchester M1 7DN (United Kingdom)Fax: ( 44) 161-3065201E-mail : [email protected]

[b] Dr. R. Latifi, Dr. L. Tahsini, Prof. W. NamDepartment of Chemistry and Nano Science and Department of Bio-inspired ScienceEwha Womans UniversitySeoul 120–750 (Korea)E-mail : [email protected]

Supporting information for this article is available on the WWWunder http://dx.doi.org/10.1002/asia.201000586.

Figure 1. Extract of the crystal structure of P450cam with the substrate(camphor) indicated.

Chem. Asian J. 2011, 6, 493 – 504 � 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 493

is donated to the iron–heme.[3] Heme peroxidases, by con-trast, contain a heme–histidine linkage,[4] at which the axialligand withdraws electrons from the heme in a “pull-effect”.As a consequence, heme-peroxidases are unable to reactwith substrates by hydrogen-atom abstraction but they areable to convert hydrogen peroxide into water molecules.

The axial ligand effect on the difference in reactivity andcatalytic properties of cyt P450 enzymes versus peroxidaseshas prompted many biomimetic studies on model com-plexes.[5] Thus, biomimetic iron(IV)–oxo porphyrins weresynthesized, and reactivity patterns were studied with re-spect to aliphatic hydroxylation and epoxidation reactions.[6]

In particular, detailed studies focused on the axial ligandeffect on substrate monoxygenation by iron(IV)–oxo por-phyrins. One of the first experimental studies that estab-lished differences in rate constants and spectroscopic prop-erties due to a difference in axial ligand was reported byGross and co-workers.[7] Thus, studies using iron(IV)–oxotetramesitylporphyrin (TMP) cation radical with variableaxial ligands showed a pronounced axial ligand effect on theepoxidation of styrene. In particular, systems with anionicaxial ligands (X= F�, Cl�, CH3CO2

�) gave enhanced reactiv-ity for styrene epoxidation compared to that of nonligatinganions (X=CF3SO3

� and ClO4�).[7a] Further studies by Nam

and co-workers on the difference in reactivity patterns ofiron(IV)–oxo porphyrins with either chloride or acetonitrileaxial ligands established critical differences between anionicand neutral axial ligands.[8] These studies highlighted differ-ences in reactivity between [FeIV=O (TPFPP C)(Cl)] and[FeIV=O (TPFPP C)NCCH3] (TPFPP= meso-tetrakis(penta-fluorophenyl)porphyrin). These differences include the se-lectivity of cis- versus trans-olefins, the oxidizing power inalkane C�H activation, the kinetic isotope effect (KIE), theregioselectivity of aromatic ring oxidation versus C�H hy-droxylation in ethylbenzene hydroxylation, and of C=C ep-oxidation versus C�H hydroxylation in olefin oxygenation.

Recently, we published a DFT study on the regioselectivi-ty of aliphatic (benzyl) hydroxylation versus aromatic (para)hydroxylation of ethylbenzene by using [FeIV=O(Por C)(Cl)]and [FeIV=O(Por C)(NCCH3)] ; Por=porphyrine).

[9] In sup-port of experimental data,[8b] the calculations predicted thealiphatic hydroxylation process to be dominant for [FeIV=O-(Por C)(Cl)], whereas aromatic hydroxylation was favourablefor [FeIV=O(Por C)(NCCH3)] . The computational studies

[9]

indicated that the axial ligand influences the high-lying oc-cupied and virtual orbitals, and thereby influences the possi-ble electron-transfer processes in the reaction. Clearly, inheme systems the axial ligand plays a crucial role in the or-dering and energy levels of the high-lying occupied and low-lying virtual orbitals, and thereby affects thermochemicalproperties such as electron affinity, proton affinity etc. Togain further insight into axial ligand effects, here we presenta DFT study where we investigate the regioselectivity of ali-phatic versus aromatic hydroxylation with a non-hemeiron(IV)–oxo complex. Thus, non-heme iron(IV)–oxo com-plexes lack the porphyrin cation radical that heme systemsuse to accept one electron. As a consequence, differences in

reactivity patterns between heme and non-heme iron(IV)–oxo species are very common.[10–12]

Non-heme iron(IV)–oxo complexes are potent catalysts ofhydroxylation reactions and are found in enzymatic, andbiomimetic systems.[13] The first biomimetic non-hemeiron(IV)–oxo complex that was successfully characterized byusing spectroscopic methods contained a tetradentate TMCligand system (TMC =1,4,8,11-tetramethyl-1,4,8,11-tetraaza-cyclotetradecane).[14] The complex was investigated by usingMçssbauer, crystallography, electrospray mass spectrometry,EPR, and infrared spectroscopy. EPR studies showed a trip-let spin ground state, while the crystal structure revealed anFe�O distance of 1.646 �. Fourier transform infrared spec-troscopy detected the Fe�O vibration at 834 cm�1, whichdown-shifts by 34 cm�1 upon replacement of the oxo groupfrom 16O to 18O.

Since the first characterization of [FeIV=O(TMC)-(NCCH3)]

2 , many studies on this and related chemical sys-tems were performed. In particular, because of the fact thatthe sixth ligand (NCCH3) is easily replaced by other ligands,this model has become the template for non-heme axialligand effect studies.[10] Spectroscopic studies showed criticaldifferences in the Fe�O stretch vibration (nFeO) dependenton the axial ligand with values ranging from 814–854 cm�1,while resonance Raman studies on 16O versus 18O bindingrevealed a red-shift of nFeO by 30–37 cm

�1. Despite the largevariation in Fe�O stretch vibrations, the EXAFS data gaveFe�O bond lengths of these complexes within a narrowrange of 1.64–1.68 �. Supporting DFT calculations showedthat the s- and p- donor properties of the axial ligand per-turb the iron–oxo orbitals, which can weaken the Fe�Obond.

Further theoretical studies of a series of complexes withvariable axial ligands predicted a trend in the oxo-transferreaction towards PPh3 with increased reactivity in the orderTMCS< [TMC(N3

�)]< [TMC(CF3COO�)]< [TMC

(NCCH3)], whereas for a series of hydrogen abstraction re-actions of 9,10-dihydroanthracene the opposite trend wasobserved.[11a] TMCS represents an 1-mercaptoethyl-4,8,11-trimethyl-1,4,8,11-tetraazacyclotetradecane ligand where athiolate group is located trans to the oxygen-binding site.[11b]

The reactivity trends were explained as originating fromtwo-state-reactivity patterns due to blending of quintet spinbarrier heights with weighted contributions from the tripletspin barriers.

494 www.chemasianj.org � 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Chem. Asian J. 2011, 6, 493 – 504

FULL PAPERS

To gain further insight into the reactivity patterns of non-heme iron(IV)–oxo species, we have performed a DFTstudy into the axial ligand effect on aliphatic, and aromatichydroxylation reactions of ethylbenzene by using [FeIV=O-(TMC)(L)]n . The results show that the axial ligand has astrong effect on the potency of the oxidant, but no differen-ces in regioselectivity are observed here.

Results and Discussion

We investigated the axial ligand effect on the reactivity ofnon-heme iron(IV)–oxo complexes bearing a TMC equato-rial ligand system, with either acetonitrile (NCCH3) or chlo-ride (Cl�) as an axial ligand: [FeIV=O(TMC)(L)]n (L=NCCH3 or Cl

�). In this work we focus on aliphatic and aro-matic hydroxylation reactions using ethylbenzene as a sub-strate. The aliphatic hydroxylation of the benzyl position ofethylbenzene and the aromatic hydroxylation at the para-position of the substrate were investigated.

Before discussing the reactivity patterns as a function ofthe axial ligands, we considered first the optimized geome-tries of reactant complexes (RL) in the singlet, triplet, andquintet spin states (Figure 2). In this nomenclature, the axialligand (L) is given in subscript after the label and the spinmultiplicity as a superscript before the label; 5RCl representsthe reactant complex of [FeIV=O(TMC)(Cl)] in the quintetspin state. Optimized geometries of 3,5RNCCH3 are very closeto those previously reported[12] with Fe�O distances of1.638 � and Fe�NCCH3 distances of 2.120 (triplet) and2.092 � (quintet). In agreement with the experimental ob-servation,[14] we found a triplet spin ground state that isbelow the quintet spin state by 1.9 kcal mol�1. Earlier studiesusing similar methods,[12] however, predicted equal energiesfor the triplet and quintet spin states. Nevertheless, it isclear that 3RNCCH3 and

5RNCCH3 are close in energy (withinabout a few kcal mol�1) so that environmental perturbations

may change the ordering, and relative energies of the indi-vidual spin states. In both structures (RCl and RNCCH3), thesinglet spin state is high in energy, and will not participate inthe reaction mechanism. We will, therefore, focus on thetriplet and quintet spin states, while details of the singletspin state calculations can be found in the Supporting Infor-mation.

Interestingly, the spin state ordering is reversed for 3,5RCl,and we found a quintet spin ground state that is well sepa-rated from the triplet spin state by 4.0 kcal mol�1. Analysisof the group spin densities of 5RCl versus

5RNCCH3 shows thatthere is loss of radical character on the metal from 1Fe = 3.30in 5RNCCH3 to 1Fe =3.10 in

5RCl. At the same time, the oxygenspin density increases from 1O =0.54 in

5RNCCH3 to 1O = 0.63in 5RCl. Thus, due to the fact that the acetonitrile axialligand is a neutral ligand and chloride is an anionic ligand,these ligands have different effects on the high-lying occu-pied molecular orbitals.

To explain the differences in molecular orbitals, we showthe metal-based molecular orbitals in Figure 3 as taken from3RCl. These molecular orbitals are very similar to those de-scribed before for heme and non-heme iron(IV)–oxo com-plexes.[12,15] The lowest lying molecular orbital is the p*xy or-bital, which is in the xy-plane of symmetry, that is, orthogo-nal to the O-Fe-axial ligand axis. This orbital is doubly occu-pied in the triplet spin state, and is mostly a nonbonding or-bital on the metal. Somewhat higher in energy are two p*orbitals for the antibonding interactions of the metal 3dxz/3dyz orbitals with 2px/2py on the oxo-group; p*xz and p*yz.These orbitals, to a certain extent, also contain antibondinginteractions with the axial ligand but to a much lesserdegree than the iron–oxo interaction. Both orbitals aresingly occupied in the triplet spin state to give an overallelectronic configuration; p*xy

2 p*xz1 p*yz

1. Higher in energyand virtual in the triplet spin state are the s*z2 and s*x2-y2 or-bitals for the s* antibonding interactions along the O-Fe-axial ligand orientation, and for the metal with the nitrogenatoms of the TMC ring, respectively. The quintet spin stateresults in one-electron excitation from p*xy to s*x2-y2 in thetriplet spin state to give an overall electronic state: p*xy

1

p*xz1 p*yz

1 s*x2-y21. Finally, 1RCl and

1RNCCH3 represent aclosed-shell singlet spin state with p*xy

2 p*xz2 occupation.

Most orbitals of 3RCl show large similarities to thosefound for 3RNCCH3 with few exceptions. The main differenceobtained is in the p*xy orbital, which is depicted in Figure 3for both 3RCl and

3RNCCH3. As can be seen from Figure 3 thep*xy orbital in

3RNCCH3 contains spin density contributions onthe oxo group, whereas the one for 3RCl is a pure metal-based orbital. Because of the antibonding contributions top*xy in RCl, it is raised in energy. A comparison of the orbitalenergy levels at the B3LYP/B2 level of 5RCl and

5RNCCH3shows a difference in energy between the LUMO, and thep*xy orbital, which is 2.4 kcal mol

�1 less for 5RNCCH3 with re-spect to 5RCl. The s*x2-y2 orbital in these structures is stabi-lized by 4.1 kcal mol�1 in 5RCl at the same time. These com-bined effects result in an energy difference between the p*xyand s*x2-y2 orbitals of 109.8 kcal mol

�1 for 5RCl and 111.5 kcal

Figure 2. Optimized geometries of 1,3,5RCl and1,3,5RNCCH3 reactant com-

plexes with bond lengths in angstroms. Also given are the relative ener-gies (DE ZPE) with energies obtained with basis set B2 and ZPE withbasis set B1 in Jaguar. D is the average displacement of the metal fromthe plane through the four nitrogen atoms.

Chem. Asian J. 2011, 6, 493 – 504 � 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.chemasianj.org 495

Hydroxylation by Non-Heme Iron(IV)–oxo Biomimetic Complexes

mol�1 for 5RNCCH3. Differences in orbital interactions alsoaffect the geometries, where the metal is located closer tothe plane of symmetry in RNCCH3 as compared to that of RCl.Previous axial ligand effect studies[11] also showed an effectof the axial ligand on the triplet–quintet energy splittingthat was dependent on the p*xy/s*x2-y2 energy difference. Inour system, however, we also find a large effect on the sx2-y2/s*x2-y2 energy difference. Thus, for

5RCl, the sx2-y2/s*x2-y2energy difference is 62.7 kcal mol�1, whereas a value of58.2 kcal mol�1 is obtained for 5RNCCH3. The energy gap istherefore reduced by 4.5 kcal mol�1 by changing the ligandfrom an anionic to a neutral ligand. A similar energy differ-ence (4.1 kcal mol�1) is found for the shift in the HOMO–LUMO energy gap, which is reduced with an acetonitrileaxial ligand. As a consequence, the electron affinity of theiron(IV)–oxo complex is lower for 5RNCCH3 with respect to5RCl, where we find gas-phase values of 211.1, and 133.5 kcalmol�1, respectively. In summary, the axial ligand has a majoreffect on the high-lying occupied and low-lying virtual orbi-tals of [FeIV=O(TMC)(L)], whereby the orbital energylevels of the p*xy and s*x2-y2 shift in energy depending on thenature of the axial ligand. As, the latter orbital is theHOMO, this also affects the electron abstraction ability ofthe oxidant.

Subsequently, we investigated the aliphatic hydroxylationof ethylbenzene at the benzyl position and aromatic hydrox-

ylation at the para-position of ethylbenzene with 3,5RL (L=NCCH3 and Cl

�). The obtained potential energy profiles aresummarized in Figure 4 and Figure 5 when L=NCCH3 andCl�. We first focus on the aliphatic hydroxylation mecha-nism. Aliphatic hydroxylation starts with a hydrogen-atomabstraction via transition state TSHA to form an iron(III)–hy-droxo complex (A). Rebound of the hydroxo group on theradical gives benzyl alcohol products (PA). In all cases, thelatter step is concerted and we were unable to locate re-bound transition states for these processes. All attempts tocharacterize the rebound transition state failed and led toproduct complexes instead. Geometry scans with fixed C�OH distances for all processes on the triplet and quintetspin states showed the rebound barrier to be negligible (typ-ically less than 0.5 kcal mol�1 in energy). This is consistentwith earlier substrate hydroxylation studies on [FeIV=O-(TMC)(NCCH3)]

2 with cyclohexane, which also failed tolocate rebound transition states.[12b]

The reaction mechanism from the center to the left ofFigure 4 and Figure 5 represents the aliphatic hydroxylationreaction, in which the initial barrier (via TSHA) is the rate-limiting step in the reaction process. In both cases thelowest lying barrier is on the quintet spin state surface,while the triplet is 14.6 and 21.5 kcal mol�1 higher in energyfor L=NCCH3 and Cl

�, respectively. This is consistent withprevious computational studies on aliphatic hydroxylation

Figure 3. High-lying occupied and low-lying virtual orbitals of 3RCl. Also shown is the p*xy orbital of3RNCCH3 for comparison. Orbital diagrams taken

from the b-set of orbitals.


FULL PAPERSS P. de Visser, W. Nam et al.

with non-heme iron(IV)–oxo complexes, which gave prefer-ential quintet over triplet spin mechanisms.[12,15, 16] The quin-

tet spin state remains theground state for the rest of thereaction mechanism for all pro-cesses studied here. Due to thelarge energy difference between3,5TSHA structures, the spin statecrossing from triplet to quintetwill precede the hydrogen-transfer transition state. Therate-determining step in the re-action mechanism, therefore,will be dependent on the trip-let/quintet spin-orbit couplingand the barrier height of 5TSHA.

Geometrically, 5,3TSHA,NCCH3structures have the transferringhydrogen atom midway be-tween the donating carbon andthe accepting oxygen atom,where the C�H distance isslightly longer in the quintetspin state, but in the triplet spinstate the O�H distance is slight-ly elongated. The C�H�Oangle is close to being linear inboth structures and the imagi-nary frequency in the transitionstate is large, which means thata significant amount of tunnel-ling might be expected in thereaction process. The 5,3TSHA,Clstructures have even largervalues for the imaginary fre-quencies, which should result ina larger KIE in the reaction for5RCl as compared to

5RNCCH3.[17]

The Fe�O distance is signifi-cantly longer in 3,5TSHA,Cl thanthat of 3,5TSHA,NCCH3 by 0.036and 0.078 � for the quintet andtriplet spin states, respectively.This, however, does not seemto lead to bond weakening andlowering of the barrier heights,as the reaction barriers are con-siderably higher for RCl thanRNCCH3. The FeCl distances of2.362 (2.375) � for 5TSHA,Cl(3TSHA,Cl) are similar to relatediron–chloride complexes calcu-lated before.[18]

All aliphatic hydroxylationreactions proceed with largeexothermicity and without re-bound barriers to form alcohol

product complexes. This is in good agreement with previousstudies on aliphatic hydroxylation reactions by iron(IV)–oxo

Figure 4. Free energy profile of benzyl and phenyl hydroxylation with 3,5RNCCH3. Energies obtained withUB3LYP/B2 on UB3LYP/B1 optimized geometries and with zero-point, entropic, and thermal corrections atUB3LYP/B1. Also shown are optimized geometries of the rate-determining transition states with bond lengthsin angstroms and angles in degrees.

Figure 5. Free energy profile of benzyl and phenyl hydroxylation with 3,5RCl. Energies obtained with UB3LYP/B2 on UB3LYP/B1 optimized geometries and with zero-point, entropic, and thermal corrections at UB3LYP/B1. Also shown are optimized geometries of the rate-determining transition states with bond lengths in ang-stroms and angles in degrees.



oxidants of heme and non-heme systems.[19] Formation of in-termediates A is highly exothermic on the quintet spin stateby �14.1 kcal mol�1 for 5ANCCH3, but slightly endothermic for5ACl ( 4.3 kcal mol

�1), while in both cases the triplet spinstates are significantly higher in energy and will not contrib-ute to the reaction mechanism. The ordering of the spinstates is the same in the intermediate and product com-plexes with the quintet spin state much lower in energy thanthe triplet spin state. Thermodynamically, a hydrogen-atomabstraction from a substrate (SubH) by an iron(IV)–oxocomplex to give an iron(III)-hydroxo and Sub radical has areaction enthalpy (DHr), that can be described as the differ-ence in bond dissociation energy (BDE) of the C�H bondof the substrate that is broken (BDECH) and the BDE of theO�H bond of the iron(III)–hydroxo complex that is formed(BDEOH), Eqs. (1)–(3).

½FeIV¼OðTMCÞðLÞ�nþþSubH! ½FeIIIðOHÞðTMCÞðLÞ�nþþSubð1Þ

DHrðEq 1Þ ¼ BDECH�BDEOH ð2Þ

BDEAH ¼ DHðAHÞ�DHðAÞ�DHðHÞ ð3Þ

Thus, by using our methods and techniques, a BDECHvalue of DE ZPE= 82.5 kcal mol�1 was calculated for ethyl-benzene,[20] whereas BDEOH values of 85.8 and 88.6 kcalmol�1 for [FeIV=O(TMC)(Cl)] and [FeIV=O(TMC)-(NCCH3)]

2 , respectively, were calculated. Based on theseBDE data and Equation 2, estimated values of DHHA =�3.3and �6.1 kcal mol�1 are obtained for the reactions originat-ing from either [FeIV=O(TMC)(Cl)] or [FeIV=O(TMC)-(NCCH3)]

2 . The DE ZPE value for 5ACl of �7.5 kcal mol�1is close to this estimated BDE difference, and shows thatthe energies follow thermodynamic principles. The reactionenergy for 5ACl is slightly lower in energy than the differencein BDE values, as the BDE values are based on isolatedmolecules and A is a product complex of the iron(III)–hy-droxo with the substrate radical rest group. Due to electro-static interactions between the iron(III)–hydroxo complexand the radical, its reaction energy is a few kcal mol�1 lower.

Further support that 3,5ACl are the result of a hydrogen-atomabstraction follows from the group spin densities, which givea spin density of approximately one on the substrate, whilethe metal has the most dominant spin density contribution:1Fe =4.14 for

5ACl and 1Fe =2.99 for3ACl. Thus, the group

spin densities and charges of 5,3ACl characterize these struc-tures as [FeIII(OH)(TMC)(Cl)]—SubC with orbital occupa-tion p*xy

1 p*xz1 p*yz

1 s*z21 s*x2-y2

1 fSub1 for 5ACl and p*xy

2

p*xz1 p*yz

1 s*z21 fSub

1 for 3ACl. Group spin densities andcharges of all 3,5TSHA and

3, 5A structures calculated are dis-played in Figure 6.

Based on the difference in BDE values [Eq. (2)], for a hy-drogen-atom abstraction reaction from ethylbenzene with[FeIV=O(TMC)(NCCH3)]

2 a reaction energy of between�6 and �10 kcal mol�1 for 5ANCCH3 would have been expect-ed, but a value DE ZPE=�25.4 kcal mol�1 was found. Acareful analysis of the group spin densities and charges,however, indicates a hydride-transfer process instead(Figure 6). Thus, in 5ANCCH3, the substrate rest group haslittle unpaired spin density (1Sub =�0.15), but the charge ishigh (QSub =0.84), which is the result of an initial hydridetransfer from the substrate. In the accompanying transitionstate (5TSHA,NCCH3) there is radical character on the substraterest group (1Sub =�0.64), and little charge (QSub =0.05).Therefore, on the quintet spin state, [FeIV=O(TMC)-(NCCH3)]

2 reacts by an initial hydrogen-atom abstractionvia barrier 5TSHA,NCCH3, followed by a fast electron transferen route from the transition state to form the charge-sepa-rated structure 5ANCCH3, which is formally a hydride transferintermediate. Consequently, the hydride transfer is not apure hydride transfer but a sequential hydrogen atom andelectron transfer instead, in which the hydrogen atom andelectron-transfer processes do not happen simultaneously,but rather sequentially. Similar observations were made fora hydride transfer from 10-methyl-9,10-dihydroacridine hy-droxylation by [FeIV=O(Por C)(Cl)], which also proceededwith a hydrogen-atom abstraction barrier, followed by anelectron transfer en route to the intermediate.[21] As, 5RNCCH3reacts by a hydride transfer with ethylbenzene, the reactionexothermicity to form 5ANCCH3 is large, and lower in energyas would have been expected for a hydrogen-atom abstrac-

Figure 6. Group spin densities (1) and charges (Q) of 5,3TSHA and5,3A for L=NCCH3 and Cl

� as obtained from UB3LYP/B2//UB3LYP/B1.



tion instead. The direct hydrogen atom transfer reaction issignificantly higher in energy than the hydride-transfer pro-cess.

To further analyze the differences in hydrogen abstractionversus the hydride abstraction ability of [FeIV=O-(TMC)(Cl)] with respect to [FeIV=O(TMC)(NCCH3)]

2 weset up thermodynamic cycles for the individual electron andhydrogen/hydride-transfer processes for these oxidants, andthe results are summarized in Figure 7. Note that the data inFigure 7 exclude the nature of the substrate. The process in

the vertical direction that connects [FeIV=O(TMC)(L)]n

and [FeIII(OH)(TMC)(L)]n essentially is the hydrogen-atom abstraction described above in Equation (3), and hasreaction enthalpy DHHA, which is the enthalpy differencebetween these species and a hydrogen atom, that is, it isequal to -BDEOH. The process on the top-left to the right isthe reduction of the ferryl–oxo complex into a ferric–oxocomplex, and it represents the electron affinity of the oxi-dant with reaction enthalpy DHEA. Finally, the diagonal re-action is the enthalpy difference between the oxidant, a hy-dride ion, and a [FeII(OH)(TMC)(L)](n–1) product with hy-dride-transfer reaction enthalpy DHHT, which is also given inEq. (4).

½FeIV¼OðTMCÞðLÞ�nþþSubH!½FeIIðOHÞðTMCÞðLÞ�ðn�1ÞþþSubþ

ð4Þ

If it is assumed that the rate constants of hydride transferversus hydrogen-atom transfer are correlated with the reac-tion exothermicity of these processes; then based on the dif-ferences of the hydride transfer and the hydrogen-atom ab-straction enthalpies, we can predict the likelihood of theseprocesses to occur within our chemical systems. Thus, asboth reactions have the same reactants, the difference inenergy between the hydrogen-atom abstraction [Eq. (1)]and hydride transfer [Eq. (4)], as described in Equation (5),is seen to be dependent on the difference in energy betweenthe electron affinity of the ferric–hydroxo complex

(DHEA,FeIIIOH) and the ionization potential of Sub (IESub).

DHðEq 4Þ�DHðEq 1Þ ¼ DHEA,FeIIIOH�IESub ð5Þ

Therefore, in the case in which DHEAFeIIIOH is larger thanIESub, the reaction is more likely to produce products origi-nating from hydride transfer, whereas in the reverse situa-tion a hydrogen-atom abstraction is to be expected. Our cal-culated value for IESub is 155.4 kcal mol

�1 in the gas-phase,this is midway between the DHEA,FeIIIOH values for

[FeIII(OH)(TMC)(Cl)] and[FeIII(OH)(TMC)(NCCH3)]

2

of 130.1 and 205.9 kcal mol�1,respectively. Consequently, thethermodynamic analysis pre-dicts hydride transfer for the re-action of [FeIV=O(TMC)-(NCCH3)]

2 with ethylbenzene,because DHEA,FeIIIOHNCCH3>IESub. The reverse is obtainedwhen L=Cl� ; this indicates apreferential hydrogen-atom ab-straction. The group spin densi-ties support this completely,and show that 5ANCCH3 is a cat-ionic intermediate, whereas3,5ACl are radical intermediates.As, both [FeIV=O(TMC)(L)]n

oxidants with L=Cl� or acetonitrile have the same orbitaloccupation, their electron affinity is affected by the low-lying virtual orbitals. Therefore, it appears that the overallcharge of the system does not affect the hydrogen-atom ab-straction or hydride-transfer reaction, but it is dependent onthe thermodynamics of reaction 5.

The previously studied reaction[9] of [FeIV=O(Por C)(Cl)]with ethylbenzene gave hydrogen-atom abstraction exclu-sively, and no evidence of hydride transfer was found. In thecase of [FeIV=O(Por C)(Cl)] the corresponding value of theelectron affinity of the [FeIV(OH)(Por)(Cl)] complex isDHEA,FeIVOHPor = 74.3 kcal mol

�1.[21] This value is lower thanthe IESub of ethylbenzene, therefore the iron(IV)-oxo por-phyrin cation radical will not react with ethylbenzene by hy-dride transfer but solely by hydrogen-atom abstraction, asindeed observed. Although the electron affinity of[FeIII(OH)(TMC)(Cl)] is larger than that for [FeIV(OH)-(Por)(Cl)], it is not sufficient to overcome the large IESubvalue, thus in both cases the hydrogen-atom abstraction isdominant over hydride transfer. Similarly, to the discussionof 5RCl versus

5RNCCH3, the electron affinities of [FeIII(OH)-

(TMC)(Cl)] versus [FeIII(OH)(TMC)(NCCH3)]2 are also

affected by the energy levels for the p*xy orbitals in particu-lar. The [FeIV(OH)(Por)(Cl)] complex has a triplet spinground state with orbital occupation dxy

2 p*xz1 p*yz

1. An elec-tron abstraction by this complex adds a second electron tothe p*xz orbital to give a doublet spin state. By contrast, thenon-heme complexes [FeIII(OH)(TMC)(L)]n have a sextetspin ground state with orbital occupation p*xy

1 p*xz1 p*yz

1

Figure 7. DFT calculated hydrogen abstraction enthalpies (DHHA), hydride transfer enthalpies (DHHT), andelectron affinities (DHEA) for the processes starting from [Fe

IV=O(TMC)(NCCH3)]2 and [FeIV=O-

(TMC)(Cl)] . All enthalpies are in kcal mol�1 for the reaction identified and are calculated with UB3LYP/B2//UB3LYP/B1. Solvent corrected enthalpies are given in parenthesis and are obtained from UB3LYP/B2 calcu-lations in Gaussian 03.



s*z21 s*x2-y2

1. Electron abstraction by this complex fills thep*xy orbital with a second electron to give a quintet spinground state. Thus, the electron abstraction by the non-heme complex [FeIII(OH)(TMC)(L)]n fills a low-lying p*xyorbital, whereas a high-lying p*xz orbital is filled in theheme complex [FeIV(OH)(Por)(Cl)] instead. As a conse-quence of this, more energy is released in the non-heme re-action mechanism, thereby resulting in a possible hydridetransfer, while the lesser energetic porphyrin complex reactsby hydrogen-atom abstraction instead. Furthermore, for[FeIII(OH)(TMC)(L)]n with L=Cl� the p*xy orbital israised in energy with respect to that found for L=NCCH3,and also the electron affinity is much larger for the latter.By using the [FeIII(OH)(TMC)(NCCH3)]

2 complex theelectron affinity is now so large that it can overcome theIESub and the system reacts by hydride transfer rather thanhydrogen-atom abstraction. Indeed, this is what is observedin the reaction mechanisms described in Figure 4 andFigure 5.

Let us now turn our attention to the aromatic hydroxyl-ation mechanism as shown on the right-hand side ofFigure 4 and 5. Aromatic hydroxylation follows a differentmechanism from aliphatic hydroxylation, and it starts withnucleophilic attack of the oxo group on one of the carbonatoms of the aromatic ring via a transition state TSarom. Thisgives an intermediate B, whereby one of the carbon atomsof the aromatic ring has lost its aromaticity and forms a tet-rahedral center bound to two carbon atoms of the ring, onehydrogen atom (ipso-proton) and the oxo group. In a subse-quent step, the ipso-proton is transferred to one of the nitro-gen atoms of the ligand (TMC), whereby the aromatic ringregains its aromaticity and converts to a phenolate ligand.[22]

This proton is reshuttled to the oxo group to give phenolproducts PB. Generally, the first step in aromatic hydroxyl-ation mechanisms is rate determining, therefore, we focusedon this step only here. The proton-shuttle mechanism for ar-omatic hydroxylation, so far has been shown for severalheme as well as non-heme iron(IV)–oxo species.[22,23]

Similar to aliphatic hydroxylation, aromatic hydroxylationhas also the lowest lying barrier on the quintet spin statesurface, while the triplet spin barriers (5TSarom,NCCH3 and5TSarom,Cl) are 13.1 and 18.1 kcal mol

�1, respectively, higher inenergy. Therefore, aliphatic and aromatic hydroxylation by[FeIV=O(TMC)(L)]n , L=NCCH3 or Cl

�, takes place withsingle-state reactivity on a dominant quintet spin state sur-face. As, the ground state of the reactant is in the tripletspin state this will require a spin state crossing from tripletto quintet spin. However, the triplet and quintet barrier arevery large apart, which suggests that the spin state crossingwill probably occur very early in the reaction mechanism,that is, before the transition state.

As shown from the 3,5TSarom,NCCH3 and3,5TSarom,Cl structures

depicted in Figure 4 and Figure 5, the nucleophilic attack ofthe oxygen atom on the aromatic ring appears under analmost linear Fe�O�C angle, that is, the aromatic ring is or-thogonal to the Fe�O axis. With acetonitrile as an axialligand, the transition states are late with short C�O distan-ces of 1.759 and 1.774 � for 5TSarom,NCCH3 and

3TSarom,NCCH3,respectively, while values of 1.944 and 1.833 � are obtainedfor the corresponding structures with chloride as an axialligand. The reaction towards intermediates is highly endo-thermic for para-activation of ethylbenzene by [FeIV=O-(TMC)(Cl)] , with a reaction energy of 26.6 kcal mol�1 onthe quintet spin state surface. This high energy requirementprobably prevents this reaction from happening.

Group spin densities and charges of the 5,3TSarom and5,3B

structures for the reaction of ethylbenzene with [FeIV=O-(TMC)(L)]n (L =NCCH3 or Cl

�) are given in Figure 8. Asfollows, all transition states have significant radical characteron the substrate: 1SubH =�0.72 for 5TSarom,NCCH3, 1SubH =�0.66 for 3TSarom,NCCH3, 1SubH =�0.46 for 5TSarom,Cl and1SubH =�0.48 for 3TSarom,Cl. Therefore, the rate-determiningstep in the aromatic hydroxylation is via TSarom, and involvesa single-electron transfer from the substrate to theiron(IV)–oxo moiety. However, the reaction mechanismfrom the transition state to the intermediate diverges be-

Figure 8. Group spin densities (1) and charges (Q) of 5,3TSarom and5,3B for L=NCCH3 and Cl

� as obtained from UB3LYP/B2//UB3LYP/B1.



tween the two ligand systems. Thus, when L=Cl� the inter-mediate is radical in character with group spin densities of1SubH =�0.88 (�0.92) for 5BCl (3BCl), while the charge on thisgroup is QSubH =0.03 (0.06). An acetonitrile axial ligand, onthe other hand, gives a cationic intermediate with groupspin densities 1SubH =0.02 (0.01), and charge QSubH = 0.73(0.70) for 5BNCCH3 (

3BNCCH3). Thus, two completely differentmechanisms of aromatic hydroxylation with [FeIV=O-(TMC)(L)]n complexes are found in which the neutralligand gives a cationic intermediate, and the anionic ligandgives a radical intermediate, which means a double electrontransfer has taken place with an acetonitrile ligand, and onlya single electron transfer has occurred in the system whenchloride is an axial ligand. Previous computational studieson tetrahydrobiopterin-dependent hydroxylases using an hy-droxo-iron(IV)-oxo versus a water-iron(IV)-oxo oxidant ob-tained similar results in the hydroxylation of aromatic sub-strates.[24] Thus, a hydroxo-iron(IV)-oxo oxidant was foundto react by a one-electron transfer to give a radical inter-mediate, whereas the water-iron(IV)-oxo complex abstract-ed two electrons from the substrate to give a cationic inter-mediate. For the reaction mechanism using [FeIV=O(TMC)-(NCCH3)]

2 we were able to locate a radical intermediateby swapping orbitals, 3B NCCH3. This structure, however, has11.6 kcal mol�1 more free energy than 3BNCCH3 as shown inFigure 4, and therefore is a high-lying excited state, and willnot contribute to the reaction mechanism. Attempts to swapthe orbitals of 3,5BCl and obtain cationic intermediates failed,and converged back to the radical intermediates. It appearsthat the cationic intermediate of 3,5BCl is high in energy, andinaccessible for the process. Previous computational studieson the aromatic hydroxylation of benzene and toluene with[FeIV=O(Por C)(SH)], and of ethylbenzene with [FeIV=O-(Por C)(Cl)] suggested mechanisms that involved cationicmechanisms.[22] The alternative radical pathways were foundto be substantially higher in energy.

If, we assume that the formation of the C�O bond in thefirst step of the aromatic hydroxylation mechanism is pro-portional to the formation of a H�O bond, then we can pre-dict the probability of radical over cationic mechanisms inaromatic hydroxylation, thereby following a similar thermo-dynamical analysis as given in Equation 5. Thus, we assignthe enthalpy for formation of a radical intermediate asDHrad, and the enthalpy for formation of a cationic inter-mediate as DHcat. Analogous to Equation (5) for aliphatichydroxylation, we can then derive Equation (6) for the dif-ference in enthalpy between the cationic and radical pro-cesses. It follows that the difference in enthalpy is propor-tional to the difference in enthalpy of the electron affinityof [FeIII(OH)(TMC)(L)]n , that is, DHEA,FeIIIOH, and the ioni-zation potential of the substrate (IESubH). Recent studies ofsubstrate epoxidation with iron(IV)–oxo oxidants showedthat formation of a C�O bond is indeed proportional to theformation of a H�O bond, whereby the height of the barrierof propene epoxidation by a range of iron(IV)–oxo oxidantswas found to show a linear correlation with BDEOH, that is,

BDEOH is a reasonable mimic for the C�O bond formationenergy.[25]

DHcat�DHrad1DHEA,FeIIIOH�IESubH ð6Þ

The calculated ionization energy of ethylbenzene is194.5 kcal mol�1, which is in reasonable agreement with anexperimentally reported datum of 202 kcal mol�1.[26] Thevalue of DHEA,FeIIIOH for [Fe

III(OH)(TMC)(NCCH3)]2 is

larger than IESubH, therefore an aromatic hydroxylationmechanism via a cationic intermediate may be expected.The group spin densities shown in Figure 8 support this as-signment. On the other hand, the DHEA,FeIIIOH value for[FeIII(OH)(TMC)(Cl)] is significantly lower than IESubH,thus indicating that the aromatic hydroxylation reactiongoes through a radical intermediate instead. The thermody-namic cycles for aliphatic and aromatic hydroxylation, there-fore support the observed electron-transfer mechanisms ob-served in the calculations.

In summary, the DFT calculations of aliphatic versus aro-matic hydroxylation by using [FeIV=O(TMC)(L)]n with L=Cl� or acetonitrile gave dramatic differences in mechanismdue to the change of the axial ligand. Thus, an acetontrileaxial ligand lowers the p*xy molecular orbital significantly,and thereby raises the electron affinity values considerably.As a result of that, [FeIV=O(TMC)(NCCH3)]

2 reacts withaliphatic groups via a hydride-transfer process, whereas[FeIV=O(TMC)(Cl)] reacts through hydrogen-atom ab-straction. Similar observations are found for aromatic hy-droxylation with these two oxidants, where [FeIV=O(TMC)-(NCCH3)]

2 reacts via cationic intermediates, and [FeIV=O-(TMC)(Cl)] reacts via a radical intermediate. Thermody-namic analysis, and electron transfer energies explain thesedifferences. Overall, [FeIV=O(TMC)(NCCH3)]

2 as well as[FeIV=O(TMC)(Cl)] preferentially react by aliphatic hy-droxylation over aromatic hydroxylation. This is in agree-ment with experimental studies that detected products origi-nating from aliphatic hydroxylation only.[11]

The reaction of ethylbenzene with either [FeIV=O(Por C)-(NCCH3)] or [Fe

IV=O(Por C)(Cl)] gives aliphatic hydroxyl-ation products for the latter, and aromatic hydroxylationproducts for the former.[8] Moreover, replacement of the hy-drogen atoms of ethylbenzene with deuterium atoms causeda change in regioselectivity, from aliphatic hydroxylation toaromatic hydroxylation, when [FeIV=O(Por C)(Cl)] was usedas an oxidant. Computational studies showed that the differ-ence in regioselectivity originates from stabilization of theporphyrin radical, which is due to interactions of an anionicaxial ligand. As a consequence, the HOMO–LUMO gap islarger for [FeIV=O(Por C)(Cl)] compared to that of [FeIV=O-(Por C)(NCCH3)] , which gives a larger electron affinity for[FeIV=O(Por C)(NCCH3)]

2 than [FeIV=O(Por C)(Cl)] . Inthe non-heme oxidants described in this reserach, theHOMO is a s*x2-y2 orbital in the quintet spin state, and ap*yz orbital in the triplet spin state. Neither of those orbitalsaccepts an extra electron in the reaction process. Instead, avacant virtual orbital is filled during the first step of the re-



action mechanism. Differences in the orbital energy levelsbetween heme and non-heme iron(IV)–oxo complexes,therefore give differences in reactivity patterns, and the re-gioselectivity of substrate hydroxylation. Electron abstrac-tion by non-heme iron(IV)–oxo species fills a virtual orbital,whereas in iron(IV)–oxo porphyrin cation radical species asingly occupied porphyrin orbital (a2u) is filled in the reac-tion mechanism. The electron affinity is smaller for theheme oxidant, and as a consequence aromatic hydroxylationprocesses are easier. Therefore, the regioselectivity of ali-phatic hydroxylation is favoured over aromatic hydroxyl-ation with [FeIV=O(TMC)(L)]n+ .

In the case that formation of the C�O bond in the aro-matic hydroxylation mechanism is proportional to the for-mation of a H�O bond, the first step in aromatic hydroxyl-ation should be proportional to DHHA for a process leadingto a radical intermediate, and to DHHT for one affording acationic intermediate. Therefore, aromatic hydroxylation ofa substrate, for example, ethylbenzene, by a range of non-heme iron(IV)–oxo complexes should not be dependent onthe oxidant if all reactions only lead to either radical or cat-ionic intermediates. In general, the regioselectivity of ali-phatic over aromatic hydroxylation is dependent on thestrength of the C�H bond of the substrate, the strength ofthe O�H bond of the oxidant, the ionization potential of thesubstrate, and the hydrogen abstracted substrate rest group.A combination of all these factors contributes to the overallregioselectivity preference. The BDEOH values of [Fe

IV=O-(TMC)(L)]n+ with L= Cl� or acetonitrile are close to thosefound for [FeIV=O(Por+C)(Cl)]; this implies that the hydro-gen abstraction ability is very similar. All complexes areknown to efficiently abstract hydrogen atoms from aliphaticsubstrates.[8,11] There are, however, strong differences inelectron affinity, which is the largest for [FeIV=O(TMC)-(NCCH3)]

2+ , and the weakest for [FeIV=O(Por+C)(Cl)]. How-ever, as the BDEOH value is essentially the sum of the elec-tron affinity of the oxidant, and its pKa value,

[27] this meansthat the change in electron affinity between these oxidantsis cancelled by the reversed change in pKa value, which isthe smallest for [FeIV=O(TMC)(NCCH3)]

2+ . Recent studieson 9,10-dihydroanthracene dehydrogenation with a manga-nese(V)-oxo corrolazine complex showed a strong axialligand effect on the barrier heights proportional to a dra-matic change in the BDEOH value of the oxidant.

[28] Thiswas analyzed, and mainly caused by a significant change inthe pKa value.

Conclusions

DFT calculations have been reported on the effect of axialligands on the regioselectivity of aliphatic versus aromatichydroxylation by non-heme iron(IV)–oxo species. We haveshown that [FeIV=O(TMC)(Cl)]+ reacts via radical inter-mediates, whereas [FeIV=O(TMC)(NCCH3)]

2+ favors cation-ic intermediates. This difference is the result of variations inelectron affinity of the ferric-hydroxo complexes in the reac-

tion mechanism due to the elevated level of the p*xy orbitalfor the system with L=Cl�. Therefore, the reaction pro-ceeds via a hydride transfer from ethylbenzene to [FeIV=O-(TMC)(NCCH3)]

2+ , but through a hydrogen atom transferwith [FeIV=O(TMC)(Cl)]+ . Similar differences are seen forthe calculated aromatic hydroxylation mechanisms. Theoryshows that aliphatic hydroxylation is favoured over aromatichydroxylation; this is in agreement with experimental obser-vations. We have analyzed the thermodynamics of the vari-ous reaction steps and explained the regioselectivity differ-ences, as well as the hydride transfer/hydrogen-atom ab-straction differences by using thermodynamic cycles and or-bital energies.

Methods Section

The calculations reported in this work were performed withthe Jaguar 7.0 and Gaussian-03 program packages.[29,30] Fol-lowing previous experience in the field, we used the unre-stricted B3LYP hybrid density functional method,[31] as itwas shown to reproduce free energies of activation of aro-matic hydroxylation and styrene epoxidation by iron(IV)–oxo oxidants within 3 kcal mol�1 of experiment.[23a, 32] Initialgeometry optimizations were done in Jaguar by using anLACVP basis set on iron, and 6-31G on the rest of theatoms (basis set B1),[33] and followed by an analytical fre-quency calculation. The latter confirmed each optimizedstructure as a local minimum or first-order saddle point(transition state) with one imaginary frequency for the cor-rect mode. Free energies of activation were taken from theJaguar frequency calculations and contain zero-point, ther-mal, and entropic corrections at 298 K. All stationary struc-tures were characterized by real frequencies only, and thetransition states had a single imaginary mode. Single pointcalculations with a triple-z type basis set containingLACV3P+ on iron and 6-311+G* on the rest of the atomswere done to improve the energetics; basis set B2. Free en-ergies reported in this work use energies calculated withbasis set B2, and zero-point, entropic and thermal correc-tions were evaluated at basis set B1.

Solvent calculations were performed as single point calcu-lations (UB3LYP/B2) in Gaussian-03 by using the polariza-ble conductor calculation model (CPCM) with acetonitrileas a solvent, and atomic radii described by the united atomtopology model.

Acknowledgements

The National Service of Computational Chemistry Software (NSCCS) isacknowledged for generous CPU time. R.L. and L.T. thank the BritishCouncil for an Exchange Grant and S. P. dV thanks the Royal Society ofChemistry for an RSC Journal Grant. W.N. acknowledges financial sup-port from the NSF/MEST of Korea through the CRI Program and theWCU Program (R31-2008-000-10010-0).



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Received: August 18, 2010Published online: November 24, 2010



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