Catalytic Activity Tuning of a Biomimetic HO−FeVO Oxidant for

J. Phys. Chem. B 2007, 111, 2711-2718

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Catalytic Activity Tuning of a Biomimetic HO-FeVdO Oxidant for Methane Hydroxylation by Substituents on Aromatic Rings: Theoretical Study Yuguang Ma and Perla B. Balbuena* Department of Chemical Engineering, Texas A&M UniVersity, College Station, Texas 77843 ReceiVed: NoVember 9, 2006; In Final Form: January 6, 2007

HO-(TPA)FeVdO (TPA ) tris(2-pyridylmethyl)amine) has been proposed in the literature as the key highvalent iron-oxo intermediate involved in alkane hydroxylation. Here the structure of this species is investigated theoretically in the framework of density functional theory (DFT). A detailed electronic structure analysis leads to the presumption that the properties of the FeVdO bond can be modified by introducing substituents to the aromatic rings of TPA and thus the reactivity of HO-(TPA)FeVdO for the hydrogen atom abstraction of methane hydroxylation can be tuned on the quartet potential energy surface. The validity of our presumption is verified by DFT calculations. According to the rebound mechanism, the H-abstraction step is examined by using five complexes with TPA and TPA-derivative ligands and the corresponding reaction energies and energy barriers are obtained and compared with each other. The results are fully in agreement with our qualitative model, showing that electron-withdrawing groups are able to lower the barrier and facilitate the reaction, whereas the electron-donating groups increase the barrier and reduce the reactivity.

Introduction Dioxygen activation is one of the most important processes in many kinds of bioorganisms. It has been found that some classes of iron enzymes are able to catalyze hydrocarbon oxidation to produce alcohols, aldehydes, and carboxylic acids.1-5 The highly efficient and selective reactions have intrigued scientists for many years, and numerous investigations have been dedicated to understanding the oxygen activation mechanisms. High-valent iron-oxo species have been proposed as key intermediates in alkane hydroxylation by heme and noneheme enzymes: For heme enzymes such as cytochrome P450, the reactive intermediate is generally characterized as a (porphyrin radical) FeIVdO species.3,6,7 For methane monooxygenase (MMO), an (FeIV)2(µ-O)2 is suggested as the reactive species.8 For mononuclear, non-heme iron enzymes such as Rieske dioxygenases, the existence of formally FeIV-oxo or FeV-oxo species is supported by experiments9-13 and density functional theory (DFT) calculations,14-17 although the experimental evidence is indirect for the FeV-oxo species.18 For better understanding the enzymatic activities and the corresponding oxidation mechanisms, some biomimetic complexes based on the active sites of non-heme iron oxygenases have been synthesized and their chemistry has been investigated experimentally5,11-13,19,20 and theoretically.14-17,21 The studies provide many structural and mechanistic details on oxygen activation and hydrocarbon oxidation. In particular, Que and co-workers have examined a family of none-heme complexes, [FeII(TPA)(CH3CN)2]2+, which carry out highly stereoselective alkane hydroxylation, olefin epoxidation, and olefin cis-dihydroxylation by using H2O2 as an oxidant.11-13 Moreover, they have proposed a catalytic mechanism, involving a key HOFeVdO intermediate, to explain the oxidation of hydrocarbons. According to the mechanism, the (TPA)FeII complex is oxidized by H2O2 as the first stage of the reactions. Solvent water subsequently binds to the intermediate, leading to a H2O* Corresponding author. E-mail: [email protected].

(TPA)FeIII-OOH species. Then the active oxidant, cis-HO(TPA)FeVdO, is formed by the heterolysis of the O-O bond. Like the high-valent iron-oxo intermediate in the chemistry of cytochrome P450,3 the species is responsible for carrying out the observed alkane hydroxylation reactions. Although the cis-HO-FeVdO intermediate has not been detected yet, isotopic labeling experiments and theoretical computations have strongly suggested its existence.11,14 Alkane hydroxylation undergoes a so-called rebound mechanism:22 The first step involves hydrogen atom abstraction from the alkane to generate an alkyl radical. With or without rearrangement, the alkyl radical rebounds to form an alcohol complex, which can later decompose to the final hydroxylated product and the (TPA)FeII species. The formation of the active oxidant and the proposed methane hydroxylation mechanism are illustrated in Scheme 1. The reliability of DFT methods has already been demonstrated for various non-heme iron complexes.23-26 Good agreement between experiment and theory has been achieved in these studies. Recently, alkane hydroxylation by HO-(TPA)FeVdO has been explored theoretically.15 It has been reported that the energy barrier for the H-abstraction step of methane hydroxylation is as high as 17.0 kcal/mol. This triggers our interest to improve the reactivity of HO-FeVdO for methane hydroxylation. In this paper, we study the relationship between the ligand structures and the reactivity and evaluate the substitute effect on the pyridyl rings of TPA. The investigations may provide new insights into the design of novel biomimetic catalysts for hydrocarbon oxidation. Computational Details Density functional theory with the Becke three parameter hybrid exchange functional27 and the Lee-Yang-Parr correlation functional28 (B3LYP) was employed for geometry optimization, transition state searching, and vibrational frequency computation. All the calculations were performed using the Gaussian 03 program.29 Mixed basis sets were utilized for

10.1021/jp067429i CCC: $37.00 © 2007 American Chemical Society Published on Web 02/22/2007

2712 J. Phys. Chem. B, Vol. 111, No. 10, 2007

Ma and Balbuena different elements: iron is described by the Hay and Watt basis set with effective core potentials (ECP),30 and all other atoms are characterized with the 6-31G(d′) basis set developed by Petersson and co-workers.31,32 Atomic charge and spin density assignments are based on Mulliken and natural bond orbital (NBO) methods.33-37 The accuracy of DFT for the investigated molecular systems has been ascertained by previous theoretical studies on TPA complexes15 and other similar systems.38 In this work, spin unrestricted DFT calculations were always carried out for the diamagnetic species. Spin contamination is quite small in our calculations and was corrected by an annihilation step. Transition state structures were searched by using synchronous transit quasi-Newton (STQN) method.39,40 All the local minima and transition states on the potential energy surface were confirmed by vibrational frequency analysis. Results and Discussion

Figure 1. Calculated structure of the cis-HO-(TPA)FeVdO species and Mulliken spin densities on Fe and O atoms. Important bond lengths (in Å) are shown. The bond lengths in parentheses are from ref 15.

HO-(TPA)FedO Species. Previous theoretical studies showed that the HO-(TPA)FeVdO intermediate is generated via a heterolytic O-O bond cleavage of H2O-(TPA)FeIIIOOH,14 and the methane hydroxylation reactions mediated by the active species were explored by following the rebound mechanism. It was revealed that H-abstraction possesses a higher energy barrier than the methyl radical rebound step and hence

Figure 2. Calculated molecular spin orbital diagram of the cis-HO-(TPA)FeVdO complex. For R- and β-spin orbitals, HOMO and LUMO are marked and the corresponding energy gaps are illustrated by blue arrows.

SCHEME 1: Formation of the HO-FeVdO Species and Proposed Rebound Mechanism for Alkane Hydroxylation by the Intermediate

Catalytic Activity Tuning of HO-FeVdO Oxidant

J. Phys. Chem. B, Vol. 111, No. 10, 2007 2713

Figure 3. Contour plots of some spin molecular orbitals possibly involved in the H-abstraction reaction. The value of each isocontour surface is 0.04 au.

is identified as the rate-determining step.15 In this paper, we focus on the hydrogen atom abstraction step and evaluate the reactivities for the high-valent iron-oxo species by using a group of TPA derivatives as the ligands. The ground state for cis-HO-(TPA)FeVdO with a free water molecule is a quartet (S ) 3/2) according to DFT calculations.15 As the first step of our study, we calculate the structure of the cis-HO-(TPA)FeVdO species. As shown in Figure 1, the bond lengths for FeVdO and FeV-OH are 1.635 and 1.773 Å, respectively. The relatively short FeVdO bond indicates a strong interaction between the two atoms, which can be explained by ligand field theory (LFT): In a symmetrical octahedral field, the five degenerate Fe 3d orbitals split up into a t2g (dxy, dxz, dyz) and an eg (dx2-y2, dz2) set. The lower energy t2g orbitals interact with the ligands to form π bonds, whereas the higher energy eg orbitals involve the formation of σ bonds. The molecular orbital diagram between the iron and oxo atoms in the complex is illustrated qualitatively in Scheme 2: The interaction of the Fe dz2 orbital and one O 2p orbital generates a pair of σFeO and σ*FeO bonds. The other two O 2p orbitals are able to combine with two t2g (dxz, dyz) orbitals, leading to two bonding π orbitals and two antibonding π* orbitals. The dxy and dx2-y2 orbitals do not participate in the Fe-O bonding and thus are denoted as nonbonding orbitals. Nine electrons respectively occupy σFeO,

SCHEME 2: Qualitative Orbital Diagram Showing the Electronic Structure of FeVdO Bond and the Spin Density of the HO-FeVdO Complex

πFeO, dxy, and π*FeO orbitals, and thus the bond order of Fe-O is determined as 2. The FeVdO bond, which shares an electronic structure similar to that of the O-O bond in triplet dioxygen, is presumed to be strong. It should be pointed out here that our model is based on an ideal octahedral field with Oh symmetry and the orbital split and the combination mode in the HO-

2714 J. Phys. Chem. B, Vol. 111, No. 10, 2007

Ma and Balbuena SCHEME 3: Qualitative Orbital Diagram Describing the Relationship between the FeVdO Bond Strength and the Splitting Energy of Fe 3d Orbitalsa

a Blue shows that a smaller splitting energy destabilizes the FeVdO bond, whereas red indicates that a larger splitting energy stabilizes the bond.

Figure 4. Backbone structures of the reactant, transition state, and product for H-abstraction in methane hydroxylation along the quartet potential energy surface. For clarity the TPA ligands are only partially depicted.

FeVdO complex could be much more complicated in the lower symmetric ligand field (Cs). However, the model is still valid for a qualitative description of the FeVdO bond. As indicated in Scheme 2, the three unpaired β electrons are located on Fe dxy and π*FeO orbitals; therefore, the spin densities should be around 2 on the iron atom and 1 on the oxo atom. Our DFT calculations give close results with the spin populations of 1.73 on Fe, 1.04 on the oxo atom, and 0.26 on the hydroxo ligand. In view of the bond length of Fe-OH (∼1.77 Å), the spin density on the hydroxo ligand may be attributed to the orbital overlap between the Fe 3d and the p orbitals of the hydroxo oxygen. Notably, little spin density is found on the TPA ligands, indicating negligible couplings of the unpaired-electronoccupied orbitals of the HO-FeVdO unit and the TPA ligand. Although we do not include a free water molecule in the structure, our calculations for the cis-HO-(TPA)FeVdO species agree well with those reported in a previous theoretical study.15 As shown in Figure 1, the difference of bond lengths is less than 0.03 Å. The properties of the spin-unrestricted molecular orbitals have also been analyzed. Since the hydrogen atom with one electron shifts from methane to the complex in the hydrogen atom abstraction step, the LUMOs probably play a role as σ acceptor orbitals in the reaction with the hydrogen atom. As shown in Figure 2, the orbital energy of the R-spin LUMO (R) is higher than those of several β-spin vacant orbitals (LUMO β, β, and β). Accordingly, a β-electron transfer from the σCH orbital of methane to a vacant β-spin orbital of the iron-oxo complex in the H-abstraction step is energetically feasible. In the process, the spin on the oxo atom is significantly reduced with the electron transfer and the O-H bond formation, and the methyl radical with an unpaired

R-electron develops a new spin density of ∼1. As the newly formed σOH bond is localized, the spin density on Fe still approximately remains constant. Figure 3 shows the contour plots of some important orbitals that are possibly involved in the H-abstraction reaction: β, the HOMO, is mainly composed of π* antibonding orbitals on the aromatic rings. β, the LUMO, is largely contributed by Fe dx2-y2 and a 2p orbital on the hydroxo ligand. β and β are almost degenerated. Both of them are mainly composed of Fe 3d and oxo 2p orbitals. All three vacant orbitals possess π* bonding properties. Since the H-abstraction takes place on the oxo group, β or β possibly plays the role of electron acceptor. Hydrogen Atom Abstraction. Among alkanes, methane belongs to one of the most difficultly hydroxylated molecules due to the high C-H bond dissociation energy (∼105 kcal/ mol).41 For the HO-(TPA)FeVdO species discussed above, the hydrogen atom abstraction step on the quartet energy surface (S ) 3/2) undergoes a pathway in which one hydrogen atom of methane shifts to the oxo group of the complex. According to the process illustrated in Figure 4, the reaction passes through a transition state and leads to the formation of an HO-(TPA)FeIV-OH species with one-electron reduction of the iron atom. As the energy barrier for the step is as high as 17.0 kcal/mol,15 approaches for improving the reactivity could be very important, including the study of novel biomimetic catalysts for alkane hydroxylation. In this paper, we explore the relative catalytic activities of HO-(TPA)FeVdO oxidants by introducing different substituents to the pyridyl rings of TPA. Remarkably, a group of non-heme iron complexes coordinated by TPA derivatives have been synthesized successfully.11-13 Therefore, our work may be confirmed by experiments in the near future. According to the electronic structure of HO-(TPA)FeVdO described above, the stability of the FeVdO bond may impede the hydrogen atom transfer to the oxo group. Hence weakening the FeVdO bond can effectively improve the reactivity of the complex. Since little spin density is distributed on the TPA ligand, the mixing of the ligand orbitals and the partially occupied orbitals of the HO-FeVdO unit can be neglected. The main function of TPA here is thus assigned to alter the splitting energy of the Fe 3d orbitals. It is found that the FeVdO bond

Catalytic Activity Tuning of HO-FeVdO Oxidant

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TABLE 1: Key Bond Lengths (in Å) of Reactants, Transition States, and Products for the H-Abstraction Reaction along the Quartet Potential Energy Surfacea ligands

dFe-N1 dFe-N2 dFe-N3 dFe-O1 dFe-O2 dO1-H1 dFe-N1 dFe-N2 dFe-N3 dFe-O1 dFe-O2 dO1-H1 dC1-H1 dFe-N1 dFe-N2 dFe-N3 dFe-O1 dFe-O2 dC1-H1 a

1′ b

1

2

3

4

5

2.00 1.97 2.06 1.67 1.79 2.71

2.025 1.982 2.086 1.635 1.767 2.844

reactants 2.013 1.972 2.090 1.635 1.776 2.826

2.032 1.985 2.087 1.635 1.763 2.834

2.031 1.983 2.087 1.635 1.764 2.790

2.044 1.989 2.044 1.640 1.760 2.823

1.77 1.80 1.19 1.37

2.020 1.983 2.061 1.744 1.778 1.198 1.355

transition states 2.010 1.974 2.064 1.747 1.785 1.189 1.360

2.026 1.988 2.065 1.743 1.774 1.207 1.356

2.026 1.984 2.068 1.739 1.774 1.214 1.343

2.035 1.991 2.026 1.745 1.771 1.225 1.335

1.78 1.81 2.01

2.020 1.983 2.060 1.765 1.783 2.097

products 2.007 1.972 2.059 1.773 1.787 2.128

2.034 1.990 2.073 1.754 1.782 2.046

2.037 1.991 2.077 1.750 1.783 2.029

2.052 1.996 2.040 1.753 1.780 2.032

The atoms are indicated in Figure 4. b DFT calculations for structure 1 from ref 15.

strength can be varied with the splitting energy, as shown in Scheme 3. Bigger splitting energies, generated by stronger ligand fields, are responsible for lowering the energy of the t2g orbitals and lead to a more stable FeVdO bond by orbital combinations. In contrast to strong ligands, weaker ligands usually produce smaller splitting energies, corresponding to higher energy t2g orbitals and a less stable FeVdO bond. On the basis of this principle, the FeVdO bond strength can be tuned by introducing different ligands. In this work, we keep the TPA backbone and utilize different substituents to adjust the field strength of the ligands. Four TPA derivatives, 4-(MeO)3-TPA, 4-(NO2)3-TPA, 5-(NO2)3-TPA, and 3,5-(NO2)6-TPA are employed as the ligands of HO-FeVdO (Scheme 4). The H-abstraction reaction for each species is investigated and compared with HO-(TPA)FeVdO complex. The MeO- and NO2- substituents pertain to electrondonating and electron-withdrawing groups, respectively. The former is capable of providing surplus negative charge to the nitrogen atom on a pyridyl ring and leads to strong coordination with the iron atom, while the latter withdraws the negative charge on the nitrogen atom and thus weakens the ligand-metal interaction. 4-MeO- is able to donate electrons through conjugation and 3-, 4-, and 5-NO2-’s can grab electrons from the pyridyl-N atom by both conjugation and induction effect. The substituents are not placed on the 6-position on the rings because they may significantly change the geometry for H-abstraction. In brief, 4-(MeO)3-TPA ligand is presumed to stabilize the FeVd O bond and decrease the reactivity of HO-FeVdO, whereas others are expected to enhance the reactivity. For the reactant, transition state, and product, the calculated geometries of structure 1 are close to those in a previous theoretical study.15 As shown in Table 1, the difference of intramolecular bond lengths is only 0.01-0.03 Å while the discrepancy of intermolecular distances is around 0.1 Å. The DFT calculations are essentially in accord with our presumption based on the above qualitative orbital analysis. According to the geometric parameters listed in Table 1, the backbone geometries for different HO-FeVdO complexes are analogous to each other. The 4-(MeO)3-TPA complex possesses the

SCHEME 4: Structures of TPA Ligands Used in This Paper

shortest bonds between pyridyl-N and Fe, indicating the relatively strong coordination bonds. The bond lengths of 4-(NO2)3-TPA, 5-(NO2)3-TPA, and 3,5-(NO2)6-TPA derivatives, however, are slightly longer than those of the original TPA complex. Surprisingly, the FeVdO bond length remains almost constant except for the 3,5-(NO2)6-TPA complex, in which the bond is 0.005 Å longer than the others. This suggests that the bond length may not accurately reflect the strength of FeVdO. In addition, we note that the transition state resembles the reaction product by comparing the corresponding bond lengths for each complex. As the Hammond principle states, the H-abstraction reaction should be endergonic. This is verified by the calculated reaction energies listed in Table 2.

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Ma and Balbuena

TABLE 2: DFT Energies of the HO-FeVdO Complexes with Different Ligands for the H-Abstraction Reactiona ligands Ereac (hartree) ETS (hartree) Eprod (hartree) ∆Eq (kcal/mol) ∆E (kcal/mol) Greac (hartree) GTS (hartree) Gprod (hartree) ∆Gq (kcal/mol) ∆G (kcal/mol)

1

2

3

4

5

-1230.215 356 -1230.187 600 -1230.197 293 17.4 11.3 -1229.872 465 -1229.847 414 -1229.858 049 15.7 9.0

-1573.818 034 -1573.787 984 -1573.797 898 18.9 12.6 -1573.388 389 -1573.359 631 -1573.368 656 18.0 12.4

-1843.628 503 -1843.603 053 -1843.612 879 16.0 9.8 -1843.292 566 -1843.271 284 -1843.279 130 13.4 8.4

-1843.631 270 -1843.607 240 -1843.616 762 15.1 9.1 -1843.294 800 -1843.275 010 -1843.282 340 12.4 7.8

-2457.037 668 -2457.015 594 -2457.026 080 13.9 7.3 -2456.708 199 -2456.689 077 -2456.697 820 12.0 6.5

a E and G refer to total SCF energies and free energies with thermal and ZPE corrections, respectively; ∆E ) Eprod - Ereac, ∆Eq ) ETS - Ereac, ∆G ) Gprod - Greac, and ∆Gq ) GTS - Greac.

TABLE 3: Mulliken and NBO Charges on Some Important Atoms of the Reactantsa ligands 1

2

3

4

5

0.590 -0.328 -0.327 -0.351 -0.284 -0.553

0.583 -0.339 -0.340 -0.349 -0.272 -0.556

0.567 -0.365 -0.367 -0.359 -0.272 -0.541

0.950 -0.458 -0.418 -0.489 -0.247 -0.674

0.948 -0.462 -0.423 -0.492 -0.234 -0.681

0.940 -0.463 -0.422 -0.488 -0.245 -0.661

Mulliken charges Fe N1 N2 N3 O1 O2

0.582 -0.327 -0.326 -0.346 -0.294 -0.562

0.581 -0.345 -0.343 -0.344 -0.307 -0.573

Fe N1 N2 N3 O1 O2

0.956 -0.459 -0.424 -0.489 -0.259 -0.693

0.961 -0.481 -0.449 -0.487 -0.272 -0.717

NBO charges

a

The corresponding atoms are indicated in Figure 4.

TABLE 4: Spin Distribution of the HO-FeVdO Complexes with Different TPA Derivative Ligands for Reactants, Transition States, and Products in the H-Abstraction Reactiona ligands Fe O1 O2 C1

a

reac TS prod reac TS prod reac TS prod reac TS prod

1

2

3

4

5

1.720 1.578 1.630 1.027 0.683 0.278 0.280 0.217 0.201 0.004 0.642 1.022

1.746 1.605 1.644 1.011 0.663 0.252 0.238 0.190 0.185 0.004 0.650 1.034

1.685 1.540 1.650 1.041 0.702 0.298 0.302 0.234 0.182 0.005 0.634 0.999

1.682 1.541 1.662 1.049 0.708 0.298 0.295 0.226 0.175 0.005 0.626 0.986

1.664 1.519 1.672 1.060 0.709 0.301 0.310 0.241 0.175 0.005 0.640 0.975

Fe, O1, O2, and C1 are denoted in Figure 4.

For each complex, relative energies (∆E and ∆Eq) and free energies (∆G and ∆Gq) with zero-point-energy (ZPE) and thermal corrections are given in Table 2. It can be found that the relative energies and free energies exhibit the same trend for H-abstraction. The free energy barrier (∆Gq) for the TPA complex is 15.7 kcal/mol. Introducing an electron-donating group (MeO-) to the aromatic rings leads to a higher ∆Gq of 18.0 kcal/mol. In contrast to 4-(MeO)3-TPA, the 4-(NO2)3-TPA, 5-(NO2)3-TPA, and 3,5-(NO2)6-TPA ligands lower the free energy barrier. In particular, the 3,5-(NO2)6-TPA complex, with two electron-withdrawing NO2- groups on each aromatic ring, has the lowest ∆Gq of 12.0 kcal/mol. In addition, we note that the reaction is endothermic for all the complexes and the free energy (∆G) varies from 12.4 kcal/mol with 4-(MeO)3-TPA to 6.5 kcal/mol with 3,5-(NO2)6-TPA. The ∆G with different

ligands shows the same trend as the free energy barrier, indicating that more stable products are formed by using electron-withdrawing ligands. Mulliken and natural atomic (NBO) charges for the reactants are reported in Table 3. For O1 and O2, MeO- substituent gives more negative charge due to its electron-donating properties, while the electron-withdrawing substituents make both the Mulliken and NBO charges less negative. However, no other direct relationship between the charges and reactivity has been identified. The charges on N1 and N2 cannot reflect the coordination ability accurately in view of the conjugation on the aromatic rings. Analyzing the charge on Fe is difficult since it is affected by three different ligands: TPA, hydroxo group, and oxo group. The spin density on the iron atom does not have an obvious change in the H-abstraction process. As shown in Table 4, the

Catalytic Activity Tuning of HO-FeVdO Oxidant species with the biggest spin change is 4-(MeO)3-TPA complex: the spin density varies from 1.746 in the reactant to 1.644 in the product. It is also noted that a new spin develops on the methyl radical with the loss of unpaired electrons on the FeO1 bond. The rearrangement of the spin density can be interpreted as follows: the 3d orbitals of Fe in HO-(TPA)FeIV-OH are split in an octahedral field formed by the TPA and two OH ligands and the t2g4 configuration yields two unpaired electrons, so the total spin density of iron remains around 2. On the other hand, the formation of an O-H bond depletes the spin density of O1. However, some spin is delocalized on the two OH groups due to relatively strong interaction between Fe and the ligands. Furthermore, it is found that spin density can be used to reflect the FeVdO bonding strength in different complexes. For each reactant, the spin density of Fe diminishes by introducing electron-withdrawing groups to the pyridyl rings, whereas the spin density of O1 increases under the same condition. As discussed before, these weak ligands cannot stabilize the FeV as well as those strong ones and thus lead to a relatively weak FeVdO bond, in which more spin disperses around the oxo atom. The high spin density on the oxo atom facilitates the H-abstraction reaction owing to the higher probability of forming an electron pair between the R-electron of O1 and the β-electron of H. Conclusions The electronic structure of HO-(TPA)FeVdO species, as a key intermediate in alkane hydroxylation, was studied. A qualitative molecular orbital model was proposed on the basis of DFT calculations. According to the model, we presumed that the catalytic reactivity could be improved by adjusting the ligand field around the HO-FeVdO unit. For the H-abstraction step, it was demonstrated that the reactivity of the HO-(TPA)FeVd O intermediate can be tuned using different substituents on pyridyl rings. In particular, introducing electron-withdrawing groups, such as NO2, makes the reaction more kinetically and thermodynamically favorable. In addition, the geometries, atomic charges, and spin densities for the reactants, transition states, and products were discussed. It was found that spin densities on the iron and oxo atoms are able to reflect the reactivity of the complexes. The principle described in the paper is not limited to ironTPA complexes. It can be applied to other heme and non-heme systems. Recently, Que and co-workers introduced a carboxylate ligand trans to an oxo group in an Fe(TMC) complex and observed enhanced reactivity. They hypothesized that the higher reactivity probably originates from a weakening of the ligand field that provides greater access to a more reactive S ) 2 surface.20 The higher reactivity can be clearly interpreted in terms of our qualitative model: a weak ligand such as -O2CCF3 increases the orbital energies for πFeO and π*FeO by Fe 3d orbital splitting and recombination to O 2p orbitals. The FeIVdO bond is thus weakened and exhibits high reactivity. Theoretical studies are able to provide new insights into the catalysis field. For the non-heme iron-TPA complexes, we have demonstrated an important relationship between structure and reactivity. This may provide an approach for designing novel catalysts for alkane hydroxylation with high catalytic activities. Acknowledgment. Financial support from the Army Research Office through Contract No. DAAD 19-02-D-0001 is gratefully acknowledged. Supercomputer time was provided by Texas A&M University Supercomputer Center and NCSA.

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