A Mononuclear Non-Heme High-Spin Iron(III)–Hydroperoxo

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A Mononuclear Nonheme High–Spin Iron(III)–Hydroperoxo Complex as an Active Oxidant in Sulfoxidation Reaction Yun Mi Kim, Kyung-Bin Cho, Jaeheung Cho, Binju Wang, Chunsen Li, Sason Shaik, and Wonwoo Nam J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja404152q • Publication Date (Web): 30 May 2013 Downloaded from http://pubs.acs.org on June 3, 2013

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A Mononuclear Nonheme High–Spin Iron(III)–Hydroperoxo Complex as an Active Oxidant in Sulfoxidation Reaction Yun Mi Kim,† Kyung–Bin Cho,† Jaeheung Cho,†,§ Binju Wang,‡ Chunsen Li,‡ Sason Shaik,*,‡ and Wonwoo Nam*,† †

Department of Bioinspired Science, Ewha Womans University, Seoul 120–750, Korea.

‡

Institute of Chemistry and the Lise Meitner–Minerva Center for Computational Quantum Chemistry, The Hebrew University of Jerusalem, 91904 Jerusalem, Israel. §

Department of Emerging Materials Science, DGIST, Daegu 711–873, Korea.

Supporting Information Placeholder ABSTRACT: We report the first direct experimental evidence showing that a high–spin iron(III)–hydroperoxo complex bearing an N–methylated cyclam ligand is capable of conducting the oxidation of thioanisoles. DFT calculations show that the reaction pathway involves a heterolytic O–O bond cleavage and that the choice of heterolytic vs. homolytic pathway is spin–state selective and it depends on the number of electrons in the dxz orbital of the iron(III)–hydroperoxo species. Elucidation of the nature of reactive intermediates in the catalytic cycles of dioxygen activation and oxygenation reactions by heme and nonheme iron enzymes has been the subject of intense research in bioinorganic and biological chemistry. High–valent iron– oxo species, such as FeIVO porphyrin –cation radicals in cytochromes P450 (P450) and nonheme FeIVO intermediates, have been invoked as active oxidants that effect the oxygenation of organic substrates.1,2 In biomimetic studies, it has been demonstrated that FeIVO complexes are strong oxidants capable of oxygenating various organic substrates, such as in hydroxylation and sulfoxidation reactions.3 In addition to the FeIVO intermediates, iron(III)–hydroperoxo species (FeIII–OOH) have been proposed as a “second electrophilic oxidant” in oxygenation reactions,4,5 particularly in the sulfoxidation of thioether substrates by P450 and its analogues.6 The FeIII– OOH species have also been proposed as active oxidants in nonheme iron systems, including bleomycin, Rieske dioxygenases, and synthetic iron catalysts.7 However, experimental evidence against the FeIII–OOH species as a second electrophilic oxidant appeared recently in iron model reactions.8 In addition, computational studies by one of us have shown that FeIII–OOH species are sluggish oxidants in oxygenation reactions, including in sulfoxidation by FeIII–OOH porphyrin species known as Compound 0 (Cpd 0) in P450.9 Thus, there has been an intriguing, continuing controversy on the involvement of FeIII–OOH species as a second electrophilic oxidant in the reactions of heme and nonheme iron enzymes and their model compounds.4–9 Recently, a high–spin (HS) FeIII–OOH complex bearing a macrocyclic N–methylated cyclam as a supporting ligand,

[(TMC)FeIII(OOH)]2+ (1, TMC = 1,4,8,11–tetramethyl– 1,4,8,11–tetraazacyclotetradecane), was synthesized and characterized with various spectroscopic methods.10 Interestingly, this HS FeIII–OOH complex showed reactivities in nucleophilic and electrophilic reactions,10a providing direct experimental evidence for the involvement of a HS FeIII–OOH complex in the oxidation of organic substrates. More recently, reactivities of HS and low–spin (LS) nonheme FeIII–OOH complexes were investigated experimentally and theoretically in hydrogen atom (H–atom) abstraction reactions, showing that the HS FeIII–OOH complex is an active oxidant in the H–atom abstraction.11 As mentioned above, the involvement of Cpd 0 in sulfoxidation by P450 and its analogues has been debated over two decades.6 Similarly, no direct experimental evidence has been obtained for the involvement of FeIII–OOH species as active oxidants in oxygen atom transfer (OAT) reactions by nonheme iron models. We now report that a HS FeIII–OOH complex (1) is a competent oxidant in the oxidation of sulfides to give the corresponding sulfoxide products. In contrast, a LS FeIII–OOH complex is shown to be a sluggish oxidant in the sulfoxidation reaction. The mechanisms of the sulfoxidation by 1 and a LS FeIII–OOH complex are investigated by density functional theory (DFT)12 calculations, proposing a heterolytic O–O bond breaking transition state in the OAT reaction by 1 (Figure 1). Complex 1, which was prepared by adding 10 equiv of HClO4 to a solution of [(TMC)FeIII(O2)]+ in acetone/CF3CH2OH (3:1) at -20 oC, decayed with the rate of kobs = 3.3 x 10–3 s–1 (Figure 2a,

Figure 1. DFT–optimized transition state of the sulfoxidation of thioanisole by 1. Hydrogens, except for O–H, are omitted for clarity; Fe, purple; N, blue; O, red; S, yellow; C, black; H, white. Fe–O, O–O, and O–S distances are shown in Å .

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Figure 2. (a) UV–vis spectral changes showing the conversion of [(TMC)FeIII(O2)]+ (1 mM, blue line) to [Fe(TMC)(OOH)]2+ (1) (red line) upon addition of 10 equiv HClO4 and the reaction of 1 with 4– methoxythioanisole (100 mM) in acetone/CF3CH2OH (3:1) at –20 °C. Insets show the time courses of the absorbance change of 1 at 526 nm for the natural decay (● ) and the reaction of 4–methoxythioanisole (●). (b) Hammett plot of log k2 against σp+ of para–X–Ph–SCH3 (left panel) and plot of log k2 against Eox of para–X–Ph–SCH3 (right panel).

inset), resulting in the formation of [(TMC)FeIV(O)]2+ (2) (Supporting Information (SI), Figure S1).10a Interestingly, upon addition of 4–methoxythioanisole to the solution of 1, this intermediate disappeared at a faster rate (kobs = 2.1 x 10–2 s–1 at –20 oC) under the condition of pseudo–first–order kinetics (Figure 2a). The rate constant increased linearly with the increase of the substrate concentration (SI, Figure S2 and Table S1). The reaction rate was dependent on reaction temperature, from which a linear Eyring plot was obtained between 233 K and 263 K to give the activation parameters of H‡ = 39 kJ mol–1 and S‡ = 119 J mol–1 K–1 (SI, Figure S3). When 1 was reacted with para–substituted thioanisoles, para–X–C6H4SCH3 (X = OCH3, CH3, F, and H), to investigate the electronic effect of substrates on the sulfoxidation reaction, a ρ value of –1.1 was obtained in the Hammett plot of the second– order rate constants vs. σp+ (Figure 2b, left panel; SI, Figure S4 and Table S1). This result indicates the electrophilic character of the hydroperoxo group of 1 in the sulfoxidation of sulfides, as frequently observed in sulfoxidation reactions by high–valent metal–oxo complexes.13 In addition, we observed a good linear correlation with the slope of –2.5 when the rates were plotted against oxidation potentials (Eox) of para–X–C6H4SCH3 (Figure 2b, right panel; SI, Table S1), suggesting that the oxidation of sulfides by 1 occurs via a direct oxygen atom transfer (OAT) mechanism.13 Product analysis of the reaction solution revealed that methyl phenyl sulfoxide was produced as a sole product with a high yield (~80% based on the amount of 1 used), and the source of oxygen in the sulfoxide product was found to be the hydroperoxo ligand of 1

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when the thioanisole oxidation was performed with 18O–labeled 1 (i.e., [(TMC)FeIII(18O18OH)]2+) (SI, Figure S5). In addition, by analyzing the reaction solution with electron paramagnetic resonance (EPR) spectroscopy and electrospray ionization mass spectrometer (ESI MS), we found that FeII species was formed as a major decomposed product of 1 (SI, Figures S6 and S7).14 For comparison, the reactivity of a LS FeIII–OOH complex, [(N4Py)FeIII(OOH)]2+ (3, N4Py = N,N–bis(2–pyridylmethyl)– N–bis(2–pyridyl)methylamine),15 was investigated in the sulfoxidation reaction. Addition of para–X–C6H4SCH3 (e.g., 4– methoxythioanisole) to a reaction solution of 3 in CH3OH at 25 oC did not affect the disappearance rate of 3 much (SI, Figure S8),16 suggesting that the LS FeIII–OOH complex is a sluggish oxidant for the oxidation of thioanisoles. The reactivity of 1 was also compared with that of the corresponding FeIVO complex 2. Interestingly, 1 was more reactive than 2 by a factor of 10 in the oxidation of 4–methoxythioanisole (e.g., 1.8 x 10–1 and 1.7 x 10–2 M–1 s–1 for 1 and 2, respectively) (SI, Figure S9). However, by considering the proton effect on the reactivity of nonheme FeIVO complex,17 2 was more reactive than 1 in the presence of HClO4 (10 equiv to 2) (SI, Figure S10). It is worth noting that, different from the FeIVO complexes, there is no significant proton effect on the reactivity of the FeIII–OOH complex in the sulfoxidation reaction (SI, Figure S11). DFT Calculations. A deeper understanding of the reaction itself can be obtained by use of theoretical calculations. As a starting point to model 1, we have used the published X–ray structure of [(TMC)FeIII(O)2]+, wherein the TMC methyl substituents are cis to Fe–OO.10a Figure 3 shows the energetics for the sulfoxidation reaction of thioanisole by 1 at B3LYP/LACVP*+//LACVP level18 including CPCM19 solvation (trifluoroethanol) correction with Gaussian 09.20 In agreement with experiments,10,11 the S = 5/2 high–spin state of 1 was found to be the ground state, with an orbital configuration of dxy1, dxz1, dyz1, dx2-y21, and dz21 on Fe. We define here our coordinate system as the x–axis along the O–OH bond and the z–axis along the Fe–O bond, and we disregard the orbital mixings with the peroxide moiety for simplicity (see also SI, DFT Section text). The energetically lowest reaction proceeds through a concerted pathway, where the O–O bond break occurs concomitantly with the bond formation to the substrate S (Figure 1). Mulliken spin density distribution (SI, Table S5) shows that the leaving OH group has only 0.06 in spin at the transition state (TS), indicating that the bond break is heterolytic. Further orbital analyses characterize the constituent groups at TS as [FeIIIO]+ and OH+ (vide infra). This reaction is followed by a barrier–less second step where a proton transfer (PT) occurs involving a return of the OH proton to form [(TMC)FeIIIOH]2+. The energy barrier for this reaction was found to be 14.5 kcal mol-1 (Figure 3); hence, the reaction is feasible also from a theoretical point of view in agreement with experiments. The intermediate spin–state S = 3/2 (dxy2, dxz1, dyz1, dx21 0 y2 , dz2 ) was found to follow the same reaction pathway but with a considerably higher transition barrier (25.5 kcal mol-1) and is therefore ruled out. Interestingly, computationally the low–spin S = 1/2 (dxy2, dxz2, dyz1, dx2-y20, dz20) state reaction follows a stepwise pathway with a distinct intermediate. The spin density distribution on the leaving OH group corresponds to half a radical at the intermediate

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Figure 3. Calculated energy profile for the sulfoxidation reaction of thioanisole by 1. While the S = 1/2 state proceeds through a stepwise, homolytic mechanism, the S = 3/2 and 5/2 states occur through a concerted heterolytic mechanism.

stage with another half radical on the substrate S (SI, Table S5). Together with orbital analyses, we interpret these data as showing a homolytic O–O bond cleavage, forming an [FeIVO]2+ compound with a loosely associated HO–S moiety sharing an unpaired electron. In the second step, the O–S bond is consolidated and a proton–coupled electron–transfer (PCET) occurs to form [(TMC)FeIIIOH]2+. Even though the rate–limiting barrier for the low–spin state is too high to matter (31.7 kcal mol-1), it still poses a fundamental question about the origins of this spin–selective reactivity. Therefore, an in–depth analysis of the orbitals involved in the reaction was done in order to discern what factors govern the choice of heterolytic vs. homolytic O–O bond cleavages. Figure 4 describes the sulfoxidation reaction seen from an orbital mixing point of view. We found that during the O–O bond–breaking reaction, the most important orbitals on the hydroperoxide ligand are the doubly occupied bonding x orbital and the unoccupied anti–bonding *x orbital (Figure 4, top center). During the O–O bond breaking, these two orbitals split into their constituent px orbitals localized on each of the oxygen. The leaving OH group will then form a bond with the substrate S (Figure 4, right), where the orbital mixings result in a bonding SO orbital and an anti–bonding *SO orbital. On the other hand, the px orbital of the proximal O will mix with the dxz orbital of the iron to form the bonding xz and anti–bonding *xz orbitals (Figure 4, left). If dxz is doubly occupied, as it is in the low–spin case, its two electrons plus the one coming from the peroxide x orbital will create a three–electron xz/*xz system, whereas the remaining electron from peroxide x will follow the leaving OH group to populate the *SO orbital (i.e., homolytic O–O bond break). This electron will then follow the positively charged proton back to the [(TMC)FeIVO]2+ moiety in the second step during PCET. On the other hand, if dxz is originally singly occupied, as in the case of intermediate– and high–spin states, the electron deficiency in the xz/*xz system will favor a heterolytic O–O bond break, where both electrons originating from the peroxide x orbital will stay with the proximal oxygen. The final step of the reaction is therefore a pure PT. Hence, we find that the number of electrons in the dxz orbital

governs the choice of heterolytic vs. homolytic O–O bond cleavage in sulfoxidation reactions. Although the above description is a

Figure 4. The most important orbitals involved in a sulfoxidation reaction by an FeIII–OOH species. Blue arrows represent electrons present only in the high–spin configuration, and red only in the low–spin configuration (black is present in both). The fate of the two electrons in the x orbital is different depending on a homolytic (low–spin) or heterolytic (high–spin) bond break. This is governed by the number of electrons in the dxz orbital of the iron, which will form xz and *xz orbitals with the px orbital of the proximal O (see text).

somewhat simplified view (see SI, DFT Section text), it is found sufficiently useful to describe the underlying principles governing the reactions in all the calculations we present in this study, including different spin states and ligands (vide infra). In order to assess the generality for the above orbital interaction description, we also calculated the sulfoxidation reaction catalyzed by 3 (see SI, Tables S3, S6, S9 and Figure S12). In the FeIVO species with N4Py, the ground state of 3 is in a low–spin S = 1/2 state, again in concord with experiments.11,15 The rate–limiting barriers here are 20.3, 29.3, and 19.6 kcal mol-1 for S = 1/2, 3/2, and 5/2, respectively. The high and low–spin barriers are on the verge of what is considered to be possible barriers for the reactions to proceed, hence predicting a slow or no reaction using this ligand. This is therefore compatible with our experimental result showing no reactivity of this compound under the reaction conditions. Still, the calculations show the same homolytic/heterolytic path selection depending on the dxz occupation, as described above. Interestingly, we find for the high–energy S = 3/2 state an example of a homolytic, concerted reaction, indicating that the homolytic and heterolytic bond breakings are not always equivalent to stepwise and concerted mechanisms, respectively. The spin selection rule is kept for a third tested ligand (TPA, tris(2–pyridylmethyl)amine) (see SI, Tables S4, S7 and S10). The above results can be put in further general context. In a recent theoretical work11 using 1 and 3 for C–H activation reactions with xanthene, the former one (in a ground state of S = 5/2) was found to break the O–O bond heterolytically, with the substrate showing a spin of 0.33 at TS. This is in striking similarity to our sulfoxidation reaction described here. For 3 (with a ground state of S = 1/2), the O–O bond break occurred homolytically. While no electrons were donated from the substrate in this case, it is anyway not required for a homolytic O–O bond break, and it is still in accord with our pathway selection rules.

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In conclusion, we have provided the first direct experimental evidence demonstrating that HS FeIII–OOH species can perform sulfoxidation reactions, whereas LS FeIII–OOH species are less reactive in OAT reactions. Furthermore, we have suggested a homolytic/heterolytic pathway selection rule based on the dxz orbital occupancy in the sulfoxidation reactions by nonheme FeIII–OOH species. If the dxz orbital is doubly occupied, the reaction will occur homolytically, and heterolytically otherwise. This rule applies to all the nonheme cases we have investigated here regardless of ligands and spin states.

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ASSOCIATED CONTENT Supporting Information. Experimental and DFT details, Tables S1 – S10, Figures S1 – S12. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION (10)

Corresponding Author * E–mail: [email protected], [email protected]

ACKNOWLEDGMENT W.N. acknowledges research support of this work by the NRF of Korea through CRI and GRL (2010–00353). S.S. acknowledges support by the Israeli Science Foundation. J.C. acknowledges the R & D program of the MEST of Korea (13–BD–0403).

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