Theoretical Study of Non-heme Mn(V)-oxo Complexes: Formation Mechanism, Electronic Nature, and Hydroxylation Reactivity

WEN Zi-Hao LI Shuang ZHANG Min-Yi①

a (College of Chemistry and Material Science, Fujian Normal Uniνersity, Fuzhou 350007, China)

b (State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou 350002, China)

ABSTRACT Many non-heme manganese complexes exhibit high reactivity and enantioselectivity for the activation of C-H bonds. Recently, Mn(PDP) complexes (PDP = N,N′-bis(pyridine-2-ylmethyl)-2,2′-bipyrrolidine)have been reported to activate C-H bonds selectively in the presence of carboxylic acids. In this study, we performed density functional theory calculations to investigate the formation and hydroxylation mechanisms of Mn(PDP) complexes. Our calculation results showed that Mn(III)(PDP) complexes react with H2O2 and carboxylic acid to form Mn(V)-oxo oxidation intermediate. The main oxidation intermediate, [(PDP)Mn(IV)(O··OC(O)CH3)2-·]2+,was found to have the characteristics of S(Mn) = 3/2 manganese(IV) center antiferromagnetically coupled to a σ*O-O radical, where the O-O bond is not completely broken. Furthermore, [(PDP)Mn(IV)(O···OC(O)CH3)2-·]2+ was shown to have two single electron-accepting orbitals (α Mn-dxy and β σ*O-O) that can simultaneously interact with a doubly occupied electron-donating orbital (σC-H) of substrate. Therefore, [(PDP)Mn(IV)(O···OC(O)CH3)2-·]2+species can act as a two-electron oxidant for the C-H bond functionalization. As a result, the C-H bond hydroxylation by [(PDP)Mn(IV)(O···OC(O)CH3)2-·]2+ species was a single step. Following the H-abstraction with a low barrier of 4.5 kcal/mol, hydroxyl group would immediately rebound to the radical carbon without barrier. These results provide new insights toward the further development of non-heme manganese catalysts.

Keywords: C-H bond activation, non-heme manganese complex, homogeneous catalysis, density functional theory calculations; DOI: 10.14102/j.cnki.0254-5861.2011-3209

1 INTRODUCTION

The activation of C-H bonds via hydroxylation is the focus of current research[1-5]. Many metalloenzymes, such as heme and non-heme iron enzymes, have remarkable activity toward the C-H bonds of substrates[6-9]. However, capturing the key intermediates in these catalytic reactions remains a difficult aspect of enzyme chemistry. The development of biomimetic chemistry has allowed the synthesis of metalloenzymes that can perform extremely challenging C-H bond activation reactions, such as the synthesis of iron porphyrins and similar compounds in cytochrome P450[10-13]. In recent years, a high-valent iron-oxo complex, [Fe(IV)(O)(Por)+·]+(Cpd1),has been widely recognized as a key intermediate in the hydroxylation of alkanes. For example, Cpd1 can selectively abstract a hydrogen atom from a substrate to form[Fe(IV)(OH)(Por)]+and substrate radicals[1]. According to the kinetic isotope effect experiments, H-abstraction is typically the key step in the entire reaction[14,15]. After H-abstraction,the hydroxyl group in [Fe(IV)(OH)(Por)]+quickly recombines with the substrate radical to give hydroxylation products, which is called the oxygen rebound mechanism[16,17].

Recently, many Mn-oxo compounds have also been found to hydroxylate and oxidize C-H bonds selectively[18-20].Similar to P450, manganese porphyrin compounds also activate the C-H bond of alkanes. By modifying manganese porphyrins, recombinant myoglobin can efficiently and selectively hydroxylate substrates such as ethylbenzene[21,22].Compounds containing chiral manganese complexes with carboxylic acid additives have been found to hydroxylate compounds like cyclohexane. Recently, Ottenbacher et al.have found that a [(PDP)Mn(II)(OTf)2] complex (PDP =N,N′-bis(pyridin-2-ylmethyl)-2,2′-bipyrrolidine) is efficient for the selective hydroxylation of benzyl to form alcohols with high stereoselectivity[18]. However, the active intermediate has not yet been captured and the hydroxylation mechanism remains controversial.

Indirect experimental evidence has suggested that a Mn(V)-oxo species, obtained by Mn(III) activation with carboxylic acid and H2O2, is an active intermediate[23-25].However, for other non-heme manganese complexes, anS=3/2 signal has been observed using electron paramagnetic resonance spectroscopy, indicating that Mn(IV)-oxo species may also be reactive intermediates in catalytic reactions[26].According to a study on the oxidation mechanism of nonheme iron, the electron transfer mechanism during H2O2activation often determines the oxidation state of the metal center in a reactive intermediate[27]. To obtain a deeper understanding of the reaction process, we employed the density functional theory (DFT) method to explore the H2O2activation of non-heme manganese complexes and the reaction mechanism of selective hydroxylation catalyzed by non-heme manganese oxidation intermediates. In particular,we studied the mechanism of a hydroxylation reaction catalyzed by a Mn-oxo species with a coordinated carboxylate (OAc). Similar to non-heme iron, we found three Mn(V)-oxo species as possible oxidation intermediates,namely [(PDP)Mn(V)(O)(OAc)]2+(2),[(PDP)Mn(IV)(O···OC(O)CH3)2-·]2+(3), and[(PDP)Mn(III)(OOAc)-]2+(4) (Scheme 1)[28]. For oxidation intermediate 3, AcOH played a “magic” role in the catalytic oxidation of non-heme manganese, with the carboxylic acid and Mn-oxo forming radicals with single-electron orbitals(σ*O-O) that assist the reaction. Finally, the formed oxidation intermediate, [Mn(IV)(O···OC(O)CH3)2-·]2+, acts as a two-electron oxidant to promote the single-step two-electron oxidation of a C-H bond[29].

Scheme 1. (a) Oxidation intermediates (2～4) obtained by the oxidation of [(R,R)-PDP]Mn(II)(OTf)2 by H2O2 activation with carboxylic acid additives. (b) Selective catalytic hydroxylation of ethylbenzene by Mn(PDP) complexes

2 COMPUTATIONAL DETAILS

In this study, DFT calculations were performed using the B3LYP hybrid density functional[30]with two basis sets: (a)the Def2-SVP basis set, denoted as B1, was used for all atoms to optimize the minimal point and transition state and to analyze the frequency; and (b) the Def2-TZVP basis set[31],denoted as B2, was used for all atoms to perform single-point energy corrections. Frequency calculations to check the reactants, intermediates, and products showed only real frequencies, whereas those for transition states showed single imaginary frequencies. The dispersion corrections computed using Grimme’s D3BJ method were added to all calculations[32]. The self-consistent reaction field (SCRF) was used for optimization and single-point energy calculations.Acetonitrile (ε= 35.688) was introduced as the solvent using the polarizable continuum model (PCM)[33]. For the reactants,other functionals (B3P86, PBE0, TPSSh, M06L, etc.) were also tested. To consider the DFT self-interaction error[34]caused by multiple positive charges (+1 or +2) in the system,the OTf (Triflate, CF3SO3-) group was added to obtain neutral species for calculation. Similar results were obtained for the calculations in the presence and absence of added OTf ions.Zero-point energy (ZPE) corrections were calculated for all species, and energies reported in this work are B2 values with corresponding ZPE corrections (at the B1 level). All DFT calculations were performed using the Gaussian 09 software package[35].

3 RESULTS AND DISCUSSION

3. 1 Potential oxidation intermediates

Although there is little information available on non-heme manganese oxidation intermediates, there have been many studies on non-heme iron oxidation intermediates. According to previous reports[28,36,37], three non-heme iron oxidation intermediates, [Fe(V)(O)(OAc)], [Fe(IV)(O)(OAc·)], and[Fe(III)-OOAc], are in dynamic equilibrium. Considering that the structure of Mn(PDP) complex is similar to that of non-heme iron complexes, we simulated three possible oxidation intermediates (2～4). The optimized structures and relative energies of these oxidation intermediates are presented in Fig. 1. Oxidation intermediates 2～4 have triplet(S= 1) ground states (Table S1). In32, the O2acatom of the carboxylate is far away from the Mn=O moiety, and the distance between Ooxoand O2acis 4.754 Å. In33, the O2acatom of the carboxylate is close to the Mn=O moiety, and the distance between Ooxoand O2acis 2.117 Å. The distances between Mn and Ooxoin32 and33 are 1.676 and 1.650 Å,respectively. Some studies on non-heme iron have also suggested cyclic isomers as potential oxidation intermediates[27,28]. In our calculations, cyclic isomer34 has a shorter Ooxo-O2acdistance of 1.461 Å. A comparison of the relative energies of the triplet ground state of 2～4 showed that33 is the most stable structure, being 11.4 and 8.1 kcal/mol lower in energy than32 and34, respectively.According to the spin density analysis of the oxidation intermediates in Fig. 1, the spin density of Mn in33 is 2.74,whereas those of Ooxoand O2acare -0.21 and -0.34,respectively. Interestingly, the spin density of Mn in32 (2.74)is similar to that in33, but that of O2acis only 0.04 and that of Ooxois -0.67. Furthermore, for34, the spin density of Mn is only 2.07. To better understand the electronic structures of different oxidation intermediates, we examined their unrestricted corresponding orbitals (UCOs, Fig. 2).

Fig. 1. Optimized structures of oxidation intermediates 2～4 and spin densities for the lowest spin state. Bond lengths are in Å unit.The relative energies (based on oxidation intermediate 33), including zero-point energy (ZPE) and solvent corrections,were calculated at the UB3LYP/B2 level. The hydrogen atoms on the ligand skeleton are omitted for clarity

As shown in Fig. 2,32 has threeα-electron single-occupied orbitals corresponding to the Mnd-orbitals and aβ-electron occupied orbital corresponding to thepOoxoorbital. By analogy to the electronic structure of many non-heme iron complexes[40,41], the electronic structure of32 corresponds to[Mn(V)(O)(OAc)]2+. In contrast,33 is shown to have threeα-electron single-occupied orbitals corresponding to the Mn-dorbitals and aβ-electron remaining in theσ*Ooxo+Oacorbital. Furthermore, the spin densities of O2acand Ooxo(-0.34 and -0.21, respectively) indicate that the singleβ-electron is located on the orbital between O2acand Ooxo.Similar conclusions have been reported in many non-heme iron calculation studies[27,29,42]. Therefore, it has been suggested that these structures contain OAc radicals[27], with an electronic structure of oxo-iron(IV)-AcO·. In contrast,based on CASSCF calculations of non-heme iron, Mondal et al.[29]proposed that the electronic structure is similar to[Fe(IV)(O…OC(O)CH3)2-·]2+. As theσ*O-Oorbital in33 is composed of Ooxoand O2acinstead of being localized on the carboxylate, we regard the electronic structure of33 as[Mn(IV)(O…OC(O)CH3)2-·]2+. Cyclic isomer34 has one filledd-orbital and twoα-electron single-occupied orbitals, consistent with an electronic structure of [Mn(III)-OOAc]2+.

Fig. 2. Unrestricted corresponding orbitals (UCOs) and occupation numbers for oxidation intermediates (a) 2, (b) 3, and (c) 4. A positive occupation number indicates α occupation and a negative occupation number indicates β occupation. Only the double-occupied d orbitals of the Mn atoms are shown. All orbital graphics were created using Multiwfn[38] and VMD software[39]

Since the electronic configuration of33 has a specialσ*Ooxo+Oacorbital, in order to consider whether this is only a special case of the B3LYP functional, we used different DFT functionals to clarify the electronic configuration of33. Table 1 shows key data for the structure of33 optimized by using different DFT functionals. All the optimized structures have similar geometries and electronic structures. For example, the Ooxo-Mn-O1ac-O2acdihedral angle is usually less than 10°,and the distance between O2acand Ooxois approximately 2.1 Å. Furthermore, the spin natural orbitals (SNOs) obtained using different DFT functionals reveal anσ*O-Oorbital (Table 1 and Fig. 3). Although the occupancy rates of theσ*O-Oorbitals differ, all the DFT functionals assume that aσ*O-Oorbital exists in33. Therefore, we believe that the active intermediate is a Mn(V)-oxo species but intermediate33 has the characteristics of [Mn(IV)(O···OC(O)CH3)2-·]2+, whereS(Mn) = 3/2 and aσ*O-Oradical is present.

Table 1. Optimization of 33 Using Different DFT Functionals

Fig. 3. Spin natural orbitals (SNOs) and corresponding occupation numbers for 33 at the BP86/B1 level. A negative occupation number corresponding to a β spin

3. 2 Mechanism of oxidation intermediate formation

To further study the relationship between oxidation intermediate 3 and other oxidants, we investigated the formation mechanism of oxidation intermediate 3 from precursor 1. DFT calculations suggested that complex 1,[(PDP)Mn(III)(OOH)(AcOH)], undergoes an O-OH bond homolytic cleavage process via the transfer of a hydrogen atom from AcOH, resulting in the generation of H2O and the formation of complex 3. Fig. 4 shows the formation mechanism results for the triplet (S= 1) and quintet (S= 2)states. According to previous theoretical results[43,44], the ground state of complex 1 is a quintet state, and the calculated energy of the triplet state is 10.8 kcal/mol higher than that of the ground quintet state. After cleavage of the O-OH bond, oxidation intermediate 3, [(PDP)Mn(IV)-(O···OC(O)CH3)2-·]2+, is formed. The lowest transition state is3TS13with an activation energy of 15.0 kcal/mol. The direct cleavage of the O-OH bond of complex 1 on the triplet state surface generates the most stable oxidation intermediate (3).We also examined the formation mechanism of oxidation intermediate 4, [(PDP)Mn(III)(OOAc)-]2+. An energy barrier of 6.5 kcal/mol exists for bond formation between Ooxoand O2acto obtain cyclic intermediate 4, and the relative energy of 4 is higher than that of 3 (Fig. S2). Therefore, the theoretical results clearly show that in the presence of acetic acid, 3 is the most likely oxidant in the non-heme manganese catalytic system.

Fig. 4. Energy profiles for the conversion of 1 to 3 with H2O2 (in kcal/mol). The energies, including zero-point energy(ZPE) and solvent corrections, were calculated at the UB3LYP/B2 level

3. 3 Hydroxylation of ethylbenzene by 3[(L)Mn(IV)(O…OC(O)CH3)2-·]2+

Subsequently, we studied the hydroxylation reaction with oxidation intermediate 3 to establish the C-H bond activation ability of this species. According to the above analysis of oxidation intermediate 3, theσ*O-Oorbital with radical character spans the Ooxoand O2acatoms. Therefore, it was speculated that either O2acor Ooxocould abstract the H atom during the H-abstraction process. However, our calculation results showed that H-abstraction from the substrate by Ooxois much more favorable, with an energy barrier of 4.5 kcal/mol on the triplet state surface (Fig. 5a). In contrast,H-abstraction from the substrate by O2acis more difficult,with a higher activation energy of 14.5 kcal/mol (Fig. S5).

As shown in Fig. 5b,33RC is composed of oxidation intermediate33 and ethylbenzene. In33RC, the Mn, Ooxo, and OAc groups (O2ac, O1ac, and C) are almost on the same plane,and the distance between Ooxoand O2acis 2.117 Å. The substrate, ethylbenzene, is far away from oxidation intermediate 3, with a H-Ooxodistance of 3.492 Å. During the H-abstraction process, when the Ooxo-H distance is approximately 1.792 Å, transition state33TS is formed. Fig. 5b shows the geometric structure of33TS, which is a“reactant-like” transition state. The characteristics of this early transition state are consistent with a lower energy barrier, as the C-H bond is only slightly stretched (1.145 Å)and the Ooxo-H bond is long (1.792 Å). Notably, the Ooxo-O2acdistance increased from 2.117 Å in33RC to 2.939 Å in33TS. During the formation of the transition state, the substrate spin density changes from 0 in33RC to -0.42 in33TS, and the spin density of the OAc group changes from-0.28 in33RC to -0.02 in33TS. These observations indicate that C-H bond cleavage proceeds, with the electrons fromσC-Hin the substrate being transferred to theσ*O-Oorbital,leading to a longer distance between Ooxoand O2ac. Upon completion of the H-abstractions process, the reaction proceeds directly to the hydroxylated product. According to the previous analysis of the H2O2activation mechanism, the hydroxylated product is then replaced by a H2O2molecule to re-form complex 1 and start a new reaction cycle.

Fig. 5. (a) Energy profiles for the hydroxylation of oxidation intermediate 3 with ethylbenzene (in kcal/mol). The energies,including zero-point energy (ZPE) and solvent corrections were calculated at the UB3LYP/B2 level(OSS: open-shell singlet, CSS: closed-shell singlet); (b) Structures of oxidation intermediate3 3 during hydroxylation. Distances (in Å), spin densities, and imaginary frequencies are shown

To understand the hydroxylation reactivity of 3, we carefully analyzed the evolution of its electronic structure during the hydroxylation process. For33RC (Fig. 6), there are threeα-electron single-occupied orbitals (π*xy,π*xz, andπ*yz), which mainly correspond to thed-orbitals (dxy,dxz, anddyz) of Mn, and oneβ-electron single-occupied orbital corresponding toσ*O-O(35% Ooxo+ 39% O2ac). In33TS, the C-H bond approaches the Ooxoatom at a Mn-Ooxo-H angle of 113°. The calculated valence orbitals of33TS reveal that the three single-occupied orbitals on the Mn atom do not change,but theβ-electron single-occupied orbital changes from theσ*O-Oorbital in33RC to a newly mixed orbital ofσC-HandπMn-O(Mn: 8%, Ooxo: 18%, C: 29%, H: 8%) in33TS (Fig. 6a).This obvious change in the valence orbital indicates that theα-electron ofσC-His transferred to theσ*O-Oorbital during the formation of33TS. However, as the newly formed mixed orbital in33TS mainly consists of theσC-Horbital with a small contribution from the Mn-dorbital, subsequentβ-electron transfer from the mixed orbital to theα-electron single-occupiedπ*xyorbital could be favorable, resulting in the formation of33PC. These results show that oxidation intermediate 3 has two single electron-accepting orbitals (αMn-dxyandβσ*O-O), which can accept two electrons in a single step. Fig. 6b shows a schematic diagram of the electron transfer processes during C-H bond activation. The two electrons of theσC-Horbital in the reactant could be transferred in a single step to obtain the hydroxylated product quickly. This electronic structure analysis verifies that oxidation intermediate 3 can act as a two-electron oxidant for C-H bond activation[29].

Fig. 6. (a) Schematic UCO diagrams for the H-abstraction reactant (33RC), transition state (33TS), and product(33PC). (b) Diagram of orbital occupancy and electron transfer during hydroxylation

3. 4 Reactivity comparison with Mn(IV)-oxo species (5)

To confirm the advantages of the [(L)Mn(IV)(O···OC(O)-CH3)2-·]2+species (3) for the hydroxylation reaction, we also studied the hydroxylation reaction mechanism of the Mn(IV)-oxo species (5). Similar to many other non-heme species[45],the ground state of the Mn(IV)-oxo species is usually a quartet state, with the energy of the doublet being 9.4 kcal/mol higher than that of the quartet (Fig. 7a). The C-H bond hydroxylation reaction with the Mn(IV)-oxo species requires two steps. First, a stable intermediate configuration is obtained by a H-abstraction process, and then the hydroxylated product is obtained by oxygen rebound. Both the doublet and quartet states have high activation energies(15.7 and 17.6 kcal/mol, respectively) for the H-abstraction process. A high activation energy is also required for oxygen rebound from the stable intermediate. As shown in Fig. 7b,for the double state (S= 1/2), in the first step, oneα-electron ofσC-His transferred toπ*yzwith oneβ-electron remaining on ethylbenzene. In the second step, during oxygen rebound, the electron on the ethylbenzene radical is transferred toπ*yz.Unlike the single-step electron transfer process with oxidation intermediate 3, a two-step electron transfer process is required with the Mn(IV)-oxo species and the theoretical reaction rate is very low. Therefore, the reaction of ethylbenzene with the Mn(IV)-oxo species is much less favorable than that with oxidation intermediate 3.

Fig. 7. Hydroxylation mechanism of ethylbenzene with Mn(IV)-oxo species 5. (a) Energy profiles for the hydroxylation of ethylbenzene with 5 (in kcal/mol). The energies, including zero-point energy (ZPE) and solvent corrections, were calculated at the UB3LYP/B2 level. (b) Diagram of orbital occupancy and electron transfer during hydroxylation

4 CONCLUSION

In summary, we performed DFT calculations to explore the activation and hydroxylation mechanisms of a non-heme manganese complex. The calculation results showed that after H2O2activation, the non-heme manganese complex can form Mn(V)-oxo intermediates, with oxidation intermediate 3 being the main species involved in the hydroxylation reaction.This oxidation intermediate corresponds to[(PDP)Mn(IV)(O…OC(O)CH3)2-·]2+with aS(Mn) = 3/2 center and aσ*O-Oradical, where the O-O bond is not completely broken. With oxidation intermediate 3, C-H bond hydroxylation was found to proceed via a single step to produce a hydroxylated product. Our analysis of the changes to the electronic structure of oxidation intermediate 3 during C-H bond hydroxylation revealed the presence of two electron-accepting orbitals (αMn-dxyandβσ*O-O), which could simultaneously interact with the doubly occupied electron-donating orbital (σC-H) of the substrate. Therefore,oxidation intermediate 3 can act as a two-electron oxidant for C-H bond activation. In comparison, the hydroxylation reaction with [(PDP)Mn(IV)(O)(OAc)]+required a higher activation energy. Therefore, theσ*O-Oorbital formed by O2acand Ooxois beneficial to the reaction system and explains the experimental observation of improved reactivity in the presence of carboxylates. These findings provide new insights into the catalytic effects of additives such as acetic acid on the non-heme Mn/H2O2system, which may aid experimentalists in designing improved catalysts with higher efficiencies.