Understanding the catalase-like activity of a bio-inspired manganese(II) complex with a pentadentate NSNSN ligand framework. A computational insight into the mechanism

The mechanism of H2O2 dismutation catalyzed by the recently reported 2,6-bis[((2pyridylmethyl)thio)methyl]pyridine-Mn(II) complex ([MnS2Py3(OTf)2]) has been investigated by density functional theory using the S12g functional. The complex has been analyzed in terms of its coordination properties and the reaction of [MnS2Py3] in a distorted square pyramidal coordination geometry with two hydrogen peroxide molecules has been investigated in our calculations. The sextet, quartet and doublet potential energy profiles of the catalytic reaction have been explored. In the first dismutation process the rate-determining step (RDS) is found to be the asymmetric O-O bond cleavage, which occurs on the sextet potential energy profile. A subsequent spin crossover from sextet to quartet can take place generating a stable Mn(IV) dihydroxo intermediate. This could disfavor the ping-pong mechanism commonly considered to describe the 2 H2O2 dismutation reaction, where the binding of the first H2O2 substrate leads to the release of one H2O product and the conversion of the catalyst into a Mn(IV) oxo complex. The formation of this stable intermediate, featuring a peculiar trigonal prismatic coordination geometry paves the way for an alternative reaction pathway for the second dismutation process, termed the dihydroxo mechanism, where two water molecules and dioxygen are easily and simultaneously formed. The competing channels have different spin states: the sextet reaction pathway corresponds to the pingpong mechanism, whereas the quartet reaction follows preferably the dihydroxo mechanism. The doublet reaction path is energetically disfavored for both channels. For the ping-pong mechanism, the RDS in the second dismutation process is represented by the second hydrogen-abstraction from H2O2, with a calculated energy barrier very close to that of the RDS in the first dismutation reaction. Explicit solvent molecules, counterions and trace amounts of water are found to further support the preference for the asymmetric O-O bond breaking, by favoring the end-on coordination mode of H2O2 to the catalyst.

and catalases (CAT), which catalyze the dismutation processes of superoxide and hydrogen peroxide, respectively. Although the majority of CATs rely on the heme group for catalysis, an alternative class of manganese-dependent CATs (MnCATs) has been identified in three different bacteria. 3) Crystallographic studies have revealed that these MnCATs contain a dinuclear Mn core with bridging carboxylate and oxide ligands. 4) Several studies have been dedicated to develop novel synthetic MnCATs biomimetic complexes. 5 The first example of a dinuclear Mn(II) catalyst mimicking the natural enzyme function has been reported by Dismukes and coworkers. 6 More recently, catalase biomimetics include single-site Mn complexes, often showing both SOD and CAT activity, which can be used as artificial small molecule catalysts for ROS detoxification and are promising as therapeutics. 7 Indeed, some Mn(III)-porphyrin (for example AEOL10150), Mn(III)salen (for example EUK-113) and seven-coordinated Mn(II)-macrocyclic polyamine complexes (for example M40403) have entered clinical tests. [8][9][10][11][12] Although Mn-polyamine complexes show very high SOD-mimetic activity, 13 certain Mn-porphyrin and Mn-salen complexes exhibit dual SOD and CAT activity. [14][15][16][17] Additional functions of manganese complexes are known such as oxidation, [18][19][20] reduction, 21 or sulfur-oxygenation. 22 In a recent paper by Britovsek, Bonchio and coworkers, 23 23 The CAT-like activity of the [MnS 2 Py 3 (OTf) 2 ] complex, which is stable in an aqueous environment, is also higher than that of salen-type complexes, which decompose irreversibly in water after several minutes. The pH of the solution appears to have a major influence on the stability of the catalyst. A very active and remarkably stable catalyst performance is generated by the addition of base (NaOH, 1M, 10µL) as well as by addition of imidazole in aqueous solution using a borate buffer (pH 9). The different reactivity of [MnS 2 Py 3 (OTf) 2 ] containing sulfur donors compared to related ligands with N or O donors is unclear at this stage. However, a special role of sulfur ligation in biological systems based on manganese and related metal complexes, in particular cytochrome P450, is well documented. [18][19][20][21][22]24,25 The ability of sulfur donors to stabilize high valent metal complexes, while being susceptible to oxidation themselves, is not fully understood but must require careful balancing of the electronic and steric requirements. Noteworthy in this context, the sulfur donors in a manganese complex with a pentadentate thio-ketone-containing SNNNS ligand were found to inhibit antioxidant activity. 26 An understanding of the mechanism of the catalase reaction is a fundamental task for ligand rational design and tuning of single-site manganese-based catalytic complexes in order to achieve improved Theoretical studies on the mechanism of functional biomimetics of enzymes, although fundamentally important for a better understanding of the enzyme and the design of MnCATs with improved therapeutic properties, is a challenging task: different spin states are usually involved but many standard DFT functionals fail to predict the correct energy relationship between them. 31,32 For our investigations we used the S12g functional which has been recently recognized as a reliable tool for providing a correct picture of the spin state energy order in complicated transition metal systems and its accurate performance is well documented. [33][34][35] We are not aware of any studies in the literature on the mechanism of catalase-type reactions catalyzed by the pentadentate NSNSN-Mn(II) complex. This is precisely the aim of this work. We present here our S12g DFT investigation on the mechanism of H 2 O 2 dismutation reaction catalyzed by the [Mn(II)S 2 Py 3 (OTf) 2 ] complex on the three different potential energy surfaces of the doublet, quartet and sextet spin states.

Methods and Computational Details
A comprehensive DFT computational study was performed using the ADF2014.05 36-38 and the related Quantum-regions Interconnected by Local Descriptions (QUILD) program 39) to identify the structures of the reactant complexes, intermediates, transition states and product complexes of the hydrogen peroxide dismutation reaction catalyzed by [MnS 2 Py 3 ] 2+ . For geometry optimizations, calculations were carried out using the GGA functional BP86, 40 functions (core small) for all atoms. As mentioned above, the S12g functional has been shown to be a reliable tool for the energetics of spin states and to improve significantly the prediction of the reaction barriers in transition metal systems. 34,48 This spin-state consistent S12g density functional was designed to work well for spin states based on the observation 49

Results and Discussion
The initial complex To avoid uncertainties connected with using an incomplete model, 29 Figures S1-S4). The most stable species is shown in Figure 1 (left), where the ligand has a fmf coordination mode, with one triflate ligand in the axial position, in agreement with the octahedral geometry supported by NMR spectroscopy. [OTf] in Figure S1 in the SI) of the representing the apical position of the pyramid (see Figure 1 middle). This geometry is also seen in related Group 12 metal complexes of zinc and mercury with this ligand. 57 Due to the absence of any crystal field stabilization energy for d 10 and HS d 5 metal complexes, the coordination geometries are largely dictated by steric effects.
For our mechanistic study we therefore considered [MnS 2 Py 3 ] 2+ with an open coordination site at the axial position of a pseudo octahedral geometry (see Figure 1 right) in a sextet spin ground state as the initial catalyst precursor complex, which is in agreement with both the experimental 19 F NMR spectrum and the experimental magnetic moment value of 5.9-6.0 µ B (Fig. S4 and S1 ESI in ref. 23 ). A description of the spin density distribution in the [MnS 2 Py 3 ] 2+ initial complex (IC) is given in Figure 1 (middle). In the sextet spin state the spin density on Mn is 3.54, less than the   .

The reactant complex
The optimized geometries of the reactant complexes, denoted RCx (x=s for sextet, x=q for quartet and x=d for doublet), in the three different spin states are shown in Figure 3.   The transition state TSIs asymm structure is shown in Figure S6 in the SI.
From these results, we conclude that the O-O bond cleavage in H 2 O 2 leading to the Mn dihydroxo species is highly exothermic (ΔG=-25.5 kcal/mol with respect to the free reactants) and it takes place asymmetrically, through a transition state located on the sextet spin state followed by a spin crossover from the sextet to the quartet spin state, with a relatively low activation barrier ( The main geometrical parameters are displayed in Figure S7 in the SI.  In Figure 7 we see that the energy of the five Mn 3d singly occupied α-spin orbitals is lower than that of the empty H 2 O 2 σ* (α-and β-spin) orbitals in RCs side-on . In the Mn 3d singly occupied α-spin set, the lowest dδ(xz) has mainly metal character, whereas dπ(xy) and dπ(yz) are pushed up in energy by antibonding interaction with filled H 2 O 2 π* orbitals (with a contribution of 6%, and 12%, respectively). Remarkable S ligand atoms character can be found in dπ(yz) (16% 3p z S + 15% 3p z contribution (12% 2p y N). The electronic structure of RCs side-on accounts for the spin density distribution described in the previous section. Evolution of RCs side-on towards I OH s leads to the electronic structure also depicted in Figure 7. In I OH s one of the five α-spin unpaired electrons in (see Fig.5 and 7). In I OH the spin density on Mn and hydroxyl bonded to it is close to two, which can be similarly assigned to a Mn(IV), with roughly the third unpaired electron localized on the oxygen atom of the non-coordinating OH (0.47) (Fig. 6). Notably, I OH in the quartet state bears a much less radical character than that in I OH in the sextet spin state. Finally, in the I OHOH in the doublet state, one unpaired electron is delocalized on the Mn center (0.84) and on one oxygen atom of an hydroxyl group (0.17) (see Fig.5), whereas in I OH an antiferromagnetically coupled spin between the non-coordinating OH oxygen atom (about one beta-spin unpaired electron) and Mn (two alpha-spin unpaired electrons) has been found (see Fig. 6).  Figure   S8 in the SI.   there are three occupied bonding orbitals (pdσ, pdπ x and pdπ z , see the black up and down arrows in the α-and β-spin orbitals in Figure 9), and there are two unpaired electrons (red arrows) in the antibonding dpπ* x and dpπ* z . Notation pdσ and pdπ is used here for the low-lying bonding combinations of O 2p with Mn 3p orbitals, which are nominally "oxygen levels" (leading p contribution), whereas dpσ* and dpπ* denote the higher-lying antibonding orbitals, which are nominally "d orbitals" (leading d contribution). The difference of the MnO 2+ electronic structure with the basic O 2 -type bonding scheme is in the presence of the two nonbonding 3d orbitals on Mn of δ symmetry with respect to the Mn-O axis (here the y axis), the dz 2 and dxz orbitals. They contain two unpaired electrons (all unpaired electrons are denoted with red arrows) which, with the two unpaired electrons in the π* levels, add up to four. The fifth unpaired electron leading to the sextet spin state resides in the bonding pdπ x (Figure 9 top)). The sextet spin configuration (pdσ α) 1 (pdσ β) 1 (pdπ z α) 1 (pdπ z β) 1 (pdπ x α) 1 (pdπ x β) 0 (dpπ* x α) 1 (dpπ* z α) 1 (dz 2 α) 1 (dxz α) 1  complexes. [76][77][78] This high-spin configuration reverts to the quartet spin configuration (pdσ α) 1 (pdσ β) 1 (pdπ z α) 1 (pdπ z β) 1 (pdπ x α) 1 (pdπ x β) 1 (dpπ* x α) 1 (dpπ* z α) 1 (dz 2 α) 0 (dxz α) 1 ,where both the pdπ (π bonding) orbitals are occupied and the δ nonbonding is empty, leading to a Mn-O bond order of 2 and getting stabilized by 31.2 kcal/mol (Figure 8). In the sextet spin state the lowest-lying vacant orbital is pdπ x β, which is bonding between the Mn dxy and O p x orbitals, whereas in the quartet state the lowest-lying vacant orbital is dpπ* x β, which is antibonding between the Mn dxy and O p x orbitals (see Figure 9). The energy of the lowest vacant orbital and its oxygen p orbital contribution are the two important factors in predicting the electrophilicity of a MO 2+ moiety. Generally speaking, the lower the acceptor orbital lies in energy and the higher the % oxygen p orbital contribution is, the more electrophilic the MO 2+ will be: in our case they are both in favor of a large electronic donation from the H-OOH bond into the MnO 2+ acceptor orbital. Based on these two factors, a much higher reactivity of the Mn oxo intermediate in the sextet spin state is expected, since both the energy of the acceptor pdπ x β orbital is lower (-6.65 eV vs. -4.19 eV for dpπ* x β in the quartet state) and the % oxygen p x orbital contribution is higher (59% vs. 15% for dpπ* x β in the quartet state). The spin density distribution resulting from electronic structure in PC oxoI intermediates is shown in Figure 8. In PC oxos the spin density on the metal/ligand system is overall close to four, with roughly three unpaired electrons on the single metal, assigned to high-spin Mn(IV), and with the fifth unpaired electron localized on the oxo oxygen, leading to an overall electronic structure in the sextet state. In PC oxoq the spin density is 0.64 on the oxo oxygen and close to two on Mn which sums up to three unpaired electrons on the whole complex. Finally, in PC oxod one unpaired electron is delocalized over the Mn center and the oxo oxygen. In Table S1 in the SI the Multiple Derived Charges (MDC) spin densities 56 are reported for all the species (initial complexes (IC), reactant complexes (RC I ), intermediates (I OHOH , I OH ) and product complexes (PC Ioxo )) involved in the first dismutation reaction.
In conclusion, the [MnS 2 Py 3 ] 2+ -catalyzed first dismutation reaction can be described as a multichannel process combining both ping-pong and dihydroxo pathways. The competing channels have different spin states: the sextet reaction pathway corresponds to a ping-pong mechanism, the doublet should allow both a ping-pong and a dihydroxo mechanism, and the quartet would preferably follow a dihydroxo mechanism. Importantly, the two mechanistic channels are characterized by different coordination geometries of the involved species: octahedral in the pingpong route, trigonal prismatic in the dihydroxo path, suggesting that the reaction mechanism is controlled by spin transitions triggered by Mn coordination switching and vice versa. Both the Mn oxo (sextet and quartet spin state) and the Mn dihydroxo (quartet spin state) species have spin density on oxygen, a factor that has been found to be crucial in promoting hydrogen abstraction. 79

Second dismutation reaction
A manganese(IV) dihydroxo compound in a quartet spin state has been obtained as a thermodynamically stable product from the first dismutation reaction. The second dismutation reaction should convert hydrogen peroxide to two water molecules and dioxygen. Due to the complex picture of the second dismutation reaction as a multichannel process with different spin states, we present our findings for each spin state separately.
All of the reaction profiles for the three different spin states and for the two pathways (ping-pong and dihydroxo) are compared in Figure 10, where the energy of the separate reactants I OHOH q + H 2 O 2 and PC oxo q + H 2 O 2 are taken as zero reference energy. Two very interesting features can be observed from Figure 10: firstly, the strong hydrogenabstraction ability of PC oxo s is responsible for the sextet energy profile to be the lowest energy path for the ping-pong route. A second spin transition from quartet to sextet occurs after the TSIoxoq has been reached with an activation energy barrier of 6.8 kcal/mol for the first hydrogen abstraction from H 2 O 2 . Secondly, the high reactivity of I OHOH q results in a very low barrier along the quartet energy profile for the dihydroxo route. These two features make the ping-pong path on the sextet spin state and the dihydroxo path on the quartet spin state the two minimum energy channels. The rate determining step of the second dismutation reaction is the second hydrogen abstraction from H 2 O 2 , namely by TSII OHOH q and TSII OH s in Figure 10. However, the activation energy barrier along the quartet energy profile is much lower than that along the sextet (1.8 vs. 10.5 kcal/mol, respectively).

Sextet state reaction pathway.
As mentioned above, only the ping-pong mechanism has been considered for the sextet state and a stepwise path has been calculated as depicted in Figure 10 (black dashed line energy profile) . The optimized geometries for the involved species can be found in Figure S9 in the SI. Despite many attempts, we failed to find a stable reactant complex RCII oxo s starting from PC oxo s and a vicinal  The electronic structure analysis of II OH s shows that the lowest α-spin vacant orbital can be described as a σ* orbital between the oxygen atom of the OH (8% p y ) and Mn (27% dxy + 20 dx 2y 2 ) which is a suitable acceptor orbital in the hydrogen abstraction reactivity. Both its relatively high energy (-4.623 eV with respect to -5.268 eV of the lowest β-spin vacant orbital of OOH π* character) and low oxygen p orbital contribution (8%) are responsible for the calculated 10.5 kcal/mol energy barrier. The spin density distribution resulting from its electronic structure is shown in Figure 10. The II OH s has four unpaired electrons on the metal complex (roughly three on Mn and one delocalized over the S donor atoms and OH oxygen atom), and one unpaired electron on OOH moiety, the latter showing a radical character, which leads the overall species to a sextet spin state.
In conclusion, in the sextet reaction channel a ping-pong mechanism would be feasible, with the second proton transfer being the rate-determining step of the second dismutation reaction.

Quartet state reaction pathway.
It was found that the reaction in the quartet spin state could proceed through a dihydroxo mechanism. When the second H 2 O 2 substrate approaches the dihydroxo intermediate I OHOH q, two possible conformations for the reactant complex RCII OHOH can be obtained, based on the two hydrogen bonds which can be formed between the hydrogen atoms of H 2 O 2 and the two OH groups coordinated to Mn. In the first configuration, denoted as RCII OHOH q, H 2 O 2 acts as a proton donor for one bond and as a proton acceptor for the other. In the second configuration, denoted as RC'II OHOH q, H 2 O 2 acts as proton donor for both bonds. The optimized geometries of the two reactant complexes are depicted in Figure S10 in the SI. The most stable reactant complex is RCII OHOH q, which is less stable than the sum of the Gibbs free energies of the isolated reactants (I OHOH q + H 2 O 2 ) by 6.9 kcal/mol. The alternative reactant complex in the quartet spin state, RC'II OHOH q, is 12.0 kcal/mol higher in energy than the free reactants. In the RCII OHOH q structure an  Figure 10 and S10) which is more stable than RCII OHOH q by 3.6 kcal/mol. A water molecule is released with the hydroperoxo group substituting the leaving H 2 O ligand in the Mn coordination sphere. Note that the Mn coordination features in I OHOOH q (in particular the elongated Mn-N pyridine bond trans to the two hydroxo ligands leading to the trigonal prismatic coordination geometry in I OHOH q) are retained (see Figure S10). Starting from the geometry of I OHOOH q, the TSII OHOOH q structure can be obtained by forcing the H atom of the hydroperoxide ligand towards the oxygen of the hydroxide ligand. In the TSII OHOOH q geometry (see Figure S10) A very modest amount of energy (1.8 kcal/mol) is needed to activate this step. The PCIIq product complex is more stable than RCII OHOH q by 14.6 kcal/mol and it is also more stable than PCIIs by 11.0 kcal/mol. Our study reveals that the intermediate I OHOH q formed in the first dismutation reaction rapidly evolves to give two H 2 O and one O 2 product molecules, with a very low energy cost (dihydroxo mechanism). The lowest α-spin vacant orbital of II OHOOH q has a mainly metal character (13% dxy + 16 dx 2 -y 2 + 9% dz 2 + 8% dxz) with a small contribution from the oxygen atom of OH (4% p z + 2% p y ), interacting in an antibonding fashion. This orbital can be a suitable acceptor orbital in the hydrogen abstraction, with a relatively low energy (-5.284 eV), although the oxygen p orbital contribution (6%) is also low. The II OHOOH q has somewhat more than two unpaired electrons on the metal complex, roughly two on Mn and the remaining delocalized over the OH (0.16) and OOH (0.11) oxygen atoms (see Figure 10).
However, as mentioned above, one may argue that the catalyst could be temporarily deactivated for the ping-pong mechanism if it entered the dihydroxo reaction route in the first dismutation process, due to formation of the thermodynamically stable I OHOH q. The issue we want to address now is what happens if the catalyst does not enter the I OHOH q reaction path but it follows the ping-pong mechanism.
The energy profile for this stepwise path is depicted in Figure 10 as dashed red lines. The optimized geometries of the involved species can be found in Figure S11 in the SI.
The reaction starts with the reactant complex RCIIoxoq which is less stable than the separate reactants PC oxo q + H 2 O 2 by 5.8 kcal/mol. The hydrogen abstraction by the Mn-oxo requires an activation energy barrier of 6.8 kcal/mol through a transition state characterized by a very productlike structure (TSIoxoq), leading to intermediate I OH q in Figure 10 and S11. Geometry rearrangement to yield the structure denoted II OH q further destabilizes I OH q by 1.1 kcal/mol, and, as for the sextet, it shows the hydroperoxo group hydrogen-bonded to Mn-OH acting as a hydrogendonor, with a OOH-OH distance of 1.418 Å. Analogously to the sextet spin route, in the OOH hydrogen approach to OH-Mn, the energy goes uniformly uphill and neither a transition state nor a product complex with a water molecule bound to Mn could be calculated, but, rather, a transition state for the second proton transfer can be reached by allowing an oxygen atom of OOH to interact with Mn. The TSII OH q geometry is depicted in Figure S11  The geometry is shown in Figure S14 in the SI, where the alternative product complex with a H 2 O molecule coordinated to Mn (PC'IIo) has also been calculated. Incidentally, PC'IIo, with the O 2 molecule in the second coordination sphere and thus without magnetic coupling, is more stable than PCIIo by 9.9 kcal/mol. On comparing the PCIIo geometry with that of the initial catalyst shown in Finally, we briefly comment on the lack of reactivity in the hydrogen abstraction for II OH q species in Figure 10. Inspection of its electronic structure reveals that the lowest lying vacant orbital has mainly OOH character, and no suitable acceptor orbitals containing OH contribution are available at low energies.
For the doublet state reaction pathway, we note that the doublet spin state has shown intermediate features between those of the quartet and the sextet reactions. The second dismutation process in the doublet state can in principle proceed via both a ping-pong and a dihydroxo mechanism, since both PC oxo d and I OHOH d are accessible species. However, the energy profiles for both mechanisms are always higher than those for the sextet and quartet spin states, therefore the doublet state reaction pathway seems unfavorable in the second dismutation reaction for both channels. Results for the second dismutation reaction in the doublet spin state are discussed in detail in the SI (Figures S12 and S13 ).
Spin density values for all the species involved in the second dismutation reaction can be found in the SI (Tables S2-S5).

Solvent, counterion and water effects on the O-O bond breaking of H 2 O 2
The role of solvent, counterion and trace amount of water in acetonitrile can be important in the   Figure S15 in the SI) is taken as zero reference energy. ΔG # values represent the free energy barriers with respect to the reactant complex.
In each case we calculated the corresponding initial complex IC solv , IC OTf and IC H2O , respectively (geometries are shown in Figure S15 in the SI) and the Gibbs free energies of the separate reactants IC + H 2 O 2 are taken as zero reference energy. We should recall here that in the reactant complex in the sextet spin state two different coordination modes around Mn have been found using only COSMO: in the RCs end-on mmf structure coordination of H 2 O 2 occurs in cis position with respect to the central Py ring of the ligand, whereas in the RCs side-on fmf structure it takes place trans to it, retaining the initial catalyst coordination mode (see Figure 3). Interestingly, inclusion of additional  Figure S15 in the SI). This finding suggests that H 2 O 2 coordinated in the end-on form represents the actual reactive species also in the RCs side-ontype structure and further corroborates the preference for the asymmetric O-O bond breaking process we found before. Notably, the presence of two explicit acetonitrile molecules significantly stabilizes the RC cis solv with respect to the reference COSMO RCs end-on (by 5.3 kcal/mol, compare RC cis solv with RCs end-on in Figure 3), whereas it only slightly destabilizes the RC trans solv with respect to RCs side-on (by 0.2 kcal/mol, compare RC trans solv with RCs side-on in Figure 11). Inclusion of trace amounts of water destabilizes the RC trans H2O with respect to RCs side-on by 3.5 kcal/mol, with RC cis H2O and RC trans H2O having the same energy (see Figure 11) .  Figure 11), thus decreasing the free energy barrier with respect to the reactant complex ΔG # (7.9 vs. 9.0 kcal/mol for TSI trans solv and TSIs side-on , respectively). bond breaking, which is slightly decreased (7.9 and 8.6 vs. 9.0 kcal/mol, respectively). Both trace amounts of water and OTfincrease the reactant complex and the transition state energy with respect to the separate reactants , which will not favor this process. Finally, since we have found that the activation energy barrier for the RDS of the first dismutation reaction is slightly decreased by inclusion of explicit solvent molecules, we expect that insertion of two explicit acetonitrile molecules will influence the activation energy barrier for the RDS of the second dismutation reaction along the sextet pathway. Optimization calculations performed on II OH s and TSII OH s are depicted in Figure S16 in the SI. Similarly, ΔG # is found to decrease slightly from 10.5 kcal/mol (COSMO only) to 9.0 kcal/mol. On the basis of these findings, we can reasonably conclude that O-O bond breaking process in the first dismutation reaction can be considered the RDS for the overall reaction for the dihydroxo pathway, whereas both the O-O bond breaking in the first dismutation reaction and the second hydrogen abstraction from H 2 O 2 in the second dismutation process have very close activation barriers (7.9 and 9.0 kcal/mol, respectively) for the ping-pong pathway.
Molecular dynamic calculations, which are beyond the scope of this paper, would be useful to definitely discriminate the RDS for the overall reaction between these two steps and to elucidate the role of a viable H 2 O 2 coordination in a cis position with respect to the central Py ring of the ligand in the reactant complex in the first dismutation reaction.

4.Conclusions
The present work describes a DFT S12g functional computational study on the mechanism of H 2 O 2 dismutation reaction catalyzed by the [MnS 2 Py 3 (OTf) 2 ] complex that acts as a catalase mimic and for which experimental data are available. 23 In our calculations the complex has been preventively analyzed in terms of coordination properties since experimental X-ray structural data were lacking.
We found that a [MnS 2 Py 3 ] 2+ complex in a distorted square pyramidal coordination geometry is the proper catalyst for the reaction with the peroxide molecule. The sextet, quartet and doublet potential energy profiles of the catalytic reaction have been explored.
In the first dismutation reaction the rate-determining step is found to be the asymmetric O-O bond cleavage, which occurs on the sextet potential energy profile. A subsequent spin crossover from sextet to quartet, driven by a geometry coordination change at the metal center, can take place generating a stable Mn(IV) dihydroxo intermediate which represents a deactivated form of the catalyst in the ping-pong mechanism. However, we have shown that the formation of this stable intermediate paves the way to an alternative reaction pathway for the second dismutation process, termed the dihydroxo mechanism. These two competing channels have different spin states: the sextet reaction pathway corresponds to a ping-pong mechanism, whereas the quartet reaction follows preferably a dihydroxo mechanism where the two water molecules and dioxygen are very easily and simultaneously formed in the second dismutation process. The reaction mechanism is controlled by a spin state crossover triggered by Mn coordination switching from octahedral (in the ping-pong route) to trigonal prismatic (in the dihydroxo path). The doublet reaction path is unimportant for both channels since it is always energetically disfavored. Our results suggest that the bottleneck for the whole dismutation process is however

Notes
The authors declare no competing financial interest.