Control of C–H Bond Activation by Mo-Oxo Complexes: pKa or Bond

Article pubs.acs.org/IC

Control of C−H Bond Activation by Mo-Oxo Complexes: pKa or Bond Dissociation Free Energy (BDFE)? Azadeh Nazemi and Thomas R. Cundari* Department of Chemistry, Center of Advanced Scientific Computing and Modeling (CASCaM), University of North Texas, 1155 Union Circle, #305070, Denton, Texas 76203-5017, United States S Supporting Information *

ABSTRACT: A density functional theory (DFT) study (BMK/631+G(d)) was initiated to investigate the activation of benzylic carbon−hydrogen bonds by a molybdenum-oxo complex with a potentially redox noninnocent supporting liganda simple mimic of the active species of the enzyme ethylbenzene dehydrogenase (EBDH) through deprotonation (C−H bond heterolysis) or hydrogen atom abstraction (C−H bond homolysis) routes. Activation free-energy barriers for neutral and anionic Mo-oxo complexes were high, but lower for anionic complexes than neutral complexes. Interesting trends as a function of substituents were observed that indicated significant Hδ+ character in the transition states (TS), which was further supported by the preference for [2 + 2] addition over HAA for most complexes. Hence, it was hypothesized that C−H activation by these EBDH mimics is controlled more by the pKa than by the bond dissociation free energy of the C−H bond being activated. Therefore, the results suggest promising pathways for designing more efficient and selective catalysts for hydrocarbon oxidation based on EBDH active-site mimics.

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INTRODUCTION

Based on previous work in our group, deprotonation of a methyl ligand by a nucleophile/base is a problematic side reaction in reductive functionalization of metal-methyl complexes (see Scheme 1). Therefore, to assess which one of the pathways in Scheme 1 is more plausible, pKa values of hydrocarbon C−H bonds in the coordination sphere of transition metals must be better studied.10 Research in our group indicated that, among 3d metal (VII through CuII)-methyl complexes, only reductive functionalization of CrII-methyl complex competes with the analogous deprotonation reaction. Thus, the investigation of Group 6 complexes was proposed as a promising objective for moreselective C−O bond formation.11 Among the metal-based enzymes, ethylbenzene dehydrogenase (EBDH) has been much less, experimentally and computationally, subjected to detailed study, in comparison to other metalloenzymes such as cytochrome P-450. Furthermore, EBDH is a molybdenum (and, thus, Group 6) enzyme that hydroxylates the alkylaromatic and alkylheterocyclic substrates.12 Considering the active species of EBDH, and a previous computational and experimental study of [(dadi)Cr = NR] (where dadi = diamidediimine), 13 an oxo (isovalent to imide) complex of molybdenum (in the same group at Cr) was chosen for the present study. In this research, a density functional theory (DFT) study was performed to understand the extent to which the pKa of a C−H bond impacts productive C−H activation

The importance of the activation and functionalization, especially in a selective manner, of the kinetically inert and thermodynamically strong carbon−hydrogen bonds of light alkanes has attracted much attention, because of the desire to exploit hydrocarbon mixtures from oil and natural gas as feedstocks for the chemical industry. Hence, overcoming the stability of C(sp3)−H bonds, which is an obstacle to achieving functionalized hydrocarbons under mild conditions, has been a well-studied topic in catalysis for the past several decades.1−3 The development of new catalysts to selectively and efficiently activate C−H bonds has led to extensive studies into the chemistry of metal-oxo complexes that are inspired by the active species of metalloenzymes. Cytochrome P-4504−6 and particulate methane monooxygenase (pMMO),7,8 whose active sites contain the Earth-abundant 3d transition metals iron and copper, respectively, are two metal-based enzymes that have been studied to design transition metal-oxo complexes for C− H activation by mimicking the active species of these proteins. C−H activation by these metal-oxo catalysts normally goes through a radical rebound route, which follows the abstraction of a hydrogen atom from the target substrate (RH), and involves a carbon-based radical and metal−OH species, which then merge to result in the oxidized hydrocarbon (ROH) and the reduced metal complex.9 Since the mechanism is a radical process, usually very unselective for abiological systems, finding new metal-oxo complexes that catalyze hydrocarbons via deprotonation pathways is of interest. © XXXX American Chemical Society

Received: July 12, 2017

A

DOI: 10.1021/acs.inorgchem.7b01738 Inorg. Chem. XXXX, XXX, XXX−XXX

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Scheme 1. Reductive Functionalization of 3d Metal(II)-Methyl Complexes and the Competitive Pathway (a) Hydroxylation of the Methyl Group (Red), and (b) Deprotonation of the Methyl Group (Blue). Adapted, with permission, from refs 10 (Copyright 2015, Elsevier, Amsterdam) and 11 (Copyright 2016, American Chemical Society, Washington, DC)

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processes. Initially, three levels of theory were calibrated by optimizing 18 hydrocarbons for which experimental pKa values are available to attain the most suitable basis set/functional (BMK/6-31+G(d)) for subsequent calculations. The BMK/631+G(d) level of theory was selected based on the work of Ho and Coote, who tested several levels of theory for calculating the proton affinities of different types of carbon acids, such as amino acids and derivatives.14 Second, this level of theory was applied to benzylic C−H activation of six para-substituted and six meta-substituted (−NO2, −NMe2, −CN, −OCH3, −SiH3, −CH3) toluenes by a Mo-oxo complex with a potentially redox noninnocent supporting ligand (dadin, where, typically, n has values between 2− and 4−). The purpose of the present research is to assess whether pKa or the bond dissociation free energy (BDFE)or perhaps some other factoris more important for facile C−H bond activation via deprotonation (C−H bond heterolysis) or Hatom abstraction (C−H bond homolysis) pathways. Based on literature precedent, two plausible transition states for benzylic C−H bond activation by a Mo-oxo complex were studied: hydrogen atom abstraction (HAA) or [2 + 2] addition, the reactions of interest and two possible pathways are shown in Scheme 2.15−17 An HAA pathway implies radical character or

COMPUTATIONAL METHODS

Calculations were performed using the Gaussian 09 software package18 for all molecules in dimethyl sulfoxide (DMSO) (with a dielectric constant of ε = 46.7) solvent applying the SMD continuum solvent model19 at standard temperature (298.15 K) and pressure (1 atm). DFT calculations were calibrated by initially testing three levels of theory, B3LYP/6-31G(d), B3LYP/6-31+G(d),20−25 and BMK/631+G(d),14,26 for modeling 18 hydrocarbons. After geometry optimization, their ΔGcalc and pKa’ values, which were calculated utilizing the equations below (eqs 1 and 2), were compared to experimental data.27 BMK/6-31G+(d) data are reported in Table 1.

RH + DMSO → [DMSO−H]+ + R− pK a =

ΔGcalc

(1)

ΔGcalc 2.303RT

(ΔG (in kcal/mol), R = 0.00198 kcal/mol, T = 298.15 K) (2) 2

Based on the coefficient of determination (R ) values shown in the plots of calculated versus experimental data (see Figure S-1 in the

Table 1. Calculated, BMK/6-31+G(d), and Experimentala pKa Values of Hydrocarbons (Acidity in Dimethylsulfoxide (DMSO))

Scheme 2. Reactions of Interest and Two Plausible Transition States for Benzylic C−H Activation by dadi-Mooxo Complex: (a) [2 + 2] Addition and (b) Hydrogen Atom Abstraction (HAA)a

a X = para- or meta-H, NO2, NMe2, CH3, CN, SiH3, OCH3; Ar = phenyl.

homolytic cleavage of the substrate C−H bond, while the [2 + 2] pathway suggests proton character or heterloytic cleavage of the substrate C−H bond. To evaluate potential design criteria for more efficient and selective Mo-oxo catalysts, calculated activation free energies for all six p-/m-substituted toluenes have been compared with relevant calculated pKa values and BDFEs.

a

B

Data taken from ref 27. DOI: 10.1021/acs.inorgchem.7b01738 Inorg. Chem. XXXX, XXX, XXX−XXX

Article

Inorganic Chemistry Supporting Information), there were small differences among the three tested levels of theory, with respect to predicting pKa values of hydrocarbons. However, calculated pKa values by BMK/6-31+G(d) were somewhat more in harmony with experimental data, showing the lowest y-intercept, compared to other linear regression plots. Thus, based on this calibration, and also the work of Ho and Coote,14 the BMK/6-31+G(d) level of theory was chosen for all subsequent calculations. Calculations on Mo-oxo complex models have been done using the BMK functional, in conjunction with the CEP-121G28−30 pseudopotential/valence basis set for Mo and the 6-31+G(d) all-electron basis set for other elements. In the present study, all Gibbs free energies are reported in units of kcal/mol. No imaginary vibrational frequencies are calculated for ground states, whereas transition states possess only one imaginary frequency, which is related to the motion of the active hydrogen between the benzylic carbon of the substrate and the oxygen of the Mo-oxo complex.

oxo complexes, triplet (neutral) and doublet (anion) states had lower free energies (see Table S-1 in the Supporting Information). Since the triplet and doublet states are lowest for the neutral and anionic complexes, respectively, and both are open-shell structures, analysis has been done to assess the spin density (Figure 1) in these reactants. In the case of the triplet, neutral

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RESULTS AND DISCUSSION Structural Analysis of Reactants. The overall reaction of interest is hydrogen atom transfer to the Mo-oxo complex to form the corresponding hydroxide. At the beginning stage of the reaction, the catalyst model reacts with different para-/ meta-substituted toluenes. The modeled active species consists of a Mo-oxo chelated by a diamide-diimine redox noninnocent (RNI) tetradentate ligand, [dadi]n (typically, n has a value between 2− and 4−). The oxo plays the role of an actor ligand, while dadi is a supporting ligand. Literature precedent suggests13 that dadi typically lies between two electronic descriptions: one has a “double−single−double bond” arrangement (the NC−CN, diimine or dadi2− form) and the other extreme possesses a “single−double−single bond” (the N−CC−N, diamide or dadi4− form). There are possible redox states between these two extremes, including the radical trianion and the triplet form of the “diimine” structure (see Scheme 3).

Figure 1. Spin density (isovalue = 0.01) plots of triplet neutral dadiMo-oxo complex. Bond lengths are given in Å.

(dadi)MoO, spin density plots and Mulliken population analysis indicated that the unpaired electrons are not concentrated on the metal alone, suggesting redox noninnocent behavior for the dadi ligand. Given the one unpaired electron calculated to reside on the Mo, the metal has reduced the dadi valency to 3− and is itself formally 5+ (d1), so the complex may be defined as 3[(dadi)3−(d1-Mo)5+(=O)2−]. For the doublet, anionic complex, spin density and Mulliken population analysis show the existence of only very little unpaired electron density on either the dadi ligand or the oxo oxygen atom, which suggests a redox innocent state for the former. Moreover, bond lengths for the doublet anionic complex indicate that the ligand is close to the “single−double−single” extreme (see Figure 2), which infers the oxidation state of the dadi as −4. Thus, the ground state of the anionic complex may be best described as 2 [(dadi)4−(d1-Mo)5+(=O)2−]−.

Scheme 3. Two Resonance Structures of the (dadi)n Ligand: (a) “Diamine” Form of dadi (dadi2−) and (b) “Diamide” Form of dadi (dadi4−)

Dadi is a redox active ligand by which the electronic properties of the metal to which it is coordinated may be adjusted.31 Neutral and anionic dadi-Mo-oxo complexes were considered for the purposes of this study. For example, consider the dadi2− or dadi4− descriptions for the neutral complex, if the oxo oxygen is formally 2−, the formal charge of Mo will be 4+ (d2) or 6+ (d0), respectively. In the case of the anionic complex, Mo possesses 3+ (d3) and 5+ (d1) formal oxidation states if one considers dadi2− and dadi4− formulations, respectively. Assuming a square pyramidal geometry (with the oxo at the apex), akin to the reported [(dadi)Cr-imide] structure,13 four plausible multiplicities, two each for neutral and anionic Mooxo complexes, were studied to identify the more stable spin states for each: singlet and triplet for the neutral, doublet and quartet for the anionic Mo-oxo complex. For the reactant Mo-

Figure 2. Spin density (isovalue = 0.01) plots of doublet anionic dadiMo-oxo complex. Bond lengths are given in Å.

Analysis of Mo−OH Products of C−H Activation. To study the products, all plausible spin states of neutral and anionic dadi-MoOH were optimized. Both neutral and anionic complexes were sought and the calculations indicate that the doublet and singlet are the lowest free energy for neutral and C

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were no significant unpaired electrons on the dadi ligand and oxygen atom, hence, the major portion of the unpaired electron density is on the metal, indicating that this complex contains a redox innocent dadi ligand: [(dadi) 4−(d2-Mo)4+(OH)−]− (Figure 4). Based on the spin density analysis, the “best” Lewis structure description of the neutral reaction is

anionic Mo-hydroxyl complexes, respectively (see Table S-2 in the Supporting Information). Spin density plots for optimized hydroxyl products have also been analyzed, and they are shown in Figures 3 and 4. Spin

RH + 3[(dadi)3 − (d1‐Mo)5 + (O)2 − ] → R• + 2[(dadi)3 − (d2‐Mo)4 + (OH)− ]

(3)

and, for anionic Mo-oxo complex, is RH + + 2[(dadi)4 − (d1‐Mo)5 + (O)2 − ] → R• + [(dadi)4 − (d2‐Mo)4 + (OH)− ]−

(4)

Hence, the DFT calculations suggest electronic reorganization, as a result of the C−H scission event, for which it would be of interest to further investigate by multiconfiguration SCF (MCSCF) methods. Homolysis and Heterolysis of the Substrate C−H Bond. To understand the nature of the carbon−hydrogen bond being broken in the transition state, two limiting mechanisms were considered, i.e., homolysis and heterolysis of the benzylic C−H bond (Scheme 4). For this purpose, C−H Scheme 4. Heterolytic and Homolytic C−H Bond Cleavage

Figure 3. Spin density (isovalue = 0.01) plots of (a) a doublet neutral dadi-Mo−OH complex and (b) a quartet neutral dadi-Mo−OH complex. Bond lengths are given in Å.

bond scission of toluene was used as a standard, and several para-/meta-substituted toluenes were computed to determine if the calculated ΔG⧧ correlated more closely with either the computed pKa or the computed BDFE of the benzylic C−H bond being activated (see Table 2). With respect to homolytic C−H bond cleavage of the substituted toluenes, electron-withdrawing groups (EWGs) such as nitro (NO2) and cyano (CN) lowered the pKa of toluene (51.5), by resonance effects in para position, NO2 (35.1) and CN (42.6), more than inductive effects from the Table 2. BMK/6-31+G(d) Calculated BDFEs and pKa Values of p-/m-Substituted Toluene

Figure 4. Spin density (isovalue = 0.01) plots of the triplet anionic dadi-Mo−OH complex state. Bond lengths are given in Å.

density and orbital analysis of the doublet neutral hydroxyl, which is 4.0 kcal/mol more stable than the quartet, were performed. Three metal-containing spin orbitals were identified with spin density spread across both the supporting ligand and metal, which is in harmony with a Mulliken population analysis that indicates a redox noninnocent dadi ligand and no spin density on the oxygen atom; thus, the best assignment for this complex is 2[(dadi)3−(d2-Mo)4+(OH)−] (Figure 3a). The quartet neutral product also contains redox noninnocent dadi ligand, and 2 unpaired electrons (e−) on Mo, suggesting a [(dadi)3−(d2-Mo)4+(OH)−] description (see Figure 3b). Regarding the anionic hydroxyl complex, spin density and Mulliken population analysis of the triplet indicated that there

benzylic compound

pKa

BDFE (kcal/mol)

σp/σma

toluene p-NO2-toluene m-NO2-toluene p-NMe2-toluene m-NMe2-toluene p-xylene m-xylene p-CN-toluene m-CN-toluene p-SiH3-toluene m-SiH3-toluene p-OCH3-toluene m-OCH3-toluene

51.5 35.1 46.6 53.7 52.9 52.5 51.7 42.6 47.7 47.3 50.2 52.9 52.3

82.4 81.9 83.2 79.1 83.2 83 82.6 83.4 83.1 82.5 81.7 78.4 82.5

0 0.78 0.71 −0.83 −0.16 −0.17 −0.07 0.66 0.56 0.1 0.05 −0.27 0.12

49.0 ± 5.3

82.1 ± 1.6

average ± SD a

D

Data taken from ref 32. DOI: 10.1021/acs.inorgchem.7b01738 Inorg. Chem. XXXX, XXX, XXX−XXX

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calculated ΔGrxn in Table 3, all reactions preferred hydrogen atom transfer over both proton and hydride transfer other than the product generated via benzylic activation of p-NO2-toluene; for the case of p-NO2-toluene, deprotonation was the preferred the reaction pathway; furthermore, ΔGrxn, in this case, had the least endergonic value (35.4 kcal/mol). In the case of H+ transfer, comparing the resonance effect with the inductive effect of −NO2 indicating that p-NO2, ΔGrxn(H+) = 35.4 kcal/ mol, Table 3, lowered the Gibbs free energy of reaction for toluene (57.9 kcal/mol), by 15.8 kcal/mol more than observed for m-NO2-toluene (ΔGrxn(H+) = 51.2 kcal/mol). Regarding H• transfer, there is a small difference in the thermodynamics of H atom transfer between para- and meta-NO2-toluene. For pCN-toluene, the energies of H+ and H• transfer are close, ΔΔGrxn ≈ 3 kcal/mol, whereas, for the meta versions, ΔΔGrxn ≈ 10 kcal/mol. This suggests that proton and H atom transfer pathways are close for EWG functional groups (NO2 and CN) due to a combination of resonance (para > meta) and inductive factors. For p-NMe2, the energies of H− and H• transfer are very close, ΔΔGrxn ≈ 1 kcal/mol, but the hydrogen atom abstraction was preferred. Structural Study of the Transition States. Two mechanisms of C−H activationand, hence, two transition state typesare expected for these Mo-oxo complexes: hydrogen atom abstraction (HAA) and [2 + 2] addition (see Scheme 2). In HAA, there is a three-center (almost-linear O··· H···C) active site; the oxo oxygen abstracts a hydrogen from the benzylic carbon, generating a benzyl radical or, in the case of p-NO2-toluene for the neutral (dadi)MoO complex, a carbocation. Mo−Cbenzyl direct interaction is minimal in the HAA transition state. The [2 + 2] or four-center transition state is kite-shaped and entails the addition of the target C−H bond across the Mo-oxygen multiple bond to simultaneously form Mo−Cbenzyl and O−H bonds. The [2 + 2] pathway may be expected to reflect proton character in the transition state of C−H bond activation given that this pathway is largely the domain of electrophilic (often d0) transition-metal ions bound to nucleophilic activating ligands, while the HAA pathway may be expected to signify a more radical hydrogen in the TS. Figures 5 and 6 display two typical transition states obtained in our calculations, [2 + 2] and HAA, in which Mo-oxo complex reacts with toluene. As mentioned above and shown in Figure 5, four atoms are involved in the [2 + 2] active site for which angles of O−Mo−C, Mo−O−H, and O−H−C are 71.3°, 76.6°, and 162.5°, respectively; the optimized O−H, H− C, Mo−O, Mo−C, and Mo−H bond lengths are 1.24, 1.43, 1.84, 2.57, and 2.00 Å, respectively, for this kite-shape transition state for toluene C−H activation. Regarding the HAA transition state for toluene depicted in Figure 6, calculated O−Mo−C, Mo−O−H, and O−H−C angles were 34.9°, 119.5°, and 174.0°, respectively, and O−H, H−C, Mo−O, and Mo−C bond lengths were 1.07, 1.68, 1.90, and 4.08 Å. The obtuse angle of Mo−O−H (119.5°) plus a long Mo−C bond length (4.08 Å) indicate that this TS is of the HAA type and that the metal does not directly participate in this pathway. Comparing TS Energies of Two meta-Conformations. Two conformations of m-NO2-toluene were studiedone with the functional group on carbon C19 (pointing away from Mo) and the other on carbon C20 (pointing toward Mo)to assess whether there are any substantial free-energy differences between TS conformers (Figure 7). The results show that conformations arising from meta group placement do not

meta position, NO2 (46.6) and CN (47.7). The mean and standard deviation (SD) of all 13 computed pKa values were 49.0 ± 5.3; some substituents affected the acidity of the benzylic C−H bond more significantly, like the impact upon pKa of a nitro group in the para position, which was greater than other substituents; p-NO2 decreased the pKa of toluene by 17 units. Investigating homolytic C−H bond breakage, the average calculated BDFE value was 82.1 ± 1.6, entailing small differences (%SD ≈ 2%) in BDFEs of the studied substrates. It is worth noting that there is congruity between calculated BDFEs and experimental data in this regard. Hence, it is calculated, not unexpectedly, that pKa values vary more with p-/ m-substitution than do BDFEs. Therefore, one may hypothesize that greater (lesser) sensitivity of the free energies of C−H activation by this Mo-oxo complex more likely reflects Hδ+ (H•) character in the transition states. In turn, such information is useful in terms of determining strategies for designing improved catalysts based on the EBDH active site motif. Reaction Free Energies. By comparing the C−H and O− H bond lengths in the reactant, transition state, and product, one can conclude that the position of the oscillating hydrogen between carbon and oxygen defines a late transition state, since the transition state more closely resembles the product than the reactant. This is in accord with the Hammond postulate, since the reactions were computed to be endothermic. ΔG H+

[Ln−Mo−O]⊖ + ArCH3 ⎯⎯⎯⎯→ [Ln−Mo−OH] + ArCH⊖ 2 (5) ΔG H•

[Ln−Mo−O]⊖ + ArCH3 ⎯⎯⎯⎯⎯→ [Ln−Mo−OH]⊖ + ArCH•2 (6) ΔG H−

[Ln−Mo−O] + ArCH3 ⎯⎯⎯⎯⎯→ [Ln−Mo−OH]⊖ + ArCH⊕ 2 (7)

Reaction Gibbs free energies (ΔGrxn) for proton, hydride, and hydrogen atom transfer (see eqs 5−7) were calculated and the results are reported in Table 3. The computed thermodynamics of the given reaction indicate the reaction was endergonic, regardless of whether it is modeled as a heterolytic or homolytic C−H bond cleavage. Comparing the Table 3. BMK/CEP-121G and 6-31+G(d) Calculated Reaction Free Energies ΔGrxn (kcal/mol) substituent toluene p-NO2 m-NO2 p-NMe2 m-NMe2 p-CH3 m-CH3 p-CN m-CN p-SiH3 m-SiH3 p-OCH3 m-OCH3 average ± SD

H+ transfer

H• transfer

H− transfer

57.9 35.4 51.2 60.9 59.8 59.2 58.0 45.7 52.7 52.1 56.1 59.8 58.9

42.9 41.5 42.8 38.7 42.8 42.7 42.3 43.0 42.8 42.1 41.4 38.0 42.1

66.6 79.6 75.5 39.8 64.6 61.4 65.1 76.5 73.3 68.4 65.9 50.9 67.5

54.4 ± 7.2

41.8 ± 1.6

65.7 ± 10.7 E

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Figure 5. BMK/CEP-121G and 6-31+G(d)-optimized [2 + 2] transition state (top) and active site (bottom) for neutral, triplet dadi-Mo-oxo reaction with toluene. Bond lengths are given in Å, and bond angles are given in degrees.

Figure 6. BMK/6-31+G(d)-optimized HAA transition state (top) and active site (bottom) for neutral, quartet dadi-Mo-oxo reaction with toluene. Bond lengths are given in Å, and bond angles are given in degrees.

significantly impact TS energies for this small dadi model ligand (Table 4); therefore, steric hindrance was minimal in this case. Calculated Activation Energy Barriers. The activation energy barriers (ΔG⧧) of all neutral and anionic oxo complexes were calculated to determine the more-stable multiplicities for the transition states (see Table 5). As for the reactants, in the transition state, the more favorable spin multiplicity for neutrals was triplet and for anions was doublet. Exceptions include the transition states that contained p-NO2-toluene (neutral complex), p-CN-toluene (anionic complex), and m-xylene (anionic complex), which preferred a HAA pathway; transferring a hydrogen atom could be the reason for flipping of the spin from the ground state to a transition state in the examples that preferred HAA activation. For all 64 optimized transition states, [2 + 2] addition is favored over the HAA pathway, except for those mentioned above and the quartet TS for toluene activation.

values were very high and kinetically unfavorable but nonetheless showed interesting trends, as a function of substituent, and provided valuable insight into the factors controlling C−H activation in these simple EBDH active site models. To understand which factor, pKa or BDFE, controls the C− H activation kinetics more, calculated pKa and BDFE values of p-/m-substituted-toluene were plotted against ΔG⧧ for both neutral and anionic complexes (see Figure S-2 in the Supporting Information). Based on the coefficient of determination (R2) values in eqs 8−11, activation energy barriers for both neutral and anionic activating complexes were more linearly correlated with the pKa of the C−H bond being activated than its BDFE. The equations of lines of best fit for the neutral Mo-oxo complex:

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SUMMARY, CONCLUSIONS, AND PROSPECTUS In this work, a DFT study (BMK/CEP-121G and 6-31+G(d)) was performed to study the activation of benzylic carbon− hydrogen bonds by a molybdenum-oxo complex (related to the active site of ethylbenzene dehydrogenase) via deprotonation (C−H bond heterolysis) or H atom abstraction (C−H bond homolysis) pathways. Activation free-energy barriers for neutral and anionic Mo-oxo complexes are listed in Table 5; ΔG⧧

y = 1.7711x − 68.132 y = 0.2894x + 62.873

(R2 = 0.547) pK a 2

(R = 0.166) BDFE

(8) (9)

and for anionic Mo-oxo complex: F

DOI: 10.1021/acs.inorgchem.7b01738 Inorg. Chem. XXXX, XXX, XXX−XXX

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Table 5. Activation Energy Barriers of Neutral and Anionic Mo-oxo Complexes ΔG⧧ (kcal/mol) substituent

neutral

anion

toluene p-NO2-toluene m-NO2-toluene p-NMe2-toluene m-NMe2-toluene p-CH3-toluene m-CH3-toluene p-CN-toluene m-CN-toluene p-SiH3-toluene m-SiH3-toluene p-OCH3-toluene m-OCH3-toluene average ± SD

66.9 59.3 66.5 66.9 68.0 67.9 66.4 66.9 66.0 66.7 66.4 64.1 67.0 66.1 ± 2.0

61.6 79.5 78.1 63.6 63.9 63.3 62.9 65.7 65.7 59.6 61.0 61.3 62.2 65.5 ± 6.4

Figure 8 compares activation energy barriers for neutral versus anionic Mo-oxo complexes for the 13 substrates

Figure 8. Comparison of activation energy barriers of neutral and anionic Mo-oxo complexes. ΔG⧧ values are given in kcal/mol.

Figure 7. Two conformations of the m-NO2-toluene [2 + 2] activation transition states. The functional group pointing away from Mo (top) and pointing toward Mo (bottom). Bond lengths are given in Å.

investigated. For the neutral complexes, calculated ΔG⧧ values were very close to each other, despite the different p- and msubstituents: ΔG⧧neutral = 66.1 ± 2.0 kcal/mol (Table 5). Interestingly, the standard deviation in ΔG⧧neutral is very close to the standard deviation of the calculated substrate BDFEs, 82.1 ± 1.6 kcal/mol (see Table 2). The greatest deviation from the mean is observed in the reaction of the neutral Mo-oxo complex with p-NO2-toluene, which is 59.3 kcal/mol and, thus, 6.8 kcal/mol lower than the mean. As shown in Table 2, pNO2-toluene has the lowest calculated pKa value (35.1), among the substrates studied. Interestingly, unlike neutral complexes, the activation free energies of the anionic complexes displayed more variations, ΔG⧧anionic = 65.5 ± 6.4, mimicking the standard deviation in substrate pKa values (49.0 ± 5.3) (see Table 2). In conjunction with the greater correlation between ΔG⧧ and pKa values than with BDFEs, the greater variation of the activation energies is further evidence indicating significant proton character (Hδ+) in the C−H activation transition states. The calculations indicate kinetic advantages for anionic complexes versus neutral Mo-oxo complexes. In the most cases, the ΔG⧧ value for anionic TSs (65.5 ± 6.4) were less than that observed for the corresponding neutrals (66.1 ± 2.0), except the ΔG⧧ values of p-NO2-toluene (79.5 kcal/mol) and m-NO2toluene (78.1 kcal/mol), which were huge. Because of the

Table 4. TS Energies of meta-Conformations of NO2Toluene with −NO2 Group on Carbon C19 (Pointing Away from Mo) and Carbon C20 (Pointing toward Mo) ΔG⧧ (kcal/mol) spin

charge

carbon C19

carbon C20

singlet triplet doublet quartet

0 0 −1 −1

72.3 72.9 55.4 84.0

71.8 72.5 55.2 84.0

y = −0.2264x + 62.928

(R2 = 0.247) pK a

y = −0.0279x + 83.717

(R2 = 0.029) BDFE (11)

(10)

Therefore, one may surmise significant proton character in these transition states, suggesting a possible design criterion for more-active Earth-abundant catalysts for the hydroxylation of light alkanes. Future research could include more-thorough Hammett analyses32 and the study of additional benzylic substrates to determine better structure−property correlations for anionic and neutral Mo-oxo complexes. G

DOI: 10.1021/acs.inorgchem.7b01738 Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry

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generally lower C−H activation energies for anionic complexes versus neutrals for the same substrate, Figure 8, it was hypothesized that it is more desirable to utilize anionic complexes for activation and functionalization. Hence, a very powerful molecular reducing agent, acenaphthylene anion,33 was applied to convert neutral Mo-oxo complex to anion (see Scheme 5). However, this reaction was endergonic by 25.3

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Azadeh Nazemi: 0000-0002-7326-6796 Notes

The authors declare no competing financial interest.

3

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Scheme 5. Reduction of a Neutral dadi-Mo-oxo Complex to the Anionic 2dadi-Mo-oxo Complex by Acenaphthylene Anion

ACKNOWLEDGMENTS This study was supported by the National Science Foundation (NSF) under Grant No. CHE-1464943. The authors also acknowledge the National Science Foundation for their support of the UNT Chemistry CASCaM high-performance computing facility through Grant No. CHE-1531468.

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kcal/mol (∼1 eV), implying that it will be hard to reduce neutral to anionic MoO with the dadi supporting ligand. Therefore, a profitable line of future research will be to analyze modifications of the supporting ligand to identify ways to make LnMoO easier to reduce. Also, modeling reactivity in solvent other than DMSO, both more and less polar, to determine how this changes ΔGrxn and ΔG⧧ is worthwhile, given the eventual goal to devise EBDH mimics for light alkane activation and functionalization. The present research, entailing the investigation of pKa and BDFE values of 13 substituted toluenes and their reactions with neutral and anionic molybdenum-oxo complexes, indicates that there are fluctuations in activation energies of anionic complexes that are consistent with the substrate pKa values. The different observations, taken together, imply the existence of significant Hδ+ character in the C−H activation transition states, which is further supported by the preference for [2 + 2] addition over HAA mechanisms for most substrates modeled. Hence, we hypothesize that C−H activation by the anionic Mooxo complex is controlled more by pKa than by the BDFE of the C−H bond of the substrate, which implies that the hydrogen in the C−H activation transition state has substantial protic (Hδ+) character. As such, this suggests possible routes to lower these high barriers. Favoring the heterolytic pathway in catalytic hydroxylation of light alkanes seems to be a plausible route for bringing down the high ΔG⧧. Stated differently, one may propose that Mo-oxo complexes based on the active species of EBDH need to be more basic to affect light alkane oxidation. The extent to which the redox poise of the supporting ligand may modulate the basicity of the MoO core is currently under investigation.

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Article

REFERENCES

(1) Gutekunst, W. R.; Baran, P. S. C-H functionalization logic in total synthesis. Chem. Soc. Rev. 2011, 40, 1976−1991. (2) Labinger, J. A.; Bercaw, J. E. Understanding and exploiting C−H bond activation. Nature 2002, 417, 507−514. (3) Xue, X.-S.; Ji, P.; Zhou, B.; Cheng, J.-P. The Essential Role of Bond Energetics in C-H Activation/Functionalization. Chem. Rev. 2017, 117, 8622. (4) Green, M. T. C-H bond activation in heme proteins: the role of thiolate ligation in cytochrome P450. Curr. Opin. Chem. Biol. 2009, 13, 84−88. (5) Groves, J. T. High-valent iron in chemical and biological oxidations. J. Inorg. Biochem. 2006, 100, 434−447. (6) Rittle, J.; Younker, J. M.; Green, M. T. Cytochrome P450: the active oxidant and its spectrum. Inorg. Chem. 2010, 49, 3610−3617. (7) Balcells, D.; Clot, E.; Eisenstein, O. CH Bond Activation in Transition Metal Species from a Computational Perspective. Chem. Rev. 2010, 110, 749−823. (8) Solomon, E. I.; Sundaram, U. M.; Machonkin, T. E. Multicopper Oxidases and Oxygenases. Chem. Rev. 1996, 96, 2563−2606. (9) Borovik, A. Role of metal-oxo complexes in the cleavage of C−H bonds. Chem. Soc. Rev. 2011, 40, 1870−1874. (10) Fallah, H.; Cundari, T. R. Reductive functionalization of 3d metal−methyl complexes: The greater importance of ligand than metal. Comput. Theor. Chem. 2015, 1069, 86−95. (11) Fallah, H.; Horng, F.; Cundari, T. R. Theoretical Study of Two Possible Side Reactions for Reductive Functionalization of 3d Metal− Methyl Complexes by Hydroxide Ion: Deprotonation and Metal− Methyl Bond Dissociation. Organometallics 2016, 35, 950−958. (12) Szaleniec, M.; Dudzik, A.; Kozik, B.; Borowski, T.; Heider, J.; Witko, M. Mechanistic basis for the enantioselectivity of the anaerobic hydroxylation of alkylaromatic compounds by ethylbenzene dehydrogenase. J. Inorg. Biochem. 2014, 139, 9−20. (13) Heins, S. P.; Morris, W. D.; Wolczanski, P. T.; Lobkovsky, E. B.; Cundari, T. R. Nitrene Insertion into C[BOND]C and C[BOND]H Bonds of Diamide Diimine Ligands Ligated to Chromium and Iron. Angew. Chem., Int. Ed. 2015, 54, 14407−14411. (14) Ho, J.; Coote, M. L. pKa Calculation of Some Biologically Important Carbon AcidsAn Assessment of Contemporary Theoretical Procedures. J. Chem. Theory Comput. 2009, 5, 295−306. (15) Carsch, K. M.; Cundari, T. R. DFT Modeling of a Methane-toMethanol Catalytic Cycle via Group 6 Organometallics. The Role of Metal in Determining the Mode of C-H Activation. Comput. Theor. Chem. 2012, 980, 133−137. (16) Moulder, C. A.; Cundari, T. R. 5d Metal(IV) Imide Complexes. The Impact (or Lack Thereof) of d-Orbital Occupation on Methane Activation and Functionalization. Inorg. Chem. 2017, 56, 1823−1829. (17) Olatunji-Ojo, O. A.; Cundari, T. R. C−H Activation by Multiply Bonded Complexes with Potentially Noninnocent Ligands: A Computational Study. Inorg. Chem. 2013, 52, 8106−8113.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.inorgchem.7b01738. Plots of experimental versus calculated pKa values at three levels of theory for 18 hydrocarbons, calculated relative free energies of plausible multiplicities for ground state of neutral and anionic dadi-Mo-oxo or dadi-Mohydroxy complexes, plots of BDFEs and pKa versus calculated activation energy barriers for neutral and anionic MoO(dadi) (PDF) Cartesian coordinates of all calculated species (XYZ) H

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Inorganic Chemistry (18) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J., Gaussian 09, Revision D.01; Gaussian, Inc.: Wallingford, CT, 2009. (19) Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. Universal Solvation Model Based on Solute Electron Density and on a Continuum Model of the Solvent Defined by the Bulk Dielectric Constant and Atomic Surface Tensions. J. Phys. Chem. B 2009, 113, 6378−6396. (20) Becke, A. D. Density-functional thermochemistry. III. The role of exact exchange. J. Chem. Phys. 1993, 98, 5648−5652. (21) Francl, M. M.; Pietro, W. J.; Hehre, W. J.; Binkley, J. S.; Gordon, M. S.; DeFrees, D. J.; Pople, J. A. Self-consistent molecular orbital methods. XXIII. A polarization-type basis set for second-row elements. J. Chem. Phys. 1982, 77, 3654−3665. (22) Lee, C.; Yang, W.; Parr, R. G. Development of the Colle-Salvetti correlation-energy formula into a functional of the electron density. Phys. Rev. B: Condens. Matter Mater. Phys. 1988, 37, 785. (23) Rassolov, V. A.; Pople, J. A.; Ratner, M. A.; Windus, T. L. 31G* basis set for atoms K through Zn. J. Chem. Phys. 1998, 109, 1223− 1229. (24) Stephens, P.; Devlin, F.; Chabalowski, C.; Frisch, M. J. Ab initio calculation of vibrational absorption and circular dichroism spectra using density functional force fields. J. Phys. Chem. 1994, 98, 11623− 11627. (25) Vosko, S. H.; Wilk, L.; Nusair, M. Accurate spin-dependent electron liquid correlation energies for local spin density calculations: a critical analysis. Can. J. Phys. 1980, 58, 1200−1211. (26) Boese, A. D.; Martin, J. M. Development of density functionals for thermochemical kinetics. J. Chem. Phys. 2004, 121, 3405−3416. (27) Reich, H. J. http://www.chem.wisc.edu/areas/reich/pkatable/ (accessed June 2017). (28) Cundari, T. R.; Stevens, W. J. Effective core potential methods for the lanthanides. J. Chem. Phys. 1993, 98, 5555−5565. (29) Stevens, W. J.; Basch, H.; Krauss, M. Compact effective potentials and efficient shared-exponent basis sets for the first- and second-row atoms. J. Chem. Phys. 1984, 81, 6026−6033. (30) Stevens, W. J.; Krauss, M.; Basch, H.; Jasien, P. G. Relativistic compact effective potentials and efficient, shared-exponent basis sets for the third-, fourth-, and fifth-row atoms. Can. J. Chem. 1992, 70, 612−630. (31) Heins, S. P.; Wolczanski, P. T.; Cundari, T. R.; MacMillan, S. N. Redox non-innocence permits catalytic nitrene carbonylation by (dadi)TiNAd (Ad = adamantyl). Chem. Sci. 2017, 8, 3410−3418. (32) Hansch, C.; Leo, A.; Taft, R. A Survey of Hammett Substituent Constants and Resonance and Field Parameters. Chem. Rev. 1991, 91, 165−195. (33) Connelly, N. G.; Geiger, W. E. Chemical Redox Agents for Organometallic Chemistry. Chem. Rev. 1996, 96, 877−910.

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DOI: 10.1021/acs.inorgchem.7b01738 Inorg. Chem. XXXX, XXX, XXX−XXX