pubs.acs.org/Organometallics Article Direct Benzene Hydroxylation with Dioxygen Induced by Copper Complexes: Uncovering the Active Species by DFT Calculations Elena Borrego, Laura Tiessler-Sala, Jesus J. Lázaro,* Ana Caballero,* Pedro J. Pérez,* and Agustí Lledós* Cite This: Organometallics 2022, 41, 1892−1904 Read Online ACCESS Metrics & More Article Recommendations * sı Supporting Information See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles. ABSTRACT: The direct oxidation of benzene into phenol using molecular oxygen at very mild temperatures can be promoted in the presence of the copper complex TpBr3Cu(NCMe) in the homogeneous phase in the presence of ascorbic acid as the source of protons and electrons. The stoichiometric nature, relative to copper, of this Downloaded via 158.109.55.75 on October 5, 2022 at 16:52:45 (UTC). transformation prompted a thorough DFT study in order to understand the reaction pathway. As a result, the dinuclear species TpBr3CuII(μ-O•)(μ-OH)CuIITpBr3 is proposed as the relevant structure which is responsible for activating the arene C−H bond leading to phenol formation. ■ INTRODUCTION One of the pillars of industrial chemistry is phenol given its oxidant. DFT studies allowed us to propose the active species for such oxidation and the nuclearity of relevant intermediates. wide use in the production of several chemicals at multiton scale.1 Despite such importance, the method employed is far of being efficient in terms of yields, which is below 10% based on ■ RESULTS AND DISCUSSION Benzene Hydroxylation with Molecular Oxygen benzene. This so-called cumene process consists of three steps Induced by Copper. Our previous studies7,8 on C−H and employs O2 as the oxidant (Scheme 1a).2 The ideal bond oxidation reactions with H2O2 were performed with two transformation would consist of the direct hydroxylation of the complexes bearing trispyrazolylborate ligands, TpBr3Cu- benzene C−H bond (Scheme 1b),3 which has been described (NCMe) and Tp*,BrCu(NCMe). However, the latter displays with several oxidants such as H2O2, N2O, or O2. The use of high reactivity toward O2, which leads to decomposition in a molecular oxygen is a quite challenging transformation due to few minutes, whereas the former needs heating under O2 for the bond dissociation energies of both the dioxygen molecule several hours to decompose. Therefore, we chose TpBr3Cu- and the arene C−H bond. (NCMe) (1) as the promoter of the reaction between benzene Studies aimed at the aerobic benzene hydroxylation have and phenol in a homogeneous phase. The probe experiment mainly employed heterogeneous catalysts.4 In the homoge- was set with a solution of benzene (1 mmol) and complex 1 neous counterpart, examples are scarce, with a vanadium-based (0.05 mmol, 5 mol %) in acetonitrile (6 mL) and water (8 system dominating the area.5 In all cases, moderate to low mL). Since the process requires the addition of two electrons yields have always been described, with a 20% yield barely and two protons for each molecule of benzene converted into surpassed. Most of these systems require the support of a phenol, 1 mmol of ascorbic acid was added, acting both as a reductant which is consumed in a stoichiometric manner reducing agent and as a proton source. Table 1 contains the relative to produced phenol. relevant experiments for this study. The reaction was first Copper has been widely employed to promote oxidation in performed for 1 h (entries 1−3) at room temperature under 1, view of its role in biology through metalloenzymes.6 Our group 20, and 40 bar of O2, only in the latter case observing the has previously described the use of copper(I) complexes formation of products derived from benzene in substoichio- containing tris(pyrazolyl)borate ligands for the direct oxidation metric amounts relative to the copper complex. In this case, of C−H bonds of benzene as well as of alkanes,7,8 employing phenol was detected in a 60% yield (referred to 1) as the sole hydrogen peroxide as the oxidant (Scheme 1c). Some of those oxidated arene. Prolonged reaction times (entries 4 and 5) led to mixtures of compounds, derived from overoxidation TpxCu(L) complexes are also capable of reacting with dioxygen and promoting the intramolecular oxidation of C(sp3)−H bonds.9 On the basis of this, we wondered about Special Issue: Sustainable Organometallic Chemistry the use of such copper complexes in the reaction of benzene Received: April 30, 2022 and dioxygen under mild conditions, aimed at forming phenol Published: July 14, 2022 and understanding the reaction mechanism. Herein, we report the results of such study, where we have found that phenol is obtained in a process involving ascorbic acid as the sacrificial © 2022 The Authors. Published by American Chemical Society https://doi.org/10.1021/acs.organomet.2c00202 1892 Organometallics 2022, 41, 1892−1904 Organometallics pubs.acs.org/Organometallics Article Scheme 1. Benzene Oxidation into Phenol overoxidation products. Blank experiments carried out in the absence of 1 or ascorbic acid were unproductive (entries 9 and 10). Therefore, the selectivity observed in entry 3 is lost when employing longer reaction times or higher temperatures. Regarding the ascorbic acid degradation, the major product observed by NMR was dehydroascorbic acid, as expected upon delivering electrons and protons. Despite the low yield, it is worth mentioning the simplicity of this system, employing a soluble copper complex10 and operating at room temperature, for the activation of O2 and oxidation of the Csp2−H bond of benzene. All attempts to enhance the yield failed upon modifying the reaction conditions. We believe that this may be related to the decomposition of ascorbic acid under the reaction conditions since blank experiments revealed its degradation under the O2 atmosphere employed. However, ascorbic acid seems crucial for this transformation, and we have not found a surrogate for it. Thus, we have run experiments employing trifluoroacetic, citric acid, acetic acid, or sodium biphosphate under the same conditions in which ascorbic acid participated in the formation of phenol: none of them induced the oxidation of benzene to phenol at any extent. What makes ascorbic acid so special for this transformation? Why is this reaction stopped at the early stages? Given the importance of the benzene-to-phenol conversion, DFT studies have been performed to shed light on the mechanism of this transformation, aiming at designing more active systems in the future. DFT Studies: Generation of the Active Species. The nature of copper−oxygen active species for C−H/O−H activations in either biological or synthetic systems is controversial. Several mononuclear and binuclear copper− processes, in which hydroquinone, benzoquinone, and o- oxygen species arising from the interaction of copper(I) cathecol were detected. Actually, after a 6 h reaction time at complexes with O2 have been proposed.6,11 Clear identification room temperature, no phenol was detected (entry 5), with of such species in the reaction medium is usually very hydroquinone being the major oxidated arene compound in challenging, as it happens in our system. Computational the final mixture. studies can help to propose reactive intermediates, but careful The next variable changed was the temperature, which was exploration of all possible active species is mandatory. set at 40 °C. Experiments run for 15, 45, and 90 min (entries Calculations are aimed to clarify how putative oxidants are 6−8) led to mixtures of the four compounds, i.e., phenol and formed and to propose which is (are) responsible for attacking Table 1. Copper-Mediated Hydroxylation of Benzene with O2 in the Presence of Ascorbic Acida,b entry temp (°C) pO2 (bar) time (h) phenol (PhOH) hydroquinone (HQ) benzoquinone (BQ) o-cathecol (CA) 1 25 1 1 2 25 20 1 3 25 40 1 60% 4 25 40 3 20% 20% 1.5% <1% 5 25 40 6 40% 1.5% 10% 6 40 40 0.25 40% 8% - 2% 7 40 40 0.75 40% 20% 4% 2% 8 40 40 1.5 20% 20% 8% 9c 25 40 1 10d 25 40 1 a See Experimental Section for details. bYields are referred to the copper complex. cNo copper compound added. dNo ascorbic acid added. 1893 https://doi.org/10.1021/acs.organomet.2c00202 Organometallics 2022, 41, 1892−1904 Organometallics pubs.acs.org/Organometallics Article the substrate C−H bond. Suitable candidates should be radical considered 2 as a possible active species for hydrogen-atom species formed by means of reactions with low or moderate abstraction (HAA) along the triplet spin surface, but we must barriers, should have stabilities similar to reactants, and must discard this possibility: when the H atom approaches the be able to abstract a hydrogen atom from the substrate with a oxygen ligand, no transition state is found; the energy increases low or moderate reaction barrier. steadily. Separated products of the HAA reaction (CuII−OOH Scheme 2 summarizes the mono- and binuclear copper− and Ph•) are found 52.3 kcal mol−1 above the reactants, oxygen species that have been computationally tested as making this pathway unfeasible. As mentioned in the Experimental Section, ascorbic acid is Scheme 2. Mononuclear and Binuclear Copper−Oxygen present in the reaction medium, either in the neutral form Complexes Computationally Tested as Active Species for AAH2 or in the deprotonated form AAH− (pKa1 of AAH2 = Benzene Hydroxylation with Their Spin State and Relative 4.17). In this scenario, starting from Cu−superoxo species, Gibbs Energya there may exist two competing pathways. One is HAA from ascorbic acid (AAH2) or ascorbate anion (AAH−), and the other one is addition of a second Cu(I) complex to form a bimetallic species (to be discussed in the next section). Abstraction by 2 of a hydrogen atom from a O−H bond of ascorbic acid (AAH2) is much more favorable than that from the C−H bond of benzene. Ascorbate coordinates to the copper center during the process, inducing the displacement of the O2 ligand from side on to end on. This intermediate (SM1, Figure S10, Supporting Information) lies 15.1 kcal mol−1 above the separated reagents (TpBr3Cu, O2, and AAH2) and in an almost barrierless process affords the TpBr3CuII(OOH)- (AAH) triplet species (at 17.0 kcal mol−1 SM3, Figure S10, Supporting Information). Formation of the copper(II)− hydroperoxo species is even more favorable with the ascorbate anion. The initial intermediate [TpBr3CuII(O2)(AAH)]− is 3.3 kcal mol−1 below TpBr3Cu, O2 (SM1′, Figure S10) and AAH−• and transfers one hydrogen to O2 with a barrier of only 4.3 kcal mol−1 (SM1-TS′, Figure S10). After dissociation of the a ascorbate radical anion, the Cu(II)−hydroperoxo complex is In kcal mol−1. formed, 7.6 kcal mol−1 above the separated reagents. Energetically, formation of this copper(II)−hydroperoxo potential benzene oxidants. Their relative Gibbs energies in species could not be discarded. Therefore, we checked whether acetonitrile with respect the reactants as well as their spin it could be the active species that forms the phenyl radical. states are also displayed. For species containing hydrogen However, products from the HAA process are 46.6 kcal mol−1 atoms, it is assumed that ascorbic acid (AAH2) is the hydrogen above the reactants. We also performed the HAA reaction with source. Accordingly, the energy of AAH2 and AAH• has been the doublet species TpBr3CuII(OOH) arising from dissociation added to estimate their relative energies. Optimized structures of AAH• (Scheme 2). This pathway must be ruled out as well: of all of them are collected in the Supporting Information the transition state for hydrogen abstraction is found to be 54.5 (Figures S7 and S8). kcal mol−1 above the reactants (SM4-TS, Figure S10, Mononuclear Copper Complexes. Dioxygen activation Supporting Information). by mononuclear copper(I) complexes may generate various We also considered the possibility of the involvement of copper−oxygen intermediates, such as Cu(II)−superoxo, copper(II)−oxyl species. Such complex can be formed by Cu(II)−hydroperoxo, and Cu(II)−oxyl (Scheme 2).11b The breaking the O−O bond in the CuII−(OOH) complex. The reaction starts from TpBr3Cu(NCMe) (1), which can easily resulting CuII(O•)(OH) intermediate has been computed dissociate the acetonitrile ligand (ΔG = 11.3 kcal mol−1). This (Scheme 2, see also Figure S7 in the Supporting Information). species can uptake O2 in a slightly endergonic process (ΔG = It has a quartet spin state and is 38.8 kcal mol−1 above the 3.7 kcal mol−1), in agreement with the high pressure of O2 reactants, an energy that allows discarding it as an active required for its formation (Table 1). TpBr3Cu(O2) (2) is a species. side-bound dioxygen adduct (Figure 1), structurally similar to Further details about the mononuclear pathways checked are the recently characterized (EMindL)Cu(O2) (EMind: 1,1,7,7- given in the Supporting Information. We conclude that no one tetraethyl-1,2,3,5,6,7-hexahydro-3,3,5,5-tetramethyl-sinda- of the mononuclear complexes tested (copper(II)−superoxo, cene), described as a CuII(O2•−) cupric superoxide.12 copper(II)−hydroperoxo, and copper(II)−oxyl) is able to However, the dioxygen ligand in 2 is less activated (O−O = abstract a hydrogen atom from benzene. Therefore, all of them 1.30 Å) than in that in (EMindL)Cu(O2) (O−O = 1.35 Å). must be discarded as active species in the benzene Species 2 has a triplet ground state, therefore also displaying a hydroxylation by TpBr3Cu cores. CuII(O2•−) nature. The singlet state CuIII(O22−) is found 15.1 Binuclear Copper Complexes. Interaction of a second kcal mol−1 above the triplet. A side-on Cu(II)−superoxo unit of the TpBr3Cu(I) complex with the copper(II)−superoxo complex was also characterized with the TptBu,iPr ligand.13 2 yields a μ-η2:η2-peroxodicoopper(II) complex 3 (Scheme 2) Both side-on14 and end-on15 mononuclear CuII−O2 species in a thermodynamically favored process: 3 is 3.2 kcal mol−1 have been invoked as active species for hydrogen-atom more stable than the separated reactants. This stabilization is abstraction of substrate C−H bonds. Accordingly, we very similar to that attained by coordination of AAH− to the 1894 https://doi.org/10.1021/acs.organomet.2c00202 Organometallics 2022, 41, 1892−1904 Organometallics pubs.acs.org/Organometallics Article Figure 1. Optimized structures along the pathway for formation of the active species 7 (Gibbs energy profile in Figure 2). mononuclear copper(II)−superoxo complex. However, ener- very different from that of the mononuclear copper(II)− getically the ulterior evolution of the bimetallic complex 3 is hydroperoxo. The optimized geometry of 3 (O−O = 1.43 Å; 1895 https://doi.org/10.1021/acs.organomet.2c00202 Organometallics 2022, 41, 1892−1904 Organometallics pubs.acs.org/Organometallics Article Figure 2. Gibbs energy profile for formation of active species 7 with neutral ascorbic acid as a hydrogen-atom donor. Cu stands for TpBr3Cu. Relative Gibbs energies in acetonitrile in kcal mol−1. Cu−Oavg = 1.99 Å, Figure 1) is similar to that experimentally Cleavage of the O−OH bond of the μ-hydroperoxo ligand 6 determined for [(TpiPr,iPr)2CuII2(O2)] (O−O = 1.41 Å; Cu− turns into a 5.4 kcal mol−1 more stable species 7, containing Oavg = 1.91 Å).16 Species 3 has a triplet ground state and thus a one μ-O• ligand and one μ-OH ligand. The transition state for diradical character, potentially suitable to abstract a hydrogen O−O bond breaking in the doublet PES is 10.2 kcal mol−1 atom from a C−H bond. Its singlet isomer 3S is 5.6 kcal mol−1 above 6 (SB4-TS, Figure S11, Supporting Information). The above the triplet. However, 3 cannot be the active species: computed doublet structure of 7 (SB5, Figure S11, Supporting HAA from benzene by 3 gives an intermediate 36.1 kcal mol−1 Information) has a broken symmetry nature and, in fact, above the reagents (SB1, Figure S11, Supporting Information). involves three unpaired electrons (two alpha and one beta). Interconversion of μ-η2:η2-peroxodicopper(II) complexes to Indeed, 7 is 5.7 kcal mol−1 more stable as a quartet (Figure 1) the isomeric bis(μ-oxo)dicopper is very common and has been than as a doublet, and 6 to 7 interconversion takes place more extensively studied.17 O−O breaking in 3S affords the CuIII(μ- easily by changing the spin state from doublet to quartet. The O)2CuIII complex (at 19.0 kcal mol−1) (SB2, and Figure S11, minimum energy crossing point between both potential energy Supporting Information). Its triplet form CuII(μ-O)2CuII is surfaces (MECP1, Figure 1) has been located, 8.2 kcal mol−1 26.4 kcal mol−1 above the reactants (Scheme 2 and Figure S8 above 6. Species 7 lies 7.7 kcal mol−1 below the reactants, has a in the Supporting Information). However, in the presence of quartet spin state, and can be described as a CuII(μ-O•)(μ- ascorbic acid, this is not the favored evolution of 3. Instead of OH)CuII complex. The bridging oxygen has a strong oxyl transforming into the bis(μ-oxo)dicopper, a facile hydrogen- character (Mulliken spin population of 1.18). It is formed by a atom abstraction from a O−H bond of AAH2 generates a sequence of steps involving low barriers (see the Gibbs energy profile for its formation in Figure 2). As we will show in the bimetallic hydroperoxo complex. As found for the same next section, this species is able to perform H abstraction from process in the mononuclear complex, AAH 2 initially benzene with a low barrier. Hence, 7 fulfills the required coordinates to one copper center (intermediate 4, Figure 1) conditions to be the active species able to oxidize benzene and then in a practically barrierless HAA the hydroperoxo formed in the reaction medium. complex 5 is formed (Figure 1).18 This reaction occurs in the Computing accurate energy differences between different triplet potential energy surface. Dissociation of AAH• yields spin states by DFT methods is challenging: results can be the doublet species 6, which we describe as CuI(μ-OOH)CuII highly dependent on the functional, particularly on the (see spin analysis in the Discussion). In 6, the bridging percentage of Hartree−Fock exchange in the functional.19 All hydroperoxo ligand is bound to both copper centers through of the energies reported herein have been obtained with the its proximal oxygen (Figure 1). Similarly to the mononuclear hybrid meta-GGA TPSSh functional supplemented with species, we also considered the anionic form AAH− as the Grimme’s dispersion correction D3 using an extended basis species that takes part in the formation of the CuI(μ- set (basis-II, BS2, see the Computational Details). This OOH)CuII intermediate. The obtained energy profile has the methodology has proven to provide very good results same shape, although the relative Gibbs energies of all of the predicting both the correct ground state and the right energy species are lowered (Figure S9, Supporting Information). window for spin-crossover on first-row transition-metal Species 6 is placed only 3.4 kcal mol−1 above the reactants complexes.20 Nevertheless, to assess the reliability of the (taking AAH2) or 4.9 kcal mol−1 below (with AAH−). doublet−quartet crossing, the relative energies of the doublet However, abstraction of a benzene C−H hydrogen by this (6) and quartet (7) intermediates (referred to reactants) have species involves a rather high barrier of 28.8 kcal mol−1, been computed with 12 functionals containing variable discarding its role as an active species (SB3-TS, Figure S11, percentages of Hartree−Fock exchange using an extended Supporting Information). basis set (BS2). Although this energy difference is very 1896 https://doi.org/10.1021/acs.organomet.2c00202 Organometallics 2022, 41, 1892−1904 Organometallics pubs.acs.org/Organometallics Article dependent on the functional, all of the functionals but one CuII(μ-OH)2CuII core and a phenyl radical. In 9, three agreed in showing 7 to be more stable than the reactants and unpaired alpha electrons (quartet state) are found. As pairing more stable than 6 as well, assessing the proposal of 7 as the of one alpha with one beta electron should occur in the active species (see Table S1 in the Supporting Information). formation of the C−OH bond, crossing to the doublet PES to We also tested the possibility of abstraction of a O−H form the broken symmetry doublet species 10 with two alpha hydrogen atom of AAH2 by 7, which easily leads to the CuII(μ- and one beta electrons happens as well. The minimum energy OH)2CuII triplet complex. Indeed, this is a very stable species crossing point between the quartet and the doublet PES (Scheme 2, Figure S8 in Supporting Information), but we (MECP2) was located 1.1 kcal mol−1 above 9. found that this complex is not able to abstract a hydrogen atom From 10, coupling of the phenyl and O(H) radicals in the from benzene. doublet PES forms the C−OH bond, after crossing transition Summarizing this section, extensive exploration of potential state TS-CO. The Gibbs energy barrier for this step is low (8.2 mononuclear and dinuclear copper−oxygen complexes as kcal mol−1 from 10). This step is highly exergonic and leads to active species for benzene oxidation led us to propose a complex 11, with the phenol bonded to one copper center CuII(μ-O•)(μ-OH)CuII complex 7 as such species. In the next (Cu1) and a bridging hydroxo ligand (Figure 4). section, we will analyze benzene oxidation to phenol promoted In 11, the oxygen of the μ-OH ligand keeps a radical by this complex. character (Mulliken spin population 0.15) and can interact DFT Studies: Mechanism of Benzene Oxidation. The with AHH• radicals that are present in the reaction medium oxygen rebound mechanism is the most commonly proposed (intermediate 12, triplet PES, Figures 3 and 4). Crossing from mechanism for copper−oxygen-mediated C−H activation the triplet to the singlet PES (through MECP3) entails transfer processes.11b,21 In the rebound mechanism for C−H of a hydrogen atom from AAH• to OH, forming a H2O ligand hydroxylation, an initial hydrogen-atom abstraction from the coordinated to copper (Cu2) (13, Figure 4) and dehydroas- R−H substrate by a highly electrophilic species generates a corbic acid. Release of the phenol product for Cu1 leads to a substrate radical R• and a metal hydroxide intermediate. In the bimetallic copper(I)−copper(I) complex with a bridging water subsequent rebound step, the organic radical attacks the M− ligand (14). OH center to give an alcohol group (Scheme 3, path A).22 An alternative mechanism has been proposed for arene hydroxylation catalyzed by cytochrome P450 enzymes. This Scheme 3. Possible Mechanisms for Benzene Hydroxylation mechanism involves an initial attack on the π system of the Promoted by Copper−Oxyl Active Species 7 benzene by the electrophilic species of oxyl nature to produce a σ complex. In a second step, a proton shuttle, mediated in P450 by the porphyrin ring, transfers the proton from the ipso carbon to the oxygen, yielding the phenol (Scheme 3, path B).23 We also assessed the viability of the σ-complex-based mechanism for the benzene hydroxylation promoted by active species 7. The Gibbs energy profile for benzene hydroxylation by 7 with a σ-complex-based mechanism is shown in Figure 5. Optimized structures of intermediates and transition states along this path are depicted in Figure 6. The electrophilic attack of the copper−oxyl on the π system of benzene takes place with a rather low barrier (16.0 kcal mol−1, TS-CO-σ, Figures 5 and 6). In this step, which occurs in the quartet potential energy surface, one electron has been pulled off from the π system by the oxyl, giving a radical character to the benzene ring. The resulting σ complex is slightly more stable as a broken symmetry doublet species. The proton in the ipso carbon of the σ complex must end up in the C−O oxygen to form the phenol. We found that an ascorbate anion can play the same role of proton shuttle for this hydrogen migration as one of the nitrogen atoms of the porphyrin ring plays in P450. Proton migration happens in the doublet potential energy The oxygen-rebound mechanism for benzene hydroxylation surface. The ascorbate anion coordinates one copper center by the Cu−oxyl species 7 is initiated by the hydrogen-atom and, in an essentially barrierless process (TS-deprot, Figures 5 abstraction (HAA) from the substrate by the bridging oxyl to and 6), deprotonates the ipso carbon, yielding a phenoxy anion form the Cu2(μ-hydroxo)2 species and the carbon radical, and and reducing one copper center to CuI (PhO-AAH2, Figures 5 it is followed by a radical rebound step to build the C−O bond and 6). With a very low barrier (TS-prot, Figures 5 and 6), the between the carbon radical and the Cu-bonded hydroxide. proton is transferred from the O−H group of aspartic acid to Figure 3 displays the Gibbs energy profile for benzene the phenoxy oxygen, yielding the phenol product coordinated hydroxylation by 7 with an oxygen-rebound mechanism. The to a copper center (PhOH-AAH). From this intermediate, optimized structures of intermediates and transition states release of an AAH• radical gives a [CuI(μ-OH)CuI]− complex along the reaction pathway are shown in Figure 4. and the phenol. Abstraction of a H atom from a benzene C−H bond takes The σ-complex-based mechanism entails an overall barrier of place in the quartet PES through transition state TS-CH with a 16.0 kcal mol−1, only slightly higher than that of the oxygen- barrier of only 14.3 kcal mol−1 with respect to separated rebound mechanism (14.3 kcal mol−1), showing that both reactants (7 + benzene) and affords intermediate 9 involving a mechanisms could be competitive for benzene hydroxylation 1897 https://doi.org/10.1021/acs.organomet.2c00202 Organometallics 2022, 41, 1892−1904 Organometallics pubs.acs.org/Organometallics Article Figure 3. Gibbs energy profile for benzene hydroxylation promoted by 7 via an oxygen-rebound mechanism (path A, Scheme 3). Cu stands for TpBr3Cu. Relative Gibbs energies in acetonitrile in kcal mol−1. by active species 7. In summary, computation of the reaction stepwise proton transfer (PT)/electron transfer (ET) with pathway for benzene oxidation to phenol provides evidence of mechanistically distinct PT and ET steps.25 the role of CuII(μ-O•)(μ-OH)CuII complex 7 as the active The spin density of the bridging oxygen of the hydroperoxo species that promotes this reaction. ligand is low in 6 (0.18). However, this situation dramatically Spin Density Changes along the Reaction Pathway. changes after breaking the O−OH bond. In 7, with a quartet In the previous sections, we tentatively described the species ground state, the bridging oxygen has a strong oxyl character involved in the reaction mainly from structural parameters and (spin density = 1.18). This oxyl ligand will behave as a strong in terms of formal oxidation states. In this section, we will look oxidant, able to abstract a hydrogen atom from strong C−H more closely at the spin state changes along the reaction bonds. Spin density in the oxygen atom of the bridging pathway to discuss more in depth the reaction mechanism. The hydroxo ligand is low (0.25), while that in the copper centers oxidation state is a formal concept, very useful for a chemical has increased. In this way, 7 is formally a CuII(μ-O•)(μ- description but hardly computable. We described Cu(II) as the OH)CuII complex. Figure 8 shows spin-density plots for both copper centers with spin populations higher than 0.35e and species 6 and 7, illustrating the changes that have occurred. Cu(I) as those with spin populations lower than 0.25e. Figure In the presence of benzene substrate, 7 abstracts a hydrogen 7 displays the evolution of Mulliken spin populations along the atom from a C−H bond (TS-CH and 9), generating a phenyl generation of the active species (from 1 to 7) and benzene radical and significantly decreasing the spin density in the hydroxylation (from 8 to 13). All of the values can be found in oxygen O1 that forms the O−H bond. The spin density in both copper centers remains constant at 0.63 (Cu1) and 0.64 the Supporting Information (Table S2). (Cu2), corresponding to formally copper(II) ions. As O2 uptake by the copper(I) complex TpBr3Cu causes spin commented above, the spin change of one electron, from polarization in copper, which is formally a monoxidation of alpha to beta, is required in order to couple unpaired electrons copper to yield the CuII−superoxo complex 2, although spin that will form the C−OH bond. This happens in the broken- density in the formal O2−• unit is much larger (1.52) than in symmetry doublet 10 (spin density = −0.98 in CPh and 0.24 in that copper (0.39). Coordination of the second copper(I) unit O1), from which C−O bond formation starts, in a step usually to 2 increases the spin density in the copper ions and decreases called an oxygen-rebound mechanism. After formation of the spin density in the oxygen atoms. Species 3 is formally a phenol, the spin density in both oxygens (0.15 in O1 and 0.03 CuII(peroxo)CuII complex, although in fact there is one in O2) and in Cu2 (0.20) has notably decreased in 11. unpaired alpha electron shared between both copper centers However, the remaining spin density in the oxygen atom of the and another unpaired electron shared between both oxygen O−H ligand of 11 (0.15) allows abstracting a hydrogen atom atoms. Coordination of AAH2 to form 4 increases the radical of a AAH• radical in a triplet to singlet crossing that ends up character of both copper centers and decreases that of the with a water ligand bridging two copper(I) centers and a oxygen atoms. Spin polarization in the coordinated AAH2 is dehydroascorbic acid molecule (13). very low (0.16). Ascorbic acid is transferring a proton to O2, We checked the hydrogen-abstracting capability of 7 with thus decreasing its radical character (TS−OH and 5). Spin two other substrates with Csp3−H bonds: cyclohexane and density in both copper ions remains almost constant as well as methane. For the alkane substrates, only the oxygen-rebound in the ascorbic acid moiety. However, ascorbic acid dissociates mechanism (Path A, Scheme 3) can be at work. Indeed, 7 is as an AAH• radical,24 inducing a reduction of Cu1 in 5, which able to abstract a hydrogen atom from both alkanes with is a doublet complex, formally CuI(μ-OOH)CuII. Hydrogen- transition states similar to that of benzene (see the TS atom abstraction from the O−H bond of ascorbic acid involves geometries in the Supporting Information, Figure S12: 1898 https://doi.org/10.1021/acs.organomet.2c00202 Organometallics 2022, 41, 1892−1904 Organometallics pubs.acs.org/Organometallics Article Figure 4. Optimized structures along the rebound pathway for benzene hydroxylation promoted by 7. TS_CycHx and TS_Met) and very low barriers: 4.4 and 12.8 responsible for hydroxylation of substrates with strong C−H kcal mol−1 with respect to 7 + alkane for cyclohexane and bonds. It is important to point out that this high-spin species is methane, respectively). Thus, 7 appears as the active species only stable in the presence of two copper centers. Whereas 1899 https://doi.org/10.1021/acs.organomet.2c00202 Organometallics 2022, 41, 1892−1904 Organometallics pubs.acs.org/Organometallics Article Figure 5. Gibbs energy profile for benzene hydroxylation promoted by 7 via a σ-complex mechanism (path B, Scheme 3). Cu stands for TpBr3Cu. Relative Gibbs energies in acetonitrile in kcal mol−1. monometallic CuII(O•)(OH) is found 38.8 kcal mol−1 above system) that involves O−OH cleavage can take place easily by the reactants (Scheme 2), making it unreachable under the means of a spin-state crossing from doublet to quartet. Overall, reaction conditions, bimetallic CuII(μ-O•)(μ-OH)CuII is 7.7 the mechanism of substrate hydroxylation by the active species kcal mol−1 below the reactants and can be formed through a is the same as that in binuclear copper monooxygenases and in sequence of steps having low barriers (Figure 2). However, the our TpBr3Cu+O2 + AAH2 system. high oxyl character of 7, responsible for its easiness to perform HAA from the C−H bond of substrates, can also be the reason for its deactivation. With ascorbic acid present in the reaction ■ CONCLUSIONS We experimentally proved that TpBr3Cu(NCMe), in the medium, 7 can perform the HAA from a O−H bond of AAH2 presence of ascorbic acid, can promote the direct hydroxylation yielding the CuII(μ-OH)2CuII triplet complex, which is very of a benzene C−H bond with O2 as the oxidant, yielding stable (Scheme 2, Figure S8 in Supporting Information), but is phenol as a main product. However, the reaction is stopped at not able to abstract a hydrogen atom from benzene. the early stages, and benzene oxidation products are obtained Very recently, a thorough computational study has afforded in substoichiometric amounts relative to the copper complex. a new perspective for O2 activation and substrate hydroxylation No reaction intermediate or the active species could be by binuclear copper monooxygenases.26 As in our system, the identified. Thus, we turned to DFT calculations to get proposed active species for substrate hydroxylation has a information about this process that could help to improve it. CuII(μ-O•)(μ-OH)CuII nature. Scheme 4 compares the key A thorough exploration allowed us to propose a bimetallic steps for the formation of such species for binuclear copper TpBr3CuII(μ-O•)(μ-OH)CuIITpBr3 intermediate as the active monooxygenases with our results for TpBr3Cu. species responsible for the oxidation process. Ascorbic acid is Although these enzymes contain two copper(I) cofactors crucial for its formation as hydrogen-atom abstraction from the very far away (about 11 Å, “open” conformation), this study O−H bond of ascorbic acid (or ascorbate anion) in a stepwise showed that in the presence of cosubstrate ascorbate proton transfer (PT)/electron transfer (ET) gives its precursor hydrogen-atom abstraction leads to the formation of a hydroperoxo complex TpBr3CuII(μ-OOH)CuITpBr3, which is Cu(II)−OOH intermediate that is inert toward H abstraction not active for HAA. Any mononuclear species is clearly from the substrate. However, by approaching the copper atoms unfeasible. Identification of the active species for C−H bond (“closed” conformation), a stable binuclear CuI(μ-OOH)CuII hydroxylations can pave the way for further preparation of species affords the more stable species CuII(μ-O•)(μ-OH)CuII, more robust synthetic compounds that could catalyze such which is the reactive intermediate responsible for substrate reactions. hydroxylation.11b,26 This is the same active species 7 we found for the hydroxylation of benzene promoted by TpBr3Cu, proving for first time that it can also operate in synthetic systems. As for the enzyme, neither CuII−superoxo nor ■ EXPERIMENTAL SECTION General Methods. Preparation of TpBr3Cu(NCMe) was carried CuII(hydroperoxo) is reactive toward substrate hydroxylatio- out using literature methods. Solvents were distilled and degassed n.22a Formation of the active species also follows a similar before use. Oxidated arenes were purchased from Aldrich. HPLC studies were performed in an Agilent 1260 Infinity II. NMR spectra pathway. In our case, the bimetallic complex is formed by were recorded on an Agilent 400 MR or Agilent 500 DD2 device. coordination of a TpBr3Cu molecule to the initial CuII(O2−•) PARR Micro Bench Top reactors were employed for the oxidation intermediate, and from this point the bimetallic complex is reactions. kept. We also showed that the interconversion between CuI(μ- General Catalytic Experiment. The oxidation reactions were OOH)CuII and CuII(μ-O•)(μ-OH)CuII (from 6 to 7 in our carried out in a 100 mL high-pressure reactor in which benzene (1 1900 https://doi.org/10.1021/acs.organomet.2c00202 Organometallics 2022, 41, 1892−1904 Organometallics pubs.acs.org/Organometallics Article Figure 6. Optimized structures along the σ-complex pathway for benzene hydroxylation promoted by 7. mmol), ascorbic acid (1 mmol), and the catalyst (0.05 mmol) were calibration calculations employing a set of functionals spanning a large dissolved in an acetonitrile/water (3:1 v-v, 8 mL) mixture. The range of percentages of Hartree−Fock exchange were carried out for reactor was charged with O2 at 40 bar and was stirred for the desired certain structures (see Table S1 in the Supporting Information). Basis time. After depressurization of the vessel, the reaction mixture was set BS1 was used for the optimizations. BS1 includes the 6-31G(d,p) diluted to an exact volume with acetonitrile, and the solution was basis set for the main-group elements31 and the scalar relativistic evaluated by HPLC using calibration curves. After that, for double Stuttgart−Dresden SDD pseudopotential and its associated double-ζ checking, the volatiles were removed under reduced pressure and the basis set32 complemented with a set of f polarization functions for the crude was analyzed by 1H NMR spectroscopy using 1,3,5- copper atoms.33 Frequency calculations were carried out for all of the trimethoxybenzene as an internal standard. Computational Methodology. Theoretical calculations were optimized geometries in order to characterize the stationary points as performed at the DFT level of theory using Gaussian09 software.27 either minima or transition states. Connections between the transition The structures of all of the intermediates and transition states were states and the corresponding minima were checked by displacing in optimized in acetonitrile solvent (ε = 35.688) with the SMD both directions, following the transition vector, the geometry of the continuum model28 using the hybrid meta-GGA TPSSh functional29 transition states, and subsequent geometry optimization until a supplemented with Grimme’s dispersion correction D3.30 Additional minimum was reached. 1901 https://doi.org/10.1021/acs.organomet.2c00202 Organometallics 2022, 41, 1892−1904 Organometallics pubs.acs.org/Organometallics Article Scheme 4. Formation of Active Species for C−H Bond Hydroxylation in Binuclear Copper Monooxygenases and TpBr3Cu Complex Figure 8. Spin-density plots and Mulliken spin populations of 6 and 7. geometries, the thermal and entropic corrections obtained with BS1. BS2 consists of the def2-TZVP basis set for the main-group elements and the quadruple-ζ def2-QZVP basis set for Cu.34 A correction of 1.9 kcal mol−1 was applied to all Gibbs values to change the standard state from the gas phase (1 atm) to solution (1 M) at 298.15 K.35 In this way, all of the energy values in the energy profiles are Gibbs energies in acetonitrile solution calculated using the formula G = E(BS2) + G(BS1) E(BS1) + G1atm 1M where ΔG1 atm→1M = 1.9 kcal mol−1 is the Gibbs energy change for compression of 1 mol of an ideal gas from 1 atm to the 1 M solution- phase standard state. To locate the minimum energy crossing points (MECP) between the singlet and the triplet potential energy surfaces, the program developed by the group of Harvey was employed.36 To confirm that the MECP connects the two intermediates located in the two energy surfaces, the MECP structure was optimized in the different spin states involved in the crossing. The Gibbs energies in solution of the MECP were estimated by adding to the calculated potential energy of the MECP thermal and entropic corrections calculated with the option freq = projected of the Gaussian 09 program.37 Three- dimensional structures were generated using CYLview.38 ■ * ASSOCIATED CONTENT sı Supporting Information The Supporting Information is available free of charge at Figure 7. Evolution of Mulliken spin densities over the course of the https://pubs.acs.org/doi/10.1021/acs.organomet.2c00202. reaction. Experimental details and extended description of the Gibbs energies in acetonitrile were calculated at 298.15 K, adding computational results (PDF) to the potential energies in acetonitrile, obtained with single-point Cartesian coordinates of all the optimized structures calculations using an extended basis set (BS2) at the BS1-optimized (XYZ) 1902 https://doi.org/10.1021/acs.organomet.2c00202 Organometallics 2022, 41, 1892−1904 Organometallics pubs.acs.org/Organometallics Article ■ AUTHOR INFORMATION Corresponding Authors Biologically Relevant Cu/O-2 Model Systems to Organometallic Transformations. Chem. Rev. 2019, 119, 2954−3031. (b) Quist, D. A.; Díaz, D. E.; Liu, J. J.; Karlin, K. D. Activation of dioxygen by copper Jesus J. Lázaro − Cepsa Research Center, Compañía Española metalloproteins and insights from model complexes. J. Biol. Inorg. de Petróleos S.A., Madrid 28850, Spain; Chem. 2017, 22, 253−288. Email: jesusjavier.lazaro@cepsa.com (7) (a) Conde, A.; Diaz-Requejo, M. M.; Pérez, P. J. Direct, copper- Ana Caballero − Laboratorio de Catálisis Homogénea, catalyzed oxidation of aromatic C−H bonds with hydrogen peroxide Unidad Asociada al CSIC, CIQSO-Centro de Investigación under acid-free conditions. Chem. Commun. 2011, 47, 8154−8156. en Química Sostenible and Departamento de Química, (b) Vilella, L.; Conde, A.; Balcells, D.; Díaz-Requejo, M. M.; Lledós, Universidad de Huelva, Huelva 21007, Spain; A.; Pérez, P. J. A competing, dual mechanism for catalytic direct Email: ana.caballero@dqcm.uhu.es benzene hydroxylation from combined experimental-DFT studies. Pedro J. Pérez − Laboratorio de Catálisis Homogénea, Unidad Chem. Sci. 2017, 8, 8373−8383. Asociada al CSIC, CIQSO-Centro de Investigación en (8) (a) Conde, A.; Vilella, L.; Balcells, D.; Díaz-Requejo, M. M.; Química Sostenible and Departamento de Química, Lledós, A.; Pérez, P. J. Introducing Copper as Catalyst for Oxidative Universidad de Huelva, Huelva 21007, Spain; orcid.org/ Alkane Dehydrogenation. J. Am. Chem. Soc. 2013, 135, 3887−3896. 0000-0002-6899-4641; Email: perez@dqcm.uhu.es (b) Á lvarez, M.; Molina, F.; Fructos, M. R.; Urbano, J.; Á lvarez, E.; Agustí Lledós − Departament de Química, Universitat Sodupe, M.; Lledós, A.; Pérez, P. J. Aerobic intramolecular carbon− Autònoma de Barcelona, Barcelona 08193, Spain; hydrogen bond oxidation promoted by Cu(I) complexes. Dalton orcid.org/0000-0001-7909-422X; Email: agusti.lledos@ Trans. 2020, 49, 14647−14655. (9) Mairena, M. A.; Urbano, J.; Carbajo, J.; Maraver, J. J.; Á lvarez, uab.cat E.; Díaz-Requejo, M. M.; Pérez, P. J. Effects of the Substituents in the Authors TpxCu Activation of Dioxygen: An Experimental Study. Inorg. Chem. Elena Borrego − Laboratorio de Catálisis Homogénea, 2007, 46, 7428−7435. (10) A reviewer has noted a concern about copper being Unidad Asociada al CSIC, CIQSO-Centro de Investigación decomposed into nanoparticulated material by the action of ascorbic en Química Sostenible and Departamento de Química, acid. In an experiment employing the copper complex, ascorbic acid, Universidad de Huelva, Huelva 21007, Spain under an O2 atmosphere for 1 h, we detected (by 11B NMR) the Laura Tiessler-Sala − Departament de Química, Universitat initial copper complex in solution along with other species attributable Autònoma de Barcelona, Barcelona 08193, Spain to Cu(II) species. The oxidant atmosphere seems to prevail over the Complete contact information is available at: reducing action of ascorbic acid under the experimental conditions. https://pubs.acs.org/10.1021/acs.organomet.2c00202 (11) (a) Lewis, E. A.; Tolman, W. B. Reactivity of Dioxygen-Copper Systems. Chem. Rev. 2004, 104, 1047−1076. (b) Wu, P.; Zhang, J.; Funding Chen, Q.; Peng, W.; Wang, B. Theoretical perspective on We thank the Spanish Ministerio de Ciencia e Innovación for mononuclear copper-oxygen mediated C−H and O−H activations: A comparison between biological and synthetic systems. Chin. J. Catal. Grants PID2020-113797RB-C21 (also financed by FEDER 2022, 43, 913−927. (c) Cramer, C. J.; Tolman, W. B. Mononuclear “Una manera de hacer Europa”) and PID2020 116861GB-I00. Cu−O2 Complexes: Geometries, Spectroscopic Properties, Electronic We also thank Junta de Andaluciá (P18-RT-1536), the Structures, and Reactivity. Acc. Chem. Res. 2007, 40, 601−608. Universidad de Huelva (P.O.Feder UHU-1260216,) and (12) Carsch, K. M.; Iliescu, A.; McGillicuddy, R. D.; Mason, J. A.; Cátedra CEPSA for funding. E.B. thanks CEPSA for a Ph. D. Betley, T. A. Reversible Scavenging of Dioxygen from Air by a Copper fellowship. L.T.-S. thanks the Spanish Ministerio de Uni- Complex. J. Am. Chem. Soc. 2021, 143, 18346−18352. versidades (grant FPU18/05895). (13) Fujisawa, K.; Tanaka, M.; Moro-Oka, Y.; Kitajima, N. A Notes Monomeric Side-On Superoxocopper(II) Complex: Cu(O2)(HB(3- The authors declare no competing financial interest. tBu-5-iPrpz)3). J. Am. Chem. Soc. 1994, 116, 12079−12080. (14) Chen, P.; Solomon, E. I. Oxygen Activation by the Noncoupled ■ REFERENCES (1) (a) Sheldon, R. A.; Kochi, J. K. Metal-Catalyzed Oxidations of Binuclear Copper Site in Peptidylglycine α-Hydroxylating Mono- oxygenase. Reaction Mechanism and Role of the Noncoupled Nature of the Active Site. J. Am. Chem. Soc. 2004, 126, 4991−5000. Organic Compounds; Sheldon, R. A., Kochi, J. K., Eds.; Academic (15) Cowley, R. E.; Tian, L.; Solomon, E. I. Mechanism of O2 Press: New York, 1981; pp 315−339. (b) Weber, M.; Kleine- Activation and Substrate Hydroxylation in Noncoupled Binuclear Boymann, M. Ullmann’s Encyclopedia of Industrial Chemistry; Wiley- Copper Monooxygenases. Proc. Natl. Acad. Sci. U.S.A. 2016, 113, VCH: Weinheim, 2004. 12035−12040. 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Self-consistent molecular orbital methods. XXIII. A 1904 https://doi.org/10.1021/acs.organomet.2c00202 Organometallics 2022, 41, 1892−1904