Why Can Normal Palladium Catalysts Efficiently Mediate Aerobic C–H

Article Cite This: Inorg. Chem. XXXX, XXX, XXX−XXX

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Why Can Normal Palladium Catalysts Efficiently Mediate Aerobic C− H Hydroxylation of Arylpyridines by Intercepting Aldehyde Autoxidation? A Nascent Palladium(III)−Peracid Intermediate Makes a Difference Lili Yang,† Qiaohong Zhang,‡ Jiali Gao,*,§,∥ and Yong Wang*,‡ Inorg. Chem. Downloaded from pubs.acs.org by UNIV AUTONOMA DE COAHUILA on 03/21/19. For personal use only.

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Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry, Jilin University, Changchun 130023, China ‡ Institute of Drug Discovery Technology, School of Material Science and Chemical Engineering, Ningbo University, Ningbo 315211, China § Department of Chemistry and Supercomputing Institute, University of Minnesota, Minneapolis, Minnesota 55455, United States ∥ School of Chemical Biology and Technology, Peking University Shenzhen Graduate School, Shenzhen 518055, China S Supporting Information *

ABSTRACT: The direct C(sp2)−H hydroxylation of 2arylpyridines catalyzed by normal palladium catalysts via interception of aldehyde autoxidation possesses a number of advantages, including convenient operating conditions, nontoxic and inexpensive aldehydes, and being economical in terms of steps and atoms. In this paper, we report a computational study of the mechanism of this catalytic process using density functional theory, revealing a novel catalytic cycle. We find that the rate-limiting step is C−H bond activation that occurs via a concerted metalation deprotonation mechanism, which is consistent with Guin’s experimental kinetic isotope effect observations. The byproduct of the C−H bond activation, Brønsted acid HCl, promotes formation of a hexacoordinated Pd(III)−peracid intermediate. It provides a reservoir for the robust highvalent Pd(IV)−OH species via an easy O−O homolysis. The pathway that does not involve HCl is also energetically feasible but albeit less probable. Furthermore, the involvement of another radical OOH•, besides the acylperoxo radical nPrOO•, is needed to recover the tetracoordinated Pd(II) catalyst during the catalytic cycle. Our computational work sheds lights on the elusive oxygenation involving a radical that is mediated by palladium catalysts and will play a positive role in the further design of a rational reaction strategy and new catalysts.

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valent iron(V)−oxo active species acts as the key oxidant.16 Our theoretical studies (with Shaik and Que) further revealed that acetic acid also plays a vital role in the O−O bond heterolysis of the Fe(III)−OOH species to form a key Fe(III)−peracid reaction intermediate, a precursor of the transient high-valent iron(V)−oxo active species.17,18 In addition to the improvement of processes involving group 8 elements,19−27 catalysts based on group 10 elements,28−37 especially palladium catalysts, have been found to be an alternative in oxygenation chemistry.38−49 Palladium-catalyzed C−H activation with oxygen or air as the sole oxidant addresses the demands of green and sustainable chemistry due to its highly economical use of atoms and steps. Therefore, it is of interest to develop a highly efficient, direct hydroxylation of aromatic C−H bonds catalyzed by Pd reagents with O2 as the sole oxidant.50−57 In 1990, Fujiwara and co-workers reported hydroxylation of benzene to phenol by molecular oxygen, using

INTRODUCTION Biological functionalization of organic compounds to introduce oxygen must cope with the formation of reactive oxygen species (ROS), which are toxic in the cell.1 Examples include enzymatic processes involving a high-valent iron cofactor such as cytochrome P450 enzymes and methane monooxygenases.2−4 In these cases, high-valent iron−oxo active species are generated to efficiently and selectively oxidize substrates to enrich biochemical diversity.5−7 Inspired by these amazing enzymes, a large number of biomimetic heme and nonheme catalysts have been designed and synthesized to carry out similar tasks,8−11 including the Fe(PDP) catalyst.12−14 White and co-workers found that the Fe(PDP)/H2O2 reaction system, in the presence of acetic acid, catalyzes C−H bond oxygenation at the methyl and methylene sites of many natural substrates with excellent selectivity. Further mechanistic investigations revealed that the additive acetic acid plays a significant role in stabilizing the catalyst to provide the observed efficiency and selectivity.15 Que and co-workers proposed an acid-assisted reaction mechanism in which a high© XXXX American Chemical Society

Received: December 17, 2018

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DOI: 10.1021/acs.inorgchem.8b03515 Inorg. Chem. XXXX, XXX, XXX−XXX

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Inorganic Chemistry Pd(OAc)2 as the catalyst.58 However, the yield was low and the reaction conditions were harsh. Yu and co-workers discovered an efficient ortho hydroxylation of the carboxyldirecting arenes with O2 and Pd(OAc)2.59 Mechanistic investigations via isotope labeling with 18O2 and H218O revealed that molecular oxygen is the sole oxidant source of the direct C−H bond oxygenation rather than an acetoxylation/hydrolysis process. These findings ruled out the involvement of the Pd(II)/Pd(0) conjugate pair in the catalytic cycle, which is a key question in the reaction mechanism. However, direct hydroxylation of arenes with other substituents is generally slow. To improve catalytic efficiency, Jiao and co-workers noted that in the presence of NHPI (N-hydroxyl-phthalimide), PdCl2 is an effective catalyst for C−H hydroxylation of phenylpyridines.60 Further investigations revealed that the OH• radical, produced in the serial reaction of homolysis of NHPI, is crucial to form the highvalent palladium−hydroxyl active species. Very recently, Guin and co-workers reported another radical-assisted, direct C−H hydroxylation of arylpyridines using a palladium catalyst, in which the reactive free radical was formed by intercepting an aldehyde autoxidation process under aerobic conditions.61 The free radical chain mechanism for the latter process was established nearly a century ago by Bäckström in 1927.62 In Scheme 1a, aldehyde I transfers a

catalyst Pd(CH3CN)2Cl2 to form complex E, which intercepts the radical chain process of aldehyde autoxidation by incorporating an active peroxyacyl radical B to form a transient peroxo−palladium intermediate C, which decomposes to an elusive Pd(IV)−OH intermediate F. After reductive elimination, hydroxylated product 2a is formed and the catalyst Pd(CH3CN)2Cl2 is regenerated. Direct C−H hydroxylation under aerobic conditions by palladium catalysts, intercepting an intermediate of aldehyde autoxidation, has several advantages. The aldehyde involved effectively acts as a dioxygen activator, which is nontoxic and inexpensive. Furthermore, the operation conditions are convenient and scalable. Because dioxygen is the sole oxidant, the overall reaction may be regarded to meet the requirements of being green and sustainable.64−67 Although the experimental conditions have been thoroughly investigated, key mechanistic details are still missing, including the nature of the key transient peroxo−palladium intermediate C (Scheme 1b). The valency of Pd in C is likely +3; if so, then what is the valency of Pd in palladium−hydroxyl species F? Importantly, it is still not clear how the catalytically active species is regenerated if the valency of Pd is +3 after reductive elimination without an additional radical being introduced in the catalytic cycle. In this report, we have carried out computational studies to gain insights into the mechanistic details of the aerobic C−H hydroxylation catalyzed by Pd(CH3CN)2Cl2.

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Scheme 1. (a) Well-Known Radical Chain Mechanism of Aldehyde Autoxidation and (b) Mechanism of Aerobic C−H Hydroxylation of 2-Arylpyridines by Interception of Aldehyde Autoxidation Postulated by Guin and Co-Workers

METHODS

Density functional theory (DFT) calculations were carried out using the Gaussian 1668 suite of programs. The spin-unrestricted B3LYPD3(BJ) functional69−71 was used with the addition of Grimme’s D3 dispersion and Becke−Johnson damping.72,73 Two mixed basis sets were employed. The first, denoted as B1, includes the lanl2tz basis set74,75 (obtained from the EMSL Basis Set Library76,77) for the Pd atom and the 6-31G** basis set for the remaining atoms. The second, larger basis set, designated as B2, consists of lanl2tz for Pd and 6311+G** for the remaining atoms. B1 was employed in geometry optimizations, and basis set B2 was used in subsequent single-point energy (SPE) calculations. Solvation effects [the experimental solvent z-1,2-dichloroethene (DCE) was chosen; ε = 9.2] were introduced in all calculations using the conductor-like polarizable continuum model (CPCM)78,79 as implemented in Gaussian 16. An experimental reaction temperature of 373.15 K was adopted in the Gibbs free energy calculations. Transition states were optimized by using the keyword TS and ascertained by vibrational frequency analysis to possess one and only one negative frequency corresponding to the mode along the reaction coordinate. Mulliken spin densities and charges were analyzed to gain insights into the electronic properties of the key reaction species. The energy values in the text are calculated at the SPE/B2//B1+ZPE(B1) level. Other energy values are presented in the Supporting Information.

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RESULTS AND DISCUSSION Based on our computational results, the catalytic cycle of the hydroxylation catalyzed by the Pd catalyst is depicted in Scheme 2. Starting from the resting state (RS) of the palladium catalyst Pd(CH3CN)2Cl2, a ligand-exchange process occurs, replacing the acetonitrile ligand by the substrate 2-arylpyridine via a Pd−N coordination. Subsequently, a direct C−H bond activation takes place, leading to the five-membered-ring intermediate IM1 and HCl. The key step in the catalytic cycle occurs next, which is the interception of the acylperoxo radical, generated in situ from aerobic aldehyde autoxidation (center of Scheme 2) to yield IM2/IM2′. The ligation of the acylperoxo radical to the Pd core is preferred to the direct

hydrogen atom to dioxygen to generate acyl radical II, which is followed by addition of another O2 to yield peroxyacyl radical III. Hydrogen abtraction of I by III leads to peracid IV and acyl radical II to propagate the chain reaction. Finally, Baeyer− Villiger reaction63 via intermediate V completes the reaction, yielding 2 equiv of acid VI. As reported by Guin et al. in Scheme 1b, the substrate arylpyridine was activated by the B

DOI: 10.1021/acs.inorgchem.8b03515 Inorg. Chem. XXXX, XXX, XXX−XXX

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Inorganic Chemistry Scheme 2. Proposed Catalytic Cycle of Palladium-Catalyzed Aerobic C(sp2)−H Hydroxylation of 2-Arylpyridines by Interception of Aldehyde Autoxidation

Figure 1. Energy proflie (in kilocalories per mole) for palladium-catalyzed aerobic C(sp2)−H hydroxylation of 2-arylpyridines by interception of aldehyde autoxidation. Energies outside of parentheses denote those of the HCl-promoted major route, while those inside parentheses denote those in the minor route that does not involve HCl.

attack of the radical on the carbon of adjacent phenyl carbon [ligation to Pd is a barrierless step, while attacking the phenyl carbon has a barrier of 11.1 kcal mol−1 (Figures S3 and S4)]. We have also considered a minor route, IM2′, without hydrogen bonding interactions with HCl. In the case of the HCl-promoted pathway, a proton relay from the more acidic

HCl can take place to stabilize the six-coordinated palladium(III)−peracid species IM2. Subsequently, an O−O bond homolysis occurs to form IM3, a Pd(IV)(OH)(nPrO•) (nPrO• denotes the n-butyracid radical) complex. The nascent hydroxyl group attacks the ortho position of the phenyl of the substrate, coupled with a second proton relay from the C

DOI: 10.1021/acs.inorgchem.8b03515 Inorg. Chem. XXXX, XXX, XXX−XXX

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Inorganic Chemistry

Figure 2. (a) Energy profiles and (b) geometric and spin information for the reaction intermediate in the conversion from IM2 to IM4 via the acylperoxo radical oxidation with HCl in the ground states. Energies are in kilocalories per mole, bond lengths in angstroms, bond angles in degrees, and imaginary frequencies in inverse centimeters. Calculations were performed at the UB3LYP-D3(BJ)/Lanl2tz(Pd), 6-31G**(C,H,O,N,Cl) level.

nascent phenol group to Cl− to recover the acid HCl. After reductive elimination, the Pd core is still +3 and the nascent intermediate IM4 is five-coordinated. In the case of the nonHCl pathway, the reaction sequences are similar without proton transfers. An O−O bond homolysis occurs to form an oxyl-Pd(IV)(nPrO) (nPrO denotes the n-butyracid anion) complex IM3′. A reductive elimination occurs after the attack of oxyl on the phenyl ring to form also a Pd(III) complex IM4′. Both IM4 and IM4′ are five-coordinated. Thus, the Pd(III) core can ligate to a hydrogen peroxide radical (OOH•) in situ from the aldehyde autoxidation to form IM5, which can easily lead to the intermediate IM6. Then, after a homolytic Pd−O bond cleavage, the Pd(III) core was reduced to the Pd(II) oxidation state and a triplet dioxygen was generated (product state PC). Finally, the Pd(II) catalyst was regenerated (RS state) following ligand exchange and O2 release, which may be used in the subsequent aldehyde autoxidation. The energy profile of the catalytic cycle is presented in Figure 1. Ligand exchange of acetonitrile by the substrate 2-

arylpyridine to generate the reagent complex state (RC) is exothermic by 10.8 kcal mol−1. The subsequent direct C−H activation is the rate-limiting step of the overall catalytic process with a barrier of 22.9 kcal mol−1. For TS1 (Table S3), the Pd−C distance is 2.098 Å, the Pd−H distance is 2.179 Å, the C−H distance is 1.329 Å, and the H−Cl2 distance is 1.682 Å. The C−H−Cl2 angle is 164.4°. It is a typical geometry for the well-known concerted metalation−deprotonation (CMD) process.80−84 The five-member cyclopalladated intermediate IM1 lies 11.8 kcal mol−1 higher in energy than the reagent complex. The next step of the transition from tetracoordianted Pd(II) complex IM1 to hexacoordinated Pd(III) complex IM2 is another exothermic process (by 6.1 kcal mol−1). The O−O homolysis step has an activation barrier of 11.8 kcal mol−1 for the HCl-promoted pathway (TS2), which is 1.1 kcal mol−1 lower than that of the pathway that does not involve HCl (TS2′); thus, the HCl-promoted pathway is a major route, and the pathway that does not involve HCl is a minor route. The Pd(IV)(OH)(nPrO•) complex IM3 lies 6.4 kcal mol−1 lower than IM2 (for the pathway that does not involve HCl, IM3′ D

DOI: 10.1021/acs.inorgchem.8b03515 Inorg. Chem. XXXX, XXX, XXX−XXX

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Inorganic Chemistry

Figure 3. (a) Energy profiles and (b) geometric and spin information for the reaction intermediate in the conversion from IM2′ to IM4′ via the acylperoxo radical oxidation without HCl in the ground states. Energies are in kilocalories per mole, bond lengths in angstroms, bond angles in degrees, and imaginary frequencies in inverse centimeters. Calculations were performed at the UB3LYP-D3(BJ)/Lanl2tz(Pd), 631G**(C,H,O,N,Cl) level.

lies 2.8 kcal mol−1 lower than IM2′). The attack of OH on the ortho position of phenyl is separated by a barrier of only 7.8 kcal mol−1, leading to a species that is highly exothermic by 44.4 kcal mol−1 (for the pathway that does not involve HCl, the activation barrier is 6.6 kcal mol−1 and the exothermicity is 52.4 kcal mol−1). Binding of the OOH• radical releases an additional 10.2 kcal mol−1 to form IM5. The proton transferassisted Pd−OO bond formation of the Pd(III)(OO•) species IM6 is a very fast step, with only a small barrier of 2.6 kcal mol−1. The following dissociation of the OO moiety forms the triplet O2 and the Pd(II) complex (PC). After ligand exchange of the hydroxylated product with the acetonitrile ligand with an exothermic energy of 3.5 kcal mol−1, the Pd(II)(L2)(Cl2) catalyst is regenerated and the state returns to the resting state for the next catalytic cycle. The preferred oxygenation in a Brønsted acid HClpromoted pathway compared to that in a pathway that does not involve HCl is due to the different chemistry of active intermediates formed in these two pathways (Figures 2 and 3). In the presence of HCl (Figures 2), the Pd(III)−OO species abstracts a proton from HCl and forms a Pd(III)−peracid species (IM2), which is hydrogen bonding to the chlorine anion Cl−, while in the absence of HCl (Figure 3), the

Pd(III)−OO species is an acylperoxo−Pd(III) species (IM2′). After O−O homolysis, a Pd(IV)(OH)(nPrO•) (IM3) or Pd(IV)(O•)(nPrO−) (IM3′) species is formed. Both intermediates are on the doublet ground state; the excited quartet/ sextet states lie much higher in energy [>40 kcal mol−1 (Table S5)]. For IM2 (Figure 2), the Pd−O2 distance is 2.262 Å, the O1−O2 distance is 1.448 Å, and the H−Cl2 distance is 1.725 Å. The spin on Pd is 0.71; thus, it is a hydrogen-bonded Pd(III)−peracid species. For 2TS2, the Pd−O2 distance is reduced to 2.033 Å, with a concomitant increase in the O1− O2 bond length to 1.737 Å. The spin of the PdO2H moiety is 0.52, and the spin of nPrO is 0.38. Thus, it is a homolytic bond dissociation. For 2IM3, the Pd−O2 distance is 1.948 Å and the O1−C2 distance is 1.249 Å. The O1−O2 distance is 2.174 Å, and the O2−Pd−O3−O1 dihedral angle is only −10.5°. The spin of Pd is nearly zero, and the one spin mainly delocalized on the O2H moiety (0.54) and the acid ligand nPrO (0.43). Thus, this unusual spin population might be caused by strong delocalization between the OH moiety and the acid moiety. For 2IM2′ (Figure 3), the Pd−O2 distance is 2.094 Å and the O1−O2 distance is 1.448 Å. The spin on Pd is 0.65; thus, this species is an acyl−peroxo−Pd(III) species. For 2TS2′, the Pd− O2 distance is 1.972 Å and the O1−O2 distance is 1.791 Å, E

DOI: 10.1021/acs.inorgchem.8b03515 Inorg. Chem. XXXX, XXX, XXX−XXX

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Figure 4. (a) Energy profiles and (b) geometric and spin information for the reaction intermediate generated in the conversion from IM5 to PC via the hydrogen peroxide radical oxidation progress. Energies are in kilocalories per mole, bond lengths in angstroms, bond angles in degrees, and imaginary frequencies in inverse centimeters. Calculations were performed at the UB3LYP-D3(BJ)/Lanl2tz(Pd), 6-31G**(C,H,O,N,Cl) level.

which is ∼0.05 Å longer than that in 2TS2. The spin of PdO is 0.72, and the spin of nPrO is 0.25, making it also a homolysis step. For 2IM3′, the Pd−O2 distance is 1.900 Å and the O1− C2 distance is 1.230 Å. The spin of Pd is nearly zero, while there is nearly one full spin density on the O2 atom. The PdO moiety is a Pd(IV)−oxyl species. The O1−O2 distance is 2.354 Å, and the O2−Pd−O3−O1 dihedral angle is only −1.8°, which means that there is strong conjugation between the PdO moiety and the acid ligand. On the basis of analysis of this electronic and geometric information, we conclude that the preference for the Brønsted acid HCl-promoted O−O homolysis over the alternative is caused by stabilization of hydrogen bonding interactions and the relative stability of the formed Pd(IV)−OH species IM2 versus the Pd(IV)−O• species. For the reductive elimination step, the pathway that does not involve HCl is preferred to the HCl-promoted pathway (Figures 2 and 3). For 2TS3 (Figure 2), The Pd−O2 distance is 1.961 Å, the O2−C1 distance is 2.196 Å, and the Pd−C1 distance is 2.034 Å. The O1−C2 distance is 1.220 Å, and the spin in the n-butyracid ligand nearly zero. There is an electron

transfer from the acid ligand (0.43 spin in IM3) to the arylpyridine ligand, in which the spin becomes 0.36. For 2IM4, a pentacoordinated Pd complex is formed. The spin of Pd is 0.47, and that of the chlorine ligand (Cl1) is 0.37. The Pd−Cl1 distance is 2.545 Å. This is caused by an antibonding σ*z2 orbital located on the Pd−O moiety (see Figure S8). For 2 TS3′ (Figure 3), the Pd−O2 distance is 1.922 Å, the O2−C1 distance is 2.029 Å, and the Pd−C1 distance is 2.040 Å. For 2 IM4′, a pentacoordinated Pd complex is also formed. The spin of Pd is 0.48, and that of the chlorine ligand (Cl1) is 0.34. Thus, both intermediates after reductive elimination are near the same species in the presence and absence of HCl. We also investigated the possibility of a direct attack of the Pd-ligated peracid on the ligated phenyl carbon and found that the activation energy is as large as 26 kcal mol−1 (Figures S10 and S12) in the presence and absence of HCl. Comparing that value to the barrier (11.8 kcal mol−1) of the stepwise O−O homolysis/reductive elimination process, we can eliminate the direct attack pathway. Due to in situ radical formation during aldehyde autoxidation in the reaction system, we propose that the F

DOI: 10.1021/acs.inorgchem.8b03515 Inorg. Chem. XXXX, XXX, XXX−XXX

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Inorganic Chemistry nascent OOH• binds the vacant position of the pentacoordinated Pd(III) intermediate, and computation shows a binding energy as large as 10.2 kcal mol−1. In addition to the interaction between the Pd core and the oxygen of OOH• (the Pd−O5 distance is 2.524 Å), there is also a hydrogen bond (the H2−O3 distance is 1.450 Å) that forms a proton relay pathway. On 3TS5, the O4−H2 distance is 1.092 Å and the H2−O3 distance is 1.377 Å. On the other hand, the Pd−O5 distance is 2.234 Å and the O5−O4 distance is 1.314 Å. Thus, such proton transfer promotes Pd−O bond formation and generates a Pd(III)−superoxo species (3IM6). The Pd(III)− O2• intermediate is unstable, and an elongation of the Pd−O distance will form the reduced Pd(II) core and a triplet O2 molecule (the PC state) (Figure 4).

21873052, 21872075, 21503089, and 21533003) and the open fund of the State Key Laboratory of Molecular Reaction Dynamics.

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CONCLUSION The direct C−H hydroxylation of arylpyridines catalyzed by a palladium catalyst that intercepts a free acylperoxo radical species from aerobic aldehyde autoxidation has the advantages of mild reaction conditions, nontoxic and inexpensive auxiliary compounds (aldehydes), and the economical use of atoms. The mechanism of the catalytic process was probed by means of density functional theory calculations. Our computational results support the proposal that the palladium(II) catalytic cycle involves a key step of injecting a peracid radical from an in situ aerobic aldehyde autoxidation. The introduction of a peracid radical leads to the formation of an active Pd(III)− peracid/acylperoxo−Pd(III) intermediate, the precursor to the widely accepted active high-valent Pd(IV)−OH intermediate. The conversion of the Pd(III)−peracid/acylperoxo−Pd(III) intermediate into a high-valent palladium−oxyl/hydroxyl intermediate is an O−O hemolysis step. We found that it is necessary to include another radical OOH•, in addition to the acylperoxo radical nPrOO•, to balance the spin of the system and ultimately to regenerate the closed-shell PdCl2 catalyst. This computational study sheds light on the elusive palladium catalyst-catalyzed oxygenation that involves a radical and will play a positive role in the further design of rational reaction strategies and catalysts.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.inorgchem.8b03515. Seventeen tables and 16 figures on the calculation details and also Cartesian coordinates of all key intermediates reported in the text and Supporting Information (PDF)

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REFERENCES

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Yong Wang: 0000-0002-7668-2234 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors acknowledge the financial support received from the National Natural Science Foundation of China (Projects G

DOI: 10.1021/acs.inorgchem.8b03515 Inorg. Chem. XXXX, XXX, XXX−XXX

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DOI: 10.1021/acs.inorgchem.8b03515 Inorg. Chem. XXXX, XXX, XXX−XXX