A Combined Experimental and Theoretical Investigation of Oxidation Catalysis by cis-[VIV(O)(Cl/F)(N4)]+ Species Mimicking the Active Center of Metal-Enzymes

Reaction of VIVOCl2 with the nonplanar tetradentate N4 bis-quinoline ligands yielded four oxidovanadium(IV) compounds of the general formula cis-[VIV(O)(Cl)(N4)]Cl. Sequential treatment of the two nonmethylated N4 oxidovanadium(IV) compounds with KF and NaClO4 resulted in the isolation of the species with the general formula cis-[VIV(O)(F)(N4)]ClO4. In marked contrast, the methylated N4 oxidovanadium(IV) derivatives are inert toward KF reaction due to steric hindrance, as evidenced by EPR and theoretical calculations. The oxidovanadium(IV) compounds were characterized by single-crystal X-ray structure analysis, cw EPR spectroscopy, and magnetic susceptibility. The crystallographic characterization showed that the vanadium compounds have a highly distorted octahedral coordination environment and the d(VIV–F) = 1.834(1) Å is the shortest to be reported for (oxido)(fluorido)vanadium(IV) compounds. The experimental EPR parameters of the VIVO2+ species deviate from the ones calculated by the empirical additivity relationship and can be attributed to the axial donor atom trans to the oxido group and the distorted VIV coordination environment. The vanadium compounds act as catalysts toward alkane oxidation by aqueous H2O2 with moderate ΤΟΝ up to 293 and product yields of up to 29% (based on alkane); the vanadium(IV) is oxidized to vanadium(V), and the ligands remain bound to the vanadium atom during the catalysis, as determined by 51V and 1H NMR spectroscopies. The cw X-band EPR studies proved that the mechanism of the catalytic reaction is through hydroxyl radicals. The chloride substitution reaction in the cis-[VIV(O)(Cl)(N4)]+ species by fluoride and the mechanism of the alkane oxidation were studied by DFT calculations.


■ INTRODUCTION
In recent years, the coordination chemistry of vanadium has drawn a lot of interest, mainly due to its biological, medicinal and catalytic applications. 1−11 Vanadium exhibits a wide variety of oxidation states (−III to + V), with the oxidation states of +III to +V mainly found in molecular systems of biological relevance. Enzymes, such as the vanadium-dependent haloperoxidases found in algae, are able to utilize vanadium's wide range of oxidation states in order to oxidize halides in nature. 12 Moreover, vanadium plays a key role in the vanadium nitrogenase enzyme, which is a vanadium analogue of the iron−molybdenum enzyme that reduces dinitrogen to ammonia. 13−15 In addition, vanadium has a significant effect on cell growth, signaling processes, antitumor activity, and insulinmimetic properties. 16−26 The synthesis of metal compounds, which are metal enzymes' active site analogues, has played an important role in understanding the mechanisms of enzyme activity and in the development of small molecules with activity similar to relevant enzymes. 27 The particular function of the metal-enzymes requires specific oxidation states, ligands, and coordination geometries for the metal-ion in the active site. 27 The coordination geometries around the metal-ions in the enzymes' active site, enforced by the rigidity of the protein backbones, are irregular. These enforced geometries define the activity of the enzyme. 28,29 Small changes of these structural features are crucial for the specificity of the enzymes. In contrast, in the small metal compounds, there are few or no constraints dictating the geometry. Therefore, the arrangement of the ligands around the metal ions in these compounds relies on the preference of the metal ion.
Vanadium's low-molecular-weight coordination compounds mimic the activity of enzymes, such as haloperoxidases. 30 −33 Vanadium's wide range of oxidation states and coordination numbers and its Lewis acid character are the key characteristics that enable the use of vanadium compounds in various catalytic reactions, mimicking haloperoxidases, such as alcohol oxidation, sulfoxidation, epoxidation, and alkane oxidation reactions. 34−41 In particular, the oxidation of alkanes has a high industrial significance, since it enables the functionalization of inert alkanes to more valuable and reactive organic materials such as alcohols and ketones in the presence of a suitable oxidant like H 2 O 2 or O 2 , under mild conditions. 42−45 Some of the most commonly used ligands are nitrogen-based tetradentate pyridine or quinoline ligands, which have the ability to strongly bind and stabilize vanadium ions in the +IV or +V oxidation state. Moreover, these ligands are highly resistant to oxidation and decomposition under the catalytic conditions, and their compounds with iron(II) are some of the most efficient catalysts for alkane oxidation. 46 However, in order to mimic metal-enzymes outstanding oxidative activity and synthesize efficient low-molecular-weight catalysts, it is important to understand the effect of the distortion of the coordination environments of the metal ions in the active site of the enzyme and its contribution to the catalytic action.
Herein, we describe the synthesis, physicochemical, and structural characterization and the catalytic properties in alkane oxidation reactions of various oxidovanadium(IV) compounds with the nonplanar N 4 quinoline-based/amine ligands and their dimethylated analogues (Scheme 1).
The tetradentate nonplanar N 4 ligands (Scheme 1) were chosen because their ligation to V IV O 2+ induces a severely distorted octahedral geometry (Scheme 2), since our aim was to study the effect of structural distortions on the catalytic properties and the substitution reactions of these cis- [ . The dimethylated organic molecule H 2 bqch was prepared according to Britovsek and co-workers in 69% yield. 46 The purity of dbqen was confirmed with positive HR-ESI-MS, and 1 H, 13 (2') suitable for X-ray structure analysis were prepared as follows: Compound 2 (50 mg, 0.09 mmol) was dissolved in water (10 mL) under magnetic stirring, and NH 4 BF 4 (9.8 mg, 0.09 mmol) was added to it. Upon addition of NH 4 BF 4 , a light green precipitate was formed which was filtered and dried. Dissolution of the green solid in CH 3 CN and layering of diethyl ether to it resulted in the formation of crystals of Crystals of cis-[V IV (O)(Cl)(dbqch)]ClO 4 (2'') suitable for X-ray structure analysis were prepared using the same method reported for 2' except that NaClO 4 was used instead of NH 4 BF 4 .
Caution!Perchlorates are powerful oxidizers, they are potentially hazardous, especially in contact with reducing material, and they may explode when exposed to shock or heat. 47 Cis-chlorido[N,N′-Bis (8-quinolyl) (5). To a stirred solution of 1·H 2 O (100 mg, 0.19 mmol) in water (20 mL) was added in one portion solid KF (12 mg, 0.21 mmol). Upon addition of KF, the light brown color of the solution changed to orange. The solution was stirred for an additional hour. Then solid NaClO 4 (26 mg, 0.21 mmol) was added to it in one portion, and an orange precipitate was formed. The mixture was stirred for 3 h and filtered, washed with cold water (2 × 5 mL), and dried in vacuum to get 78 mg of the orange solid. Yield: 74% (based on 1·H 2 O). Anal. Calcd (%) for C 24

Synthesis of the Ligands and Oxidovanadium(IV) Compounds.
The synthesis of the ligands dbqch and dbqen is depicted in Scheme 3 and includes three steps: The first step involves the reaction of the diamine (1 equiv) with 8hydroxyquinoline (2 equiv) to get the secondary amines H 2 bqch and H 2 bqen. The secondary amines were prepared by slight modification of the method of Britovsek 46 and coworkers to increase their yield by 10−15%. The second step involves the deprotonation of the secondary amines with 2 equiv of n-BuLi. In the third step, the methylation by CH 3 I (two equivalents) of the deprotonated amines was carried out to afford the dimethylated ligands.
According to Table 3, the oxidovanadium(IV) compounds 1−6 are able to oxidize cyclohexane with hydrogen peroxide at room temperature. More specifically, oxidation of cyclohexane   Figure 3). The addition of 100 μmoles of HCl in the catalytic reaction led to reduced total yields, i.e., 20.3 and 19.8% for 1 and 3, respectively. The corresponding methylated oxidovanadium-(IV) compounds 2 and 4 without HCl provided total yields for cyclohexane oxidation 7.7 and 10.2%, respectively, which increased in the presence of 100 μmoles of HCl, 19.5% and 17.3%, respectively ( Figure 3). The nonmethylated fluorido compounds 5 and 6 gave total yields 11.1% and 29.3%, respectively, which were higher than their chlorido analogues (Table 3). Cyclohexane oxidation catalyzed by 5 and 6 was not affected by HCl as a promoter; its presence resulted in even lower yields (24.1% and 23.4% respectively). TONs achieved by the catalysts 1−6 ranged from 77 to 293 and are visualized in Figure 4. Based on our catalytic data, the addition of HCl to the cyclohexane oxidation, catalyzed by the methylated oxidovanadium(IV) compounds 2 and 4, increases the yield of oxidation products. For the nonmethylated compounds 1, 3, 5, and 6, the addition of HCl decreases the catalytic activity. Analogous negative effect on catalytic cyclohexane oxidation was observed when HCl was replaced by 2-pyrazine carboxylic acid (PCA) or HNO 3 (data not shown). The use of PCA as promoter in alkane oxidation catalyzed by oxidovanadium(IV) compounds is well-known due to its assistance for H + migration from a coordinated H 2 O 2 to the oxido-ligand. 45 Here, the observed chemical behavior of 1, 3, 5, and 6 reveals that the two −NH− groups in conjunction with the oxidoligand are able to manage the hydrogen peroxide deprotonation which is coordinated to vanadium center toward homolytic O−O bond cleavage and generation of • OH radicals. Cyclohexane oxidation most probably occurs via these • OH radicals which abstract a cyclohexane hydrogen atom to form cyclohexyl radicals. The alkyl radicals in oxygenated organic solvents readily form alkyl hydroperoxides (cyclohexyl hydroperoxide in our case) as primary inter-mediate oxidation product which transformed to cyclohexanol and cyclohexanone. 58−60 Magnetism and X-Band Continuous-Wave (cw) EPR Spectra of 1−6. The magnetic moments of compounds 1−6, at 298 K, have magnetic moments in the range of 1.70−1.74 μ B , in accord with the spin-only value expected for d 1 , S = 1/2 systems. These μ eff values constitute clear evidence that the oxidation of vanadium in 1−6 is IV.
The X-band cw EPR parameters, of the frozen (120 K) solutions (DMSO) of the oxidovanadium(IV) compounds 1− 6 are depicted in Table 4 Table 3 for further details on reaction conditions. × 10 −4 for the five-coordinate (structure A) and six-coordinate (structure B) respectively. The theoretically predicted A z values are ∼2.5% lower than the experimental, due to the accuracy of the method used, and this deviation is similar to the deviation reported for the Gaussian calculations of charged vanadium complexes at the same level of theory. 62 The A || or A z parameters depend on the donor atoms in the equatorial plane of the vanadium(IV) compounds and can be calculated from the empirical additivity relationship (eq 4). 63

,64
A ||,i is the contribution of each donor atom to A || .
The donor atoms in the equatorial plane of 1−4 consist of a Cl − , two quinoline N (N q ), and one aromatic amine N (N ArNH2 ) atoms. The A ||,i contributions N q and N ArNH2 have not been determined previously. The A ||,i value of other aromatic heterocyclic N donor atoms, such as imidazole, pyridine, etc., and N RNH2 were used instead for the contribution of N q and N ArNH2 respectively. 65 The calculated A || value using eq 4 is approximately −165 × 10 −4 cm −1 . However, the experimental and the calculated values of A || are significantly lower for the octahedral species B and significantly higher than the five-coordinate species A.
The dramatic decrease of the experimental A || values of species B, compared with the values calculated from the additivity relationship, is attributed to the coordination of the    66 Tolis et al. have also suggested that axial donor atoms induce a radial expansion of the vanadium d xy orbital, resulting in a reduced electron density on the V IV and decrease of A z . 67 On the other hand, the much higher A z (−177.5 × 10 −4 cm −1 ) experimental values of species A in comparison to the predicted A z values for 1−6 from the additivity relationship are attributed to the distortion in the equatorial plane by the elongation of V−N(1) (2.307 Å), due to the tension in the N(3)---N(1) eight-membered ring (Scheme 7). Apparently, the weakening of the bonding at the equatorial plane results in an increase of A z values.
The equilibrium between species A and B is shifted toward B, when the amine hydrogen atoms of the ligands (H 2 bqch, H 2 bqen, in compounds 1, 3) are replaced with the bulky methyl groups (dbqch, dbqen in compounds 2, 4). In addition, theoretical calculations revealed that 3(A) is thermodynamically more stable than 3(B), whereas 4(B) is thermodynamically more stable than 4(A). In addition, from the quantities of B in the solution being 21% and 0% for the compounds 1 (the cyclohexane derivative) and 3 (the ethylenediamine derivative), respectively, it is reasonable to conclude that cyclohexane-1,2-diamine chelate ring is more rigid than the 1,2ethylenediamine one. The chelate ring defined by the vanadium(IV) atom and the two amine nitrogen atoms is stretched due to the elongation of the bond V IV −N am.axial . Moreover, the attachment of the methyl groups to the amine nitrogen atoms increases the steric interactions between Cl − and the −CH 3 group (Scheme 8) forcing equatorial N amine to remain ligated to vanadium nucleus, forming the six-coordinate species B (Scheme 6). Dissociation of the equatorial N amine atom results in the formation of an eight-membered chelate ring (Scheme 7) similar to the chelate rings for other V IV compounds reported and characterized by crystallography. 68 The EPR parameters calculated from the simulation of the experimental spectra reveal that compounds 5 and 6 acquire the structure A in DMSO. This might be attributed to the stronger trans effect of F − than Cl − on N(3) (Scheme 7). On the basis of the additivity relationship, 63,64,69,70 (Table 4). In marked contrast, the A z values of 5 and 6 were slightly higher. Theoretical calculation of 6(B) (Scheme 7) at BHandHLYP/6-311g (d,p) level gives a value for A z (−178.3 × 10 −4 cm −1 ) which is very close to the experimental one. The higher experimental A z values of 5 and 6 than 1−4 and the higher A z calculated values using eq 4, are attributed to higher trigonality index of 5 and 6 (∼0.70) than 1−4 (∼0.51). 61,66 The stronger trans effect of F − than Cl − causes lengthening of the V−N(3) bond (Scheme 7), increasing the tension in the chelate rings. The energy of the compounds 5 and 6, decreases by adopting trigonal bipyramidal structure in solution. The increase of the trigonality index in 5A and 6A increases the distance between the vanadium atom and N(2), resulting only in five-coordinate species in the solutions of 5 and 6. 61 The failure to synthesize the V−F compounds with the sterically hindered dbqch and dbqen ligands (the dimethylated molecules) is attributed to the high energy, required for these ligands, to adopt trigonal bipyramidal structure in solution (Scheme 8). The sterically hindered dbqch and dbqen ligands in 2, and 4, force N(2) close to the vanadium atom (vide supra), taking octahedral or distorted square pyramidal structures only. The low spin - 19  The X-band cw EPR spectra of the frozen solution of the compounds 1−6 in CH 3 CN gave a broad unresolved peak centered at g = 1.982 ( Figure 6). This spectrum improves with the addition in CH 3 CN of solvents with high dielectric constants such as H 2 O, DMSO etc. In contrast, the X-band EPR spectra of the CH 3 CN solutions at room temperature of 1−6 gave well resolved octaplets of both isomers confirming that A and B are present in CH 3 CN solutions ( Figure S9).
Addition of aqueous HCl into the CH 3 CN solution of 4· 3H 2 O ( Figure 6I) and 5 ( Figure 6II) results in well-resolved spectra that contain both species A and B. Increasing the quantity of aqueous HCl into the CH 3 CN solution of 1−6 the equilibrium is shifted toward A, and this is in line with the theoretical calculations (vide inf ra). Extrapolation of the quantities of A vs the quantity of aqueous HCl in CH 3 CN shows that both A and B are present in pure CH 3 CN. The Xband cw EPR spectra of the CH 3 CN solutions of 1−6 gave well resolved octuplets of both isomers confirming that A and B are present in CH 3 CN solutions ( Figure S9).  Figure S12. After the addition of H 2 O 2 into the CH 3 CN solution of 3 + DMPO at zero time the EPR spectrum shows a strong peak at g = 2.0153 assigned to the radical of DMPO adduct with various radicals that might be formed in solution including superperoxide and hydroxide radicals. This peak after ∼30 min turned to an 9-fold peak at g = 2.0044 and A N ∼ 7 G and A H ∼ 4G identified as 5,5-dimethyl-pyrrolidone-(2)-oxyl-(DMPOX ' ) the oxidation product of DMPO-·OH as assigned previously. 72−74 In conclusion, the V IV of the catalysts is oxidized to V V upon addition of H 2 O 2 and the ligands remain bound to the vanadium atom under the conditions of catalysis, whereas, the mechanism of the catalytic reaction is through hydroxyl radicals. Substitution of Cl − by F − ligand is not reasonable to follow the I a mechanism, since all attempts to identify a 7-coordinate transition state or intermediate in these reactions were not successful. The dissociative mechanism (Figure 7) is not favored since the dissociation of Cl − needs relatively high activation energy ∼32.5 kcal/mol for the formation of the 5coordinate intermediate. It is more likely that the substitution reaction follows the concerted dissociative interchange I d pathway. This pathway is "free" of any activation barrier, since the formation of the 7-coordinate transition state releases    Their catalytic oxidation reactions of the highly distorted octahedral V IV O 2+ compounds, mimicking the irregular geometries of the coordination environment of the metal ions in proteins, with the nonplanar N 4 tetradentate amine ligands were examined. The distortion of the coordination sphere of the V IV O 2+ cation induced by the N 4 ligands was further enforced by partially replacing ligand's H-with bulky cyclohexyl-and/or methyl-groups and by introducing F-or Cl-coligands in the V IV O 2+ coordination sphere.

Mechanistic Details for the Reactivity of the cis-[V IV (O)(Cl)(N 4 )] + Compounds, with F
The experimental EPR parameters of these distorted V IV O 2+ compounds deviate from those calculated from the empirical additivity relationship. The deviation has been assigned either to the coordination of the axial nitrogen donor atom or the trigonal distortion of the V IV coordination environment. cw Xband EPR speciation studies in frozen polar solvents reveal that the introduction of the hindered cyclohexyl-and methylgroups causes retention in solution of the octahedral solid-state crystal structure, whereas, ligands without steric hindrance allow dissociation of one of the ligand's amine donor atom from the six-coordinate sphere of V IV ion in solution, resulting in five-coordinate structures. Based on the equilibrium between six-and five-coordinate species, we concluded that the steric hindrance in the V IV O 2+ compounds is increasing according to the following series, -HNCH 2 CH 2 NH-> -HNC 6 H 10 NH-> -(CH 3 )NCH 2 CH 2 N(CH 3 )-> -(CH 3 )NC 6 H 10 N(CH 3 )-. cw Xband EPR spectra of the V IV O 2+ compounds in frozen CH 3 CN show that 1−6 five-or both five and six-coordinate structures, however addition of aqueous HCl into their CH 3 CN solution results in the full dissociation of the equatorial amine group and the formation of only five-coordinate species. The sterically hindered compounds 2 and 4, containing the dimethylated ligands, inhibit the approach of the nucleophiles (F − , H 2 O 2 ) to the vanadium nucleus, resulting in unsuccessful replacement of Cl − ligand by the F − and lower oxidative catalytic activity compared with the less sterically hindered 1 and 3, which contain the nonmethylated ligands.
The variation of the oxidative catalytic activities between the chloride and fluoride V IV compounds is attributed to two different mechanisms of catalytic action controlled by the V-X (X = F − , Cl − ) bond strengths (V−F is stronger than V−Cl). of the coordination environment of the V IV ion, mimicking the active site of metal-proteins, can be used as a highly desirable methodology allowing for the modification of the functionality of the metal compounds such as in the case of oxidative catalysis.
The vanadium(IV) of the compounds 1−6 is oxidized to vanadium(V) upon addition of H 2 O 2 and the ligands remain bound to the vanadium atom under the conditions of catalysis, as it was evidenced with 51 V and 1 H NMR spectroscopies. cw X-band EPR trap studies proved that the mechanism of the catalytic reaction is through hydroxyl radicals.
Suitable ligands that introduce the desirable amount of distortion on the metal ion's coordination environment can result in a fruitful design approach for the development of effective catalysts tailored for specific applications. ■ ASSOCIATED CONTENT