Cyclohexene Oxidation with H 2 O 2 over Metal-Organic Framework MIL-125 ( Ti ) : The Effect of Protons on Reactivity

The catalytic performance of the titanium-based metal–organic framework MIL-125 was evaluated in the selective oxidation of cyclohexene (CyH) with environmentally friendly oxidants, H2O2 and tBuOOH. The catalytic activity of MIL-125 as well as the oxidant utilization efficiency and selectivity toward epoxide and epoxide-derived products can be greatly improved by acid additives (HClO4 or CF3SO3H). In the presence of 1 molar equivalent (relative to Ti) of a proton source, the total selectivity toward CyH epoxide and trans-cyclohexane-1,2-diol reached 75–80% at 38–43% alkene conversion after 45 min of reaction with 1 equivalent of 30% H2O2 at 50 ◦C. With 50% H2O2 as the oxidant, the total selectivity toward heterolytic oxidation products increased up to 92% at the same level of alkene conversion. N2 adsorption, powder X-ray diffraction (PXRD), and infrared (IR) spectroscopy studies before and after the catalytic oxidations confirmed the absence of structural changes in the Metal–organic framework (MOF) structure. MIL-125 was stable toward titanium leaching, behaved as a truly heterogeneous catalyst, and could easily be recovered and reused several times without any loss of the catalytic properties.


Introduction
Epoxides are key intermediates used in the manufacture of many valuable bulk and fine chemicals [1][2][3].The selective epoxidation of an alkene C=C double bond by stoichiometric amounts of organic peroxy acids or via the chlorohydrin route is widely employed in the industry [1,2].The development and implementation of greener and more sustainable catalytic epoxidation processes using environmentally benign oxidants is a challenging goal in modern organic syntheses.Hydrogen peroxide is, along with molecular oxygen, the most sought-after oxidant in terms of environmental sustainability because it produces water as its only byproduct [4][5][6].
It has been widely recognized that titanium-containing molecular sieves are among the best catalysts for selective oxidations with hydroperoxides.Microporous titanium-silicalite TS-1 discovered by the EniChem group has opened a real perspective of H 2 O 2 applications in organic synthesis [7][8][9].
Metal-organic frameworks (MOFs) are currently of great interest due to their potential applications in gas storage and separation, molecular recognition, as well as drug delivery [10][11][12][13][14][15][16][17][18][19][20].MOFs are also considered prospective materials for heterogeneous catalysis because of their extremely high surface areas, structural nanoporosity and tunable functionality .Another important feature of MOFs is a high content of active metal sites which are uniformly spatially distributed and accessible by reagents, provided the size of the pore entrances allows for the penetration of the reactant molecules [42].
Titanium dioxide, TiO 2 , is considered nowadays one of the most successful photocatalysts due to its high efficiency, chemical stability, abundance, and rather low toxicity.In this context, titanium-based MOFs are viewed as one of the most appealing subclasses of the MOFs family, owing to their promising optoelectronic and photocatalytic properties, including photocatalytic redox reactions, water splitting, and organic pollutant degradation [43][44][45][46][47].Among the reported Ti-based MOFs, a titanium-oxo-hydroxo-cluster-based MOF MIL-125 is the most studied one since it was the first MOF that revealed photoactivity [48][49][50][51][52][53][54][55][56].Moreover, MIL-125 exhibited catalytic activity in the high-pressure cycloaddition of CO 2 to epichlorohydrin and oxidative desulfurization of heterocyclic aromatic sulfur compounds with organic hydroperoxides [57,58].Recently, some of us demonstrated that MIL-125 reveals a superior selectivity toward p-benzoquinones in the oxidation of alkyl-substituted phenols with aqueous H 2 O 2 [59,60].Although the crystal structure of MIL-125 was destroyed under the turnover conditions, the MOF acts as a precursor for the highly active, selective and recyclable catalyst [59,60].More recently, oxidative desulfurization using H 2 O 2 as the oxidant and MIL-125 and MIL-125_NH 2 as catalysts was also reported [61,62], but mesoporous carbons containing TiO 2 nanoparticles obtained by the pyrolysis of MIL-125_NH 2 appeared to be more active than the original MOF [61].To explore further the potential of MIL-125 for environmentally benign liquid-phase oxidations, we investigated the epoxidation of a representative alkene, cyclohexene, with aqueous hydrogen peroxide and tert-butyl hydroperoxide.The aim of this work was not to develop a practical method for the synthesis of epoxides but to clarify factors that govern the catalytic performance of this MOF, comprising well-defined Ti-oxo-hydroxo-clusters.We have found a simple tool that allows alkene epoxidation selectivity to be considerably improved without changes in the MOF crystalline structure.

Catalysts Synthesis and Characterization
MIL-125 materials were synthesized by a conventional solvothermal procedure as reported elsewhere [63].Samples with three different sizes of crystallites (0.5, 1.5, and 5.0 µm) designated as MIL-125-S, MIL-125-M and MIL-125-L, respectively, were prepared using benzoic acid and water as a modulator to alter the particle size [59].
PXRD patterns of the MOF samples given in Figure 1 confirm the quasi-cubic tetragonal structure of MIL-125 built up from cyclic octamers of edge-and corner-sharing TiO 5 (OH) octahedra connected to 12 other cyclic octamers through 1,4-benzenedicarboxylate linkers [48].
Textural parameters of the MIL-125 samples acquired from the N 2 adsorption measurements are presented in Table 1 along with the average particle size estimated by scanning electron microscopy (SEM) (Figure 2).Specific BET surface areas and micropore volumes are close to the characteristic values reported for MIL-125 [48].FTIR spectra of MIL-125 (Figure 3, curves A and B) reveal strong characteristic bands of carboxylate groups (1350-1700 cm -1 ) and O-Ti-O vibrations (400-800 cm −1 ) [48,51,58].A weak shoulder at the 1710 cm -1 characteristic of free terephthalic acid may indicate the presence a minor amount of the free linker within the micropores, while the broad band around 3400 cm −1 signifies the presence of intercrystalline water/solvent [48,51,58].The minor sharp band at 3676 cm −1 corresponds to the isolated OH groups of the TiO5(OH) clusters.FTIR spectra of MIL-125 (Figure 3, curves A and B) reveal strong characteristic bands of carboxylate groups (1350-1700 cm -1 ) and O-Ti-O vibrations (400-800 cm −1 ) [48,51,58].A weak shoulder at the 1710 cm -1 characteristic of free terephthalic acid may indicate the presence a minor amount of the free linker within the micropores, while the broad band around 3400 cm −1 signifies the presence of intercrystalline water/solvent [48,51,58].The minor sharp band at 3676 cm −1 corresponds to the isolated OH groups of the TiO5(OH) clusters.FTIR spectra of MIL-125 (Figure 3, curves A and B) reveal strong characteristic bands of carboxylate groups (1350-1700 cm −1 ) and O-Ti-O vibrations (400-800 cm −1 ) [48,51,58].A weak shoulder at the 1710 cm −1 characteristic of free terephthalic acid may indicate the presence a minor amount of the free linker within the micropores, while the broad band around 3400 cm −1 signifies the presence of intercrystalline water/solvent [48,51,58].The minor sharp band at 3676 cm −1 corresponds to the isolated OH groups of the TiO 5 (OH) clusters.2, entry 10).

Catalytic Studies
The catalytic properties of the MIL-125 materials were assessed in cyclohexene (CyH) oxidation with aqueous H2O2 in acetonitrile.The main results are collected in Table 2. CyH is one of the most difficult substrates to be epoxidized selectively since it possesses highly reactive H atoms in the allylic position, which can be easily abstracted by radical species to give rise to allylic oxidation products [64].
The addition of 1 molar equivalent (relative to Ti atoms in the MOF) of HClO4 increased the reaction rate and attainable CyH conversion (42% conversion in 45 min vs. 26% conversion in 60 min without acid) and significantly changed the product composition, favoring the formation of the heterolytic oxidation products (Table 2, compare entries 3 and 4).CF3SO3H produced a similar effect but also increased the ratio of diol relative to epoxide (Table 2, entry 5).Thus, the total selectivity  2, entry 10).

Catalytic Studies
The catalytic properties of the MIL-125 materials were assessed in cyclohexene (CyH) oxidation with aqueous H 2 O 2 in acetonitrile.The main results are collected in Table 2. CyH is one of the most difficult substrates to be epoxidized selectively since it possesses highly reactive H atoms in the allylic position, which can be easily abstracted by radical species to give rise to allylic oxidation products [64].
As compared to the 'blank' experiment without any catalyst (Table 2, entry 1), MIL-125 revealed activity in CyH oxidation with 1 equivalent of H 2 O 2 (Table 2, entry 3) and produced a set of products that included cyclohexenyl hydroperoxide (HP), 2-cyclohexene-1-ol (enol), 2-cyclohexene-1-one (enone), epoxide, and the epoxide ring opening product trans-cyclohexane-1,2-diol (diol).Homolytic (allylic) oxidation products (HP, enol and enone) predominated over heterolytic ones (epoxide and diol), pointing to the homolytic mechanism of H 2 O 2 activation.The addition of 1 molar equivalent (relative to Ti atoms in the MOF) of HClO 4 increased the reaction rate and attainable CyH conversion (42% conversion in 45 min vs. 26% conversion in 60 min without acid) and significantly changed the product composition, favoring the formation of the heterolytic oxidation products (Table 2, compare entries 3 and 4).CF 3 SO 3 H produced a similar effect but also increased the ratio of diol relative to epoxide (Table 2, entry 5).Thus, the total selectivity toward epoxide and diol reached 75-80% in contrast to only 35% without acid additives.It is worthy to note that selectivity to homolytic oxidation products in the 'blank' experiment without any catalyst also decreased (from 65 to 47%) upon addition of acid (Table 2, compare entries 1 and 2), but the effect was less pronounced than in the presence of MIL-125 (from 60 to 22%), and the CyH conversion reached only 8% (Table 2, entry 2).Lowering the reaction temperature from 50 to 30 • C reduced the maximum conversion of CyH and changed the ratio between the heterolytic oxidation products, suppressing the diol formation (Table 2, compare entries 4 and 6).With 0.5 equivalent of H + , we also observed the rate-accelerating effect and improvement of selectivity, but the levels of conversion and selectivity were lower than with 1 equivalent of acid (Table 2, entries 7 and 8).On the other hand, enlargement of the amount of acid to 1.5 equivalent further increased the reaction rate and practically suppressed the formation of homolytic oxidation products (total selectivity toward epoxide and diol reached 88%; Table 2, entry 9).
Table 3 shows a comparison of the catalytic performance of MIL-125 in the presence of t BuOOH, 30% H 2 O 2 , and 50% H 2 O 2 .When using t BuOOH as an oxidant, the addition of acid also increased the total CyH conversion (46 vs. 25%); however, the amount of homolytic oxidation products did not decrease significantly (45 vs. 54% in the absence of acid) (Table 3, entries 1 and 2).In contrast to the CyH oxidation with H 2 O 2 , the reaction with t BuOOH also produced the product of diol overoxidation, 2-hydroxycyclohexanone.Reducing the amount of water in the reaction system, namely, the use of 50% H 2 O 2 instead of 30% H 2 O 2 , led to a significant growth of the ratio of heterolytic oxidation products (total selectivity 92% vs. 76-78% with 30% H 2 O 2 ) and produced practically no effect on the reaction rate and alkene conversion (Table 3, compare entries 3 and 5 with entries 4 and 6, respectively).In polyoxometallate chemistry, triggering the catalytic activity and/or selectivity by protonation has long been known [65][66][67][68][69][70][71][72][73][74].Thus, Ti(IV)-monosubstituted Keggin phosphotungstate Na 5-n H n PTiW 11 O 40 (n = 2-5) catalyzed H 2 O 2 -based CyH oxidation to yield diol as the main reaction product, while the Ti-POM with n = 1 produced allylic oxidation products, enol and enone, along with comparable amounts of the corresponding epoxide and diol [67].Density functional theory (DFT) calculations showed that the formation of epoxide through the Ti-hydroperoxo intermediate is energetically more favorable than through the peroxo intermediate and that the protonation of polyanion is crucial for the activation of the Ti-hydroperoxo species towards heterolytic oxygen-atom transfer because it reduces the corresponding energy barrier [71].
Numerous kinetic and spectroscopic studies implemented on heterogeneous Ti catalysts showed that a hydroperoxo moiety TiOOH and not a peroxo one Ti(η 2 -O 2 ) is the species that performs alkene epoxidation with peroxides [8,[75][76][77].Given that, we may assume that, in the case of MIL-125, the addition of a source of protons also favors the formation of the active TiOOH intermediates responsible for alkene epoxidation.
The structure of MIL-125 has two types of cages, namely, an octahedral one (12.5 Å diameter) and a tetrahedral one (6 Å diameter), accessible through triangular windows of 5-7 Å [48].In order to elucidate the impact of internal diffusion in the case of MIL-125, samples with different sizes of crystallites (0.5, 1.5, and 5 µm; see Figure 2) have been examined in CyH oxidation with H 2 O 2 .As one can judge from the kinetic curves shown in Figure 4, the initial rate of CyH oxidation was not affected by the size of the crystallites.Therefore, we may conclude that no diffusion limitation takes place in the course of the catalytic oxidation of CyH over MIL-125.The catalytic properties (CyH conversion and product selectivity) of MIL-125-S and the M and L materials were also close (Table 2, entries 4, 8 and 10).
Catalysts 2019, 9, x FOR PEER REVIEW 6 of 14 to elucidate the impact of internal diffusion in the case of MIL-125, samples with different sizes of crystallites (0.5, 1.5, and 5 μm; see Figure 2) have been examined in CyH oxidation with H2O2.As one can judge from the kinetic curves shown in Figure 4, the initial rate of CyH oxidation was not affected by the size of the crystallites.Therefore, we may conclude that no diffusion limitation takes place in the course of the catalytic oxidation of CyH over MIL-125.The catalytic properties (CyH conversion and product selectivity) of MIL-125-S and the M and L materials were also close (Table 2, entries 4, 8 and 10).Incomplete CyH conversions with 1 equivalent of the oxidant may be caused by either blockage of MOF micropores or active sites by the reaction products during the reaction course or unproductive H2O2 decomposition competing with the target oxidation reaction.Indeed, the addition of products in the amount close to that found at the end of the reaction (0.015 mmol of epoxide and 0.015 mmol of diol) retarded the oxidation process (Figure 5a), while the addition of water (0.3 mmol)-the product derived from the oxidant-stopped the reaction immediately (Figure 5b), thus indicating that the adsorption of the reaction products could be the reason for catalyst deactivation.Another reason for the low CyH conversions could be the high rates of the unproductive decomposition of H2O2 relative to the rates of the catalytic oxidation of CyH over MOF, i.e., a rather low efficiency of the oxidant utilization.Indeed, Figure 6 shows that H2O2 decomposition over MIL-125 occurs with an appreciable rate.While the target CyH oxidation was strongly accelerated by acid Incomplete CyH conversions with 1 equivalent of the oxidant may be caused by either blockage of MOF micropores or active sites by the reaction products during the reaction course or unproductive H 2 O 2 decomposition competing with the target oxidation reaction.Indeed, the addition of products in the amount close to that found at the end of the reaction (0.015 mmol of epoxide and 0.015 mmol of diol) retarded the oxidation process (Figure 5a), while the addition of water (0.3 mmol)-the product derived from the oxidant-stopped the reaction immediately (Figure 5b), thus indicating that the adsorption of the reaction products could be the reason for catalyst deactivation.
Catalysts 2019, 9, x FOR PEER REVIEW 6 of 14 to elucidate the impact of internal diffusion in the case of MIL-125, samples with different sizes of crystallites (0.5, 1.5, and 5 μm; see Figure 2) have been examined in CyH oxidation with H2O2.As one can judge from the kinetic curves shown in Figure 4, the initial rate of CyH oxidation was not affected by the size of the crystallites.Therefore, we may conclude that no diffusion limitation takes place in the course of the catalytic oxidation of CyH over MIL-125.The catalytic properties (CyH conversion and product selectivity) of MIL-125-S and the M and L materials were also close (Table 2, entries 4, 8 and 10).Incomplete CyH conversions with 1 equivalent of the oxidant may be caused by either blockage of MOF micropores or active sites by the reaction products during the reaction course or unproductive H2O2 decomposition competing with the target oxidation reaction.Indeed, the addition of products in the amount close to that found at the end of the reaction (0.015 mmol of epoxide and 0.015 mmol of diol) retarded the oxidation process (Figure 5a), while the addition of water (0.3 mmol)-the product derived from the oxidant-stopped the reaction immediately (Figure 5b), thus indicating that the adsorption of the reaction products could be the reason for catalyst deactivation.Another reason for the low CyH conversions could be the high rates of the unproductive decomposition of H2O2 relative to the rates of the catalytic oxidation of CyH over MOF, i.e., a rather low efficiency of the oxidant utilization.Indeed, Figure 6 shows that H2O2 decomposition over MIL-125 occurs with an appreciable rate.While the target CyH oxidation was strongly accelerated by acid Another reason for the low CyH conversions could be the high rates of the unproductive decomposition of H 2 O 2 relative to the rates of the catalytic oxidation of CyH over MOF, i.e., a rather low efficiency of the oxidant utilization.Indeed, Figure 6 shows that H 2 O 2 decomposition over MIL-125 occurs with an appreciable rate.While the target CyH oxidation was strongly accelerated by acid additives, practically no effect was found for H 2 O 2 dismutation (Figure 6).The addition of an extra portion of the oxidant (another 0.1 mmol of H 2 O 2 ) after the reaction stopped just slightly increased the CyH conversion (from 41 to 55%).In line with this, iodometric titration confirmed that a significant amount of unreacted H 2 O 2 remained at the end of the catalytic reactions both in the presence and in the absence of HClO 4 .With 1 equivalent of H 2 O 2 (entry 4, Table 2), conversion of H 2 O 2 reached 59% before the reaction stopped, while 61% conversion was attained without acid (entry 3, Table 2).Therefore, H 2 O 2 utilization efficiency increased from 45% to 75% due to the addition of protons.
Catalysts 2019, 9, x FOR PEER REVIEW 7 of 14 additives, practically no effect was found for H2O2 dismutation (Figure 6).The addition of an extra portion of the oxidant (another 0.1 mmol of H2O2) after the reaction stopped just slightly increased the CyH conversion (from 41 to 55%).In line with this, iodometric titration confirmed that a significant amount of unreacted H2O2 remained at the end of the catalytic reactions both in the presence and in the absence of HClO4.With 1 equivalent of H2O2 (entry 4, Table 2), conversion of H2O2 reached 59% before the reaction stopped, while 61% conversion was attained without acid (entry 3, Table 2).Therefore, H2O2 utilization efficiency increased from 45% to 75% due to the addition of protons.

Catalyst Recyclability and Stability
The catalyst stability toward leaching of the active species under turnover conditions, as well as the nature of the catalysis, are indispensable properties of solid catalysts, which should be carefully investigated in liquid phase oxidation processes [78].First of all, we performed a hot filtration test and found a slight increase of CyH conversion after the removal of MIL-125 (Figure 7), which could originate from minor titanium leaching into the solution [78].However, only a trace amount of titanium (<0.3 ppm) was determined in the filtrate by ICP-AES.This unambiguously proves that the observed catalysis in the presence of MIL-125 is truly heterogeneous, i.e., the reaction occurs on the catalyst surface rather than in the solution as a result of active metal leaching.On the other hand, the slight increase of CyH conversion after the removal of the catalyst might be caused by the accumulation of the radical species in the reaction system due to the thermal decomposition of H2O2 [79,80].Indeed, a similar trend was observed in hot catalyst filtration experiments implemented during the [Cu(2-pymo)2]-catalyzed oxidation of tetraline and the MIL-101(Cr)-catalyzed oxidation of propylene glycol, where no active metal species were found in the filtrate [79,80].

Catalyst Recyclability and Stability
The catalyst stability toward leaching of the active species under turnover conditions, as well as the nature of the catalysis, are indispensable properties of solid catalysts, which should be carefully investigated in liquid phase oxidation processes [78].First of all, we performed a hot filtration test and found a slight increase of CyH conversion after the removal of MIL-125 (Figure 7), which could originate from minor titanium leaching into the solution [78].However, only a trace amount of titanium (<0.3 ppm) was determined in the filtrate by ICP-AES.This unambiguously proves that the observed catalysis in the presence of MIL-125 is truly heterogeneous, i.e., the reaction occurs on the catalyst surface rather than in the solution as a result of active metal leaching.On the other hand, the slight increase of CyH conversion after the removal of the catalyst might be caused by the accumulation of the radical species in the reaction system due to the thermal decomposition of H 2 O 2 [79,80].Indeed, a similar trend was observed in hot catalyst filtration experiments implemented during the [Cu(2-pymo) 2 ]-catalyzed oxidation of tetraline and the MIL-101(Cr)-catalyzed oxidation of propylene glycol, where no active metal species were found in the filtrate [79,80].
MIL-125 could be easily recovered from the reaction mixture by simple filtration, regenerated by washing it with methanol to remove the reaction products adsorbed within the micropores, and reused in, at least, four consecutive runs without the deterioration of its catalytic properties (Table 4).Interestingly, the ratio of heterolytic oxidation products and, in particular, that of epoxide, increased during the recycling, which might be, at least partially, caused by an accumulation of protons in the reaction system during the recycling process.MIL-125 could be easily recovered from the reaction mixture by simple filtration, regenerated by washing it with methanol to remove the reaction products adsorbed within the micropores, and reused in, at least, four consecutive runs without the deterioration of its catalytic properties (Table 4).Interestingly, the ratio of heterolytic oxidation products and, in particular, that of epoxide, increased during the recycling, which might be, at least partially, caused by an accumulation of protons in the reaction system during the recycling process.a Reaction conditions: CyH 0.1mmol, H2O2 0.1 mmol, catalyst 0.01 mmol Ti, HClO4 0.01 mmol, CH3CN 1 mL, 50 °C, 1 h.b Sum of allylic oxidation products (HP + enol +enone).
Importantly, there was no decrease in the CyH oxidation rate during the recycling process (Figure 8), which is also consistent with the absence of metal leaching.Importantly, there was no decrease in the CyH oxidation rate during the recycling process (Figure 8), which is also consistent with the absence of metal leaching.MIL-125 could be easily recovered from the reaction mixture by simple filtration, regenerated by washing it with methanol to remove the reaction products adsorbed within the micropores, and reused in, at least, four consecutive runs without the deterioration of its catalytic properties (Table 4).Interestingly, the ratio of heterolytic oxidation products and, in particular, that of epoxide, increased during the recycling, which might be, at least partially, caused by an accumulation of protons in the reaction system during the recycling process.Importantly, there was no decrease in the CyH oxidation rate during the recycling process (Figure 8), which is also consistent with the absence of metal leaching.The stability of the MOF structure under the conditions of CyH oxidation with H 2 O 2 was probed by the SEM, N 2 adsorption, PXRD, and FTIR techniques.The shape and size of the MIL-125-L particles remained practically unchanged after catalysis (see Figure 2).In sharp contrast to the previously reported oxidation of alkylphenols with H 2 O 2 over MIL-125 (0.4 M H 2 O 2 , 80 • C), where the structure of MIL-125 underwent transformation into an X-ray amorphous mesoporous solid [59], the structure of this MOF retained under the milder conditions used for the CyH oxidation (0.1 M H 2 O 2 , 50 • C).Indeed, the PXRD pattern of MIL-125-L separated after the catalytic reaction (Figure 1, curve D) completely coincided with that of the initial sample (Figure 1, curve C).The FTIR spectrum of the recovered MOF (Figure 3, curve C) also showed no changes as compared to the spectrum of the fresh sample (Figure 3, curve B).The N 2 adsorption study revealed a minor decrease in the specific surface area and micropore volume of the reused MIL-125-L which might have been caused by adsorption of the reaction products within the pores (Table 1).

Materials
Terephthalic acid (98%), titanium isopropoxide (Ti(OiPr) 4 , 97%), N,N-dimethylformamide (DMF) and methanol (99.9%) were purchased from Sigma-Aldrich (St. Louis, MO, USA).Acetonitrile (HPLC-grade, Panreac Quimica SLU, Barcelona, Spain) was dried and stored over activated 4 Å molecular sieves.The concentration of H 2 O 2 (ca.30 or 50 wt % in water) and t BuOOH (ca.5.5 M in decane) was determined iodometrically prior to use.Cyclohexene was purchased from Sigma-Aldrich (St. Louis, MO, USA) and purified prior to use by passing it through a column filled with neutral alumina to remove traces of possible oxidation products.All the other compounds were of the best available reagent grade and used without further purification.

Catalyst Preparation and Characterization
MIL-125 was prepared by a solvothermal method according to the reported protocol [63] using titanium isopropoxide and terephthalic acid in a solvent mixture of DMF and methanol.In a typical synthesis, terephthalic acid (7.6 mmol) and Ti(OiPr) 4 (5.1 mmol) were dissolved in the mixture of DMF (40 mL) and dry methanol (10 mL) and loaded into a three-neck round bottom flask (100 mL), equipped with a reflux condenser at 20 • C. The resulting mixture was crystallized by stirring under reflux conditions at 100 • C for 72 h.After the reaction, the mixtures were allowed to cool down to room temperature, leading to the formation of a white crystalline product in the solution.It was further filtered and then washed with DMF.For further purification, the as-synthesized product was re-dispersed at 60 • C in DMF for 2 h (100 mL of DMF per 1g of product) and then in methanol for 2 h (100 mL of methanol per 1 g of product).Finally, it was dried overnight at 90 • C under nitrogen.Additionally, MIL-125 samples were dried under vacuum at 130 • C for 6 h prior to use in the catalytic reactions.The particle size of MIL-125 was controlled by the addition of benzoic acid (benzoic acid/Ti(OiPr) 4 molar ratio = 10) as a modulator and the addition of water (H 2 O/Ti(OiPr) 4 molar ratio = 1) at the initial mixing of the precursors [59].

Catalytic Oxidations
Catalytic oxidations were performed under vigorous stirring (600 rpm) in thermostated glass vessels.Typical reaction conditions for CyH oxidation were as follows: CyH 0.1 mmol, H 2 O 2 0.1 mmol, catalyst 2 mg MIL-125 (0.01 mmol Ti), HClO 4 0.01 mmol (if any), CH 3 CN 1 mL, 50 • C. Reactions were started by the addition of H 2 O 2 .Samples of the reaction mixture were withdrawn periodically during the reaction course by a syringe.The oxidation products were identified by gas chromatography-mass spectrometry (GS-MS).The product yields and substrate conversions were quantified by gas chromatography (GC) using an internal standard, biphenyl.For GC analysis, the method described by Shul'pin was used [81], which involves the treatment of the reaction mixture with PPh 3 in order to reduce the unreacted H 2 O 2 and possible organic peroxides formed.Each experiment was reproduced at least 2 times.The concentration of H 2 O 2 after the catalytic reaction was determined by iodometric titration.The H 2 O 2 utilization efficiency was calculated as the total yield of products based on the oxidant consumed, taking into account the stoichiometric coefficients.
Catalyst reusability was examined in 2-3 time-scaled experiments (the total reaction mixture volume 2-3 mL).After the reactions, the catalyst was filtered off, stirred in 1 mL of methanol for 2 h at 50 • C, filtered off again, dried in air at room temperature and then reused.The nature of catalysis was verified by hot filtration tests.

Instrumentation
GC analyses were performed using a gas chromatograph Tsvet-500 equipped with a flame ionization detector and a quartz capillary column (30 m × 0.25 mm) filled with DB-5MS (Agilent Technologies, Santa Clara, CA, USA).GC-MS analyses were carried out using an Agilent 7000B system with a triple-quadrupole mass-selective detector Agilent 7000 and a GC Agilent 7890B apparatus (quartz capillary column 30 m × 0.25 mm/HP-5 ms).
Infrared spectra were recorded as 0.5-2.0wt % samples in KBr pellets on a Cary 600 FTIR spectrometer (Agilent Technologies, Santa Clara, CA, USA).
Nitrogen adsorption measurements were carried out at 77 K using an automatic adsorption analyzer Autosorb-6B-Kr instrument (Quantachrome Instruments, Boynton Beach, FL, USA), equipped with 10 Torr absolute pressure transducer, within the partial pressure range 10 −4 -1.0.The catalysts were degassed at 110 • C for 16 h before the measurements.Surface areas were determined by the BET analysis of low-temperature N 2 adsorption data.Pore size distributions were calculated from the adsorption branches of the nitrogen isotherms by means of the NLDFT method using kernel for nitrogen at 77 K adsorbed on silica with cylindrical pores applied to the adsorption branch of the isotherm.Calculations were made by the ASWin 2.02 software supplied by Quantachrome Instruments (ASWin 2.02, Quantachrome Instruments, Boynton Beach, FL, USA).
Scanning electron microscopy images were acquired by means of a JSM-6460 LV microscope (JEOL Ltd., Tokyo, Japan).
The titanium content in the filtrate, which remained after the separation of the catalysts from the reaction mixture, was determined by ICP-OES using an Optima-430 DV instrument (PerkinElmer Inc., Waltham, MA, USA).

Conclusions
The MIL-125 catalyzed the oxidation of cyclohexene using equimolar amounts of H 2 O 2 or t BuOOH and produced a mixture of products (cyclohexenyl hydroperoxide, 2-cyclohexene-1-ol, 2-cyclohexene-1-one, cyclohexene epoxide and trans-cyclohexane-1,2-diol) characteristic of the homolytic mechanism of peroxide activation.The addition of a source of protons (HClO 4 or CF 3 SO 3 H) in the amount of 1 molar equivalent (relative to Ti) significantly increased the catalytic activity and alkene conversion and changed the product distribution, favoring the formation of heterolytic oxidation products.The effect of protons on the selectivity of epoxidation (the primary reaction en route to diol and ketol) was more significant for H 2 O 2 than for t BuOOH.With one equivalent of protons, the total selectivity toward epoxide and diol reached 80 and 92% for 30 and 50% H 2 O 2 , respectively, at 38-43% substrate conversions, while it attained only 52% at a similar conversion when using t BuOOH.Moreover, the H 2 O 2 utilization efficiency improved from 45 to 75% owing to the addition of protons.
The addition of acid was not critical for the stability of the MOF structure.N 2 adsorption, PXRD, and FTIR studies confirmed the retention of the structural integrity of MIL-125 under the turnover conditions employed for cyclohexene oxidation.MIL-125 did not suffer titanium leaching, behaved as a truly heterogeneous catalyst and could be easily recovered by filtration, regenerated by treatment with methanol and reused at least four times without the loss of catalytic performance.

Figure 5 .
Figure 5.The effect of the addition of reaction products on the course of CyH oxidation with H 2 O 2 in the presence of 1 equivalent of HClO 4 over MIL-125-L.Reaction conditions: CyH 0.1mmol, H 2 O 2 0.1 mmol, catalyst 0.01 mmol Ti, HClO 4 0.01 mmol, CH 3 CN 1 mL, 50 • C, (a) epoxide 0.015 mmol and diol 0.015 mmol or (b) water 0.3 mmol added at ca. 20% CyH conversion.
a Micropore volume calculated by NLDFT; b After cyclohexene oxidation with H 2 O 2 in the presence of 1 equivalent of HClO 4 (reaction conditions as in Table2, entry 10).
a Reaction conditions:

Table 3 .
The effect of the nature of an oxidant on CyH oxidation over MIL-125 a .

Table 4 .
The reuse of MIL-125-L in CyH oxidation with H2O2 in the presence of 1 equivalent of HClO4.a

Figure 7 .
The hot catalyst filtration test for CyH oxidation with H 2 O 2 over MIL-125.Reaction conditions as in Table 1, entry 3.

Table 4 .
The reuse of MIL-125-L in CyH oxidation with H2O2 in the presence of 1 equivalent of HClO4.a b Sum of allylic oxidation products (HP + enol +enone).