Water co-catalysis in aerobic olefin epoxidation mediated by ruthenium oxo complexes

We report the development of a versatile Ru-porphyrin catalyst system which performs the aerobic epoxidation of aromatic and aliphatic (internal) alkenes under mild conditions, with product yields of up to 95% and turnover numbers (TON) up to 300. Water is shown to play a crucial role in the reaction, significantly increasing catalyst efficiency and substrate scope. Detailed mechanistic investigations employing both computational studies and a range of experimental techniques revealed that water activates the RuVI di-oxo complex for alkene epoxidation via hydrogen bonding, stabilises the RuIV mono-oxo intermediate, and is involved in the regeneration of the RuVI di-oxo complex leading to oxygen atom exchange. Distinct kinetics are obtained in the presence of water, and side reactions involved in catalyst deactivation have been identified.


Introduction
2][3][4] Traditional methods for synthesizing epoxides use (super)stoichiometric amounts of organic peroxides on olens or the dehydrochlorination of chlorohydrins with base. 57][8][9] Molecular oxygen (O 2 ) represents the cleanest and most easily available oxidant, but harnessing it for selective oxidation catalysis remains a challenge due to its propensity to undergo radical reactions that are difficult to control and typically lead to low selectivity as well as limited substrate scope (Fig. 1b). 10 A popular strategy to tame dioxygen for aerobic oxidation chemistry is to employ sacricial co-reductants that increase selectivity and allow for a wider substrate scope, but in turn diminish the sustainability of the reaction (Fig. 1c). 11][17][18][19][20][21][22] However, all of these still require high catalyst loadings (2-10 mol%) affording low turnover numbers (TON < 50) with a narrow substrate scope to date.Further improvement of this promising but underdeveloped area of catalysis is hampered by a limited understanding of the reaction mechanism.
Here we report the development of an efficient and broadly applicable homogeneous catalytic system based on a ruthenium porphyrin complex along with important mechanistic insights derived from detailed investigations using orthogonal operando analytics, isotopic labelling, and quantum chemical calculations to elucidate the mechanistic origin of our nding that water signicantly improves catalyst performance.

Initial considerations
The reason why efficient aerobic oxidation catalysis without sacricial co-reductants is difficult to achieve lies in the requirement for two challenging features to be combined in a single catalyst: (i) the generation of a highly oxidising yet selective catalyst intermediate from O 2 , and (ii) the effective utilisation of both oxygen atoms to close the catalytic cycle via a reduced state that can bind and activate O 2 again.Groves' [(TMP)Ru VI (O) 2 ] complexes showed promise in fullling both of these requirements, but with limited efficiency in terms of rate and stability. 15Building on this seminal work, Che and coworkers reported that the addition of aqueous NaHCO 3 was found to improve the activity of a Ru-porphyrin catalyst in aerobic epoxidation-isomerisation reactions for converting aryl alkenes to their corresponding aldehydes. 23,24Following earlier reports that peroxocarbonate species can be effective oxidants for epoxidation reactions, [25][26][27] we set out to investigate whether this could be a strategy to improve these catalytic systems.We thus prepared a range of porphyrin ligands (Fig. 2a) and their corresponding trans-dioxo ruthenium complexes for a systematic study of their catalytic behaviour in olen epoxidation under various conditions.When [(L1)Ru VI (O) 2 ] was tested for the aerobic epoxidation of styrene (1) in CDCl 3 at 30 °C using 8% O 2 in N 2 (40 bar) only ∼30% of styrene oxide (1a) was obtained at 1 mol% catalyst loading (Fig. 2b, entry 1), a result which is consistent with previous reports. 15The use of 8% O 2 in CO 2 did not improve reactivity; in fact, it provided slightly lower product yields (Fig. 2b, entry 2).As reported by Che, the addition of aqueous NaHCO 3 improved the catalytic activity of [(L1) Ru VI (O) 2 ] to a 57% yield of 1a.Intriguingly, a control experiment revealed that the addition of water alone signicantly improved the catalysis, providing conversions of 80% with a 72% yield of 1a in the absence of any CO 2 (Fig. 2b, entry 5).Katsuki and coworkers previously found that water was important in the asymmetric sulde oxidation and alkene epoxidation using [(salen)Ru(NO)] complexes. 18,19They proposed reaction pathways where water acted as proton transfer mediator, but limited mechanistic studies were carried out to support this hypothesis.We thus set out to investigate this intriguing nding and understand how water inuences these aerobic oxidation reactions to further improve the catalysis.

Reaction optimisation
Using 1 mol% [(L1)Ru VI (O) 2 ], we examined the effect of water on the aerobic epoxidation of 1 with various solvents and additives under non-oxygen limiting conditions (Tables S1-S3 †).The employment of moderately polar solvents (e.g.dichloromethane, chloroform, 1,2-dichloroethane, toluene, tri-uorotoluene, chlorobenzene) led to higher product yields compared to more coordinating solvents such as acetone and acetonitrile, suggesting competition with substrate or O 2 binding to the catalyst.No reactivity was observed in methanol and ethanol, and even small quantities of ethanol in chloroform were sufficient to shut down catalytic turnover (entry 12, Table S1 †).This is likely due to alcohol oxidation, which is known for Ru oxo species, 30 overriding alkene epoxidation. 31Within the range of weakly coordinating solvents, the catalytic activity increased with the solubility of water (Fig. 2c).Excellent catalytic performance was obtained with dichloromethane (DCM) as the solvent when an excess of water was added, affording full conversion of 1 and a 93% yield of 1a within 5 hours at 30 °C (Fig. 2c).Control experiments found that using an excess of water to ensure complete saturation (creating a biphasic system) gave the same results as using single-phase DCM saturated with water, showing the catalysis to be genuinely homogeneous (Fig. S3a †).Good performance could also be achieved using CDCl 3 or PhCF 3 with the addition of a small amount of ethyl acetate which seemed effective in affording good activity by increasing the water content of the solvent without deactivating the catalyst (Table S1 †).To investigate ligand effects, dioxo-Ru-porphyrin complexes bearing different meso-substituted tetraarylporphyrins (L1-4) and sterically hindered b-pyrrole substituted porphyrins (L5 and L6) were tested in the aerobic epoxidation of 1 under these optimised reaction conditions (Fig. 2d).Both conversion and yield of 1a decreased noticeably when bulkier, more electron-withdrawing substituents were introduced to different positions in the porphyrin ligand of the catalyst, and Groves' electron-rich L1 (ref.15) emerged as the best ligand to be taken forward in our investigation.

Kinetic analysis
In order to understand the origin of the much improved performance [(L1)Ru VI (O) 2 ] in the presence of water, we monitored the epoxidation of 1 with high-resolution FlowNMR spectroscopy in a recirculating batch setup (for details see method C in the ESI †). 32Reaction progress was monitored by 1 H FlowNMR with a 2 min time interval which allowed us to track the starting material and products in real time, providing highquality concentration proles suitable for reaction progress kinetic analysis (RPKA) via variable time normalisation analysis (VTNA). 33,34Using 10 bar of air (21% O 2 ) and 0.5 mol% catalyst the reaction proceeded well in water-saturated DCM at 30 °C, steadily consuming 1 with apparent zero order kinetics at a rate of 0.30 mM min −1 to reach 86% conversion and a yield of 78% 1a within 7 hours (Fig. 3a).We could also observe the slow, gradual isomerisation of the epoxide 1a into aldehyde 1c (up to 6%) and the formation of a small amount of benzaldehyde 1b (<1%).Control experiments found no signs for oxygen limitation under the conditions applied when different partial pressures of O 2 were used (Table S3 and Fig. S8 †).When the reaction was carried out using laboratory grade DCM without water added (with a residual concentration of 14 mM) the reaction proceeded with identical selectivity but approximately four times slower (r = 0.07 mM min −1 ) than the reaction with an excess of water (Fig. 3a vs. 3b).When an excess of D 2 O was used instead of H 2 O a rate of 0.09 mM min −1 was observed (Fig. 3c), corresponding to a H/D kinetic isotope effect (KIE) of 3.5.This value clearly shows the involvement of water in the catalysis and indicates O-H/D bond breaking to be part of a kinetically signicant step in the catalytic cycle (further discussed below).Evidence of O 2 being the terminal oxidant in the catalysis was obtained from an experiment in which 1 mol% of [(L1)Ru VI (O) 2 ] was tested with 1 in wet DCM under an N 2 atmosphere and only 1% of 1a was obtained aer 6 hours at 30 °C (Fig. S4a †).
Systematically varying catalyst, substrate and water concentration revealed a rst order dependence on [(L1)Ru VI (O) 2 ] (Fig. 3d), zero order in substrate 1 (Fig. 3e), and rst order in water (Fig. 3f and S3b †) in the initial part of the reaction before deactivation led to a deviation of the kinetics from about 65% conversion (TON = 130) onwards (see below section discussing catalyst deactivation).The catalytic rate law thus obtained differs from that previously reported by others using the same and similar Ru-porphyrin catalysts.Che and co-workers studied catalysts with para-substituted tetraphenylporphyrins and observed a rate law for alkene epoxidation of rate = k[Ru VI ] [alkene] using dried organic solvents. 3517]35 Our results also differ from unpublished data in the PhD thesis of Ahn 36 who studied [(L1)Ru VI (O) 2 ] in detail, including testing the effect of added water but unfortunately under limiting oxygen conditions.,36 1 H NMR spectroscopic analysis of the dry DCM reaction showed that 47% of [(L1)Ru VI (O) 2 ] remained in the post-reaction mixture, whereas all of the [(L1)Ru VI (O) 2 ] had been consumed in the more efficient, water-saturated DCM reaction (Fig. S4b and c †) showing again the pronounced effect of water in facilitating catalytic turnover.

Catalyst speciation and deactivation
The reaction progress data (Fig. 3) from the operando FlowNMR measurements showed a deviation from the initial zero order behaviour towards the end of the reaction (Fig. 3a-c), indicative of either inhibition or deactivation.Catalyst productivity and lifetime are important metrics for industrial application, but deactivation mechanisms are rarely investigated in academic studies. 37To gain insight into catalyst speciation and deactivation during turnover, 1  formed aer oxygen atom transfer (OAT) to the substrate could only be detected transiently under the most efficient conditions of using water-saturated DCM.Both of these observations align with the faster catalytic rates observed under these conditions and point towards a shi in the turnover-limiting step of the catalytic cycle in the presence of water, as also shown by the rate law.The carbonyl complex [(L1)Ru II (CO)(H 2 O)] formed at a steady rate throughout the reaction to reach ∼20-25% of the total Ru loading aer 8 hours as the only ruthenium species detectable by 1 H NMR spectroscopy in the post-reaction mixture.As previously suggested 39 and conrmed independently (Fig. S4d †), this carbonyl complex is inactive in the aerobic epoxidation and thus an irreversibly deactivated state of the catalyst.
Since there are limited studies that explicitly consider deactivation pathways in this reaction, we carried out a series of experiments to better understand the formation of [(L1) Ru II (CO)] during catalysis.As shown in Fig. 3, in the oxidation of styrene (1) along with the desired epoxide (1a) benzaldehyde (1b) and phenylacetaldehyde (1c) were also formed.1c may form via the isomerisation of 1a, 23 whereas 1b contains one carbon atom less than the starting material.Although we have not detected any observable amounts of diols under our catalytic conditions it is known that epoxides may hydrolyse in situ, and control experiments conrmed that 1a could be slowly hydrolysed to 1-phenylethane-1,2-diol (1d, 8%) in water-saturated DCM at 30 °C (Fig. S17a †). 40When the diol 1d was added to [(L1)Ru VI (O) 2 ] complete consumption of the complex and formation of [(L1)Ru II (CO)] was observed (Fig. 5a).Furthermore, (Fig. 5b).
It is also known that metal-peroxo or hydroperoxo complexes can catalyse the deformylation of aldehydes. 41A control experiment showed that 1c could react with [(L1)Ru VI (O) 2 ] and lead to the formation of 1b (4%) and [(L1)Ru II (CO)] in 16% yield (Fig. 5c).When 2.5% of 1d was used as an additive in the aerobic epoxidation of 1 with [(L1)Ru VI (O) 2 ], 1 H FlowNMR data showed that product formation was greatly retarded in the rst 100 min, but once all of 1d had been oxidised the rate of production of 1a increased (Fig. S17b †).This observation showed diols not to be a strong catalyst poison but to exhibit an inhibitory (or rather diverting) effect on the epoxidation.With 4% of 1c as an additive, the aerobic epoxidation of 1 led to a much faster formation of [(L1)Ru II (CO)] at the beginning of the reaction (Fig. S17c †).We thus conclude that the CO ligand in [(L1)Ru II (CO)] originates from both the deformylation of aldehyde 1c as well as oxidative C-C bond cleavage of small amounts of diol produced in situ, leading to the irreversible formation of inactive [(L1) Ru II (CO)] and benzaldehyde 1b.
The amount of [(L1)Ru II (CO)] formed during the catalysis did not account for all of the activity loss, however, and a signicant amount of the total Ru loading escaped the operando 1 H FlowNMR analyses towards the end of the reaction (Fig. 4a).We thus looked for other Ru species using UV-vis spectroscopy and high-resolution electrospray mass spectrometry   MS under the same conditions (Fig. 6b and S21 †), showing the reduced monomer and its dimer detected during the reaction to be generated by catalytic turnover.Several Ru-porphyrins have been reported to form m-oxo dimers under oxidative conditions. 42Indeed, UV-Vis spectroscopic analysis of the postreaction mixture showed weak but characteristic absorptions of such m-oxo-Ru dimers around 600 nm (Fig. S23 †), 42 suggesting that even with the bulky tetramesityl-substituted porphyrin ligand L1 some association to inactive, NMR-silent dimers may occur during the catalysis in aqueous organic solvent.

Isotopic labelling
To gain further insight into the role of water in the epoxidation catalysis we employed oxygen isotope labelling.When using 10 equiv. of 18 OH 2 relative to 1 under 10 bar of air containing 16 O 2 , 1 was converted to 1a with 89 atom% 18 O incorporation (Fig. 7a and S9 †).In line with the kinetic relevance of water and the pronounced H/D KIE observed (see above), this nding further indicated that water is involved in a kinetically relevant step of the cycle to facilitate effective turnover.Similar data has previously been reported by Hirobe and co-workers 43 and Ahn 36 who studied the same catalyst.Katsuki and co-workers examined 18 OH 2 with their [(salen)Ru(NO)] catalyst and found lower levels of 18 O incorporation, suggesting a different mechanism for their photo-assisted system. 19In situ Raman spectroscopy of our reaction showed the doubly 18 O-labelled mono-oxo complex [(L1)Ru IV ( 18 O)( 18 OH 2 )]or its trans-dihydroxy isomer [(L1) Ru IV ( 18 OH) 2 ]forming from [(L1)Ru VI ( 16 O) 2 ] during turnover with 18 OH 2 and 16 O 2 (Fig. 7b and c; for details of the FlowRaman setup and band assignments see Supplementary Method D, Table S4 and Fig. S10-S15 †).Thanks to a characteristic 18/16 O isotope shi of 46 cm −1 in the n(Ru]O) band we were able to follow the interconversion of [(L1)Ru VI ( 16 O) 2 ] into [(L1) Ru VI ( 18 O) 2 ] under these conditions (Fig. 7d), providing spectroscopic proof for dynamic oxygen exchange between highvalent ruthenium oxo complexes and water.
These observations paired with superior catalytic activity in the presence of water made us wonder if the epoxidation may proceed via an active species other than [(L1)Ru VI (O) 2 ], for example, a ruthenium hydroperoxide intermediate, with reactivity more typical of catalysis with H 2 O 2 . 9In water oxidation catalysis the interaction of high-valent metal oxo compounds with H 2 O is a key step in the formation of the O-O bond, and with high-valent Ru]O complexes in particular it is well recognised that water can form Ru-OOH intermediates via water nucleophilic attack (WNA) on an electrophilic oxo ligand. 44,457][48][49][50] In addition, the conversion of Fe III -OOH complexes to Fe IV/V oxo species has been reported to occur via water assisted or Lewis acid activation pathways. 51It is also known that [(HOO)(HO) Mn III (por)] complexes can be generated from Mn III (por) with H 2 O 2 , which then act as precursors to [(O) 2 Mn V (por)] species under basic conditions. 52Looking for other ruthenium oxo species in situ, we thus exposed [(L1)Ru VI ( 16 O) 2 ] to 17 OH 2 (35-40 atom%) in dry CDCl 3 and analysed the mixture by 17 O NMR spectroscopy (supplementary method E †).Aer 30 min at 30 °C the formation of doubly exchanged [(L1)Ru VI ( 17 O) 2 ] was clearly observed in the 17 O NMR spectrum at 780 ppm 53 (Fig. 8) but no other 17 O containing Ru species could be resolved.This result showed dynamic oxygen atom exchange between Ru VI ]O and H 2 O to be possible even in the absence of catalytic turnover that generates reduced ruthenium complexes, without detecting any intermediates of this exchange reaction, however.Similar observations have previously been made by Ahn who also Fig. 7 18 O isotope labelling experiments.(a) 18 O isotopic labelling experiment using 18   However, as we and others have consistently found olen epoxidation with [(L1)Ru VI (O) 2 ] to be very slow in anhydrous organic solvents (even stoichiometrically), 15,36 water must have an activating effect on the dioxo complex.If the closed-shell O] Ru VI ]O is insufficiently electrophilic to react with an olen (or indeed H 2 O) in non-polar media, we wondered if water perhaps activated the oxo through hydrogen bonding.Cenini and coworkers have reported NMR spectroscopic evidence for hydrogen bonding between water and some Ru(por)-dioxo complexes in organic solution, 54 but this effect has not yet been considered in the context of OAT catalysis with such complexes.6][57][58] We thus compared the reaction coordinates from [(L1)Ru VI (O) 2 ] and styrene to [(L1)Ru IV (O)] and epoxide in the absence and presence of specic water solvation in addition to the continuum solvent model applied for dichloromethane (Fig. 10).
Without H 2 O, the direct epoxidation of styrene by the singlet dioxo-Ru VI complex 1 A initially yields a triplet oxo-epoxide-Ru IV complex 3 F which is thermochemically accessible at D r G = −11 kcal mol −1 (red trace in Fig. 10).The net reaction thus involves spin crossing from the diamagnetic closed-shell 1 A to the triplet spin surface, 59 passing through a rate-limiting transition structure at 24 kcal mol −1 with an open-shell singlet electronic structure.In this broken-symmetry singlet TS, a p*(Ru]O) orbital is singly populated, effectively generating an oxyl radical for the initial C-O bond formation.A closed-shell singlet transition state as well as all subsequent intermediates are less stable as alternative electromers (see ESI †).Crossing from the broken-symmetry singlet TS onto the triplet product surface on the lowest free energy pathway involves a minimum energy crossing point (MECP) 60 of 13-16 kcal mol −1 where the primary alkoxide is formed and one unpaired electron is fully transferred into the p system of the alkene.On the triplet energy surface, the resulting ruthenium-alkoxide complex 3 E was found at 7 kcal mol −1 .Aer passing a small barrier of 3 kcalmol −1 for the formation of the second C-O bond en route to the epoxide complex at −11 kcal mol −1 , liberation of the epoxide product via a dissociation barrier of 8 kcal mol −1 leads to the coordinatively unsaturated triplet mono-oxo- Commencing from a bis-aqua bound dioxo-Ru VI complex 1 A w2 lowers the broken-symmetry singlet transition state for the electrophilic attack of the olen by 6 kcal mol −1 so that it is now located 18 kcal mol −1 above the reactants (blue trace in Fig. 10).The inclusion of two explicit water molecules as a model for micro-solvation 54 is thus shown to signicantly accelerate the reaction: whereas a barrier of 24 kcal mol −1 translates into a t 1/2 z 12 h, the reduced barrier of 18 kcal mol −1 in the bis-aqua ligated model corresponds to a half-life of less than two seconds.Spin states were not noticeably affected by the hydrogen bonding interactions and the respective closed-shell species were all higher in energy, as in the absence of water.A broken symmetry singlet-triplet BS/3 MECP w2 at 8-11 kcal mol −1 was found which was signicantly more favourable than the 19-22 kcal mol −1 of the corresponding closed-shell singlet-triplet 1/ 3 MECP w2 for the hydrated version of the reaction (see ESI †), and also lower than the BS/3 MECP at 13-16 kcal mol −1 found in the anhydrous path.This bis-aqua ligated BS/3 MECP w2 is a late structure on the potential energy surface (i.e.closer to C-O bond formation) and yields swi downhill access to the bis-aqua ligated oxo-epoxide-Ru IV complex 3 F w2 at −13 kcal mol −1 without passing through another intermediate.Aer liberation of the epoxide product and rebound of H 2 O, the water-bound triplet mono-oxo-Ru IV complex 3 D w2 is obtained with an overall D r G of −18 kcal mol −1 .The presence of water thus not only accelerates the OAT to styrene but also stabilises the mono-oxo ruthenium intermediate, consistent with the experimentally observed catalyst speciation proles (Fig. 4).
As neither the complex geometries nor their spin states were found to be affected by water hydrogen-bonding to the oxo

Chemical Science
Edge Article , the accelerating effect of microsolvation on the OAT to styrene may be rationalised by the relative stabilisation of the LUMO which is involved in the electrophilic attack of the alkene.To compare relative LUMO energy changes, the HOMO is a suitable reference since it is fully localised on the porphyrin ligand and thus largely unperturbed by water ligation (Fig. 11).The difference in HOMO-LUMO energy gaps in the water-free and micro-solvated systems of DD3 LUMO z −0.2 eV can thus serve as a measure for the electronic inuence of micro-solvation.In the micro-solvated case, the LUMO was found at −4.3 eV and thus closer in energy to the HOMO of styrene (−5.7 eV).As shown in the ESI, † the HOMO of the broken-symmetry singlet TSresult of the interaction of the ruthenium-dioxo LUMO and the HOMO of styrenealso benets from water ligation by about 0.1 eV (Fig. S35 †).

Mechanistic interpretation and further optimisation
Taking all our ndings together with previous reports, we can suggest a mechanism for the water-promoted aerobic epoxidation of alkenes catalysed by oxo ruthenium porphyrin complexes (Fig. 12).The catalytic cycle consists of three main parts: oxygen atom transfer, disproportionation, and reoxidation. 57,61,62While we have been able to monitor the singlet Ru VI di-oxo, the triplet Ru IV mono-oxo and the singlet Ru II carbonyl during turnover, the reduced catalyst state(s) reacting with O 2 (presumably Ru II ) 15,38,61,62 have not been experimentally observed in operando.We also cannot fully rule out alternative pathways proceeding via Ru III and Ru V intermediates, Comparing the reaction kinetics and catalyst speciation proles in the absence and presence of water (Fig. 4) suggests the accelerating effect of water on substrate epoxidation by [(L1) Ru VI (O) 2 ] to shi the turnover-limiting step of the cycle from oxygen-atom transfer under anhydrous conditions to catalyst reoxidation under the more efficient aqueous conditions.The rst order reaction rate dependence in H 2 O, observation of extensive 16/18 O scrambling, and the signicant H/D kinetic isotope effect of 3.5 in water indicate rapid exchange of oxygen atoms with concomitant O-H bond breaking during the turnover-limiting disproportionation/reoxidation part of the water-assisted catalytic cycle. 36Although it is well established that O-H bond breaking is important in electron transfer mechanisms with Ru complexes, 30,64 65 Alternative pathways such as proton-coupled electron transfer are known to give rise to similar values, 64 but the exact origin of the H-D KIE in our water-assisted aerobic epoxidation with Ruporphyrins remains to be investigated.merely drains active material from the cycle, the reaction of [(L1)Ru VI (O) 2 ]$(H 2 O) 2 with diols and aldehydes produces side products that diminish reaction selectivity and yield.The Lewis acid catalysed rearrangement of epoxides into aldehydes 69 is thus particularly detrimental to this reaction, as is in situ epoxide hydrolysis.
We briey investigated whether it is possible to suppress these deactivation pathways by further ne-tuning of the reaction conditions.Lowering the [Ru] concentration should slow down dimerisation, and pH control might suppress epoxide hydrolysis and facilitate proton shuttling 64 in the reoxidation of the catalyst.Indeed, using 0.25 mol% [Ru] with a sodium acetate buffer (pH = 5.7) almost doubled the catalyst TON to 300 for the epoxidation of 1 (Fig. S24 and S25 †).Further improvements are likely possible with more extensive reaction engineering.

Substrate scope
With an efficient catalyst system for the mild and selective epoxidation of styrene in hand, we decided to explore its applicability to other unsaturated substrates, as limited substrate scopes have been reported in previous studies. 6Using 1 mol% [(L1)Ru VI (O) 2 ] in either DCM or CDCl 3 /EtOAc mixtures with water added, we were pleased to nd excellent functional group tolerance across a range of different substrates (Fig. 13 and S24 †).Electron-withdrawing substituents such as halides, esters and NO 2 were well tolerated (4a-6a, 8a, 9a), and even internal aliphatic alkenes were epoxidised in good to very good yields (12a-18a/a 0 ).Strongly coordinating functionalities such as nitriles led to lower catalyst activity (an effect similar to that seen in the solvent screening), and the epoxide products of electron-rich systems such as 4-methyl-styrene, 4-tert-butoxystyrene, 2-vinylnaphthalene partially isomerised to the corresponding aldehydes in situ as also observed by others. 23pplication to stereogenic terpene substrates such as D-limonene and a-pinene, whose epoxides are valuable building blocks for biorenewable polymers, 70,71 afforded a 76 : 24 mixture of diastereomeric 1,2-limonene oxide (16a/a 0 ) in 81% yield (with no 8,9-oxide formed) and up to 40% a-pinene oxide (17a) from a sterically challenging substrate.Oxidation of the large steroid cholesteryl acetate proceeded with full conversion to afford the corresponding epoxide (18a/a 0 ) with a remarkable b : a stereoselectivity of 99 : 1, attributable to steric repulsion between the porphyrin ligand and the axial hydrogen atoms on C-3 and C-7 on the a-face of the substrate. 72Limitations were only met with terminal aliphatic alkenes such as 1-octene and highly sterically demanding substrates.For example, while the catalyst cleanly epoxidised cis-stilbene in high yield trans-stilbene was not a suitable substrate (Table S5 †), as also found with other Rucatalysed epoxidations using pyridine N-oxide as the oxidant. 73mportantly, the stereoselectivity found in products such as 18a showed that the oxidation is catalyst-controlled rather than proceeding via an autoxidation mechanism. 74This is further supported by the results of 18 O labelling experiments (see above) and no ring-opening products formed during the oxidation of the radical clock substrate 1-cyclopropylvinylbenzene (entry 6, Table S5 †). 75,76

Conclusions
Water has been shown to co-catalyse the aerobic epoxidation of alkenes mediated by porphyrin ruthenium oxo complexes, a nding that gives rise to an order of magnitude improvement in activity over the previous ve decades of research in homogeneous aerobic epoxidation catalysis.This protocol provides an efficient, clean and sustainable method for catalytic epoxide synthesis that does not operate via radical pathways such as autoxidation which typically governs aerobic systems.The reaction proceeds under mild conditions with gentle heating to 30 °C and operates within safe limiting oxygen concentrations (LOC) such as 8% O 2 (ref.77) in non-ammable solvent mixtures.From the different ligands investigated Groves' original TMP ligand emerged as the most efficient catalyst for this reaction, which under our optimised conditions reached a TON up to 300 with epoxide selectivity of >80%.A wide range of diand tri-substituted aromatic and aliphatic alkenes were tolerated for the rst time with our protocol, and high face-selectivity can be achieved with sterically demanding substrates due to the bulky TMP ligand.Mechanistically, the system elegantly fulls the key criteria for an efficient aerobic oxidation catalyst, where the di-oxo complex selectively epoxidises the substrate and is effectively regenerated via disproportionation and reoxidation by O 2 without the need for sacricial co-reductants.The collective evidence from multiple in situ and operando analytics, isotope labelling experiments and computational analyses indicate that water activates [(L1)Ru VI (O) 2 ] for OAT to the alkene by lowering its LUMO energy through hydrogen bonding such that catalyst reoxidation becomes turnover-limiting in the water-assisted system.We note that little is still known about this important step of the catalytic cycle where extensive oxygen atom scrambling and kinetically relevant O-H breaking occurs.We believe that a deeper understanding of the steps involved in the regeneration of the Ru VI di-oxo complex would allow for further improvements.Our results represent another example of the importance of solvent effects and specic solvation in homogeneous oxidation catalysis, 78,79 and we hope that future developments will be able to take advantage of our ndings to improve catalyst activity further to apply them to challenges in asymmetric epoxidation, perhaps even the industrially important short-chain aliphatic a-olens.
H FlowNMR spectroscopy and orthogonal techniques (see below) were used to detect ruthenium intermediates during the reaction.By use of a high-sensitivity cryoprobe we were able to identify and monitor not only [(L1) Ru VI (O) 2 ] (d = 8.81 ppm) but also the formation of [(L1) Ru II (CO)(H 2 O)] (d = 8.40 ppm) and the paramagnetic [(L1) Ru IV (O)(H 2 O)] (d = −9.11ppm) intermediates 38 during the aerobic epoxidation of 1 under our optimised reaction conditions (Fig. S7 †).As indicated by incomplete mass balances towards the end of the reaction not all Ru species were detectable by 1 H NMR, but some important trends are reected in the data recorded.As shown in Fig. 4, the amount of [(L1)Ru VI (O) 2 ] decreased steadily over the course of the reaction, but about twice as quickly in the presence of H 2 O than with D 2 O or when anhydrous.The in-cycle mono-oxo complex [(L1)Ru IV (O)(H 2 O)]

Fig. 3
Fig. 3 Kinetic analysis from operando 1 H FlowNMR spectroscopy.(a) Reaction progress in DCM saturated with an excess of H 2 O.(b) Reaction progress in laboratory grade DCM (residual H 2 O content 14 mM).(c) Reaction progress in DCM saturated with an excess of D 2 O (99.9 atom% D).(d) Determination of the order in catalyst using VTNA.(e) Determination of the order in 1 using VTNA.(f) Determination of the order in H 2 O using VTNA.

Fig. 4
Fig. 4 Operando catalyst speciation studies.(a) Distribution of ruthenium species observed by 1 H FlowNMR spectroscopy in DCM saturated with an excess of H 2 O.(b) Distribution of ruthenium species observed by 1 H FlowNMR spectroscopy in laboratory grade DCM (14 mM).(c) Distribution of ruthenium species observed by 1 H FlowNMR spectroscopy in DCM saturated with an excess of D 2 O (99.9% atom% D).

Fig. 5
Fig.5Investigation of the formation of [(L1)Ru(CO)] species during aerobic olefin epoxidation.Dashed boxes refer to conversion of starting Ru complex (wrt = "with regard to") and yield of corresponding CO complex.Solid boxes refer to conversion of organic substrates and yields of corresponding products.
Fig.718 O isotope labelling experiments.(a)18 O isotopic labelling experiment using18 OH 2 .Conversion and yield determined by quantitative 1 H NMR spectroscopy, 18 O incorporation in 1a determined by GC-MS.(b) 18 O/ 16 O isotope labelled ruthenium species observed by FlowRaman spectroscopy.(c) Profile of Ru species observed by FlowRaman spectroscopy (reaction conditions as in Fig. 7a).(d) Profile of Ru species observed by in situ Raman spectroscopy (see Fig. S14 in the ESI †).
63 noting that up to 2/3 of the[Ru] was in NMR-inactive states at the end of the catalysis.However, the high selectivity of the reaction and absence of autoxidation pathways (see substrate scope below) strongly indicate the catalytic ux to proceed via activated, closed-shell [(L1)Ru VI (O) 2 ]$(H 2 O) 2 , and that NMR-silent species such as dimers or other paramagnetic complexes formed at later stages of the reaction to be deactivated states unrelated to the product-forming cycle (like the detected [(L1)Ru II (CO)]).

Fig. 10 Fig. 12
Fig.10Gibbs free energy reaction profile for selected intermediates of the water-free and micro-solvated epoxidation path including two broken-symmetry singlet/triplet minimum energy cross points (MECP) and transition structures (TS) computed at the M06L-D3(SMD)/def2TZVP level.The lowest energy closed-shell singlets (S = 0) are shown in light orange and light blue, the broken-symmetry singlets (BS) in orange and blue, the triplet (S = 1) in dark red and dark blue.In the text, all species are labelled with capital letters with the multiplicity in superscript and the presence of two water molecules indicated with a 'w2' subscript.