Deeper mechanistic insight into Ru pincer-mediated acceptorless

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Deeper mechanistic insight into Ru pincer-mediated acceptorless dehydrogenative coupling of alcohols: exchanges, intermediates and deactivation species Duc Hanh Nguyen, Xavier Trivelli, Frederic Capet, Youssef Swesi, Alain Favre-Réguillon, Laurent Vanoye, Franck Dumeignil, and Régis M. Gauvin ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b00995 • Publication Date (Web): 17 Apr 2018 Downloaded from http://pubs.acs.org on April 17, 2018

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Deeper mechanistic insight into Ru pincer-mediated acceptorless dehydrogenative coupling of alcohols: exchanges, intermediates and deactivation species. Duc Hanh Nguyena,*, Xavier Trivellib, Frédéric Capeta, Youssef Swesi,c Alain Favre-Réguillon,c Laurent Vanoye,c Franck Dumeignila, Régis M. Gauvina,* a

: Univ. Lille, CNRS, Centrale Lille, ENSCL, Univ. Artois, UMR 8181 - UCCS - Unité de Catalyse et Chimie du Solide, F-59000 Lille, France.

b

: Univ. Lille, CNRS, UMR 8576 - UGSF - Unité de Glycobiologie Structurale et Fonctionnelle, F-59000 Lille, France.

c

: Laboratoire de Génie des Procédés Catalytiques, LGPC, CNRS - CPE Lyon - Université de Lyon, F-69616 Villeurbanne, France.

TOC Graphic

ABSTRACT: The mechanism of acceptorless dehydrogenative coupling reaction (ADC) of alcohols to esters catalyzed by aliphatic pincer PHNP ruthenium complexes was experimentally studied. Relevant intermediate species involved into the catalytic cycle were isolated and structurally characterized by single crystal X-ray diffraction studies, and their reactivity (including towards substrates related to the catalytic process) was probed. VT NMR studies unveiled several chemical exchanges connecting the Ru amido hydride, the Ru alkoxide and the alcohol substrate. Under catalytic conditions, insitu IR spectroscopy monitoring demonstrated the production of ester via aldehyde as intermediate. Tishchenko-like pathway is proposed as the main path for the production of ester from aldehyde, involving alkoxide and hemiacetaloxide Ru species (the latter being identified in the reaction mixture by NMR). Catalytic system deactivation under base-free conditions was found to be related to water traces in the reaction medium (either as impurity or derived from aldol reactions) that lead to the formation of catalytically inactive acetato Ru complexes. These react with alkali metal alkoxides to afford catalytically-active Ru species. In line with this observation, running the ADC reaction in the presence of water scavengers or alkoxides allows maintaining sustained catalytic activity.

KEYWORDS. Dehydrogenative coupling, pincer complexes, metal-ligand cooperativity, Ru chemistry, Catalyst deactivation, Mechanistic studies.

INTRODUCTION Primary alcohols acceptorless dehydrogenative coupling (ADC) reaction is an environmentally friendly, oxidantfree and atom-efficient catalytic oxidation process that simultaneously produces esters and hydrogen gas as a

sole by-product (Scheme 1).1,2 Importantly, this approach can be further extended to synthesize value-added products including amide derivatives, carboxylic salts, amines and heterocyclic compounds.2,3

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Scheme 1. ADC reaction of alcohols to esters.

Well-defined transition metal complexes based on the ligand-metal cooperativity concept are remarkably active when compared to catalytic systems involving conventional (“innocent”) ligands,1a,b,4,5 Among the reported Ru,6 Os,7 Rh,8 Ir9, Re10 and more recently Earth-abundant Fe,11 Co,12 and Mn13 catalysts, Ru complexes remain the most efficient ones, catalyzing the reaction under mild conditions and at low catalyst loading (Chart 1).6 Usually, the reaction is conducted under basic conditions that allow generating active species in-situ but also lead to undesired base-promoted side-reactions.6g Therefore, performing the reaction under base-free conditions is highly desirable. Beller’s group has reported the in-situ formed dihydride ruthenium [Ru(H)2(CO)[NH(C2H4PR2)2] catalysts bearing aliphatic PNP pincer ligand that are remarkably active for base-free ADC reaction of ethanol to ethyl acetate under mild conditions.6a However, a rapid catalyst deactivation was observed and an alkali metal alkoxide

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additive (EtONa) is required to maintain steady catalyst activity.6a On the other hand, Gusev et al. reported the ADC and hydrogen transfer reactions catalyzed by analogous dihydride Os and Ru complexes and also described the beneficial effect of base in some cases.6c,e The general ADC reaction pathway involves a dehydrogenative coupling sequence. The alcohol is primarily dehydrogenated into an aldehyde intermediate that further reacts with a second molecule of alcohol to give a hemiacetal intermediate, which finally undergoes dehydrogenation into an ester.3,6,14 Alternatively, two molecules of aldehyde can be involved in a Tishchenko-type disproportionation to produce one molecule of ester.15 In fact, the alcohol dehydrogenation is thermodynamically an uphill process: the release of H2 gas under open system conditions (entropy factor) is thus the main driving force that shifts the equilibrium toward ester formation. Along these lines, we have recently demonstrated that the ADC kinetics are limited by the rate of transfer from the liquid to gas phase of the hydrogen produced in the reaction.6g

Chart 1. Selected examples of reported catalysts for ADC reactions.

Regarding catalytic cycles, both outer and inner sphere mechanisms were proposed depending on the lability of tridentate ligands.2,6,16 Inspired from Noyori’s metalligand bifunctional mechanism,17 the generally accepted catalytic cycle for the aliphatic pincer-type PNP systems consists of the alcohol dehydrogenation on the 16e- amido monohydride ruthenium(II) species via a concerted metal-ligand cooperative pathway to produce aldehyde and a trans-dihydride ruthenium(II) complex (Scheme 2a).6a The catalytic cycle is then completed by H2 release and

regeneration of the active amido species. In parallel, a similar cycle converts the hemiacetal (generated from the coupling reaction of aldehyde with alcohol) into the ester.11c,18 The formation of the hemiacetal intermediate could be promoted by an alkoxide species according to DFT calculations.11c Intermediate species relevant to this process were intercepted by Gusev in gas phase by using ESI-MS.19 Based on VT-NMR studies, we and then Hazari and Bernskoetter et al. showed that isoelectronic Mn/Fe alkoxide species may be considered as off-catalytic cycle

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species since these are converted back into the corresponding amido complexes when raising the reaction temperature.13,20 Noteworthy, the amino-amido couple complexes are also proposed as the main catalytic intermediate species for the reverse reaction, i.e. hydrogenation of esters.2b,21 On the other hand, Gordon and Dub reported a revised Noyori mechanism for the related ketone hydrogenation that preferentially proceeds in stepwise fashion via ionpair intermediates (rather than via classical concerted mechanism) with retention of the N-H bond. Both hydride amido and alkoxide species are not considered as intermediate species within the catalytic cycle but rather as off-loop species.22 Gusev followed on this idea and further suggested that in the alcohol ADC case, the alkoxide metal complex may be a key species in the production of ester from aldehyde, since it efficiently catalyzes the Tishchenko reaction (Scheme 2b).23 However, under ADC reaction conditions and in the presence of a large excess of aldehyde, Beller et al. found that Ru-based catalysts are a)

Concerted mechanism

b)

Stepwise mechanism

poisoned.6a Similarly, rapid catalyst deactivation was observed during the hydrogenation of neat aldehyde or aldehyde/ester mixture (that are reverse reactions of alcohol ADC).6d Beller suggested that the concentration of aldehyde should have to be kept as low as possible and the beneficial effect of EtONa would be to act as an aldehyde scavenger forming deprotonated hemiacetal intermediate.6a Nevertheless, under basic conditions, the catalytic cycle involving deprotonated species may have to be taken into account.24 In the present contribution, we re-examine the base-free ADC reaction of ethanol to ethyl acetate catalyzed by Rualiphatic PNP systems, using in-situ spectroscopic methods (NMR and IR) and by isolating relevant species. More specifically, we investigate the various stages of the ADC reaction as mediated by Ru PNP complexes, from entry into the catalytic cycle to deactivation. Furthermore, based on these findings, we also rationalize the reactivation process of the catalytic system.

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Scheme 2. Simplified catalytic cycles for alcohol ADC reaction (R= iPr, R’= Me).

RESULTS AND DISCUSSIONS Studies on the 2/1-H couple in the absence of alcohol. In the reaction mixture at the onset of catalysis, the ruthenium species that can be involved are the couple amino [Ru(H)2(CO)(NH(C2H4PiPr2)2)] 1-H and amido [Ru(H)(CO)(N(C2H4PiPr2)2)] 2.25 These are (formally) linked by hydrogen addition or extrusion onto or from the Ru-N framework. When dissolving 1-H in an aprotic solvent as toluene-d8, no H2 release was observed at room temperature and in a closed system even after two weeks. This observation indicates that 1-H is stable under these conditions. On the opposite, sterically crowded [Ru(H)2(CO)(NH(C2H4PtBu2)2)]6g or electron-rich [Ru(H)2(PMe3)(NH(C2H4PiPr2)2)]26, as well as earth abundant [M(H)2(CO)(NH(C2H4PiPr2)2)] (M = Fe,11,27 Mn13) analogues readily lose hydrogen to form the corresponding amido complexes at room temperature and under reduced pressure, probably via a four-center type transition state. Heating the colorless solution of 1-H at 80 °C in a closed system leads to the formation of the amido monohydride [RuH(CO)(N(C2H4PiPr2)2)] 2 in ca. 10% yield after 2h. Further maintaining the solution at the same temperature for prolonged reaction times does not modify the amount of 2 indicating that the equilibrium between 1-H and 2 is reached (See SI 3). At lower tempera-

ture (60°C), the dehydrogenation of 1-H to 2 needs longer reaction times (5 h) to reach the equilibrium with the respective 2/1-H ratio of about 8/92. Beller et al. reported that in dioxane and at 100 °C, 20% of 2 was obtained after 50 min.24b Noteworthy, under an argon stream and in an open system at 80°C, H2 release took place smoothly with a color change initially to orange and then to red: 2 is generated in ratio of 87/13 with respect to 1-H after 3 days (Scheme 3).28 Indeed, the constant evacuation of H2 product by argon flow allows to shift the equilibrium toward the formation of the amido 2. However, this straightforward H2 release proceeds with very low rate that is not consistent with overall observed ADC reaction rate (with TOF of about 500 h-1 at 80 °C, see below).6a,g When considering the proposed concerted mechanism (Scheme 2a), the amido 2 is the entry point, which dehydrogenates the substrate, to afford amino 1-H and oxidized substrate. 1-H should then release H2 to regenerate 2. For the stepwise mechanism (Scheme 2b), 2 is however considered as an off-catalytic cycle species. To get a better understanding of mechanism and reactivity under catalytically relevant conditions, we investigated the reactivity of 2 and 1-H towards ethanol, with detailed studies on exchange processes.

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H

Closed system: 80°C, 2 h: 1-H/2 = 90/10 60°C, 5 h: 1-H/2 = 92/8 Open system: 80°C, 3 days: 1-H/2 = 13/87

H N

Ru

P iPr2 H

PiPr2

-H 2

CO

N

Argon stream

P iPr2 H 2

1-H EtOH, RT: 1 equiv.: 1-H/1-OEt = 80/20 10 equiv.: 1-H/1-OEt = 25/75 15 equiv.: 1-H/1-OEt = 20/80 100 equiv.: 1-H/1-OEt = 8/92

-H2

EtOH

O N

Ru

P iPr2 H

H PiPr2 CO

+

1-OEt

PiPr2 CO

EtOH, 183 K: 10 equiv.: 1-OEt/2 = 100/0 0.4 equiv.: (1-OEt+1-OEt')/2 = 30/70

EtOH

H

Ru

H N

Ru

PiPr2

P iPr2 O

CO

1-OEt'

Scheme 3. Reactivity of Ru complexes.

Reaction of 2 with ethanol. In a first step, the reaction of amido ruthenium species 2 with ethanol was investigated (Scheme 3). Even at very low temperature (200 K), 2 readily reacts with ethanol (~ 10 molar equiv.) to exclusively afford the new trans-ethoxide ruthenium hydride of formula [Ru(H)(OEt)(CO)(NH(C2H4PiPr2)2)] 1-OEt in stereoselective manner. Such high reactivity toward alcohol was previously demonstrated for related Noyori-type Ru amido complexes.29 In line with this observation, DFT calculations revealed that the alkoxylation reaction is exergonic and proceeds with very small energy barriers.11c,13 For instance, Beller et al. calculated that the reaction of 2 with methanol is slightly endogenic (0.9 kcal.mol-1) and involves a small barrier of 4.4 kcal.mol-1.24b Single crystals of 1-OEt suitable for X-ray determination were grown from an ethanol solution and its molecular structure was determined by X-ray diffraction studies (Figure 1). In the solid state, it features a distorted octahedral geometry, similar to the analogous isopropoxide derivative [Ru(H)(iPrO))(CO)(NH(C2H4PiPr2)2)].(HOiPr) reported by Gusev et al.6c The PNP tridentate ligand is coordinated in meridional configuration. The ethoxide ligand is arranged in syn-fashion with the N-H function and is located in trans-position to the hydride one. In addition, there is one molecule of ethanol in the crystal structure that is incorporated via intermolecular hydrogen bonding interactions bridged between the NH hydrogen and the ethoxide oxygen (RuO(Et)———HO(Et)———HN) to form a six-membered cyclic adduct 1-OEt.EtOH (Figure 1).30 The Ru-O2 bond length (2.2028(16) Å) is comparable to that of analogous complexes.6c,31

Figure 1. ORTEP view of solid-state structure of 1OEt.EtOH. All H-atoms (except the H on Ru and N) are omitted for clarity. Selected bond distances (Å): Ru1-P1 = 2.3152(6), Ru1-P2 = 2.3104(6), Ru1-O2 = 2.2028(16), Ru1-N1 = 2.1944(19), Ru1-C17 = 1.827(2), Ru1-H = 1.40(3), N1-H1 = 0.82(3), O1-C17 = 1.165(3), O2-C18 = 1.401(3). Selected angles (deg): P1-Ru1-H = 86.0(14), P2-Ru1-P1 = 163.82(2), P2Ru1-H = 87.0(14), O2-Ru1-P1 = 95.66(5), O2-Ru1-P2 = 90.04(5), O2-Ru1-H = 174.5(14), N1-Ru1-P1 = 82.76(6), N1Ru1-P2 = 83.07(6), N1-Ru1-O2 = 81.95(7), N1-Ru1-H = 93.1(13), C17-Ru1-P1 = 97.42(7), C17-Ru1-P2 = 96.48(7), C17Ru1-O2 99.92(8), C17-Ru1-N1 = 178.09(9), C17-Ru1-H 85.0(13).

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1-OEt was not stable enough to be characterized as a neat compound as it gradually converted to 1-H and ethyl acetate (See below). However, complex 1-OEt was stable in ethanol solution at low temperature and was characterized by multinuclear NMR spectroscopy at 260 K. On the 1 H NMR spectrum, the ruthenium hydride and NH proton respectively resonate as a triplet centered at -17.62 ppm (3JHP = 19 Hz) and as a broad signal at 5.33 ppm. The 31 1 P{ H} NMR spectrum displays a singlet at 74.0 ppm. The 15 N chemical shift value was determined to be 48 ppm, according to the 2D 1H-15N HSQC NMR spectrum. On the 13 C{1H} spectrum, the CO ligand gives rise to a triplet centered at 207.6 ppm (2JCP = 6 Hz). The 13C signal of the carbon atom adjacent to oxygen of [Ru]-OEt is at 66.9 ppm, shifted downfield by 9.2 ppm from the signal for the free ethanol. Noteworthy, the observation of positive cross-peaks between two pairs of protons (NH of 1-OEt/ free HOCH2CH3 and [Ru]-OCH2CH3 of 1-OEt/free HOCH2CH3) demonstrates that the free ethanol and the Ru-ethoxide moiety are involved in a chemical exchange. This is further evidenced by VT-NMR studies from 200 to 300 K: Both 1H NMR signals belonging to -OCH2 methylene of 1-OEt and free EtOH broaden and then coalesce, with a coalescence temperature of ca. Tc = 300 K (See SI 5.4). Similar exchange processes have been observed for the analogous manganese [Mn(OCH2Ph)(CO)2(NH(C2H4PiPr2)2)],13 iron [Fe(OCH3)(CO)2(NH(C2H4PiPr2)2)]20 and related Ru alkoxide complexes.32 Plausible chemical exchange mechanisms, involving the amido intermediate species 2 and/or an ion-pair, can proposed based on the literature (Scheme S6 in SI).22,33 Interestingly, addition of a sub-stoichiometric quantity of ethanol (~0.4 molar equiv.) to a solution of 2 at low temperature initially affords a mixture of two ethoxide stereoisomers 1-OEt and 1-OEt’ (along with unreacted 2) that was further investigated by VT-NMR spectroscopy (Scheme 3, Figures S31 and S33 in SI). This revealed an intramolecular exchange of the two 1-OEt and 1-OEt’ isomers (Coalescence temperature of 204 K, ΔH≠ = 7 kcal.mol-1 and ΔS≠ = 16 cal.K-1.mol-1), which are themselves in exchange with amido species 2, with a coalescence temperature of 234 K (see SI5.5 for details). Reaction of 1-H with ethanol. At low temperature (200 K) and in a closed system, the dihydride 1-H34 does not react with ethanol, which indicates a lower reactivity of 1H with respect to the amido 2. At room temperature, reaction of 1-H with ethanol generated 1-OEt as sole organometallic species along with H2 release. Indeed, ethanol acts as a proton transfer shuttle that facilitates H2 release from 1-H, which proceeds faster than in the absence of alcohol (See above).11c,21b,35 The resulting relative 1-OEt/1-H ratio strongly depends on the ethanol amount added: This varies from 20/80 to 92/8 when increasing the amount of ethanol from 1 to 100 molar equiv., respectively (See Scheme 3 for corresponding values). Indeed, increasing the amount of ethanol favors the formation of

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the alkoxide species 1-OEt. Similar reactivity was also observed with methanol.24b Furthermore, under these conditions, the ADC of ethanol was triggered, leading to the production of ethyl acetate. For instance, treatment of 1-H with 1.0 molar equiv. of ethanol afforded, within 30 minutes, 1-OEt (20 %), along with ethyl acetate (7%). H N

H

Ru P iPr2 H

PiPr2 CO [Ru]-H

[Ru]-H 304K 294K 284K 274K 264K 254K 244K 234K 224K 214K 204K 194K -5.5

-6.0

-6.5

-7.0

-7.5

-8.0

-8.5

ppm

1

Figure 2. Stacked VT H NMR spectra showing the stereoselective proton/hydride exchange process for the 1-H / excess ethanol system.

Stereoselective hydroxyl proton/hydride exchange was demonstrated by NMR studies. Regarding the solution of 1-H (containing 20% of 1-OEt) and in the presence of ethanol (~20 equiv.), 2D NOESY {1H-1H} NMR spectrum features a strong positive cross-peak between the synhydride ligand of 1-H and free EtOH acidic proton. The positive NOE cross-peak between the anti-hydride ligand and free EtOH acidic proton was also observed but is much weaker. This observation is indicative of proton/hydride exchanges that are operative at much higher rate for [Ru]-Hsyn. This highly stereoselective chemical exchange is further evidenced by VT-NMR studies: As function of increasing temperature, the proton/hydride exchange rate is faster on the NMR timescale (along with concomitant conversion of 1-H to 1-OEt) that results in the significant broadening of the 1H NMR signal of [Ru]Hsyn and the breakdown of the 2J(Hsyn-Hanti) coupling constant (Figure 2).

Scheme 4. Proposed mechanism for stereoselective proton/hydride exchange process between 1-H and EtOH.

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Similar chemical exchange has been reported for [Ru(H)2(PMe3)(NH(C2H4PiPr2)2)] in the presence of water.26 Most likely, the selective proton/hydride exchange process is directed by the cooperative (RuH···HO(Et)···HN) hydrogen bonding interactions, as suggested by Schneider,26 and involves dihydrogen amido adduct and/or ion-pair intermediate species (Scheme 4).22,23a,36 These latter species can further release H2 and undergo alkoxylation to form 1-OEt.23a In line with hydrogen bonding interactions with alcohol, 1H hydride chemical shift values for both 1-H and 1-OEt are sensitive to the ethanol amount present in the medium (for chemical exchange of 1-OEt with EtOH, see above). For example, in presence of 1 and 15 equiv. of ethanol, 1H hydride chemical shift values at room temperature for 1-H are -6.3 (br) and -6.49 ppm (t), and -6.5 (t) and -6.94 ppm (t), respectively, whereas for 1-OEt the hydride resonates at are -17.0 and 17.5 ppm, respectively. In situ studies within the catalytic regime. After these preliminary investigations, we proceeded with studies under conditions related to those of the catalytic ADC reaction. In a closed system, heating a solution containing

1-H and EtOH in stoichiometric ratio at 353 K allows ethanol to be smoothly converted to ethyl acetate to reach an equilibrium at which both ADC of ethanol and its reverse hydrogenation reaction of ethyl acetate take place with similar rates: 60% of ethanol was converted and the 1H/1-OEt ratio remained constant. Similarly, heating the ethanolic solution (9 equiv. of EtOH) of 1-OEt in the 290340 K temperature range resulted in the formation of both 1-H and ethyl acetate, unlike Mn and Fe analogues, which gave back the amido complexes.13,20 Acetaldehyde and hemiacetal, which are commonly suspected as organic intermediate species during the production of ester, were not detected. The same experiment was carried out in an open system under an argon stream, which flushes hydrogen away and therefore shifts the equilibrium toward ester formation. Indeed, full conversion of the ethanol was achieved. Notably, when free ethanol has been fully consumed, the amido complex 2 starts to be formed that is in fast chemical exchange with 1-OEt, thus broadening both the 1H hydride and 31P phosphorous NMR signals, as observed above when studying the behavior of the 2/ethanol system.

Figure 3. a) Three-dimensional IR spectra in the carbonyl region vs. wavenumber vs. time. b) Absorbance profiles of ethanol, acetaldehyde and ethyl acetate vs. time during ADC reaction (540 ppm of 1-H, reflux conditions).

In order to reach spectroscopic information under conditions that are identical to those of catalytic runs, we resorted to in situ IR spectroscopy. Indeed, when monitoring ethanol ADC reaction, this technique is particularly well-suited to obtain real-time structural and kinetic information. Such an approach has rarely been used in the context of hydrogen borrowing and related reactions. For instance, Sanford recently used in-situ Raman studies to monitor iron-catalyzed hydrogenation of amides. 37 Indeed, monitoring the evolution of ethanol in the presence of 1-H (540 ppm) in an open system revealed the presence of both ethyl acetate and acetaldehyde as deduced from the characteristic ν(C=O) at 1744 and 1727 cm1 , respectively (Figure 3a). These assignments were confirmed by comparison to authentic samples. Figure 3 features the qualitative evolution of the reaction mixture (at this stage, no quantification was performed), as deduced from spectral decomposition using the dedicated

iC-IR software from Mettler-Toledo. Most interestingly, absorbance profiles of ethanol, acetaldehyde and ethyl acetate vs. time are typical for consecutive reactions operating via acetaldehyde as an intermediate species which builds up and is then gradually consumed (Figure 3b). Elements for the Tishchenko pathway. The observation of the often postulated yet rarely observed aldehyde intermediate raised questions on its reactivity towards catalytically relevant species such as 2, 1-H and 1-OEt. This prompted further investigations, as aldehyde coupling into ester (Tishchenko reaction) was recently reported using related Os pincer complexes.23b Thus, when reacting acetaldehyde with 1-H ([acetaldehyde]/[1-H] ≈ 630) at room temperature for 30 minutes, full conversion was achieved, with strong exothermicity. The selectivity toward ethyl acetate is of only 60 % selectivity, with products resulting from aldol-type reactions being also formed (vide infra). Regarding detected Ru species

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formed/involved at the end of reaction, neither 1-H, 2 nor 1-OEt were observed. Only the acetate derivative 1-OAc (See below for detailed investigations) and a parent carboxylate species were observed in respective ratio of 55/45. In order to get back to conditions that are closer to those of the actual catalytic system, where aldehydes amount for only a fraction of the components, we next investigated the fate of a mixture of aldehyde and alcohol in the presence of 1-H. Thus, in the presence of both ethanol (270 equiv.) and acetaldehyde (550 equiv.), 1-H was found to be catalytically very active at room temperature: Acetaldehyde was fully consumed, as after only 30 min (time required to prepare the sample and measure it by NMR spectroscopy), ethyl acetate is formed as the main product with selectivity of about 90%. The quantity of ethanol present in the reaction mixture was unchanged, indicating that the ethanol was not consumed (See below for a comparative study involving acetaldehyde and propanol to get further understanding). Analysis by GC/MS and 1H NMR shows the presence of ethyl 3-hydroxybutyrate and 1,3-butanediol as major side-products. The formation of these compounds can be explained by acetaldehyde aldolisation to form 3-hydroxybutanal (non-detected), which can further couple with acetaldehyde (via Tishchenko reaction) to yield the ester ethyl 3hydroxybutyrate, or be reduced into 1,3-butanediol.38 Regarding the organometallic species, we identified the ethoxide 1-OEt (30%), along with two Ru carboxylate species (including 30% 1-OAc) accounting for 70%.39 Interestingly, even under very mild conditions (268 K, 650 equiv. of EtOH, 360 equiv. CH3CHO), the catalyst was shown to be very active and more importantly, highly selective, since the reaction is complete within 40 min and only ethyl acetate was produced (>99%). Paraldehyde was formed at the beginning of the reaction and was further consumed. Notably, at the end of reaction, 1-OEt was detected as the main organometallic species (90%) along with small amount of 1-OAc (10%).40

Scheme 5. Interception of Ru-intermediate species at 183 K from reaction of 1-H with acetaldehyde.

In order to investigate on the active species involved and to account for the difference in selectivity when compar-

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ing the conversion of aldehyde in the presence or in the absence of ethanol, stoichiometric reactions of 1-H with acetaldehyde and acetaldehyde/ethanol mixture were studied by VT-NMR. At 183 K, the reaction of 1-H with acetaldehyde (~ 6 equiv.) takes place readily, affording a complex mixture. Amido 2 was not detected (contrary to what was reported in Noyori-type systems41) according to 1 H-15N HMBC (sp2-hybridized nitrogen within 2 characteristically resonates downfield at 193 ppm42). Among the several ruthenium hydride species obtained, we could assign 1-OEt (inter alia thanks to the characteristic 13C signal of the methylene carbon atom adjacent to oxygen located at 65.2 ppm), and two new compounds (along with 1-OAc in 15%): an enolato [RuH(CO)(OCH=CH2)(NH(C2H4PiPr2)2)] 1-OCHCH2 (28%) and a hemiacetaloxide [RuH(CO)(OCH(CH3)(OEt))(NH(C2H4PiPr2)2)] 1OCH(CH3)(OEt) (30%), based on multinuclear NMR studies and on similarity of their signals to those of related 1-OEt (Scheme 5). For 1-OCHCH2, the Ru hydride resonates as a triplet centered at -11.98 ppm (JHP = 20 Hz), shifted downfield by 5.9 ppm from the hydride signal for 1-OEt. The 1H NMR chemical shifts for the [Ru]OCH=CH2 enolate were determined to be 8.24 ppm (JHH = 10 Hz) and 2.90 and 2.51 ppm, assigned to the methine proton adjacent to the oxygen atom ([Ru]-OCH=) and to two inequivalent terminal methylene protons (=CH2), respectively, thanks to 1H-1H COSY and 1H-1H TOCSY. 1H13 C HSQC and 1H-13C TOCSY-HSQC allow determining the corresponding 13C chemical shifts at 163.2 ppm for [Ru]OCH= and 35.3 ppm for the =CH2 moiety. 31P and 15N chemical shifts are located at 75.53 and 54.7 ppm, thanks to 1H-31P and 1H-15N HSQC NMR, respectively. Accordingly, the chemical shift for the amino proton was determined to 3.5 ppm. The assignment to the O-bound form of the complex, and not to the isomeric C-bound form 1CH2C(=O)H,43 namely [RuH(CO)(CH2CHO)(NH(C2H4PiPr2)2)], was proposed as in the latter case the formyl carbon would resonate at lower field (~ 200 ppm).44 Thus, formation of 1-OCHCH2 could be reasonably ascribed to the reaction of the amido intermediate 2 (not detected, generated from reaction between 1-H and one equivalent of acetaldehyde into 2 and one equivalent of ethanol) with the enol tautomer (vinyl alcohol), as reported by Morris45 or to an alkoxide/enolate exchange within 1-OEt (itself being generated from reaction between 1-H and one equivalent of ethanol). The hemiacetaloxide 1-OCH(CH3)(OEt) complex was identified based on the following NMR analyses (See SI 10.9): the Ru hydride appears as a triplet centered at 17.66 ppm (JHP = 19 Hz). 1H NMR signals for the >CHCH3 moiety are located at 5.14 (>CH-) and 1.68 ppm (-CH3). For the ethoxide group, the two diastereotopic methylene protons resonate at 4.17 and 3.53 ppm, and the 1H chemical shift value for the methyl protons is 1.36 ppm. The 13C NMR signals of [Ru]-OCH(CH3)(OEt) are located at 107.1 (-OCHCH-OH), AB system 2.32 (dd, 1H, >CHCH2, JHH = 7.8, 15.4 Hz) and 2.19 (dd, 1H, >CHCH2, JHH = 5, 15.4 Hz)). (39) Along with well-characterized 1-OEt and 1-OAc, there is a third unknown complex (~40%) of which the characteristic NMR data (δ[Ru]H = -18.46 ppm (JHP = 18 Hz), δNH = 8.23 ppm, δP = 76.05 ppm) are very close to that of 1-OAc. This is probably a Ru carboxylate derivative originating from reaction of higher aldehydes (from aldol condensation) with water, just as 1-OAc stems from reaction of acetaldehyde with water. (40) When performing the reaction at 243 K ([ethanol]/[1-H] ≈ 260, [acetaldehyde]/[1-H] = 380), no formation of ethyl acetate was observed yet, but instead were partially formed paraldehyde and hemiacetal derivatives, as evidenced by characteristic 13C chemical shift values at 90-95 ppm, from 1H-13C HSQC NMR sequence. In parallel, the formation of a new hydride organometallic compound was observed: its hydride resonates as a triplet centered at -12.33 ppm (JHP = 20 Hz) while the phosphorous atoms resonate as a coupled AB spin system (δPA = 76.08 and δPA = 75.05 ppm, JPAPB = 225 Hz). The reaction was next carried out at 260 K that proceeds with a rate appropriate to be monitored by 1 H NMR. As the reaction progresses, the organometallic species smoothly evolved into other unidentified hydride species that finally gave rise to 1-OEt as the major organometallic compound when all aldehyde derivatives have been consumed (after ~1 h 30). Under similar conditions and in the presence of only acetaldehyde as substrate, this intermediate species was also detected. Thus, the nature of the unknown Ru intermediate is related to the presence of aldehyde amount in the reaction medium.

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