Deeper Mechanistic Insight into Ru Pincer-Mediated Acceptorless Dehydrogenative Coupling of Alcohols: Exchanges, Intermediates, and Deactivation Species

Article abstract of DOI:10.1021/acscatal.8b00995

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 in the catalytic cycle were isolated and structurally characterized by single-crystal X-ray diffraction studies, and their reactivity (including toward 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, in situ IR spectroscopy monitoring demonstrated the production of ester via aldehyde as intermediate. A 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.

Full text of DOI:10.1021/acscatal.8b00995

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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
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ACS Catalysis
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Deeper mechanistic insight into Ru pincerꢀmediated acceptorꢀ
less dehydrogenative coupling of alcohols: exchanges, inꢀ
termediates and deactivation species.
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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 Villeur-
banne, 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, in-
situ 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 reac-
tions) 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 deacti-
vation, Mechanistic studies.
INTRODUCTION
sole by-product (Scheme 1).1,2 Importantly, this approach
can be further extended to synthesize value-added prod-
ucts including amide derivatives, carboxylic salts, amines
and heterocyclic compounds.2,3
Primary alcohols acceptorless dehydrogenative coupling
(ADC) reaction is an environmentally friendly, oxidant-
free and atom-efficient catalytic oxidation process that
simultaneously produces esters and hydrogen gas as a
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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 analo-
gous dihydride Os and Ru complexes and also described
the beneficial effect of base in some cases.6c,e
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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 conven-
tional (“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 condi-
tions 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 desira-
ble. Beller’s group has reported the in-situ formed dihy-
dride 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 ace-
tate under mild conditions.6a However, a rapid catalyst
deactivation was observed and an alkali metal alkoxide
The general ADC reaction pathway involves a dehydro-
genative coupling sequence. The alcohol is primarily de-
hydrogenated into an aldehyde intermediate that further
reacts with a second molecule of alcohol to give a hemi-
acetal intermediate, which finally undergoes dehydro-
genation into an ester.3,6,14 Alternatively, two molecules of
aldehyde can be involved in a Tishchenko-type dispropor-
tionation 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 condi-
tions (entropy factor) is thus the main driving force that
shifts the equilibrium toward ester formation. Along the-
se 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
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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 metal-
ligand 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 met-
al-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 es-
ter.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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ACS Catalysis
poisoned.6a Similarly, rapid catalyst deactivation was ob-
species since these are converted back into the corre-
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sponding amido complexes when raising the reaction
temperature.13,20 Noteworthy, the amino-amido couple
complexes are also proposed as the main catalytic inter-
mediate species for the reverse reaction, i.e. hydrogena-
tion of esters.2b,21
served during the hydrogenation of neat aldehyde or
aldehyde/ester mixture (that are reverse reactions of al-
cohol 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 alde-
hyde scavenger forming deprotonated hemiacetal inter-
mediate.6a Nevertheless, under basic conditions, the cata-
lytic cycle involving deprotonated species may have to be
taken into account.24
On the other hand, Gordon and Dub reported a revised
Noyori mechanism for the related ketone hydrogenation
that preferentially proceeds in stepwise fashion via ion-
pair intermediates (rather than via classical concerted
mechanism) with retention of the N-H bond. Both hy-
dride 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 alkox-
ide 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
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In the present contribution, we re-examine the base-free
ADC reaction of ethanol to ethyl acetate catalyzed by Ru-
aliphatic PNP systems, using in-situ spectroscopic meth-
ods (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 reactiva-
tion process of the catalytic system.
a) Concerted mechanism
b) Stepwise mechanism
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Scheme 2. Simplified catalytic cycles for alcohol ADC reaction (R= iPr, R’= Me).
RESULTS AND DISCUSSIONS
ture (60°C), the dehydrogenation of 1-H to 2 needs longer
reaction times (5 h) to reach the equilibrium with the
Studies on the 2/1-H couple in the absence of alcohol.
In the reaction mixture at the onset of catalysis, the ru-
thenium species that can be involved are the couple ami-
no [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
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 prod-
uct by argon flow allows to shift the equilibrium toward
the formation of the amido 2. However, this straightfor-
ward 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
[Ru(H)2(CO)(NH(C2H4PtBu2)2)]6g
or
electron-rich
[Ru(H)2(PMe3)(NH(C2H4PiPr2)2)]26, as well as earth abun-
dant [M(H)2(CO)(NH(C2H4PiPr2)2)] (M = Fe,11,27 Mn13)
analogues readily lose hydrogen to form the correspond-
ing amido complexes at room temperature and under
reduced pressure, probably via a four-center type transi-
tion state. Heating the colorless solution of 1-H at 80 °C in
a closed system leads to the formation of the amido mon-
ohydride [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 modi-
fy the amount of 2 indicating that the equilibrium be-
tween 1-H and 2 is reached (See SI 3). At lower tempera-
When considering the proposed concerted mechanism
(Scheme 2a), the amido 2 is the entry point, which dehy-
drogenates the substrate, to afford amino 1-H and oxi-
dized 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 catalyt-
ically relevant conditions, we investigated the reactivity of
2 and 1-H towards ethanol, with detailed studies on ex-
change
processes.
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Closed system:
80°C, 2 h: 1ꢀH/2 = 90/10
60°C, 5 h: 1ꢀH/2 = 92/8
1
2
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Open system
:
1ꢀH 2
/ = 13/87
80°C, 3 days:
H
H
PiPr2
-H2
N
PiPr2
N
Ru
Ru
CO
P
CO
Argon stream
P
iPr2
iPr2
H
H
1ꢀH
2
EtOH, RT:
1ꢀH/1ꢀOEt
EtOH, 183 K:
9
EtOH
1 equiv.:
= 80/20
10 equiv.: 1ꢀH/1ꢀOEt = 25/75
1ꢀOEt 2
10 equiv.: /
= 100/0
1ꢀOEt 1ꢀOEt' 2
)/ = 30/70
-H2
EtOH
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0.4 equiv.: (
+
1ꢀH/1ꢀOEt
100 equiv.:
15 equiv.:
= 20/80
1ꢀH/1ꢀOEt
= 8/92
H
O
Ru
H
H
H
Ru
O
PiPr2
N
PiPr2
CO
N
+
CO
P
P
iPr2
iPr2
1ꢀOEt
1ꢀOEt'
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 investi-
gated (Scheme 3). Even at very low temperature (200 K), 2
readily reacts with ethanol (~ 10 molar equiv.) to exclu-
sively 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 alco-
hol 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 barri-
ers.11c,13 For instance, Beller et al. calculated that the reac-
tion 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 octa-
hedral 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 hydro-
gen bonding interactions bridged between the NH hydro-
gen 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
Figure 1. ORTEP view of solid-state structure of 1-
OEt.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 an-
gles (deg): P1-Ru1-H = 86.0(14), P2-Ru1-P1 = 163.82(2), P2-
Ru1-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), N1-
Ru1-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), C17-
to that of analogous complexes.6c,
31
Ru1-O2 99.92(8), C17-Ru1-N1
85.0(13).
= 178.09(9), C17-Ru1-H
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1-OEt was not stable enough to be characterized as a neat the alkoxide species 1-OEt. Similar reactivity was also
1
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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 character-
ized by multinuclear NMR spectroscopy at 260 K. On the
1H 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
31P{1H} NMR spectrum displays a singlet at 74.0 ppm. The
15N chemical shift value was determined to be 48 ppm,
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
H
PiPr2
N
Ru
H
CO
P
iPr2
9
1
according to the 2D H-15N HSQC NMR spectrum. On the
[Ru]-H
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13C{1H} spectrum, the CO ligand gives rise to a triplet
[Ru]-H
13
304K
294K
284K
274K
264K
254K
centered at 207.6 ppm (2JCP = 6 Hz). The C 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.
244K
234K
Noteworthy, the observation of positive cross-peaks be-
tween two pairs of protons (NH of 1-OEt/ free HOCH2CH3
and [Ru]-OCH2CH3 of 1-OEt/free HOCH2CH3) demon-
strates that the free ethanol and the Ru-ethoxide moiety
are involved in a chemical exchange. This is further evi-
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 stereose-
lective proton/hydride exchange process for the 1-H / excess
ethanol system.
1
denced by VT-NMR studies from 200 to 300 K: Both H
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 ex-
change 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 alkox-
ide complexes.32 Plausible chemical exchange mecha-
nisms, involving the amido intermediate species 2 and/or
an ion-pair, can proposed based on the literature (Scheme
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 syn-
hydride 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 pro-
ton/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
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 tem-
perature initially affords a mixture of two ethoxide stereo-
isomers 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).
1
the significant broadening of the H NMR signal of [Ru]-
2
Hsyn and the breakdown of the J(Hsyn-Hanti) coupling con-
stant (Figure 2).
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 1-
H with respect to the amido 2. At room temperature,
reaction of 1-H with ethanol generated 1-OEt as sole or-
ganometallic species along with H2 release. Indeed, etha-
nol acts as a proton transfer shuttle that facilitates H2
release from 1-H, which proceeds faster than in the ab-
b,35
sence of alcohol (See above).11c,
The resulting relative
21
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., respec-
tively (See Scheme 3 for corresponding values). Indeed,
increasing the amount of ethanol favors the formation of
Scheme 4. Proposed mechanism for stereoselective pro-
ton/hydride exchange process between 1-H and EtOH.
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1-H and EtOH in stoichiometric ratio at 353 K allows eth-
Similar chemical exchange has been reported for
1
2
3
4
5
6
7
8
[Ru(H)2(PMe3)(NH(C2H4PiPr2)2)] in the presence of wa-
anol 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 1-
H/1-OEt ratio remained constant. Similarly, heating the
ethanolic solution (9 equiv. of EtOH) of 1-OEt in the 290-
340 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 organ-
ic 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 to-
ward ester formation. Indeed, full conversion of the etha-
nol 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 broad-
ter.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 hydro-
1
gen bonding interactions with alcohol, H hydride chemi-
9
cal 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.
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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
ening both the H 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 condi-
tions that are identical to those of catalytic runs, we re-
sorted to in situ IR spectroscopy. Indeed, when monitor-
ing 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
iC-IR software from Mettler-Toledo. Most interestingly,
absorbance profiles of ethanol, acetaldehyde and ethyl
acetate vs. time are typical for consecutive reactions oper-
ating via acetaldehyde as an intermediate species which
builds up and is then gradually consumed (Figure 3b).
Elements for the Tishchenko pathway. The observa-
tion 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 cou-
pling into ester (Tishchenko reaction) was recently re-
ported 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
37
to monitor iron-catalyzed hydrogenation of amides.
Indeed, monitoring the evolution of ethanol in the pres-
ence of 1-H (540 ppm) in an open system revealed the
presence of both ethyl acetate and acetaldehyde as de-
duced from the characteristic ν(C=O) at 1744 and 1727 cm-
1, respectively (Figure 3a). These assignments were con-
firmed by comparison to authentic samples. Figure 3
features the qualitative evolution of the reaction mixture
(at this stage, no quantification was performed), as de-
duced from spectral decomposition using the dedicated
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Page 8 of 18
formed/involved at the end of reaction, neither 1-H, 2 nor ing the conversion of aldehyde in the presence or in the
1
2
3
4
5
6
7
8
1-OEt were observed. Only the acetate derivative 1-OAc
(See below for detailed investigations) and a parent car-
boxylate species were observed in respective ratio of
55/45.
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
1H-15N HMBC (sp2-hybridized nitrogen within 2 character-
istically 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
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 investigat-
ed 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: Acet-
aldehyde 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 prod-
uct with selectivity of about 90%. The quantity of ethanol
present in the reaction mixture was unchanged, indicat-
ing that the ethanol was not consumed (See below for a
comparative study involving acetaldehyde and propanol
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with
[RuH(CO)(OCH=CH2)(NH(C2H4PiPr2)2)]
(28%) and
[RuH(CO)(OCH(CH3)(OEt))(NH(C2H4PiPr2)2)]
1-OAc
in
15%):
an
enolato
1-OCHCH2
a
hemiacetaloxide
1-
OCH(CH3)(OEt) (30%), based on multinuclear NMR
studies and on similarity of their signals to those of relat-
ed 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]-
1
to get further understanding). Analysis by GC/MS and H
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 al-
dolisation to form 3-hydroxybutanal (non-detected),
which can further couple with acetaldehyde (via Tish-
chenko reaction) to yield the ester ethyl 3-
hydroxybutyrate, 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 In-
terestingly, 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 fur-
ther 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
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),
1
1
1
respectively, thanks to H-1H COSY and H-1H TOCSY. H-
13C 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 H-31P and H-15N HSQC NMR, respectively. According-
ly, the chemical shift for the amino proton was deter-
mined to 3.5 ppm. The assignment to the O-bound form
of the complex, and not to the isomeric C-bound form 1-
1
1
CH2C(=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 alkox-
ide/enolate exchange within 1-OEt (itself being generated
from reaction between 1-H and one equivalent of etha-
nol).
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 -
1
17.66 ppm (JHP = 19 Hz). H 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
1
protons resonate at 4.17 and 3.53 ppm, and the H chemi-
Scheme 5. Interception of Ru-intermediate species at 183 K
from reaction of 1-H with acetaldehyde.
13
cal shift value for the methyl protons is 1.36 ppm. The C
NMR signals of [Ru]-OCH(CH3)(OEt) are located at 107.1
(-OCH<) and 24 ppm (-CH3) for O(CH)CH3 moiety and
62.04 (-OCH2) and 16.2 ppm (-CH3) for the ethoxide
In order to investigate on the active species involved and
to account for the difference in selectivity when compar-
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group. As
ACS Catalysis
comparison, the free hemiacetal 1-
a
Noteworthy, treatment of 1-H with ethanol/acetaldehyde
mixture (6.0 and 10 equiv. respectively) at 193 K gave a
complex mixture of organometallic species that was grad-
ually evolves into 1-OEt as the main organometallic spe-
cies when raising the temperature from 193 to 300 K. This
observation is in line with the higher selectivity towards
ethyl acetate in the presence of ethanol (90%) with re-
spect to that without ethanol (60%). In addition, the
formation of hemiacetal derivatives was evidenced at low
temperature (243 K), according to the observation of
characteristic 13C chemical shift values at 90-95 ppm.46
ethoxyethanol tertiary carbon resonates at 102.9 ppm.46
The amino proton and nitrogen resonate at 4.67 and 48.5
ppm, respectively.47 To the best of our knowledge, the
direct observation of hemiacetaloxide complexes is ex-
tremely scarce. Bergen reported an analogous hemiaceta-
loxide complex by reaction of a dihydride Noyori-type
complex with lactone at low temperature.48 Gusev also
1
2
3
4
5
6
7
8
detected
related
ethoxyethanolate
and
[Ru(H)(OCH(CH3)(OEt))(CO)(PNN)]
9
[Ru(H)(OCH(CH3)(OEt))(CO)(SNS)] by ESI-MS.19
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Scheme 6. Aldehyde disproportionation pathways to ester mediated by 1-H.
These observations on the extremely efficient Tishchenko
conversion of aldehyde into ester bring new elements for
the refinement of our understanding of the ADC reaction.
From a mechanistic viewpoint, the ester product can be
formed at least via two distinct paths: formation of hemi-
efficiently catalyzed the acetaldehyde (450 equiv.) cou-
pling into ester in the presence of ethanol (210 equiv.) to
afford ethyl acetate with the same yield as 1-H (full con-
version and 90% selectivity within measurement time at
room temperature).
acetal from aldehyde and alcohol followed by “concerted”
It is important to note that the reaction outcome (selec-
tivity toward ester) depends on the presence of alcohol in
the medium. This could be related to the relative ratio of
various catalytically active Ru species. Under ethanol-free
conditions, 1-H likely reacts with acetaldehyde to form 1-
OEt, 1-OCHCH3OEt and 1-OCHCH2 and other unidenti-
fied Ru derivatives. As a result, the presence of the latter
species may be an origin to promote competitive undesir-
able reactions. On the other hand, when using the mix-
ture of ethanol/acetaldehyde, the above mentioned
scrambling of the Ru-OR species (resulting in etha-
naol/vinylalcohol exchange around the metal center) will
shift toward the formation of 1-OEt as the major organo-
metallic species (from in situ NMR studies). This leads to
the selective formation of ethyl acetate, as the pathway
affording aldol products is significantly hindered as the
ethoxide species take over. In order to illustrate the influ-
ence of alcohol/Ru alkoxides chemical exchange, we per-
formed the catalytic reaction from a mixture of n-
propanol (410 molar equiv.) and acetaldehyde (780 equiv.)
3,6,14
dehydrogenation involving the amido 2
or “stepwise”
Tishchenko-like disproportionation15,49 involving 1-OEt
and 1-OCHCH3OEt (Scheme 6), as recently proposed by
Gusev.23 In both hypotheses, the formation/regeneration
of the catalytic amido 2 (undetectable) or alkoxide 1-OEt
(detected) species from 1-H is assisted by acetaldehyde
acting as hydrogen-acceptor rather than by ethanol. This
is shown on the one hand by the fact that the reaction of
EtOH with 1-H is entropically unfavorable under closed
system and proceeds with very low rate at low tempera-
ture with respect to that of overall aldehyde coupling to
ester (see above). On the other hand, the reaction of 1-H
with acetaldehyde is very fast, leading to the full conver-
sion of the former even at very low temperature (193 K).50
The observation of 1-OEt but not of 2 as a major organo-
metallic species under catalytic and stoichiometric condi-
tions is in favor of the Tishchenko rather than of the con-
certed pathway (Scheme 6). This is further supported by
the fact that 1-OEt (generated in-situ from 2 and ethanol)
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Page 10 of 18
Scheme 8. Synthesis of 1-OAc.
at room temperature. This leads to a mixture of ethyl
1
2
3
4
5
6
7
8
acetate, propyl acetate, ethanol and propanol in relative
ratio of 1/1.5/2/1.6 within NMR measurement time. In-
deed, the formation of propyl acetate and ethanol can be
explained as following: 1-H reacts with acetaldehyde to
form 1-OEt that further undergoes a chemical exchange
with free propanol to form ethanol and 1-OnPr
([RuH(CO)(OCH2CH2CH3)NH(C2H4PiPr2)2)]). The latter
can react with acetaldehyde to produce propyl acetate.
Furthermore, the fact that no propionate esters were
detected indicates that the dehydrogenation of propanol
to propanal does not take place under these conditions.
This likely requires higher energy barrier when compared
to that for dehydrogenation of hemiacetal to ester. In
other terms, dehydrogenation of the hemiacetal into the
ester is very fast compared to dehydrogenation of the
alcohol into aldehyde.
1
The reaction course was monitored by H NMR spectros-
copy evidencing the production of ethyl acetate in very
selective manner. TON values vs. reaction times were
collected at 500 ppm [Ru] loading and at 90°C (reflux
conditions) and under neat conditions (Figure 4). Under
base-free conditions, the reaction reaches a plateau after
4 h that corresponds to a TON value of about 500. In
order to understand why the catalyst is no longer active,
the resulting catalytic mixture (after 11 h) was evaporated
to remove volatile compounds. NMR characterization of
the obtained residual solid indicates the presence of the
acetato complex [RuH(CO)(OAc)(NH(C2H4PiPr2)2)] (1-
OAc) as major organometallic species (90%). This com-
plex was independently prepared in good isolated yield
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(83%)
by
treatment
of
the
[RuH(CO)(Cl)(NH(C2H4PiPr2)2)] chloro derivative (1-Cl)
with silver acetate (1.2 equiv.) at room temperature
(Scheme 8). The reaction of 1-H or of amido 2 with excess
of acetic acid (~20 equiv.) also immediately afforded 1-
OAc in quantitative manner (with concomitant liberation
of H2 in the former case, as evidenced by a peak at 4.47
ppm on the 1H NMR spectrum) (Scheme 8).
Deactivation processes. After having investigated the
ADC reaction initiation and catalysis regimes, we pro-
ceeded to probe its deactivation mode(s). Ruthenium
dihydride complex 1-H was catalytically evaluated for
acceptorless dehydrogenative coupling reaction (ADC) of
ethanol in the presence of various additives (Scheme 7).
The solid state structure of 1-OAc was determined by
single crystal X-ray diffraction. The molecular structure
features a distorted octahedral geometry, similar to that
of [Ru(H)(HCOO)(CO)(NH(C2H4PR2)2)] reported by sev-
eral groups.24,51 The PNP tridentate ligand is coordinated
in meridional fashion. The terminal carbonyl ligand and
nitrogen atom are in mutually trans-configurations. The
acetato ligand is arranged in syn configuration with re-
spect to the N-H function and is accordingly located in
trans-position to the hydride (Figure 5). Noteworthy, the
intramolecular distance and the corresponding angle (N1-
H1···O3) of 1.987(2) Å and 158.03°(2), respectively are in-
dicative of a medium-strength hydrogen bonding interac-
tion involving (N-H···O=C(CH3)O[Ru]) atoms.52 IR spec-
trum shows an intense, characteristic band at 1902 cm-1
assigned to the terminal CO ligand. The IR stretching
C=O frequency of the carboxylate ligand is located at 1575
cm-1. In addition, N-H stretching band is observed at 3058
cm-1 that is shifted toward lower wavenumber of 114 cm-1
with respect to that of 1-H (3172 cm-1)6g, which is con-
sistent with intermolecular hydrogen bonding.
2000
EtONa (1.3 mol%)
MS 3A (7% w.t.)
1500
1000
500
t(h)
0
0
4
8
Scheme 7. ADC reaction of ethanol to ethyl acetate.
Figure 4. Ethanol ADC reaction catalyzed by 1-H in the pres-
ence of no additive, of sodium ethoxide and of 3A molecular
sieves (500 ppm, under reflux conditions, flow of argon).
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ACS Catalysis
within the same order of magnitude, of about 187 and 244
h-1.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Figure 6. ORTEP view of solid-state structure of 1-OH.
All H-atoms (except those on Ru and N) are omitted
for clarity. Selected bond distances (Å): Ru1-P1 =
2.3169(4), Ru1-P2 = 2.3209(4), Ru1-O2 = 2.2149(10), Ru1-
N1 = 2.1867(12), Ru1-C17 = 1.8286(15), Ru1-HB = 1.54(2),
O2-H2 = 0.767(15), N1-H1 = 0.842(18). Selected angles
(deg): P1-Ru1-P2 = 165.128(17), P1-Ru1-HB = 89.0(8), P2-
Ru1-HB = 87.4(8), O2-Ru1-P1 = 89.42(3), O2-Ru1-P2 =
90.81(3), O2-Ru1HB = 166.7(8), N1-Ru1-P1 = 82.10(3), N1-
Ru1-P2 = 83.39(4), N1-Ru1-O2 = 78.17(4), N1-Ru1-HB =
88.5(8), C17-Ru1-P1 = 97.44(5), C17-Ru1-P2 = 96.92(5),
C17-Ru1-O2 = 104.15(5), C17-Ru1-N1 = 177.64(6), C17-Ru1-
HB = 89.2(8).
Figure 5. ORTEP view of solid-state structure of 1-
16
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OAc. All H-atoms (except those on Ru and N) are
omitted for clarity. Selected bond distances (Å): Ru1-P2
= 2.3208(3), Ru1-P1 = 2.3256(3), Ru1-O2 = 2.2246(9),
Ru1-N1 = 2.1902(11), Ru1-C17 = 1.8321(13), Ru1-H =
1.535(18), N1-H1 = 0.881(17). Selected angles (deg): P2-
Ru1-P1 = 164.725(13). P2-Ru1-H = 90.2(6), P1-Ru1-H =
90.0(6), O2-Ru1-P2 = 91.42(3), O2-Ru1-P1 = 87.34(3),
O2-Ru1-H = 175.6(7), N1-Ru1-P2 = 82.13(3), N1-Ru1-P1 =
82.66(3), N1-Ru1-O2 = 90.49(4), N1-Ru1-H = 85.7(7),
C17-Ru1-P2 = 96.91(4), C17-Ru1-P1 = 98.34(4), C17-Ru1-
O2 = 98.17(5), C17-Ru1-N1 = 171.32(5), C17-Ru1-H =
85.7(7).
We have previously reported that 2 (and 1-H to a lesser
extent) react readily with excess water to afford the hy-
droxide species [Ru(H)(CO)(OH)(NH(C2H4PiPr2)2)] (1-
OH).42 Attempts at isolating 1-OH were not successful, as
reverse reaction occurred upon drying, affording amido
species 2.42 Fortunately, single crystals suitable for X-ray
characterization were grown into water/toluene/n-
pentane mixture at low temperature. The molecular
structure displays a distorted octahedral geometry, simi-
1
On the H NMR spectrum, the Ru hydride resonates as a
triplet centered at -17.98 ppm (JHP = 18 Hz). The NH pro-
ton signal is unusually located downfield at 9.24 ppm.6g
This is consistent with the retention of the hydrogen
bond (N-H···O) in solution that increases the NH proton
acidity. 31P NMR displays a singlet at 76.6 ppm while
HSQC {15N-1H} NMR sequence allows determining the
chemical shift of 15N at 41 ppm. In addition, two signals
observed at 181.4 and 207.0 ppm on the 13C NMR spectrum
are assigned to the acetato and terminal carbonyl ligands,
respectively.
lar
to
that
of
[Ru(H)(OH))(CO)((NC5H3)(CH2NH2)(CH2PtBu2))] report-
ed by Milstein et al.55 The hydroxo ligand is arranged in
syn-configuration with respect to the N-H function and is
located in trans-position to the hydride moiety (Figure 6).
The Ru-O2 bond length (2.2149(10) Å) is comparable to
that of the Milstein complex55 (2.261(2) Å) and of related
compounds.56
Complex 1-OAc was further evaluated for ADC reaction of
ethanol and no catalytic activity was observed. Indeed,
the generation of the catalytically inactive 1-OAc species
during the ADC reaction accounts for the fact that the
reaction does not proceed further after about 4 h. On the
other hand, the isolation of analogous carboxylato com-
plexes has been reported during the acceptorless oxida-
In the presence of an ethanol/water mixture (10 equiv.
total, ethanol/water ratio 6/≤1) in d8-toluene at 260K, 1-H
affords the hydroxide 1-OH and the ethoxide 1-OEt (90 %
conversion) initially in respective ratio of about ~1/4.4.
This ratio is inconsistent with the water/ethanol ratio
employed (≤1/6). This can be reasonably explained by the
weaker pKa value of water that leads to the hydroxylation
operating with higher rate than the competitive alkoxyla-
tion. The 1H NMR spectrum at 260 K features the hydride
tion of alcohols with water to carboxylic acid salts.42,53,
54
We therefore suspected the presence of water traces in
the reaction medium as a cause for catalysts deactivation.
This hypothesis was supported by comparing the catalytic
activity profiles of dihydride 1-H in the presence of 3A
molecular sieves (as water scavengers) and without any
additive (Figure 4). Indeed, in the presence of molecular
sieves (7 %wt.), reaction proceeds up to 76% conversion
in 9 h (1520 TON), whereas in the absence of additive,
conversion reaches a plateau at about 22%. It is worth
noting that the respective initial reaction rates TOF0 are
signal for 1-OH as a triplet centered at -17.32 ppm (2JHP
=
18 Hz)42 that is located at slightly lower field in compari-
son with that of 1-OEt (Δδ = 0.5 ppm). Notably, the posi-
tive cross-peak between 1-OH and 1-OEt observed in the
1
hydride region of the H-1H 2D NOESY NMR spectrum is
indicative of their mutual chemical exchange that is likely
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promoted by ethanol or/and water excess. In line with Considering that most of the reported ADC systems in-
1
2
3
4
5
6
7
8
this observation, raising the temperature induced the
chemical exchange being operative with higher rate: the
coalescence temperature was found at Tc = 300 K (See
SI7.5). Such interconversion was recently reported for
related manganese systems.57
volve addition of an alkali metal alkoxide base to trigger
activity (for instance starting from chloride precursors) or
even to enforce higher activity, we re-investigated the role
of this type of additive in these systems.6a In the presence
of EtONa (1.3 mol%), the ethanol ADC reactivity profile
recorded over time is very similar to that obtained in the
presence of molecular sieves, reaching 88% conversion
within 9 h, without significant catalyst deactivation (Fig-
ure 4). The initial TOF0 value of 220 h-1 is also close to that
of additive-free case (187 h-1). Interestingly, a small quan-
tity of insoluble white material was isolated and identified
as sodium acetate. Apparently, during the reaction
course, the sodium ethanolate allows maintaining the
catalyst under active form (1-H or 2), along with the gen-
eration of acetate salt as a side-product. In order to inves-
tigate the role of the base as a catalyst re-activator, we
probed the reactivity of 1-OAc with tBuOK (3 molar
equiv.) in C6D6. The reaction proceeds smoothly and effi-
ciently, forming the amido derivative 2. Under similar
conditions, treatment of EtONa with 1-OAc in C6D6 over-
night does not result in any change, which is due to the
very low solubility of the metal alkoxide. Further addition
of about 2.8 molar equiv. of ethanol triggers the reaction,
affording a mixture of dihydride 1-H (53%) and ethoxide
1-OEt (37%), along with residual unreacted starting mate-
rial 1-OAc (10%). This is accompanied with the formation
of ethyl acetate after 14 h. These observations confirm
that alkoxide additives reactivate the catalytic system by
forming the organometallic species 1-H, 1-OEt and 2 rele-
vant to the catalytic cycle. This is further illustrated by
comparing the catalytic activity of 1-OAc in the presence
of NaOEt and without any additive. Whereas 1-OAc is
catalytically inactive, it develops catalytic activity in the
presence of the alkoxide additive, though with a slightly
lower initial rate than with dihydride 1-H.
In parallel, the amount of the acetate complex 1-OAc
increased. At a temperature as high as 353 K and after 1 h
30, 1-OH/1-OEt majoritarily converted to 1-OAc, with
formation of ethyl acetate. Likely, 1-OAc was formed from
reaction of 1-OH with intermediate aldehyde.58 Indeed,
successive addition of water (~ 10 equiv.) and acetalde-
hyde (~110 equiv.) to the solution of 1-H at RT immediate-
ly afforded 1-OAc as the sole Ru species (along with ca.
0.25 equiv. of ethyl acetate and 0.5 equiv. of ethanol, inter
alia). This contrast with isoelectronic manganese PNP
complex, where this reaction is unselective.59 In addition,
performing the reaction of 1-H with wet acetaldehyde (3
equiv., ~4% water content) resulted in the formation of 1-
OAc, 1-OEt and 1-H (in respective ratio of ~1/1/7) and
ethyl acetate and ethanol (in relative ratio of 1.3/1, acetal-
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dehyde being fully converted). The reaction of 1-H with
37,60
water is slow
while the reactions of 1-H with acetal-
dehyde to form 1-OEt and of 1-OH with acetaldehyde to
form 1-OAc are comparably very fast. The formation of
ethanol can be then reasonably explained by the reaction
of the ethoxide 1-OEt with water (Scheme 9). Morris
reported a similar reaction for a related Ru-carbene NCN
complex.61
The impact of oxygen on the catalyst deactivation was
also examined. Heating an ethanolic solution of 1-H (~50
equiv. of EtOH) under dry air at 70°C for 2 h induced
formation of 1-OEt (85%) and 1-OAc (10%) (with 5% re-
sidual 1-H). After 6 h, the amount of 1-OAc increased up
to 75%. Noteworthy, no formation of phosphine oxides
(from comparison to authentic sample of oxidized PNP
ligand) was detected, which is consistent with the high
robustness of pincer PNP-metal bonds. Furthermore, we
also investigated halide poisoning, as it was primarily
observed by Beller et al. for Fe-catalyzed ester reduction
in the presence of LiCl with no reported rationalization.21a
We also observed the negative effect of KBr on the Mn-
catalyzed ADC reactions.13 In the present case, addition of
NaCl to the solution of 2 and in presence of water leads to
the formation of catalytically inactive 1-Cl.
Scheme 9. Reaction of 1-H with wet acetaldehyde.
Regarding mechanistic implications, this deactivation
pathway enters into play as water competes with alcohol
into a productive catalytic cycle. Whatever the mecha-
nism (concerted or Tishchenko), formation of
CH3CH(OH)(OR) (R= H for water and R= Et for ethanol)
proceeds in fine with generation of acetic acid or
ethylacetate, the former leading to inactive 1-OAc while
the latter does not interrupt the productive catalytic cycle
(See proposed mechanism in SI 8.3). In addition, Ru ace-
tate species is proposed as main catalytic intermediate for
acceptorless dehydrogenative alcohol oxidation in basic
water to carboxylic acid salt.42,53,54,58
General comments. Under catalytic ADC conditions,
the formation of aldehyde as intermediate species was
unambiguously evidenced by in-situ IR spectroscopy.
Furthermore, the aldehyde can be formed in selective
manner by performing the dehydrogenation reaction
under much diluted conditions and by using a sacrificial
hydrogen acceptor (acetone) and at comparably lower
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cies barely detectable.19 Regarding 1-OEt, this compound
temperature.54 From a mechanistic viewpoint, in the liter-
is not a dead-end21b for the catalytic cycle related to alde-
hyde production (regardless of the mechanistic pathway),
as it is involved in the chemical exchange process with
free EtOH via amido and/or ion-pair intermediate deriva-
tives that can be viewed as preliminary steps for alcohol
dehydrogenation into aldehyde (Schemes S6 and S29 in
SI). Thus, for the first part of the ADC reaction, it is not
possible to completely rule out one mechanism over the
other, though the amido species (involved in the concert-
ed mechanism) is not detected under catalytically rele-
vant conditions. This may plead in favor of a stepwise
pathway.
1
2
3
4
5
6
7
8
ature, aldehyde has been proposed to be formed either via
a classical concerted mechanism6 (Schemes 2a) involving
amido hydride complex 2 or via a stepwise mechanism
(Schemes 2b and S29) involving highly-energy ion-pair
intermediates with retention of N-H bond.22,23 Our exper-
imental studies show that the amido species 2 is spectro-
scopically only observable when the alcohol substrate has
been fully consumed. The presence of excess of alcohol
exclusively induced the formation of the kinetic and
thermodynamic product alkoxide 1-OEt.13,23a This indi-
cates a very short lifetime of 2 in an alcohol-rich medium
(such as under catalytic conditions) that makes this spe-
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Scheme 10. Identified Ru complexes and their interconversion under stoichiometric conditions.
For the second part of the catalytic cycle that consists of
the production of ester from aldehyde, both concerted
and Tishchenko-like mechanisms involving 2 and 1-OEt
as catalytic species, respectively, were postulated.11c,23
Regarding experimental evidences, after having detected
acetaldehyde in the catalytic mixture, we have shown that
the direct conversion of the aldehyde into the ester can be
mediated by either 1-H or 1-OEt. The coupling reaction
proceeds with very high rate (even at low temperature)
with respect to the aldehyde formation step. This is indic-
ative of a higher energy barrier required for the latter.11c,35
Under catalytic conditions (80 °C, 500 ppm [1-H], Figure
3b), the build-up of acetaldehyde (after 4 h), as observed
by in-situ IR spectroscopy, may be related to temperature
dependence of reaction rate for each step within the cata-
lytic cycle. However, when monitoring the ADC reaction
by NMR spectroscopy, aldehyde intermediate was barely
detected (usually accounting for less than 1.0%6g,13). This
is due to the fact that samples were measured at room
temperature, thus under conditions at which the alde-
hyde consuming reactions including Tishchenko reaction
and hydrogenation (with dissolved hydrogen in the reac-
tion medium) are very fast.62 Regarding the organometal-
lic fragments identified in this context, both ethoxide 1-
OEt and hemiacetaloxide 1-OCH(CH3)(OEt) ruthenium
species were intercepted under Tishchenko reaction con-
ditions. These elements are in favor of the Tishchenko
mechanism being most plausible at this stage.
The last step of the catalytic cycle consists of the regener-
ation of active species 2 (not detected) for the concerted
mechanism and/or 1-OEt (observed) for the stepwise
mechanism (Tishchenko reaction) from 1-H, along with
H2 release. While the straightforward H2 release from 1-H
is very slow in the absence of EtOH and under heating
conditions, this takes place with higher rate in the pres-
ence of the alcohol. The latter plays as a proton transfer
shuttle that promotes the H2 elimination by lowering the
energy barrier compared to the straightforward H2 release
path.11c,35 The beneficial effect of an alcohol proton shuttle
on the proton transfer has also been demonstrated by
DFT calculations in the reverse H2 activation process.21b,50
Catalyst deactivation must be addressed when consider-
ing further process development. Contaminants within
the substrate63 like carboxylic acids, water, peroxide de-
rivatives, oxygen and halides (the latter being present in
commercial pre-catalysts, as observed by us on some
occasions) poison the Ru catalyst by forming catalytically
inactive 1-OAc and 1-Cl species in the latter case. While
the presence of carboxylic acid (stoichiometric equiv.
relative to [Ru]) immediately deactivates the catalytic
system, water as well as oxygen more slowly afford 1-OAc
(either by reacting with aldehyde or with Ru-based inter-
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Page 14 of 18
mediates), resulting in progressive catalyst deactivation. er than those of ADC, and involve alkoxide and (NMR
1
2
3
4
The origin of water in the reaction medium can be very
diverse. This may come from alcohol substrates that
would be non-properly dried prior use. In some specific
cases, formation of water could stem from dehydrative
characterized) hemiacetaloxide Ru species. Thus, in the
case of the second phase of the ester production, we sug-
gest that a Tishchenko-like reaction is operative, involv-
ing reaction of aldehyde with an alkoxide ruthenium
species.
side-reactions,64
such
as
aldol
condensa-
5
6
7
8
9
tion/crotonization,45 and acetalization.65 However, under
our conditions, the respective alkene/ether, aldol and
acetal co-products were formed probably in very small
amounts, being barely detectable. The in situ NMR obser-
vation of the enolate 1-OCHCH2 (when reacting 1-H with
acetaldehyde) is in line with the hypothesis that water
form via aldol condensation.38,45 This agrees with the
NMR detection during Tishchenko reactions of catalyti-
cally inactive carboxylate species that derive from aldol
condensation. This relates to earlier reports on rapid
catalyst deactivation under base-free conditions observed
by Beller6a and Gusev6d during alcohol ADC or ester hy-
drogenation in the presence of large excess of aldehyde.66
Accordingly, we have also demonstrated that addition of
an alkoxide-type base allows maintaining or restoring
catalytic activity. This was rationalized by generation of
either 1-H/1-OEt or 2 from the carboxylate deactivation
species, affording a re-entry into the catalytic cycle.6d
Finally, the main catalyst deactivation pathway under
base-free conditions was found to be related to water.
This leads to the formation of catalytically inactive car-
boxylato Ru complexes, resulting from reaction between
(structurally characterized) hydroxide species and acetal-
dehyde. In line with this observation, running the ADC
reaction in presence of water scavengers like molecular
sieves or alkali metal alkoxides allows inhibiting the cata-
lyst deactivation. The same deactivation species also
forms in the presence of oxygen. Interestingly, catalytic
system reactivation is thus possible thanks to reaction
with an alkoxide reagent which allows formation of cata-
lytically-active species.
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This contribution underlines the complexity of the reac-
tion manifolds involved in this seemingly simple catalytic
transformation, and provides elements to better under-
stand hydrogen-borrowing reactions, as well as the corre-
sponding reverse reactions (namely, hydrogenation, as all
elementary steps are reversible) that currently attract
CONCLUSION
considerable interest. 3,
67
In conclusion, the mechanism of base-free ADC reaction
of alcohols into esters catalyzed by Ru-aliphatic pincer
PHNP complexes was studied in detail. In-situ IR spec-
troscopy monitoring confirmed the production of ester
via aldehyde as intermediate species. Relevant Ru-based
intermediates species involved into the catalytic cycle
were identified by multinuclear NMR, and in some in-
stance isolated and structurally characterized by single
crystal X-ray diffraction studies. Their reactivity was
probed, unveiling information on catalytic steps (Scheme
10). Under the studied experimental conditions, both
dihydride 1-H and alkoxide 1-OEt complexes are formed
as predominant organometallic species and their relative
ratio is related to various parameters including tempera-
ture, reaction times and alcohol concentrations. The 16e-
amido hydride complex 2 is spectroscopically only ob-
served when alcohol has been fully consumed. Most par-
ticularly, VT NMR studies evidenced chemical exchanges
involving the alcohol substrate, that can be viewed as
preliminary steps for alcohol dehydrogenation into alde-
hyde. Thus, regarding the first step of the ADC of alco-
hols, though no clearcut evidence emerges, a stepwise
mechanism appears as more plausible than a concerted
one with 1-OEt behaving as an off-catalytic cycle species.
AUTHOR INFORMATION
Corresponding Author
* E-mail: regis.gauvin@ensc-lille.fr, duc-hanh.nguyen@ensc-
lille.fr.
ASSOCIATED CONTENT
Experimental methods, synthetic details, additional spectro-
scopic data and catalytic procedures. The Supporting Infor-
mation is available free of charge on the ACS Publications
website at DOI: xxxxx.
ACKNOWLEDGMENT
This article is dedicated to Prof. Philippe Kalck on the occa-
sion of his 74th birthday. This work was performed in part-
nership with the SAS PIVERT, within the frame of Institut
pour la Transition Energétique P.I.V.E.R.T. (www.institut-
pivert.com) selected as an Investment for the Future (“Inves-
tissements d’Avenir”). This work was supported, as part of
the Investments for the Future, by the French Government
under the reference ANR-001-01. Chevreul Institute (FR
2638), Ministère de l’Enseignement Supérieur et de la Re-
cherche, Région Nord – Pas de Calais and FEDER are
acknowledged for supporting and funding partially this work.
We thank Dr. G. Raffa for preliminary experiments and for
fruitful discussions.
We have also shown that the same catalysts which per-
form the ADC reaction are highly active in Tishchenko-
like reaction, affording ester from aldehyde. Importantly,
the reaction conditions in this case are significantly mild-
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(38) Ethyl 3-hydroxybutyate was further partially characterized
1
Based on the H-31P HSQC NMR spectrum, it seems to be that
1
1
by H NMR (Selected H NMR data: 4.09 (m, 1H, >CH-OH), AB
system 2.32 (dd, 1H, >CHCH2, JHH = 7.8, 15.4 Hz) and 2.19 (dd, 1H,
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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 alde-
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(40) When performing the reaction at 243 K ([ethanol]/[1-H] ≈
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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 H-13C HSQC NMR
1
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centered at -12.33 ppm (JHP = 20 Hz) while the phosphorous
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= 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
1H 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
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