Bis-N-heterocyclic Carbene Aminopincer Ligands Enable High Activity in Ru-Catalyzed Ester Hydrogenation

Article abstract of DOI:10.1021/jacs.5b04237

Bis-N-heterocyclic carbene (NHC) aminopincer ligands were successfully applied for the first time in the catalytic hydrogenation of esters. We have isolated and characterized a well-defined catalyst precursor as a dimeric [Ru₂(L)₂Cl₃]PF₆ complex and studied its reactivity and catalytic performance. Remarkable initial activities up to 283 000 h^-1 were achieved in the hydrogenation of ethyl hexanoate at only 12.5 ppm Ru loading. A wide range of aliphatic and aromatic esters can be converted with this catalyst to corresponding alcohols in near quantitative yields. The described synthetic protocol makes use of air-stable reagents available in multigram quantities, rendering the bis-NHC ligands an attractive alternative to the conventional phosphine-based systems.

Full text of DOI:10.1021/jacs.5b04237

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Communication
Bis-N-heterocyclic carbene aminopincer ligands enable
high activity in Ru-catalyzed ester hydrogenation
Georgy A. Filonenko, Mae Joanne B. Aguila, Erik N. Schulpen, Robbert van Putten,
Jelena Wiecko, Christian Mueller, Laurent Lefort, Emiel J. M. Hensen, and Evgeny A Pidko
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 08 Jun 2015
Downloaded from http://pubs.acs.org on June 8, 2015
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Bis-N-heterocyclic carbene aminopincer ligands enable high activity
in Ru-catalyzed ester hydrogenation
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Georgy A. Filonenko,a,b Mae Joanne B. Aguila,c Erik N. Schulpen,a Robbert van Putten,a Jelena Wiecko,d Chris-
tian Müller,d Laurent Lefort,c Emiel J. M. Hensen,a,b and Evgeny A. Pidkoa,b,*
a Inorganic Materials Chemistry group, Schuit Institute of Catalysis and b Institute for Complex Molecular Systems, Eindhoven Uni-
versity of Technology, P.O. Box 513, 5600 MB Eindhoven, The Netherlands.
c DSM Innovative Synthesis BV, P.O. Box 18, 6160 MD Geleen, The Netherlands
d Freie Universität Berlin, Institut für Chemie und Biochemie, Fabeckstraße 34-36, D-14195 Berlin, Germany
Supporting Information Placeholder
productivity (TOF) and stability (TON). These Ru-PNNX (X=P,N)
catalysts are efficient at very low Ru loadings of 10-100 ppm with
respect to the ester substrate. For example, TON up to 80 000 and
estimated TOF of >10 000 h-1 are obtained with Zhang’s Ru-PNNP
catalyst (D, Scheme 1) at 80°C and 50 bar H2.
ABSTRACT: Bis-N-heterocyclic carbene (NHC) aminopincer lig-
ands were for the first time successfully applied in catalytic hydrogena-
tion of esters. We have isolated and characterized a well-defined cata-
lyst precursor as a dimeric [Ru2(L)2Cl3]PF6 complex and studied its
reactivity and catalytic performance. Remarkable initial activities up to
283 000 h-1 were achieved in hydrogenation of ethyl hexanoate at only
12.5 ppm Ru loading. A wide range of aliphatic and aromatic esters can
be converted with this catalyst to corresponding alcohols in near quan-
titative yields. The described synthetic protocol makes use of air stable
reagents available in multigram quantities rendering the bis-NHC
ligands an attractive alternative to the conventional phosphine-based
systems.
Scheme 1. Selected examples of active catalysts for ester hydro-
genation
The reduction of organic compounds with molecular hydrogen is a
powerful synthetic tool. A key factor for putting this reaction in prac-
tice is the availability of a potent catalyst that drives the hydrogenation
reaction. One of the reactions where the active catalyst is much desired
is the reduction of carboxylic acid esters to alcohols. It currently relies
on the conventional approaches utilizing stoichiometric amounts of
inorganic hydrides and producing vast amounts of wastes. Therefore,
the catalytic reduction of esters with H2 is viewed as a green alternative
for conventional reduction protocols. The early examples of such
catalytic processes1 required very harsh reactions conditions (ca. 85 bar
H2, T >100°C). Tremendous progress in the field was made by the
groups at Firmenich,2 Takasago3 and the group of Milstein,4 who
described several bifunctional ester hydrogenation catalysts that oper-
ated under significantly milder conditions. Following these reports, the
field of ester hydrogenation witnessed a rapid development with cata-
lyst performances steadily improving. Progress was mainly associated
with the introduction of tri- and tetradentate aminopincer ligands.1c, 5
Recently, Gusev and co-workers6 reported a family of Ru and Os-PNN
pyridine aminophosphine pincer catalysts, with which turnover num-
bers (TONs) of ca. 18 000 were reached in hydrogenation of methyl
benzoate at 100°C and 50 bar H2 pressure (Scheme 1, A). The same
group also disclosed an Ru-SNS pincer complex producing ca. 60 000
turnovers in ethyl acetate hydrogenation at only 40°C and 50 bar H2
(Scheme 1, B).7 Recent reports by the groups of Zhou8 and Zhang9
feature tetradentate phosphine-based Ru catalysts (Scheme 1, C and
D), which are currently the most active catalysts in terms of the
With the exception of Ru-SNS (Scheme 1, B), the most potent ester
hydrogenation catalysts rely on phosphine ligands that are prepared
from often expensive and air- or moisture-sensitive organophosphorus
reagents. On the contrary, N-heterocyclic carbene ligands (NHCs) are
air-stable and can be prepared from abundant building blocks.10 Ru-
NHC complexes have already found widespread catalytic application,
for example in metathesis reactions11 and various hydrogenation pro-
cesses.12 However, their application in the catalytic hydrogenation of
esters is scarce and the performance of the Ru-NHCs13 is still inferior
to that of the phosphine-based catalysts. In this work we demonstrate
that the use of bis-NHC aminopincer ligands for Ru-catalyzed hydro-
genation of esters can lead to remarkable activity that rivals the one of
the phosphine-based catalysts.
Bis-NHC aminopincer ligand precursors14 are readily prepared via a
simple reaction of the corresponding imidazoles with nitrogen mustard
derivatives (Scheme 2). While the ligand L1H is prepared in a one-step
reaction, the synthesis of other ligands (L2H-L5H) requires a three-
step procedure that involves the protection/deprotection of the amine
site with the benzyl group to avoid the degradation of 1. Following
these methods we obtained a ligand library containing 10 bis-NHC
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ligands with different substituents at the amine site and imidazolium
ring.
reacting the imidazolium salt L1H with Ag2O in the presence of NaOH
in a biphasic CH2Cl2/H2O medium, complex 3 is generated within 2
hours in 82% yield without exclusion of air.
Scheme 2. Structure and synthesis of bis-NHC aminopincer lig-
ands.
Table 1. Results of the ligand screening in hydrogenation of ethyl
hexanoate and ethyl benzoate.
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Entry
1
Ligand
L1Bn
L2Bn
L4Bn
Ester R1
n-C5H11
S/Ru
Yalc , %
0
TON
0
2
15000
0
0
3
0
0
4
n-C5H11
Ph
15000
5000
95
83
1
14250
4150
150
0
L1H
L2H
L3H
L4H
L5H
5
6
n-C5H11
Ph
15000
5000
Mes = 2,4,6-trimethylphenyl; Dipp = 2,6-diisopropylphenyl.
7
0
Initially, we performed hydrogenation of ethyl hexanoate and ethyl
benzoate at 70°C and 50 bar H2 pressure using Ru catalysts with differ-
ent bis-NHC ligands to identify the most competent one. The catalysts
were generated in situ by treating a suspension of the imidazolium salts
in THF with LiHMDS (lithium hexamethyldisilazide) followed by the
addition of the metal precursor – Ru(PPh3)4Cl2. The use of a strong
base was necessary to ensure the deprotonation of the imidazolium
ligand precursors and the formation of the free NHCs capable of coor-
dination.14a The results of the catalytic tests are summarized in Table 1.
8
n-C5H11
Ph
15000
5000
100
65
40
50
2
15000
3250
6000
2500
300
1850
9
10
11
12
13
n-C5H11
Ph
15000
5000
n-C5H11
Ph
15000
5000
The structure of the ligand had a strong influence on the activity of
in situ generated Ru catalysts (Table 1). In line with the observations
made by Gusev and co-workers,7 substitution, i.e. benzylation, at the
NH site of the ligand yields inactive catalysts (Entries 1-3, Table 1).
The substituents at the NHC groups were also found to have an impact
on the performance. The best catalysts were formed form mesityl-
(L1H, entries 4-5) and diisopropylphenyl (L3H, entries 8-9) substitut-
ed ligands. The remaining ligands with meta and para substituted
phenyl groups (L4H and L5H) or methyl substituents (L2H) on the
imidazolium rings resulted in no to moderate activity. The inferior
performance of L2H, L4H and L5H may be explained by the lower
stability of free-NHCs derived from these ligands with reduced bulk
around the carbene center.10a Alternatively, one can expect a reactivity
of L4H and L5H towards cyclometallation by Ru that is notorious for
its negative impact on the activity in metathesis reaction.15 The type of
the ruthenium precursor employed for the in situ catalysis also had an
impact on the catalytic performance with RuHCl(CO)(PPh3)3 being
significantly less active that the Ru(PPh3)4Cl2 discussed above (see
Table S1 in Supporting Information).
37
Conditions: 5 mmol ester, 2%mol KOtBu, 2 mL THF, 70°C, 50 bar H2,
16 h, S/Ru – Substrate-to-Ruthenium molar ratio
The NHC transfer from 3 to Ru(PPh3)4Cl2 at 70°C in dichloro-
methane led to a single new Ru complex. The electrospray ionization
mass spectrometry (ESI-MS) shows a signal at 1193 a.m.u. corre-
sponding to the dimeric [Ru2(L1H)2Cl3]+ species 4+. The use of the
phosphine containing Ru(PPh3)4Cl2 precursor is undesired since it
leads to the formation of Ag(PPh3)n byproducts that could not be
separated from the target compound.17 Therefore, the preparation and
isolation of 4+ was further attempted using an air stable phosphine-free
precursor Ru(DMSO)4Cl2 instead.
Scheme 3. Synthesis of 4*PF6.
Inspired by the promising performance of precatalysts formed form
L1H/Ru(PPh3)4Cl2, we sought to isolate the corresponding well-
defined Ru-CNC complex. Because the reaction of the free NHCs
derived from L1H with Ru(PPh3)4Cl2 led to complex mixtures, we
employed an alternative synthetic strategy involving a transmetallation
from the Ag-NHC complex with L1H to the ruthenium centre
(Scheme 3). The corresponding Ag-NHC complex 3 (Scheme 3) was
previously reported by Edworthy et al.14b The original procedure in-
volved the reaction of L1H with Ag2O in dry CH2Cl2 in the presence of
molecular sieves (4Å) over several days. We have greatly simplified the
preparation of 3 using the approach originally described for preparing
Ag benzimidazol-2-ylidene complexes by Lin and co-workers.16 By
Much to our satisfaction, the reaction of Ru(DMSO)4Cl2 with 3 in
CH2Cl2 or THF yields the same cationic 4+ as evidenced by NMR and
ESI-MS. Initially 4+ was obtained as a cationic dimer [Ru2(L1H)2Cl3]+
with a dibromoargenate [AgBr2]- counterion that could be observed in
the negative mode ESI-MS. To avoid the potential light sensitivity
induced by the dibromoargenate anion, the crude product was further
treated with excess KPF6 to obtain the analytically pure complex 4*PF6
as a crystalline solid (Scheme 3).
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urements (double pulsed field gradient spin echo NOESY). Using this
approach one can also reveal the broad resonance of NH proton at δ ca.
6
3 ppm that otherwise overlaps with other resonances in the spectrum.
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The X-ray crystal structure analysis of 4*PF6 reveals the bis trigonal
antiprism geometry of the complex. Two ligand units occupy the
opposite faces of the octahedrally coordinated Ru, which is consistent
with their apparent equivalence in solution as follows from 1H NMR
spectroscopy. The formation of L2Ru2(μ-Cl)3 units is well known for
ruthenium complexes with tridentate ligands that prefer facial coordi-
nation, e.g. TriPhos.18
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Complex 4*PF6 is an active ester hydrogenation catalyst. Under 50
bar H2 pressure at 70°C, it can convert a wide range of aliphatic and
aromatic esters to their corresponding alcohols in quantitative yields
(Scheme 4). Full conversions of hexanoic acid esters were obtained at
substrate-to-ruthenium (S/Ru) ratio of 10 000. Aromatic esters includ-
ing rather challenging phthalide and benzyl benzoate substrates can
also be fully converted at S/Ru = 2 500-4 000. A very high TON of
79 680 was obtained with ethyl hexanoate, which is nearly identical to
the value reported by Zhang et al. for hydrogenation of ethyl acetate at
a slightly higher temperature and a longer reaction time (80°C, 50 bar
H2, 30 h) with the tetradentate Ru-PNNP catalyst.9 Diethylsuccinate
and γ-butyrolactone are readily converted to 1,4-butanediol in quanti-
tative yields at S/Ru=10 000-15 000. Hydrogenation of dimethyl
itaconate was fully chemoselective for the reduction of C=C bond and
yielded no alcohol product. Finally, the hydrogenation of methyl cin-
namate yields a mixture of the saturated and the unsaturated alcohol
with up to 70% of cinnamyl alcohol indicating that our hydrogenation
catalyst exhibits a certain selectivity favoring the ester group reduction.
Apart from esters, 4*PF6 is also active in hydrogenating aldehydes and
ketones to corresponding alcohols. This reaction is more facile then the
ester reduction and proceeds readily at room temperature (See Section
3 of the Supporting Information).
Figure 1. Molecular structure of 4*PF6 in the crystal. Displacement
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ellipsoid are shown at the 50% probability level. All hydrogens except
NH group are omitted for clarity. Selected bond lengths [Å]: Ru1-C3
1.969, Ru1-C17 1.987, Ru1-N1 2.145, Ru2-N6 2.160, Ru2-C31 1.973,
Ru2-C45 1.988.
a
Scheme 4. Results of ester hydrogenation with 4*PF6 (Substrate-
to-Ru ratio and alcohol yieldsb).
O
C2H5
O
4*PF6
O
R2
R -CH OH
+ R2-OH
1 2
R1
O
40 000; 100 %
80 000; 96.6 %
4 000; 36.9% (20°C)c
THF, 50 bar H2
S/Ru; Yield
°
16h, 70 C
O
O
O
O
O
O
O
O
O
O
15 000; 100 %
4 000; 99.4 %
10 000; 100 % 2 500; 99.5 %
10 000; 93.7 %
O
O
O
O
O
O
O
C3H7
O
10 000; 100 %
O
O
Cl
4 000; 100 %
O
4 000; 99.8 %
4 000; 100 %
O
O
O
O
Ph
C6H13
O
O
10 000; 100 %
4 000; 100 %
10 000; 100 % 15 000; 100 %
Chemoselectivity:
O
10 %
C=O&C=C
0 %
MeOOC
COOMe
O
71.6 %
C=O only
C=C only
0 %
0 %
100 %
2 500
2 500
aConditions: 5 mmol ester, 2 ml THF, 70°C, 50 bar H2, 2%mol KOtBu,
16 h; b Yields are given for alcohols derived from the acyl group of the
c
ester, lactone and diester reduction provided diol products; Reaction
at 20°C: 38/62 % selectivity to hexanol/hexyl hexanoate at 97% con-
version
The two CNC ligand units in 4*PF6 appear equivalent in the 1H
NMR spectrum (see Figure S2 in the Supporting Information). How-
ever, the symmetry within the CNC ligand itself is not retained upon
the complexation. The imidazole backbone protons appear as four
Figure 2. ESI-MS spectra of the reaction mixture of NMR scale ethyl
acetate hydrogenation (3 bar H2, THF-d8, ca. 10 eq. KOtBu per Ru,
S/Ru = 500): untreated (a) and quenched with HCOOH (b);
S = CH3CN
3
separate doublets with JHH = 2Hz and aromatic protons of the mesityl
Aiming at getting an insight into the nature of the catalytically active
species, we further investigated the transformations of the precatalyst
4*PF6 during the hydrogenation of ethyl acetate using NMR spectros-
copy combined with ESI-MS. The reaction was carried out in an NMR
substituents give four singlets. In addition, eight ethylene linker pro-
tons appear separately, which indicates that geminal protons within the
CH2 groups of the linkers are not equivalent. The accurate assignment
of these resonances can be done using selective excitation NMR meas-
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tube at 3 bar H2 in THF-d8 in the presence of KOtBu base (ca. 10 eq.
nary studies, the active state of the catalyst is a monometallic species.
4
5
6
7
8
9
per Ru). No notable color change occurred upon the addition of the
catalyst to reaction mixture. Interestingly, although ca. 25 % conversion
of ethyl acetate was reached already at room temperature, no products
of the transformations of the initial dimeric complex could be observed
within the detection limit of NMR (see Figure S8 in Supporting Infor-
mation). Heating of the reaction mixture to 70°C led to further conver-
sion of ethylacetate to 61 %19 accompanied by the partial transfor-
mation of the initial Ru complex to a new species. Mass spectrometry
allows for identifying the newly formed species as the monomeric Ru
complex bearing 1-ethoxyethanolate ligand (I-1, Figure 2a) that is
similar to the intermediates observed earlier by Gusev20 and Bergens21
for related reactions. Species I-1 rapidly disappears when the reaction
mixture is quenched with 0.1% HCOOH in acetonitrile, producing a
monomeric Ru-formate complex I-2 (Figure 2b). This is consistent
with I-1 containing the alkoxide ligand that is rapidly protonated in the
presence of the acid. A Ru carbonyl complex I-3 was also observed in
the catalytic mixture. The carbonylation of metal centre was previously
proposed to be the main source of catalyst deactivation.2,3 The inter-
mediate formation of the aldehyde product during ester hydrogenation
may be responsible for the carbonylation of the metal centre. Indeed,
the formation of benzaldehyde could be observed during the methyl
benzoate hydrogenation with 4*PF6 (See Table S2 in the Supporting
Information). Although these results do not constitute a definite proof
for the nature of the active catalyst, they suggest that the dimeric struc-
ture of the initial Ru complex is not retained under the catalytic condi-
tions and that the Ru species formed in the catalytic reaction are mon-
omeric.
The catalytic performance of 4*PF6 ranks it among the most active
ester hydrogenation catalysts up-to-date bringing this methodology a
step closer towards its implementation on industrial scale.
ASSOCIATED CONTENT
Supporting Information
Synthesis and characterization details, hydrogenation procedures are
described in Supporting Information available free of charge via the
Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
Evgeny A. Pidko (e.a.pidko@tue.nl)
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
EAP acknowledges the Technology Foundation STW and the Nether-
lands Organization for Scientific Research (NWO) for his personal
VENI grant. MJBA thanks the European Union (Marie Curie ITN
SusPhos, Grant Agreement No. 317404) for financial support.
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To further investigate the catalytic activity of 4*PF6 we performed a
series of kinetic measurements with ethyl hexanoate as a substrate on
100 mmol scale. At S/Ru=10 000 very high initial TOF0 values up to
78 600 h-1 were observed (Figure 3). The ester conversion was > 99%
with a selectivity of 99.7% to 1-hexanol. No straightforward reaction
order with respect to catalyst concentration could be derived from
these experiments indicating a complex behavior associated with the
formation of the active species. Consistent with the proposed mono-
meric nature of the active species, the initial TOF substantially increas-
es upon lowering the pre-catalyst concentration. At S/Ru of 80 000, an
initial TOF0 of 283 200 h-1 and a TON of 53 900 in 1 hour were ob-
tained, confirming the remarkable productivity of 4*PF6.
(9) Tan, X.; Wang, Y.; Liu, Y.; Wang, F.; Shi, L.; Lee, K.-H.; Lin, Z.; Lv, H.;
Zhang, X., Org. Lett. 2015, 17, 454.
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Figure 3. Kinetic traces of large scale ethyl hexanoate hydrogenation
with 4*PF6. Conditions: 40 bar H2, 70°C, 100 mmol ester, 2 %mol
KOtBu, S/Ru indicated on the graph. Xfin - final conversion, TOF0
initial rate.
-
To summarize, we report the first well-defined Ru catalyst based on
bis-NHC pincer ligands that is highly active for the hydrogenation of
esters. After performing a ligand screening using in situ generated
catalysts, we were able to isolate a dimeric catalyst precursor 4*PF6 that
is extremely active under basic conditions. According to our prelimi-
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