Dehydroalkylative Activation of CNN- A nd PNN-Pincer Ruthenium Catalysts for Ester Hydrogenation

Article abstract of DOI:10.1021/jacs.9b09326

Ruthenium-pincer complexes bearing CNN- A nd PNN-pincer ligands with diethyl-or diisopropylamino side groups, which have previously been reported to be active precatalysts for ester hydrogenation, undergo dehydroalkylation on heating in the presence of tricyclohexylphosphine to release ethane or propane, giving five-coordinate ruthenium(0) complexes containing a nascent imine functional group. Ethane or propane is also released under the conditions of catalytic ester hydrogenation, and time-course studies show that this release is concomitant with the onset of catalysis. A new PNN-pincer ruthenium(0)-imine complex is a highly active catalyst for ester hydrogenation at room temperature, giving up to 15500 turnovers with no added base. This complex was shown to react reversibly at room temperature with two equivalents of hydrogen to give a ruthenium(II)-dihydride complex, where the imine functionality has been hydrogenated to give a protic amine side group. These observations have potentially broad implications for the identities of catalytic intermediates in ester hydrogenation and related transformations.

Full text of DOI:10.1021/jacs.9b09326

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Article
Dehydroalkylative Activation of CNN- and PNN-
Pincer Ruthenium Catalysts for Ester Hydrogenation
Tianyi He, John C. Buttner, Eamon F. Reynolds, John Pham,
Jack C. Malek, Jason M. Keith, and Anthony R. Chianese
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b09326 • Publication Date (Web): 07 Oct 2019
Downloaded from pubs.acs.org on October 7, 2019
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Journal of the American Chemical Society
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Dehydroalkylative Activation of CNN- and PNN-Pincer Ruthenium
Catalysts for Ester Hydrogenation
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Tianyi He, John C. Buttner, Eamon F. Reynolds, John Pham, Jack C. Malek, Jason M. Keith,* and
Anthony R. Chianese*
Department of Chemistry, Colgate University, 13 Oak Drive, Hamilton, NY 13346
ABSTRACT: Ruthenium-pincer complexes bearing CNN- and PNN-pincer ligands with diethyl- or diisopropylamino side
groups, which have previously been reported to be active precatalysts for ester hydrogenation, undergo dehydroalkylation
on heating in the presence of tricyclohexylphosphine to release ethane or propane, giving five-coordinate ruthenium(0)
complexes containing a nascent imine functional group. Ethane or propane are also released under the conditions of
catalytic ester hydrogenation, and time-course studies show that this release is concomitant with the onset of catalysis. A
new PNN-pincer ruthenium(0)-imine complex is a highly active catalyst for ester hydrogenation at room temperature,
giving up to 15,500 turnovers with no added base. This complex was shown to react reversibly at room temperature with
two equivalents of hydrogen to give a ruthenium(II)-dihydride complex, where the imine functionality has been
hydrogenated to give a protic amine side group. These observations have potentially broad implications for the identities
of catalytic intermediates in ester hydrogenation and related transformations.
Introduction
In the intervening years, significant improvements in
activity for ester hydrogenation have been achieved by
many research groups through systematic modification of
the catalyst structure. Chart 1 shows a selection of the most
highly active catalysts for ester hydrogenation reported to
date.13 Almost all of the known “elite” catalyst systems
feature an N-H functional group or anionic nitrogen donor
reminiscent of Noyori’s ruthenium catalysts for
asymmetric ketone and imine hydrogenation;14 a notable
exception is Zhou’s RuPNNN catalyst.13d For the Firmenich
Ru(PN)2,13a the Gusev RuSNS,13c and the Pidko RuCNC13e
catalysts, the N-H group was demonstrated to be essential
for high catalytic activity through the synthesis of control
ligands where N-H was replaced with N-Me, N-Bn, or O.
The highly beneficial effect of the N-H group has been
taken as evidence that it is intimately involved in the
Classical methods for the reduction of esters involve the
use of stoichiometric hydride reagents that produce
inorganic by-products and have low atom economy.
Catalytic hydrogenation offers
a
more sustainable
approach, especially at the industrial scale. The
development of practically useful catalysts for ester
hydrogenation was spurred by Milstein’s 2006 report of the
ruthenium-pincer complex RuPNNdearom
, formed by
reaction of the hydridochloride precursor RuPNNHCl with
KOtBu (Equation 1).1 Using RuPNNdearom, several esters
were cleanly hydrogenated to full conversion at 115 °C with
up to 100 catalytic turnovers. The same complex is active
for the microscopic reverse reaction, the acceptorless
dehydrogenative coupling (ADC) of primary alcohols to
give esters.2 RuPNNdearom was subsequently demonstrated
to catalyze several mechanistically analogous reactions
including amine-alcohol coupling,3 couplings of amines4 or
alcohols5 with esters, organic carbonate hydrogenation,6
carbon dioxide hydrogenation,7 and amide -alkylation
with alcohols.8 More distantly related transformations
including light-induced oxygen evolution,9 alkene
isomerization,10 oxa-Michael addition,11 and reduction of
alkyl and aryl halides12 were also reported to be catalyzed
catalytic
mechanism,
either
through
protonation/deprotonation of nitrogen during the
catalytic cycle or by acting as a hydrogen-bond donor.
Density functional theory analyses have provided support
for this involvement in many cases.13c, 13f, 13h, 13i, 15
efficiently by RuPNNdearom
, either used directly or
generated in situ by reaction of RuPNNHCl with a strong
base.
CO
CO
KOtBu
H
tBu2P
H
tBu2P
Ru NEt2
Ru NEt2
N
Cl
N
THF
-32 °C
RuPNNHCl
RuPNNdearom
(1)
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Chart 1. A selection of highly active catalysts for ester
hydrogenation.
RuPNNdearom 19 In particular, catalytic oxygen evolution,20
.
amide formation,21 and carbonate hydrogenation22 have
received the most attention, although ester hydrogenation
or its microscopic reverse, ADC, have been studied as well.
In a DFT study by Wang focusing on the selectivity for
RuPNNdearom to catalyze amide formation over ester
formation under dehydrogenative conditions, mechanisms
involving metal-ligand cooperativity (MLC) were
identified for both substrate dehydrogenation and H2
1
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8
H2 Cl H2
Cl
Cl
Ph2
P
Et
S
N
N
PPh3
SEt
PPh3
N
Ru
Cl
Ru
Ru
P
P
N
N
Ph
Ph
H
H
Ph
Ph
Cl
Cl
Firmenich, 2007
Gusev, 2012
Gusev, 2013
+
H
N
tBu2 H
Et2N
Cl
release from RuPNNH2, and
a pathway involving
9
N
N
HN
P
CO
N
dechelation of the NEt2 group was excluded.21a Since this
study reports a complete minimum-energy pathway for
ADC, it is possible to apply the analysis to the microscopic
reverse, ester hydrogenation. In this case, an application of
the of the energetic span model23 for the minimum-energy
pathway reported by Wang predicts a high overall free-
energy barrier of 38.5 kcal/mol for ester hydrogenation
catalyzed by RuPNNdearom, which would be consistent with
it being largely inactive under the experimental catalytic
conditions. More recently, Zhang has reported a DFT study
Ru
tBu2P Ru
N
Os
Cl
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N
N
N
Cl
N
H
Mes
Mes
2
Cl Cl Cl
Zhou, 2014
Gusev, 2015
Pidko, 2015
H
N
Ph2 Cl
P
Ru
N
Ph2
P
N
Ph2P
2
N
Ru
PPh2
H
+
N
Ph3P
H
[RuCl2(p-cymene)]2
Cl
CO
Zhang, 2015
Zhang, 2015
Sun 2017
directly
focusing
on
ester
hydrogenation
by
RuPNNdearom 24
.
Again, an MLC pathway involving
An interesting subclass of ester-hydrogenation catalysts
features ligands with a dialkylamino side group, but no N-
H functionality (Chart 2). This subclass includes the
reversible deprotonation of the CH2 linker between
phosphorus and the pyridine ring was identified, although
in this case a more experimentally viable overall free-
energy barrier of 27.2 kcal/mol was calculated.
Interestingly, Hasanayn has identified a very different non-
cooperative pathway for the reduction of esters by
RuPNNH2, consisting of a direct H/OR metathesis with no
metal-ligand cooperativity.25 Two additional studies
consider the conversion of alcohols to aldehydes26 or
ketones27 instead of esters. Detailed mechanistic analyses
have not yet been reported for the other catalyst systems
shown in Chart 2.
original Milstein catalyst RuPNNdearom 1
,
RuCNN
complexes reported by Sánchez,16 Song,17 us,18 and Zhou’s
RuPNNN catalyst.13d
Chart 2. Catalysts for ester hydrogenation featuring a
dialkylamino group.
R
N
CO
Ru
N
Mes
H
CO
Ru
N
CO
Ru
N
H
tBu2P
N
H
NEt2
NEt2
Br
N
N
N
Cl
In attempting to characterize the stoichiometric
reactivity of our RuCNN precatalysts under conditions
relevant to ester hydrogenation, we recently observed that
our RuCNN hydridochloride catalyst precursors
rearranged to a CC binding mode upon reaction with
NaOtBu and tertiary phosphines, resulting from
dissociation of the dialkylamino group and C-H activation
of the pyridine ring (Equation 3).28 The RuCC complexes
were also active catalysts for ester hydrogenation without
the need for added base. Interestingly, the ligand
structure-activity relationship was the same for the CNN18b
and CC28 forms of the precatalysts: in both cases, NMe2-
substituted variants were poorly active while NEt2 and
NiPr2 variants were highly active. This suggested that the
CNN and CC forms may operate through a common
catalytic pathway. We established through DFT that a
reversion from the CC to the CNN binding mode is
kinetically and thermodynamically viable under the
catalytic conditions.28
Sánchez
Milstein
Et2N
Song; R = dipp, Mes
R
N
CO
H
Cl
N
tBu2P Ru
Ru NR'2
N
Cl
N
Cl
N
Chianese
R = dipp
i
R'
= Et, Pr
Zhou
In their 2006 paper, Milstein and co-workers reported
that RuPNNdearom reversibly activates H2 to form the
rearomatized dihydride complex RuPNNH2 (Equation 2).
The NR2 group appeared essential for ester hydrogenation
catalysis, as analogous RuPNP complexes were
significantly less active. Based on these observations, they
proposed a mechanism for ester hydrogenation that
involves heterolytic splitting of H2 by RuPNNdearom to form
RuPNNH2, followed by dechelation of the NEt2 arm and
inner-sphere transfer of hydrogen to the substrate.1
CO
dipp
CO
CO
dipp
6 eq. NaOtBu
6 eq. PCy3
H
Cy3P
H
CO
Ru
N
N
H2
tBu2P
Ru
H
N
N
H
tBu2P
Ru NEt2
Ru NEt2
NR2
N
- H2
PCy3
H
N
N
toluene, rt
i
Cl
R
= Me, Et, Pr
N
RuCC-R
RuCNN-RHCl
RuPNNdearom
RuPNNH2
NR2
(3)
(2)
Further studies of the stoichiometric reactivity of our
RuCC catalyst precursors uncovered a surprising result:
Much computational effort has been dedicated to
understanding the mechanisms of reactions catalyzed by
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Journal of the American Chemical Society
when the NEt2 or NiPr2 variants are simply heated in
reactions were conducted in toluene-d8 in sealed NMR
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8
toluene, they react to form five-coordinate ruthenium(0)
complexes with concomitant loss of ethane or propane,
where the amine group has converted to an imine group
(Scheme 1, below). Even more surprisingly, we observed
that the Milstein catalyst RuPNNdearom undergoes an
analogous reaction when heated in the presence of PCy3
(Scheme 2, below). The newly synthesized CNN and PNN-
pincer ruthenium(0)-imine complexes are highly active
catalysts for ester hydrogenation. Herein we present
tubes, the actual products were indeed confirmed to be
1
ethane and propane, as identified by H NMR, 13C NMR,
and HSQC.
The NMR spectra of RuCNN-Etimine, RuCNN-iPrimine
,
and RuPNNimine are consistent with the structures shown
in Schemes 1 and 2. In particular, the new imine hydrogens
appear at 7.53-8.08 ppm, in each case showing splitting
only by the phosphorus atoms. To unequivocally confirm
their structures, all three complexes were characterized by
X-ray crystallography; their solid-state structures are
shown in Figures 1-3. The three structures are closely
analogous, with imine C=N bond lengths of 1.337 – 1.347 Å
indicating a clear double-bond character, and with nearly
equal C-C bond lengths in the pyridine ring consistent with
an aromatic structure, as opposed to the alternation
9
evidence that the dehydroalkylation reaction is
a
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prerequisite for catalytic activity, which has profound
implications for the catalytic mechanism.
Results and Discussion
Catalyst Dehydroalkylation Reactions. When
solutions of RuCC-Et or RuCC-iPr were heated overnight
in toluene at 105 °C, conversion to a new major product
occurred. Through spectroscopic and crystallographic
analysis, we identified the products as the dark green, 18-
electron, 5-coordinate ruthenium(0) complexes RuCNN-
Etimine and RuCNN-iPrimine (Scheme 1, left). The same
products were formed if RuCNN-EtHCl or RuCNN-iPrHCl
were heated with excess NaOtBu and a slight excess of PCy3
(Scheme 1, right). As the RuCC complexes are synthesized
by rearrangement of the CNN hydridochloride
complexes,28 the latter route is more efficient and was
preferred to isolate usable quantities of the products.
around the ring observed for RuPNNdearom 1
The
.
geometries about ruthenium can be described as distorted
square-pyramidal, where the carbonyl and pincer ligands
form the base and PCy3 binds at the apex. The 
parameter29 is 0.24 for RuCNN-Etimine and RuPNNimine
,
and 0.22 for RuCNN-iPrimine, consistent with a structure
closer to square-pyramidal than trigonal bipyramidal.
Scheme 1. Synthesis of RuCNN-imine complexes by
dehydroalkylation.
2 eq. NaOtBu
1.05 eq. PCy3
mesitylene
HR
+
dipp
CO
dipp
CO
Cl
Ru
Cy3P
CO
N
dipp
N
toluene
Ru
H
PCy3
NR
NR2
N
N
Ru
N
Et
: 2 h,
PCy3
N
H
N
16 h
105 °C
140 °C;
iPr: 16 h,
120 °C
N
N
NR2
RuCNN-Etimine
RuCNN-iPrimine
RuCNN-EtHCl, 57%
RuCNN-iPrHCl, 42%
RuCC-Et
RuCC-iPr
R
= Et
,
i
R
= Pr
,
When a solution of RuPNNdearom was heated to 100 °C
for one hour in the presence of a slight excess of PCy3, the
analogous dehydroalkylation reaction was again observed,
as the intensely purple product RuPNNimine was formed
cleanly (Scheme 2, left). RuPNNimine could also be more
conveniently synthesized from the thermally stable
precursor RuPNNHCl (Scheme 2, right), generating
RuPNNdearom in situ with KOtBu. All three ruthenium(0)-
imine complexes were observed to be highly air-sensitive,
as their dark green or purple solutions decolorized nearly
instantaneously upon exposure to air.
Figure 1. X-ray crystal structure of RuCNN-Etimine, showing
50% probability ellipsoids. Hydrogen atoms have been
omitted for clarity. Selected bond lengths (Å) and angles (°):
Ru(1)–C(32), 1.9844(13); Ru(1)–N(21), 2.0041(11); Ru(1)–N(24),
2.0569(11); Ru(1)–P(2), 2.3315(3); Ru(1)–C(52), 1.8578(14);
C(23)–N(24), 1.3451(18); C(32)–Ru(1)–N(21), 77.27(5); N(21)–
Ru(1)–N(24), 76.34(5).
Scheme 2. Synthesis of RuPNN-imine complexes by
dehydroalkylation.
ethane
+
1.2 eq. PCy3
CO
CO
2 eq. KOtBu
H
H
1.2 eq. PCy3
CO
tBu2P
NEt2
Cy3P
tBu2P
tBu2P
NEt2
Ru
N
Ru
N
NEt
Ru
N
toluene
1 hr
100 °C
toluene
Cl
1 hr, 80 °C
then 20 min,
100 °C
RuPNNdearom
RuPNNimine
RuPNNHCl
, 64%
The formation of the ruthenium(0)-imine complexes
requires the formal loss of an equivalent of ethane (RuCC-
Et and RuPNNdearom) or propane (RuCC-iPr). When these
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almost completely inactive as catalysts for ester
hydrogenation.28 Intriguingly, attempts to convert these
catalytically inactive NMe2 derivatives to ruthenium(0)-
imine complexes analogous to those described above were
unsuccessful: decomposition to an intractable mixture was
observed, with no evidence of the analogous imine
complex or methane observed by 1H NMR (Scheme 3).
1
2
3
4
5
6
7
8
9
Scheme 3. No dehydroalkylation is observed for an
NMe2-substituted derivative.
dipp
CO
dipp
CO
Ru
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12
13
14
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17
18
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22
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6 NaOtBu
1.05 PCy3
mesitylene
Cy3P
N
Cl
N
N
Ru
H
NMe2
Decompostion
No Ruo-imine
No methane
toluene
PCy3
N
H
N
16 h
105 °C
16 h
105 °C
N
RuCNN-MeHCl
NMe2
RuCC-Me
Ester Hydrogenation: Comparison of Amine and
Imine Precatalyst Forms. In preliminary testing, we
found that the new complexes RuCNN-Etimine, RuCNN-
iPrimine, and RuPNNimine were active catalysts for ester
hydrogenation, without the need for added base. Since
these imine-pincer complexes are formed by
Figure 2. X-ray crystal structure of RuCNN-iPrimine, showing
50% probability ellipsoids. Hydrogen atoms have been
omitted for clarity. Selected bond lengths (Å) and angles (°):
Ru(1)–C(24), 1.970(3); Ru(1)–N(21), 1.994(3); Ru(1)–N(49),
2.067(3); Ru(1)–P(2), 2.3493(9); Ru(1)–C(53), 1.857(3); C(48)–
N(49), 1.346(5); C(24)–Ru(1)–N(21), 77.30(13); N(21)–Ru(1)–
N(49), 76.28(12).
dehydroalkylation from amine-pincer complexes that are
28
known catalysts for ester hydrogenation,1,
we
hypothesized that the dehydroalkylation reaction might be
a necessary step in catalyst activation. We began assessing
this possibility by conducting comparative hydrogenation
experiments side-by-side under the same conditions
(toluene, 20 bar H2, 0.125 M hexyl hexanoate, 0.5%
catalyst). Side-by-side monitoring was most conveniently
conducted at 105 °C for the CNN-Et and CNN-iPr catalysts,
and at 85 °C for the PNN catalysts. In addition to
measuring the conversion of hexyl hexanoate into 1-
hexanol over time, we monitored the headspace by gas
chromatography to observe the formation of ethane or
propane throughout the experiment.
Figure 4 shows the time course comparisons for the
CNN-Et, CNN-iPr, and PNN catalysts. In each case, the
ruthenium(0)-imine derivative is at least as active as its
ruthenium(II)-amine precursor. The graphs on the left
show the comparison of RuCNN-Etimine with RuCC-Et.
While RuCC-Et shows a moderate induction period before
the onset of catalysis, RuCNN-Etimine is active nearly from
the start of the reaction. The middle graphs show the
comparison of RuCNN-iPrimine with RuCC-iPr, which
convert hexyl hexanoate at nearly identical rates. The
rightmost graphs show the comparison of RuPNNdearom
Figure 3. X-ray crystal structure of RuPNNimine, showing 50%
probability ellipsoids. Hydrogen atoms have been omitted for
clarity. Selected bond lengths (Å) and angles (°): Ru(1)–P(21),
2.3221(6); Ru(1)–N(24), 2.0686(18); Ru(1)–N(27), 2.0527(19);
Ru(1)–P(2), 2.3575(6); Ru(1)–C(41), 1.841(2); C(26)–N(27),
1.336(3); P(21)–Ru(1)–N(24), 79.18(5); N(24)–Ru(1)–N(27),
76.58(7).
with RuPNNimine
.
While RuPNNdearom shows a long
induction period before the onset of catalysis, RuPNNimine
is active at the very beginning of the reaction, and
hydrogenation is 99% complete within 20 minutes.
We previously reported that the NMe2-substituted
catalyst variants RuCC-Me and RuCNN-MeHCl were
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Figure 4. Ester hydrogenation time course comparisons for three ruthenium(0)-imine catalysts (filled circles) vs. their
ruthenium(II)-amine precursors (open circles). The top graphs show the conversion of hexyl hexanoate over time, and the bottom
graphs show the evolution of alkane in the headspace of reactions catalyzed by the ruthenium(II)-amine complexes. Reactions
with CNN or CC ligands were conducted at 105 °C, while reactions with PNN ligands were conducted at 85 °C.
The lower graphs in Figure 4 show the formation of
ethane from RuCC-Et or RuPNNdearom, and propane from
RuCC-iPr, as monitored over the course of each catalytic
experiment. RuCC-Et and RuCC-iPr lose alkane rapidly at
the start of the reaction, consistent with the short
induction periods observed for these catalysts.30
RuPNNdearom releases ethane more slowly, consistent with
the longer induction period observed under the conditions
employed. No ethane or propane was produced in
reactions catalyzed by any of the ruthenium(0)-imine
forms, indicating that further loss of the second alkyl group
does not occur in reactions catalyzed by the ruthenium(0)-
imine complexes. No propane was produced when RuCC-
Et or RuPNNdearom were used and no ethane was produced
when RuCC-iPr was used: this observation confirms that
the observed ethane and propane come from the ligand
dealkylation reaction, rather than some other, unidentified
source.
esters was hydrogenated using 1 mol % RuPNNdearom at 115
°C in 1,4-dioxane under 5.3 atm H2, with reaction times
ranging from 4 to 24 hours. In our above comparisons,
RuPNNimine catalyzed the hydrogenation of hexyl
hexanoate to 99% conversion in 20 minutes at 85 °C in
toluene, with 0.5% catalyst loading and 30 bar H2.
Encouraged by the high rate of reaction at 85 °C, we
conducted a screen of solvents at room temperature, with
a
higher, more practically useful 1.0 M substrate
concentration and a lower 0.1 mol % catalyst loading
(Figure 5). Ester hydrogenation did not occur appreciably
in acetonitrile, and proceeded at a moderate rate in THF
and toluene. Gratifyingly, the reaction proceeded to
completion in isopropyl alcohol in five hours. The
identification of a catalyst that operates efficiently under
neutral conditions at room temperature is unique. Several
catalyst systems have been reported to be active for
hydrogenation of a broad range of ester substrates at13d, 31 or
near13b, 13c, 15a, 32 room temperature, but the use of alkoxide
base as co-catalyst has typically been necessary. On the
other hand, many catalyst systems have been developed
that operate without the need for added base,1, 15g, 33 but
elevated (≥80 °C) temperatures have been required for
efficient conversion.
These results, taken together, are consistent with the
hypothesis that the dialkylamine variants of all three
complexes represent precatalysts that must first undergo
dehydroalkylation to generate the active catalyst, while the
imine
variants,
having
already
undergone
dehydroalkylation, can enter the catalytic cycle more
rapidly (RuCNN-Etimine and RuPNNimine) or at a similar
rate (RuCNN-iPrimine).
Optimization and Substrate Scope for RuPNNimine
.
Perhaps the most practically significant result of the above
experiments is the observation that RuPNNimine is an
exceedingly active base-free catalyst for ester
hydrogenation. In Milstein’s original report,1 a range of
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Table 1. Substrate Scope for Ester Hydrogenation
Catalyzed by RuPNNimine
1
2
3
4
RuPNNimine
H2, 30 bar
O
+ R'OH
OH
R
R'
R
O
isopropyl alcohol
rt, 16 h
5
6
7
[Sub]
/[Ru]
Entry
Substrate
% Yield
O
O
8
9
8,000
99
1
16,000 83
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
O
2
3
4
4,000
92
O
4
8,000
8,000
95
99
O
5
O
O
16,000 83
Figure 5. Comparison of solvents for room-temperature
hydrogenation of hexyl hexanoate catalyzed by RuPNNimine
O
O
.
5
6
1,000
94
With the identification of optimal reaction conditions,
we proceeded to survey the substrate scope (Table 1).
O
O
16,000 97
RuPNNimine is
a highly effective catalyst for the
hydrogenation of a range of aliphatic and aromatic esters
(Entries 1-8), giving turnover numbers up to 15,500 (Entry
6). The hydrogenation of -chiral esters without
racemization is challenging: Kuriyama has reported an
effective base-free ruthenium catalyst system for this
transformation,33a and Clarke has successfully employed
the weak base K2CO3 to minimize racemization in a
O
O
7
8,000
8,000
2,000
98
O
8
8
94
O
CH3
O
9a
98, 97% ee
transformation.34
(S)-ethyl ibuprofen
Using
our
was
O
manganese-catalyzed
optimized conditions,
hydrogenated effectively, but
O
O
10b
11b
8,000
96, 99.9% sel
a
small amount of
racemization was observed, as the alcohol product had
only 97% ee (Entry 9). The chemoselective hydrogenation
of esters in the presence of other reducible functional
groups such as alkenes is also an important goal, and some
catalyst systems have been reported to offer such
selectivity.13f, 15j, 32c, 35 Under our optimized conditions, an
ester was hydrogenated completely with nearly perfect
selectivity in the presence of an internal alkene (Entry 10).
When a substrate containing a terminal alkene was
employed (Entry 11), we observed complete ester
hydrogenation accompanied by 14% alkene hydrogenation
at 0.1% catalyst loading, and a lower 83% yield at 0.05%
loading, albeit with only 1% hydrogenation of the double
bond. Thus, RuPNNimine was highly selective against the
hydrogenation of an internal alkene, and moderately
selective against the hydrogenation of a terminal alkene.
O
1,000
2,000
99, 86% sel
83, 99% sel
O
aThe reactant (S)-ethyl ibuprofen had >99% ee, as
determined by GC. bYields given represent the sum of all
alkene and alkane alcohol products from ester hydrogenation.
Reported % selectivities represent the percentage of product
resulting from no hydrogenation or isomerization of the C=C
bond.
Reaction of RuPNNimine with Hydrogen. The high
catalytic activity of RuPNNimine for ester hydrogenation at
room temperature prompted us to examine its reaction
with hydrogen. When a dilute (0.2 mM) solution of
RuPNNimine in toluene-d8 was placed under 10 bar
hydrogen, complete conversion to a nearly colorless
product occurred in approximately 20 minutes at room
temperature (Equation 4). We have assigned the product
as RuPNNHEt, on the basis of its 1H, 31P, COSY, and NOESY
spectra, informed by the close structural similarity to the
previously reported1 compound RuPNNH2 (Equation 2),
which differs only by its amine substituents (NHEt vs
NEt2), and the resulting loss of a time-averaged plane of
symmetry. Removal of the solvent under vacuum resulted
in complete reversion back to RuPNNimine, indicating the
reversibility of both the net oxidative addition to
ruthenium(0) and the hydrogenation of the ligand’s imine
functionality at room temperature. Attempts to prepare a
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Journal of the American Chemical Society
more concentrated sample for more detailed spectroscopic dehydroalkylation reactions described above: 1) three
1
2
3
4
5
6
7
8
analysis resulted in the formation of a second, unidentified
product, complicating the analysis.
different ruthenium(0)-imine complexes formed via
dehydroalkylation were shown to be kinetically competent
catalysts, leading to either the same catalytic rate as their
ruthenium(II)-amine precursor (RuCC-iPr) or showing a
shorter induction period (RuCC-Et and RuPNNdearom); 2)
Reactions catalyzed by the ruthenium(II)-amine
precursors showed release of ethane or propane,
concomitant with the onset of catalysis; and 3) an
analogous NMe2-substituted variant of our RuCC
precatalysts is nearly inactive for ester hydrogenation,28
and also does not undergo dehydroalkylation to form a
ruthenium(0)-imine complex.
The facile formation of RuPNNHEt from RuPNNimine
(Equation 4) raises the intriguing possibility that
RuPNNHEt is an on- or off-cycle intermediate in catalytic
ester hydrogenation. Although we have not yet
experimentally characterized the reactivity of RuCNN-
Etimine and RuCNN-iPrimine with hydrogen, we have shown
computationally that a doubly hydrogenated complex
analogous to RuPNNHEt is thermodynamically accessible
for the NHC-based RuCNN-Etimine as well. We noted in the
introduction the overwhelming preponderance of the N-H
functional group in the most highly active catalysts for
ester hydrogenation (Chart 1). In the extensive
computational literature on ester hydrogenation,13c, 13f, 13h, 13i,
15 a common theme involves the heterolytic cleavage of H2
by its addition to a ruthenium-amido intermediate,
followed by concerted or stepwise transfer of hydrogen to
the substrate. Recently, Dub and Ikariya15b and Dub and
Gordon37 have demonstrated that a mechanism where the
N-H group functions only as hydrogen-bond donor
without being deprotonated as part of the catalytic cycle is
energetically preferable in some cases. Such mechanisms
involving N-H deprotonation or hydrogen-bond donation
are clearly unavailable to the NR2-substituted precatalysts
shown in Chart 2, which lack the requisite N-H group.
CO
CO
Cy3P
tBu2P
H
10 bar H2
vacuum
Ru NEt + 2 H2
N
tBu2P
Ru NHEt
+ PCy3
H
N
RuPNNimine
RuPNNHEt
(4)
The NMR spectra of RuPNNHEt are broad at room
temperature, and are sharpest at –30 °C. The Ru-bound
phosphorus atom resonates at 120.6 ppm, and free PCy3 is
observed as expected. The two chemically inequivalent
ruthenium-hydrides appear at –4.42 and –5.07 ppm, and
show slightly different H-P coupling constants of 13.4 and
17.6 Hz, respectively. Linewidths of 5-6 Hz preclude
measurement of the H-H coupling constant, which is
expected to be small based on closely analogous
compounds.36 The broad N-H resonance appears at 4.13
ppm at 22 °C and 5.77 ppm at –30 °C. (See the Supporting
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
Information for H NMR spectra taken from -70 °C to 60
°C.)
Thermodynamic Analysis by DFT. As an additional
validation of the structural assignment of RuPNNHEt, we
have computed the thermodynamics of the reaction shown
in Equation 4 using density functional theory. To assess
whether the analogous double hydrogenation reaction is
thermodynamically feasible for the N-heterocyclic carbene
derivatives, we also analyzed the analogous reaction of
RuCNN-Etimine to give RuCNNHEt, which we have not yet
studied experimentally. Scheme 4 shows the calculated
standard-state free energies for these transformations,
calculated
at
the
B3LYP-D3/6-
311G(d,p)/LANL08(f)//M06/6-311G(d,p)/LANL08(f) level
of theory. The hydrogenation of RuPNNimine to release
PCy3 and give RuPNNHEt is calculated to be endergonic by
only 0.1 kcal/mol, consistent with the observation that the
reaction is reversible at room temperature. Similarly, the
analogous hydrogenation of RuCNN-Etimine is endergonic
by only 0.8 kcal/mol.
However,
these
mechanisms
are
possible
if
dehydroalkylation followed by hydrogenation can occur, as
we have demonstrated for RuPNNdearom. Our current
working hypothesis is that many, if not all, of the NR2-
substituted precatalysts shown in Chart 2 may actually
operate in ester hydrogenation by first losing an equivalent
of alkane, then being hydrogenated to give an NHR-
substituted derivative that serves as the actual catalyst, i.e.
the NR2 group may serve as a latent NHR group under
catalytic conditions.
Scheme 4. Relative standard-state free energies at
298.15 K for ruthenium(0)-imine complexes and their
doubly hydrogenated derivatives. Energies are given
in kcal/mol.
CO
CO
Cy3P
tBu2P
H
Ru NEt + 2 H2
N
tBu2P
Ru NHEt
+ PCy3
H
N
Broader
Mechanistic
Implications.
Because
RuPNNdearom has been reported to be an active catalyst for
a wide array of additional transformations, the possibility
exists that catalyst dehydroalkylation occurs in more cases
than the one presently discussed, and could potentially be
a prerequisite for catalysis in other scenarios, especially
when elevated temperatures are employed. Many
dehydrogenative coupling reactions3-5, 8 have been reported
to be catalyzed by RuPNNdearom or RuPNNHCl activated in
situ by base, all of which occur at temperatures greater
than 100 °C where the dehydroalkylation might be
expected to occur rapidly. Similarly, hydrogenation of
dimethyl carbonate to methanol catalyzed by
RuPNNdearom occurs at 145 °C,6 and hydrogenation of
RuPNNimine
, 0.0
RuPNNHEt
, +0.1
CO
CO
PCy3
Ru NEt
dipp
dipp
N
H
N
+ 2 H2
Ru NHEt
N
+ PCy3
N
H
N
N
RuCNN-Etimine
RuCNNHEt
, 0.0
, +0.8
Implications for the Catalytic Mechanism. Several
lines of evidence support the hypothesis that ruthenium
precatalysts based on NR2-substituted CNN- and PNN-
pincer ligands are not significantly active catalysts for ester
hydrogenation prior to the occurrence of the
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Journal of the American Chemical Society
Page 8 of 12
carbon dioxide to formate occurs at 120 °C.7 In contrast,
containing an imine functionality, with loss of ethane or
catalytic alkene isomerization10 and oxa-Michael addition
to nitriles11 occur rapidly at room temperature, where
dehydroalkylation is potentially slower.
propane. We have demonstrated that the resulting
ruthenium(0)-imine complexes are active catalysts for
ester hydrogenation, and experiments are consistent with
the hypothesis that the dehydroalkylation is a prerequisite
for catalytic activity in these systems. The observed double
hydrogenation of RuPNNimine to give RuPNNHEt suggests
that a catalytic mechanism involving the N-H functional
group may be operative in ester hydrogenation and related
transformations. Additionally, we have demonstrated that
RuPNNimine is one of the most highly active catalysts for
base-free ester hydrogenation reported to date, giving in
excess of 15,000 turnovers at room temperature with no
added base. Experimental and computational studies to
understand the mechanisms of ligand dealkylation, double
hydrogen addition to the resulting ruthenium(0)-imine
complexes, and catalytic ester hydrogenation are
underway.
1
2
3
4
5
6
7
8
Separately, it is noteworthy that Milstein and coworkers
have identified the complex RuPNNHtBu (Figure 6) as a
highly active catalyst (in combination with base) for a
variety of reactions, including ester hydrogenation and the
reverse ADC reaction,31 as well as related reactions with
potential application in hydrogen storage.38 This complex
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
could
conceivably
undergo
base-promoted
dehydrochlorination followed by addition of H2 to give a
dihydride complex analogous to RuPNNHEt. This raises the
possibility that RuPNNHtBu operates in a mechanistically
analogous fashion to RuPNNimine and RuPNNdearom. The
PNNHtBu ligand has been applied in manganese33i, 39 and
cobalt40 catalysis, where its NEt2variant has been
substantially less active. De Bruin and coworkers have
synthesized a related rhodium complex of a PNNH-type
pincer ligand, and demonstrated dynamic ligand reactivity
including the stepwise dehydrogenation of the amine
group to an imine.41 Related PNN pincer ligands containing
the imine functionality have been applied in a variety of
hydrogenations and hydrosilylations.42 The observation of
reversible ligand hydrogenation (Equation 4) suggests that
hydrogenation or hydrosilylation of the imine
functionality may be plausible in these systems as well.
Associated Content
Supporting Information
The Supporting Information is available free of charge
on the ACS Publications website at DOI:xxx.
Experimental procedures, images of NMR spectra and
detailed NMR assignments for new compounds, and
computational details (PDF). Crystallographic details
(CIF). Atomic coordinates for all computed molecular
structures, compiled as one file readable by the free
program Mercury45 (XYZ).
CO
Cl
tBu2P
Ru NHtBu
Author Information
H
N
Corresponding Author
*E-mail: achianese@colgate.edu
Notes
RuPNNHtBu
The authors declare no competing financial interest.
Figure 6. Ruthenium-pincer complex containing an N-H
group reported by Milstein.
Acknowledgements
Mechanistic
Hypotheses
for
Catalyst
We thank the National Science Foundation (CHE-1665144) for
support of the research project, and (CHE-1726308) for the
acquisition of an upgraded NMR spectrometer.
Dehydroalkylation. The dehydroalkylation reactions
shown in Schemes 1 and 2 are unexpected, and we are
actively interrogating their mechanisms in a combined
experimental and computational study. Although we are
unable to make conclusions at this time, our hypotheses
draw on the observed reactivity of ethyl and isopropyl
groups and the lack of reactivity of methyl groups.
Plausible mechanisms include: 1) -CH-activation followed
by -amido elimination,43 then hydrogenation of the
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