Selective Base-free Transfer Hydrogenation of α,β-Unsaturated Carbonyl Compounds using iPrOH or EtOH as Hydrogen Source

Article abstract of DOI:10.1002/chem.201705423

Commercially available Ru-MACHO^TM-BH is an active catalyst for the hydrogenation of several functional groups and for the dehydrogenation of alcohols. Herein, we report on the new application of this catalyst to the base-free transfer hydrogenation of carbonyl compounds. Ru-MACHO^TM-BH proved to be highly active and selective in this transformation, even with α,β-unsaturated carbonyl compounds as substrates. The corresponding aliphatic, aromatic and allylic alcohols were obtained in excellent yields with catalyst loadings as low as 0.1–0.5 mol % at mild temperatures after very short reaction times. This protocol tolerates iPrOH and EtOH as hydrogen sources. Additionally, scale up to multi-gram amounts was performed without any loss of activity or selectivity. An outer-sphere mechanism has been proposed and the computed kinetics and thermodynamics of crotonaldehyde and 1-phenyl-but-2-en-one are in perfect agreement with the experiment.

Full text of DOI:10.1002/chem.201705423

A Journal of
Accepted Article
Title: Selective base-free transfer hydrogenation of α,β-unsaturated
carbonyl compounds using i-PrOH or EtOH as hydrogen source.
Authors: Ronald Farrar-Tobar, Zhihong Wei, Haijun Jiao, Sandra
Hinze, and Johannes Gerardus de Vries
This manuscript has been accepted after peer review and appears as an
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To be cited as: Chem. Eur. J. 10.1002/chem.201705423
Link to VoR: http://dx.doi.org/10.1002/chem.201705423
Supported by

Chemistry - A European Journal
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FULL PAPER
Selective base-free transfer hydrogenation of α,β-unsaturated
carbonyl compounds using i-PrOH or EtOH as hydrogen source
[a]
[a]
[a]
[a]
[a]
Ronald A. Farrar-Tobar, Zhihong Wei, Haijun Jiao, Sandra Hinze, Johannes G. de Vries*
TM
Abstract: Commercially available Ru-MACHO -BH is an active
catalyst for the hydrogenation of several functional groups and for
the dehydrogenation of alcohols. Herein, we report on the new
application of this catalyst to the base-free transfer hydrogenation of
produced from oil by cracking. The Ostromislensky process is
[
11]
still in use today in China, India and Russia.
A major
drawback of this process is the low selectivity towards butadiene
which never exceeded 60 %. In the last years, much research
was devoted to improve the heterogeneously catalyzed
TM
carbonyl compounds. Ru-MACHO -BH proved to be highly active
[
12]
and selective in this transformation, even with α,β-unsaturated
carbonyl compounds as substrates. The corresponding aliphatic,
aromatic and allylic alcohols were obtained in excellent yields with
catalyst loadings as low as 0.1-0.5 mol% at mild temperatures after
very short. This protocol tolerates i-PrOH and EtOH as hydrogen
sources. Additionally, scale up to multigram amounts was performed
without any loss of activity or selectivity. An outer-sphere mechanism
has been proposed and the computed kinetics and thermodynamics
of crotonaldehyde and 1-phenyl-but-2-en-one are in perfect
agreement with the experiment.
process, and yet, a process competitive to the production of
butadiene from oil was not found. The mechanism for the
synthesis of butadiene from EtOH remains unclear and is still
[
13]
studied intensively.
The most accepted mechanistic proposal
includes EtOH dehydrogenation to acetaldehyde followed by
aldol condensation to give crotonaldehyde, which is reduced to
crotyl alcohol using ethanol as reductant. Dehydration of crotyl-
alcohol delivers butadiene (Scheme 1).
(i) Dehydrogenation
O
OH
(
ii) Aldol
condensation
MH2
H O
2
Introduction
O
OH
(
iv) Dehydration
(iii)
Selective transfer
[
1]
work)
hydrogenation (this
The dwindling supply of fossil fuels demands new strategies to
cover our needs in terms of fuels and chemicals. For the
production of chemicals, non-edible biomass is the alternative
feedstock of choice. Several biomass-derived platform
chemicals are already available and much research is devoted
towards their conversion into existing and new bulk and fine
Scheme 1. Most accepted mechanism for the synthesis of 1,3-butadiene from
EtOH.
[
2]
We envisioned an entirely new approach to increase the
overall selectivity to butadiene: (a) to separate all steps; (b) to
optimize each step with respect to conversion and selectivity
and (c) to recombine all steps in a sequential flow process.
One of the key steps of the process is the third step, namely the
transfer hydrogenation of crotonaldehyde to crotyl alcohol. We
intend to use the starting material ethanol as reductant (Scheme
chemicals.
Bioethanol,
a well-known renewable platform
[3]
chemical, is already produced on large scale via fermentation
using lignocellulose as raw material. EtOH constitutes a
starting material for a number of interesting compounds such
as butanol, ethylene, or 1,3-butadiene. Butadiene has a
huge economic value as bulk chemical with projected
[
4]
[
5]
[
6]
[7]
[8]
a
5
[9]
worldwide production of 12.7x10 t/a in the year 2017. It is
mainly used in rubber production.
1) as the formed acetaldehyde can be used in the aldol
condensation (step ii). Although the selective hydrogenation of
α,β-unsaturated aldehydes is a well-researched area, much less
has been published about the selective transfer hydrogenation
During World war II butadiene was produced from ethanol
using the Lebedev and Ostromislensky processes, where the
first one is a one-step process using SiO
2
2 5
-MgO-Ta O at up to
[
14]
of these substrates.
With heterogeneous catalysts selectivity
4
50°C, and the second one is a two-step process using (2%
[
10]
rarely exceeds 90%. Higher selectivities can be obtained with
homogeneous metal catalysts. In particular ruthenium
complexes have been used. Surprisingly little is known about the
use of ethanol as reductant in the transfer hydrogenation of
aldehydes and ketones. So far, three examples were published
reporting on homogeneous Ru, Rh and Ir complexes with
sophisticated ligands, which are active with ethanol as hydrogen
2 5 2
Ta O / 98% SiO ) at 350°C. However, once World War II was
over, and oil became readily available again, butadiene was
[a]
R.A. Farrar-Tobar, Z. Wei, Dr. H. Jiao, Dr. S. Hinze, Prof. Dr. J.G. de
Vries
Leibniz Institut für Katalyse e. V. an der Universität Rostock
Albert-Einstein-Straße 29a, 18055 Rostock (Germany)
E-mail: johannes.devries@catalysis.de
[15]
source (Figure 1). None of these catalysts has been reported
to be active for the selective reduction of α,β-unsaturated
carbonyl compounds though. Reports on the selective transfer
hydrogenation of α,ß-unsaturated carbonyl compounds utilize
Supporting information for this article is given via a link at the end of
the document.
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Chemistry - A European Journal
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FULL PAPER
[
16]
different kinds of hydrogen sources but not ethanol.
To the
with KOtBu rapidly leads to a multitude of products. Therefore, a
base-free system was required. Since most modern transfer
hydrogenation catalysts need activation with an excess of base,
best of our knowledge, there is no homogeneous catalyst which
is applicable for this purpose and meets the requirements for a
catalyst system, namely, being cost-effective, robust and readily
available.
[
16d, 24]
this rather reduces the number of available catalysts.
Table 1. Catalyst screening for the transfer hydrogenation of
[
a]
crotonaldehyde.
(
Ar)
2
N
O
Cl
O
OH
H
O
P
N
H
N
Rh
PPh
Ru
N
t
Ir
N
O Bu
cat. 1
mol%
3
H
H
X
*
=
Additive
EtOH, T, t
9a
O
8a
1
2
3
[b]
[b]
Temp.
Conv.
[%]
Yield
Adolfsson
Qui-Lin Zhou
Grützmacher
Entry
Cat.
Additive
[°C]
[°C]
>99
0
[
c]
Figure 1. Active complexes reported for the transfer hydrogenation of
1.
3
4
5
6
7
7
-
rt
>99
>99
40
aldehydes and ketones with ethanol as hydrogen source.
2
3
4
5
.
t-BuOK
rt
.
.
.
-
45
50
32
8
Results and Discussion
(CH
3 3
) NO
66
We started off with a catalyst screening (Figure 2, Table 1)
for the transfer hydrogenation of crotonaldehyde (8a) to crotyl
alcohol (9a). Having previously developed ruthenacycles as
transfer hydrogenation catalysts we started the screening with
complex 4. Also, the Shvo catalyst (5) and its Fe analogue,
Knölker’s complex (6) were candidates in view of their known
-
refl.
refl.
>99
>99
70
97
[
d]
6.
-
[
17]
[18]
[a] Reaction conditions: substrate(1mmol), solvent EtOH (10 ml), reaction
advance monitored by T.L.C. and GC, system equipped with an exist for
gases, overnight reactions. [b] Determined by GC with dodecane as internal
standard. [c] Reaction time: 2 minutes. [d] i-PrOH used as hydrogen source
and solvent
[
19]
activity in transfer hydrogenation. Finally, commercially available
Ru-MACHO -BH (7) was also tried. This last catalyst is well-
TM
[20]
known for hydrogenation of challenging functional groups such
[
21]
Since the Shvo catalyst (5) does not need base activation it
is an interesting candidate. Nevertheless, conversion and yield
remained low even after optimization of the temperature (Entry
3). Use of the Knölker catalyst (6) did not lead to better results
as esters or nitriles,
secondary alcohols, and other transformations.
for the dehydrogenation of primary and
[
22]
[23]
-
Ph
H
Ph
PF6
O
O
(
Entry 4). Presumably, trimethylamine formed from the additive
+
Ph
Ph
Ru
trimethylamineoxide, which is needed for its activation, is
catalysing non-desired reactions.
NCMe
NHMe
Ph Ph
H
Ph Ru
Ru Ph
OC CO OC CO
On the other hand, when crotyl aldehyde was dissolved in
EtOH with Ru-MACHO -BH (7), 70% of the desired product
4
5
TM
Ruthenacycle
Shvo
was formed after only 10 minutes. This result is very gratifying
taking into account all the possible by-products that could form
through condensation between crotyl aldehyde, crotyl alcohol,
EtOH and acetaldehyde.
Next, the reaction conditions were optimized with regard to
conversion and selectivity (Table 2). Using ethanol as hydrogen
source at room temperature in an over-night experiment led to
very low conversion (Entry 1). Raising the temperature clearly
improved the yield of crotyl alcohol and allowed a drastic
reduction of the reaction time to 10 minutes (Entries 2 and 3).
Thus, a maximum yield of 70% was achieved at complete
conversion. Similar yields were obtained using 0.1 mol% of 7
H
SiMe3
H
N
PPh2
O
Ru
H
SiMe3
P
CO
Fe
Ph
2
OC
CO
OC
BH3
7
6
Ru-MACHOTM-BH
Knöllker
Figure 2. Selected complexes for the catalyst screening.
Catalyst 3 turned out to be very active and selective in the
desired transformation (Entry 1). Nevertheless, the price of both
metal and ligand in addition to the instability of the catalyst make
this catalyst less suitable for our goals. The use of catalyst 4 in
combination with KOtBu led to full conversion of crotonaldehyde
but no yield of the desired product was observed (Entry 2). This
result may be due to the instability of α,β-unsaturated carbonyl
compounds in basic media. Indeed, treatment of crotonaldehyde
(
Entry 4). At lower catalyst loadings no reaction was observed at
all. Consequently, we defined the conditions in Table 2, entry 4
as standard conditions.
We also tested the tolerance of the protocol to water by
2
running the reaction in a mixture of EtOH/H O (9/1). The
reaction worked, but slowed down tremendously: after 3h a yield
of 17% was obtained at a conversion of 47% (Entry 5).
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TM
Table 2. Optimization of reaction conditions for the Ru-MACHO -BH (7)
catalysed transfer hydrogenation of crotonaldehyde to crotyl alcohol.[a]
O
OH
OH
8a
9a
11
O
OH
OH
O
Ru-MACHOTM-BH
Alcohol, T, t
H
8a
9a
[
b]
[b]
Temp.
Cat.
[mol%]
Time
[min]
Conv.
[%]
Yield
[%]
Entry
Alcohol
[°C]
1
2
3
4
5
6
EtOH
EtOH
EtOH
EtOH
rt
1
1
16h
60
12
98
5
50
56
refl.
refl.
refl.
refl.
1
10
>99
>99
39
70
0.1
1
10
69
[
c]
EtOH/H
2
O
60
14
i-PrOH
1
6.5
>99
>99
>99
Scheme 3. Monitoring reaction of the transfer hydrogenation in i-PrOH.
[
d]
7
i-PrOH
refl.
90
0.1
0.1
6.5
6.5
>99
>99
[e]
(
89)
Cyclohexanone was detected in the reaction mixture as a
consequence of the transfer hydrogenation. This reductant
allows isolation by distillation of low boiling alcohols.
Cyclo-
hexanol
8
>99
[
a] Reaction conditions:4.7 mmol croton aldehyde, 20 mL alcohol. [b]
Next, the reactions in EtOH and i-PrOH as solvents were
followed over time (Schemes 2, 3). We not only observed
differences in rate and yield, but also in selectivity. When EtOH
was used, ethyl acetate was detected in the reaction mixture as
a major side product, which is formed upon reaction of EtOH
with acetaldehyde to the hemiacetal, followed by its
dehydrogenation (Scheme 2). Previous reports on transfer
hydrogenation reactions with EtOH also report on ester
Determined by GC with dodecane as internal standard. [c] Ratio:
EtOH/H2O=9/1. [d] 24.3 mmol crotonaldehyde (2 mL), 80 mL solvent. [e]
Isolated yield.
In addition, i-PrOH used as hydrogen source turned out to be
more active and selective (Entries 6 and 7). In order to prove the
applicability of this process, the reaction was scaled up to 2 mL
of substrate, without any loss in selectivity (Entry 7). The desired
product crotyl alcohol was isolated in 89% yield. Other heavier
secondary alcohols, such as cyclohexanol, can also be applied
successfully as hydrogen source in our protocol (Entry 8).
[
15a, 25]
formation.
We assume that some acetaldehyde also reacts
with 8a and 9a as this accounts for the unidentified side
products found in this reaction. Additional proof for the formation
of acetaldehyde in this type of borrowing hydrogen chemistry
can be found in the work of Krische and co-workers who reacted
+
O
OH
Byproducts
8a
9a
[26]
ethanol with dienes via its dehydrogenation to acetaldehyde.
OH
O
O
When i-PrOH was used as hydrogen source and solvent
(Scheme 3) acetone was detected as the dehydrogenation
product of i-PrOH. In contrast to the results obtained in EtOH,
the saturated alcohol is the major by-product in i-PrOH, which
could be due to its slightly higher reflux temperature. However,
this by-product is only formed after full conversion, and this
allows us to stop the reaction on time to isolate the desired
product in high selectivities.
+
O
Intrigued by this new and efficient procedure for the selective
reduction of crotonaldehyde, we set off to explore its scope and
limitations in both solvents at reflux and 0.1 mol% catalyst
loading (Table 3). Aliphatic and aromatic aldehydes and ketones
were selectively reduced with very good conversions and yields
(
Table 3, entries 1-6). Representative examples of an aliphatic
aldehyde (8b) and ketone (8c) led to the corresponding alcohol
with high yields using EtOH as H source (89% and 80%
Scheme 2. Monitoring reaction of the transfer hydrogenation in EtOH.
2
respectively, Table 3, entries 1-2). Also, benzaldehyde (8d), for
was converted to benzyl alcohol (9d) in good yields in EtOH and
i-PrOH (71% and 87%, respectively, Table 3, entry 1). The α,β-
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O
O
OH
unsaturated substrates are of course more challenging, as
formation of the saturated side-product needs to be prevented.
Gratifyingly, our protocol delivered excellent yields and
selectivities towards the unsaturated primary alcohols in the
transfer hydrogenation of α,β-unsaturated aldehydes (Table 3,
entries 7-14, 62 to 99% isolated yields). Taking citral (8h) as
example, we were able to show that both EtOH and i-PrOH can
be used as hydrogen source, giving very good isolated yields
[e]
1
0
73
8
j
9j
OH
O
O
11
>99
8k
8l
9k
O
OH
(
Table 3, entry 6, 97% in both cases). In addition,
[
e]
e]
12
95
94
TM
9l
Table 3. Substrate scope of the Ru-MACHO -BH catalysed transfer
[
a]
hydrogenation.
O
OH
OH
OH
[
R2
O
R2 OH
R1 R4
13
Ru-MACHOTM-BH
8m
9m
9n
R1
R4
Alcohol
reflux
R3
R3
9
O
8
1
4
5
62
8n
Entry
1
Substrate
Product
Yield [%]
O
O
OH
[
b][e]
1
91
[
b]
89
80
8
b
c
9b
8
8
o
9o
9p
O
OH
[
b]
2
3
4
HO
O
O
O
[
e]
8
9c
9d
16
84
p
O
OH
OH
87
[b]
O
OH
71
8
d
e
[
e]
1
7
8
64
O
O
O
8q
9q
79
O
O
8
9e
[
d][e]
1
74
O
OH
5
6
>99
8
r
9r
8
f
9f
O
OH
O
OH
0
[b]
1
9
[
e]
c]
0
72
O
O
8s
9s
8
g
a
9g
9a
O
OH
O
OH
[
7
8
89
[d]
2
0
1
>99
8
O
O
8
t
9t
O
OH
O
O
[
b][e]
97
[
d][b]
[d]
6
6
O
O
2
3
5
8h
9h
8u
9u
Ph
Ph
O
OH
[a] Reaction Conditions: substrate (4.7 mmol), i-PrOH (20 mL), cat. loading 0.1%
mol, reflux, reaction run until starting material was consumed (from 2 to 30 mins
depending on the substrate), monitored by T.L.C. and CG using dodecane as
internal standard. All yields are isolated unless mentioned otherwise. [b] Isolated
yield of reaction in EtOH (20 mL). [c] Crotonaldehyde (24.1), i-PrOH (80 mL),
reflux, 6.5 mins. [d] CG-yield. [e] Catalyst loading 0.5 mol%.
9
97
8i
9i
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α,β-unsaturated ketones were also converted successfully to the
corresponding α,β-unsaturated secondary alcohols (entries 15-
reaction (Scheme 4). In this mechanism, it is presumed that
[
21c]
complex 7 loses BH
3
to give complex 7a.
In contrast to
1
8). In the case of β–Ionone (8o) EtOH again proved to be an
efficient hydrogen donor allowing the isolation of β-Ionol (9o) in
1% yield (entry 15). Interestingly, only the sterically less
previous work in which the pre-catalyst is activated by using
strong base, this catalyst works well under base-free conditions.
9
This is because BH
3
(or B
2
H
6
) can easily react with alcohol [B
2 6
H
hindered carbonyl group was reduced when α,β-unsaturated
dione (8p) was subjected to the transfer hydrogenation protocol
+ ROH → H
catalyst 7.
2
+ B(OR)
3
+ BH(OR) ] and thus activates the pre-
2
(
Table 3, entry 16). This was confirmed by a multiplet at 4.5 ppm
1
in the H-NMR for the corresponding proton attached to carbon
number 4 (See supporting information). The sterically more
demanding carbonyl functionality was previously reported to be
R3
R3
R4
R4
H
[
27]
H
reduced in alkaline media.
N
PPh2
CO
N
P
PPh2
CO
H2
Additionally, it is worth mentioning that non-conjugated C-C
double bonds also remained untouched under the reaction
conditions of this protocol (entries 8, 10, 15, 17, 19).
Unfortunately, this transfer hydrogenation protocol was not
successful for the reduction of cis-Jasmone (8s). No conversion
was observed even after increasing the catalyst loading to
Ru
Ru
H
P
Ph2
Ph2
H
7a
OH 7b
O
R1
R2
R
1
R
2
H
1
mol%. As shown in Scheme 9 (vide infra), the transfer
hydrogenation of 8s has a positive Gibbs free energy and is thus
not favored thermodynamically.
Scheme 4. Proposed hydrogenation mechanism.
In the case of 1-phenyl-but-2-en-one (8r), the selectivity was
completely reversed (Table 3, entry 18). We obtained the
saturated ketone (9r) as main product in 74% GC-yield, while
only a minor amount of the unsaturated alcohol was detected.
This is likely due to steric hindrance. We also notice that steric
hindrance determined the selectivity in the transfer
hydrogenation of 8p (Table 3, entry 16) and is also the most
[
21c]
In our previous work,
2
we found that H elimination from
7a to 7b has a free energy barrier of 21.3 kcal/mol, and the
reaction is slightly endergonic by 0.46 kcal/mol, and the barrier
of the reverse H
well established equilibrium and reversibility between 7a to 7b
atmosphere and the equilibrium state can be easily
adjusted by changing H pressure on the one hand; and on the
2
addition is 20.9 kcal/mol. This reveals possible
likely explanation for the moderate yield in 8q (Table 3, entry 17). under H
2
Additionally, we tested α,β-unsaturated ester (8u) in this
transfer hydrogenation protocol (Table 3, entry 21), and obtained
saturated ester (9u) as the main product using both EtOH and i-
PrOH as hydrogen sources.
2
other hand, it demonstrates their potential use as effective
hydrogenation and dehydrogenation catalysts.
2
Since both EtOH and i-PrOH are used as H source in our
In summary, Ru-MACHO-BH (7) is a very efficient catalyst
for the base-free transfer hydrogenation of aldehydes and
ketones and very selective for α,β-unsaturated aldehydes and
ketone compounds.
work, we computed their dehydrogenation on the basis of 7a to
7b. As shown in Scheme 5, EtOH dehydrogenation has a free
energy barrier of 15.6 kcal/mol and is endergonic by 6.0 kcal/mol,
while i-PrOH dehydrogenation has a free energy barrier of 18.0
TS(iPrOH)
18.0 [3.1]
Mechanism of the Reaction
TS(EtOH)
5.6 [1.8]
1
To understand the observed activity and selectivity, we
carried out density functional theory computation on the phenyl
substituted PNP amine and amido Ru catalysts (Ru-MACHO-BH,
[
28]
7
a and 7b, respectively) by using the Gaussian 09 program.
[
29]
All structures were optimized at the B3PW91
TZVP
level with the
for metals). All optimized
7a
+
[
30]
[31]
basis set (LANL2DZ
CH CHO
3
structures were characterized as either energy minimums
without imaginary frequencies or transition states with only one
imaginary mode by frequency calculations; and the imaginary
model connects the initial and the final states. The thermal
correction to Gibbs free energy at 298°K from the frequency
analysis was added to the total electronic energy.
7a
6.0 [4.2]
+
7b
+
CH COCH
3
-
3
2
.0 0.2]
i
PrOH
(or
0.0 [0.0]
EtOH)
[
kcal/mol and is only endergonic by 2.0 kcal/mol.
On the basis of the experimental and computed results
previously reported for PNP-ligated Fe and Ru catalysts for
hydrogenation reactions, we propose an outer-sphere ligand to
metal cooperative mechanism for the transfer hydrogenation
Scheme 5. Potential energy surface of EtOH and i-PrOH dehydrogenation
using 7b as catalyst.
[
32]
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For our study we took (E)-but-2-enal (8a,
R
=
H,
using isopropanol as hydrogen source. The computed potential
energies surfaces are shown in Schemes 7 and 8.
crotonaldehyde) and (E)-1-phenylbut-2-en-1-one (8r, R = Ph) as
substrates. As shown in Scheme 6, there are three competitive
hydrogenation routes, the first one is the 3,4-route in which the
C=O bond is hydrogenated, resulting in the formation of the allyl
alcohol; the second one is the 1,2-route in which the C=C bond
is hydrogenated, resulting in the formation of the saturated
carbonyl compound; and the third one is the 1,4-reduction
forming the enol, which can tautomerize to the saturated
carbonyl compound. Therefore, both 1,2- and 1,4-routes of
hydrogenation give the same product. Since the by-products of
the reduction using ethanol are much more complicated than
those of isopropanol due to the formation of dehydrogenative
coupling of aldehydes and alcohol (ethanol and crotyl alcohol as
well as crotyl addehyde and acetaldehyde), our discussion is
mainly focused on the potential energy surfaces obtained by
[
1,2]
4
O
4
OH
4
O
1
1
1
3
R
[1,4]
3
R
3
R
R
2
2
2
[
3,4]
1
[3,4]
4
OH
4
OH
1
R = H, Ph
3
R
3
2
2
Scheme 6. Proposed hydrogenation routes
OH
4
O
OH
OH
O
OH
H C
CH3
H
2
1
C
H
C
H
2
H
H
H
3
H
H
H
H
8a
9a
9ab
9aa
9bb
TS(C=C)
3.8 [19.1]
N
E
E
3
Ru
H
4
CO
O
3
C
2
1 CH3
C
C
CH3
H
H
4
3
1
O
C
HC
H
2
H
4
3 CH
C
2
1 CH3
H
C
H
C
O
N
E
E
H
H
H
Ru
H
CO
H
H
H
N
E
E
N
E
E
TS1(1,2)
0.4 [5.8]
Ru
H
Ru
H
2
CO
CO
TS1(1,4)
TS2(1,2)
5.2 [1.0]
TS(C=O)
4.3 [-0.3]
15.7 [1.7] Interm(1,2)
14.7 [0.8]
1
1
CH3
H C
2
7
2
a + 9a
.4 [0.4]
CH
H
2
O
C
H
Interm(1,4)
TS2(1,4)
H
N
5.8
[-9.6]
7
2
a + 8a
.0 [-0.2]
5.0 [-9.2]
E
Ru
H
H
H
C
3
2
C
E
H
H
CO
7
b + 9a
.4 [0.6]
3
2
C
1
4
O
CH3
H
4
O
C
C
1 CH3
0
C
TS( C- =O)
-2.2 [ 16.3]
H
7
b + 8a
H
H
7b + 9ab
-3.4
H
H
0.0 [0.0]
[
-3.1]
N
E
N
E
E
Ru
H
Ru
H
E
CO
CO
7
1
a + 9aa
1.7 [ 13.9]
-
-
7
1
b + 9aa
3.7 [ 13.7]
-
-
b + 9bb
7.5 [ 17.5]
- 7b
+
9bb
17.5 [ 17.5]
7
1
-
-
-
Scheme 7. Potential energy surface of crotonaldehyde (8a) hydrogenation using i-PrOH as hydrogen source
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Chemistry - A European Journal
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At first we computed the selective transfer hydrogenation of
Since the barriers of all these favored transformation are
lower than that of isopropanol dehydrogenation into acetone, the
latter should be the rate-determining step. In addition, it is
interesting to discuss the driving force of the formation of allyl
alcohol (9a). On the basis of the reaction equation [8a +
isopropanol = 9a + acetone], this reaction is endergonic by 0.4
kcal/mol and slightly less favored thermodynamically. The
driving force can be the excess of isopropanol as solvent and
hydrogen source, which can shift the reaction toward formation
of product 9a. Another mechanism to drive the reaction forward
might be the formed acetone, which has lower boiling point than
isopropanol (56 vs. 83°C) and passes from the liquid phase into
the gas phase at the boiling point of isopropanol. Such a change
in physical state can also shift the reaction to product 9a.
Furthermore, we also used cyclohexanol as hydrogen
source, both cyclohexanol and cyclohexone have higher boiling
points (161.8 and 155.6°C, respectively ) than isopropanol and
the reaction takes place at 90°C (Table 2, entry 8). Alike
isopropanol as hydrogen source, the reaction with cyclohexanol
as hydrogen source [8a + cyclohexanol = 9a + cyclohexanone]
is slightly endergonic by 1.5 kcal/mol and less favored
thermodynamically. The driving force must be the excess of
cyclohexanol as solvent and hydrogen source, which can shift
the reaction toward the formation of product 9a. In addition, the
reaction using ethanol as hydrogen source resulting in the
formation of crotyl alcohol and ethyl acetate [2×ethanol + 2×8a =
2×9a + ethyl acetate] is computed to be exergonic by 3.03
kcal/mol, a thermodynamically favoured process.
(
E)-but-2-enal (8a) catalyzed by 7a. For the hydrogenation of the
C=O bond (3,4-route) resulting in (E)-but-2-en-1-ol (9a) [8a + 7a
9a + 7b], a concerted two-bond asynchronous transition state
corresponding mainly to hydride transfer is located; this step has
a barrier of 12.3 kcal/mol and is exergonic by 1.6 kcal/mol. For
the 1,2- and 1,4- reduction routes, we found a stepwise reaction
mechanism. For the 1,2-route resulting in butyraldehyde (9aa)
=
[
8a + 7a = 9aa + 7b], the first step goes through the transition
state for Ru-H transfer to the C1, breaking the Ru−H bond and
forming the C1-H bond, resulting in an ionic intermediate; and
the second step goes through the transition state of N−H
transfer to the C2, breaking the N−H bond and forming the
terminal C2−H bond. The free energy barrier of the Ru−H
hydride transfer is 18.4 kcal/mol. The intermediate is endergonic
by 12.7 kcal/mol, and the N−H proton transfer has a free energy
barrier of 13.2 kcal/mol. The formation of butyraldehyde (9aa) is
exergonic by 15.7 kcal/mol.In the 1,4-route resulting in (E)-but-1-
en-1-ol (9ab) [8a + 7a = 9ab + 7b], the first step goes via the
transition state for Ru-H transfer to the C1, breaking the Ru−H
bond and forming the C-H bond, resulting in an enolate
intermediate. The second step goes via the transition state of
breaking the N−H bond and forming the terminal O−H bond. The
free energy barrier of the Ru−H transfer is 13.7 kcal/mol. The
intermediate is endergonic by 3.0 kcal/mol, and the N−H proton
transfer has a free energy barrier of 3.8 kcal/mol. The formation
of 9ab is exergonic by 5.4 kcal/mol. It shows that the 1,4-
addition is more favored kinetically than the 1,2-addition by 4.7
kcal/mol. The tautomerization of 9ab to 9aa is exergonic by 10.3
kcal/mol.
For the hydrogenation of (E)-1-phenylbut-2-en-1-one, only
the 1,4-route of alkene hydrogenation was found (Scheme 8), all
attempts to optimize the transition state of the 1,2-hydrogenation
route results in the 1,4-hydrogenation route.
In addition, we computed the subsequent hydrogenation of
E)-but-2-en-1-ol (9a) and butyraldehyde (9aa) to butanol (9bb)
(
for comparison. For 9a hydrogenation to 9bb, the barrier is as
high as 31.4 kcal/mol and the reaction is highly exergonic by
For the 1,4-hydrogenation route resulting in the formation of
(E)-1-phenylbut-1-en-1-ol (9ra) [8r + 7a = 9ra + 7b], the barrier
for Ru-H transfer is 12.9 kcal/mol. The formation of the
intermediate is endergonic by 1.9 kcal/mol, and the N-H transfer
has a barrier of 2.5 kcal/mol. The formation of (E)-1-phenylbut-1-
en-1-ol (9ra) is exergonic by 5.6 kcal/mol. The tautomerization of
(E)-1-phenylbut-1-en-1-ol (9ra) to 1-phenylbutan-1-one (9r) is
exergonic by 12.4 kcal/mol.
For the 3,4-route of C=O hydrogenation with the formation of
(E)-1-phenylbut-2-en-1-ol (9rb) [8r + 7a = 9rb + 7b], the Gibbs
free energy barrier is 21.2 kcal/mol, and the reaction is
endergonic by 1.1 kcal/mol.
19.9 kcal/mol; indicating a kinetically hindered reaction.
Therefore, 9a once formed, cannot be easily further
hydrogenated, despite the favored thermodynamics. For the
hydrogenation of 9aa to 9bb, we also found a concerted two-
bond asynchronous transition state corresponding mainly to
hydride transfer and the barrier is 9.5 kcal/mol and the reaction
is exergonic by 5.8 kcal/mol. This indicates that butyraldehyde
(
9aa), once formed, can be easily hydrogenated to butanol (9bb
or 11). On the basis of these competitive hydrogenation steps,
one can get the selectivity between 9a and 9aa. As shown in
Scheme 7, the barrier difference between the competitive 3,4-
and 1,4-routes is only 1.4 kcal/mol, in favor of the 3,4-route.
Our results also explain the findings shown in Scheme 3
regarding isopropanol as hydrogen source. After about five
minutes, 8a is fully converted and 9a is the major product in very
high yield, while 9bb is the minor product in very low yield. After
elongated reaction time up to 25 minutes, the amount of 9a
decreases slowly, whereas the mount of 9bb increases. Since
the barrier (9.5 kcal/mol) of the hydrogenation of 9a to 9bb is
lower than that (13.8 kcal/mol) of the reverse reaction of 9a to 8a
and that (13.7 kcal/mol) of 8a to 9b, butyraldehyde (9aa)
formation cannot be observed. This agreement validates our
computational models and methods.
For comparison, we computed the hydrogenation of 1-
phenylbutan-1-one (9r) and (E)-1-phenylbut-2-en-1-ol (9rb) into
1-phenylbutan-1-ol (9rc). For the hydrogenation of 9rb to 9rc, a
concerted
two-bond
asynchronous
transition
state
corresponding mainly to hydride transfer was located, and the
barrier is as high as 28.0 kcal/mol and the reaction is highly
exergonic by 19.5 kcal/mol; indicating a kinetically hindered
reaction. Therefore, once 9rb formed, it cannot be easily further
hydrogenated, despite the favored thermodynamics.
For the hydrogenation of 9r to 9rc, we also found a
concerted
two-bond
asynchronous
transition
state
corresponding mainly to hydride transfer and the barrier is 21.3
kcal/mol and the reaction is exergonic by 0.4 kcal/mol. This
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Chemistry - A European Journal
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indicates that once 9r formed, it also cannot be easily
hydrogenated to 9rc. This is in good agreement with the
experimental result that 9r is the major product of the
hydrogenation of 8r.
On the potential energy surface (Scheme 7), one can see
that the 1,4-hydrogenation to the enol is more favored both
kinetically and thermodynamically than the C=O hydrogenation
by 8.3 and 19.1 kcal/mol, respectively. This is in perfect accord
Since the barrier from 8r to 9ra is lower than that of
isopropanol dehydrogenation into acetone, the latter should be
the rate-determining step.
In addition, the reaction [8r + isopropanol = 9r + acetone] is
highly exergonic by 16.0 kcal/mol, and this should be the driving
force. For using ethanol as hydrogen source, the reaction
[2×ethanol + 2×8r = 2×9r + ethyl acetate] is computed to be
exergonic by 35.35 kcal/mol, a thermodynamically very favoured
process.
with the experimental data (Table 3, Entry 18).
OH
CH
CH3
Ph
C
C
H
4
O
OH
OH
O
OH
H
H
1
H
N
E
2
Ph
3
Ph
Ph
Ph
Ph
E
CH3
Ru
H
1
8r
9rb
9ra
9r
9rc
CO
HC
2
CH
4
3
O
C
TS(C=C)
3.1 [17.9]
Ph
3
H
H
N
E
E
Ru
H
CO
Ph
H
2
3
4
O
C
C
1 CH3
C
TS(C=O)
3.2 [6.8]
H
2
H
H
CH3
N
E
E
H
C
2
Ru
H
CH2
Ph
CO
O
H
C
H
Ph
H
2
3
TS1(1,4)
4.9 [0.1]
4
O
C
C
1 CH3
1
C
N
E
E
H
Ru
H
H
H
CO
N
E
Ru
H
TS(C=O)
-
7
5
a + 9rb
.1 [3.0]
E
CO
7
.3 [ 9.9]
Interm(1,4)
.9 [-10.1]
TS2(1,4)
.5 [-10.2]
7
2
a + 8r
.0 [-0.2]
4
3
7
b + 9rb
3.1 [3.2]
7
0
b + 8r
.0 [0.0]
7b + 9ra
3.6 [ 3.7]
-
-
7
a + 9r
4.0 [ 16.1]
-
-
1
7
1
b + 9rc
4.4 [ 15.0]
7b + 9rc
14.4 [ 15.0]
-
-
-
-
7
b + 9r
6.0 [ 15.9]
-
-
1
Scheme 8. Potential energy surface of (E)-1-phenylbut-2-en-1-one (8r) hydrogenation using iPrOH as hydrogen source.
In addition, we computed the hydrogenation of 2,3-
dimethylcyclopent-2-enone as a model substrate for Jasmone
respectively, indicating that this step is not favored
thermodynamically. Instead, the reverse reaction, the
dehydrogenation from the alcohol back to the ketone is favored
thermodynamically. This endergonic property explains nicely
why Jasmone (8s) could not be reduced in the transfer
hydrogenation to the corresponding allyl alcohol.
(
8s, Table 3, entry 19). Basically, we computed only the
thermodynamics on the basis of molecular H and i-PrOH as
2
hydrogen sources; and the results are listed in Scheme 9. It was
found that the hydrogenation of the C=O double bond of 2,3-
dimethylcyclopent-2-en-1-one is endergonic by 6.3 and 8.8
Although the competitive C=C bond hydrogenation is favored
kcal/mol with molecular H
2
and i-PrOH as hydrogen source,
2
thermodynamically with molecular H as hydrogen source (ΔG =
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Chemistry - A European Journal
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[
33a]
-
4.2 kcal/mol), and it becomes less exergonic (ΔG = -1.8
Although an inner-sphere mechanism
seems very
kcal/mol) with i-PrOH as hydrogen source, the barrier for this
reaction on the tetra-substituted internal C=C double bond is
expected to be very high for steric reasons.
unlikely, there have been two reports on the prevalence of an
inner-sphere mechanism with a ruthenium catalyst containing an
NH in the ligand. One was on the hydrogenation of ketones
using a ruthenium catalyst, the ligand of which contained a
Further calculations show that the hydrogenation of 2,3-
[
33b]
dimethylcyclopent-2-enol
(allyl
alcohol)
into
2,3-
primary amine.
The other pertained to an acceptor-less
dimethylcyclopentanol is favored thermodynamically with
molecular H2 and i-PrOH hydrogen sources (ΔG = -13.1 and -
alcohol dehydrogenation using a ruthenium complex containing
[
33c]
a secondary amine in the ligand.
For this reason we decided
1
0.7 kcal/mol, respectively), but this may also not be accessible
to perform additional calculations to establish if this mechanism
is reasonable in our case. In this mechanism it is presumed that
due to the high barrier caused by the sterics.
The hydrogenation of 2,3-dimethylcyclopentanone into 2,3-
3
the ruthenium-Macho-BH catalyst first dissociates BH to form
dimethylcyclopentanol is less exergonic with molecular H
2
and i-
7a. This then reacts with the carbonyl substrate to form 7b. In
the next step 7b reacts with the alcohol forming the ruthenium
alkoxide complex in which the nitrogen is protonated. In order to
regenerate 7a from this complex, the alkoxide has to undergo β-
hydride elimination. In order for this to be possible, however, a
free coordination site is needed. This can only be created either
by CO ligand dissociation or by dissociation of one of the
phosphine ligands. The CO dissociation is however highly
PrOH as hydrogen source (ΔG = -2.5 and -0.1 kcal/mol,
respectively). Finally, we computed the thermodynamics and
kinetics of the hydrogenation of 2,6,6-trimethylcyclohex-2-ene-
1
,4-dione (8p) (Scheme 9). For the reduction of the less
hindered C=O double bond, the reaction is exergonic with
molecular H as reductant (ΔG = -0.4 kcal/mol), whereas it
2
becomes endergonic (ΔG = 2.0 kcal/mol) with i-PrOH as
hydrogen source. In addition, the Gibbs free energy barrier for
the C=O hydrogenation is 16.9 kcal/mol, which is lower than the
barrier (18.0 kcal/mol) of isopropanol dehydrogenation. This
indicates that it is possible to hydrogenate the sterically less
hindered C=O double bond with excess isopropanol as solvent.
On the other hand, hydrogenation of the more hindered C=O
endergonic, e.g.; CO dissociation resulting in the singlet/triplet
i
state of PNHP-Ru-OCH
2
CH
3
-CO, PNHP-Ru-OPr-CO and
PNHP-Ru-H-CO is endergonic by 48.7/54.8, 44.7/52.1 and
50.5/57.9 kcal/mol, respectively, for the Ru-ethoxide, Ru-
isopropoxide as well as the 7a complexes. The de-coordination
of one of phosphine ligands is also highly endergonic by 35.2
kcal/mol. As these energy costs are much higher than the barrier
for the outer-sphere hydrogenation mechanism we can safely
conclude that the inner-sphere mechanism is highly unlikely.
double bond is more exergonic with molecular H
2
as reductant
(
ΔG = -0.9 kcal/mol) and less endergonic (ΔG = 1.5 kcal/mol)
with i-PrOH. The Gibbs free energy barrier is 32.8 kcal/mol;
which is nearly double of that of the less hindered C=O
hydrogenation, indicating a kinetically severely hindered reaction.
-
G = 2.5
-
-
∆
OH
∆G = 13.1
-
Conclusions
[
∆G = 0.1]
[∆G = 10.7]
TM
For the first time, commercial Ru-MACHO -BH was used in an
efficient and straightforward base-free transfer hydrogenation
using low catalyst loading and short reaction times. The system
allows the reduction of aromatic and aliphatic carbonyl
compounds as well as α,β-unsaturated ketones and aldehydes,
such as crotonaldehyde. In the transfer hydrogenation, not only
the commonly used i-PrOH, but also EtOH can be used as
hydrogen source. On the basis of the proposed outer-sphere
mechanism, B3PW91 density functional theory computations
were carried out and the results are in accord with a bifunctional
catalysis mechanism where allylic alcohol is formed as the
kinetic product from crotonaldehyde, whereas the hydrogenation
of (E)-1-phenylbut-2-en-1-one into butyrophenone via the
O
O
OH
-
-
∆
G = 4.2
∆G = +6.3
[∆G = +8.8]
[
∆G = 1.8]
O
O
O
O
O
OH
-
-
∆
[
G = 11.6
∆G = 9.2]
∆G = 0.4
-
[∆G = +2.0]
-
∆
[
G = 0.9
∆G = +1.5]
HO
O
formation of (E)-1-phenylbut-1-en-1-ol as
a result of 1,4-
reduction is favored both kinetically and thermodynamically. The
transfer hydrogenation of 2,3-dimethylcyclopent-2-enone is
thermodynamically not favored. These results are in complete
accord with the experimental results.
Scheme 9. Computed thermodynamics (kcal/mol) of the reduction of 2,3-
dimethylcyclopent-2-en-1-one and 2,6,6-trimethylcyclo-hex-2-ene-1,4-dione
2
(8p) with molecular H and iPrOH as hydrogen source (in square brackets)
Experimental Section
Although the C=C double bond hydrogenation is highly
favored thermodynamically with molecular H and i-PrOH as
2
TM
General procedure for the Ru-MACHO -BH catalysed transfer
hydrogen sources (ΔG = -11.6 and -9.2 kcal/mol, respectively),
the Gibbs free energy barrier for the C=C hydrogenation is as
high as 31.0 kcal/mol which indicates a kinetically hindered
reaction. This is in full agreement with the experimentally result
hydrogenation.
A dry 50 ml Schlenk round-bottom flask provided with a stirring bar was
purged with 3 argon-vacuum cycles and charged with a solution of 4.7
mmol substrate in 20mL of solvent. The corresponding catalyst loading
(
Table 3, entry 16).
2 2
was added via syringe as a stock solution in anhydrous CH Cl (17mM).
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Chemistry - A European Journal
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The reaction mixture was stirred at alcohol reflux. Reaction progress was
monitored with TLC and GC until starting material was fully converted
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Leibniz institute for Catalysis for their careful and dedicated job.
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Entry for the Table of Contents (Please choose one layout)
Layout 1:
FULL PAPER
OH
H
O
Without prodding
Ronald A. Farrar-Tobar, Zhihong
Wei, Haijun Jiao, Sandra Hinze,
Johannes G. de Vries*
R1
R2
R1
R2
Transfer hydrogenation of α,β-
unsaturated aldehydes and
ketones with EtOH or I-PrOH can
be effected using 0.1 mol% of Ru-
MACHO-BH as catalyst. This
catalyst does not need any base
activation, thus resulting in very
high selectivities.
H
Ru
H
H
N
PPh2
CO
N
PPh2
CO
Page No. – Page No.
Ru
H
P
Ph2
P
Ph2
Selective base-free transfer
hydrogenation of α,β-unsaturated
carbonyl compounds using i-PrOH
or EtOH as hydrogen source.
R4
OH
R4
O
R3
R6
R3
R6
H
R5
R5
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