Scope and Mechanistic Analysis for Chemoselective Hydrogenolysis of Carbonyl Compounds Catalyzed by a Cationic Ruthenium Hydride Complex with a Tunable Phenol Ligand

Article abstract of DOI:10.1021/jacs.5b06097

A cationic ruthenium hydride complex, [(C₆H₆)(PCy₃)(CO)RuH]⁺BF₄^- (1), with a phenol ligand was found to exhibit high catalytic activity for the hydrogenolysis of carbonyl compounds to yield the corresponding aliphatic products. The catalytic method showed exceptionally high chemoselectivity toward the carbonyl reduction over alkene hydrogenation. Kinetic and spectroscopic studies revealed a strong electronic influence of the phenol ligand on the catalyst activity. The Hammett plot of the hydrogenolysis of 4-methoxyacetophenone displayed two opposite linear slopes for the catalytic system 1/p-X-C₆H₄OH (ρ = -3.3 for X = OMe, t-Bu, Et, and Me; ρ = +1.5 for X = F, Cl, and CF₃). A normal deuterium isotope effect was observed for the hydrogenolysis reaction catalyzed by 1/p-X-C₆H₄OH with an electron-releasing group (k_H/k_D = 1.7-2.5; X = OMe, Et), whereas an inverse isotope effect was measured for 1/p-X-C₆H₄OH with an electron-withdrawing group (k_H/k_D = 0.6-0.7; X = Cl, CF₃). The empirical rate law was determined from the hydrogenolysis of 4-methoxyacetophenone: rate = k_obsd[Ru][ketone][H₂]^-1 for the reaction catalyzed by 1/p-OMe-C₆H₄OH, and rate = k_obsd[Ru][ketone][H₂]⁰ for the reaction catalyzed by 1/p-CF₃-C₆H₄OH. Catalytically relevant dinuclear ruthenium hydride and hydroxo complexes were synthesized, and their structures were established by X-ray crystallography. Two distinct mechanistic pathways are presented for the hydrogenolysis reaction on the basis of these kinetic and spectroscopic data. (Chemical Equation Presented).

Full text of DOI:10.1021/jacs.5b06097

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Journal of the American Chemical Society
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Scope and Mechanistic Analysis for Chemoselective Hydro-
genolysis of Carbonyl Compounds Catalyzed by a Cationic
Ruthenium-Hydride Complex with Tunable Phenol Ligand
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Nishantha Kalutharage and Chae S. Yi*
Department of Chemistry, Marquette University, Milwaukee, Wisconsin 53201-1881 United States
+
-
ABSTRACT: A cationic ruthenium-hydride complex [(C
6
H
6
)(PCy
3
)(CO)RuH] BF (1) with phenol ligand was found to ex-
4
hibit high catalytic activity for the hydrogenolysis of carbonyl compounds to yield corresponding aliphatic products. The
catalytic method showed exceptionally high chemoselectivity toward the carbonyl reduction over alkene hydrogenation.
Kinetic and spectroscopic studies revealed a strong electronic influence of the phenol ligand on the catalyst activity. Ham-
mett plot of the hydrogenolysis of 4-methoxyacetophenone displayed two opposite linear slopes from the catalytic system
1
/p-X-C
served for the hydrogenolysis reaction catalyzed by 1/p-X-C
Et), whereas an inverse isotope effect was measured from 1/p-X-C
6
H
4
OH (ρ = -3.3 for X = OMe, t-Bu, Et, Me; ρ = +1.5 for X = F, Cl, CF
OH with electron-releasing group (k
OH with electron-withdrawing group (k
). The empirical rate law was determined from the hydrogenolysis of 4-methoxyacetophenone: rate =
3
). Normal deuterium isotope effect was ob-
/k = 1.7-2.5; X = OMe,
/k = 0.6-
6
H
4
H
D
6
H
4
H
D
0
.7; X = Cl, CF
3
-
1
]0 for the reaction cata-
k
obs[Ru][ketone][H
2
] for the reaction catalyzed by 1/p-OMe-C
6
H
4
OH, and rate = kobs[Ru][ketone][H
2
lyzed by 1/p-CF
3
-C
6
H
4
OH. Catalytically relevant dinuclear ruthenium-hydride and -hydroxo complexes were synthesized,
and their structures were established by X-ray crystallography. Two distinct mechanistic pathways are presented for the
hydrogenolysis reaction on the basis of these kinetic and spectroscopic data.
INTRODUCTION
drodeoxygenation of biomass-derived furans into alkanes
using H
.8 A number of Lewis acid catalysts have also been
2
Transition metal-catalyzed C=O cleavage reactions of ox-
ygenated organic compounds continues to attract broad
interests in catalysis research fields because of their fun-
damental importance in both industrial-scale petroleum
and biomass feedstock reforming processes as well as in
used for silane-mediated reductive deoxygenation of car-
9
boxylic acid derivatives. In the field of homogeneous ca-
talysis directed to organic synthesis, one of the central
challenges has been centered on the design of catalytic
hydrogenolysis methods which exhibit high chemoselectiv-
ity toward the carbonyl reduction over olefin hydrogena-
tion.
1
organic synthesis of biologically active molecules. In tradi-
tional organic synthesis, both Clemmensen and Wolff-
Kishner methods have been widely used for the reduction
of aldehydes and ketones to corresponding aliphatic prod-
Hydrogenolysis (deoxygenation) of alcohols and ether
compounds constitutes another highly versatile functional
group transformation in organic synthesis.10 A number of
direct and indirect deoxygenation methods for alcohols
and ethers have been developed over the years, and these
have been successfully utilized to synthesize complex or-
ganic molecules.11 Since these classical methods employ
stoichiometric amount of metal reductants, recent re-
search efforts have been focused on the development of
catalytic C–O bond hydrogenolysis methods for ethers and
related oxygenated organic compounds. In a seminal re-
port, Hartwig and co-workers reported a highly effective
Ni-catalyzed hydrogenolysis of aryl ethers to form arenes
and alcohols.12 A number of soluble transition metal cata-
lysts have been successfully employed to promote C–O
cleavage reactions of lignin analogs.13 Transition metal-oxo
complexes have been found to exhibit promising catalytic
activity for the deoxygenation of bio-derived alcohols and
polyols.14 In heterogeneous catalysis, mesoporous zeolite-
supported metal catalysts have been shown to be particu-
larly effective for selective hydrogenolysis of biomass-
2
ucts. However, these classical methods pose significant
environmental and economic problems especially in large-
scale industrial processes because they use stoichiometric
reducing agents such as Zn/Hg amalgam and hydra-
zine/KOH. To overcome such shortcomings associated
with the stoichiometric methods, considerable efforts have
been devoted to develop catalytic reduction methods for
carbonyl compounds. In a pioneering study, Milstein and
co-workers pertinently demonstrated catalytic activity of
Ru-pincer complexes toward hydrogenation and hydro-
3
4
genolysis of esters and related carbonyl compounds. Guan
and Leitner groups independently employed pincer-ligated
Fe catalysts to achieve highly selective hydrogenation of
5
esters to alcohols. Pincer-ligated iridium-hydride catalysts
have been found to be particularly effective for direct hy-
drogenation of carboxylic acid derivatives and glycols as
well as hydrosilylation of glucose.3a,6 Ligand-modified het-
erogeneous Pd catalysts have been found to be effective for
the hydrogenolysis of carbonyl substrates, but these cata-
7
lysts require silane as the reducing agent. Heterogeneous
Pd and Pt catalysts have been successfully utilized for hy-
1
5
derived polyols and ethers. Heterogeneous zeolite cata-
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Page 2 of 11
lysts have also been used for commercial-scale methanol- (1 atm) also gave the carbonyl reduction product 2b with-
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
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2
2
2
2
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4
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4
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4
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4
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5
5
6
to-olefin process to produce liquid hydrocarbon commodi-
ties.16 From the viewpoint of achieving green and sustain-
able chemistry, efficient catalytic C–O bond cleavage meth-
ods are critically important for the conversion of oxygen
rich biomass feedstock into a renewable source of fine
chemicals and liquid hydrocarbon fuels.17
out forming the ether product. These initial results dis-
closed that phenol acted as the ligand for the Ru catalyst in
steering its activity toward the carbonyl hydrogenolysis
over the etherification reaction, where 2-propanol or H
can be used as the reducing agent.
2
Table 1. Optimization Study for the Hydrogenoly-
a
We recently discovered that a well-defined cationic ru-
sis of 4-Methoxyacetophenone
+
-
thenium hydride catalyst [(C
6
H
6
)(PCy
3
)(CO)RuH] BF (1)
4
en
catalyst
ligand
phenol
phenol
aniline
solvent
Yieldb
is a highly effective catalyst precursor for a number of de-
hydrative C–H coupling reactions of alkenes and arenes
with alcohols.18 We also found that the complex 1 catalyzes
selective dehydrative etherification of alcohols and ke-
tones.19 Since the formation of water has been served as
the driving force for mediating selective C–O bond cleav-
age of alcohol substrates in these coupling reactions, we
have been exploring the synthetic utility of dehydrative
coupling reactions of carbonyl compounds. In this report,
we delineate full details of the discovery, substrate scope
and mechanistic study of the catalytic hydrogenolysis of
carbonyl compounds to corresponding aliphatic products.
The unique features of the hydrogenolysis method are that
0
1
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3
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5
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1
1
1
1
1
1
1
1
1
3
dioxane
PhCl
95
89
<5
35
<5
73
54
<5
<5
95
0
2
3
PhCl
4
2-NH
2
PhCOMe
PhCl
5
PhCONH
2
PhCl
6
1,2-catechol
1,1’-BINOL
toluene
toluene
toluene
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
7
8
1,2-C H (NH )
6
4
2
2
9
phenol
phenol
phenol
phenol
phenol
phenol
phenol
10
3/HBF
[Ru(cod)Cl
RuCl ·3H
Ru
(PPh
[(PCy
CN) RuH]BF
Reaction conditions: 4-methoxyacetophenone (1.0 mmol), H
4 2
·OEt
1
1
2 x
]
it employs cheaply available H as the reducing agent, and
2
utilizes tunable ligand-modified ruthenium-hydride cata-
lysts to achieve high activity and chemoselectivity for the
catalytic reduction of ketones to aliphatic products without
forming any wasteful byproducts.
12
13
3
2
O
0
3
(CO)12
0
1
1
4
5
3
)
3
(CO)RuH
2
0
3
)
2
(CO)(CH
3
30
2
4
RESULTS AND DISCUSSION
a
2
(2
atm), catalyst (3 mol %), ligand (10 mol %), solvent (2 mL), 130 °C,
1
benzoate as an internal standard.
In an effort to extend the scope of dehydrative coupling
methods, we initially explored the catalytic activity of 1 for
the dehydrative coupling of ketones with alcohols (Scheme
2 h. b The product yield was determined by H NMR by using methyl
1
Encouraged by these initial results, we screened a num-
ber of oxygen and nitrogen donor ligands as well as ruthe-
nium catalysts for the hydrogenolysis of 4-
1
). Following the previously optimized set of conditions,19b
the treatment of acetophenone (1.0 mmol) with 2-
propanol (2.5 mmol) in the presence of the catalyst 1 (2
mol %) in chlorobenzene (3 mL) at 110 °C resulted in the
methoxyacetophenone with H (2 atm) (Table 1). The cati-
2
onic Ru-H complex 1 with phenol ligand exhibited the
highest activity among screened oxygen- and nitrogen do-
nor ligands under the specified set of conditions (entries 1-
8). Bidentate oxygen and nitrogen ligands showed a mod-
est activity for the hydrogenolysis of 4-methoxyphenone
(entries 3-8). The cationic Ru-H complex formed in-situ
from the reaction of the tetranuclear Ru-H complex
selective
formation
of
the
ether
product
PhCH(Me)OCHMe
2
in 72% yield. In a dramatically altered
reactivity pattern, the analogous coupling of 2-
acetylphenol with 2-propanol under otherwise similar
reaction conditions unexpectedly formed 2-ethylphenol
product 2a instead of the anticipated ether product. The
product 2a apparently resulted from the carbonyl reduc-
tion of 2-acetylphenol.
{[(PCy
3
)(CO)RuH]
4
(µ
4
-O)(µ
3
-OH)(µ
2
-OH)}
(3)
with
HBF ·OEt and phenol ligand also showed identical activity
4
2
Scheme 1.
as 1/phenol for the hydrogenolysis reaction (entry 10),20
and this procedure has been found to be particularly useful
for measuring the kinetics (vide infra). Among screened
solvents, both 1,4-dioxane and chlorobenzene were found
to be most suitable for the hydrogenolysis reaction.
OH
H
H
H
OH
or
H
O
H2 (1 atm)
1 (3 mol %)
C6H5Cl, 110 o
1
(3 mol %)
PhOH (10 mol%)
C6H5Cl, 110
X = H)
C
X
O
(X = H)
2
b
o
C
(
OH
or
H2 (1 atm)
Reaction Scope. We surveyed the substrate scope of
the hydrogenolysis reaction by using the catalytic system
of 1/PhOH (Table 2). Both aliphatic and aryl-substituted
aldehydes were effectively reduced to the corresponding
alkyl products without forming any alcohols or other side
products (entries 1-4). For the hydrogenolysis of an ali-
phatic enal substrate, a highly chemoselective hydrogenol-
ysis of the aldehyde group was observed to form the prod-
uct 2f, without the C=C bond hydrogenation (entry 4). The
hydrogenolysis of both aliphatic and aryl-substituted ke-
tones smoothly proceeded to afford the corresponding
OH H
H
BF4
Ru
1
(3 mol %)
C6H5Cl, 110 oC
X = OH)
H
PCy3
OC
1
(
2a
Suspecting that the phenol group might have assisted in
the carbonyl reduction, we next examined the reaction of
acetophenone with 2-propanol by using a catalytic amount
of 1 (3 mol %) and phenol (10 mol %). Indeed, the reac-
tion selectively formed ethylbenzene 2b over the ether
product. The analogous treatment of acetophenone with H
2
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Journal of the American Chemical Society
aliphatic products 2g-2t (entries 5-20). The hydrogenoly-
sis of aliphatic ketones typically required a higher pressure
of H than the aryl-substituted ketones, and in these cases,
the hydrogenolysis using 2-propanol was found to be con-
venient in yielding the aliphatic products (entries 15, 16).
High chemoselectivity for the carbonyl hydrogenolysis for
an enone substrate formed the corresponding olefin-
product 2r (entry 18). The hydrogenolysis of ketones con-
taining oxygen and nitrogen atoms led to the correspond-
ing aliphatic products 2q-2t (entries, 17, 19, 20).
and ketone groups to form the corresponding aliphatic
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
products (-)-2u and (-)-2v, respectively, without giving
any olefin hydrogenation products. In the case of proges-
terone, a 1:1 mixture of olefin isomerization products was
obtained. For chloroamphenicol, chemoselective hydro-
genolysis of benzylic alcohol was observed over the ali-
phatic alcohol in forming (-)-2w, while the regioselective
hydrogenolysis of the carbonyl anti to the catechol group
for alizarin was achieved to give the product 2x. The hy-
drogenolysis of haloperidol and ebastine cleanly yielded
the corresponding aliphatic products 2y and 2z, respec-
tively, without forming any side products. The catalytic
method exhibits high selectivity toward the hydrogenoly-
sis of alcohol and ketone groups while tolerating common
oxygen and nitrogen functional groups.
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Table 2. Catalytic Hydrogenolysis of Aldehydes
a
and Ketones
entry carbonyl compound
CHO
product(s)
method time (h) yield (%)
CH3
HO
HO
Table 3. Hydrogenolysis of Biologically Active
X
X
a
Alcohols and Carbonyl Compounds
1
2
X = H
X = OMe
2c
A
B
12
12
90
95
2d
CHO
CH
3
O
3b
A
A
8
92
72
ArO
ArO
8
H
H
2e
CHO
4
12
H
H
H
H
H C
H C
2
2
f
2
8
OH
X
O
OH
(-)-2u 67%
(-)-2v 52% (1:1)
O
OH
R
R
H2
C
H
N
CHCl
OH
2
X
O
N
5
6
7
8
X = H R = Me
2a
2g
A
B
A
B
8
8
8
8
94
91
92
91
O N
Cl
C
X = H R = Et
X = H R = CH
X = F R = Et
2
OH
(-)-2w 45%
H
CH
2
Ph 2h
2
2
2i
2x (71%)
CMe3
O
H2
C
OH
Ph
N
C
H
2
X
X
n
X
n
9
X = H
n = 1
2j
A
A
16
16
90
88
F
Ph
O
1
0
X = OMe n = 2
2k
O
(-)-2y 68%
2z 84% (rsm 10%)
a
Reaction conditions: alcohol/ketone (1.0 mmol), H
2
(2 atm), 1 (3
X
mol %)/4-methoxyphenol (10 mol %), dioxane (2 mL), 130 °C, 12 h.
1
1
1
1
1
X = H
X = Cl
2b
2l
A
B
A
B
12
12
12
12
79
81
92
95
2
3
4
X = Me
X = OMe
2m
2n
Kinetics and Mechanistic Study: Hammett Study.
We performed the following kinetic studies to probe de-
tailed mechanism of the catalytic hydrogenolysis reaction.
First, to gauge electronic effect of phenol ligand on the cat-
alytic activity, we compared the rates of the hydrogenoly-
sis reaction by using a series of para-substituted phenols
O
7
1
1
5
6
A
A
24
24
65
54
7
O
2o
Ph
Ph
2
p
O
O
O
O
1
7
A
12
95
p-X-C
noted before, the Ru catalyst generated in-situ from
/HBF ·OEt /PhOH was used in these kinetic experiments
6
H
4
OH (X = OMe, t-Bu, Et, Me, H, F, Cl, CF ) (eq 1). As
3
2
q
3
4
2
Ar
Ar
1
8b
A
B
A
12
24
12
85
55
85
because it gives cleaner kinetics without any induction
period compared to the isolated Ru-H catalyst 1/PhOH.
2
r
O
1
9
O
H H
3 (1 mol %)
N
N
H
O
.
2
s H
HBF OEt (4 mol %)
4
2
O
O
O
O
+
H2
(1)
p-X-C H OH
20
6 4
MeO
MeO
(
4 mol %)
(
1.0 mmol) (2 atm)
2n
2
t
dioxane, 130 oC
X = OMe, t-Bu, Et, Me, H, F, Cl, CF3
a
Method A: carbonyl compound (1.0 mmol), 2-propanol (2 mL), 1 (3
mol %)/4-methoxyphenol (10 mol %), 130 °C. Method B: carbonyl
compound (1.0 mmol), H (2 atm), 1 (3 mol %)/4-methoxyphenol
10 mol %), 130 °C, dioxane (2 mL). b Ar = 4-methoxyphenyl.
The rate of the hydrogenolysis of 4-methoxyacetophenone
with H (2 atm) in the presence of 3 (1 mol %)/HBF ·OEt
(4 mol %)/p-X-C OH (4 mol %) in dioxane was moni-
2
4
2
2
6
H
4
(
tored by NMR. The appearance of the product peak was
normalized against an internal standard (methyl benzo-
ate) in 30 min intervals, and the kobs of each catalytic reac-
tion was determined from a first-order plot of -ln[(4-
To further demonstrate its synthetic utility, we examined
the hydrogenolysis of a number of highly functionalized,
biologically active alcohol and carbonyl substrates (Table
3
). For example, the treatment of cholesterol and proges-
methoxyacetophenone)
t
/(4-methoxyacetophenone)
0
] vs time.
terone led to the chemoselective hydrogenolysis of alcohol
The Hammett plot of log(k
X
/k ) vs σ showed two opposite
H
p
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Journal of the American Chemical Society
Page 4 of 11
linear correlation patterns (Figure 1). Thus, a highly nega-
tive linear slope was observed from the phenols with elec-
tron-donating group (ρ = -3.3 ± 0.3; X = OMe, t-Bu, Et, Me,
H), while a positive slope resulted from the phenols with elec-
time, and k
(Figure 2). The experiment was repeated by using other
para-substituted phenol ligands p-X-C OH (X = OMe, Et,
for each case (Figure S2, SI).
H
/k
D
was calculated from the ratio of the slopes
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
6
H
4
F, Cl, CF
3
) to obtain k
H
/k
D
tron withdrawing group (ρ = +1.5 ± 0.1; X = F, Cl, CF
with an overall V-shaped Hammett correlation.21
3
),
100
1
.2
OMe
8
6
4
2
0
0
0
0
0
1.0
0
0
.8
.6
tBu
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Et
CF3
Me
0.4
0
2000
4000
6000
0
0
.2
.0
Cl
time/s
H
F
Figure 2. First Order Plot for the Hydrogenolysis
of 4-Methoxyacetophenone with H (p) and with
(˜) Catalyzed by 3/HBF ·OEt /p-OMe-C
-0.2
-0.3
2
-0.1
0.1
0.3
0.5
D
H
OH.
2
4
2
6
4
σp
Scheme 2.
Figure 1. Hammett Plot of the Hydrogenolysis of
H (2 atm)
H H
4
3
-Methoxyacetophenone
/HBF ·OEt /p-X-C OH (X = OMe, t-Bu, Et, Me,
).
Catalyzed
by
2
3
(1 mol %)
4
2
6
H
4
.
HBF OEt (4 mol %)
4
2
H, F, Cl, CF
3
p-X-C H OH
6
4
MeO
O
(4 mol %)
2
n
The V-shaped Hammett correlation has been generally
attributed to a change in reaction mechanism.22 In a recent
example, Abu-Omar and co-workers reported a V-shaped
Hammett plot in the hydrogen atom transfer reaction of
Mn-imido complexes with the para-substituted phenols,
o
dioxane, 130 C
D (2 atm)
D D
2
3
(1 mol %)
MeO
.
HBF OEt (4 mol %)
4
2
p-X-C H OH
6
4
X = OMe, Et, Cl, F, CF3
MeO
from which the authors inferred two distinct hydrogen
transfer mechanisms.22b While studying oxygen atom
(4 mol %) o
2
n-d
dioxane, 130 C
transfer reaction of Mn-oxo complexes, Goldberg and co-
workers also observed a similar V-shaped Hammett corre-
lation pattern from the reaction with para-substituted
benzothio ethers.22c In our case, the observation of V-
shaped Hammett correlation suggests that the activity of
ruthenium catalyst is dictated by two opposing electronic
effects from the phenol ligand. For the reaction catalyzed
by the Ru catalyst with an electron-releasing phenol ligand,
a relatively electron-rich Ru center would facilitate the
hydrogenolysis reaction by promoting the coordination
Table 4. Observed Deuterium Isotope Effect for
the Hydrogenolysis of 4-Methoxyacetophenone
Catalyzed by 3/HBF
4
·OEt
2
/p-X-C
6
H
OHa
4
X
k
H
/k
D
σ
p
OMe
Et
F
2.7±0.3
1.7±0.3
1.1±0.1
0.7±0.1
0.6±0.1
-0.28
-0.14
+0.15
+0.24
+0.53
Cl
and the activation of H . On the other hand, the positive
2
CF
3
Hammett slope from the correlation of phenols with elec-
tron-deficient group indicates that a relatively electrophilic
Ru catalyst promotes the hydrogenolysis reaction through
binding and activation of ketone and alcohol substrates.
a
Reaction conditions: carbonyl compound (1.0 mmol), H
2
(2 atm), 3
(1 mol %)/HBF
dioxane (2 mL).
·OEt (4 mol %)/p-X-C H OH (10 mol %), 130 °C,
4 2 6 4
Table 4 lists the observed k
genolysis reaction catalyzed by 3/HBF
H
/k
D
values from the hydro-
·OEt /p-X-C OH.
Isotope Effect Study. To probe electronic effects on
4
2
6
H
4
the H activation step, we measured the deuterium isotope
2
A normal deuterium isotope effect was observed for the
reaction catalyzed by phenols with electron-releasing
group (X = OMe, Et), while an inverse isotope effect was
measured for phenols with electron-withdrawing group (X
effect for the hydrogenolysis reaction by using the Ru-H
catalyst with a series of para-substituted phenol ligands
(
Scheme 2). The rate of hydrogenolysis of 4-
methoxyacetophenone with H (2 atm) and with D (2
atm) in the presence of in-situ formed 3 (1 mol
)/HBF ·OEt (4 mol %)/p-OMe-C OH (4 mol %) in
dioxane at 130 °C was measured separately by monitoring
2
2
=
Cl, CF
electronic effect of phenol ligand was established from the
plot of log(k /k ) vs σ (Figure S3, SI). Since a relatively
electron-rich Ru center should promote the coordination
and activation of H , the observed normal isotope effect
3
). A linear correlation of the isotope effect and
%
4
2
6
H
4
H
D
p
1
the appearance of the product signals on H NMR. The kobs
was determined from first-order plot of -ln[(4-
methoxyacetophenone) /(4-methoxyacetophenone) vs
2
a
signifies that the H–H bond activation step is irreversible
and that this elementary step is likely associated with the
t
0
]
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Page 5 of 11
Journal of the American Chemical Society
genolysis reaction for the Ru catalyst with both electron-
turnover-limiting step for the Ru catalyst with an electron-
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
releasing and -withdrawing phenol ligands.27 In support of
this notion, Singleton and co-workers showed that the ob-
servation of most pronounced carbon isotope effect has
been a definitive tool for establishing the rate-limiting step
for both C–C and C–O bond forming reactions.28 The C–O
bond cleavage step has also been commonly considered as
the turnover limiting step for catalytic reductive coupling
releasing phenol ligand.
In contrast, for the reaction catalyzed by the Ru catalyst
with an electron-withdrawing phenol ligand, a relatively
electron poor Ru center is expected to have a relatively low
H
2
binding affinity. In this case, the observed inverse iso-
tope effect is consistent with a stepwise reversible coordi-
nation of H followed by the partitioning of H resulted
from an electron-poor Ru catalyst. A linear correlation of
the magnitude of k /k with the Hammett σ values indi-
cates that the H activation step is strongly influenced by
the electronic nature of the Ru catalyst. Electronic effects
on the coordination and activation of H and related non-
polar substrates to organometallic complexes have been
2
2
29
reactions of ethers and related oxygenated compounds.
H
D
p
Deuterium Labeling Study. To examine H/D ex-
change pattern on the aliphatic products, 4-
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
methoxyacetophenone (1.0 mmol) was reacted with D
2
(2
2
atm) in the presence of 3/HBF ·OEt /p-OMe-C OH in
4
2
6
H
4
dioxane at 130 °C (Scheme 4). The reaction was stopped
after 4 h at 50% conversion, and the deuterium content of
2
3
extensively investigated.
1
2
the isolated product 2n was analyzed by H and H NMR
Figure S4, SI). The analogous treatment of 1-(4-
methoxyphenyl)ethanol (1.0 mmol) with D (2 atm) and
/HBF ·OEt /p-OMe-C OH led to the same product 2n
50% conversion after 4 h), and its deuterium content was
Inverse deuterium isotope effect has been frequently ob-
served for the transition metal-mediated C–H and H–H
bond activation reactions.24 For instance, the observed
(
2
3
4
2
6
H
4
inverse isotope effect (k
H
/k = 0.4-0.8) in reductive elimi-
D
(
nation of metal-alkyl-hydride complexes has been ex-
plained by invoking a stepwise reversible partitioning be-
tween alkyl-hydride and σ-bonded metal complexes fol-
lowed by a slow reductive elimination step of alkanes.24b
The observation of inverse isotope effects in metal-
mediated hydrogenation reactions have also been ex-
compared with the product obtained from the ketone.
Scheme 4.
5
2% D
O
D
3
(2 atm)
(1 mol %)
2
.
42% D
16% D
HBF4 OEt2 (4 mol %)
plained in terms of stepwise addition and activation of H
2
49% D
p-OMe-C H OH (4 mol %)
6
4
MeO
MeO
MeO
MeO
2
5
o
to metal complexes.
dioxane, 130
C
2n
2n
2
0% D
Scheme 3.
OH
D
3
2
(2 atm)
(1 mol %)
.
HBF4 OEt2 (4 mol %)
1
.0424
H2 (2 atm)
(1 mol %)
p-OMe-C H OH (4 mol %)
6
4
<5% D
o
3
dioxane, 130 C
.
HBF OEt (4 mol %)
4
2
p-OMe-C H OH (4 mol %)
dioxane, 130
O
6 4
MeO
MeO
o
2k
C
As illustrated in Scheme 4, substantially higher deuterium
incorporation was observed on the product 2n obtained
from the hydrogenolysis of ketone compared to the prod-
uct obtained from the alcohol. For the hydrogenolysis of 4-
1
.0627
H2 (2 atm)
3 (1 mol %)
MeO
.
HBF OEt (4 mol %)
4
2
p-CF -C H OH (4 mol %)
dioxane, 130
3
6
4
methoxyacetophenone, 42% deuterium of the β-CH group
3
o
C
2k
of the isolated product 2n suggests of a facile H/D ex-
change via a keto-enol tautomerization of the ketone sub-
strate, while 49% of deuterium on the ortho-arene posi-
tion can be explained via the chelate-assisted ortho-
metallation and the reversible H/D exchange. In chelate-
assisted C–H insertion reactions, reversible ortho-arene C–
H/C–D exchange patterns have been commonly ob-
served.30 In contrast, less than 5% of deuterium on the
ortho-arene position of the product was observed from the
alcohol substrate, because in this case, the alcohol group
could not serve as an effective chelate directing group to
promote ortho-arene H/D exchange. Similarly, 52% deu-
terium on the benzylic position of the product obtained
from the ketone supports the notion for a rapid and re-
versible H/D exchange via keto-enol tautomerization and
the subsequent hydrogenolysis processes. In contrast, a
relatively small deuterium incorporation on the ortho-
arene carbon of the product (<5% D) obtained from the
hydrogenolysis of 1-(4-methoxyphenyl)ethanol suggests
that the hydrogenolysis occurs directly without the alco-
hol-to-ketone hydrogenation-dehydrogenation process.
Also, lower than expected deuterium incorporation on the
To discern the slow step of the catalytic reaction, we
measured 12C/ C isotope effect for the hydrogenolysis of
6-methoxy-1-tetralone by employing Singleton’s NMR
technique (Scheme 3).26 To compare the electronic influ-
ence of the phenol ligand, we have chosen two electroni-
13
cally different phenol ligands, p-X-C
The hydrogenolysis of 6-methoxy-1-tetralone (10 mmol)
was performed with (2 atm) and (1 mol
)/HBF ·OEt (4 mol %)/p-X-C OH (X = OMe or CF ) (4
6
H
4
OH (X = OMe, CF ).
3
H
2
3
%
4
2
6
H
4
3
mol %) in 1,4-dioxane (8 mL) at 130 °C for 2-3 h. The
product 6-methoxytetrahydronaphthalene (2k) was iso-
lated by a column chromatography on silica gel (hex-
anes/Et O = 40:1). The most pronounced carbon isotope
2
effect on the α-carbon of the product 2k was observed
when the 13C ratio of the product at three low conversions
(
15, 18 and 20%) was compared with the sample obtained
13
at high conversion (95%) for both cases [( C at 95% con-
version)/(average of 13C at 17% conversion) at C(4) =
1
.0424 for X = OMe and C(4) = 1.0627 for X = CF
3
] (Tables
S2 and S3, SI).
The carbon isotope effect data indicated that the C–O
bond cleavage is the turnover-limiting step of the hydro-
α-carbon (20% D of CH
2
) can be readily explained by an
extensive H/D exchange between D
2
and -OH of alcohol
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Journal of the American Chemical Society
Page 6 of 11
substrates, which would lead dilute the deuterium content
on D . Transition metal-hydride complexes have been well-
Rate (ν
0
)
vs
/p-CF
H
2
Pressure Catalyzed by
OH (Bottom).
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
3/HBF ·OEt
4
2
3
-C
6
H
4
known to promote H/D exchange reactions between hy-
with deuterated alcohols and water.31
In sharp contrast, we observed disparate [H
ence for the hydrogenolysis reaction between two differ-
ent phenol ligands 3/HBF ·OEt /p-X-C OH (X = OMe,
CF ). Thus, for the hydrogenolysis of 4-
methoxyacetophenone catalyzed by 3/HBF ·OEt /p-OMe-
OH, an inverse dependence on [H ] was observed
2
] depend-
drocarbons and H
2
A
similar set of H/D exchange pattern was obtained from the
Ru catalyst having an electron-withdrawing phenol ligand
4
2
6
H
4
3/HBF
4
·OEt
2
/p-CF
3
-C
6
H OH (Figure S5, SI).
4
3
4
2
Determination of Empirical Rate Law. To further
discern the electronic effects of phenol ligands, we next
determined the empirical rate law for the hydrogenolysis
reaction of 4-methoxyacetophenone by using the Ru cata-
lyst with both electron-releasing and -withdrawing phenol
ligands. In a typical experimental setting, the active cata-
lyst was generated in-situ by combining 3 (1 mol
C
6
H
4
2
within the range of catalytically operating hydrogen pres-
sure (1-4 atm) as indicated by a linear plot of 1/initial rate
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
ν
0
) vs H
2
pressure (Figure 3). On the other hand, the plot
) vs H pressure for the hydrogenolysis of
-methoxyacetophenone catalyzed by 3/HBF ·OEt /p-CF
OH showed the rate independence on [H ] in the simi-
pressure (1-4 atm).
of initial rate (ν
4
C
0
2
4
2
3
-
6
H
4
2
%)/HBF
OMe, CF
ance of the product at five different catalyst concentrations
0.01-0.05 mM). The plot of initial rate (ν ) as a function of
3] yielded linear slope of 4.5
10-6 s-1 for
/p-OMe-C OH. The same set of experiments
4
·OEt
2
(4 mol %)/p-X-C
6
H
4
OH (4 mol %) (X =
lar range of H
2
3
). The initial rate was measured from the appear-
On the basis of these kinetic data, two separate empirical
rate laws have been compiled for the hydrogenolysis of
ketone.
(
0
[
a
×
-
1
3
/HBF
4
·OEt
2
6
H
4
Rate = kobs[Ru][ketone][H
tion catalyzed by 1/p-OMe-C
Rate = kobs[Ru][ketone][H
]0 for the hydrogenolysis reac-
tion catalyzed by 1/p-CF -C OH.
The inverse rate dependence on [H
OMe-C OH signifies that the hydrogenolysis reaction is
inhibited by H at a relatively high [H ]. In this case, the Ru
catalyst with electron-releasing phenol group is expected
to exhibit a relatively strong affinity toward H , which
2
] for the hydrogenolysis reac-
from the catalyst with electron-withdrawing phenol ligand
/HBF ·OEt /p-CF -C OH also led to a linear depend-
6
H
4
OH, and
3
4
2
3
6
H
4
2
-
6
-1
ence on [3] with the slope of 4.0 × 10 s (Figures S6 and
S7, SI). The analogous procedure was employed to deter-
mine the rate dependence on [ketone]. In both cases (X =
3
6
H
4
2
] for the catalyst 1/p-
6
H
4
OMe, CF ), the first order rate dependence on [4-
3
2
2
methoxyacetophenone] was observed under the catalyti-
cally relevant ketone concentrations (0.3-2.0 M) (Figures
S8 and S9, SI).
2
leads to competitive inhibition with the coordination of the
ketone substrate. On the other hand, the rate independ-
ence on [H
with electron-withdrawing phenol ligand indicates that an
electron-deficient Ru catalyst facilitates reversible coordi-
nation of H but with much lower binding affinity com-
8.0
7.0
2
] for the hydrogenolysis by 1/p-CF
3
-C
6
H OH
4
6
5
4
3
2
1
0
.0
.0
.0
.0
.0
.0
.0
2
pared to the ketone substrate.
Scheme 5.
X
OH
X
OH MeO
BF
.
HBF4 OEt2
OH
.OEt
, 20 oC
Ru
4
HBF
CH
4
2
3
Cy P
H
CH Cl , 80 oC
Cy
3
P
CO
Ru
CO
H
Ru PCy
2
Cl
2
CO
2
2
1
0
20
30
pH2 (psi)
40
50
60
X = H (4a), OMe (4b), Cl (4c)
H
3
BF
4
O
OH
Ru
OH
O
OH
O
H
PCy3
OC Ru
H
Ru
H
O
OH
OC
1
O
H
CO
PCy3
PCy
3
3.5
.0
.5
2.0
.5
.0
.5
0.0
3
.OEt
, 20 oC
Ru
BF
4
.
HBF4 OEt2
CH Cl
2 2
, 80 oC
HBF
CH Cl
4
2
Cy
P
H
3
3
2
2
CO
4
d
2
Isolation and Characterization of Catalytically
Relevant Ruthenium Complexes. We performed a
series reactivity studies on complex 1 to detect or isolate
catalytically relevant intermediate species (Scheme 5). In a
NMR tube reaction, the treatment of 1 with phenol in
1
1
0
1
31
1
CD
2
2
Cl was followed by H and P{ H} NMR. After 1 h of
heating at 80 °C, the formation of a 1:1 ratio of cationic Ru-
H complex 1 and the phenol-coordinated complex 4 was
observed, as evidenced by the appearance of a new set of
1
0
20
30
40
50
60
PH2 (psi)
peaks ( H NMR: δ -10.87 (d, JPH = 27.1 Hz), 31P{ H} NMR: δ
1
1
70.8 ppm). The formation of free benzene molecule was
also detected by H NMR, but no evidence for PCy
ation was detected under these conditions. In a preparato-
ry scale reaction, para-substituted phenol-coordinated Ru-
H complexes 4a-4c were conveniently synthesized from
1
Figure 3. Plot of 1/Initial Rate (ν
sure for the Hydrogenolysis
Methoxyacetophenone Catalyzed
/HBF ·OEt /p-OMe-C
0
) vs H
2
Pres-
3
dissoci-
of
4-
by
3
4
2
6
H
4
OH (Top), and Initial
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Page 7 of 11
Journal of the American Chemical Society
the treatment of the tetranuclear Ru complex 3 with the
corresponding phenol and HBF ·OEt , following the similar
due to a larger ionic radius of the bridging oxygen com-
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
4
2
pared to the hydrogen atom. Both complexes exhibited
identical catalytic activity toward the hydrogenolysis of 4-
methoxyacetophenone under the conditions specified in eq
1.
procedure used to synthesize the complex 1. The structure
of these phenol-coordinated complexes 4a-4c was com-
pletely established by X-ray crystallography (Figure 4;
Figures S13 and S14, SI). To facilitate trapping of catalyti-
cally relevant species, 2-acetylphenol-coorinated complex
4d was prepared from the analogous treatment of 3 with
Scheme 6.
H
H
O
Cy
3
P
2-acetylphenol and HBF
yield after recrystallization in CH
4
·Et
2
O, and it was isolated in 82%
Cl /n-pentane. The
+ unidentified Ru-H complexes
Ru
OC
7
O
H
H
2
2
treatment of 1 with the phenol substrates also formed the
complexes 4a-4d, but in this case, some unreacted 1 and
unidentified side products were also presented in the
crude mixture.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
H
2
CD
2
Cl
C
2
20 o
O
OH
Cy
3
P
H
CO
OC
Ru Ru PCy
O
O
3
Ru
We explored the reactivity of phenol-coordinated com-
plexes 4 to detect or trap catalytically active species. De-
spite concerted efforts using various trapping external
trapping agents and VT NMR techniques, we failed to de-
tect any intermediate species by using the complex 4a-4a
with both electron-rich and electron-poor phenol ligands.
Recognizing that a carbonyl group might serve as an inter-
nal chelate group, we next explored the reactivity of the 2-
acetylphenol-coordinated complex 4d that contains an
acyl chelate group. Thus, heating of 4d in dioxane solution
at 80 °C for 1 h led to the clean formation of a dinuclear
Ru-H complex 5 in this case (Scheme 6). A characteristical-
ly upfield-shifted bridging metal-hydride resonance ap-
Cy
3
P
H
dioxane
80
O
O
CO
4d
o
C
5
ORTEP of 5
dioxane
2
H O
2
0 o
C
H
O
Cy
3
P
CO
OC
O
Ru Ru PCy
O
3
O
O
6
ORTEP of 6
1
peared at δ -28.30 (t, JPH = 9.5 Hz) by H NMR. The obser-
The reaction of 5 (0.02 mmol) with H
2
(2 atm) in CD
2
Cl
2
vation of a single phosphine peak at δ 70.7 ppm on 31P{1H}
was monitored by NMR. At 20 °C, two sets of new peaks
NMR is also consistent with a symmetric nature of the
complex. The X-ray crystal structure confirmed the dinu-
clear Ru complex of 5, which is joined by two bridging 2-
acetylphenolate ligands, with a crystallographic two-fold
symmetry on the Ru core.
1
appeared ( H NMR: δ -19.10 (d, JPH = 16.5 Hz) and -19.20
1
(
d, JPH = 16.3 Hz); 31P{ H} NMR: δ 73.45 and 73.49 ppm)
that have characteristic features for a diastereomeric mix-
ture of Ru-H complexes. In light of the recently isolated
alcohol-coordinated Ru-H complexes,19b we tentatively
assign the new set of peaks as the alcohol-coordinated [(2-
+
-
MeCH(OH)C
6
H
4
OH)(PCy
3
)(CO)RuH] BF (7). Upon warm-
4
ing to 50 °C, the complex 7 rapidly decomposed into the
aliphatic product 2a and a number of unidentified Ru-H
complexes. The formation of the alcohol-coordinated com-
plex 7 implicates the involvement of a monomeric Ru-η2-
2
H complex.
Table 5. Kinetic Parameters Obtained from the
Hydrogenolysis of Aryl-Substituted Ketone Cata-
lyzed by 3/HBF
4
·OEt
2
/p-X-C
6
H
4
OH (X = OMe, CF )
3
Kinetic parameter
p-OMe-C
6
H
4
OH
3 6 4
p-CF -C H OH
Hammett ρ a,b
a
-3.3
2.7
+1.5
0.6
Figure 4. Molecular Structure of [(C
6
H
5
OH)-
+
-
(
PCy
3
)(CO)RuH] BF
4
(4a) Co-crystallized with a
k
H
/k
D
2
-Propanol Molecule.
] a
]-1
]0
Rate law of [H
2
[H
2
[H
2
k
12C/k13C c
1.042
1.063
The subsequent treatment of the dinuclear Ru-H complex
5
in wet 1,4-dioxane solution at room temperature
a
The data were obtained from the hydrogenolysis reaction of 4-
methoxyacetophenone. bThe values represent the correlation of a
series of para-substituted phenol ligands as shown in Figure 1. The
smoothly formed the dinclear Ru-hydroxo complex 6. The
c
1
characteristic Ru-OH signal at δ -3.18 was observed by H
data were obtained from the hydrogenolysis reaction of 6-methoxy-1-
tetralone.
NMR, and the structure of complex 6 was unambiguously
determined by X-ray crystallography. The molecular struc-
ture of complex 6 is isostructural with the complex 5, in
that each Ru center still retains a pseudo octahedral coor-
dination geometry with two bridging acetophenolate lig-
ands. A considerably longer Ru-Ru distance of 2.948 Å of 6
compared to the hydride complex 5 (2.680 Å) is probably
Proposed Mechanism. Table 5 presents a summary of
the kinetic data obtained from the catalytic hydrogenolysis
of ketones. On the basis of these kinetic data as well as
structural elucidation of the catalytically relevant species,
we compile a plausible mechanism for the hydrogenolysis
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Journal of the American Chemical Society
Page 8 of 11
of ketones (Scheme 7). We propose that the ketone hydro-
supports this notion in that the coordination of ketone or
alcohol substrate would be favored over the H binding. In
transition metal mediated H–H and C–H activation reac-
tions, an inverse deuterium isotope effect has been com-
monly interpreted as having a stepwise equilibrium parti-
tioning of coordinated substrates.24 In our case, we reason
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
genolysis occurs in two stages: the first stage involves the
hydrogenation of ketone to alcohol, and in the second
stage the hydrogenolysis of alcohol to the corresponding
aliphatic product. It has been well established that both
Shvo- and Noyori-type of bifunctional ruthenium catalysts
are highly efficient for the hydrogenation of carbonyl com-
pounds to alcohols.32,33 Extensive experimental and com-
putational studies have led to the elucidation of concerted
outer-sphere hydrogen transfer mechanism for the catalyt-
ic hydrogenation of ketones to alcohols. In our case, the
phenol-coordinated cationic ruthenium-hydride complex 4
should effectively serve as the catalyst precursor for the
hydrogenation of ketone to give the alcohol product. The
observed H/D exchange pattern of the ketone substrate
supports that the initial hydrogenation of ketone to alcohol
is relatively fast under the reaction conditions.
2
that a stepwise reversible binding and activation of H via
2
bifunctional Ru-phenoxo species 8 would be most con-
sistent with the observed kinetics, but we still cannot fully
explain why the rate is independent of [H ] even though an
2
inverse KIE has been measured from the hydrogenolysis
reaction.35 As indicated by the carbon isotope effect on the
carbonyl carbon of the product, the C–O bond cleavage
step is the turnover-limiting step of the hydrogenolysis
reaction for both electron-releasing and -withdrawing
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
phenol ligands 1/p-X-C
6
H
4
OH (X = OMe, CF ).
3
The successful isolation of the bimetallic Ru-
acetylphenoxo complexes 5 and 6 provides a strong sup-
port for the cationic Ru-phenoxo complex 8 as the catalyti-
cally active species for the hydrogenolysis reaction. To
avoid the generation of a relatively high energy Ru(IV)
species, we propose that the H–H activation is facilitated
by the bifunctional Ru-phenoxo species 8, in which an elec-
trophilic Ru center and nucleophilic phenoxy group would
promote the heterolytic cleavage of H–H bond in forming
the Ru-H species 9. The detection of structurally similar
cationic Ru-H complex 7 also shed light on the involve-
ment of a cationic Ru-H species such as 9. Many Ru-alkoxo
and -phenoxo complexes have been synthesized, as these
complexes are considered to be key species for the hydro-
genation of ketones to alcohols.36 In a notable example,
Gunnoe and Cundari showed that the σ-bond metathesis
path is favored over the classical Ru(II)/Ru(IV) oxidative
addition-reductive elimination pathway for Ru(II)-
catalyzed C–H arylation reactions on the basis of both ex-
perimental and computational studies.37 The computation-
al study on our cationic Ru(II) catalytic system is certainly
warranted in establishing detailed energetics and mecha-
nism of the C–O bond hydrogenolysis step.
Compared to the hydrogenation of ketones to alcohols,
the mechanism of hydrogenolysis of alcohols to corre-
sponding aliphatic products has been less well established.
Both isotope effect and Hammett data indicate two differ-
ent mechanistic pathways for the C–O bond hydrogenoly-
sis reaction, depending on the electronic nature of the Ru
catalyst. In case of the Ru catalyst with an electron-
releasing phenol ligand 1/p-OMe-C
deuterium isotope effect and inverse [H
consistent with a mechanistic pathway involving concerted
addition of H . In this case, a relatively electron-rich Ru
center promotes high affinity toward H , which results in a
competitive inhibition with the ketone (and alcohol) sub-
strate at relatively high [H ]. In light of extensive experi-
6
H
4
OH, both normal
2
] dependence are
2
2
2
mental and computational studies on organotransition
metal-dihydrogen complexes,23,34 we propose that the for-
mation of a Ru-dihydrogen complex has led to the inhibi-
tion of ketone (and alcohol) substrates.27
Scheme 7. Proposed Mechanism of the Catalytic
Hydrogenolysis of Acetophenone
OMe
X
OH
HO
Ru
p-X-C
6
H
4
OH
1
Ru
H
S
-C
6
H
6
H
O
3
Cy P
CONCLUSIONS
CO
H
2
4
Cy
3
P
CO
S = solvent, water
We successfully developed a highly effective catalytic hy-
drogenolysis method for carbonyl compounds and alcohols
by using a well-defined cationic Ru-H complex with tuna-
ble phenol ligand. The salient features of the catalytic
+
Ph
S
OH
-
+ H2
CF
3
X
Ph
HO
OMe
X = CF
3
X = OMe
O
O
H
S
H
2
+ H2
- S
S
S
+ H
- S
2
S
Ru
Ru
Ru
method are that it employs cheaply available H , exhibits
2
O
H
Ph
O
H
Ph
O
Ph
Cy
3
P
Cy
3
P
Cy3P
H
CO
9
high chemoselectivity toward the carbonyl reduction over
olefin hydrogenation without forming any wasteful by-
products, and its activity can be readily modulated by em-
ploying phenol ligands. The detailed kinetic and mechanis-
tic analyses revealed two distinct mechanistic pathways
that are guided by the electronic nature of the Ru catalyst
CO
CO
8
H
+
2
O
slow
O
CF
3
X
OMe
H
2
Ph
HO
Ru
O
O
slow
H
S
H
S
S
S
+
S
+ S
Ru
Ru
OH
O
H
Ph
OH
1/p-X-C
releasing phenol ligand 1/p-OMe-C
hydrogenolysis through concerted H
electron-deficient Ru catalyst 1/p-CF
stepwise binding and activation of H
6
H
4
OH. That the Ru catalyst with an electron-
OH facilitates the
addition, while the
-C OH features a
and electrophilic
Cy
3
P
Cy
3
P
2
Cy3P
H
H
H
H
H
Ph
CO
CO
OC
9
6
H
2
4
Ph
Ph
3
6
H
4
For the Ru catalyst with an electron-poor phenol ligand
/p-CF -C OH, an electron-deficient Ru center would
have a relatively low H binding affinity. In this case, the
observed inverse deuterium isotope effect is consistent
with a stepwise reversible binding and activation of H by
an electrophilic Ru catalyst. The rate independence on [H
2
1
3
6
H
4
hydrogenolysis of the alcohol substrate. The catalytic
method provides a chemoselective and cost-effective pro-
tocol for the hydrogenolysis of aldehydes and ketones un-
der environmentally sustainable conditions.
2
2
2
]
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ASSOCIATED CONTENT
Journal of the American Chemical Society
A.; Wiberg, K. B.; Schacherer, L. N.; Medeiros, M. R.; Wood, J. L. J.
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Am. Chem. Soc. 2005, 127, 12513. (e) Dieguez, H. R.; Lopez, A.;
Domingo, V.; Arteaga, J. F.; Dobado, J. A.; Herrador, M. M.; del
Moral, J. F. Q.; Barrero, A. F. J. Am. Chem. Soc. 2010, 132, 254. (f)
Herrmann, J. M.; Koenig, B. Eur. J. Org. Chem. 2013, 7017. (g)
Dang, H.; Cox, N.; Lalic, G. Angew. Chem., Int. Ed. 2014, 53, 752.
Supporting Information. Experimental procedures and
methods, kinetic and characterization data, NMR spectra and
X-ray crystallographic data of 4a-4d, 5 and 6. This material is
available free of charge via the Internet at http://pubs.acs.org.
(
12) (a) Sergeev, A. G.; Hartwig, J. F. Science 2011, 332, 439. (b)
Sergeev, A. G.; Webb, J. D.; Hartwig, J. F. J. Am. Chem. Soc. 2012,
34, 20226.
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AUTHOR INFORMATION
Corresponding Author
1
(
*
E-mail: chae.yi@marquette.edu.
3791. (b) Nichols, J. M.; Bishop, L. M.; Bergman, R. G. Ellman, J. A.
J. Am. Chem. Soc. 2010, 132, 12554. (c) Atesin, A. C.; Ray, N. A.;
Stair, P. C.; Marks, T. J. J. Am. Chem. Soc. 2012, 134, 14682. (d)
Chen, C.; Hong, S. H. Org. Lett. 2012, 14, 2992. (e) Kelley, P.; Lin,
S.; Edouard, G.; Day, M. W.; Agapie, T. J. Am. Chem. Soc. 2012,
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Notes
The authors declare no competing financial interest.
1
34, 5480. (f) Hanson, S. K.; Wu, R.; Silks, L. A. Angew. Chem., Int.
ACKNOWLEDGMENT
Ed. 2012, 51, 3410. (g) Ren, Y.; Yan, M.; Wang, J.; Zhang, Z. C.;
Yao, Y. Angew. Chem., Int. Ed. 2013, 52, 12674.
(14) (a) Gosselink, R. W.; Stellwagen, D. R.; Bitter, J. H. Angew.
Chem., Int. Ed. 2013, 52, 5089. (b) Sousa, S. C. A.; Fernandes, A. C.
Coord. Chem. Rev. 2015, 284, 67. (c) Harms, R. G.; Herrmann, W.
A.; Kuehn, F. E. Coord. Chem. Rev. 2015, 296, 1.
Financial support from the National Science of Foundation
(
CHE-1358439) is gratefully acknowledged. We thank Dr.
Sergey Lindeman (Marquette University) for X-ray structural
determination of 4a-4d, 5 and 6.
(
15) (a) Yan, N.; Zhao, C.; Luo, C.; Dyson, P. J.; Liu, H.; Kou, Y.
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(
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(
27) As expressed in the overall rate law and deuterium isotope ef-
(35) A reviewer raised an issue about an apparent inconsistency
fect, both H-H and C-O cleavage steps could be irreversible for the
hydrogenolysis reaction catalyzed by Ru catalyst with electron-rich
phenol ligand. As a reviewer pointed out, irreversible and partially
rate determining H-H activation step would still be consistent with the
observed kinetic data in this case.
between inverse KIE and [H
reaction catalyzed by Ru catalyst with electron-poor phenol ligand.
One possible explanation for the [H ] independence is that the H
2
] independence for the hydrogenolysis
2
2
activation step is much faster than the C-O cleavage step but with a
low binding affinity under “saturated” catalytic conditions. Another
possibility is that the C-O cleavage occurs prior to the H activation
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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5
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Catalytic Hydrogenolysis of Aldehydes and Ketones with H2
O
[Ru] (3 mol %)
H H
R'
R = alkyl, aryl; R' = H, alkyl
PhOH (4 mol %)
+
H2
1-3 atm)
+ H O
2
R
R'
o
R
dioxane, 110-130 C
(
Employs non-toxic and cheaply available H2
Chemselective hydrogenolysis of biologically active substrates
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Formation of water as the sole byproduct
Tunable catalytic activity using phenol ligands
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