Transfer Hydrogenation of Alkenes Using Ethanol Catalyzed by a NCP Pincer Iridium Complex: Scope and Mechanism

Article abstract of DOI:10.1021/jacs.8b01038

The first general catalytic approach to effecting transfer hydrogenation (TH) of unactivated alkenes using ethanol as the hydrogen source is described. A new NCP-type pincer iridium complex (^BQ-NC^OP)IrHCl containing a rigid benzoquinoline backbone has been developed for efficient, mild TH of unactivated C-C multiple bonds with ethanol, forming ethyl acetate as the sole byproduct. A wide variety of alkenes, including multisubstituted alkyl alkenes, aryl alkenes, and heteroatom-substituted alkenes, as well as O- or N-containing heteroarenes and internal alkynes, are suitable substrates. Importantly, the (^BQ-NC^OP)Ir/EtOH system exhibits high chemoselectivity for alkene hydrogenation in the presence of reactive functional groups, such as ketones and carboxylic acids. Furthermore, the reaction with C₂D₅OD provides a convenient route to deuterium-labeled compounds. Detailed kinetic and mechanistic studies have revealed that monosubstituted alkenes (e.g., 1-octene, styrene) and multisubstituted alkenes (e.g., cyclooctene (COE)) exhibit fundamental mechanistic difference. The OH group of ethanol displays a normal kinetic isotope effect (KIE) in the reaction of styrene, but a substantial inverse KIE in the case of COE. The catalysis of styrene or 1-octene with relatively strong binding affinity to the Ir(I) center has (^BQ-NC^OP)Ir^I(alkene) adduct as an off-cycle catalyst resting state, and the rate law shows a positive order in EtOH, inverse first-order in styrene, and first-order in the catalyst. In contrast, the catalysis of COE has an off-cycle catalyst resting state of (^BQ-NC^OP)Ir^III(H)[O(Et)···HO(Et)···HOEt] that features a six-membered iridacycle consisting of two hydrogen-bonds between one EtO ligand and two EtOH molecules, one of which is coordinated to the Ir(III) center. The rate law shows a negative order in EtOH, zeroth-order in COE, and first-order in the catalyst. The observed inverse KIE corresponds to an inverse equilibrium isotope effect for the pre-equilibrium formation of (^BQ-NC^OP)Ir^III(H)(OEt) from the catalyst resting state via ethanol dissociation. Regardless of the substrate, ethanol dehydrogenation is the slow segment of the catalytic cycle, while alkene hydrogenation occurs readily following the rate-determining step, that is, β-hydride elimination of (^BQ-NC^OP)Ir(H)(OEt) to form (^BQ-NC^OP)Ir(H)₂ and acetaldehyde. The latter is effectively converted to innocent ethyl acetate under the catalytic conditions, thus avoiding the catalyst poisoning via iridium-mediated decarbonylation of acetaldehyde.

Full text of DOI:10.1021/jacs.8b01038

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Transfer Hydrogenation of Alkenes Using Ethanol Catalyzed
by A NCP Pincer Iridium Complex: Scope and Mechanism
Yulei Wang, Zhidao Huang, Xuebing Leng, Huping Zhu, Guixia Liu, and Zheng Huang
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 08 Mar 2018
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Transfer Hydrogenation of Alkenes Using Ethanol Catalyzed by A NCP
Pincer Iridium Complex: Scope and Mechanism
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Yulei Wang, Zhidao Huang, Xuebing Leng, Huping Zhu, Guixia Liu, and Zheng Huang*
State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute
of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road,
Shanghai 200032, China.
ABSTRACT: The first general catalytic approach to effecting transfer hydrogenation (TH) of unactivated alkenes using
ethanol as the hydrogen source is described. A new NCP-type pincer iridium complex (BQ-NCOP)IrHCl containing a rigid
benzoquinoline backbone has been developed for efficient, mild TH of unactivated C–C multiple bonds with ethanol,
forming ethyl acetate as the sole byproduct. A wide variety of alkenes, including multisubstituted alkyl alkenes, aryl al-
kenes, and heteroatom-substituted alkenes, as well as O- or N-containing heteroarenes and internal alkynes, are suitable
substrates. Importantly, the (BQ-NCOP)Ir/EtOH system exhibits high chemoselectivity for alkene hydrogenation in the
presence of reactive functional groups, such as ketones and carboxylic acids. Furthermore, the reaction with C2D5OD pro-
vides a convenient route to deuterium-labeled compounds. Detailed kinetic and mechanistic studies have revealed that
monosubstituted alkenes (e.g., 1-octene, styrene) and multisubstituted alkenes (e.g., cyclooctene (COE)) exhibit funda-
mental mechanistic difference. The OH group of ethanol displays a normal kinetic isotope effect (KIE) in the reaction of
styrene, but a substantial inverse KIE in the case of COE. The catalysis of styrene or 1-octene with relatively strong binding
affinity to the Ir(I) center has (BQ-NCOP)IrI(alkene) adduct as an off-cycle catalyst resting state, and the rate law shows a
positive order in EtOH, inverse first-order in styrene, and first-order in the catalyst. In contrast, the catalysis of COE has
an off-cycle catalyst resting state of (BQ-NCOP)IrIII(H)[O(Et)⋅⋅⋅HO(Et)⋅⋅⋅HOEt] that features a six-membered iridacycle con-
sisting of two hydrogen-bonds between one EtO ligand and two EtOH molecules, one of which is coordinated to the
Ir(III) center. The rate law shows a negative order in EtOH, zeroth-order in COE, and first-order in the catalyst. The ob-
served inverse KIE corresponds to an inverse equilibrium isotope effect for the pre-equilibrium formation of (BQ
-
NCOP)IrIII(H)(OEt) from the catalyst resting state via ethanol dissociation. Regardless of the substrate, ethanol dehydro-
genation is the slow segment of the catalytic cycle, while alkene hydrogenation occurs readily following the rate-
determining step, that is, β-hydride elimination of (BQ-NCOP)Ir(H)(OEt) to form (BQ-NCOP)Ir(H)2 and acetaldehyde. The
latter is effectively converted to innocent ethyl acetate under the catalytic conditions, thus avoiding the catalyst poisoning
via iridium-mediated decarbonylation of acetaldehyde.
1. INTRODUCTION
Ethanol is a highly attractive hydrogen source given its
abundance, sustainability, and environmentally benign
nature. Although a number of transition metal complexes
are known to catalyze TH with iPrOH,12,13 ethanol has
been seldom applied to catalytic TH.14-16 Very recently,
Grützmacher reported Rh complex-catalyzed TH of ke-
tones14 and Swamy disclosed Pd complex-catalyzed TH of
ynamides15 with ethanol. Unfortunately, both systems are
inactive for TH of unactivated C–C double bonds.14,15 In-
deed, homogeneously catalytic TH reactions of unactivat-
ed alkenes using EtOH (eq 1) have remained unknown.
The catalytic hydrogenation is a reaction with enormous
applicability, ranging from fine chemical to pharmaceuti-
cal and agrochemical synthesis.1 Transfer hydrogenation
(TH), as an alternative to direct hydrogenation using mo-
lecular H2, has garnered tremendous attention because
the process does not require the use of flammable gas nor
elaborate experimental equipments.2 In addition, the
catalytic TH reactions have the potential applications in
energy storage3 and biotechnologies.4 While catalytic
methods for TH of ketones, imines, and polarized alkenes
(e.g., α, β-unsaturated ketones) have been well-
established,5-8 these catalytic systems often exhibit low
efficiency and narrow scope for TH reactions of non-
polarized, unactivated C–C double bonds. Among various
hydrogen donors, amine–borane adducts,9 water–
B2(OH)4/B2pin2 combination,10 formic acid,11 and isopro-
panol12,13 have proven effective for transition metal-
catalyzed hydrogenation of non-polarized unsaturated C–
C bonds.
catalyst
R
R
+ CH3CHO (1)
+ CH3CH2OH
R
R
The limited success of EtOH relative to iPrOH in transi-
tion metal-catalyzed TH reactions can be attributed to
the catalyst deactivation caused by the alcohol dehydro-
genation product: in contrast to acetone, acetaldehyde
readily undergoes metal-mediated decarbonylation, lead-
ing to catalytically inactive metal carbonyl species (eq 2).17
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H
H
Chart 1. PCP and NCP pincer-ligated iridium complexes
O
[M] CO
CH3
1
2
3
4
5
6
7
8
[M] + CH3CHO
(2)
[M]
a) PCP type
PtBu2
CH3
O
O
PtBu2
Featuring high thermostability, PCP-type pincer iridi-
um complexes (e.g., (PCP)Ir(H)2 118 and (POCOP)IrHCl
2,19 Chart 1a) are powerful class of catalysts for organic
substrate desaturation, mostly for alkane dehydrogena-
tion.20 Inspired by the precedents, our group has been
interested in the development of pyridine-containing
NCP-type pincer iridium complexes (Chart 1b), with a
focus on understanding the effects caused by the phos-
phine-to-pyridine substitution on the electronic proper-
ties and catalytic perfomance.21 Among a series of NCP
complexes, (NCOP)IrHCl 4a has been found to be moder-
ately active for transfer dehydrogenation of alkanes with
tert-butylethylene as the hydrogen acceptor,21a and highly
efficient for α-alkylation of esters21c and amides21d with
primary alcohols as the alkylating reagents. The juxtaposi-
tion of these results suggests that the NCP-type iridium
catalyst should be effective for the TH of alkene with al-
cohol. The main challenge now lies in the use of ethanol
as the hydrogen source for the hydrogenation of unacti-
vated alkenes. Here, we report that a new NCP pincer
iridium complex containing a rigid benzoquinoline back-
bone (BQ-NCOP)IrHCl (6, Chart 1b) is a versatile and selec-
tive catalyst for the TH of unactivated C–C multiple
bonds with ethanol under mild conditions. During the TH
transformation, ethanol is effectively converted to ethyl
acetate,22 instead of acetaldehyde, which helps avoid the
catalyst poisoning via decarbonylation. The system ena-
bles the hydrogenation of not only unactivated alkenes
with varying electronic and steric properties, but O and
N-containing heteroarenes and internal alkynes as well.
Kinetic and mechanistic studies provide insight into the
rate-determining step and the catalyst resting states for
different classes of alkenes, and elucidate the origin of the
unique compatibility between the (BQ-NCOP)Ir catalyst
and EtOH.
H
H
Cl
Ir
Ir
(PCP)Ir(H)2
(POCOP)IrHCl
H
1
2
PtBu2
b) NCP type
PtBu2
O
PtBu2
PtBu2
O
PtBu2
H
H
Ir Cl
H
Ir Cl
NaOtBu
2 L
9
Ir
L
L
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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60
- NaCl
- tBuOH
N
R
N
R
N
R
5
(RNCP)IrHCl
(RNCOP)IrHCl
R = H, 4a; tBu, 4b
R = tBu
R = H, 3a; tBu, 3b
L = DMSO or pyridine
This work:
O
PtBu2
H
Ir Cl
preclude
cyclometalation
(
BQ-NCOP)IrHCl
N
6
refluxing toluene produced (BQ-NCOP)IrHCl 6 in 88% yield
(Figure 1).
Complex 6 has been characterized by NMR spectrosco-
py and elemental analysis. The Ir–H resonance appears at
-40.56 ppm in CDCl3, which is consistent to that observed
for the pincer-ligated Ir(III) hydrido chloride complexes
adopting a square pyramidal geometry,21a,21b in which the
hydride is trans to a vacant coordination site. Growing
single crystals of 6 in THF resulted in the formation of a
BQ-
six-coordinate
THF-bound
complex,
(
NCOP)IrHCl(THF) (6-THF), as determined by X-ray dif-
fraction analysis (Figure 1.)
1) NaH
2) tBu2PCl
HBr
O
OH
N
N
N
HBr
7
8, 85%
O
PtBu2
2. RESULTS AND DISCUSION
2.1. Synthesis of (BQ-NCOP)IrHCl 6. Our earlier studies
on (tBuNCOP)IrHCl 4b revealed that, upon on dehydro-
chlorination, the pyridine moiety can dissociate from the
metal center. The subsequent rotation of the pyridine ring
and cyclometalation via C(sp2)–H bond oxidative addition
leads to an Ir(III) hydride species, which can be trapped
by two coordinating molecules, such as DMSO and pyri-
dine, to form a six-coordinate complex 5 (see Chart 1b).23
We hypothesized that the generation of such an Ir(III)
species might have a detrimental effect on catalysis in-
volving substrate activation by an Ir(I) species. To cir-
cumvent the cyclometalation event, in this work we de-
signed a new NCP ligand containing a rigid benzoquino-
line skeleton (BQ-NCOP) (Chart 1b).
Ir Cl
[Ir(COD)Cl]2
H2
O
H
PtBu2
N
9, 73%
6, 88%
O1
P1
H
Ir1
C1
Cl1
N1
O2
6-(THF)
Figure 1. Synthetic route to (BQ-NCOP)IrHCl 6 and ORTEP
diagram of 6-(THF).
The building block for the ligand precursor, 9-MeO-
benzoquinoline 7, was synthesized according to the litera-
ture procedue.24 Deprotection of the MeO group with
HBr, followed by deprotonation with NaH, and treatment
with tBu2PCl, generated BQ-NC(H)OP 9 in 73% yield. Meta-
lation of 9 with [Ir(COD)Cl]2 under H2 atmosphere in
2.2. Catalyst Evaluation for TH of Alkenes with
EtOH. The series of NCP pincer Ir(III) complexes, togeth-
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for 3 h reached a full conversion (entries 9, 10). Perform-
er with the classical PCP complexes, were tested for the
1
2
3
4
5
6
7
8
catalytic TH of unactivated alkenes with EtOH. Cy-
clooctene (COE, 10a) and 1-octene (1-oct, 10b) were cho-
sen as the model substrates because they represent unac-
tivated internal and terminal alkenes, respectively. The
results are summarized in Table 1. Upon activation with
NaOtBu, (NCP)IrHCl (3a) (1 mol%) gave only 9% cyclooc-
tane (COA, 11a) after 12 h at 30 oC for the reaction of COE
in EtOH (entry 1). Its variant (NCOP)IrHCl (4a) with a O-
atom linker between the P donor and the backbone in the
ligand showed improved activity, furnishing 68% COA
(entry 3). Complexes 3b and 4b bearing a tBu substituent
at the C6 positon of the pyridine ring are inactive for the
TH (entries 2 and 4). The PCP pincer complexes (entries 5
and 6), as well as other common late transition metal
complexes, such as Rh(PPh3)3Cl and Ru(PPh3)3(CO)HCl,
effect little, if any, catalysis (see Supporting Information)
ing the TH with three equiv of EtOH relative to COE af-
forded the desired product in >99% yield in 1h, indicating
a large excess of EtOH is not required for a high conver-
sion (entry 11). While iPrOH proved to be a suitable hy-
drogen donor, the run with MeOH gave only 13% COA
(see Supporting Information).
Examination of these NCP and PCP pincer iridium cata-
lysts for the TH of 1-oct with EtOH revealed that
(NCP)IrHCl (3a, entry 12), (NCOP)IrHCl (4a, entry 14), and
9
(
BQ-NCOP)IrHCl (6, entry 18), are effective catalysts, but
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
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42
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44
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59
60
the tBu-substituted complexes, (tBuNCP)IrHCl (3b, entry
13) and (tBuNCOP)IrHCl (4b, entry 15), showed low level of
activity. The PCP complexes are inactive for the TH (en-
o
tries 16 and 17). Finally, the TH reaction with 6 at 60 C
was found to be complete in 20 min (entry 19).
The results shown in Table 1 illustrate the profound in-
fluence of the pincer ligands on the catalytic activity. Giv-
en its superior performance in the TH reactions of both
internal and terminal alkenes, we focused on 6/NaOtBu
to explore the scope of various types of C–C multiple
bonds using EtOH as the hydrogen donor.
Encouragingly, the new complex (BQ-NCOP)IrHCl (6),
upon activation with NaOtBu, is highly productive for the
TH of COE with EtOH, furnishing COA in quantitative
o
yield after 12 h at 30 C (entry 7). EtOAc was the only de-
tectable byproduct, indicating that acetaldehyde resulting
from EtOH dehydrogenation reacts rapidly with another
molecule of EtOH to yield hemiacetal, which is dehydro-
genated further to EtOAc, probably under the influence
of iridium catalysis.22 At elevated temperature (60 oC), the
process with 0.25 mol% of 6 for 2 h or with 0.1 mol% of 6
2.3. Reaction Scope. The (BQ-NCOP)Ir/EtOH combina-
tion (“Free” (BQ-NCOP)Ir is proposed to be generated in
situ upon activation of 6 with NaOtBu19) can effect the
reductions of a wide range of unactivated C–C multiple
bonds with varying electronic and steric properties (Table
2). Most reactions employed low catalyst loadings (0.25
Table 1. Pincer Iridium Catalysts for TH of COE and 1-
Oct with EtOHa
o
mol% 6), and occurred at 60 C within hours, giving the
desired products in high isolated yields (>90%).
11a
+ 0.5 EtOAc
COE,10a
cat. (x mol%)
NaOtBu (2.2x mol%)
2.3.1. Alkyl Alkenes. Simple α-olefins, such as 1-oct
(10b), 5-Ph-1-pentene (10c), were reduced smoothly. A
variety of functional groups, including Cl (10d), Br (10e),
ketal (10f), and even unprotected OH group (10g, 10h),
were unaffected under the catalytic conditions. Allyl ben-
zene derivatives (10i) are suitable substrates. Benzyl ether
(10j) and silyl ether (10l) that are subject to C–O or Si–O
cleavage under H2/Pd/C catalysis, underwent selective C–
C double bond reduction with the protecting group re-
maining intact under our catalytic conditions. Nitrogen-
containing functionalities, such as amide, and secondary
and tertiary amines, are compatible with the catalyst
+ EtOH
or
nC6H13
or
EtOH, T, t
nC6H13
1-oct,10b
11b
T (oC)
Entry
Alkene
cat.
x mol%
t (h)
yield (%)
1
COE
COE
COE
COE
COE
COE
COE
COE
COE
COE
COE
3a
3b
4a
4b
1
30
30
30
30
30
30
30
60
60
60
60
12
12
12
12
12
12
12
0.33
2
9
<1
2
1
3
1
68
4
1
<1
5
(PCP)IrHCl
1
<2
6
2
6
6
6
6
6
1
10
7
1
>99
>99
>99
>99
>99
8
1
(10m-o). However, attempts to reduce
functionalized alkene were unsuccessful (10p).
a
nitro-
9
0.25
0.1
0.25
10b
11c
3
The TH reactions of ester-containing unactivated al-
kenes demonstrate the high chemoselectivity of (BQ-
NCOP)Ir/EtOH for the C–C double bond reduction (10q-
s). Methyl undec-10-enoate (10r) and undec-10-en-1-yl
acetate (10s) gave high yields of the desired products
without detectable ester exchange under pH-neutral con-
ditions.25 Remarkably, 1-alkene containing a terminal car-
boxylic acid functionality (10p) was selectively reduced in
the presence of one equiv of NaOtBu.
1
12
13
14
15
16
17
18
19
1-oct
1-oct
1-oct
1-oct
1-oct
1-oct
1-oct
1-oct
3a
1
1
1
1
1
1
1
1
30
30
30
30
30
30
30
60
12
12
12
12
12
12
12
0.33
>99
<15
>99
<45
2
3b
4a
4b
(PCP)IrHCl
2
6
6
2
>99
>99
In addition to cycloalkane (COE), the catalytic system
is also effective for the hydrogenation of multisubstituted,
acyclic internal alkenes (10u-x). Notably the reactions of
oleate (10w) and linoleate (10x) afforded the saturated
products in quantitative yields. Two conjugated double
aConditions: 10a or 10b (0.5 mmol), cat. (5 μmol), NaOtBu (11 μmol),
solvent (1 mL). Yield was determined by GC using mesitylene as an
internal standard. b10a (2 mmol), EtOH (2 mL). c10a (2 mmol), EtOH
(6 mmol).
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Table 2. Scope of Ir-Catalyzed TH of C–C Double Bonds with EtOHa
1
2
3
4
6 (0.25 mol%), NaOtBu (1 mol%)
R
R
+ EtOH
+ 0.5 EtOAc
R'
R'
EtOH, 60 o
C
10
11
aryl alkenes
unactivated alkenes
Ph
Ph
Ph
Ph
5
6
7
8
Cl
10d, 2 h, 97%
Br
10e, 4 h, 90%b
Ph
2
10c, 3 h, 93%
O
O
7
6
10ac, 2 h, 98%b 10ad, 2 h, 99%b 10ae, 2 h, 88%b
10f, 2 h
92%
R
10y, R = H, 2 h, >99%d
10z, R = SMe, 4 h, 94%
10aa, R = Cl, 2 h, >99%d
10ab, R = Br, 2 h, 92%
OH
MeO
Ph
Ph
HO
MeO
10i, 3 h, 93%
BnO
10ag, 2 h, 98%b
7
10af, 3 h, 99%b
7
9
10g, 2 h, 95%
10h, 2 h, 97%
10j, 2 h, 97%
electron-deficient alkenes
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
O
H
Ts
OEt
N
N
TMS
OEt
3
TBSO
OEt
O
O
Ph
Bn
10ah, 8 h, 97%b 10ai, 12 h, >99%b,f 10aj, 12 h, >99%b,f 10ak, 8 h, 97%b,g
10k, 0.5 h, 83%c
10m, 3 h, 95%
10n, 3 h, 99%b
10l, 3 h, >99%d
electron-rich alkenes
O
O
O
O2N
N
O
O
Et2N
EtO
10an, 3 h
98%b
MeO
10r, 2 h, 93%c
7
7
7
10o, 3 h, 98%
10p, 0%
10q, 2 h, 99%
10am, 3 h, >99%b,d
10al, 3 h, >99%b,d
O
heterocycles
AcO
tBu
MeO
7
3
HO
7
10t, 3 h, 99%e
O
10s, 3 h, 97%c
10u, 2 h, 99%f
10v, 12 h, 65%b,f
O
O
O
10ao, 5 h, 96%b,h 10ap, 5 h, 95%b,h 10aq, 5 h, 97%b,h 10ar, 5 h, 96%b,h
CO2Et
CO2Et
4
7
4
5
N
N
N
N
Cl
N
10w, 4 h, 99%
10x, 4 h, 99%
Ts
10as, 12 h, 91%i 10at, 24 h, 82%f,j 10au, 24 h, 63%j 10av, 24 h, 93%j 10aw, 24 h, 27%f, j
aConditions: 10 (0.5 mmol), 6 (0.25 mol%), NaOtBu (1 mol%) in EtOH (1 mL) at 60 oC. Yields shown are of isolated products. b6 (1 mol%), NaOtBu
(2.2 mol%). c6 (1 mol%), NaOtBu (1 mol%). dYield was determined by 1H NMR analysis of the crude reaction mixtures using mesitylene as an inter-
nal standard. eEtOH (2 mL), NaOtBu (1.05 equiv). fYield was determined by GC. gReduced alcoholysis product was obtained. hEtOH (0.5 mL). i6 (2
mol%). j6 (5 mol%), at 80 oC.
bonds in 10x were both hydrogenated with high efficien-
2.3.2. Heteroarenes. Reduction of heteroarenes is
thermodynamically unfavorable. Prior to this work, there
has been only one example of TH of benzofuran with al-
cohol, but with low selectivity: a Raney Ni-catalyzed TH
of benzofuran with iPrOH gave considerable amounts of
ring-opening side-products due to the C–O cleavage.27
Remarkably, (BQ-NCOP)Ir/EtOH enabled the selective re-
duction of benzofuran and its derivatives (10ao-ar), giv-
ing dihydrobenzofurans in ≥95% isolated yields (Table 3).
N-tosyl-indole (10as) was also suitable to the TH. The
C=C and C=N bonds of quinoline and its derivatives
(10at-av) were reduced in useful yields. Isoquinoline
(10aw), however, exhibited low reactivity.
cy.
Styrene and it derivatives (10y-ag) are also reactive to-
wards the TH. Substrates containing a thioether (10z) or
halide (10aa, 10ab) substituent in the para-position were
reduced cleanly to the desired products. High conversions
were obtained from the TH reactions of cis- (10ac) and
trans-stilbene (10ad), as well as indene (10ae). The reduc-
tions of diaryl and arylalkyl 1,1-disubstituted alkenes
(10af, 10ag) occurred in excellent yields.
The polarized C–C double bonds of α,β-unsaturated es-
ters (10ah-aj) underwent selective hydrogenation, as well.
The trisubstituted double bonds of 10ai and 10aj were
reduced in quantitative yield. The hydrogenation of the
double bond of coumarin (10ak) was accompanied by
ring-opening via ester exchange, resulting in the for-
mation of ethyl melilotate.
2.3.3. Alkynes. The (BQ-NCOP)Ir/EtOH system was fur-
ther applied to full reduction of internal alkynes (Table 3).
Unactivated aliphatic internal alkynes, 6-dodecyne and
alkynes bearing Cl or OH functionality (12a-c), were effi-
o
ciently reduced using 1 mol% of catalyst at 80 C. The
Catalytic methods for the TH of vinyl ethers or vinyl
amines with alcohol have remained unknown, probably
due to the relatively high insertion barriers for electron-
rich alkenes into metal–hydride.26 A brief exploration of
electron-rich alkenes revealed that (BQ-NCOP)Ir/EtOH is
capable of reducing O- or N-attached alkenes with high
efficiency. For example, the iBuO-substituted alkene
(10al) and cyclic vinyl ether (10am), were hydrogenated
in >99% yield. N-ethylcarbazole was obtained in 98% iso-
lated yield via the TH of N-vinylcarbazole (10an).
electron-deficient internal alkyne, ethyl 2-octynoate
(12d), and diaryl-substituted internal alkynes (9e-i), gave
the reduction products in >95% isolated yields using 2
mol% of 6. A comparison of the reactivity of diaryl al-
kynes (12g-i) revealed that the more sterically hindered
substrate is more reactive than the less hindered one, as
judged by the reaction times required for high conver-
sions.
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hydrogen donor (eq 5). The intramolecular TH allowed a
Table 3. Scope of Ir-Catalyzed TH of Alkynes with
EtOHa
one-step synthesis of corodane from its alcohol precursor
18 (eq 6). Such a conversion involving a tricyclodecane
structure, again, indicates that the double bond chain-
running isomerization is not a viable pathway. The utility
of Ir-catalyzed TH was further demonstrated by the high-
yielding synthesis of muscone 21, a primary contributor to
the odor of musk (eq 7). By comparison, the published
routes to corodane30 and muscone31 from their alcohol
precursors require two steps because the alcohol oxida-
tion and the internal olefin reduction operate under dif-
ferent conditions.
1
2
3
R1
6 (1%), NaOtBu (1.5%)
EtOH, 80 o
R1
R2
+ 2 EtOH
R2
+ EtOAc
OH
C
12
13
4
Cl
5
6
n-C5H11
n-C5H11 C2H5
12b, 1.5 h, 97%
n-C4H9
5
12a, 1.5 h, 97%
n-C5H11 CO2Et
12d, 15 h, 96%b,c
12c, 1.5 h, 94%
7
8
9
Ph Cy
12f, 10 h, 99%b
Ph
n-C4H9
12e, 4 h, 98%b
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
Ph
Ph
Ph
12h, 6 h, 99%b
12g, 10 h, 99%b
12i, 1 h, 98%b
aConditions: 12 (0.5 mmol), 6 (1 mol%), NaOtBu (1.5 mol%), EtOH
(2.0 mL) at 80 oC. Yields shown are of isolated products. b6 (2 mol%),
NaOtBu (3 mol%). cAt 100 oC.
2.4. Chemoselective (BQ-NCOP)Ir-Catalyzed TH of
Non-conjugated Ketone-Functionalized Alkenes. The
wide functional-group tolerance of our (BQ-NCOP)Ir/EtOH
system demonstrated by the examples of functionalized
alkenes promoted us to explore more challenging sub-
strates, non-conjugated ketone-functionalized alkenes. In
general, the polar C=O bonds are more reactive than the
non-polarized alkenes toward transition metal-catalyzed
TH, rendering the selective reduction of the latter in the
presence of the isolated ketone unit difficult. In fact, the
known examples of selective C=C hydrogenations are lim-
ited to α, β-unsaturated ketones.7 The substrates contain-
ing non-conjugated C=C and C=O bonds undergo either
selective C=O hydrogenation28 or reduction of both.12b,28
2.6. Deuterium-Incorporation by TH with C2D5OD.
Using easily accessible ethanol-D6 as the deuterium donor
enables facile deuterium-incorporation into the reduction
products (Table 4). For example, treatment of a styrene
derivative 22-D3 bearing three D-atoms in the olefinic
positions with 10 equiv C2D5OD gave 23-D5 with a perdeu-
terated Et group. The reaction of 22, however, resulted in
an uneven D-distribution: the D-incorporation level in
the benzylic position (80%) was lower than that in the Me
group (126%), implying reversible 2,1-insertion of alkene
into the Ir–D bond. By contrast, the D-atom was added
equally to the C–C double bond of 1,1-disubsituted alkene
10ag, which can be attributed to the preferential 1,2-
insertion over 2,1-insertion, presumably due to the steric
influence. Moreover, D-atom was present only at the ter-
tiary carbon and in the attached Me group (11ag-D2), thus
ruling out the possibility of olefin isomerization prior to
the reduction, at least for this substrate. Finally, the run
of diphenylacetylene with C2D5OD yielded the product
with a perdeuterated ethylene linker between two Ph
To access the ability of (BQ-NCOP)Ir/EtOH for chemose-
lective reduction of C=C over C=O bond, 11-dodecen-2-
one (14) was submitted to the standard catalytic condi-
1
tions. H NMR analysis showed the reaction formed 95%
dodecan-2-one (15) and 2% over-reduction product (11g)
after 18 min (eq 3). One possible route to 15 is the initial
hydrogenation of the C=O bond of 11 to form 11-dodecen-
2-ol (10g), followed by double bond chain-running isom-
erization.29 However, the facile TH of 10g to form 11g un-
der the catalytic conditions as shown in Table 2 suggests
that such a pathway is unlikely. In addition, the exclusive
reduction of the C=C bond in the reaction of 4-
acetylstyrene (17, 94%), with no evidence for the C=O
hydrogenation (eq 4), clearly demonstrates the desired
chemoselectivity (chain-running isomerization cannot
occur in this case).
Table 4. Deuterium-Atom Incorporation Using
C2D5OD a
6 (1%), NaOtBu (1.5%)
D-incorporated
alkene/alkyne + C2D5OD
60 oC, 4 h
reduction product
O
(10 equiv)
15, 95%
11g, 2%
O
7
7
CD2
CD
22-D3
6 (1%), NaOtBu (2.2%)
EtOH, 60 oC, 18 min
Ph
Ph
O
(3)
+
OH
O
O
O
Et
7
14
22
10ag
12g
100%
CH2D
126%
CH2D
98%
98%
CD3
CD2
98%
D2
C
O
O
same as eq 3
30 min
Ph
(4)
Ph
C
O
CHD
80%
O
CD
99%
Et
16
17, 94%
D2
98%
13a-D4, 98%b
2.5. Disproportionation Reaction. The Ir-catalyzed
TH reaction can occur in a formal intramolecular manner,
as exemplified by the conversion of 11-dodecen-2-ol (10g)
to dodecan-2-one (15, 96%) in toluene without an external
23-D5, 94%
23-D2, 90%
11ag-D2, 96%
aConditions: substrate (0.5 mmol), 6 (1 mol%), NaOtBu (1.5 mol%),
b
EtOH (2.0 mL). Yields shown are of isolated products. 6 (5 mol%),
NaOtBu (11 mol%), at 80 oC, 48 h.
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o
groups (13a-D4). Although effective, it is worth noting
that the selective D-incorporation by this method is lim-
ited to substrates that are reluctant to isomerization.
Hz at 20 C), implying a fluxional behavior on the NMR
o
1
2
3
4
5
6
7
8
time scale. Cooling the NMR sample to -75 C resulted in
31
no significant change of the P signal (δ 158.7 ppm, w1/2
21.8 Hz at -75 C), but two new multiplets at δ 4.28 and
=
o
2.7. Exploring the Mechanism of Ir-Catalyzed TH of
Alkene with EtOH.
1
4.12 ppm were observed by the low-temperature H NMR
(These two signals could not be observed at 20 oC). 1H–13C
2.7.1. Studies on the Catalyst Resting State(s). Moni-
toring the catalytic reactions of different classes of al-
kenes, COE, 1-oct, and styrene by NMR spectroscopy pro-
vided insight into the resting state(s) of the catalyst.
and H–1H COSY NMR experiments at -75 C unambigu-
ously established that these two multiplets are due to two
diastereotopic protons of the OCH2CH3 ligand (Figure
2a). These NMR data indicate that B contains Ir–H and
Ir–OEt moieties. It is pertinent to note that the Ir–H sig-
1
o
9
Treatment of 6 with 1.5 equiv of NaOtBu and 20 equiv
of COE, 1-oct, or styrene in C6D6 formed the correspond-
ing alkene complex (BQ-NCOP)IrI(alkene), A(alkene) (alkene
= COE, 1-oct, or styrene), presumably via the 14e- Ir(I)
intermediate, (BQ-NCOP)IrI, [Ir] (eq 8).18c-d, 32 A(sty) (sty =
styrene) is isolable, but attempts to isolate A(COE) and A(1-
oct) by evaporating volatiles failed and furnished unidenti-
fied species. Nevertheless, complexes A(COE) and A(1-oct) are
stable in solution in the presence of the corresponding
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
nal for B (-29.79 ppm at 20 C) is significantly downfield-
shifted as compared to those for the five-coordinate Ir(III)
complex 6 (-40.56 ppm) and other five-coordinate pincer
Ir(III) hydride complexes reported in literature,21a,21b im-
plying that the coordination site trans the hydride in B is
occupied.
Et
O
H
a)
1
31
H
{Ir}
O
EtOH (170 equiv)
COE (19 equiv)
alkene, and characterized by H and P NMR spectrosco-
pies (see Supporting Information).
31P NMR:
B
H3C
A(COE)
158.7 ppm
O
H
C6D6
H
H
NaOtBu (1 equiv), alkene (20 equiv)
Et
(
BQ-NCOP)IrI-alkene
(8)
6
-29.05 ppm
C6D6, r.t.
A(alkene)
Ir
H
{Ir} = (BQ-NCOP)IrIII
NaOtBu
alkene
alkene = COE
O
N
PtBu2
Ir
1-octene
styrene
b)
(
BQ-NCOP)IrI, [Ir]
a presumed intermediate
Ph
O
H
NaOtBu (1.1 equiv)
H
{Ir}
O
PhOH (5 equiv)
24, 92% isolated yield
6
To mimic the catalytic conditions, EtOH (170 equiv rel-
ative to Ir) was then added to the C6D6 solution of A(alkene)
and free alkene (~19 equiv). Monitoring the catalytic TH
Ph
C6H6, RT, 0.5 h
O
H
31P NMR: 159.8 ppm
Ph
31
3 OPh
reaction of 1-oct with EtOH by P NMR showed that A(1-
was the only detectable Ir species over the course of 3
oct)
h. After 4 h with 90% conversion of 1-oct, A(1-oct) was still
the major species (83%), with a new iridium species B
present in small concentration (17%). B did become the
major species after 5 h when 1-oct was fully converted to
n-octane (97%) and internal octenes (~3%, the isomeriza-
-34.28 ppm
2 OH
Ir
H
tion products). Likewise, 31P and H NMR experiments
revealed that A(sty) was the dominant species, even when
the catalytic TH reaction of styrene with EtOH was nearly
complete (see NMR data in Supporting Information).
1
c)
d)
O2
H2
1.875 Å
Ir1
N1
C1
O3
H3
In contrast to the reactions of 1-oct and styrene, the
main catalyst resting state for the TH reaction of COE is
B, even at the beginning of the reaction with high [COE].
The 31P signal for A(COE) at δ 168.0 ppm disappeared, and a
single species at δ 158.6 ppm matching the chemical shift
of B appeared immediately upon the addition of EtOH.
Complex B has remained as the major resting state until
the very late stages of the reaction (95% conversion of
COE). Multiple species were detected by 31P NMR after
the full consumption of COE.
O2
H2
1.643 Å
H
O1
Ir1
P1
O3
H3
O1
H2
O2
O1
O3
Ir1
H3
24
1
Figure 2. a) Formation of complex B and its partial H
o
NMR spectra at -75 C. b) Synthesis of a related phenox-
ide complex 24 (BQ-NCOP)IrIII(H)[O(Ph)⋅⋅⋅HO(Ph)⋅⋅⋅HOPh]
1
o
Significant effort has then been focused on the deter-
mination of the structure of B. This complex is detectable
only in the presence of excess EtOH.33 A characteristic 31P-
coupled Ir–H doublet, was detected at δ -29.79 ppm by 1H
NMR spectroscopy (JP-H = 24.9 Hz at 20 C). The P NMR
spectrum exhibits a line-broadening resonance (w1/2 = 17.8
and its partial H NMR spectra at 20 C. c) ORTEP dia-
gram of 24. d) Diagrams of the six-membered iridacycle
from different directions.
o
31
Attempts to isolate B have been unsuccessful, making
its structural characterization by X-ray diffraction analysis
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comes can be rationalized by the lower binding affinity of
difficult. One possibility for the low stability of B is the
1
2
3
4
5
6
7
8
1,2-disubstituted alkenes to the Ir(I) center in [Ir] relative
to monosubstituted alkenes, presumably due to the dom-
inant influence of steric effects.
facile β-hydride elimination involving the OEt ligand. To
our satisfaction, the substitution of PhOH for EtOH led to
a stable complex 24, which was isolated in 92% yield and
fully characterized. The isolated 24 exhibits a 31P NMR
signal at δ 159.8 ppm in C6D6, which is very similar to that
observed for B in terms of the chemical shift. The notable
1H NMR signals includes a doublet at δ -34.28 (JP-H = 24.0
2.7.2. Kinetics Studies. Next we studied the kinetics
for the Ir-catalyzed TH reactions (Figure 3). The adoption
of different resting states promoted a comparative exami-
nation of the kinetics between mono- and multisubstitut-
ed alkenes. Because the isomerization of 1-oct occurs
readily under the catalytic conditions, we therefore chose
styrene as the substrate, which permits kinetic studies
without the complication introduced by the isomeriza-
tion.
o
Hz at 20 C) for Ir–H, and a broad singlet at δ 9.40 ppm
9
corresponding to two OH groups and peaks in the range
of 6.66 to 6.99 ppm corresponding to three PhO groups
(Figure 2b). The solid-state structure of 24 was revealed
by X-ray diffraction analysis, which shows two hydrogen-
bonds, one between the OPh ligand and an uncoordinat-
ed PhOH (dO1⋅⋅⋅H3 = 1.643 Å, dO1⋅⋅⋅O3 = 2.469 Å), and the
other between the uncoordinated PhOH and another
PhOH that is coordinated to the metal (dO3⋅⋅⋅H2 = 1.875
Å, dO3⋅⋅⋅O2 = 2.649 Å). Such multiple interactions intro-
duced by these two PhOH molecules result in the for-
mation of a novel six-membered iridacycle, which is near-
ly coplanar, as illustrated in Figure 2d. The observation of
only one set of signals for the three PhO groups in (BQ-
NCOP)IrIII(H)[O(Ph)⋅⋅⋅HO(Ph)⋅⋅⋅HOPh] 24 (Figure 2b)
indicates that the barrier to the exchange between the
coordinated and uncoordinated PhOH molecules is low.
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
The reaction rates for the catalytic TH of both COE and
styrene are first-order in the precatalyst 6 (Figure 3). The
dependence of the reactions rates on the substrate con-
centration, however, varies significantly according to the
substrate. Plotting log(rate) versus log[COE] yields a
straight line of slope 0.04, implying a zeroth-order de-
pendence on [COE] (Figure 3a), whereas plotting
log(rate) versus log[styrene] yields a straight line of slope
-0.92, showing an inverse first-order dependence on [sty-
rene] (Figure 3b).
Accessing the dependence of reactions rates on [EtOH]
is more complicated. At low [EtOH] (<1.0 M), we ob-
served the catalyst decomposition during the TH process
of COE. Thus, the ethanol concentration was varied be-
tween 1.0 and 8.0 M, while keeping the [6] and [COE]
constant at 20.0 mM and 1.0 M respectively. Plotting
log(rate) versus log[EtOH] yields a straight line of slope -
0.23, showing a negative dependence on [EtOH] (Figure
3a). For the TH of styrene, the iridium catalyst exhibits
good stability even at [EtOH] as low as 0.4 M. In the low
[EtOH] range (0.4-1.0 M), a positive dependence on
[EtOH] (slope: 0.74) was observed. In the higher concen-
tration range (1.0-3.5 M), the positive dependence on
[EtOH] remained, albeit with a lower order (slope: 0.38),
likely caused by the gradual saturation in EtOH (Figure
3b). Thus, under the typical catalytic conditions, the ca-
talysis of COE is inhibited by EtOH, whereas the reaction
rate for the catalysis of styrene is enhanced at higher
[EtOH].
On the basis of NMR data and the structural infor-
mation for the closely related complexes 24, it is reasona-
BQ-
ble
to
propose
that
B
(
NCOP)IrIII(H)[O(Et)⋅⋅⋅HO(Et)⋅⋅⋅HOEt] contains
a
six-
membered iridacycle with two hydrogen-bonds involving
one EtO ligand and two EtOH molecules. The notable
downfield shift of the Ir–H resonance for B is consistent
with the formation of the six-coordinate Ir(III) species,
wherein the coordination site trans to the hydride is oc-
cupied by one Ir-bound EtOH. The resonances for two
EtOH molecules participating in the hydrogen-bond in-
teractions cannot be distinguished from that for the ex-
cess, free EtOH molecules present in the solution, even at
o
-75 C. The results indicate that the EtOH molecules in
the six-membered cycle interchange rapidly with the free
EtOH molecules on the NMR time scale, presumably
through the disruption of the hydrogen-bondings to form
the five-coordinate species (BQ-NCOP)IrIII(H)(OEt) C (eq
9), which is in accordance with the line-broadening be-
2.7.3. Kinetic Isotope Effects. To probe the rate-
determining step (RDS), kinetic isotope effects have been
studied by comparing the reaction rates using deuterated
hydrogen donors. Under the typical catalytic conditions
([ethanol] (15.6 M) is much greater than [COE] (0.5 M),
and [6] is 7.5 mM), measuring the initial rates of the TH
reactions of COE (<20% conversion) using EtOH and
31
havior detected by the P NMR experiment. Kinetic pro-
files and kinetic and equilibrium isotope effects, as dis-
cussed in the following sections, provide additional sup-
port for the structural assignment of B and for its inter-
conversion with C.
o
Et
C2D5OD in separate vessels at 26 C revealed a primary
- 2 EtOH
H
{Ir}
EtO
O
H
{Ir}
(9)
H
kinetic isotope effect (KIECOE1 = kEtOH/kC2D5OD = 1.98). Be-
cause the observed KIE may arise from the α-C–H/D or
O–H/D cleavage, C2D5OD was thus replaced with EtOD
to determine the origin of the KIE. Remarkably, an inverse
KIE was consistently obtained for the reactions with
EtOH versus EtOD (KIECOE2 = kEtOH/kEtOD = 0.68) (Figure
4a).
OEt
B
C
H
OEt
In short, the catalyst resting state depends on the na-
ture of the substrates: the reactions of 1-oct and styrene,
and probably of other α-olefins, have A(alkene) as the major
resting state throughout the catalytic process, while the
reactions of COE, and probably of other multisubstituted
alkenes mainly adopt B as the resting state. These out-
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6/NaOtBu
a)
COE + EtOH
COA + 0.5 EtOAc
1
2
3
4
5
6
7
8
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
6/NaOtBu
styrene + EtOH
PhEt + 0.5 EtOAc
b)
Figure 3. Kinetic profiles for Ir-catalyzed TH reactions of COE (a) and styrene (b) with EtOH.
Comparison of the initial rates for the reactions of sty-
rene (<20% conversion) using EtOH versus C2D5OD at 30
oC, again, established
primary KIE (KIEsty1
k’EtOH/k’C2D5OD = 3.02), which in fact is larger than that ob-
served for COE (KIECOE1 = 1.96). In contrast to the inverse
KIE obtained in the reactions of COE with EtOH versus
EtOD (KIECOE2 = 0.68), the reactions of styrene with EtOH
versus EtOD gave a normal KIE, albeit with a small value
(KIEsty2 = k’EtOH/k’EtOD = 1.37) (Figure 4b).
a)
6 (1.5%), NaOtBu (2.2%)
COE +
EtOH/C2D5OD/EtOD
26 oC
a
=
KIEcoe1 = kEtOH/kC2D5OD = 1.98
KIEcoe2 = kEtOH/kEtOD = 0.68
The primary KIEs observed for both reactions of COE
and styrene (KIECOE1 and KIEsty1), coupled with the kinetic
data presented above, suggest that β-hydride elimination
of complex (BQ-NCOP)IrIII(H)(OEt) C most likely consti-
tutes the RDS, regardless of the alkene substrates.
2.7.4. Equilibrium Isotope Effects. In order to place
these differing KIEs (a normal KIEsty2 versus an inverse
KIECOE2) observed for the reactions with EtOH versus
EtOD in context, it is important to understand how the
change in the OH* group (H* = H or D) of the hydrogen
donor affect the equilibrium isotope effects (EIEs) for the
reversible elementary steps prior to the RDS.
b)
styrene +
EtOH/C2D5OD/EtOD
6 (2%), NaOtBu (3.0%)
30 oC
KIEsty1 = k’EtOH/k’C2D5OD = 3.02
KIEsty2 = k’EtOH/k’EtOD = 1.37
The inverse first-order dependence on [styrene] ob-
served in the catalysis of styrene indicates that the de-
complexation of alkene from A(sty) (A(sty) → [Ir]) and the
oxidative addition of EtOH to [Ir] ([Ir] → C) occur revers-
ibly prior to the RDS (Figure 5). Because the catalytic pro-
cess has the styrene adduct A(sty) as the resting state, the
occurrence of the normal KIEsty2 (1.37) obtained in the
reactions of styrene with EtOH versus EtOD is readily
accounted for by a normal EIE[Ir]→C for the interconver-
sion of [Ir] and C, assuming the magnitude of the isotope
effect arising from the following β-hydride elimination of
Figure 4. Kinetic isotope effect measurements for a) TH
reactions of COE with EtOH, C2D5OD, and EtOD, and b)
TH reactions of styrene with EtOH, C2D5OD, and EtOD.
(
BQ-NCOP)IrIII(H*)(OEt) C (H*: H versus D) is very small.
The pre-equilibrium formation of C via the oxidative addi-
tion of EtOH* to the Ir(I) center in [Ir] is considered to be
more favorable for EtOH than EtOD because the zero-
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3 EtOH*, -COE
point energy difference between O–H and O–D would be
expected to be greater than that between Ir–H and Ir–D,
1
EIEB
A(COE)
2
3
4
according to the rule that “the heavier atom favors the
stronger bond”.34
-COE
EtOH*
2 EtOH*
EIEB
{Ir} H*
OEt
A(COE)
[Ir]
B
EIEC
C
[Ir]
C
5
6
7
8
RDS
EIEB
- CH3CHO
RDS
- styrene
EtOH
EIE[Ir]
{Ir}
H
{Ir}
H
H
A(COE)
A(sty)
[Ir]
= EIEB
OEt
EIEC
EIE
{Ir} H*
C
C
*
/
[Ir]
C
C
C
D
+ CH3CHO
= EIEB
H
D
[Ir]
Figure 5. The sequence for the interconversion of A(sty)
and C prior to the RDS.
[COE] = 1 M, [EtOH*] = 2 M:
9
For EtOH, [A(COE)]:[B] = 0.11:1; for EtOD, [A(COE)]:[B] = 0.19:1
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
[A(COE)][EtOH*]3
KEtOH
The inverse KIECOE2 (0.68) observed for the reaction of
COE with EtOH versus EtOD is more difficult to be inter-
preted. Given the factor that the TH of COE has B as the
resting state and β-hydride elimination of C is the RDS,
the inverse KIECOE2 may reflect an inverse EIE for the in-
terconversion of B and C (EIEB→C). The pre-equilibrium
formation of C (BQ-NCOP)IrIII(H*)(OEt), from the resting
state B via the release of two H-bound EtOH molecules, is
presumably less favorable than the release of the D-bound
EtOD molecules. In line with this contention, Dixon and
coworkers have previously reported that the H-bound
ethoxide dimer is more stable than the D-bound dimer in
the gas-phase with an equilibrium constant of ~0.46 for eq
10.35
EIEB
=
= 0.58
K =
A(COE)
KEtOD
[B][COE]
Figure 6. Equilibrium isotope effect measurements for B
o
+ COE ↔ A(COE) + 3 EtOH at 20 C by NMR spectrosco-
pies.
Applying this value of EIEB→A(COE) (0.58) and the value
of KIEsty2 (1.37) (though not rigorous, the normal KIEsty2
(1.37), to a certain extent, reflects a normal EIE[Ir]→C for the
interconversion of [Ir] and C, that is, an inverse EIEC→[Ir]
for the interconversion of C and [Ir], according to the
aforementioned analysis) to eq 11, we obtain a value of
0.79 for EIEB→C
.
EIEB
EIE
EIE[Ir]
=
C
B
A(COE)
C
(11)
= 0.79
*
K = 0.46
[EtOHOEt]- + DOEt
[EtOHDOEt]- + HOEt
(10)
= EIEB
KIEsty2
=
0.58 1.37
A(COE)
gas-phase
*
*
We have been unable to observe C, rendering the direct
Taking into account of the different reaction parameters
(concentration and temperatures), the EIEB→C value is
comparable to the KIECOE2 value (0.68). These data sup-
port the assertion that the inverse KIECOE2 is associated
with the pre-equilibrium formation of C from B, via the
release of two H-bound ethanol molecules.
measurement of EIEB→C not feasible. Thus, we sought to
measure the equilibrium constant for B + COE ↔ A(COE)
+
3 EtOH*. The interconversion of B and A(COE) entails the
following sequence: (1) dissociation of two EtOH* mole-
cules (B → C); (2) reductive elimination of EtOH* in C (C
→ [Ir]); and (3) alkene complexation to [Ir] ([Ir] →
2.7.5. Proposed Mechanism. A sizable body of data
has been obtained, which indicate that the catalytic pro-
cesses for the TH of COE and styrene/1-oct with EtOH
exhibit fundamentally different characteristics. A mecha-
nism consistent with the experimental observations is
depicted Figure 7.
A
(COE)) (cf. Figure 6). In principle, the nature of alkene
should have no influence on the EIEB→A(alkene). Thus, the
observed EIEB→A(alkene) is a composite that includes the
EIEB→C for ethanol dissociation and the EIEC→[Ir] for reduc-
tive elimination of ethanol (i.e., EIEB→A(alkene) = EIEB→C
EIEC→[Ir]).
×
For the reaction of COE, the iridium precatalyst 6 reacts
with NaOtBu to form the 14e- species [Ir], which is further
converted to (BQ-NCOP)IrIII(H)(OEt) C via the oxidative
addition of EtOH. Complex C binds to two EtOH mole-
cules reversibly to give B, which has been determined to
be the off-cycle resting state. In the RDS, the five-
coordinate ethoxy complex C undergoes β-hydride elimi-
nation to form an Ir(III) dihydride species D and release
acetaldehyde. The latter then reacts with EtOH to yield
hemiacetal, which is subsequently dehydrogenated to give
EtOAc. The primary KIECOE1 observed in the reaction of
COE with EtOH versus C2D5OD supports the proposed
RDS. Moreover, the kinetic data of first-order in the cata-
lyst and negative order in EtOH, as well as the inverse
KIECOE2 observed in the experiments of EtOH versus
EtOD, are in accordance with the proposed catalyst rest-
ing state and the RDS.
While B is the only detectable species (vide supra) un-
der the catalytic conditions with [EtOH] being much
greater than [COE], increasing [COE] relative to [EtOH]
did permit the observation of both B and A(COE). Treat-
ment of 6 (20 mM) with NaOtBu (44 mM), COE (1 M),
o
and EtOH* (2 M) in C6D6 at 20 C in 10 min resulted in a
0.11:1 A(COE):B ratio for EtOH and a 0.19:1 A(COE):B ratio for
EtOD (the conversion of COE to COA was <5% at this
point). The data yield K = 0.88 M2 for B + COE ↔ A(COE)
+
3 EtOH and 1.52 M2 for B + COE ↔ A(COE) + 3 EtOD, corre-
sponding to an inverse EIEB→A(COE) of 0.58 (Figure 6).
A key deference between the reactions of COE and sty-
rene/1-oct is the resting state. The thermodynamic stabil-
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ity of A(sty) or A(1-oct) results in its dominance and inhibi- ished/vanished by using iPrOH as the hydrogen donor,
1
2
3
4
5
6
tion on catalysis, which is consistent with the observed
inverse first order dependence on [styrene] and positive
dependence on [EtOH]. Regardless of the alkene used, β-
hydride elimination constitutes the RDS, as judged by the
assuming the hydrogen-bonding interactions between the
iPrO ligand and iPrOH, if present, would be weaker than
those in B. Consistent with the premise, a comparison of
the reaction rates revealed that the TH of COE with
iPrOH is significantly faster (~20 times) than that with
EtOH (Figure 8a).
primary KIEsty1
.
7
8
9
In sharp contrast, the reaction of styrene with iPrOH
was found to be ~2 times slower than that with EtOH
(Figure 8b). In this case, the high affinity of styrene to the
Ir(I) center in [Ir] causes the catalytic inhibition by the
substrate, rather than the hydrogen donor, and the dehy-
drogenation reactivity of the alcohol now exerts influence
on the overall catalytic efficiency. The primary alcohol,
EtOH, is more reactive towards the dehydrogenation than
the secondary alcohol, iPrOH, accounting for the superior
performance of the former in the TH of styrene.
{Ir}
Cl
H
[Ir] = (BQ-NCOP)IrI
[Ir]
A(alkene)
resting state
{Ir} = (BQ-NCOP)IrIII
6
R2 R1
EtOH
R2
for strongly bound
1-alkene
(e.g. styrene, 1-oct)
NaOtBu
[Ir]
R1
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
R1
R2
Et
{Ir}
H
F
H
{Ir}
OEt
2 EtOH
H
{Ir}
EtO
O
R1
H
R2
H
OEt
C
B
resting state
for weakly bound
multisubstituted alkene
(e.g. COE)
RDS
H
{Ir} H
OH
EtOH
R1
R2
CH3CHO
EtO
C
E
{Ir}
H
H
D
R2
D
R1
EtOAc
Figure 7. Proposed mechanism.
The rate dependence on the substrate concentration
(zeroth order in COE and inverse first order in styrene) is
consistent with the conclusion that the coordination of
alkene to the dihydride complex D, and the following hy-
dride migratory insertion in E occur after the RDS. Pro-
vided the observation of H/D scrambling in the TH of 23
with C2D5OD (see Table 4), we have concluded that the
alkene inserting into Ir−H/D bonds is reversible. Reduc-
tive elimination of Ir(III) hydrido alkyl complex F releases
the hydrogenated product and regenerates [Ir].
Although we have not detected the dihydride species D
directly by NMR spectroscopic methods, the relevant PCP
pincer-ligated Ir(III) dihydride complexes have been well-
documented.18,36 Furthermore, treatment of 10ag with
EtOD (10 equiv) under the catalytic conditions led to 11ag-
D2 with 37% D-content at the tertiary carbon and 50% D-
content in the attached Me group (eq 12). Considering
that 10ag undergoes selective 1,2-insertion as concluded
from the reaction of 10ag and C2D5OD (see Section 2.6),
the incorporation of D-atom to both carbons of the C–C
double bond at such levels provides evidence in support
of the occurrence of (BQ-NCOP)Ir(H)(D) intermediate.
50%
Figure 8. Ir-catalyzed TH of styrene (a) and COE (b) with
EtOH and iPrOH.
2.7.7. (NCP)Ir versus (PCP)Ir. One question needs to
be answered is why (BQ-NCOP)Ir complex is capable of
catalyzing the TH of alkene with EtOH, while the closely
related (PCP)Ir and (POCOP)Ir complexes effect ne-
glectable catalysis for the same transformation. To ad-
dress this issue, the reaction of 1-oct with EtOH catalyzed
by the (PCP)Ir complex was probed. Monitoring the reac-
tion in the presence of (PCP)IrHCl (5 mol% relative to 1-
oct) and NaOtBu (7.5 mol%) in C6D6 by NMR revealed the
formation of a mixture of trans and cis isomers of
(PCP)IrIII(H)(CO)(Me) 25 at the early stage of the reaction
(~10 min). These carbonyl complexes remained as the
dominant species over the course of 12 h, and a minimal
CH2D
6 (1%), NaOtBu (1.5%)
10ag
+
EtOD
(12)
O
CD
Et
60 oC, 4 h
37%
(10 equiv)
11ag-D2, 93%
2.7.6. EtOH versus iPrOH. The information gained in
the mechanistic studies indicates that EtOH can be an
inhibitor of the catalytically active intermediate C due to
the formation of the off-cycle resting state B. We envi-
sioned that such an inhibition effect might be dimin-
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Journal of the American Chemical Society
nal alkynes, some of which would be challenging to be
catalytic activity for the TH was observed (<5% conver-
1
2
3
4
5
6
7
8
sion of 1-oct to octane).
reduced by known transfer hydrogenation means. The
tolerance of many functional groups, high chemoselectivi-
ty, and formation of low-toxic byproduct (EtOAc), make
the (BQ-NCOP)Ir/EtOH combination an attractive catalytic
system for selective hydrogenation of C–C multiple bonds.
The mechanism of (BQ-NCOP)Ir-catalyzed transfer hy-
drogenation of alkene with EtOH has been elucidated.
Some important features include the following:
The trans and cis mixture was isolated (94% total yield)
from an independent experiment conducted in toluene
(Figure 9). The characteristic NMR resonances for the
1
major species, trans-25, include a H NMR triplet at δ -
11.07 for Ir–H and a broad singlet at δ 0.10 ppm for Ir–Me,
and a 13C NMR triplet at δ -182.3 ppm for Ir–CO. Moreover,
the solid-state structure of trans-25 has been determined
by X-ray diffraction analysis (Figure 9). On the basis of
these data and precedents regarding relevant pincer Ir-
9
(1) Decarbonylation of acetaldehyde by (BQ-NCOP)Ir ap-
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
pears to is less feasible than that by (PCP)Ir. Such a differ-
mediated decarbonylation of EtOH37 and MeOH,38
a
ence is likely electronic in nature, considering that the BQ
-
NCOP ligand is less electron-donating than PCP as a result
of the tBu2P-to-N(BQ) donor substitution, and therefore the
formation of (pincer)IrIII(H)(CO)(Me) bearing a strong π-
accepting CO ligand at the Ir(III) center would be ther-
modynamically less favorable for BQ-NCOP relative to PCP.
pathway involving the (PCP)Ir-mediated ethanol dehy-
drogenation, followed by the decarbonylation of the re-
sulting acetaldehyde, seems to be a reasonable one for the
formation of 25 (see Supporting Information).
It is important to note that the facile decarbonylation of
acetaldehyde leads to inactive Ir(III) carbonyl complexes
25,37,38 which is responsible for the ineffectiveness of the
PCP iridium system in the TH with EtOH. In the case of
the NCP iridium system, EtOAc is the sole byproduct ob-
served for the TH reaction, indicating that the conversion
of acetaldehyde to EtOAc must be significantly faster than
the decarbonylation, which partly account for the efficacy
of the (BQ-NCOP)Ir/EtOH combination for the catalytic
TH.
(2) Although alcohol dehydrogenation is one of the
most readily catalyzed reactions of transition metal com-
plexes, the turnover-limiting segment of the TH cycle re-
ported in this work is the ethanol dehydrogenation. Spe-
cifically, β-hydride elimination of the ethoxy Ir(III) hy-
dride complex
(
BQ-NCOP)IrIII(H)(OEt) is the rate-
determining step. The activation barriers for the hydro-
genation of unactivated alkenes (at least monosubstituted
and 1,2-disubstituted alkenes) are relatively low.
(3) The reaction rates for the Ir-catalyzed TH are sub-
strate-dependent. For alkenes with strong binding affinity
to the three-coordinate Ir(I) center, the catalysis is subject
to subject inhibition; thus, performing the reaction at low
[alkene] in neat EtOH would lead to high efficiency. For
alkenes that bind weakly to the Ir(I) center, the reversible
bonding of two EtOH molecules to (BQ-NCOP)IrIII(H)(OEt)
results in catalysis inhibition by the hydrogen donor; con-
sequently increasing [alkene] relative to [EtOH] may af-
ford a productive system.
PtBu2
PtBu2
PtBu2
NaOtBu
1-octene (excess)
EtOH (excess)
H
H
H
Ir Cl
Ir CO
Ir Me
+
Me
PtBu2
CO
PtBu2
toluene
PtBu2
(PCP)IrHCl
trans-25, ~93%
cis-25, ~6%
P2
H
C3
P1
Ir1
4. EXPERIMENTAL SECTION
Materials and Methods. All manipulations were car-
ried out using standard Schlenk, high-vacuum and glove-
box techniques unless otherwise stated. EtOH was freshly
distilled from magnesium under argon. Toluene, diethyl
ether and tetrahydrofuran (THF) were freshly distilled
from sodium benzophenone ketyl prior to use. NMR spec-
tra were recorded on Agilent 400MHz, Agilent 600 MHz
and Varian 400MHz at ambient temperature. The residual
peak of deuterated solvent was used as a reference for 1H
C1
O1
C2
trans-25
Figure 9. Formation of (PCP)IrIII(H)(CO)(Me) 25 via
(PCP)Ir-mediated decarbonylation of EtOH, and ORTEP
diagram of trans-25.
3. CONCLUSIONS
13
31
and C chemical shifts. PNMR chemical shifts were ref-
erenced to an external 85% H3PO4 standard.
We have demonstrated, for the first time, that low-cost,
renewable ethanol can serve as a general reductant for
hydrogenation of a wide variety of C–C multiple bonds.
The success of this transformation can in part be attribut-
ed to the facile conversion of acetaldehyde, the initial
EtOH dehydrogenation product, into ethyl acetate, thus
eliminating the possibility of catalyst poisoning by the
aldehyde. The scope of this TH process is very broad, cov-
ering unactivated alkyl alkenes, aryl alkenes, electron-
rich/deficient olefins, O- and N-heteroarenes, and inter-
Synthesis of Benzo[h]quinolin-9-ol hydrobromide
(8). 9-Methoxybenzo[h]quinolone 7 (1.12 g, 0.54 mmol)
and a 40% HBr (60 mL) aqueous solution were added to a
250 mL flask. The reaction was heated at 120 °C for 12 h.
Yellow-green solid precipitated when the solution cooled
to room temperature. After filtration, the precipitate was
washed with water (10 mL), cooled EtOH (10 mL), EtOAc
(20 mL) and Et2O (20 mL), affording the product as yel-
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Journal of the American Chemical Society
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1
low-green solid (1.26 g, 85%). H NMR (400 MHz, DMSO-
d6): δ 10.86 (bs, 2H), 9.15 (dd, J = 5.1, 1.1 Hz, 1H), 9.00 (d, J =
8.0 Hz, 1H), 8.45 (d, J = 1.9 Hz, 1H), 8.12 – 7.98 (m, 3H),
dried Schlenk tube. The tube was sealed with a Teflon plug
1
2
3
4
5
6
7
8
and moved out of the glovebox. The solution was heated at
o
60 C for 2 h. The reaction was quenched by exposing the
13
7.83 (d, J = 8.8 Hz, 1H), 7.47 (dd, J = 8.7, 2.1 Hz, 1H). C
solution to air and concentrated in vacuum and the residue
was purified by chromatography on silica gel.
NMR (101 MHz, CD3OD): δ 158.1, 144.5, 143.9, 138.7, 131.1,
130.2, 128.5, 128.2, 127.2, 123.3, 121.7, 121.6, 107.4. Anal. Calcd
for C13H10BrNO: C, 56.55; H, 3.65; N, 5.07. Found: C, 56.52;
H, 3.87; N, 5.00.
■
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications web site at DOI:
Crystallographic data for 6-(THF) (CCDC 1815133), 24 (CCDC
1819101) and trans-25 (CCDC 1819102) are available free of
charge via the Internet at http://pubs.acs.org.
Synthesis
of
9-((di-tert-
9
butylphosphanyl)oxy)benzo[h]quinoline (9). Under
argon atmosphere, a solution of 8 (1.1 g, 4.0 mmol) and
NaH (0.4 mg, 10.0 mmol, 60% purity) in 15 mL THF in a
100 mL sealed tube was stirred for 0.5 h at room tempera-
ture. Di-tert-butylchlorophosphine (0.82 mL, 4.8 mmol)
was added to the tube. The tube was sealed with a Teflon
plug and then heated at 100 °C for 5 h. After evaporation
of the solvent under vacuum, the residue was extracted
with Et2O (30 mL) and filtered through a pad of Celite.
Brown solid was obtained after removal of Et2O under
vacuum. The solid was washed with a small amount of
cold n-pentane (2 mL) giving the product as white solid
(1.12 g, 81% yield). 1H NMR (400 MHz, C6D6): δ 9.80 (d, J =
2.1 Hz, 1H), 8.86 (dd, J = 4.3, 1.7 Hz, 1H), 7.69 (m, 1H), 7.63
(d, J = 8.7 Hz, 1H), 7.60 (dd, J = 8.0, 1.7 Hz, 1H), 7.52 (d, J =
8.8 Hz, 1H), 7.24 (d, J = 8.8 Hz, 1H), 6.94 (dd, J = 8.0, 4.3
Hz, 1H), 1.22 (d, J = 11.7 Hz, 18H). 31P NMR (162 MHz, C6D6):
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
■
AUTHOR INFORMATION
Corresponding Author
*huangzh@sioc.ac.cn.
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENT
The authors gratefully acknowledge support from National
Key R&D Program of China (2016YFA0202900,
2015CB856600), National Natural Science Foundation of Chi-
na (21432011, 21422209), Chinese Academy of Sciences
(XDB20000000, QYZDB-SSW-SLH016), and Science and
Technology Commission of Shanghai Municipality
(17JC1401200).
13
δ 154.5. C NMR (101 MHz, C6D6) δ 159.3 (d, J = 9.7 Hz),
148.4, 146.5, 135.1, 133.8, 129.2, 128.9, 127.2, 126.6, 123.1, 121.6,
120.9 (d, J = 9.0 Hz), 112.2 (d, J = 13.2 Hz), 35.5 (d, J = 26.9
Hz), 27.2 (d, J = 15.7 Hz). HRMS (EI), m/z Calcd for
C20H28NP (M+) 339.1752, found: 339.1749.
Synthesis of Iridium Complex (BQ-NCOP)IrHCl 6.
Compound 9 (305 mg, 0.9 mmol), [Ir(COD)Cl]2 (290 mg,
0.43 mmol) and toluene (25 mL) was added in a 100 mL
Kontes flask. The flask was sealed with a Teflon plug and
then heated at 120 °C for 12 h under a hydrogen atmos-
phere. After the solvent was removed under vacuum, the
residue was washed with pentane in the glovebox. The
solid was dried under vacuum to give 0.49 g (83% yield)
product as yellow solid. The product (20 mg) was dis-
solved in THF (2 mL), and pentane (1.0 mL) was added
slowly. The solvents evaporated slowly at ambient tem-
perature in the glovebox. After a few days, yellow crystals
■
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Soloveichik, G. L., Proc. Natl. Acad. Sci. U.S.A. 2015, 112, 1687. (c)
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Organometallics 2015, 34, 5203.
13
NMR (162 MHz, CDCl3): δ 162.25 (d, J = 19.1 Hz). C NMR
(101 MHz, CDCl3): δ 163.74, 156.5, 148.9, 140.15, 137.9, 137.6,
129.3, 128.4, 126.8, 122.0 (d, J = 3.1 Hz), 121.7, 121.0, 113.5 (d, J
= 10.1 Hz), 42.4 (d, J = 27.5 Hz), 39.1 (d, J = 31.0 Hz), 28.1 (d,
J = 4.4 Hz), 27.7 (d, J = 4.2 Hz). Elemental analysis calcd
for C21H26ClIrNOP (567.11): C, 44.48; H, 4.62; N, 2.47.
Found: C, 44.12; H, 4.44; N, 2.15.
(4)
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General Procedure for Transfer Hydrogenation of
Alkenes with EtOH. In an argon filled glovebox, catalyst
6 (1.25 μmol, 0.7 mg), NaOtBu (5.0 μmol, 0.5 mg), alkene
(0.5 mmol) and EtOH (1.0 mL) were added to a 10 mL
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(33) Complex B could be synthesized in situ independently
by the reaction of 6 with NaOtBu in the presence of 170 equiv of
EtOH in C6D6, but it was detectable only at the early stages of
the reaction (~5 min) at RT. After 5 min, B decayed to unidenti-
fied species. B was reasonably stable during the catalytic TH
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H
R
R
8
R
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n EtOH
tBu2
O P
H
R
H H
H
Et
R'
O
R'
H
R'
R'
Ir
Ir
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Et
OEt
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H
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0.5n EtOAc
Ir
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