Ruthenium-Catalyzed Reductive Cleavage of Unstrained Aryl-Aryl Bonds: Reaction Development and Mechanistic Study

Article abstract of DOI:10.1021/jacs.9b11605

Cleavage of carbon-carbon bonds has been found in some important industrial processes, for example, petroleum cracking, and has inspired development of numerous synthetic methods. However, nonpolar unstrained C(aryl)-C(aryl) bonds remain one of the toughest bonds to be activated. As a detailed study of a fundamental reaction mode, here a full story is described about our development of a Ru-catalyzed reductive cleavage of unstrained C(aryl)-C(aryl) bonds. A wide range of biaryl compounds that contain directing groups (DGs) at 2,2′ positions can serve as effective substrates. Various heterocycles, such as pyridine, quinoline, pyrimidine, and pyrazole, can be employed as DGs. Besides hydrogen gas, other reagents, such as Hantzsch ester, silanes, and alcohols, can be employed as terminal reductants. The reaction is pH neutral and free of oxidants; thus a number of functional groups are tolerated. Notably, a one-pot C-C activation/C-C coupling has been realized. Computational and experimental mechanistic studies indicate that the reaction involves a ruthenium(II) monohydride-mediated C(aryl)-C(aryl) activation and the resting state of the catalyst is a η⁴-coordinated ruthenium(II) dichloride complex, which could inspire development of other transformations based on this reaction mode.

Full text of DOI:10.1021/jacs.9b11605

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Article
Ruthenium-Catalyzed Reductive Cleavage of Unstrained
Aryl#Aryl Bonds: Reaction Development and Mechanistic Study
Jun Zhu, Peng-hao Chen, Gang Lu, Peng Liu, and Guangbin Dong
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b11605 • Publication Date (Web): 01 Nov 2019
Downloaded from pubs.acs.org on November 2, 2019
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Ruthenium-Catalyzed Reductive Cleavage of Unstrained Aryl─Aryl Bonds:
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Reaction Development and Mechanistic Study
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Jun Zhu†⊥, Peng-hao Chen‡⊥, Gang Lu*§‖, Peng Liu*‖and Guangbin Dong*†‡
†Department of Chemistry, University of Chicago, Chicago, Illinois 60637, United States.
‡Department of Chemistry, University of Texas at Austin, Austin, Texas 78712, United States.
§School of Chemistry and Chemical Engineering, Shandong University, 250100, Jinan, China
‖Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States.
Abstract
Cleavage of carbon−carbon bonds has been found in some important industrial processes, e.g.
petroleum cracking, and has inspired development of numerous synthetic methods. However, non-polar
unstrained C(aryl)−C(aryl) bonds remain one of the toughest bonds to be activated. As a detailed study
of a fundamental reaction mode, here a full story is described about our development of a Ru-catalyzed
reductive cleavage of unstrained C(aryl)−C(aryl) bonds. A wide range of biaryl compounds that contain
directing groups (DGs) at 2,2’ positions can serve as effective substrates. Various heterocycles, such as
pyridine, quinoline, pyrimidine and pyrazole, can be employed as DGs. Besides hydrogen gas, other
reagents, such as Hantzsch ester, silanes and alcohols, can be employed as terminal reductants. The
reaction is pH neutral and free of oxidants, thus a number of functional groups are tolerated. Notably, a
one-pot C−C activation/C−C coupling has been realized. Computational and experimental mechanistic
studies indicate that the reaction involves a ruthenium(II) monohydride-mediated C(aryl)−C(aryl)
activation and the resting state of the catalyst is a η4-coordinated ruthenium(II) dichloride complex,
which could inspire development other transformations based on this reaction mode.
Introduction
Oxidative addition of a transition metal (TM) into a carbon−carbon (C−C) bond represents an
important means of activating C−C bonds, which has led to development of numerous synthetically
valuable methods.1 This process converts one relatively inert C−C bond into two more reactive C−TM
bonds that can undergo further transformations, affording dual functionalization of both carbon
terminuses (Scheme 1A).2 To date, a number of catalytic C−C cleavage/functionalization methods have
been developed based on such a mode of activation. However, the scope of C−C bonds that can undergo
oxidative addition with TMs is still narrow (Scheme 1B). The major class of suitable substrates contains a
three or four-membered ring, in which strain release becomes the main driving force for the C−C
cleavage.3 On the other hand, more polar C−C bonds, such as C−CN,4 C−carbonyl and C−iminyl bonds in
less strained substrates,5 can also be activated by low valent TMs due to favorable interactions between
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the low-lying σ* orbital in these moieties and TM filled d orbitals, which promotes forming the requisite
C−C/TM σ complex.
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7
A. Oxidative addition into C C bonds

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C
C
C
C
Oxidative
Addition
A
B
C
C
M
M
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TM/CC 
complex
B. Scope of C C activation substrates

O
NAr
C
R
CN
R
C
R
polar bonds
strained bonds
Scheme 1. C−C Bond Activation via Oxidative Addition
In contrast, TM insertion into non-polar and unstrained C−C bonds has been extremely rare. In 1993,
Milstein and co-workers reported a phosphine-directed activation of an aryl−alkyl bond in a pincer-type
substrate, which was driven by forming a two-five-membered-fused rhodacycle (Scheme 2A).6 The
catalytic transformation was also developed a few years later by the same group.7 Recently, Kakiuchi
and coworkers developed a novel Rh-catalyzed cleavage of unstained aryl-allyl bonds, albeit through a
β-carbon elimination mechanism.8 Activation of unstrained aryl−aryl bonds has been elusive9 until our
recent work (Scheme 2B).10 The C(aryl)−C(aryl) bonds in 2,2’-biphenols were catalytically cleaved with
hydrogen gas using a rhodium catalyst and phosphinite directing groups (DGs). Despite this promising
initial result, ortho substituents in the 2,2’-biphenol substrates were required for this transformation,
and our general understanding of activating unstrained aryl−aryl bonds is still limited. A number of
questions remain to be addressed. For example, can other types of DGs, besides those strongly
coordinative phosphorus-based ones, be used in the C(aryl)−C(aryl) bond activation? Can other TMs
besides expensive rhodium be employed as the catalyst? Can other reagents besides hydrogen gas react
with the C−C cleavage intermediate? How does a metal catalyst approach the C(aryl)−C(aryl) bond to be
cleaved? Answers to these questions could be important for expanding the substrate scope and reaction
varieties of this transformation. In this full article, we describe a detailed development of a ruthenium-
catalyzed reductive cleavage of unstrained C(aryl)−C(aryl) bonds and the mechanistic study of this
reaction (Scheme 2C). Nitrogen-based heterocycles were found to be excellent DGs and, besides
hydrogen gas, secondary alcohols and silanes could also be employed as the reductant for this
transformation.
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A. Aryl alkyl bond activation

Milstein (1993)
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Me
Me
PR2
H
Me
Me
PR2
Me
Me
PR2
Rh
H2
[
]
[Rh] Me
PR2
PR2
PR2
Me
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B. Aryl-aryl bond activation (our prior work)
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required
X
R
R
R
R
i-Pr
i-Pr
i-Pr
i-Pr
X
X
H+
Rh
cat. [ ], H2
O
O
P
P
OPiPr2
DG
H
H
X
Removable DG
C. This work
R
Heterocycle DGs
Pyridine
R
Ru(COD)Cl2
DG
Quinoline
GD
H
2 or silanes
DG
Pyrazole
secondary alcohols
or
via "RuHCl" pathway
R
H
Pyrimidine
CO2nBu
then
Ru(COD)Cl2
H2
CO2nBu
DG
Scheme 2. Activation of Non-polar Unstrained C−C Bonds
Result and Discussion
Pyridine and related heterocycles have been frequently employed as DGs in catalytic C−H activation
reactions.11 They have also been used in C−C activation of ketones.12 Thus, the 2,2’-(3-methylpyrdinyl)
substituted biphenyl (1a) was chosen as the initial substrate. Rhodium-based catalysts were naturally
examined first. Using [Rh(C2H4)Cl]2, [Rh(COD)Cl]2 or Rh(COD)2NTf2 as the catalyst, trace or no desired
product was observed (Table 1, entries 1-3). However, adding NaI as the additive to the [Rh(COD)Cl]2 –
catalyzed reaction, 39% yield of the desired C−C cleavage product was obtained (Table 1, entry 4). This
result showed the feasibility of using pyridine as DGs for C(aryl)−C(aryl) bond activation, though the
exact role of NaI is still unclear. Note that using the pyridine DG, ortho substitution at the 3,3’ positions
was not required, which is distinct from the prior 2,2’-biphenol activation.10 This motivated us to test
other readily available TM complexes as precatalysts for this transformation. While the Ni(0), Co(0), and
Ir(I) complexes gave no desired cleavage product (entries 5-7), Ru(II) dichloride complexes nevertheless
exhibited remarkable reactivity (entries 11-18). RuCl3·xH2O showed moderate reactivity (entry 10), but
12b
Ru3(CO)12 and Cp*Ru(COD)Cl were not reactive. Among various Ru complexes examined, Ru(COD)Cl2
was found to be most efficient (entry 14). Besides 1,4-dioxane, other solvents, such as toluene and THF,
were also suitable for this transformation (entries 15 and 16).
Table 1. Selected Optimization Study for the Hydrogenation Condition
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DG:
Me
2
DG
1a
transition metal catalyst
DG
2'
DG
150 psi H2, 1, 4-dioxane
130 C, 18 h
N
3'
2a
Entrya
Conditions
Yieldb
trace
n.d.
1
2
3
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5
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8
9
10 mol% [Rh(C2H4)Cl]2
10 mol% [Rh(COD)Cl]2
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10 mol% [Rh(COD)Cl]2+100 mol% NaI
20 mol% Rh(COD)2NTf2
20 mol% Ni(COD)2
39%
n.d.
n.d.
10 mol% Co2(CO)8
n.d.
10 mol% [Ir(COD)Cl2]2
6.7 mol% Ru3(CO)12
n.d.
n.d.
20 mol% Cp*Ru(COD)Cl
n.d.
10c
11
12
13
14
15
16
20 mol% RuCl3 xH2O
10 mol% [Ru(p-cymeme)Cl2]2
10 mol% [Ru(p-cymeme)I2]2
20 mol% Ru(COD)Cl2

26%
50%
66%
89%
89%(83%)
88%
77%
10 mol% Ru(COD)Cl2
10 mol% Ru(COD)Cl2, Tol. as solvent
10 mol% Ru(COD)Cl2, THF as solvent
a Reaction conditions: 1a (0.1 mmol), 20 mol% monomer or 10 mol% dimer or 6.7 mol% trimer of metal
catalyst, 1,4-dioxane (0.075 M), 130 oC, 18 h, Q-tube filled with 150 psi H2 gas. b Unless otherwise noted,
the yields were determined by 1H NMR using 1,1,2,2-tetrachloroethane as internal standard; n.d. = not
c
detected; the yield in parentheses is isolated yield. The catalyst loading was based on the formula of
RuCl3.
Alternative reductants besides H2 gas were then sought, which, if successful, could provide a more
convenient way to operate this C−C cleavage reaction (Table 2). To our delight, a variety of mild
reductants was found reactive under this Ru-catalyzed condition, and afforded the desired product. For
example, potassium formate salt and Hantzsch ester gave 9% and 58% yields of product 2a, respectively
(entries 2 and 3). Diverse secondary alcohols could also serve as a hydride source through a transfer
hydrogenation process (entries 4-8). Among all the alcohols tested, cyclopentanol proved to be most
efficient (entry 8), though an excess amount was needed for a higher conversion (entries 9-13). 84%
yield was achieved using 50 equiv of cyclopentanol with toluene as solvent. In addition, a combination
of silane and water (1:1) was found to be an excellent reductant (entries 14-18).13 An optimal result (85%
yield) was obtained when using 5.0 equiv of diphenylmethylsilane with 5.0 equiv of H2O (entry 18).
Table 2. Screening for Alternative Reductantsa
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DG:
Me
DG
1a
2
10 mol% Ru(COD)Cl2
DG
2'
DG
conditions, 1,4-dioxane
N
130 C, 24 h
3'
2a
7
8
9
Entrya
Yieldb
n.d.
Conditions
10 equiv. HCOONH4
10 equiv. HCOOK
1
2
3
4
9%
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10 equiv. Hantzsch ester
10 equiv. diphenylmethanol
2-propanol
58%
20%
11%
5c
6c
7c
2-butanol
22%
47%
3-pentanol
8c
9
cyclopentanol
70%
66%
50 equiv. cyclopentanol
30 equiv. cyclopentanol
10 equiv. cyclopentanol
10
11
12
13
14
15
16
17
18
62%
51%
50 equiv. cyclopentanol, Tol as solvent
50 equiv. cyclopentanol, THF as solvent
10 equiv. (TMS)3SiH + 10 equiv. H2O
10 equiv. Et3SiH + 10 equiv. H2O
84% (81%)
46%
12%
28%
10 equiv. PhMe2SiH + 10 equiv. H2O
10 equiv. Ph2MeSiH + 10 equiv. H2O
5 equiv. Ph2MeSiH + 5 equiv. H2O
42%
80%
85% (78%)
a Reaction condition: 1a (0.1 mmol), 10 mol% Ru(COD)Cl2, 1,4-dioxane or other solvents (1.0 mL), 130 oC,
b
1
24 h, sealed vial. Unless otherwise noted, the yields were determined by H NMR using 1,1,2,2-
tetrachloroethane as internal standard; n.d. = not detected; the yields in parentheses are isolated yields.
c The indicated alcohols were used as solvent.
With three high yielding conditions in hand, the substrate scope was investigated next (Table 3). First,
besides 3-methylpyrdine, simple pyridine can also serve as an effective DG (entry 2). Substitutions on
the arene at 3, 4 or 5 positions were all tolerated (entries 3-6), and the yield was lower for the 3,3’-
disubstiutted substrates likely due to the steric hindrance (2c). In addition, phenyl and furyl-substituted
substrates (2g and 2h) showed good reactivity. A range of functionalization groups, such as fluoride (2i),
chloride (2j and 2p), bromide (2k), trifluoromethyl (2l), OCF3 (2m), ester (2n), amide (2o), OMe (2q) and
silyl ether (2r) were found compatible. Interestingly, when a fluorine substituent is ortho to the DG
(entry 20), partial C−F bond activation/cleavage product was obtained;14 for comparison, fluorine
substitutions at other positions (2i and 2w) were intact. When a ketone moiety was present (entry 21),
partial reduction to the corresponding alcohol was observed, particularly under the transfer
hydrogenation conditions. Unsurprisingly, alcohol moieties (2u) were tolerated. The bulkier binaphthyl-
derived substrate was not reactive, likely due to the steric hindrance around of the C(aryl)−C(aryl) bond
(entry 23). Regarding the scope of DGs, substituted pyridines with various electronic properties
exhibited similar reactivity (entries 24-26). Gratifyingly, other heteroarenes, including pyrimidine (entry
27), 5-membered pyrazole (entry 28) and quinoline (entry 29), were found as competent DGs. More
labile oxazoline (1ac), oxazole (1ad) and nitrile (1ae) were ineffective. Finally, attempts to cleave an
aryl−pyridyl bond or use a mono bidentate DG were unfruitful at this stage (entries 33 and 34).
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Table 3. The Substrate Scope a
5
6
7
8
4
3
R15
Condition 3:
Cyclopentanol
Condition 1:
H2 (150 psi)
Condition 2:
H2O (5.0 equiv.)
2
DG
6
Ru(COD)Cl2 (10 mol%)
R1
DG
1
(50 equiv.)
1,4-dioxane
Ph2MeSiH (5.0 equiv.)
1.4-dioxane, 130 o
1'
DG
Condition 1, 2 or 3
6'
5'
Toluene, 130 o
C
130 o
C
C
2'
3'
R1
DG = Directing Group
24 h
18 h
24 h
4' 1
2
9
Entry 1
Entry 2
Entry 3
Entry 4
Entry 5
Entry 6
Me
Me
Me
Me
3
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
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42
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44
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50
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58
59
60
4
Me
N
N
N
N
N
N
5
Me
Me
66%
2c
23%
2b
2a
2d
2e
2
2f
70%b
70%
80%
1
3
39%
3
35%
79%
1
2
77% 56%
3
1
2
83%
80%
2
77%
74%
57%
1
2
3
3
1
2
3
85%
3
1
68%
68%
Entry 7
Entry 8
Entry 9
Entry 10
Entry 11
Entry 12
Me
N
N
N
N
N
N
O
Ph
F
Cl
80%
Br
42%
CF3
83%
2g
2
2h
70%
2i
2
2j
54%
2k
2
2l
62%c
72%
72%
73%
71%
55%
1
65%
71%
70%
50%
70%
41%
73%
2 3
1
1
2
3
1
3
1
2
3
3
1
From the
unsymmetrical substrate
Entry 13
Entry 14
Entry 15
Entry 16
Entry 17
Entry 18
From the
symmetrical substrate
Me
N
N
N
Cl
Cl
N
Cl
N
2p
N
N
OCF3
COOMe
70%
OMe
2m
2n
2o
2p
2q
80%
Cl
O
80%b
71%c
48%b
Entry 21f
58%d
73%
77%
80%
66%
81%
53%
79%
72%
60%
78%
62%
71%
3
1
2
3
1
2
3
1
1
2
3
1
2
3
1
2
3
1
2
Entry 20e
Entry 19
Entry 22
From Ketone
From 3,3'-F
F
N
N
N
N
N
N
OH
O
OH
+
+
OTBS
2s
2
2c
2r
50%
2t
2
2u
2u
2
Me
Me
23%
Me
50%b
34%b
39%b
52%b
14%
3
44%
1
3
1
2
70%
40%
61%
1
34%
39%
OMe
15%
25%
47%
42%
43%
1
2
3
1
3
1
2
3
3
Entry 26
Entry 25
Cl
Entry 23
Entry 24
Entry 28
Entry 27
F
N
N
N
N
N
N
N
N
2v
2w
71%
2x
2
2y
2
2z
2aa
49%h
25%g
27%h, i
75%
82%
40%
0%
0%
0%
67%
63%
47%
50%
69%
51%
22%
34%
Me
1
2
3
1
2
3
1
3
1
3
1
2
3
1
2
3
Entry 29
Unsuccessful substrates
Entry 30
Entry 31
Entry 32
Entry 33
Entry 34
tBu
O
O
N
N
N
N
N
H
N
N
N
N
N
N
O
O
Ph
O
2ab
2
1ad
trace product for all conditions product n.d. for all conditions
1ae
product n.d. for all conditions
1af
1ag
1ac
84%
49%
73%
1
3
product n.d. for all conditions
product n.d. for all conditions
aCondition 1: biaryl 1 (0.1-0.2 mmol), Ru(COD)Cl2 (10 mol %), 1,4-dioxane (0.075 M), 130 oC, 18 h, Q-tube
filled with 150 psi H2 gas; Condition 2: biaryl 1 (0.1-0.2 mmol), Ru(COD)Cl2 (10 mol %), 5.0 equiv of
Ph2MeSiH, 5.0 equiv of H2O, 1,4-dioxane (1.0 mL/0.1 mmol 1), 130 C, 24 h, sealed vial; Condition 3:
biaryl 1 (0.1-0.2 mmol), Ru(COD)Cl2 (10 mol %), 50 equiv of cyclopentanol, toluene (1.0 mL/0.1 mmol 1),
130 C, 24 h, sealed vial. All yields are isolation yields. Reaction time was 6 h. Reaction time was 3 h.
dReaction time was 11 h. eThe total yields are isolation yields, and the ratio of the two products were
o
o
b
c
1
f
determined by H NMR. The two products were both observed and isolated from the reaction system.
gRu(COD)Cl2 (20 mol %), 160 C. Ru(COD)Cl2 (20 mol %), 150 C. (EtO)3SiH (5.0 equiv) was used instead
o
h
o
i
of Ph2MeSiH. n.d. = not detected.
The limits of the catalyst loading and reaction temperature under the hydrogenation condition was
further investigated (Table 4). Reducing the Ru loading from 10 mol% to 2.5 mol% only marginally
affected the yield (entry 1, Table 4); further lowering the catalyst loading to 1 mol% still afforded 55%
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o
yield of the product (entry 2, Table 4). It was surprising that, at a lower temperature (110 C), a higher
o
yield (90%) was obtained (entry 4, Table 4). Further decreasing the temperature to 70 C still showed
moderate reactivity (entries 4-6, Table 4). The hydrogen pressure could be further reduced to 70 psi
without affecting the reaction efficiency (entries 7 and 8, Table 4). A lower yield (65%) was obtained
when 30 psi of hydrogen was used (entry 9, Table 4).
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45
46
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48
49
50
51
52
53
54
55
56
57
58
59
60
Table 4. Exploring the limits of hydrogenolysis of the C(aryl)−C(aryl) Bonds
DG:
Me
DG
X
Ru(COD)Cl2
(
mol%)
DG
T o
DG
1,4-dioxane,
C
N
Y
( psi), 18 h
H2
2a
1a
o
Entrya
(mol%)
2.5
1.0
10
( C)
Yieldb
80%
55%
83%
90%
59%
33%
90%
89%
65%
X
T
Y
(psi)
1c
2d
3e
4
130
130
130
110
90
150
150
150
150
150
150
110
70
10
5
10
70
6
10
7
10
130
130
130
8
10
30
9
10
aConditions: 1a (0.2 mmol), Ru(COD)Cl2, 1,4-dioxane (Ccat = 0.0075 M), 18 h, Q-tube filled with H2 gas.
bIsolated yield. c0.4 mmol 1a was used. d1.0 mmol 1a was used. e0.1 mmol 1a was used.
In addition, a one-pot C−C activation/C−C formation approach has also been established (Eq 1). After the
hydrogenolysis of the aryl−aryl bond, the ruthenium catalyst was found to remain active. Subsequent
addition of acrylate allowed for mono ortho alkylation of the C−C cleavage product in a high yield.15 This
result shows the potential to couple aryl−aryl bond activation with subsequent functionalization using a
single catalyst.
DG:
Me
Ru(COD)Cl2
DG
then
CO2nBu
3
DG
(1)
DG
1,4-dioxane, H2
130 oC, 6 h
N
COOnBu
4,
one pot
1a
81%
Mechanistic Studies
The mechanism of the Ru-catalyzed aryl−aryl bond activation was explored using a combination of
computational and experimental efforts. Three possible reaction pathways are proposed (Figure 1). Path
a involves insertion of a Ru(II) dichloride species (“RuCl2”) into the aryl−aryl bond to give a Ru(IV)
intermediate, which then undergoes hydrogenolysis to give the monomer product. Path b is initiated by
a Ru(II) monohydride monochloride species (“RuHCl”), generated via mono-hydrogenation of the
ruthenium dichloride precursor.16 Oxidative addition of the “RuHCl” into the aryl−aryl bond followed by
C−H reductive elimination affords one monomer product, and the resulting ruthenium aryl intermediate
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then reacts with H2 to deliver the other monomer product and regenerate the “RuHCl” catalyst. Path c is
based on a Ru(II) dihydride (“RuH2”) species, generated from double hydrogenation of the “RuCl2”
precursor.17 Similarly, insertion of the “RuH2” intermediate into the aryl−aryl bond, followed by double
C−H reductive elimination, should afford two monomer products. The resulting Ru(0) can then react
with H2 to regenerate the “RuH2” species (for a discussion of an alternative Ru(0)-initiated pathway, see
the Supporting Information).
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H2
Me
Me
N
N
H
H
H
Ru Cl
N
Ru Cl
N
H
Me
Me
7
8
path b
ruthenium monohydride
pathway
Me
Me
N
N
H
H
H
Ru
Ru Cl
H
Cl
N
N
1a
2a
Me
Me
6b
Me
N
H
9
Ru
Cl
N
Me
Me
1a
H
H
N
Me
Me
Me
Ru
N
2a
"RuHCl", 5b
N
H
H
Cl
Cl
Ru
H
H2
H
Cl
N
13
H2
Cl
Me
Me
Me
12
Me
N
H
N
H
N
path a
path c
Cl
Ru
Ru
N
Ru
ruthenium dichloride
pathway
H
ruthenium dihydride
pathway
H
N
Cl
N
Me
5c
Me
5a
H2
14
H2
Me
Me
Me
2a
N
H2
Cl
Cl
H
H
Ru
N
Ru(COD)Cl2
Ru
1a
N
H
H
N
Me
6a
16
Figure 1. Proposed Possible Reaction Pathways.
DFT calculation. To differentiate the three possible pathways, density functional theory (DFT)
calculations were performed. It was found that the “RuHCl” pathway (path b) was the most favorable.
The computed energy profile in Figure 2 shows that “RuHCl” complex 5b is the active catalyst species in
the catalytic cycle, which is formed from the endothermic reaction of RuCl2 species 5a with H2 via TS1
with a barrier of 21.3 kcal/mol. In both 5a and 5b, the two pyridine DGs adopt a trans geometry. This
places the target aryl−aryl bond in closer proximity to the Ru, which is evidenced by the short Ru···C
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distances of 2.3-2.6 Å in 5a and 5b (vide infra, Figure 5, the X-ray structure of 5ah). This agostic C–C/Ru
coordination leads to a low barrier of 12.2 kcal/mol for the subsequent C(aryl)–C(aryl) oxidative addition
transition state TS2b with respect to 5b. The overall activation free energy of TS2b is 24.5 kcal/mol with
respect to the resting state 5a. In contrast, the experimentally observed low reactivity of bi-aryl
substrates with only one pyridine substituent (e.g. 1af) can be attributed to the lack of the agostic C–C
coordination with the Ru (see Figure S7.2.2 for detailed computational results). The necessity of two DGs
for the C(aryl)–C(aryl) bond cleavage has also been demonstrated in the catalytic activation of the
C(aryl)−C(aryl) bonds of 2,2’-biphenols by installing phosphinites as DGs in our prior study.10 After the
C−C cleavage step, the ensuing C−H reductive elimination (TS3) and σ-bond metathesis with H2 (TS4)
both occur with low barriers, leading to two monomer products (2a) and regenerating the “RuHCl”
catalyst (5b).
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60
Gsol
(Hsol
)
Me
kcal/mol
N
Ru
N
H
Me
Cl
Cl
N
Ru
N
H
Me
H
Cl
TS2b
TS2b
Me
Me
Me
H
Me
TS1
N
Me
H
Ru
N
N
N
24.5
(24.2)
H
Me
H
TS1
21.3
Cl
Ru Cl
Ru Cl
H
N
TS3
Cl
Cl
2.42
2.42
HCl
(13.2)
N
TS4
N
Ru
N
9
TS3
6b
5b
Me
Me
12.9
8.1
12.7
(14.5)
H2
12.3
(14.7)
(14.3)
Me
Me
(10.8)
H2
TS4
1a
2a 2a
+
5a
Me
Me
9
7
7.1
(2.3)
0.4
(4.1)
N
Ru
N
6.9
(2.8)
5b
H
5a
1.7
N
Ru
N
8
Cl
H
0.0
(0.0)
(8.8)
Me
Me
Cl
N
N
Me
2.34
6b
N
H
H
Ru Cl
Me
N
Me
H
Me
1a
7
N
Ru
N
Cl
2.58
Me
CC oxidative addition
N
Me
2a
5b
8
CH reductive elimination
H2 coordination
product release
hydride formation
-bond metathesis
Figure 2. DFT-computed reaction energy profile of the C(aryl)−C(aryl) bond activation of substrate 1a
catalyzed by a Ru monohydride monochloride catalyst (path b).
The possibility of the “RuCl2” and “RuH2” pathways are also considered and the key results are
summarized in Figure 3. In the “RuCl2” pathway (path a, Figure 3A), although the oxidative addition of
C(aryl)–C(aryl) (TS2a) requires a relatively low barrier of 20.8 kcal/mol with respect to the “RuCl2”
species 5a, the resulting octahedral Ru intermediate 6a is coordinatively saturated and thus incapable of
binding with H2 and undergoing hydrogenolysis of the Ru–C(aryl) bonds. The transition state TS5 for H2
cleavage has a barrier of 28.6 kcal/mol, even higher than that of the C(aryl)–C(aryl) cleavage (TS2b) in
the “RuHCl” pathways (Figure 2). Our calculations indicated several other possible pathways of 6a
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reacting with H2, including the one via dissociation of one of the pyridine DGs or one chloride ligand,18
all require high barriers (see details in the Supporting Information, Figure S7.2.3). Figure 3B shows that
the formation of the RuH2 complex 5c from 5a is endergonic by 34.8 kcal/mol. This results in a highly
disfavored C(aryl)–C(aryl) oxidative addition transition state TS2c (ΔG‡ = 53.0 kcal/mol with respect to 5a)
via the ruthenium dihydride complex (see details in Figure S7.2.4). Taken together, these computational
results indicate that the “RuCl2” and “RuH2” pathways are both disfavored. In addition, our DFT
calculations show that although the reductive elimination of RuH2 (5c) to form a Ru(0) species is
energetically feasible, the Ru(0) pathway requires very high activation barriers for the C(aryl)–C(aryl)
oxidative addition and the further hydrogenolysis steps (see details in Figure S7.2.5). Therefore, the DFT
calculations suggested the “RuHCl” pathway (path b, Figure 1) is the most feasible.
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A
path a
)
. Ru dichloride pathway (
Me
Me
Me
Me
N
Ru
N
N
Ru
N
N
Cl
Ru
Cl
N
N
Ru
N
H
H
H2
Cl
Cl
Cl
Cl
Cl
Cl
Me
Me
Me
Me
5a
TS2a
6a
TS5
0.0
20.8
11.1
28.6
(0.0)
(18.9)
(10.7)
(18.8)
B
path c
. Ru dihydride pathway (
Me
)
Me
Me
Me
N
N
N
N
H
Cl H2
Ru
H2
H
H
H
Ru
N
Ru
N
Ru
N
H
Cl
Cl
N
HCl
HCl
Me
Me
Me
Me
5a
5b
5c
TS2c
0.0
12.3
34.8
53.0
(0.0)
(14.7)
(39.1)
(54.8)
Figure 3. DFT computed pathways for the C(aryl)−C(aryl) bond activation of substrate 1a catalyzed by Ru
dichloride and Ru dihydride catalysts. Gibbs free energies and enthalpies (in parentheses) are in
kcal/mol with respect to the RuCl2 complex 5a.
Kinetic studies. To validate the computational results that favor the “RuHCl”-mediated C−C activation
pathway, the following kinetic studies were performed. First, the fate of 1,5-cyclooctadiene (COD) on
the Ru precatalyst was determined. It was found that the COD ligand was hydrogenated to cyclooctene
and cyclooctane in high efficiency at the beginning of the reaction (Scheme 3, Eq 2). This result indicated
that COD is likely not involved in the catalytic cycle. Second, the kinetic profile of the reaction with
substrate 1a was measured. The initial-rate method was employed to determine the reaction order of
each component. The reaction was found to exhibit first order dependence on the concentration of
Ru(COD)Cl2, zero order on [substrate 1a] and [COD], and pseudo zero order on [H2] under a higher
pressure; but some rate dependence on [H2] was observed under a relatively low H2 gas pressure (<40
psi) (Scheme 3, Eq 3 and see Supporting Information, Table S5.2.3 for details).19 These kinetic data are
consistent with the DFT calculation (vide supra, Figure 2), which suggests that the oxidative addition step
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is the turnover-limiting step (TLS).
5
6
7
8
Me
Ru(COD)Cl2 (30 mol%)
+
N
(2)
N
1,4-dioxane, 130 o
H2 (150 psi)
C
Me
9
time
5 min
10 min
15 min
1.0 h
Yield:
2a
cyclooctene
13.8%
cyclooctane
17.8%
1a
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13
14
15
16
17
18
19
20
21
22
23
24
25
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31
32
33
34
35
36
37
38
39
40
41
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49
50
51
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53
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57
58
59
60
6.9%
32.4%
51%
87%
23.4%
51.2%
25.1%
56.6%
9.5%
72.6%
Me
Me
Ru(COD)Cl2
H2, 1,4-dioxane, 130 o
N
(3)
N
N
C
Me
2a
1a
Ru(COD)Cl2: First Order
1a
:
Zero Order
COD: Zero Order
H2: Dependence at low pressure
Scheme 3. Kinetic Studies with the Model Substrate
In addition, Hammett plot analysis was conducted to investigate the sensitivity of the reaction to
electronic changes (Figure 4).20 The results indicated that the electron-withdrawing substituents on the
arenes could promote the reaction to some extent, while electron-donating groups slowed down the
reaction. This observation is also consistent with the DFT calculated results, in which the oxidative
addition step is predicted to be the TLS, as the electron-deficient bonds typically promote oxidative
addition.
X(p)
Y(m)
X(p)
Me
Y(m)
Ru(COD)Cl2 (5.0 mol%)
Me
N
N
H2 (150 psi), 1.4-dioxane
130 o
C
N
Me
Y(m)
X(p)
1
2
Figure 4. Hammett Plot
Resting state. Considerable endeavors have been made to capture the DFT calculated resting state,
“RuCl2” species 5a. After numerous attempts, heating a mixture of substrate 1ah and 30 mol% of
Ru(COD)Cl2 under 150 psi H2 atmosphere in 1,4-dioxane at 130 C for 20 min afforded a dark green
o
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metal complex (5ah). The structure of complex 5ah was unambiguously determined by X-ray
crystallography (Figure 5), which is consistent with the proposed “RuCl2” resting state by DFT (vide supra,
Figure 2). In complex 5ah, the metal center exhibits octahedral geometry with the two pyridine DGs
adopting a trans spatial relationship. An interesting η4-coordination mode between two arene π bonds
and the Ru center was observed;21 in particular, the bond lengths between the Ru center and the
carbons to be cleaved are short: ca 2.2 Å. Thus, this structure shows that the Ru(II) center is very close
to the target C(aryl)−C(aryl) bond. Compared to d8 Rh(I) that favors a square planar geometry, the d6
Ru(II) can easily form a 18 electron complex through coordination with two arene π bonds. The agostic
interaction with the C(aryl)−C(aryl) bond, as illustrated in the structure of 5ah, is anticipated to be
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important for the desired C−C bond activation.
OMe
MeO
Me
Me
N
N
Cl
Cl
Ru(COD)Cl2 (30 mol%)
N
14
Ru
13
N
1,4-dioxane, H2 (150 psi)
130 oC, 20 min
Me
Me
OMe
MeO
1ah
5ah
bond length (Å)
Ru1---C20 2.368
Ru1---C14 2.217
Ru1---C13 2.223
Ru1---C7 2.409
X-ray
structure
of 5ah
Figure 5. Capture of the Resting State of the Catalyst
1
In addition, the reaction of substrate 1ah was monitored by H-NMR, in which the “RuCl2” species 5ah
1
was observable from the very beginning to almost the end of the reaction by comparing the H-NMR
spectra of the crude mixture with that of the isolated 5ah (Figure 6).
OMe
OMe
Me
Ru(COD)Cl2 (30 mol%)
Me
N
1,4-dioxane, H2 (150 psi)
130 oC, time
N
N
Me
2ah
time
(NMR yield)
OMe
1ah
20 min
40 min
60 min
100 min
140 min
33%
49%
68%
87%
90%
2ah
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45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 6. Monitoring the Reaction of Substrate 1ah
Moreover, complex 5ah is catalytically active. When 10 mol% of the 5ah was employed as the catalyst
under otherwise identical conditions, 91% yield of the desired product was obtained (Eq 4). Therefore,
all the above observations are consistent with the proposal of having the “RuCl2” species (5a) as the
resting state of the catalyst.
Me
Me
Me
1,4-dioxane
5ah
(10 mol%)
OMe
N
(4)
N
N
+
H2 (150 psi)
N
130 o
C
Me
2a
2ah,
93%
14 h
91%
nmr yield
nmr yield
5ah
1a
Based on
Other control experiments. To explore the “RuHCl”-mediated reaction pathway, a ruthenium
monohydride monochloride complex 17 was synthesized and subjected to the reaction with substrate
1a in the absence of hydrogen gas (scheme 4, Eq 5).22 To our delight, 60% yield of the desired monomer
product was obtained based on the hydride complex.23 For comparison, the analogous ruthenium
dihydride complex 1824 gave only trace product via LC-MS analysis under the same reaction conditions
(Scheme 4, Eq 6). These results suggest the important role of the chloride ligand in the Ru-catalyzed
C(aryl)−C(aryl) bond activation.
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Me
Me
Me
1,4-dioxane
Me
N
+
Me
(5)
(6)
130 oC, 24 h
Ru
N
N
N
N
2a
60% yield
Cl
H2 free
PCy3
Me
H
17
, 100 mol%
[Ru]
1a
based on
Me
Me
Me
Me
1,4-dioxane
Me
N
+
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
130 oC, 24 h
Ru
N
2a
H
H2 free
PCy3
Me
H
trace or none
Me
1a
18
, 100 mol%
Me
Me
Ru(COD)Cl2 (10 mol%)
N
(7)
+
H2 (150 psi), 130 oC, 18 h
1.4-dioxane
N
N
Me
Additives
2a
2a'
1a
None
89% (83%)
16%
trace
32%
Mn (60 mol%)
Scheme 4. Further Control Experiments
To further examine the possibility of the Ru(0)-initiated pathway, a control experiment was run with
60 mol% of Mn added to the reaction, as Mn metal is known to be capable of reducing Ru(II) to Ru(0)
(Scheme 4, Eq 7).25 To our surprise, the reaction with Mn not only gave a lower overall yield on the C−C
cleavage products, but also generated a significant amount of arene hydrogenation product 2a’. It is
intriguing that the neutral benzene ring is selectively reduced instead of the more electron-deficient
pyridine ring, implying a possible directed hydrogenation by a Ru(0) catalyst.26 For comparison, such an
over-reduction product was almost not observed under the standard reaction conditions. This
experiment suggests that the Ru(0) is unlikely to be the actual catalyst for the activation of the
C(aryl)−C(aryl) bonds.
Conclusion
In summary, to explore a fundamental reaction mode, we have conducted a detailed study of an
unusual Ru-catalyzed activation of unstrained C(aryl)−C(aryl) bonds. The reaction limits and substrate
scopes have been carefully examined. Besides hydrogen gas, a number of other reagents, such as
Hantzsch ester, silanes and alcohols, have also been found effective to serve as terminal reductants for
the reductive cleavage. Various heterocycles, such as pyridine, quinoline, pyrimidine and pyrazole, can
be employed as DGs. In addition, a range of functional groups are compatible under the reaction
conditions. Moreover, a one-pot C−C activation/C−C coupling has been realized. Finally, the reaction
mechanism has been investigated through collaborative efforts between DFT calculations and
experiments. The involvement of a ruthenium(II) monohydride-mediated C(aryl)−C(aryl) activation and a
η4-coordinated ruthenium(II) complex as the resting state should have broad implications beyond this
work. The knowledge obtained in this study may improve our understanding on activating strong, non-
polar and unstrained chemical bonds. Efforts on expanding the reaction mode to non-reductive
processes are ongoing in our laboratories.
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ASSOCIATED CONTENT
Text, figures, tables, and CIF files giving experimental procedures, kinetics data, and crystallographic information. This material
is available free of charge via the Internet at http://pubs.acs.org.
Experimental procedures; spectral data (PDF)
Crystallographic data for 5ah
Computational details, additional computational results, and Cartesian coordinates
7
8
9
AUTHOR INFORMATION
Corresponding Author
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*ganglu@sdu.edu.cn
*pengliu@pitt.edu
*gbdong@uchicago.edu
Author Contributions
⊥These authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
NIGMS (1R01GM124414-01A1) (G.D.) and the National Science Foundation (CHE-1654122) (P.L.) are acknowledged for
research support. G.L. thanks Shandong University for financial support. Dr. Ki-Young Yoon and Dr. Alexander Filatov are
acknowledged for X-ray crystallography. Dr. Jianchun Wang is thanked for helpful discussions. Calculations were performed at
the Center for Research Computing at the University of Pittsburgh and the Ex-treme Science and Engineering Discovery
Environment (XSEDE) supported by the NSF.
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23 Complex 17 can promote hydrogen transfer from 1,4-dioxane. For details, see the Supporting Information.
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[Ru(η6-arene)(L)(MeCN)2][BF4]2: X-ray Crystal Structure Determination of [Ru(η2-O2CO)(p-cymene)(PCy3)]·1/2CH2Cl2 and
[Ru(η2-O2CO)(η6-C6Me6)(PMe3)]·H2O. Eur. J. Inorg. Chem. 2006, 2006, 1174-1181.
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McKinney, R. J.; Colton, M. C. Homogeneous ruthenium-catalyzed acrylate dimerization. Isolation, characterization and
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26 (a) Prechtl, M. H. G.; Scariot, M.; Scholten, J. D.; Machado, G.; Teixeira, S. R.; Dupont, J. Nanoscale Ru(0) Particles: Arene
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R
R
Me
R
Ru(COD)Cl2
DG
N
N
H
2 or silanes
DG
DG
Cl
Cl
or secondary alcohols
H
R
Ru
DG
H
R
R
Ru
DG
=
Cl
Me
R
pyridine, quinoline,
DG
resting state
(X-ray obtained)
pyrimidine, pyrazole
proposed key
intermediate
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