Rollover cyclometalation pathway in rhodium catalysis: Dramatic NHC effects in the C-H Bond functionalization

Article abstract of DOI:10.1021/ja308205d

Organometallic chelates are readily obtained upon coordination of metal species to multidentate ligands. Because of the robust structural nature, chelation frequently serves as a driving force in the molecular assembly and chemical architecture, and they are used also as an efficient catalyst in numerous reactions. Described herein is the development of a Rh(NHC) catalytic system for the hydroarylation of alkenes and alkynes with 2,2-bipyridines (bipy) and 2,2-biquinolines; the most representative chelating molecules. Initially generated (bipy)Rh(NHC) chelates become labile because of the strong trans-effect of N-heterocyclic carbenes, thus weakening a rhodium-pyridyl bond, which is trans to the bound NHC. Subsequent rollover cyclometalation leads to the C-H bond activation, eventually giving rise to double functionalization of chelate molecules. Density functional calculations are in good agreement with our mechanistic proposal based on the experimental data. The present study elucidated for the first time the dramatic NHC effects on the rollover cyclometalation pathway enabling highly efficient and selective bisfunctionalization of 2,2-bipyridines and 2,2-biquinolines.

Full text of DOI:10.1021/ja308205d

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Article
Rollover Cyclometalation Pathway in Rhodium Catalysis:
Dramatic NHC Effects in the C-H Bond Functionalization
Jaesung Kwak, Youhwa Ohk, Yousung Jung, and Sukbok Chang
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 26 Sep 2012
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Rollover Cyclometalation Pathway in Rhodium Catalysis:
Dramatic NHC Effects in the C–H Bond Functionalization
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Jaesung Kwak,† Youhwa Ohk,‡ Yousung Jung,*,‡ and Sukbok Chang*,†
†Molecular-Level Interface Research Center and Department of Chemistry
‡Graduate School of EEWS (WCU), Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701,
Korea
KEYWORDS : Rollover cyclometalation, rhodium catalysis, NHC, trans-effects, 2,2’-bipyridine, chelates,
bishydroarylation
ABSTRACT: Organometallic chelates are readily obtained upon coordination of metal species to multidentate ligands.
Because of the robust structural nature, chelation frequently serves as a driving force in the molecular assembly and
chemical architecture, and they are used also as an efficient catalyst in numerous reactions. Described herein is the devel-
opment of a Rh(NHC) catalytic system for the hydroarylation of alkenes and alkynes with 2,2’-bipyridines (bipy) and 2,2’-
biquinolines; the most representative chelating molecules. Initially generated (bipy)Rh(NHC) chelates become labile due
to the strong trans-effect of N-heterocyclic carbenes, thus weakening a rhodium-pyridyl bond which is trans to the bound
NHC. Subsequent rollover cyclometalation leads to the C−H bond activation, eventually giving rise to double functionali-
zation of chelate molecules. Density functional calculations are in good agreement with our mechanistic proposal based
on the experimental data. The present study elucidated for the first time the dramatic NHC effects on the rollover cy-
clometalation pathway enabling highly efficient and selective bisfunctionalizaion of 2,2’-bipyridines and 2,2’-biquinolines.
ꢀ INTRODUCTION
tion of reacting C−H bonds driven by the favorable for-
mation
A recent research emphasis on the transition metal-
catalyzed direct functionalization of stable C−H bonds
has opened a new era of synthetic chemistry due to its
great simplicity in designing a synthetic route to complex
molecules when compared to the conventional methods,
in which pre-functionalized substrates are required. As a
result, synthetic chemists can now be benefited from uti-
lizing the C−H bond activation strategy to develop
straightforward and environmentally benign chemical
processes.1 Significant advances have been made in recent
years to demonstrate that well designed catalytic systems
(MLn) can activate poorly reactive C−H bonds to generate
their LmM−C organometallic intermediates.2 In order to
obtain such reactive C−M bonds more efficiently and se-
lectively, a range of strategies have been practiced with
the judicious choice of metal species. Among those ap-
proaches, the most effective way to activate the desired
C−H bond is the introduction of directing groups at the
proximity such as amides, esters, or various heterocycles
(Figure 1a).3 This strategy can reliably designate the posi-
Figure 1. (a) Classical cyclometalation strategy for the ortho-
C−H bond functionalization. (b) Formation of stable chelates
inhibiting a cyclometalation pathway.
of 5- or 6-membered metalacyclic intermediates.4 This
route to generate metalacycles in situ has been extensive-
ly
utilized
for
the
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Figure 2. Bidentate metal chelates.: (a) chelates of 2,2’-bipyridine and phenanthroline derivatives utilized in various areas of
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chemistry; (b) bidentate chelates used as a directing group in organic transformations.
Scheme 1. Present Study of the Catalytic Utilization of Rollover Cyclometalation Pathway Initiated by trans-
Effect
subsequent C−C, C−N, C−O and C−X (X: halides) bond
formation.5
pathway was previously investigated mainly in a stoichio-
metric manner, wherein scope of the studies was rather
limited to the isolation of the rollover cyclometalated
complexes,11 but following functionalizations have been
rare.12 Although the Rh-catalyzed double functionalization
of 2,2’-bipyridine was briefly reported by Miura et al., only
limited substrate scope was presented under harsh reac-
tion conditions.12a Therefore, the successful development
of a catalytic rollover cyclometalation approach would be
highly inspiring to open a new avenue in transition metal
catalysis giving rise to doubly functionalized compounds
such as IV which can still maintain the chelating ability.
Upon securing such an efficient and selective catalytic
system, a significant progress will be anticipated to follow
in the areas of catalysis, molecular assembly and materials
architecture.
In order to develop a process based on the catalytic roll-
over cyclometalation pathway of 2,2’-bipyridine deriva-
tives, the following aspects were initially envisaged to
consider: i) search for suitable ligands displaying an op-
timal trans-effect to make a trans metal-pyridyl bond
highly labile, ii) optimization of a metal catalyst system to
facilitate the C−H bond activation, iii) facile insertion of
functional groups into the metalacycles, and iv) no inhibi-
tory effects of the first introduced functional group to-
wards the second rollover cyclometalation process of
mono-functionalized 2,2’-bipyridine intermediates. Re-
cently, we have developed the highly efficient rhodi-
um(NHC)-catalyzed C−C, C−N, C−O bond formation re-
action,13 and it was found that NHCs were especially effec-
tive for the facile generation of key rhodacycle intermedi-
ates13a,c presumably due to the strong σ-donating ability
and unique steric environment of NHCs.14 Along with
these studies, we hypothesized that the nature of NHCs
might be beneficial to trigger a rollover cyclometalation
of metal-ligated 2,2’-bipyridines most desirably in a cata-
lytic manner, thus enabling eventual double functionali-
On the other hand, when organic compounds contain
more than one coordinating heteroatom, formation of
stable multidentate metal chelates is highly favored upon
the coordination of metal center to the multiple heteroa-
toms. Representatively, 2,2’-bipyridine (bipy) or 1,10-
phenanthroline (phen) readily forms stable chelates
(bipy)MLn or (phen)MLn (Figure 1b). As a result, catalytic
functionalization on the molecular backbone of those
ligating compounds has been considered to be extremely
difficult due to the robust nature of the chelation bonds.
Indeed, it was found that a wide range of compounds
bearing
bipyridyl,
2-aminomethylpyridyl,
or
8-
aminoquinolinyl unit react with metal species to furnish
metal chelates which guide site-selective activation of
most accessible C−H bonds (Figure 2).6 The facile for-
mation of metal chelates often serves as a driving force in
molecular assembly and chemical architecture.7 In addi-
tion, an excellent redox ability of these metal chelates has
been well harnessed in the development of efficient cata-
lytic reactions.8
The fact that cyclometalation of 2,2’-bipyridine and ana-
logues is extremely difficult to achieve especially in a cata-
lytic manner can be ascribed to the difficulty of the initial
decomplexation of stable metal chelates, which step is
essential for the subsequent rotation and C−H bond acti-
vation to maintain the cyclometalation cycle. In this con-
text, we hypothesized that when a strong σ-donating lig-
and (L) such as N-heterocyclic carbene (NHC) is bound to
a metal center of (bipy)MLX (I), it may exert a high trans-
effect to weaken a metal-pyridyl bond trans to L (Scheme
1).9,10 It was anticipated that this strong trans-effect of L
allows for the facile decomplexation of I leading to II,
thus enabling subsequent rotation around the bipyridyl
axis and then C−H bond activation eventually to afford a
metalacycle species III. This “rollover” cyclometalation
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zations.15 Herein, we report the realization of this novel
ꢀ RESULTS AND DISCUSSION
concept of rollover cyclometalation of 2,2’-bipyridine and
its analogues by developing Rh(NHC)-catalyzed
bishydroarylation of alkenes and alkynes.16 Mechanistic
studies and computational calculations support our pro-
posal of the dramatic NHC effects exerting trans-
influence. A synthetic application of utilizing chiral or-
ganocatalysts, accessible through this study, is also pre-
sented.
Optimization of Reaction Conditions. At the outset
of our studies, we screened optimal conditions of a Rh-
catalyzed hydroarylation of 2,2’-bipyridine (1a) with 3,3-
dimethyl-1-butene (2, Table 1). When a NHC precursor L1
(SIMes∙HCl)
was
used
in
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Table 1. Optimization of Reaction Conditionsa
entry
1
catalyst (mol %)
Rh(acac)3 (10)
Rh(acac)3 (10)
–
ligand (mol %)
L1 (10)
L1 (10)
L1 (10)
L1 (10)c
L2 (3)
base (equiv)
t-BuONa (2.1)
t-BuONa (2.1)
t-BuONa (2.1)
–
time (h)
3a (%)b
4a (%)b
2
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12
2
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–
2
24
3
–
4
Rh(acac)3 (10)
Rh(acac)3 (3)
Rh(acac)3 (3)
Rh(acac)3 (3)
Rh(acac)3 (3)
Rh(acac)3 (3)
Rh(acac)3 (3)
Rh(acac)3 (3)
Rh(acac)3 (3)
Rh(acac)3 (3)
Rh(acac)3 (3)
Rh(acac)3 (3)
[Rh(cod)Cl]2 (1.5)
Rh(cod)(IMes)Cl (3)
Pd(OAc)2 (3)
Ni(acac)2 (3)
PtCl2 (3)
–
–
5
t-BuONa (2.1)
t-BuONa (0.3)
Cs2CO3 (0.3)
t-BuONa (2.1)
t-BuONa (2.1)
t-BuONa (2.1)
t-BuONa (2.1)
t-BuONa (2.1)
t-BuONa (2.1)
t-BuONa (2.1)
t-BuONa (2.1)
t-BuONa (0.3)
t-BuONa (0.3)
t-BuONa (2.1)
t-BuONa (2.1)
t-BuONa (2.1)
–
94
97
- (5)d
1
6
L2 (3)
2
–
7
L2 (3)
2
- (16)d
8
PPh3 (3)
PCy3 (3)
L3 (3)
2
8
5
9
2
<1
<1
<1
–
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11
2
3
L4 (3)
L5 (3)
2
4
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19
20
2
<1
<1
<1
10
–
L6 (3)
L7 (3)
2
–
2
–
L8 (3)
L2 (3)
2
3
2
91
93
–
–
2
<1
–
L2 (3)
2
L2 (3)
2
–
–
L2 (3)
2
–
–
aReaction conditions: 2,2’-bipyridine (1a, 0.3 mmol), 2 (1.5 mmol) in toluene (0.4 mL) at 130 C. NMR yield (internal standard:
o
b
1,1,2,2-tetrachloroethane). cIsolated carbene (SIMes) was used. dRh(cod)(IMes)Cl (3 mol %) was used instead of Rh(acac)3/L2.
combination with Rh(acac)3 catalyst and t-BuONa base, a
mono-hydroarylated adduct 3a was obtained as a major
product along with a doubly hydroarylated compound 4a
after 2 h at 130 C albeit in a low combined yield (entry 1).
A full conversion was observed with prolonged reaction
(entry 2). Both rhodium catalyst and base were essential
to the reaction progress (entries 3−4). To our delight,
when IMes∙HCl (L2), an unsaturated analogue of L1, was
employed, reaction efficiency and selectivity were signifi-
cantly increased even with lower loading of catalyst and
base in shorter reaction time (entries 5−6). It needs to be
o
time leading to a bis-hydraoarylated adduct 4a in major
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mentioned that catalytic amounts of t-BuONa base were
pared either in situ or separately, displayed similar reac-
sufficient still giving rise to an excellent degree of the re-
action efficiency (entry 6), thus greatly improving func-
tional group tolerance. Bases other than t-BuONa were
not effective to the reaction (e.g. entry 7), and the use of
phosphine ligands instead of NHC gave poor conversion
and selectivity (entries 8−9). As predicted, structure of
NHC ligands critically influenced the reaction efficiency,
and NHCs (L3−L8) bearing modified electronic and/or
steric environment displayed only negligible reactivity
(entries 10−15). Interestingly, a Rh(I)-IMes species, pre-
tivity and selectivity when compared to the correspond-
ing Rh(III) catalyst (entries 16−17), implying that a catalyt-
ically active Rh(I) species is generated even in case of em-
ploying Rh(III) precursors.17 Despite of this result, we de-
cided to use Rh(acac)3 as a catalyst precursor in subse-
quent studies due to the ease of handling and stability of
the complex to the air and moisture. On the other hand,
the use of transition metals other than rhodium species
was completely ineffective under the employed reactions
(entries 18−20).
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Table 2. Scope of the Rh(NHC)-Catalyzed Bishydroarylation of 2,2’-Bipyridine Derivativesa
a Reaction conditions: substrates (0.3 mmol), olefins (5 equiv), Rh(acac)3 (3 mol %), IMes•HCl (3 mol %), t-BuONa (30 mol %)
o
in toluene (0.4 mL) at 130 C for 2 h. Isolated yields are indicated. b Yield was determined after hydrogenation. c 1 Equiv of base
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e
was used. d Mixture of endo- and exo-products. Ratio of linear- and branched product in parenthesis, and only major products
are shown. f 3 Equiv of olefin was used.
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Reaction Scope. Under the above optimized condi-
tions (0.03 equiv of Rh(acac)3/L2 ligand and 0.3 equiv of t-
BuONa base at 130 oC for 2 h), substrate scope of the
bishydroarylation reaction was next investigated (Table 2).
A wide range of aliphatic terminal alkenes were doubly
reacted at the 3,3’-position of 2,2’-bipyridine in excellent
yields (4a−4c). The hydroarylation was highly selective at
the terminal olefins in the presence of an internal double
bond (4d). It was interesting to note that the internal
olefin was slightly isomerized under the employed condi-
tions to imply that a rhodium hydride species might be
generated in situ during the course of the catalytic path-
way (vide infra). Terminal olefins substituted with benzyl
or cyclohexyl groups underwent the desired reaction in
high yields (4e and 4f, respectively). Alkenes bearing easi-
with 3,3-dimethyl-1-butene to furnish the corresponding
doubly hydroarylated products in high yields (4m and 4n,
respectively).
In addition to 2,2’-bipyridines, 2,2’-biquinoline also un-
derwent the olefin bishydroarylation in excellent yield
(4o), thus significantly expanding the synthetic utility of
the present protocol (vide infra). It needs to be addressed
that the hydroarylation took place exclusively at the 3,3’-
position of this substrate without forming any isomeric
side products (e.g. reaction at the 8,8’-position). This re-
sult is in complete accord with the initially postulated
“rollover” cyclometalation pathway. Interestingly, hy-
droarylation of 2-(thiophen-2-yl)pyridine occurred exclu-
sively at the thiophenyl ring under the present catalytic
conditions (4p). Such regioselectivity is exactly the same
as in a stoichiometric, not catalytic, study of rollover cy-
clometalation of 2-(thiophen-2-yl)pyridine which was
previously reported by Nonoyama et al.18
In contrast to hydroarylation of aliphatic alkenes which
proceed exclusively in an anti-Markovnikov manner lead-
ing to only linear products, reactions with aryl olefins
took place to furnish a mixture of linear- and branched
hydroarylation products, but favoring the former isomers.
For example, a reaction of 2,2’-bipyridine with styrene
under the present conditions afforded an excellent yield
of bishydroarylated isomeric products in favor of a linear
over branched one with 9.3:1 ratio (4q, herein only major
product is shown). This trend was similarly observed with
other vinylarenes regardless of electronic variation (4r, 4s
and 4t). In stark contrast, a complete control of regiose-
lectivity was attained when 2-vinylmestylene was subject-
ed to the conditions, in which a linear bishydroarylated
compound was obtained as a single product in excellent
yield (4u) to suggest that a steric factor is highly im-
portant for the control of selectivity.
ly removable hydroxy-protecting groups such as benzyl or
silyl moieties were readily reacted without causing a
problem to give the desired bishydroarylated products (4g
and 4h). While both vinyl- and allylsilanes were facile
reactants, the latter one required 1 equiv of t-BuONa base
to obtain a satisfactory product yield (4i and 4j, respec-
tively). As predicted, 4-vinyl-1-cyclohexene was reacted
exclusively at the terminal double bond (4k). On the oth-
er hand, alkenes containing strained internal double
bonds such as norbornene were smoothly reacted (4l).
Substituted bipyridine derivatives were also reacted
with alkenes in excellent efficiency and selectivity. For
instance, 5,5’-dimethyl- and 6,6’-dimethyl-2,2’-bipyridine
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underwent
the
desired
reaction
find that 4-octyne was readily reacted with 2,2’-bipyridine
to afford a doubly alkenylated product 4v in high yield
with the use of 1 equiv of t-BuONa base. It is noteworthy
that the reaction was highly stereoselective in that a syn-
addition pathway was mainly operative leading to an E-
isomer as a major product. A similar result was also ob-
served in the reaction of diphenylacetylene (4w). On the
other hand, hydroarylation of unsymmetric alkynes such
as 2-hexyne resulted in a mixture of regioisomers (4x). As
in the alkene hydroarylation of 2-(thiophen-2-yl)pyridine
(4p), an alkyne was similarly mono-hydroarylated at the
thienyl side leading to 4y in high yield.
It needs to be indicated that Miura et al. briefly reported
the Rh-catalyzed ortho-alkenylation of aromatic N-
heterocycles including 2,2’-bipyridine as mentioned in
introduction.12a In their procedure, terminal silylacety-
lenes were employed as the only one type of alkynes using
a catalyst system consisted of [RhCl(cod)]2 and PPh3 at
o
160 C. Although this previous report offered an inspiring
possibility to introduce an olefinic functional group into
heterocycles, it also revealed some critical aspects such as
limited substrate scope, and harsh reaction conditions.
Notably, as can be seen below in the mechanistic descrip-
tion, we believe that the introduction of NHC ligand
dramatically improves the activity and selectivity of the
resultant Rh-NHC catalyst system, thus solving most of
the problems associated with the use of the Rh-PR3 sys-
tem.
Next, we envisioned that the Rh(NHC)-catalyzed rollo-
ver cyclometalation process could also be applied to hy-
droarylation of alkynes.12a, 20g,h Indeed, we were pleased to
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Table 3. Bishydroarylation with Gaseous Ethylenea
ly congested 4,4’-dimethoxy-2,2’-bipyridine was also di-
ethylated at the 3,3’-position in acceptable yield (5c).
4
5
6
Scheme 2. Hydroarylation of 2-Phenylpyridine
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a
Conditions: substrates (2 mmol), ethylene (5 atm),
As anticipated, the present hydroarylation procedure
was applied to 2-phenylpyridine in a similar manner
(Scheme 2).19-21 A notable aspect in this case was that the
degree of reaction progress, obtainable products accord-
ingly, could be controlled upon choosing the stoichiome-
try of employed alkenes. Indeed, whereas a mono-
hydroarylation adduct (6) was obtained in major by using
1.2 equiv of olefin, a bishydroarylated product 7 was iso-
lated quantitatively by using 3 equiv of olefin.
Rh(acac)3 (1 mol %), IMes•HCl (1 mol %) and t-BuONa (30
mol %) in toluene (4 mL). b Substrate (1 mmol), Rh(acac)3 (3
mol %), IMes•HCl (3 mol %) and t-BuONa (1 equiv) in tolu-
ene (4 mL) at 130 oC for 36 h.
We were pleased to observe that the developed
bishydroarylation procedure could readily be applied to
gaseous alkenes, still maintaining excellent reaction effi-
ciency (Table 3). For instance, when 2,2’-bipyridines were
allowed to react with gaseous ethylene (5 atm), the corre-
sponding doubly ethylated bipyridine products were ob-
tained in quantitative yields even with a reduced catalyst
loading (1 mol %). Turnover number of the rhodium cata-
lyst was measured to reach up to 370 based on one hy-
droarylation conversion (5a). This excellent performance
was proved to be general with respect to other substrate
variants. For instance, 6,6’-dimethyl-2,2’-bipyridine was
di-ethylated in a quantitative yield (5b). Notably, sterical-
Mechanistic Studies on the Present Reaction. To
investigate the key aspect of the C−H bond cleavage pro-
cess in the present Rh(NHC)-catalyzed hydroarylation
reaction, we first performed a kinetic isotope effect (KIE)
study. An intermolecular competition reaction between
1a and 1a-d8 revealed no detectable isotopic effect (eq 1),
suggesting that the C-H bond cleavage is not
Figure 3. Reaction profiles between 2,2’-bipyridine and 2-phenylpyridine. (a) Reaction in separate vessels. (b) Reaction in the
same vessel.
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tions, 2,2’-bipyridine started the reaction first while hy-
droarylation of 2-phenylpyridine did not occur until when
2,2’-bipyridine was consumed by about 50% (Figure 3b).
This observation indicates that the reaction of 2-
phenylpyridine was significantly retarded by the presence
of bidentate compounds, herein 2,2’-bipyridine and its
hydroarylated products being 3a and 4a.25 A similar inhib-
itory effect was observed when hydroarylation of 2-
phenylpyridine was tried in the presence of substoichio-
metric 1,10-phenanthroline (eq 3). No conversion was ob-
served in this case, strongly implying that, as reported
previously,26 a highly stable chelate like 8 was generated
first being catalytically inactive.
involved in the rate-determining stage. This result is in
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sharp contrast to a precedent stoichiometric process,22 in
which KIE was observed to be 2.8 in a Pt-mediated “rollo-
ver” cyclometalation of N-(2’-pyridyl)-7-azaindole. How-
ever, it needs to be mentioned that a negligible KIE value
was also observed in a range of transition metal catalyzed
hydroarylation reactions, wherein reductive elimination
was claimed to be the rate-determining step.19e, 20b, 21a,b
As discussed above, while the present hydroarylation
was highly selective for terminal alkenes, internal acyclic
double bonds were observed to be partially isomerized to
attest the intermediacy of a rhodium hydride species (Ta-
ble 2, 4d). Moreover, when a hydroarylation reaction was
carried out in a deuterated toluene solvent, a significant
extent of deuterium incorporation took place at both the
bipyridyl backbone and alkyl part of the product (eq 2).
This scrambling result can be explained by assuming that
a rhodium hydride, which will be generated by the re-
versible oxidative addition of the rhodium center to 2,2’-
bipyridine, is exchanged reversibly with toluene-d8 sol-
vent to provide a rhodium deuteride species as seen in the
precedent literature.23 Accordingly, it is assumed that an
olefin insertion of the rhodium-hydride(deuteride) spe-
cies and subsequent β-hydride elimination should be re-
versible based on the fact that deuterium scrambling oc-
curred significantly at the double bond of recovered al-
kenes (eq 2).24
DFT Calculations. In order to obtain additional in-
sights into the mechanistic details, we performed the
density functional calculations using a model reaction of
ethylene hydroarylation with 2,2’-bipyridine. Geometry
optimization was performed using B3LYP functional27 and
a single point energy calculation was performed using
B3LYP-D3.28 We used the Stuttgart relativistic small-core
effective core-potential (SRSC-ECP) basis29 for Rh atom
and 6-31G* all electron basis for all other main group ele-
ments. To test the effect of adding f-polarization function
for Rh, we also used the Def2-TZVP basis30 for Rh and 6-
311G** for other elements. Both basis sets yielded the
similar results for the bipyridine case,31 justifying the use
of smaller SRSC and 6-31G* basis. Gibbs free energy was
corrected by the frequency calculation. All calculations
were performed using the Q-CHEM quantum chemistry
package.32
In accordance with our experimental results, a rhodium
complex Rh(O-t-Bu)(IMes)(bipy) was selected as a cata-
lytically active species entering into the catalytic cycle.
Prior to studying a full catalytic cycle, an equilibrium
structure of that species was first investigated. At the out-
set of our studies, we postulated that the key rollover cy-
clometalation pathway will be triggered by a strong trans-
effect of a NHC ligand which weakens a metal-pyridyl
bond positioned trans to NHC. Indeed, our calculations
for the bond length, bond energy, and bond activation
energy for the rollover decomplexation step all support
this postulate (Figure 4): (i) the bond distance l1 of the
trans Rh-N bond relative to NHC (IMes in this case) is
longer than l2 of the corresponding cis bond by 0.037 Å, (ii)
the trans Rh-N bond energy is smaller (weaker) than the
cis counterpart by 7.6 kcal/mol, and (iii) the activation
energy to rupture this trans Rh-N bond is smaller (easier)
than that for the cis Rh-N bond by 9.0 kcal/mol.11e The
calculated trans/cis bond length difference for the present
It was interesting to note that the hydroarylation rate
was significantly different between 2-phenylpyridine and
2,2’-bipyridine depending the employed conditions.
When each substrate was reacted in a separate vessel, 2-
phenylpyridine was rapidly consumed to reach a full con-
version within 30 min giving rise to a doubly alkylated
product 7 in quantitative yield (Figure 3a). It was evident
from the reaction profile that the bis-hydroarylation
product
7 was formed sequentially via a mono-
hydroarylated adduct 6. On the other hand, 2,2’-
bipyridine was reacted noticeably slowly when compared
to 2-phenylpyridine, taking more than 100 min to get a
full conversion giving a doubly alkylated product 4a also
via a mono-hydroarylated species 3a.
However, quite intriguingly, this reactivity pattern was
completely reversed when two substrates were allowed to
react competitively in a same vessel. Under these condi-
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system is within the range of previously reported values
(0.03~0.09 Å) obtained from other types of metal com-
plexes involving the similar trans-influence.9c
For comparison, we also considered a PPh3 ligand (Fig-
ure 4b) and analyzed the same equilibrium properties of
the Rh-N bonds in Rh(O-t-Bu)(PPh3)(bipy). We found
that substituting IMes with the phosphine ligand leads to
smaller trans/cis bond length difference (PPh3: 0.013 Å vs
IMes: 0.037 Å), a much higher bond energy for the trans
Rh-N bond (PPh3: 20.6 vs IMes: 14.6 kcal/mol), and a
higher activation barrier for breaking the trans Rh-N
bond (PPh3: 23.8 vs IMes: 16.8 kcal/mol). These calcula-
tions clearly show that a much lesser trans-effect and a
more difficult rollover decomplexation process are dis-
played with PPh3 relative to IMes. This ligand change
from IMes to PPh3, however, does not significantly alter
the properties of the corresponding cis Rh-N bond (Figure
4).
Scheme 3 depicts the calculated lowest energy path for
the postulated catalytic cycle. As described above, the
first step required for the formation of a monodentate
rhodium complex B involves an endothermic bond rup-
ture of the stable chelate Rh-bipyridyl bond where the
strong σ-donating NHC ligand (IMes herein) is believed
to help weakening the trans Rh-N bond relative to NHC.
The C−H bond is then cleaved via the oxidative addition
to generate a Rh-hydride species C. In this C−H bond ac-
tivation step, a base-assisted proton abstraction route33
was also studied but it yielded a much higher activation
barrier, 32.7 kcal/mol as compared to 23.2 kcal/mol of the
direct oxidative addition path, hence not considered fur-
ther.34 The observation that an internal double bond in
substrates was partially isomerized during the course of
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Figure 4. Equilibrium structure of Rh-bipyridine complexes:
(a) Rh(O-t-Bu)(IMes)(bipy); (b) Rh(O-t-Bu)(PPh3)(bipy). The
a
ꢀG values are in kcal/mol. The activation energy of the ini-
tial decomplexation step.
hydroarylation reaction can be attributed to the in situ
formation of a rhodium hydride, and this experimental
result also supports the oxidative addition pathway in the
C−H bond activation in accord with the calculations. This
oxidative addition step is assumed to be reversible based
on the deuterium scrambling data (eq 2) and the partial
olefin isomerization. Complexation with ethylene (D) and
subsequent structural reorganization (E) will be followed
to give a syn-geometry being suitable for the olefin inser-
tion process. Ethylene insertion occurs relatively easily via
a transition state TS3 to form F, which subsequently rear-
ranges to a stable rhodium-ethyl species G. For reasons
similar to the reversible formation of C, this ethylene in-
sertion into the rhodium hydride species (D through F) is
postulated to proceed reversibly.23,24 The final reductive
elimination of Rh(III)(IMes)(O-t-Bu)(ethyl)(bipy) com-
plex G then has the highest barrier of 25.8 kcal/mol, mar-
ginally higher than the initial rollover cyclometalation
step (23.2 kcal/mol), followed by re-complexation to de-
liver the Rh-(monoethylated)bipyridine species I. Obvi-
ously, species I will continue the same reaction sequence:
decomplexation, rollover cyclometalation, olefin insertion,
and then reductive elimination to complete the second
alkylation.
As shown in the calculated reaction profile (Scheme 3),
changing a ligand from NHC (IMes, energy values in blue)
to phosphine (PPh3, energy values in red) significantly
increases the rollover cyclometalation barrier. This overall
barrier of rollover cyclometalation can be further decom-
posed to the following terms: decomplexation, complexa-
tion (backward of decomplexation), and oxidative addi-
tion. When we compared each term, the major contribu-
tion of ligand effect was lowering the initial decomplexa-
tion, while energetics of other steps are largely unchanged.
This comparison indicates that one of the key roles of NHC
ligand is to facilitate the critical rollover process (Figure
5).35 These DFT results are consistent with the low reac-
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tivity and selectivity experimentally observed with the
PPh3 suggests that the initial rollover cyclometalation
Rh-phosphine catalyst system (Table 1, compare entries 5
and 8). Although a full examination of all employed lig-
ands for our theoretical calculations is beyond the scope
of the present study, a comparison between IMes and
process may be a key factor being responsible for the ob-
served dramatic variations of reactivity and selectivity
depending on the ligands tested (Table 1).
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7
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Scheme 3. Energy Profile of the Rh-Catalyzed Hydroarylation Reaction of 2,2’-Bipyridine with Ethylene Using
IMes (round bracket in blue) and PPh3 (square bracket in red) Ligand at the B3LYP-D3/6-31G(d) Level (IMes and
t-BuO- are shown a simpler way for clarity)
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Scheme 3), the reaction of 2-phenylpyridine does not in-
clude such a rollover step. This difference is reflected into
to a net barrier of 25.8 kcal/mol to reach TS4 (turnover
frequency determining transition state, TDTS)36 for 2,2’-
bipyridine, but the TDTS for 2-phenylpyridine is only 19.6
kcal/mol (Figure S3 in the Supporting Information) and
hence much faster. Results of the competition experi-
ments (Figure 3) can be reasoned if we compare the rela-
tive binding affinity of 2-phenylpyridine and 2,2’-
bipyridine towards the rhodium metal center (eq 4). The
calculations show that, as predicted, a bidentate chelate A
is considerably more stable than a monodentate complex
A’ by 15.7 kcal/mol, implying that the effective concentra-
tion of the Rh-(2-phenylpyridine) species (A’) would be
initially negligible due to the almost exclusive shift of
equilibrium towards the Rh-bipyridine complex (A) even
Figure 5. Schematic diagram for the NHC effect on the cata-
lytic hydroarylation.
The observation that the hydroarylation rate of 2,2’-
bipyridine was much slower than that of 2-phenylpyridine
in a separate vessel as shown in Figure 3a was explained
also by the DFT calculations. While hydroarylation of 2,2’-
bipyridine requires a decomplexation step of an initially
formed ligated complex leading to C-H bond cleavage
with a significant activation barrier (16.8 kcal/mol,
in the presence of 2-phenylpyridine.
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sors, it is postulated that a Rh(I) complex ligated to tert-
butoxide and NHC (IMes herein) is the catalytically active
species based on the experimental data. After passing
through all sequences from Rh(I)(IMes)(O-t-Bu)(bipy) A
(R’= H) to a mono-alkylated bipyridine H (R’ = CH2CH2R),
it re-enters into the second catalytic cycle by starting with
a bidentate complex I (R’ = CH2CH2R ) to follow the same
pathway as in the first catalytic cycle, eventually provid-
ing the bis-hydroarylated product.
The above computational calculations as well as the ex-
perimental data led us to propose a mechanistic pathway
of the present bishydroarylation (Scheme 4). Irrespective
of the oxidation state of the employed rhodium precur-
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Scheme 4. Proposed Mechanistic Pathway of the Rh(NHC)-Catalyzed Bishydroarylation Reaction
Scheme 5. Synthesis of Optically Active 3,3’-Diethyl-
2,2’-biquinoline N,N’-dioxide and its Catalytic Usage
in the Asymmetric Allylation
oped procedure, a preparative route was quickly estab-
lished for the formation of optically active 3,3’-dialkyl-
2,2’-biquinoline N,N’-dioxides, derivatives of which dis-
play a high promise as an efficient chiral organocata-
lyst.37,38 Hydroarylation of gaseous ethylene (5 atm) with
2,2’-biquinoline was readily performed to afford 3,3’-
diethyl-2,2’-biquinoline (9) in quantitative yield using 1
mol % of a rhodium/IMes catalyst (Scheme 5a). Subse-
quent double N-oxidation of 9 proceeded easily with me-
ta-chloroperbenzoic acid (m-CPBA) to give racemic N,N’-
dioxide 10. Optical resolution of (+/-)-10 was successfully
carried out with (-)-dibenzoyl-L-tartaric acid to provide
(S)-3,3’-diethyl-2,2’-biquinoline N,N’-dioxide (S-10) in
good chemical yield (60%) and with high optical purity
(97% ee). To our delight, the obtained compound S-10 (10
mol %) was observed to catalyze an allylation reaction of
aldehydes with trichloroallylsilane with high enantio-
meric excess (92% ee, Scheme 5b).38b For reference, no
conversion of this allylation was observed in the absence
of 10. Considering the fact that the previous synthetic
routes to the biquinoline N,N’-dioxide and its derivatives
suffer from lack of substrate scope even requiring multi-
ple synthetic steps,37 our present approach offers notable
advantages overcoming most known synthetic difficulties.
Synthetic Application. Our present study offers a
straightforward access to 3,3’-disubstituted bipyridine,
biquinoline and their derivatives with excellent regio- and
seteroselectivity. As a synthetic application of the devel-
ꢀ CONCLUSION
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(3) For recent reviews on the selective direct C−H functionali-
In summary, we have demonstrated that a NHC ligand
zations, see: (a) Campeau, L.-C.; Fagnou, K. Chem. Commun.
2006, 1253. (b) Daugulis, O.; Zaitsev, V. G.; Shabashov, D.; Pham,
Q.-N.; Lazareva, A. Synlett 2006, 3382. (c) Satoh, T.; Miura, M.
Chem. Lett. 2007, 36, 200. (d) Seregin, I. V.; Gevorgyan, V. Chem.
Soc. Rev. 2007, 36, 1173. (e) Pascual, S.; de Mendoza, P.; Echavar-
ren, A. M. Org. Biomol. Chem. 2007, 5, 2727. (f) Li, B.-J.; Yang, S.-
D.; Shi, Z.-J. Synlett 2008, 949. (g) Chen, X.; Engle, K. M.; Wang,
D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094.
displays dramatic effects on the resultant Rh(NHC) cata-
lyst system to trigger a rollover cyclometalation pathway
of chelating molecules such as 2,2’-bipyridines and 2,2’-
biquinolines. Our hypothesis that a strong trans-effect of
NHCs would be a crucial factor to weaken a Rh-pyridyl
bond trans to the ligated NHC with significant reduction
of the activation barrier of the subsequent rollover cy-
clometalation step was proved experimentally and theo-
retically. Therefore, the Rh(NHC) catalyst system allowed
highly efficient and selective hydroarylation of alkenes
and alkynes. Our result is significant in that for the first
time the “rollover” cyclometalation process was catalyti-
cally applied to the double C−H bond functionalization of
chelating molecules using a Rh(NHC) catalyst system.
The rhodium-catalyzed bishydroarylation of alkenes and
alkynes delivered alkyl- and alkeneyl bipyridine and
biquinoline products in excellent yields respectively. Syn-
thetic utility of those obtained compounds was also
demonstrated in an asymmetric organocatalytic reaction.
Equipped with the new tool, a straightforward and practi-
cal access to a broad range of derivatives of chelating
compounds is now accessible while it was not easy by the
precedent synthetic methods, and, therefore, the result of
this study is anticipated to stimulate a significant advance
in various areas such as catalysis, molecular assembly, or
materials architecture.
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(7) For selected reviews on the application of metal chelates of
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Yam, V. W. W. Acc. Chem. Res. 2011, 44, 424.
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(10) Recently, Yu et al. reported the novel C3 selective olefina-
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Ye, M.; Gao, G.-L.; Yu, J.-Q. J. Am. Chem. Soc. 2011, 133, 6964. (b)
Ye, M.; Gao, G.-L.; Edmunds, A. J. F.; Worthington, P. A.; Morris,
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Minghetti, G.; Stoccoro, S.; Cinellu, M. A.; Soro, B.; Zucca, A.
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Chem. Sci. 2012, 3, 308.
ꢀ ASSOCIATED CONTENT
Detailed experimental procedures and characterization of
new compounds, including 1H and 13C NMR spectra. Compu-
tational details including Cartesian coordinates of reported
intermediates. This material is available free of charge via the
Internet at http://pubs.acs.org.
ꢀ AUTHOR INFORMATION
Corresponding Author
ysjn@kaist.ac.kr; sbchang@kaist.ac.kr
ꢀ ACKNOWLEDGMENT
This research was supported by the Korea Research
Foundation Grant (KRF–2008–C00024, Star Faculty Pro-
gram), MIRC (NRF–2011–0001322), and WCU (R31-2008-
000-10055-0).
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