Autocatalytic intermolecular versus intramolecular deprotonation in C-H bond activation of functionalized arenes by ruthenium(II) or palladium(II) complexes

Article abstract of DOI:10.1002/chem.201203813

The activation of the C-H bond of 1-phenylpyrazole (2) and 2-phenyl-2-oxazoline (3) by [Ru(OAc)₂(p-cymene)] is an autocatalytic process catalyzed by the co-product HOAc. The reactions are indeed faster in the presence of acetic acid and water but slower in the presence of a base K ₂CO₃. A reactivity order is established in the absence of additives: 2-phenylpyridine>2-phenyl-2-oxazoline>1-phenylpyrazole (at RT). The accelerating effect of added acetate ions reveals an intermolecular deprotonation after C-H bond activation by a cationic Ru^II center (S_E3 mechanism). The reactions of 1-phenylpyrazole and 2-phenyl-2-oxazoline first lead to the neutral cyclometalated complexes A ₂ and A₃ ligated by one acetate. The latter dissociate to the cationic complexes B₂⁺ and B₃⁺, respectively, and acetate. A slow incorporation of one or two D atoms into 2, 3, and 2-phenylpyridine (1) was observed in the presence of deuterated acetic acid. The reversibility of the C-H bond activation/deprotonation takes place from the cationic complexes B_n⁺ (n=1-3). They are also involved in oxidative additions to PhI, which are rate-determining and lead to the mono- and bis-phenylated products at high temperatures. A general mechanism is proposed for the arylation of arenes 1-3 catalyzed by [Ru(OAc) ₂(p-cymene)]. In contrast, the reaction of Pd(OAc)₂ with 2-phenylpyridine (1), is much faster: Pd(OAc)₂>[Ru(OAc) ₂(p-cymene)]. Since the kinetics is not affected by added acetates, the reaction proceeds through a CMD mechanism assisted by a ligated acetate (intramolecular process) and is irreversible. A bis-cyclometalated Pd ^II^Pd^II dimer D′₁ is formed whose bielectronic electrochemical oxidation leads to a [Pd^III^Pd ^III]²⁺ dimer, in agreement with the result of a reported chemical oxidation used in arene functionalizations catalyzed by Pd(OAc) ₂. Acetate aid: The activation of the C-H bond of 1-phenylpyrazole and 2-phenyl-2-oxazoline by [Ru(OAc)₂(p-cymene)] is an autocatalytic intermolecular process aided by free acetate (see figure). In contrast, activation by Pd(OAc)₂ proceeds through a concerted metalation-deprotonation (CMD) mechanism through an intramolecular and irreversible process that is assisted by ligated acetate. A cyclometalated dimeric Pd^II Pd^II complex is formed, the bielectronic electrochemical oxidation of which leads to a dimeric [Pd^III Pd ^III]²⁺ complex. Copyright

Full text of DOI:10.1002/chem.201203813

FULL PAPER
DOI: 10.1002/chem.201203813
ꢀ
Autocatalytic Intermolecular versus Intramolecular Deprotonation in C H
Bond Activation of Functionalized Arenes by Ruthenium(II) or
Palladium(II) Complexes
Indira Fabre,[a] Niklas von Wolff,[a] Gaꢀtan Le Duc,[a] Emmanuel Ferrer Flegeau,[a]
Christian Bruneau,[b] Pierre H. Dixneuf,[b] and Anny Jutand*[a]
ꢀ
Abstract: The activation of the C H
bond of 1-phenylpyrazole (2) and 2-
by one acetate. The latter dissociate to
anism is proposed for the arylation of
arenes 1–3 catalyzed by [Ru(OAc)2A(p-
cymene)]. In contrast, the reaction of
Pd(OAc)2 with 2-phenylpyridine (1), is
much faster: Pd(OAc)2 >[Ru(OAc)2A(p-
cymene)]. Since the kinetics is not af-
fected by added acetates, the reaction
proceeds through a CMD mechanism
assisted by a ligated acetate (intramo-
lecular process) and is irreversible. A
bis-cyclometalated PdII^PdII dimer D’1
is formed whose bielectronic electro-
+
+
the cationic complexes B2 and B3
,
G
CHTUNGTRENNUNG
phenyl-2-oxazoline (3) by [Ru
(OAc)2-
respectively, and acetate. A slow incor-
poration of one or two D atoms into 2,
3, and 2-phenylpyridine (1) was ob-
served in the presence of deuterated
acetic acid. The “reversibility” of the
N
ACHTUNGTRENNUNG
catalyzed by the co-product HOAc.
The reactions are indeed faster in the
presence of acetic acid and water but
A
E
CHTUNGTRENNUNG
ꢀ
slower in the presence of
a
base
C H bond activation/deprotonation
K2CO3. A reactivity order is establish-
ed in the absence of additives: 2-phe-
nylpyridine>2-phenyl-2-oxazoline>1-
phenylpyrazole (at RT). The accelerat-
ing effect of added acetate ions reveals
an intermolecular deprotonation after
C H bond activation by a cationic Ru
center (SE3 mechanism). The reactions
of 1-phenylpyrazole and 2-phenyl-2-ox-
azoline first lead to the neutral cyclo-
metalated complexes A2 and A3 ligated
takes place from the cationic com-
+
plexes Bn (n=1–3). They are also in-
volved in oxidative additions to PhI,
which are rate-determining and lead to
the mono- and bis-phenylated products
at high temperatures. A general mech-
chemical oxidation leads to
a
[PdIII^PdIII]2+ dimer, in agreement with
the result of a reported chemical oxida-
tion used in arene functionalizations
II
ꢀ
ꢀ
Keywords: C H bond activation ·
catalyzed by PdACHTNUTRGNEUNG(OAc)2.
kinetics
·
palladium
·
reaction
mechanisms · ruthenium
ꢀ
Introduction
mechanism (CMD)[4c] is often proposed: C H bond activa-
tion by the metal and deprotonation by a ligated base (car-
boxylate, hydrogencarbonate, or carbonate) in an intramo-
lecular process.[4,5] DFT studies pointed out the formation of
ꢀ
The direct catalyzed functionalization of arene C H bonds
ꢀ
is more and more attracting for selective C C cross-coupling
reactions.[1–3] There is a general agreement for considering
transient agostic M
C
[4]
ꢀ
ꢀ
that the first step is a C H bond activation by the catalysts,
have also been proposed.[6] Indeed, the base strength (car-
boxylate, carbonate) is considerably reduced by coordina-
such as ruthenium(II)[1,2] or palladium(II) complexes.[1,3] The
mechanism of such reactions has been widely investigated
and discussed.[1,2k,4–6] A concerted metalation–deprotonation
ꢀ
tion to the metal center. The C H bond activated by the
metal by an electrophilic process[6] is deprotonated by the
more basic free base.[6a–c]
In contrast to DFT calculations, few kinetic data are avail-
[a] I. Fabre, N. von Wolff, Dr. G. Le Duc, Dr. E. Ferrer Flegeau,
Dr. A. Jutand
ꢀ
able on C H bond activation by transition metals. A pio-
Ecole Normale Supꢀrieure
Dꢀpartement de Chimie
UMR CNRS-ENS-UPMC 8640
24 rue Lhomond
75231 Paris Cedex 5 (France)
E-mail: Anny.Jutand@ens.fr
neering work on the activation of benzylamines by Pd-
AHCTUNGTRENNUNG
(OAc)2 by Ryabov et al.[1a,5b,c] concluded an intramolecular
ꢀ
process through electrophilic activation of the C H bond
leading to an arenium complex and deprotonation by the li-
gated acetate through a hydrogen bond with its carbonyl
group. A work by Jones et al. also concluded an electrophilic
[b] Dr. C. Bruneau, Prof. P. H. Dixneuf
Institut Sciences Chimiques
ꢀ
activation of a C H bond in PhN=CHPh by cationic com-
UMR6226 CNRS-Universitꢀ de Rennes
Campus Beaulieu, Universitꢀ de Rennes
35042 Rennes (France)
+
plexes [Cp*MIII OAc] (M=Rh, Ir), followed by intramo-
ꢀ
lecular deprotonation assisted by a ligated acetate.[7]
We recently reported kinetic data on the reaction of [Ru-
ACHUTNERGN(NUG OAc)2CAHTUNGTRENN(UGN p-cymene)] (I) with 2-phenylpyridine (1) in acetoni-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201203813.
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with a stoichiometric amount of
1-phenylpyrazole (2) (0.16 m)
1
was followed by using H NMR
spectroscopy (Figure 1a and the
Supporting Information, S7) in
CD3CN at 278C, as for 2-phe-
nylpyridine (1).[8] The half-life
of the reaction was estimated
from the decay of I with time:
t
1/2 =520 min (Figure 1a) to be
compared with t1/2 =45 min for
the reaction of 2-phenylpyri-
dine (1) performed under the
same experimental conditions,[8]
which is indubitably faster. As
for 1,[8] three cyclometalated
ruthenium(II) complexes were
+
formed: A2 first, and then B2
and C2 (Scheme 2), with C2
+
+
(p-cymene)].[8]
Scheme 1. Mechanism of the monophenylation of 2-phenylpyridine catalyzed by [RuACTHNUTRGNEN(UG OAc)2ACHTUNGTRENNUGN
as the major complex at long
reaction times (Figure 1a).
They were identified in the
ꢀ
trile that revealed a new C H bond-activation/deprotona-
tion mechanism: an autocatalytic process catalyzed by the
acetic acid co-product (Scheme 1).[8] The overall reaction is
indeed accelerated by acetic acid and water and retarded by
a base. Acetic acid favors the dissociation of one acetate
1H NMR spectra performed with time by comparison with
authentic samples; non-reported complexes that have been
independently synthesized and fully characterized (the Sup-
from [RuACHTUNGTRENNUNG(OAc)2ACHTUNGTRENNUNG
(p-cymene)][8] and consequently the ensuing
ꢀ
complexation of 1. The C H bond activation initially deliv-
ers the neutral complex A1 ligated to one acetate
(Scheme 1). The overall reaction is accelerated by added
ꢀ
acetates, which means that the C H bond activation pro-
ceeds through an intermolecular deprotonation of the acti-
ꢀ
vated C H bond of the ligated 2-phenylpyridine by the ace-
tate anion released from I (SE3 mechanism).[8,1h] The 18 e
+
complex A1 easily dissociates to the cationic complex B1
,
which reacts with phenyl iodide (rate-determining oxidative
addition) (Scheme 1), leading eventually to the mono- and
bis-phenylated 2-phenylpyridine.[8]
ꢀ
We report herein kinetic data that reveals that the C H
bond activation/deprotonation of 1-phenylpyrazole (2) and
2-phenyl-2-oxazoline (3) by [RuACTHUNTRGENN(UG OAc)2ACHTUNGTREN(NNGU p-cymene)] also
obeys an autocatalytic process in acetonitrile, accompanied
by an intermolecular deprotonation by the acetate ion re-
leased from [RuACHTUNGTRENNUNG(OAc)2ACHTUGNTREN(NUGN p-cymene)]. In addition, evidence
ꢀ
of the “reversibility” of the C H bond activation highlights
the multiple role of acetic acid. In contrast, new kinetic data
ꢀ
revealed that the C H bond activation of 2-phenylpyridine
(1) by Pd
A
with an intramolecular deprotonation by a ligated acetate.
ꢀ
Figure 1. Kinetics of the C H bond activation of 1-phenylpyrazole (2)
(0.16m) by [Ru
(OAc)
E
Results and Discussion
1
monitored by H NMR spectroscopy. a) ( ) Decay of I with time and for-
+
+
&
^
*
mation of complexes A2 ( ), B2
( ) and C2 (ꢂ). b) ( ) Decay of I in
ꢀ
Mechanism of the C H bond activation/deprotonation of 1-
the same conditions as in (a) but at a shorter time scale and then in the
presence of additives: (+) K2CO3 (3 equiv), ( ) KOAc (3 equiv), (
H2O (10 equiv), (&) HOAc (1 equiv), added before the introduction of 2.
phenylpyrazole (2) by [Ru
A
(p-cymene)] (I): The ki-
2A(p-cymene)] (I) (0.16 m)
*
^
)
netics of the reaction of [Ru
N
CHTUNGTRENNUNG
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Intermolecular versus Intramolecular Deprotonation
FULL PAPER
Scheme 2. Cyclometalated ruthenium(II) complexes formed in the reac-
1
tion of I and 2, as observed by H NMR spectroscopy.
ꢀ
Scheme 3. Mechanism of the C H bond activation/deprotonation of 2.
porting Information, Figures S1–S6). Complex A2 was syn-
thesized by treating the related reported complex containing
[5l]
ꢀ
a Ru Cl bond (D2) by AgOAc in CH2Cl2 (see the Sup-
+
+
porting Information). Complexes B2 and C2 were synthe-
From those experiments, one concludes that the mecha-
ꢀ
ꢀ
sized with PF6 as the counteranion, by using the same pro-
nism of the C H bond cleavage in the 1-phenylpyrazole by
+
+
cedure as for the 2-phenylpyridine derivatives[8] B1 and C1
[Ru
A
G
+
(see the Supporting Information). The equilibrium A2ÐB2
dine, that is, an autocatalytic process due to the co-product
HOAc that favors the dissociation of complex I to I+. The
formation of A2 as the first product of the reaction (and not
B2+) associated with an accelerating effect of added acetates
+
+AcOꢀ was evidenced upon addition of n-Bu4NOAc to B2
ꢀ
PF6 (see the Supporting Information).
The decay of [RuACHTNUGTRNENUG(OAc)2ACHUTNGTREN(NGUN p-cymene)] at short times was
ꢀ
not hyperbolic from the beginning as it should be for a reac-
tion performed under stoichiometric conditions (Figure 1b).
Instead, the reaction became faster and faster as the reac-
tion proceeded, revealing an autocatalytic process (i.e., cata-
lyzed by one product of the reaction). The reaction was
faster in the presence of acetic acid (Figure 1b, the Support-
ing Information, S8), establishing that HOAc, the co-prod-
indicated that the C H bond was cleaved in an intermolecu-
lar process (SE3 mechanism, Scheme 3).
ꢀ
Once the mechanism of the C H bond activation estab-
lished with the characterization of the three products A2,
B2+, and C2 formed successively (Scheme 2), it was of in-
+
terest to find out which one could react with PhI to generate
the mono- or bis-phenylated 1-phenylpyrazole, as it was ob-
served in catalytic reactions.[2v] The 18e complex A2 is in-
trinsically unreactive but was found to be in equilibrium
ꢀ
uct formed together with A2 after C H bond activation/de-
protonation of the 1-phenylpyrazole, was responsible for the
autocatalytic process by favoring the dissociation of I to I+
([Eq. (1)] in Scheme 3).[8] In agreement with this mecha-
nism, the reaction was faster in the presence of H2O (Fig-
ure 1b), which made the acetic acid more acidic than in
pure acetonitrile, and retarded in the presence of K2CO3
(Figure 1b), a base that inhibited the autocatalytic process
by neutralizing HOAc. The reaction was also accelerated in
the presence of added acetate ions (Figure 1b), which
means that external acetates are involved in the rate-deter-
mining deprotonation step. One has to face two competitive
kinetic effects in the presence of acetates. The first one is a
shift of the equilibrium ([Eq. (1)] in Scheme 3) towards
complex I, which would induce a slower overall reaction.
The second one is an acceleration of the deprotonation step
([Eq. (3)] in Scheme 3). For the acetate concentrations con-
sidered in this work, the competition was in favor of the ac-
celeration of the reaction, which means that free acetates
are involved in an intermolecular deprotonation step
([Eq. (3)] in Scheme 3), which is rate-determining.
with B2+, which was transformed to C2 at long reaction
+
+
times (Scheme 2). The formation of B2 was even enhanced
in the presence of HOAc that favored the dissociation of A2
to B2+. Indeed, the reaction of I with 2 performed in the
presence of HOAc (1 equiv) after 250 min led to the major
+
B2 (the Supporting Information, Figure S8). Whereas the
ꢀ
complex C2+PF6 (0.15 mmol) did not react with PhI
(0.375 mmol) in N-methyl-2-pyrrolidone (NMP; at 1408C
after 24 h), the complex B2+PF6 reacted with PhI under the
ꢀ
same experimental conditions since only 40% of PhI was re-
covered after work-up but no phenylated product was
formed (Scheme 4). A dark complex was formed that could
not be characterized due to its low solubility even in
DMSO; however, it was still ligated by p-cymene since free
1
p-cymene was not present in the H NMR spectrum of the
crude mixture after work-up. It is only in the presence of ad-
ditives KOAc (0.3 mmol) and K2CO3 (0.3 mmol) as in cata-
lytic reactions[2v] that the 1-(2,6-phenyl)phenylpyrazole was
formed in 47% yield (non-optimized reaction with 20% re-
covered PhI) (Scheme 4).
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A. Jutand et al.
Scheme 4. Products formed from the reaction of cyclometalated species
+
B2 and phenyl iodide in NMP at high temperature in the presence and
in the absence of KOAc/K2CO3.
This indicates that the oxidative addition of PhI to com-
+
plex B2 took place in the absence of additives but one of
the following reactions stopped, either the reductive elimi-
nation from an intermediate RuIV complex, or if the latter
took place, the 1-(2-phenyl)phenylpyrazole (not detected in
the NMR spectrum) must stick onto the cationic RuII center
ꢀ
without any further C H bond activation. It is only in the
presence of KOAc and K2CO3 (conditions of the catalytic
reactions)[2v] that the second C H bond activation took
ꢀ
place to deliver the bis-phenylated product after a second
oxidative addition to PhI (the Supporting Information, Fig-
ure S9). In both cases, the oxidative addition of B2 to PhI
+
ꢀ
Figure 2. Kinetics of the C H bond activation of 2-phenyl-2-oxazoline (3)
(0.16m) by [Ru(OAc)2A(p-cymene)] I (0.16m) in CD3CN at 278C, as moni-
tored by H NMR spectroscopy. a) ( ) Decay of I with time and forma-
G
CHTUNGTRENNUNG
ꢀ
was slower than the C H bond activation that proceeded at
1
*
room temperature (see above).
+
+
&
^
*
tion of complexes A3 ( ), B3
( ) and C3 (ꢂ); inset: ( ) decay of I with
time at a shorter time scale. See Figure S18 (in the Supporting Informa-
ꢀ
Mechanism of the C H bond activation/deprotonation of 2-
*
tion) for the reaction at long time scales (4280 min). b) ( ) Decay of I
*
alone and in the presence of additives: (+) K2CO3 (3 equiv), ( ) KOAc
phenyl-2-oxazoline (3) by [Ru
G
N
^
(3 equiv), ( ) H2O (10 equiv), (&) HOAc (1 equiv), added before the in-
ꢀ
kinetics of the C H bond activation/deprotonation of 2-
phenyl-2-oxazoline (3) (0.16m) by Ru
(0.16m) was similarly investigated by H NMR spectroscopy
in CD3CN (Figure 2a and the Supporting Information, S18).
The half-reaction time was t1/2 =157 min (Figure 2a) leading
troduction of 3.
G
G
1
ꢀ
to the following reactivity order for the C H bond activa-
tion by [Ru
A
G
tives:[9] 2-phenylpyridine>2-phenyl-2-oxazoline>1-phenyl-
pyrazole.
+
The non-reported complexes A3 and B3 formed in the
reaction (Scheme 5 and the Supporting Information, Fig-
ure S18) have been characterized by comparison to inde-
pendently synthesized authentic samples (the Supporting In-
formation, Figures S10–S17).
An autocatalytic process catalyzed by acetic acid took
place, as evidenced by the accelerating effect of added
HOAc, water and the retarding effect of carbonate (Fig-
ure 2b). The reaction was faster in the presence of added
acetates (3 equiv, Figure 2b), which means that the acetates
Scheme 5. Cyclometalated ruthenium(II) complexes formed in the reac-
tion of I and 3, as observed by H NMR spectroscopy.
1
are involved in a rate-determining intermolecular de
ACHUTGTNRNEUGpN roCAHTUNGTRNEtNUGN on-
A
E
acterized. The expected phenylated products were not
formed. It was only in the presence of KOAc and K2CO3
that the mono- and bis-phenylated products were formed
but in poor yields (Scheme 7, the Supporting Information,
Figure S19). Nevertheless such experiments show that the
by the fact that complex A3 (still ligated by one acetate de-
tected at d=1.6 ppm) was formed as the first product of the
reaction through a SE3 mechanism, as was observed for the
arenes 1[8] and 2 (see above).
ꢀ
+
The complex B3+PF6 reacted with PhI (30% recovered)
oxidative addition of PhI to the cationic B3 complex took
leading to an intermediate complex that could not be char-
place in a slow reaction.
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Intermolecular versus Intramolecular Deprotonation
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ꢀ
Scheme 6. Mechanism of the C H bond activation/deprotonation of 3.
Scheme 8. Products and mechanism of the deuteration of 3 in the pres-
ence of [RuACTHNUGTRENNUG(OAc)2ACHTUTGNREN(NGUN p-cymene)] and [D4]acetic acid.
tion). This indicates that the deuterated acetic acid DOAc
+
reacted with the complex B3 to give a cleavage of the
Scheme 7. Products formed from the reaction of cyclometalated species
B3 and phenyl iodide in NMP at high temperature in the presence of
KOAc/K2CO3.
Ru C bond by D+ leading to the formation of 2-
+
ꢀ
(2[D])phenyl-2-pyrazole and I+ (see the mechanism in
Scheme 8).
1
+
Interestingly, the H NMR spectrum of B3 was affected
during the reaction due to the formation of [D1]-B3
+
Comparison of the reactivity of B+ complexes with PhI to
form the phenylated products led to an overall decreasing
(Scheme 8). Indeed, the structure of the triplet of the proton
H4 was strongly modified whereas the integration of H5
became lower and lower as the D incorporation proceeded
(the Supporting Information, Figure S20a–c). This indicates
that the complex I+ released after the first incorporation of
+
reactivity order according to the sequence: B1+ >B2+ >B3
,
for reactions performed under similar experimental condi-
tions.
ꢀ
ꢀ
“Reversibility” of the C H bond activation of arenes 1–3:
The reaction of 2-phenyl-2-oxazoline (3) with I was found to
one D has activated the ortho-C H bond of 2-(2[D])phenyl-
+
2-oxazoline, leading to [D1]-B3 and then to a second incor-
+
be reversible. Indeed, incorporation of D atoms was ob-
poration of a D atom after reaction of [D1]-B3 with DOAc.
served when [Ru
G
E
The mechanism of the D incorporation given in Scheme 8 is
similar to that reported by Jones et al. for cationic cyclome-
with 2-phenyl-2-oxazoline (2 equiv) in the presence of
[D4]acetic acid (10 equiv) in acetonitrile (Scheme 8). This
slow reaction was followed by 1H NMR spectroscopy (the
Supporting Information, Figure S20). The first recorded
spectrum (after 10 min) did not exhibit the signals of com-
plex A3 but those of complex B3 in agreement with the
promoted dissociation of A3 to B3 by acetic acid. Extra sig-
nals were observed for the 2-phenyl-2-oxazoline in excess
(1 equiv vs. the B3 complex) but with incorporation of D
talated iridiumACTHNUGRTENNUG(III) or rhodiumACHTUNTGREN(NUNG III) complexes involving
phenylimines (e.g., PhN=CHPh).[7] Interestingly, the overall
reaction of I with 2-phenyl-2-oxazoline is “reversible” but it
includes two irreversible reactions: 1) [Eq. (6)] in Scheme 6
+
that leads to A3 but the latter was rapidly converted to B3
in the presence of acetic acid and 2) [Eq. (7)] in Scheme 8,
+
+
since the complex I3 did not lead directly to B3 but to A3
as the first complex formed in the presence of acetate
(Scheme 6).
atoms. Indeed, the integration of the doublet of the H in or-
tho,ortho’ of the phenyl group were deficient compared with
those of the meta,meta’ and para-H due to the formation of
As reported in our previous work,[8] no incorporation of
D atoms was observed when the reaction of I (0.16m) with
2-phenylpyridine (1) (2 equiv) was performed in the pres-
2-(2[D])phenyl-2-oxazoline and 2-(2,6[D])phenyl-2-ox
zoline (Scheme 8), structures which were confirmed by mass
spectroscopy after work-up (see the Supporting Informa-
N
ence of excess D2O (10 equiv) leading to the conclusion that
[8]
ꢀ
the C H bond activation/deprotonation was irreversible.
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A. Jutand et al.
Indeed, the 1H NMR spectroscopy revealed the formation
of complex A1 together with a stoichiometric amount of
non-deuterated 2-phenylpyridine. This reaction has been re-
visited. A similar experiment was performed in the presence
of [D4]acetic acid (10 equiv) instead of D2O. The first re-
recycles the starting arene (dashed arrow in Scheme 10). In
all cases, an intermolecular deprotonation by acetates is ob-
served (SE3 mechanism). The role of carbonates required as
a base in the catalytic reactions is explained by their decel-
ꢀ
erating effect in the C H bond activation that makes the
+
corded spectrum revealed the exclusive formation of B1 to-
rate of this fast reaction closer to the rate of the slow oxida-
tive addition, thus increasing the efficiency of the catalytic
cycle.[11] There may also be a second role: by neutralizing
the acetic acid, the carbonates interrupt the loop that leads
to the regeneration of the starting arene from B+ (dashed
arrow in Scheme 10).
gether with one equivalent of 2-phenylpyridine. After two
weeks, the isolated 2-phenylpyridine revealed the incorpora-
tion of D atoms in the ortho position (Scheme 9 and the
Scheme 10 exhibits the first catalytic cycle of the mono-
phenylation of an arene. Since it is difficult to stop at the
level of the first phenylation (as was observed in the catalyt-
ic reactions), this suggests that the complex I+ is not recy-
cled in the first catalytic cycle as written in Scheme 10, but a
new cationic complex is formed in which the cationic Ru
center is ligated to the monophenylated arene from which a
ꢀ
second C H bond activation/deprotonation could easily
occur in the presence of acetate ions, leading to the bisphe-
nylated arene.
Scheme 9. Products of the deuteration of 1 in the presence of [Ru
(p-cymene)] and [D4]acetic acid.
ACHTUNGERTN(NUNG OAc)2-
ACHTUNGTRENNUNG
ꢀ
Supporting Information, Figure S21), as evidenced by mass
spectroscopy. This confirms that the reaction of acetic acid
Mechanism of the C H bond activation/deprotonation of 2-
phenylpyridine (1) by Pd
ACHTUNGTRENNUNG
G
+
[3]
did proceed from the cationic complex B1 and not from
+
A1. If B1 is not formed, as when D2O was used instead of
acetic acid (as in our previous work),[8] no deuteration takes
place.
ACHTUNGTRENNUNG
A
CHTUNGTRENNUNG
Incorporation of deuterium atoms into the 1-phenylpyra-
zole (2) was also observed when the reaction of I (0.16m)
and 2 (2 equiv) was performed in the presence of [D4]acetic
ACHTUNGTRENNUNG
1
with PdACTHNURTGENNG(U OAc)2 (0.16m) were followed by H NMR spectro-
+
acid. Once again the complex A2 was not formed but B2
scopy in CD3CN at 278C. A fast reaction took place (within
less than 10 min) with precipitation of a bright-yellow solid
in the NMR tube. This yellow complex has been isolated
(46% yield) and characterized. Its X-ray structure (the Sup-
and incorporation of D into 2 (the Supporting Information,
+
Figure S22) took place from B2 (Figure S23). Therefore,
ꢀ
the “reversibility” of the C H bond activation of functional
arenes seems to be general.[10]
However, this reaction is quite
slow and cannot not interfere
significantly into the kinetics of
ꢀ
the C H bond activation.
Mechanism for the monoaryla-
tion of arenes 1–3: A general
catalytic cycle for the mono-
phenylation of the arenes 1–3
catalyzed by [RuACTHNUTRGENN(GU OAc)2ACHTUNGTERN(NUGN p-
cymene)] is now proposed in
Scheme 10.
It reveals the key role of
acetic acid that is responsible
for: 1) the autocatalytic process
ꢀ
in the C H bond activation,
2) the dissociation of A to the
cationic B+ involved in the oxi-
dative addition to PhI, 3) the
reincorporation of protons lead-
ing to a kind of loop that slowly Scheme 10. Catalytic cycle of the phenylation of arenes.
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Intermolecular versus Intramolecular Deprotonation
FULL PAPER
OAc. A’1 was characterized by a singlet at d=1.87 ppm
(close to the singlet of PdACHTNUTRGENNG(U OAc)2 at d=1.99 ppm). In addi-
tion, the N-ligated 2-phenylpyridine in A’1 was characterized
by two broad signals at d=8.95 (1H) and 8.30 ppm (2H),
shifted downfield when compared with those of the free
2-phenylpyridine at d=8.72 (d, 1H), 8.07 ppm (d, 2H), re-
spectively. B’1 was characterized by a singlet at d=1.41 ppm,
typical of a s-bonded OAc in contrast to bridging acetates
located at d=2.27 ppm as in the dimer D’1. The s-ligated
2-phenylpyridine in B’1 was characterized by two broad sin-
glets at d=8.8 and 8.6 ppm integrating for 1H each when
compared with the integration of the Me of its ligated OAc.
ꢀ
HOAc generated in the C H bond activation/deprotonation
was also detected at d=2.12 ppm and formed in the same
Scheme 11. Successive PdII complexes formed in the C H activation of 1
ꢀ
by Pd
A
amount as complex D’1 (the Supporting Information, Fig-
ure S25c).
To allow a comparison of the kinetics and mechanism of
ꢀ
porting Information, Figure S24) revealed the structure of
the C H bond activation of 1 by Pd
(OAc)2 or [Ru
E
N
the dimer D’1 (Scheme 11),[12] already reported.[12b]
cymene)] in acetonitrile,[8] the kinetics of the reaction of 1
The reaction of 1 with Pd(OAc)2 was then followed by
G
(0.08m) with Pd
(OAc)2 (0.08m) were followed by H NMR
1H NMR spectroscopy at lower concentrations (0.08m each)
in CD2Cl2 in which D’1 was more soluble (Figure 3a). A fast
decay of 1 was observed (t1/2 =ca. 6 min, Figure 3a). The
dimer D’1 was formed through two intermediate complexes
A’1 and B’1 (Scheme 11 and the Supporting Information,
Figure S25). They could not be isolated but were character-
ized by the chemical shift of the Me protons in their ligated
spectroscopy in CD3CN at 278C. The same intermediate
complexes A’1 and B’1 were formed. The reaction was too
fast (t1/2 =ca. 11 min) to allow accurate NMR data at very
short times (Figure 3b), but the decay of 1 with time ap-
peared to be classical (hyperbolic for a stoichiometric reac-
tion).
No significant effect of additives (HOAc, KOAc) on the
rate of the reaction was evidenced (Figure 3b). In contrast
to [RuACHUTNTGRENNUG(OAc)2ACHTUNGTREN(NGUN p-cymene)], no accelerating effect of KOAc
was observed (zero-order reaction for the deprotonation
step) in the case of Pd
mechanism assisted by
ACHTUNGRTEN(NUNG OAc)2, which indicates a CMD
a
ligated acetate (Scheme 12).
ꢀ
Scheme 12. Proposed intermediates for the acetate-assisted C H bond
activation and deprotonation of 1; equivalent intermediates were pro-
posed in the literature for the case of dimethylbenzylamine.
Whereas the saturated 18e [Ru
dissociate to allow coordination of 1, the unsaturated Pd-
(OAc)2 can easily coordinate 1 giving complex A’1, which is
ACHUTGTNRNE(NGU OAc)2ACHTUGNTREN(NUGN p-cymene)] should
AHCTUNGTRENNUNG
then engaged into a CMD mechanism to deliver complex
B’1 and eventually the dimer D’1 (Scheme 11). However, our
kinetic data cannot discriminate between the mechanisms
usually proposed for related reagents such as dimethylben-
zylamine, either an electrophilic substitution through a Whe-
land intermediate (Scheme 12) with subsequent intramolec-
ular deprotonation by the ligated acetate after hydrogen
bonding of its carbonyl group, as was proposed by Rya-
ꢀ
Figure 3. a) Kinetics of the C H bond activation of 2-phenylpyrydine (1)
(0.08m) by Pd
G
1
H NMR spectroscopy at 278C. ( ) Decay of 2-phenylpyridine (1) with
time and formation of PdII complexes: D’1 ( ); A’1 ( ); B’1 ( ); sum ( ).
~
&
^
*
bov[5b] or an agostic C H complex in which the agostic inter-
ꢀ
*
b) Same reaction in CD3CN. ( ) Decay of 2-phenylpyridine (1) with
ꢀ
action, even if weak, is sufficient to polarize the C H bond
~
*
time. In the presence of: ( ) HOAc (10 equiv); ( ) KOAc (3 equiv)
added to Pd(OAc)2 before 1.
G
to form an intramolecular hydrogen-bond with the ligated
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A. Jutand et al.
acetate, as was proposed by Davies and Macgregor through
DFT for dimethylbenzylamine
calculations[4a,5e]
(Scheme 12).
ꢀ
The activation of the C H bond of 2-phenylpyridine in
the absence of any additives followed the reactivity order:
Pd
N
ACHTUNGTRENNUNG(OAc)2AHCTUNGTREN(NGUN p-cymene)].
No
D
(10 equiv) was added to the dimer D’1 in CD2Cl2 after 20 h.
The NMR spectrum was not modified. Only the two bridg-
ing OAc of D’1, which exchanged by those of the deuterated
acetic acid and the Me protons of the released OAc, ap-
peared at d=2.12 ppm. No deuterated 2-phenylpyridine was
ꢀ
detected and the C H bond activation/deprotonation was
thus irreversible. No D incorporation into 1 was observed
when acetic acid[D4] (10 equiv) was added to a solution of
PdACHTUNGTRENNUNG(OAc)2 (0.08m) and 1 (2 equiv) in acetonitrile.
Electrochemical properties of the dimer D’1: The dimer D’1,
a PdII^PdII complex (Scheme 11), is oxidized by the chemi-
cal oxidant PhIACHTUNGTRENNUNG
(OAc)2 to give a neutral dimeric PdIII^PdIII
complex (s-ligated by two extra acetates) that has been iso-
lated and well characterized, as reported by Ritter et al.[3k,13]
It was thus of interest to investigate the electrochemical
properties of D’1.
Figure 4. Cyclic voltammetry: oxidation of D’1 (3 mm) at O1 in dichloro-
methane containing n-Bu4NBF4 (0.3m) at a gold-disk electrode (d=
2 mm) at a scan rate of 0.5 Vsꢀ1 at 228C.
The cyclic voltammogram of D’1 (3 mm) in dichlorome-
thane containing n-Bu4NBF4 (0.3m) as supporting electro-
lyte exhibited a chemically reversible oxidation peak at
EpO1 = +1.07 V versus SCE at
a
gold-disk electrode
Conclusion
(Figure 4).[14] The absolute number of electron(s), n, in-
volved in the oxidation process was determined according to
a reported procedure: n=2.3ꢁ0.1.[15] It means that the oxi-
dation of the dimeric PdII^PdII complex delivers a dimeric
PdIII^PdIII complex. The two electrons were transferred at
the same potential, indicating that the two PdII centers in
D’1 did not communicate and behaved as two independent
PdII moieties oxidized at the same potential without any
cleavage of the bridging acetates (chemically reversible
ꢀ
The activation of the C H bond of 1-phenylpyrazole (2) and
2-phenyl-2-oxazoline (3) by [Ru
G
N
tocatalytic process catalyzed by HOAc, analogous to that of
2-phenylpyridine (1). All reactions are accelerated by acetic
acid and water and decelerated by a base K2CO3. A decreas-
ing reactivity order is established in the absence of addi-
2-phenylpyridine>2-phenyl-2-oxazoline>1-phenyl-
pyrazole. The accelerating effect of added acetate ions re-
tives:
ꢀ
ꢀ
process). This suggests that the Pd Pd bond evidenced in
the X-ray structure (the Supporting Information, Fig-
veals an intermolecular deprotonation after C H bond acti-
vation by a cationic RuII center. The activation of 1-phenyl-
pyrazole and 2-phenyl-2-oxazoline led to neutral
cyclometalated complexes A2 and A3, respectively, ligated
by one acetate. They easily dissociate to the cationic com-
ure S24) and induced by p-stacking in the solid state,[14] dis-
appeared in solution, as was evidenced in the H NMR spec-
1
trum of complex D’1 that exhibited well-resolved aromatic
protons (the Supporting Information, Figure S25c). In the
absence of additives (e.g., acetate ions present in the chemi-
plexes B2 and B3+, respectively, and the acetate ion. A
slow incorporation of one or two D atoms into 1-phenylpyr-
azole (2), 2-phenyl-2-oxazoline (3) and 2-phenylpyridine (1)
was observed in the presence of deuterated acetic acid. The
+
cal oxidation of D’1 by PdIACHTNUGRTNEUNG
(OAc)2), a bis cationic PdIII^PdIII
complex was formed and was stable at the time scale of the
cyclic voltammetry [Eq. (8)].
ꢀ
“reversibility” of the C H bond activation/deprotonation
takes place from the cationic B2+, B3+, and B1+, respective-
+
+
ly. Cations B2 and B3 are involved in an oxidative addi-
tion to PhI, leading to bis-phenylated products at high tem-
The results of the electrochemical oxidation are thus in
agreement with those of the chemical oxidation of the same
peratures. The reaction of Pd
(1) is much faster than that of [Ru
contrast, the activation by Pd(OAc)2 proceeds through a
CMD mechanism assisted by the ligated acetate through an
intramolecular and irreversible process. A dimeric PdII^PdII
(D’1) is formed whose bielectronic electrochemical oxidation
leads to a dimeric [PdIII^PdIII]2+ complex, in agreement with
ACHTUNGTRENNUNG
G
CHTUNGTRENNUNG
PdII^PdII dimer D’1 by PhI
G
ACHTUNGTRENNUNG
volvement of PdIII species in functionalization of arenes cat-
alyzed by Pd
ACHTUNGTRENNUNG(OAc)2 when a chemical oxidant is re-
quired.[13,16]
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Intermolecular versus Intramolecular Deprotonation
FULL PAPER
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Experimental Section
ꢀ
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arenes 2 and 3 by [Ru
A
E
charged with [Ru(OAc)
N
N
ˇ
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0.079 mmol) was then added and the NMR tube was vigorously shaken.
1H NMR (300 MHz) was performed at 278C immediately after and then
from time to time.
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ꢀ
General procedure for the kinetics of the ortho-C H bond activation of
2-phenylpyridine (1) by Pd
ed with Pd
After complete dissolution of PdAHCNUTGTRENNUNG
(OAc)2: An oven-dried NMR tube was charg-
ACHTUNGTRENNUNG
0.02 mmol) was added as an internal standard, followed by 2-phenylpyri-
dine (5.6 mL, 0.04 mmol). The solution was vigorously shaken. A series of
1H NMR experiments were performed at 278C immediately after.
Acknowledgements
Centre National de la Recherche Scientifique (CNRS), Ecole Normale
Supꢀrieure (ENS) and ANR-09-BLAN-0101–02 RuCHCAT are thanked
for financial support and for a grant to E.F.F. (ANR). We also thank an
undergraduate student Romain Gaillac.
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[9] This reactivity order reflects the ability of the substrate to coordi-
nate the RuII center in agreement with the basicity of the N ligand:
pyridine (pKa 5.23)>oxazoline (pKa 4.75)>pyrazole (pKa 2.83).
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ꢀ
[10] a) Ackermann et al. have reported that the C H bond activation of
2-phenylpyridine by [Ru
A
G
evidenced by H/D exchange in a slow process (1208C in toluene),
see Ref. [2y]; b) For deuteration of 2-phenylpyridine catalyzed by
RuII complexes (CD3OD, 1208C), see Ref. [2x].
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ꢀ
A. D. Ryabov, Inorg. Chem. 1987, 26, 1252–1260; b) by C H activa-
tion with X-ray structure, see: H.-Y. Thu, W.-Y. Yu, C.-M. Che, J.
Am. Chem. Soc. 2006, 128, 9048–9049; c) For the synthesis of relat-
ꢀ
ed dimers by C H bond activation, see Ref. [3a,i].
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156; b) D. C. Powers, T. Ritter, Acc. Chem. Res. 2012, 45, 840–850;
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3
ꢀ
3311; o) In C
G
doin, E. Clot, Dalton Trans. 2010, 39, 10528–10535.
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6021–6029; d) For sp3 C H bond activation, see: L. J. L. Hꢆller,
ꢀ
M. J. Page, S. A. Macgregor, M. F. Mahon, M. K. Whittlesey, J. Am.
Chem. Soc. 2009, 131, 4604–4605.
Received: October 25, 2012
Revised: February 19, 2013
Published online: && &&, 2013
[7] L. Li, W. W. Brennessel, W. D. Jones, Organometallics 2009, 28,
3492–3500.
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Chem. Eur. J. 0000, 00, 0 – 0
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These are not the final page numbers!

Intermolecular versus Intramolecular Deprotonation
FULL PAPER
ꢀ
Acetate aid: The activation of the C
H bond of 1-phenylpyrazole and 2-
ꢀ
C H activation
phenyl-2-oxazoline by [RuACHTNUTRGENNUG(OAc)2ACHTUNGTERN(NUGN p-
I. Fabre, N. von Wolff, G. Le Duc,
E. Ferrer Flegeau, C. Bruneau,
P. H. Dixneuf, A. Jutand* ... &&&& — &&&&
cymene)] is an autocatalytic intermo-
lecular process aided by free acetate
(see figure). In contrast, activation by
Autocatalytic Intermolecular versus
Intramolecular Deprotonation in C H
Bond Activation of Functionalized
Arenes by Ruthenium(II) or Palla-
dium(II) Complexes
PdACHTUNGTRENNUNG(OAc)2 proceeds through a con-
ꢀ
certed metalation–deprotonation
(CMD) mechanism through an intra-
molecular and irreversible process that
is assisted by ligated acetate. A cyclo-
metalated dimeric PdII^PdII is formed
whose bielectronic electrochemical
oxidation leads to a dimeric
[PdIII^PdIII]2+
.
Chem. Eur. J. 2013, 00, 0 – 0
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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These are not the final page numbers!