Mechanistic origin of antagonist effects of usual anionic bases (OH -, CO32-) as modulated by their countercations (Na+, Cs+, K+) in palladium-catalyzed Suzuki-Miyaura reactions

Article abstract of DOI:10.1002/chem.201200516

The mechanism of the reaction of trans-ArPdBrL₂ (Ar=p-Z-C ₆H₄, Z=CN, H; L=PPh₃) with Ar'B(OH)₂ (Ar'=p-Z'-C₆H₄, Z'=H, CN, MeO), which is a key step in the Suzuki-Miyaura process, has been established in N,N-dimethylformamide (DMF) with two bases, acetate (nBu₄NOAc) or carbonate (Cs ₂CO₃) and compared with that of hydroxide (nBu ₄NOH), reported in our previous work. As anionic bases are inevitably introduced with a countercation M⁺ (e.g., M⁺OH ^-), the role of cations in the transmetalation/reductive elimination has been first investigated. Cations M⁺ (Na⁺, Cs ⁺, K⁺) are not innocent since they induce an unexpected decelerating effect in the transmetalation via their complexation to the OH ligand in the reactive ArPd(OH)L₂, partly inhibiting its transmetalation with Ar'B(OH)₂. A decreasing reactivity order is observed when M⁺ is associated with OH^-: nBu ₄N⁺> K⁺> Cs⁺> Na ⁺. Acetates lead to the formation of trans-ArPd(OAc)L₂, which does not undergo transmetalation with Ar'B(OH)₂. This explains why acetates are not used as bases in Suzuki-Miyaura reactions that involve Ar'B(OH)₂. Carbonates (Cs₂CO₃) give rise to slower reactions than those performed from nBu₄NOH at the same concentration, even if the reactions are accelerated in the presence of water due to the generation of OH^-. The mechanism of the reaction with carbonates is then similar to that established for nBu₄NOH, involving ArPd(OH)L₂ in the transmetalation with Ar'B(OH)₂. Due to the low concentration of OH^- generated from CO₃ ^2- in water, both transmetalation and reductive elimination result slower than those performed from nBu₄NOH at equal concentrations as Cs₂CO₃. Therefore, the overall reactivity is finely tuned by the concentration of the common base OH^- and the ratio [OH ^-]/[Ar'B(OH)₂]. Hence, the anionic base (pure OH ^- or OH^- generated from CO₃^2-) associated with its countercation (Na⁺, Cs⁺, K ⁺) plays four antagonist kinetic roles: acceleration of the transmetalation by formation of the reactive ArPd(OH)L₂, acceleration of the reductive elimination, deceleration of the transmetalation by formation of unreactive Ar'B(OH)₃^- and by complexation of ArPd(OH)L₂ by M⁺. Copyright

Full text of DOI:10.1002/chem.201200516

FULL PAPER
DOI: 10.1002/chem.201200516
Mechanistic Origin of Antagonist Effects of Usual Anionic Bases
2ꢀ
(OHꢀ, CO3 ) as Modulated by their Countercations (Na+, Cs+, K+) in
Palladium-Catalyzed Suzuki–Miyaura Reactions
Christian Amatore,* Anny Jutand,* and Gaꢀtan Le Duc[a]
Abstract: The mechanism of the reac-
tion of trans-ArPdBrL2 (Ar=p-Z-
C6H4, Z=CN, H; L=PPh3) with
Ar’B(OH)2 (Ar’=p-Z’-C6H4, Z’=H,
CN, MeO), which is a key step in the
Suzuki–Miyaura process, has been es-
tablished in N,N-dimethylformamide
(DMF) with two bases, acetate
(nBu4NOAc) or carbonate (Cs2CO3)
and compared with that of hydroxide
(nBu4NOH), reported in our previous
work. As anionic bases are inevitably
introduced with a countercation M+
(e.g., M+OHꢀ), the role of cations in
the transmetalation/reductive elimina-
tion has been first investigated. Cations
M+ (Na+, Cs+, K+) are not innocent
since they induce an unexpected decel-
erating effect in the transmetalation via
their complexation to the OH ligand in
the reactive ArPd(OH)L2, partly inhib-
order is observed when M+ is associat-
ed with OHꢀ: nBu4N+ > K+ > Cs+ >
Na+. Acetates lead to the formation of
trans-ArPdACTHUNGTRENNUNG
undergo
Due to the low concentration of OHꢀ
generated from CO3 in water, both
2ꢀ
transmetalation and reductive elimina-
tion result slower than those performed
from nBu4NOH at equal concentra-
tions as Cs2CO3. Therefore, the overall
reactivity is finely tuned by the concen-
tration of the common base OHꢀ and
Ar’B(OH)2. This explains why acetates
are not used as bases in Suzuki–
Miyaura
reactions
that
involve
Ar’B(OH)2. Carbonates (Cs2CO3) give
rise to slower reactions than those per-
formed from nBu4NOH at the same
concentration, even if the reactions are
accelerated in the presence of water
due to the generation of OHꢀ. The
mechanism of the reaction with carbo-
nates is then similar to that established
for nBu4NOH, involving ArPd(OH)L2
in the transmetalation with Ar’B(OH)2.
the ratio [OHꢀ]/
ACTHNGUTERN[UNG Ar’B(OH)2]. Hence,
the anionic base (pure OHꢀ or OHꢀ
generated from CO32ꢀ) associated with
its countercation (Na+, Cs+, K+) plays
four antagonist kinetic roles: accelera-
tion of the transmetalation by forma-
tion of the reactive ArPd(OH)L2, ac-
celeration of the reductive elimination,
deceleration of the transmetalation by
ꢀ
formation of unreactive Ar’B(OH)3
and by complexation of ArPd(OH)L2
by M+.
Keywords:
anionic
bases
·
arylboronic acid · cations · reaction
mechanisms · palladium
iting
its
transmetalation
with
Ar’B(OH)2.
A
decreasing reactivity
Introduction
We recently reported kinetic data on the transmetalation/
reductive elimination steps of Suzuki–Miyaura reactions,
thus revealing an unprecedented triple role of the base OHꢀ
(Scheme 2).[3] Two of them are positive: 1) formation of the
The cross-coupling of aryl halides (ArX) with arylboronic
acids (Ar’B(OH)2) or aryltrifluoroborates (Ar’BF4 ) is cata-
ꢀ
lyzed by palladium in the presence of a base (NaOH, TlOH,
KOH, R4NOH, TlOEt, Ag2O, K3PO4, Na2CO3, K2CO3,
Cs2CO3, Tl2CO3)[1] (Scheme 1). This reaction is a key step in
the total synthesis of natural products.[2]
Scheme 1. Suzuki–Miyaura reaction.
[a] Dr. C. Amatore, Dr. A. Jutand, G. Le Duc
Dꢀpartement de Chimie, Ecole Normale Supꢀrieure
UMR CNRS-ENS-UPMC 8640
24 Rue Lhomond, 75231 Paris Cedex 5 (France)
Fax : (+33)144-32-24-02
E-mail: Anny.Jutand@ens.fr
christian.amatore@ens.fr
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201200516.
Scheme 2. Mechanism of the Suzuki–Miyaura reaction when the base is
OHꢀ associated with nBu4N+.[3]
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reactive trans-ArPd(OH)L2 (L=PPh3) involved in the rate-
determining transmetalation with Ar’B(OH)2 and 2) acceler-
ation of the reductive elimination from trans-ArPdAr’L2
(Scheme 2). The third role is negative: 3) formation of in-
ed from ArPdXACTHNGUTERNNUG
(PPh3)2, the intermediate ArPdIIAr’ and the
cross-coupling product ArAr’, all exhibiting a known charac-
teristic reduction signal.[3] The palladium(0) formed in the
reaction was characterized by its oxidation signal. Moreover,
the rate of formation of the palladium(0) was monitored by
an electrochemical technique that takes advantage of the
fact that the oxidation current is proportional to the concen-
tration.[3] The present experiments were performed under
conditions representative of one cycle of a real catalytic se-
quence. Indeed, the kinetics were investigated from trans-
ꢀ
trinsically unreactive aryl borates Ar’B(OH)3 leading to
two kinetically antagonist effects of hydroxide, controlled by
ACHTUNGTRENNUNG
the ratio [OHꢀ]/[Ar’B(OH)2].[3] The reactivity of Ar’B(OH)2
with ArPd(OH)
Ar’B(OH)3 with ArPdX
G
ꢀ
T
work[3] was soon after confirmed by Carrow and Hartwig.[4]
We recently established that fluoride anions play the same
three roles as those established for hydroxides, with ArPdF-
ArPdXACHTNUTGRNEUG(N PPh3)2 complexes in the presence of large excesses
of Ar’B(OH)2 (from 10 to 100 equiv vs. PdII) and a base to
mimic catalytic reactions involving 10 to 1 mol% catalyst,
respectively.
ACHTUNGTRENNUNG(PPh3)2 as the key complex involved in the transmetalation
with Ar’B(OH)2.[5]
The role of the base (e.g., carbonates) in reactions involv-
ꢀ
ing Ar’BF4 has been studied. Batey and Quach have made
Decelerating effect of cations: To compare the kinetics of
the transmetalation performed in the presence of bases
MOH (M+ =Na+, K+, Cs+) to that performed in the pres-
ence of nBu4NOH in our previous work,[3] the same reagents
were investigated: trans-4-CN-C6H4-PdBrACHTNUGTRENUNG(PPh3)2 (1) (C0 =
1.9 mm) and PhB(OH)2 (2) (bC0) (Scheme 3). mOH was in-
ꢀ
the hypothesis that anionic Ar’BF3ꢀn(OH)n (n=1, 2) must
be formed from Ar’BF3 in the presence of hydroxides gen-
ꢀ
erated from the base.[6a] The successive basic hydrolysis of
Ar’BF3ꢀ to eventually Ar’B(OH)2 was established by Molan-
der,[6b–d] Hutton,[6e] Lloyd-Jones,[6f] and their co-workers. The
latter proposed a reaction of Ar’B(OH)2 with ArPd(OH)L
species in a transmetalation step.[6f]
The role of cations (Na+, K+, Cs+, Ag+, Tl+) introduced
as counterions of anionic bases or with Ar’BF3 (mainly K+
ꢀ
) has not been fully investigated. We used nBu4NOH to vol-
untarily by-pass the role of cations and to focus on the role
of the base. nBu4NOH is indeed fully dissociated in DMF
into OHꢀ and the innocent nBu4N+.[3] As pioneered by
Kishi,[7a] some countercations of bases, Ag+ in Ag2O or
more interestingly Tl+[7] in TlOH, TlOEt, and Tl2CO3 have
a beneficial effect on Pd-catalyzed Suzuki reactions, com-
pared with KOH. This is rationalized by the formation of in-
soluble AgX or TlX in THF/H2O, inducing a shift of the
equilibrium ArPdXL2/ArPd(OH)L2 (Scheme 2) towards the
reactive ArPd(OH)L2 whose concentration increases, lead-
ing to a faster reaction. Some anionic bases as carbonates[1]
are often introduced with other countercations (e.g.,
Na2CO3, K2CO3, or Cs2CO3) whose influence on the mecha-
nism of the catalytic reaction has never been investigated.
We report herein kinetic data which show that less halo-
philic cations, such as Na+, K+, and Cs+ (associated to
OHꢀ) also play an important but decelerating role in the
transmetalation step of Suzuki–Miyaura reactions. The
mechanistic role of another anionic base such as carbonate
(always associated with those countercations) has been in-
vestigated as well.
Scheme 3.
troduced at aC0 concentration (in the range 14–40 mm) from
mother solutions in methanol (1m), as for nBu4NOH.[3] The
reactions were performed at 258C, in DMF (a solvent which
is used in catalytic reactions,[1j–l,2,7d] as well as methanol[1]),
in the presence of excess PPh3 (2 equiv) to observe the for-
mation of a stable and soluble Pd0
ACHTNUTRGNE(UNG PPh3)3, characterized by
an oxidation wave (E1/2 = +0.1 V vs. SCE) at a rotating disk
electrode whose oxidation plateau current was proportional
to the Pd0
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG(PPh3)3
AHCTUNGTRENNUNG
dation signal and quantified from the value of the current at
the oxidation peak) was formed in 94% yield. The cross-
coupling product 4-CN-C6H4-Ph, (characterized by its reduc-
tion peak potential at ꢀ2.01 V and quantified from the value
of the current at the reduction peak) was formed in 95%
yield.
As it was established in our previous work,[3] Pd0
formed in a reductive elimination from intermediate trans-
ArPdAr’
(PPh3)2, which is faster in the presence of OHꢀ
than the rate-determining transmetalation reaction, in which
trans-ArPdAr’ (PPh3)3 and
(PPh3)2 is formed (Scheme 2). Pd0
ACHTUNGTRNE(NUNG PPh3)3 is
Results and Discussion
ACHTUNGTRENNUNG
The present mechanistic investigations were performed by
means of electrochemistry[8] associated with NMR spectros-
copy, as in our previous work dealing with the role of hy-
droxide anion (from nBu4NOH) in the Suzuki–Miyaura re-
actions.[3] The simultaneous use of the two methods allows
the characterization of the reactive ArPdII complex generat-
G
ACHTUNGTRENNUNG
ArAr’ (here 4-CN-C6H4-Ph) were thus formed at the same
rate as the rate-determining transmetalation step. In other
words, Pd0
ACHTNUTRGNEUGN(PPh3)3 was formed at the same rate as 1 disap-
peared in the transmetalation. The plot of lnx versus time
was linear (Figure 1b) (x=(ilimꢀit)/ilim where ilim =final oxi-
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Palladium-Catalyzed Suzuki–Miyaura Reactions
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Figure 1. Kinetics of the reaction of trans-p-CN-C6H4-PdBrACHTNUGTRNEUNG(PPh3)2
(1.9 mm) with PhB(OH)2 (20 equiv) in the presence of PPh3 (2 equiv) and
Figure 2. a) Kinetics of the reaction of trans-p-CN-C6H4-PdBrACHTUNGTRENNUNG(PPh3)2
NaOH (10 equiv). a) Variation of the oxidation current i of Pd0
AHCTUNGTRENNUNG
1
(C0 =1.9 mm) with PhB(OH)2 (20 equiv) in the presence of PPh3
versus time: i was determined by chronoamperometry at a rotating gold
disk electrode (d=2 mm) polarized at +0.05 V. b) Plot of lnx versus
(2 equiv) and MOH (a equiv) (M=nBu4N,[3] K, Cs, Na). Plots of kobs
versus a (note that kobs was plotted versus the value of the initial amount
of hydroxides introduced into the medium). Effect of H2O: (&) 30 equiv
time: x=(ilimꢀit)/ilim; ilim =final oxidation current of Pd0
ACHTUGNTRNE(UNNG PPh3)3; it =oxida-
tion current at time t. c) Comparison with the reaction involving
nBu4NOH (10 equiv)[3] instead of NaOH. All reactions were performed
in DMF containing nBu4NBF4 (0.3m) at 258C.
!
*
added to nBu4NOH; ( ) 15 equiv added to KOH and ( ) 30 equiv
^
added to CsOH. ( ): reaction performed in the presence of nBu4NOH
(15 equiv) and NaBF4 (15 equiv). b) Kinetics of the reaction of trans-p-
CN-C6H4-PdBrACHTUNRGTNEGN(U PPh3)2 (C0 =1.9 mm) with PhB(OH)2 (20 equiv) in the
~
)
presence of PPh3 (2 equiv), nBu4NOH (15 equiv) and a’ equiv of (
dation current of Pd0
ACTHUNRGTNENUG(PPh3)3, it =oxidation current at time t).
The value of the observed rate constant kobs of the transme-
*
KBF4, or ( ) NaBF4 (concentration range for MBF4: 0–42 mm). Plot of 1/
kobs versus [MBF4] expressed in equiv (a’) versus PdII complex 1. All re-
actions were performed in DMF containing nBu4NBF4 (0.3m) at 258C.
talation was obtained from the slope of the straight plot:
lnx=ꢀkobst (Figure 1b).
k
obs =0.0096 sꢀ1 (b=20, a=30,
Interestingly, the value of kobs obtained for the reaction of
1 with 2 (20 equiv) in the presence of nBu4NOH (15 equiv)
and NaBF4 (15 equiv) was similar to that obtained for the
same reaction performed in the presence of NaOH
(15 equiv); kobs =0.0104 and 0.0109mꢀ1 sꢀ1, respectively (Fig-
ure 2a), thus confirming the specific deceleration effect of
Na+. This was further confirmed in reactions performed
with nBu4NOH (15 equiv) as the base, in the presence of in-
creasing amounts (a’ equiv) of KBF4 or NaBF4 (free ions in
DMF) in the range 0–42 mm (Figure 2b). The decelerating
effect of the cations Na+ and K+ was definitively estab-
lished by linear plots of 1/kobs versus the concentration of
M+ (Figure 2b): 1/kobs =a+ba’=a+b[M+]/C0.
DMF, 258C).
A comparison of the kinetic curves obtained in the pres-
ence of NaOH (Figure 1b) or nBu4NOH (Figure 1c) at the
same initial concentrations reveals a slower reaction in the
presence of NaOH. The decelerating effect of cations M+ =
Na+, K+, Cs+ is a general feature (Figure 2a). The antago-
nist effect of OHꢀ due to the competitive formation of the
ꢀ
reactive ArPd(OH)
N
that results in the bell-shaped variation of kobs versus the
OHꢀ concentration (evidenced in our previous work),[3] was
still observed for all investigated bases (Figure 2a). When
considering the maximum value of kobs for each cation, a de-
creasing reactivity order was established:
A decrease of the concentration of the active ArPd(OH)-
ACHTUNERGN(UNG PPh3)2 (in equilibrium with ArPdBrAHCUTNGTRNE(NUGN PPh3)2, Scheme 2)
must be at the origin of the decelerating effect exerted by
cations. Cations[9] might interfere in the kinetics of the trans-
metalation via formation of ion pairs (in equilibrium with
free ions) such as [M+OHꢀ]. This would decrease the con-
nBu4NOH > KOH > CsOH > NaOH
As H2O could be introduced via the base (e.g.,
CsOH·H2O), the effect of H2O on the kinetics of the trans-
metalation was tested, leading to nonsignificant effects (Fig-
ure 2a, open symbols).
centration of the active ArPd(OH)ACTHNUTRGNEUNG(PPh3)2 and consequently
slow down the transmetalation. Cations may also ion-pair
with the anions released during the reaction, such as [M+
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A. Jutand, C. Amatore and G. Le Duc
Brꢀ], leading to increased concentrations of the active
ArPd(OH)(PPh3)2 and consequently in accelerating the
Na+ >K+ established by DFT calculations (however per-
formed in the gas phase).[10b] Theoretical data for the affinity
of Cs+ for alcohols are not available.
ACHTUNGTRENNUNG
transmetalation. Ion pairs are not expected to be formed in
polar DMF. Nevertheless, the conductivity of MOH and
MBr was measured in DMF at 258C. The conductivity of
MOH (M+ =Na+, K+, Cs+) increased linearly with its con-
centrations (in the range: 0–35 mm; see Figures S1–S3 in the
Supporting Information); the conductivity of MBr (M+ =
Na+, K+, Cs+) as well for concentrations in the range: 0–
120 mm (Figures S4–S6 in the Supporting Information). This
means that only free ions were present in solution, M+
+OHꢀ and M++Brꢀ, respectively. The decelerating effect of
cations M+ by formation of ion pairs was thus ruled out.
The complexation of the OH group of trans-ArPd(OH)-
1
N
spectrum of trans-p-CN-C6H4-Pd(OH)ACHTNUGRTNEUNG(PPh3)2 (3a) (20 mm)
in [D7]DMF exhibited the two doublets of the aryl group
(see the Supporting Information). After addition of NaBF4
(7.5 equiv, 150 mm), the two doublets were slightly shifted
downfield and two new doublets appeared upfield assigned
to the complex 3a–Na+ (Equation (1), see Experimental
Section). A new broad singlet for the OH proton of 3a–Na+
was observed at ꢀ2.58 ppm. The 31P NMR singlet of 3a
(14 mm) was shifted downfield after addition of NaBF4 (a’=
2 equiv, 28 mm) while a new singlet appeared at upper field
assigned to 3a–Na+ (Figure S7 in the Supporting Informa-
tion). The magnitude of its singlet increased at the expenses
of the magnitude of the singlet of 3a after successive addi-
tion of NaBF4 up to 105 mm (Figure S7).[11b] Therefore, Na+
1
The H NMR spectrum of Ar’B(OH)2 (Ar’=p-CN-C6H4,
Ph) in [D7]DMF was not affected by addition of NaBF4
(5 equiv), thus ruling out any interaction of Na+ with
ꢀ
Ar’B(OH)2. The aromatic protons of Ar’B(OH)3 , nBu4N+
(Ar’=p-CN-C6H4, Ph) in [D7]DMF were slightly shifted
after addition of NaBF4 (5 equiv) but a similar shift was ob-
served upon addition of nBu4NBF4 (5 equiv), therefore evi-
dencing that the shift was not due to Na+ but to a ionic
strength on the charged borate.
did effectively interact with ArPd(OH)
complexation of its hydroxide [Eq. (1)]. The equilibrium
constant KNa =x/[C0A (a’ꢀx)] was calculated from the
(1ꢀx)
slope of the linear plot of x/
(1ꢀx) versus (a’ꢀx) where x/
ACHTUNGTRENUN(NG PPh3)2 by reversible
C
ACHTUNGTRENNUNG
Alkali cations are known to bind oxygen centers as in al-
cohols.[10] The decelerating effect of the cations in the trans-
metalation might be due their complexation to the hydrox-
T
ACHTUNG-
T
Na+ and 3a, respectively (Figure S8 in the Supporting Infor-
mation). This led to KNa =75ꢁ5mꢀ1 (DMF, 278C). Since
CsBF4 is not commercially available, the complexation of
ide of ArPd(OH)
would decrease the concentration of the active ArPd(OH)-
(PPh3)2 involved in the rate-determining transmetalation
step.
ACHTUNGTRENNUNG
(PPh3)2 (3) to form 3-M+ [Eq. (1)]. This
G
trans-PhPd(OH)
ACHTUNGTRENNUNG
31P NMR in the reaction of CsOH with trans-PhPdBr
ACHTUNGTRENNUNG
in [D7]DMF (22.66 ppm for 3b–Cs+ vs. 22.41 ppm for 3b).
The experimental decelerating effect of the cation Cs+ on
the kinetics of the transmetalation (Na+ >Cs+ >K+) was
found to be inverted with respect to the expected one based
on its ionic radius (Na+ >K+ >Cs+). No simple explana-
tion seems available other than invoking specific interac-
tions of Cs+ with the DMF solvent.[11c]
The complexation of ArPd(OH)ACHTNUGRTNEUNG
(PPh3)2 by cation M+
would thus be in competition with its transmetalation by
Ar’B(OH)2 (Scheme 4). Higher the affinity of the cation for
The new kinetic law that takes into account the new equi-
librium constant KM (Scheme 5) is displayed in Equa-
ArPd(OH)
ACHTUNGTRENNUNG(PPh3)2, slower the transmetalation. From the ki-
netic curves in Figure 2a, one predicts that the affinity of
the cations for the OH group of ArPd(OH)ACHTNURTGNEUNG(PPh3)2 must de-
crease in the order: Na+ >Cs+ >K+, which is in agreement
with the decreasing affinity order of cations for alcohols:
Scheme 5. Role of the countercation M+ (Na+, K+, Cs+) of the base
OHꢀ in the mechanism of the Suzuki–Miyaura reaction (the solvent
DMF is voluntarily omitted).[9]
Scheme 4. Competitive complexation/transmetalation in the presence of
cations M+ (Na+, K+, Cs+) in DMF (solvent voluntarily omitted).[9]
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Palladium-Catalyzed Suzuki–Miyaura Reactions
FULL PAPER
tion (2).[12] Due to the excess of MOH, the concentration
[M+] may be considered as constant all along the reaction
under these catalytic-like conditions (rate=kobsACTHNUTRGNEUNG
[PdII]total).
ꢀ
ꢁꢀ
ꢁ
1
Kx½OHꢀꢂ
kobs ¼ ktmbC0
1 þ KOH½OHꢀꢂ ½Xꢀꢂ þ Kx½OHꢀꢂð1 þ KM½MþꢂÞ
ð2Þ
The theoretical variation of kobs versus [OHꢀ] exhibits
a maximum, as experimentally observed in Figure 2a. The
max
position of the maximum [Eq. (3)] and the value of kobs
Scheme 6.
depend on the concentration of the cation and the value of
KM.
[14]
PhPd(OH)ACTHNUGTRNEUNG(PPh3)2 was formed in the presence of excess
ꢀ
ꢁ
1=2
½Xꢀꢂ
PPh3 (2 equiv; Scheme 6). This evidences that in the pres-
ence of water, Cs2CO3 generated low concentrations of OHꢀ
(Equation (5) in Scheme 6)[6,13b] which played the same role
vis ꢂ vis ArPdXL2 as nBu4NOH did.[3]
½OHꢀꢂ
¼
max
ð3Þ
KxKOHð1 þ KM½MþꢂÞ
The theoretical hyperbolic decay of kobs versus [M+]
[Eq. (4)] is in agreement with the decelerating effect of M+
observed in Figure 2b, being consistent with our mechanism.
Smith et al.[13b] reported that K2CO3 in THF/H2O gener-
ates OHꢀ which reacts with Ar’B(OH)2 to generate
ꢀ
Ar’B(OH)3 . An acceleration of a Suzuki–Miyaura reaction
ꢀ
ꢁꢀ
ꢁ
1
kobs
1 þ KOH½OHꢀꢂ
½Xꢀꢂ
between ArCl and Ar’B(OH)2 was observed upon increasing
¼
1 þ
þ
Kx½OHꢀꢂ
the amount of water.[13b] At that time (1994), the accelerat-
ktmbC0
ð4Þ
ꢀ
ð1 þ KOH½OHꢀꢂÞ
ing effect was explained by the formation of Ar’B(OH)3
which was supposed to be more reactive than Ar’B(OH)2.
ꢃ KM½Mþꢂ ¼ a0 þ b0½Mþꢂ
ktmbC0
ꢀ
However, we established in 2011 that Ar’B(OH)3 is intrins-
Scheme 5 updates our former mechanism of the Suzuki–
Miyaura reaction through including the role of cations M+
=Na+, K+, Cs+ (counterions of the anionic base, here
OHꢀ) which in contrast to Ag+ or Tl+ are at the origin of
a decelerating transmetalation via their complexation to the
ically unreactive.[3] Hence, the cause of the accelerating
effect must be rather found in the formation of reactive
ArPd(OH)L2 as evidenced above (Schemes 1 and 6).
As established in previous works,[3,15] trans-PhPd(OH)-
AHCTUNGTRENNUNG
reactive ArPd(OH)ACHTUNGTRENNUNG(PPh3)2. Hence, the base not only plays
a role via the ratio [OHꢀ]/
G
complex trans-p-CN-C6H4-Pd-PhACHTNGUTERNNU(G PPh3)2 detected in cyclic
ciated countercation M+. Moreover, other sources of cations
voltammetry by its reduction signal (Epred =ꢀ1.47 V). The
need to be considered with care, e.g., K+ when Ar’BF3 K+
addition of “dry” Cs2CO3 (2.5 equiv) resulted in the slow
are used as precursors of Ar’B(OH)2.[6]
formation of Pd0
ACHTGNUTERNNU(G PPh3)3 (t1/2 =1 h 30) together with the
cross-coupling product p-CN-C6H4-Ph, both detected by
their oxidation and reduction signals, respectively. The reac-
tion was considerably slower than that observed when
Carbonate as base: Carbonate ions are often used as
bases in Suzuki–Miyaura reactions involving arylboronic
acids.[1,13a,b] They are mainly introduced with a countercation,
as in Cs2CO3, K2CO3, or Na2CO3 and are moderately soluble
even in sufficiently polar solvents such as DMF.[13c] Their
low solubility is often compensated by the introduction of
a small amount of water.[1,13b] As (nBu4N)2CO3 was not
available, Cs2CO3 was selected because it is more soluble in
DMF than K2CO3.[13c] However, one has to keep in mind
that that Cs+ exerts a decelerating effect in the transmetala-
tion by a factor of about 2.4 when comparing nBu4NOH
and CsOH at similar concentrations (compare the respective
values of kobsmax in Figure 2a).
nBu4NOH was added to the same intermediate trans-p-CN-
2ꢀ
C6H4-Pd-PhACTHNUTRGNEUNG
(PPh3)2 (t1/2 =2 min).[3] This suggests that CO3
may favor the reductive elimination from trans-p-CN-C6H4-
Pd-Ph
AHCTUNGTRENNUNG
of carbonates with water traces [Eq. (5)], through formation
of anionic pentacoordinated bisaryl-PdII complexes
(Scheme 7).[16] This by-passed the classical overall slow re-
ductive elimination due to the endergonic formation of cis-
ArPdAr’L2 from trans-ArPdAr’L2.[3]
The reaction of “dry” Cs2CO3 (10 equiv) with trans-
1
PhPdBr
N
[D7]DMF. No reaction took place, the singlet of trans-
PhPdBr(PPh3)2 (24.06 ppm) remained unchanged. It was
ACHTUNGTRENNUNG
only after addition of water (10% in volume) that the two
Scheme 7. Transmetalation and OHꢀ-assisted reductive elimination from
singlets characteristic of cis (32.94 ppm) and trans
(32.4 ppm) [PhPd
G
G
trans-ArPdAr’L2.
Chem. Eur. J. 2012, 00, 0 – 0
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A. Jutand, C. Amatore and G. Le Duc
afford Pd0
ACHTNUGTRNEUNG(PPh3)3 and the cou-
pling product p-CN-C6H4-Ph.
This indicates that in the pres-
ence of “dry” Cs2CO3, under
our experimental conditions,
the time scales of the transme-
talation and the reductive elimi-
Scheme 8.
nation were close to each other
It was therefore of interest to investigate the kinetics of
the reaction of trans-ArPdX(PPh3)2 with arylboronic acids,
and that the reductive elimination was not considerably
faster than the transmetalation, in contrast to what was ob-
served when nBu4NOH was used as the base.[3]
When the same reaction was performed in the presence
of added H2O (d=25 equiv), the induction period was short-
AHCTUNGTRENNUNG
Ar’B(OH)2 in DMF in the presence of “dry” Cs2CO3 and
then in the presence of increasing amounts of added water
(Scheme 8).
The kinetics of the formation of Pd0
N
ened (compare Figure 4a and b) and the Pd0
ACTHUNGETRN(NUG PPh3)3 forma-
by chronoamperometry at a rotating gold disk electrode
tion became faster. Both effects were reinforced in the pres-
ence of a larger amount of water (d=1750 equiv; Fig-
ure 4c).
(see above). The evolution of the oxidation current of Pd0-
ACHTUNGTRENNUNG
1
(a equiv). The reaction was first performed with “dry”
Cs2CO3 (15 equiv) in the absence of water. Whereas the
same reaction performed in the presence of nBu4NOH
(15 equiv) led to the formation of Pd0
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
Cs2CO3 (15 equiv), even after long duration times (>3 h). In
the presence of higher amounts of PhB(OH)2 (50 equiv) and
Cs2CO3 (25 equiv), a slow reaction took place (t1/2 =14300 s;
Figure 3a). The reaction was accelerated (t1/2 =3250 s) by in-
creasing both concentrations: PhB(OH)2 (100 equiv) and
Cs2CO3 (50 equiv) while keeping the same ratio a/b (Fig-
ure 3b). Though, the reaction remained slower than those
performed with nBu4NOH[3] instead of dry Cs2CO3 at the
same concentration.
Figure 4. Evolution of the molar fraction x’ of Pd0
formed in the reaction of trans-p-CN-C6H4-PdBr(PPh3)2 1 (1.9 mm) with
ACHTUNGTRENN(NUG PPh3)3 versus time
AHCTUNGTRENNUNG
PhB(OH)2 (50 equiv) in the presence of Cs2CO3 (25 equiv) and PPh3
(2 equiv): a) without any water, b) in the presence of H2O (25 equiv),
c) in the presence of H2O (1750 equiv). All reactions were performed in
DMF containing nBu4NBF4 (0.3m) at 258C. Molar fraction of Pd0
ACHTUNGTRENNUNG
x’=it/ilim (it =oxidation current of Pd0
ACHTUNGTRENNUNG
tration), ilim =final oxidation current). The current intensities were deter-
mined at a rotating gold disk electrode (d=2 mm) polarized at +0.05 V
versus SCE.
All these experiments established that the transmetalation
resulted very slow in the presence of “dry” Cs2CO3 because
of the lack of a significant concentration of OHꢀ which con-
sequently led to a low concentration of the reactive trans-p-
CN-C6H4-Pd(OH)ACHTUNTRGNEG(UN PPh3)2. The reductive elimination was
also slow due to the lack of OHꢀ. The half-reaction time of
the reductive elimination was estimated to t1/2 =7ꢃ103 s by
considering the part of the kinetic curve at longest times in
Figure 4a. In the presence of increasing amounts of water,
i.e., in the presence of increasing amounts of OHꢀ [Eq. (5)],
the transmetalation was accelerated through increasing
Figure 3. Evolution of the molar fraction x’ of Pd0
the reaction of trans-p-CN-C6H4-PdBr(PPh3)2
ACHTUNGTRENNUNG
G
1
a) PhB(OH)2 (50 equiv) and Cs2CO3 (25 equiv); b) PhB(OH)2
(100 equiv) and Cs2CO3 (50 equiv). Both reactions were performed in
DMF containing nBu4NBF4 (0.3m) in the presence of PPh3 (2 equiv) at
258C. Molar fraction of Pd0
Pd0
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ArPd(OH)ACTHNUGRTNEUNG(PPh3)2 concentration. The reductive elimination
tion current). The currents were determined at a rotating gold disk elec-
was accelerated as well because promoted by OHꢀ (com-
pare the kinetic curves at long times in Figure 4). Neverthe-
less, reactions involving Cs2CO3, even in the presence of
large amounts of water, were considerably slower than those
involving nBu4NOH at equal concentrations. This cannot be
attributed to the decelerating effect of the cation Cs+ (a de-
trode (d=2 mm) polarized at +0.05 V versus SCE.
Interestingly, the formation of Pd0
ACHTNUTRGNE(UNG PPh3)3 exhibited an in-
duction period (Figure 3) which evidenced the formation of
an intermediate complex, such as trans-p-CN-C6H4-Pd-Ph-
ACHTUNGTRENNUNG(PPh3)2 (see above). The latter evolved at longer times to
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Palladium-Catalyzed Suzuki–Miyaura Reactions
FULL PAPER
celerating effect of a factor 2.4 was expected, see Figure 2a)
but to the low concentration of hydroxides generated from
Cs2CO3 in water [Eq. (5)]. Once again, the rates of the
transmetalation and reductive elimination were controlled
by the concentration of hydroxides. However, accurate ki-
netic data could not be obtained since the concentration of
hydroxides generated from Cs2CO3 could not be evaluated
with certainty.[6f] Moreover, reaction rates were found to be
very dependent on the quality of Cs2CO3, “dry” or not,
bought from different companies, a feature already observed
should do in a classical Suzuki–Miyaura reaction. According
to other authors, an extra base as OHꢀ is required to per-
form the second cross-coupling, suggesting that acetates are
not a good base for cross-coupling of Ar’B(OR)2.[1c,19,20a] Up
to our knowledge, acetates are not an efficient base for the
Suzuki–Miyaura reaction performed from Ar’B(OH)2.[19,20b]
This incited us to investigate the role of acetates in Suzuki–
Miyaura reactions. They were introduced as nBu4NOAc in
order to by-pass the role of countercations as Na+ or K+
(see above).
ꢀ
by Meyers et al. in palladium-catalyzed C N cross-coupling
The formation of trans-PhPd
reaction of nBu4NOAc with trans-PhPdXACTHUNGTRENNUNG
ACHUTGTNRENNUG(OAc)ACHTUGNTRENNNUG
reactions.[17]
Therefore, Suzuki–Miyaura reactions performed in the
presence of ꢄdry“ carbonates as base are considerably
slower even in the presence of water than those performed
in the presence of hydroxide (nBu4NOH) at identical con-
centrations. However, the mechanism remains similar, in-
volving the same reactive ArPd(OH)L2 (Scheme 9). The re-
actions are slower due to the low concentration of OHꢀ gen-
erated from carbonates which is at the origin of 1) a slow
transmetalation because of the low concentration of the re-
Cl) has been already evidenced in our group [Eq. (6)] and
the equilibrium constant KX/OAc determined in DMF.[18]
active ArPd(OH)ACHTUNGTRENNUNG(PPh3)2 and 2) a slow reductive elimination
because promoted by hydroxides present at low concentra-
tions (Scheme 9).
As observed in our previous work,[3] no reaction took
place between trans-PhPdBrACHTNUGTRNEUNG(PPh3)2 (1.9 mm) and p-MeO-
C6H4-B(OH)2 (b=20 equiv) in the presence of PPh3
(2 equiv) in DMF at 258C. Addition of nBu4NOAc (from
a=10 to 50 equiv) did not lead to the formation of the cou-
pling product p-MeO-C6H4-Ph neither at 258C, nor at 508C
(Scheme 10). Similarly, no reaction took place between
Scheme 10.
Scheme 9. Mechanism of the Suzuki–Miyaura reaction when the base is
carbonate in DMF/water. The role of the countercation (here Cs+) is not
mentioned in this Scheme (see Scheme 5 for the role of the countercat-
ion).
trans-p-CN-C6H4-PdBrACTHNUTRGEN(UGN PPh3)2 (1.9 mm), PhB(OH)2 (from 10
to 20 equiv) in the presence of PPh3 (2 equiv) and
nBu4NOAc (from to 10 to 50 equiv) in DMF at 258C
(Scheme 10).
Acetate as base: Acetate ions are used as base in cross-cou-
pling reactions of aryl halides ArX and (RO)2B-B(OR)2
leading to Ar-B(OR)2.[1c] Miyaura and Suzuki reported that
Addition of nBu4NOAc (5 equiv) to p-CN-C6H4-PdBr-
AHCTUNGTRENNUNG
the reaction of trans-PhPdBrACTHNUTRGNE(UNG PPh3)2 with (RO)2B-B(OR)2
((RO)2 =pinacolato)[1c,f] which generates PhB(OR)2 was ac-
N
ACHTUNGTRENNUNG
celerated in the presence of acetate ions (KOAc in DMSO),
ACHTUNGTRENNUNG
via the formation of trans-PhPd
change.[1c,f,18] A transmetalation of trans-PhPd
by (RO)2B-B(OR)2 was supposed to generate trans-PhPd-
B(OR)2A(PPh3)2 and then PhB(OR)2 by subsequent reductive
elimination. Surprisingly, PhB(OR)2 did not further couple
with trans-PhPd(OAc)
(PPh3)2 to generate PhPh,[1c,f] as it
A
U
their reduction peak potentials (Epred =ꢀ1.91 V and ꢀ1.80 V
respectively) [Eq. (6)]. The intermediate complex trans-
ArPdAr’L2 (Ar=p-CN-C6H4, Ar’=Ph) was not formed
since its reduction peak (at Epred =ꢀ1.47 V, see above) was
A
ACHTUNGTRENNUNG
CHTUNGTRENNUNG
not observed. Consequently, trans-ArPd
G
ACHTUNGTRENNUNG(PPh3)2
A
U
formed by reaction of acetate with trans-ArPdBrACHTUNGTRENNUNG
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A. Jutand, C. Amatore and G. Le Duc
not undergo any transmetalation with Ar’B(OH)2 [Eqs. (6)–
(7)].
results more intense on the reductive elimination leading to
the observation of an induction period for the generation of
Even if the intermediate trans-ArPdAr’L2 was not formed
[Eq. (7)], it was nevertheless of academic interest to test the
effect of AcOꢀ on the fate of this stable intermediate that
easily undergoes reductive elimination in the presence of
OHꢀ, as evidenced in our previous work.[3] The complex
Pd0
ACTHUNGETRNNU(G PPh3)3.
In Suzuki–Miyaura reactions involving a fast oxidative ad-
dition (aryl iodides and bromides), one needs to increase
the rate of the rate-determining transmetalation. This re-
2ꢀ
quires: 1) to select the best base: OHꢀ >CO3 @AcOꢀ,
trans-p-CN-C6H4-Pd-Ph
trans-p-CN-C6H4-Pd(OH)
(10 equiv) in the presence of PPh3 (2 equiv) (Figure S9). No
Pd0
(PPh3)3 was formed upon addition of nBu4NOAc
(15 equiv) after 1 h. It is only after addition of nBu4NOH
(15 equiv) that Pd0
(PPh3)3 and p-CN-C6H4-Ph were formed,
T
2) to optimize the ratio [OHꢀ]/
ACHTUNGTRENNUNG
N
>
nBu4N+ >K+ >Cs+ >Na+. This optimization is of course
less crucial if the oxidative addition is rate determining as
for aryl chlorides. However, the mechanism of the transme-
talation/reductive elimination, elucidated in the present
work for carbonates and in our previous work for hydrox-
ides[3] remains valid.
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
in agreement with our previous results (Figure S9 in the
Supporting Information).[3] Therefore, even if the intermedi-
ate complex trans-ArPdAr’L2 were formed in the transmeta-
lation, it did not undergo any reductive elimination in the
presence of acetate ions [Eq. (8)]. This definitively explains
why acetates are not good bases for Suzuki–Miyaura reac-
tions performed from arylboronic acids.[19,20c]
Experimental Section
Reaction of NaBF4 with trans-p-CN-C6H4-Pd(OH)ACHTNUTRGNENU(G PPh3)2 AHCTUNGTRENN(GUN 3a) as Moni-
tored by 1H NMR (250 MHz, [D7]DMF) and 31P NMR (101 MHz,
[D7]DMF): The two doublets at 7.16 and 6.72 ppm of the aryl group of p-
CN-C6H4-Pd(OH)ACTHNURGTNEUNG(PPh3)2 (3) (10 mmol, 20 mm) in 0.5 mL of [D7]DMF
Conclusion
(see the Supporting Information) were slightly shifted of 0.025 ppm
downfield after addition of 8 mg (75 mmol, 7.5 equiv) of NaBF4. Two new
doublets appeared at upfield at 7.01 ppm (d, JHH =8 Hz) and 6.63 ppm
(d, JHH =8 Hz), assigned to the complex 3a–Na+, formed by complexa-
tion of the OH of 3a by Na+ [Eq. (1)]. The OH singlet in 3a–Na+ was
observed at ꢀ2.58 ppm.
Cations M+ (Na+, K+, Cs+) inevitably introduced as coun-
tercations of anionic bases in palladium-catalyzed Suzuki–
Miyaura reactions exert an unexpected decelerating effect
in the transmetalation step (a key step in Suzuki–Miyaura
reactions) with the following decreasing reactivity order:
nBu4NOH >KOH >CsOH >NaOH. This results from
In another experiments, the 31P NMR singlet of p-CN-C6H4-Pd(OH)-
AHCTUNTGREGUN(NN PPh3)2 (3a) (7 mmol, 14 mm) at 22.41 ppm was shifted to 22.68 ppm after
addition of 1.5 mg (14 mmol, 2 equiv, 28 mm) of NaBF4, while a new sin-
glet appeared at upper field at 21.82 ppm for complex 3a–Na+, in the
ratio 3a–Na+/3a=0.93 (Figure S7 in the Supporting Information). After
addition of again 3.1 mg (total 28 mmol, 4 equiv, 56 mm) of NaBF4, the
ratio became 3a–Na+/3a=3.1 (Figure S7). Further addition of 2.7 mg
(total 52.5 mmol, 7.5 equiv, 105 mm) of NaBF4 gave 3a–Na+/3a=7.39.
The equilibrium constant KM was calculated from the 31P NMR data (see
above and Figure S8 in the Supporting Information).
a
complexation of the hydroxo
ACHUTGTNRENNlGU iACTHNGUTERNNUgG and of the reactive
ArPd(OH)
ACHTUNGTRENNUNG
Though decreased, the overall reactivity remains finely
tuned by the concentration of the base OHꢀ and the ratio
[OHꢀ]/
ACHTUNGTRENNUNG[Ar’B(OH)2].
The mechanism of the transmetalation/reductive elimina-
tion already established when the base is nBu4NOH has
been investigated for other bases, carbonates and acetates.
Acetates (from nBu4NOAc) are not an efficient base.
Indeed, they react with trans-ArPdX
ArPd(OAc)(PPh3)2 which did not transmetalate with
Ar’B(OH)2. This explains why acetates are not used in
Suzuki–Miyaura reactions performed from ArB(OH)2.
Even if the reactions are accelerated upon addition of
water, carbonates (from Cs2CO3) lead to much slower reac-
tions than those performed from nBu4NOH at the same
concentration. However, they proceed through a similar
mechanism, that is via the formation of the reactive trans-
The same reaction was performed in the presence of 42 mg (125 mmol,
1
250 mm) of nBu4NBF4 without any effect on the H NMR, ruling out any
effect of the ionic strength.
No significant effect of KBF4 was observed at 150 mm. This establishes
that the affinity of Na+ for 3a is considerably higher than that of K+, ex-
plaining why the rate of the transmetalation was more affected by Na+
than by K+ (Figure 2a and b). Experiments with higher amounts of
KBF4 could not be done because of the lack of solubility of KBF4.
ACHTUNGTRENUN(NG PPh3)2 to form trans-
G
ACHTUNGTRENNUNG
Typical Procedure for the kinetics of the reaction of p-CN-C6H4-PdBr-
AHCTUNGTRENN(GUN PPh3)2 with PhB(OH)2, in the Presence of MOH, as monitored by chro-
noamperometry at a rotating disk electrode at 258C: All experiments
were performed under argon atmosphere at 258C in a thermostated
three-electrode cell connected to a Schlenk line. The counterelectrode
was a platinum wire of ca. 1 cm2 apparent surface area; the reference was
a saturated calomel electrode (SCE) separated from the solution by
a bridge filled with 2 mL of a 0.3m nBu4NBF4 solution in DMF. 16 mL of
degassed DMF containing 0.3m nBu4NBF4 were poured into the cell, fol-
ArPd(OH)ACHTUNGTRENNUNG(PPh3)2 from hydroxide ions generated through
the reaction of carbonates with water (Scheme 9 to be com-
pared with Scheme 1). Carbonates (via hydroxides) promote
the reductive elimination from intermediate trans-ArPdAr’-
lowed by 24 mg (0.03 mmol, 1.9 mm) of p-CN-C6H4-PdBrACHTNUTGRENUNG(PPh3)2, 16 mg
(0.06 mmol) of PPh3 and 73 mg (0.6 mmol) of PhB(OH)2. The kinetic
measurement was performed at a rotating gold disk electrode (d=2 mm,
inserted into a Teflon holder, EDI 65109, Radiometer) with an angular
velocity of 105 rad.sꢀ1 (Radiometer controvit) at 258C. The rotating elec-
ACHTUNGTRENNUNG(PPh3)2. However, due to the relatively low concentration of
hydroxide ions generated from carbonates in water, both
transmetalation and reductive elimination result slower than
those performed in the presence of nBu4NOH (at the same
concentration as carbonate). Noteworthy, this deceleration
trode was polarized at +0.05 V on the oxidation wave of Pd0
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
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Palladium-Catalyzed Suzuki–Miyaura Reactions
FULL PAPER
versus time up to a constant limit value, attesting to the end of the reac-
as the catalytic reaction proceeds:[3] c) For related proposition of
transmetalation of Ar’B(OH)2 on imine-palladacycle-OH, see: J. L.
Serrano, L. Garcꢆa, J. Pꢀrez, E. Pꢀrez, J. Garcꢆa, G. Sꢇnchez, P.
Sehnal, S. De Ornellas, T. J. Williams, I. J. S. Fairlamb, Organometal-
lics 2011, 30, 5095–5109.
tion. The solution turned to yellow, the color of Pd0
ACHTUNTRGNEUNG(PPh3)4 in DMF. A
cyclic voltammetry at the same steady electrode was then first performed
towards oxidation potentials and revealed the oxidation peak of Pd0-
ACHTUNGTRENNUNG
[5] C. Amatore, A. Jutand, G. Le Duc, Angew. Chem. 2012, 124, 1408–
1411; Angew. Chem. Int. Ed. 2012, 51, 1379–1382.
ACHTUNGTRENNUNG
reduction potentials and revealed the reversible reduction peak of p-CN-
C6H4-Ph. Its yield (95%) was determined from the increase of its reduc-
tion peak current after addition of 6.6 mg (0.037 mmol) of an authentic
sample of p-CN-C6H4-Ph (commercially available).
[6] a) R. A. Batey, T. D. Quach, Tetrahedron Lett. 2001, 42, 9099–9103;
b) G. A. Molander, T. Ito, Org. Lett. 2001, 3, 393–396; c) G. A. Mo-
lander, B. Biolatto, Org. Lett. 2002, 4, 1867–1870; d) G. A. Moland-
er, B. Biolatto, J. Org. Chem. 2003, 68, 4302–4314; e) A. K. L. Yuen,
C. A. Hutton, Tetrahedron Lett. 2005, 46, 7899–7903; f) M. Butters,
J. N. Harvey, J. Jover, A. J. J. Lennox, G. C. Lloyd-Jones, P. M.
Murray, Angew. Chem. 2010, 122, 5282–5286; Angew. Chem. Int.
Ed. 2010, 49, 5156–5160.
In other experiments, the amount of base was varied and the nature of
the base (KOH, CsOH) as well.
Typical procedure for the kinetics of the reaction of p-CN-C6H4-PdBr-
ACHTUNGTRENNUNG(PPh3)2 with PhB(OH)2, in the presence of carbonate (Cs2CO3), as moni-
[7] a) J.-I. Uenishi, J.-M. Beau, R. W. Armstrong, Y. Kishi, J. Am.
Chem. Soc. 1987, 109, 4756–4758; b) S. A. Frank, H. Chen, R. K.
Kunz, M. J. Schnaderbeck, W. R. Roush, Org. Lett. 2000, 2, 2691–
2694; c) D. A. Evans, J. T. Starr, J. Am. Chem. Soc. 2003, 125,
13531–13540; d) D. A. Evans, J. T. Starr, Angew. Chem. 2002, 114,
1865–1868; Angew. Chem. Int. Ed. 2002, 41, 1787–1790.
[8] For the elucidation of the mechanism of catalytic reactions by
means of electrochemistry, see: A. Jutand, Chem. Rev. 2008, 108,
2300–2347.
[9] The investigated cations must be solvated by DMF. Since one does
not know many molecules are involved, the solvent DMF around
the cations is voluntarily omitted in all relevant schemes and equa-
tions.
[10] a) B. E. Douglas, D. H. N. McDaniel, J. J. Alexander, Concepts and
Models of Inorganic Chemistry, Wiley, New York, 1994; b) L. Ma,
F. M. Siu, C. W. Tsang, Chem. Phys. Lett. 2000, 322, 65–72.
[11] a) Due to the lack of sensitivity of the NMR spectroscopy compared
to cyclic voltammetry, the NMR were performed at higher concen-
tored by chronoamperometry at a rotating disk electrode: The same cell
as above was employed. 16 mL of degassed DMF containing 0.3m
nBu4NBF4 were poured into the cell, followed by 24 mg (0.03 mmol,
1.9 mm) of p-CN-C6H4-PdBrACTHNUTRGEN(UGN PPh3)2, 16 mg (0.06 mmol) of PPh3 and
244 mg (0.75 mmol) of dry Cs2CO3. The solution was stirred during
30 min. The rotating gold disk electrode was polarized at +0.05 V on the
oxidation wave of Pd0
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
was recorded versus time. After an induction period, the current grew up
to a constant limiting value, attesting to the end of the reaction. Mean-
while, the solution turned to yellow, the color of Pd0
ACHTUNTRGNEUNG(PPh3)4 in DMF.
Similar reactions were performed in the presence of 13.5 mL (0.75 mmol)
of water introduced just after Cs2CO3. The amount of water was then in-
creased up to 52.5 mmol.
Acknowledgements
trations of ArPd(OH)ACTHNUTRGNEUNG(PPh3)2 complexes (in the range 14–20 mm)
than those used in the kinetics (1.9 mm) investigated by electro-
chemistry. However the concentrations of NaBF4 added to
This work has been supported in part by the Centre National de la Re-
cherche Scientifique (UMR CNRS-ENS-UPMC 8640) and the Ministꢅre
de la Recherche (Ecole Normale Supꢀrieure). We thank Johnson Mat-
they for a generous loan of palladium salt.
ArPd(OH)
ACHTUNGTRENNUNG
kinetics or higher to keep the ratio [NaBF4] /CTHUNGTRENNUNG
to those used in the kinetics; b) All reactions were performed in
DMF. We established on the basis of conductivity measurements
that no electrostatic ion pairs were present (Figures S1–S6). There-
fore, all cation interaction with the various species involved necessa-
rily complexation. This is fully coherent with the observation of two
distinct 31P NMR singlets for the coordinated and free ArPd(OH)-
[1] a) A. Suzuki, Pure Appl. Chem. 1985, 57, 1749–1758; b) A. Suzuki,
Pure Appl. Chem. 1991, 63, 419–422; c) N. Miyaura, A. Suzuki,
Chem. Rev. 1995, 95, 2457–2483; d) N. Miyaura, in Advances in
Metal-Organic Synthesis, Vol. 6: Synthesis of Biaryls via the Cross-
Coupling Reaction of Arylboronic Acids, JAI Press, London, 1998,
pp. 187–243; e) A. Suzuki, J. Organomet. Chem. 1999, 576, 147–
168; f) N. Miyaura, J. Organomet. Chem. 2002, 653, 54–57; g) F.
Alonso, I. P. Beletskaya, M. Yus, Tetrahedron 2008, 64, 3047–3101;
h) G. A. Molander, Angew. Chem. 2009, 121, 9404–9425; Angew.
Chem. Int. Ed. 2009, 48, 9240–9261; i) A. J. J. Lennox, G. C. Lloyd-
Jones, Isr. J. Chem. 2010, 50, 664–674; j) For a screening of bases
and solvents, see: T. Watanabe, N. Miyaura, A. Suzuki, Synlett 1992,
207–210; k) P. D. Hobbs, V. Upender, J. Liu, D. J. Pollart, D. W.
Thomas, M. I. Dawson, Chem. Commun. 1996, 923–924; l) C. Liu,
Q. Ni, F. Bao, J. Qiu, Green Chem. 2011, 13, 1260–1266.
AHCTUNTGREGUN(NN PPh3)2 (Figure S7); c) In this connection, it is of interest to remark
that owing to its larger size, the Cs+ ion generally involves a coordi-
nation number of 8 while smaller alkali cations prefer 6.
[12] The kinetic law is derived from that reported in our previous
work.[3]
[13] a) N. Miyaura, T. Yanagi, A. Suzuki, Synth. Commun. 1981, 11, 513–
519; b) G. B. Smith, G. C. Dezeny, D. L. Hughes, A. O. King, T. R.
Verhoeven, J. Org. Chem. 1994, 59, 8151–8156; c) Solubility in
DMF: [Cs2CO3]=7.2 mm, [K2CO3]=2.2 mm. Solubility in water:
[Cs2CO3]=0.77m. Source: Chemetall GmbH.
[14] a) Due to the presence of the Cs+ ion (from Cs2CO3) and its com-
plexation to the OH linked to ArPd(OH)ACHTNUTRGNE(UNG PPh3)2 complexes (see
[2] K. C. Nicolaou, P. G. Bulger, D. Sarlah, Angew. Chem. 2005, 117,
4516–4563; Angew. Chem. Int. Ed. 2005, 44, 4442–4489.
[3] C. Amatore, A. Jutand, G. Le Duc, Chem. Eur. J. 2011, 17, 2492–
2503.
above), the 31P NMR singlet of trans-PhPd(OH)
ACHTNUGTRNEUNG(PPh3)2 (3b) usually
observed at 22.41 ppm[3] in [D7]DMF was replaced by another sin-
glet at 22.66 ppm assigned to 3b–Cs+ [Eq. (1)]; b) The same singlet
was observed upon addition of CsOH to trans-PhPdBrACTHUNTRGNE(UNG PPh3)2 in the
presence of the same amount of water (10% in volume) as in
Ref. [14a].
[4] a) B. P. Carrow, J. F. Hartwig, J. Am. Chem. Soc. 2011, 133, 2116–
ꢀ
42119; b) Ar’B(OH)3 is intrinsically unreactive.[3] It is however in
equilibrium with Ar’B(OH)2 and OHꢀ, the latter being able to gen-
ꢀ
[15] C. Adamo, C. Amatore, I. Ciofini, A. Jutand, H. Lakmini, J. Am.
Chem. Soc. 2006, 128, 6829–6836.
erate ArPd(OH)L2. Ar’B(OH)3 could then react with ArPd(OH)L2
via Ar’B(OH)2 (Scheme 2) but in a slow reaction because the equi-
[16] a) For the formation of anionic pentacoordinated PdII species, see:
C. Amatore, A. Jutand, Acc. Chem. Res. 2000, 33, 314–321; b) For
reductive elimination induced by a fifth ligand on square planar
d10 complexes, see: R. Giovannini, P. Knochel, J. Am. Chem. Soc.
ꢀ
librium lays in favor of Ar’B(OH)3 leading to low concentration of
the active Ar’B(OH)2.[3,4] Moreover, the halide X of ArPdXL2 be-
comes less and less easily substituted by OHꢀ to generate the active
ArPd(OH)L2 because the concentration of the released Xꢀ increases
Chem. Eur. J. 2012, 00, 0 – 0
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A. Jutand, C. Amatore and G. Le Duc
1998, 120, 11186–11187 and c) G. Jarvis, I. J. S. Fairlamb, Curr. Org.
Chem. 2011, 15, 3175–3196.
[19] E. Ferrer Flegeau, M. E. Popkin, M. F. Greaney, Org. Lett. 2006, 8,
2495–2498.
[20] a) G. A. Molander, S. L. J. Trice, S. D. Dreher, J. Am. Chem. Soc.
[17] C. Meyers, B. U. W. Maes, K. T. J. Loones, G. Bal, G. L. F. Lemiꢅre,
R. A. Dommisse, J. Org. Chem. 2004, 69, 6010–6017.
[18] For X/OAc exchange, see: a) C. Amatore, A. Jutand, M. A.
M’Barki, Organometallics 1992, 11, 3009–3013; b) C. Amatore, E.
Carrꢀ, A. Jutand, M. A. M’Barki, G. Meyer, Organometallics 1995,
14, 5605–5614. KX/OAc =0.3 (X=I), 0.10 (X=Br), 0.04 (X=Cl) in
DMF at 278C.
2010, 132, 17701–17703; b) For transmetalation of PdACHTNUTRGNEUNG(OAc)2 by ar-
ylboronic acids in DMF/H2O, see: A. F. Schmidt, A. A. Kurokhtina,
E. V. Larina, Russ. J. Gen. Chem. 2011, 81, 1573–1574; c) This is
also observed for ArBF3ꢀ, a reservoir of Ar’B(OH)2, G. Molander:
personal communication.
Received: January 20, 2012
Published online: && &&, 2012
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Palladium-Catalyzed Suzuki–Miyaura Reactions
FULL PAPER
Not that innocent: Unexpectedly, some
countercations (Na+, Cs+, K+) of the
anionic bases used in the Suzuki–
Reaction Mechanisms
C. Amatore,* A. Jutand,*
Miyaura reactions decelerate the trans-
metalation reaction in comparison with
inert countercations such as nBu4N+,
due to a competitive complexation of
the reactive ArPd(OH)
(see scheme).
G. Le Duc ..................... &&&& — &&&&
Mechanistic Origin of Antagonist
Effects of Usual Anionic Bases (OHꢀ,
CO32ꢀ) as Modulated by their Counter-
cations (Na+, Cs+, K+) in Palladium-
Catalyzed Suzuki–Miyaura Reactions
(PPh3)2 by M+
ACHTUNGTRENNUNG
Chem. Eur. J. 2012, 00, 0 – 0
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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These are not the final page numbers!