Hexacationic Dendriphos ligands in the Pd-catalyzed Suzuki-Miyaura cross-coupling reaction: Scope and mechanistic studies

Article abstract of DOI:10.1021/ja904042h

The combination of Pd₂dba₃·CHCl₃ and hexacationic triarylphosphine-based Dendriphos ligands (1-3) leads to a highly active catalytic system in the Suzuki-Miyaura cross-coupling reaction. Under relatively mild reaction conditions, nonactivated aryl bromides and activated aryl chlorides can be coupled at a low Pd loading (0.1 mol %). The observed activity of this catalytic system, in particular in coupling reactions of aryl chlorides, is dramatically higher than that of conventional Pd catalysts employing triarylphosphine ligands. Through control and poisoning experiments, it is concluded that a homogeneous Pd(0)-Dendriphos complex is the active species in this catalytic system. Despite their triarylphosphine-based structure, Dendriphos ligands behave as very bulky phosphine ligands and lead to a preferential formation of coordinatively unsaturated and catalytically active Pd(0) species, which explains the observed high catalytic activity for these systems. The presence of six permanent cationic charges in the backbone of this class of ligands is proposed to result in a significant interligand Coulombic repulsion and plays a crucial role in their bulky behavior. In the coupling reactions of activated aryl chlorides, a positive dendritic kinetic effect was observed among the different Dendriphos generations, indicating an increased ability of the higher ligand generations to stabilize the active species due to steric effects. For aryl bromides, no dendritic effect was observed due to a shift in the rate-determining step in the catalytic cycle, from oxidative addition for aryl chlorides to transmetalation for aryl bromides.

Full text of DOI:10.1021/ja904042h

Published on Web 07/29/2009
Hexacationic Dendriphos Ligands in the Pd-Catalyzed
Suzuki-Miyaura Cross-Coupling Reaction: Scope and
Mechanistic Studies
Dennis J. M. Snelders, Gerard van Koten, and Robertus J. M. Klein Gebbink*
Chemical Biology and Organic Chemistry, Debye Institute for Nanomaterials Science, Faculty of
Science, Utrecht UniVersity, Padualaan 8, 3584 CH Utrecht, The Netherlands
Received May 18, 2009; E-mail: r.j.m.kleingebbink@uu.nl
Abstract: The combination of Pd
2
dba
3
3
·CHCl and hexacationic triarylphosphine-based Dendriphos ligands
(1-3) leads to a highly active catalytic system in the Suzuki-Miyaura cross-coupling reaction. Under
relatively mild reaction conditions, nonactivated aryl bromides and activated aryl chlorides can be coupled
at a low Pd loading (0.1 mol %). The observed activity of this catalytic system, in particular in coupling
reactions of aryl chlorides, is dramatically higher than that of conventional Pd catalysts employing
triarylphosphine ligands. Through control and poisoning experiments, it is concluded that a homogeneous
Pd(0)-Dendriphos complex is the active species in this catalytic system. Despite their triarylphosphine-
based structure, Dendriphos ligands behave as very bulky phosphine ligands and lead to a preferential
formation of coordinatively unsaturated and catalytically active Pd(0) species, which explains the observed
high catalytic activity for these systems. The presence of six permanent cationic charges in the backbone
of this class of ligands is proposed to result in a significant interligand Coulombic repulsion and plays a
crucial role in their bulky behavior. In the coupling reactions of activated aryl chlorides, a positive dendritic
kinetic effect was observed among the different Dendriphos generations, indicating an increased ability of
the higher ligand generations to stabilize the active species due to steric effects. For aryl bromides, no
dendritic effect was observed due to a shift in the rate-determining step in the catalytic cycle, from oxidative
addition for aryl chlorides to transmetalation for aryl bromides.
4
1
. Introduction
The use of core-functionalized dendrimers as macromolecular
dendrons which have been applied as noncovalent supports for
5
homogeneous catalysts. Dendriphos ligands combine the triph-
enylphosphine motif, located at their core, with six permanent
cationic substituents (ammonium groups), which furthermore
allow for variations in ligand size and solubility by means of
alteration of the ammonium substituent, ranging, e.g., from a
benzyl group (1) to first (2) and second (3) generation Fr e´ chet
dendrons. Through coordination of the phosphine functionality
to an appropriate metal source, these ligands allow in situ
formation of core-functionalized dendritic homogeneous catalysts.
Several examples of dendritic structures in which a phosphine
functionality is located at the core of the dendrimer
their applications in catalysis have been reported. In contrast
to dendritic catalysts containing multiple phosphine function-
alities located at the periphery of the dendrimer, such dendritic
catalysts is of great interest, as they offer the possibility to
control the local environment of the catalytic site. As an effect
of dendritic encapsulation, an improved stability of the catalyst
may be observed. Furthermore, advantages such as substrate
preconcentration or selectivity may arise from control of the
polarity or steric crowding of the local environment of the
catalytic site. However, the use of this type of catalyst often
has negative kinetic consequences due to a decreased acces-
1
sibility of the catalytic site. Core-functionalized dendritic
catalysts leading to faster reaction rates are therefore quite rare.
2b,e,6
and
2
Recently, we have developed the hexacationic Dendriphos
3
ligands (1-3, Figure 1). This family of ligands was designed
in analogy to octacationic dendrimers containing Fr e´ chet-type
7
phosphines offer the possibility to control the coordination
sphere of a single metal center by site isolation effects. For
(
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J. AM. CHEM. SOC. 2009, 131, 11407–11416 9 11407

A R T I C L E S
Snelders et al.
substituents on triarylphosphines can significantly influence their
structural features. We therefore anticipated that Dendriphos
ligands, combining as many as six permanent cationic charges
in their structure with a large, sterically demanding dendritic
shell, could exhibit interesting properties when applied as ligands
in transition metal catalyzed reactions.
In a previous report, we showed the rate-enhancing effect of
the 3,5-bis[(benzyldimethylammonio)methyl] substitution pat-
tern in G0-Dendriphos (1) when this ligand was employed in
combination with Pd(dba)
reaction of methyl 4-bromobenzoate with 4-tolylboronic acid.
2
in the Suzuki-Miyaura coupling
10
We tentatively attributed this effect to a Coulombic interligand
repulsion, facilitating the in situ formation of coordinatively
unsaturated and catalytically active Pd(0) species. Encouraged
by these observations, we have extended our studies to the
application of 1 and the higher generation Dendriphos ligands
2
and 3 for the catalytic conversion of more challenging
substrates, in particular aryl chlorides. Here, we present the
scope and limitations of this catalytic system in the Suzuki-
Miyaura reaction, as well as investigations into the nature of
the in situ formed active species, through control and poisoning
experiments and kinetic investigations. Furthermore, the effects
of both the charged groups and the sterically demanding
dendrons in the ligand structure of 1-3 on the properties of
these ligands and their corresponding catalysts are discussed.
2. Results
2
.1. Optimization of Reaction Conditions. We initially set
out to optimize the reaction conditions and to extend the scope
(
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Van Leeuwen, P. W. N. M. Chem. Commun. 1999, 1119–1120. (b)
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(
h) Fujihara, T.; Yoshida, S.; Ohta, H.; Tsuji, Y. Angew. Chem., Int.
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Caminade, A. M.; Majoral, J. P. Organometallics 2000, 19, 4025–
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Brad Peori, M.; Kakkar, A. K. Coord. Chem. ReV. 2002, 233-234,
Figure 1. Hexacationic Dendriphos ligands.
2
23–235. (e) Angurell, I.; Muller, G.; Rocamora, M.; Rossell, O.; Seco,
example, the great steric demand of dendritic wedges attached
to a phosphine functionality can lead to coordinatively unsatur-
ated and highly reactive metal centers.
M. Dalton Trans. 2003, 1194–1200. (f) Heuz e´ , K.; M e´ ry, D.; Gauss,
D.; Blais, J. C.; Astruc, D. Chem.sEur. J. 2004, 10, 3936–3944. (g)
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2
b
(
(
The consequences of introducing charged groups in coordi-
8
nating ligands are studied far less frequently. Although several
9
examples of phosphine ligands bearing ionic substituents exist,
2
005, 24, 962–971. (c) Moore, L. R.; Western, E. C.; Craciun, R.;
in most of these published works, focus lies on enhancing the
solubility of catalysts in polar or nonconventional media,
enabling their recycling, e.g., through a biphasic setup. Recently,
Spruell, J. M.; Dixon, D. A.; O’Halloran, K. P.; Shaughnessy, K. H.
Organometallics 2008, 27, 576–593. (d) Chisholm, D. M.; McIndoe,
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c
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1
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2
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1
1408 J. AM. CHEM. SOC. 9 VOL. 131, NO. 32, 2009

Dendriphos Ligands in Suzuki-Miyaura Cross-Coupling
A R T I C L E S
a
Table 1. Effect of the Solvent in Reaction 1
Table 3. Effects of Varying the L:Pd Ratio and the Pd Loading in
a
Reaction 1
b
Entry
Solvent
Yield (%)
b
Entry
Mol% Pd
L:Pd
Time (h)
Yield (%)
1
2
3
4
5
MeOH
EtOH
DMF
DME
toluene
88
88
89
19
18
c
1
2
3
4
5
6
7
0.1
0.1
0.1
0.1
1.0
0.01
0.001
1.0
2.0
2.5
4.0
2.5
2.5
2.5
3
3
24
85
c
c
3 (22)
3
3
3 (22)
3
79 (99)
73
c
88
a
Reaction conditions: 4-bromotoluene (1.0 mmol), phenylboronic
acid (2.0 mmol), NaOH (2.2 mmol), solvent (6.3 mL), H O (0.7 mL),
Pd (dba) ·CHCl (0.5 mol %), 1 (2.5 mol %, L:Pd ) 2.5), 65 °C, 3 h.
Yield of 4-phenyltoluene, determined by GC, using pentadecane as
internal standard. Formation of Pd-black was observed.
85 (85)
36
2
2
3
3
b
a
Reaction conditions: 4-bromotoluene (1.0 mmol), phenylboronic
acid (2.0 mmol), NaOH (2.2 mmol), MeOH (6.3 mL), H O (0.7 mL),
c
2
b
reflux. Yield of 4-phenyltoluene, determined by GC using pentadecane
as internal standard, average of two independent runs. Pd-black forma-
a
c
Table 2. Effect of the Base in Reaction 1
tion was observed.
b
Entry
Base
Yield (%)
a
1
2
3
4
5
6
7
8
Na
NaOH
3
PO
4
84
79
76
59
56
51
44
36
Table 4. Optimization of Reaction Conditions for Reaction 2
b
c
Entry
Base
Solvent
Temp (°C)
Time (h)
Yield (%)
K
2
CO
Na CO
Cs CO
3
1
2
3
4
5
6
7
8
NaOH
NaOH
KF
MeOH/10% H
2
O
68
100
66
90
90
90
90
90
3
16
16
16
16
16
16
16
0
2
3
DMF/10% H
THF
2
O
26
68
94
55
98
>99
83
2
3
CsF
KF
KF
dioxane
dioxane
dioxane
dioxane
Et
3
N
K
2
CO
3
Cs CO
2
3
a
Reaction conditions: 4-bromotoluene (1.0 mmol), phenylboronic
acid (2.0 mmol), base (2.2 mmol), MeOH (6.3 mL), H O (0.7 mL),
Pd (dba) ·CHCl (0.05 mol %), 1 (0.25 mol %, L:Pd ) 2.5), reflux, 3 h.
Yield of 4-phenyltoluene, determined by GC using pentadecane as
internal standard.
CsF
CsF
2
dioxane/10% H
2
O
2
3
3
b
a
Reaction conditions: 4-nitrochlorobenzene (1.0 mmol), phenylbo-
(dba)
(0.05 mol %), 1 (0.25 mol %, L:Pd ) 2.5). Reaction times
ronic acid (2.0 mmol), base (2.2 mmol), solvent (7.0 mL), Pd
2
3
·
b
CHCl
3
c
were not optimized. Yield of 4-nitrobiphenyl, determined by GC using
pentadecane as internal standard.
of Suzuki-Miyaura couplings catalyzed by the combination of
Pd
2
dba
3
3
·CHCl and 1. The cross-coupling of the nonactivated
substrates 4-bromotoluene and phenylboronic acid yielding
-phenyltoluene (reaction 1) was selected as a benchmark
experiments, as it forms homogeneous solutions in aqueous
MeOH, which entails practical advantages for using the Chem-
speed automated setup for these reactions. Using the optimal
base/solvent combination, the concentration of 1 with respect
to Pd (L:Pd ratio) was varied (Table 3). At a ratio of 1.0, Pd-
black formation was observed and a low yield was obtained.
Increasing the ratio to 2.5 led to a stable catalytic system, giving
high yields without formation of Pd-black. Further increasing
the L:Pd ratio did not lead to a significant change in the reaction
yield (Table 3, entries 1-4). The effect of varying the Pd
loading, while keeping the ligand:Pd ratio constant (i.e., 2.5)
was also investigated. It was found that the obtained yield after
4
reaction. The catalytic screening experiments were performed
using a Chemspeed ASW 2000 workstation, allowing automated
sampling and workup of the samples. The reactions were
initiated by addition of a solution of the Pd precursor to a hot
mixture of the other materials. The reactions were monitored
by GC analysis after appropriate intervals up to 3 h. Initially,
the effect of the solvent was investigated (Table 1). Toluene
and DME were not suitable due to the low solubility of the
ligand in these solvents, which led to precipitation of elemental
Pd (Pd-black). The use of either aqueous MeOH, EtOH, or DMF
in combination with NaOH as the base, each gave high coupling
yields at a Pd loading of 1 mol %. Provided that the reactions
were carried out under an inert atmosphere, Pd-black formation
was not observed in these solvents and the reaction mixtures
remained clear yellow solutions throughout the course of the
reaction. Analysis of the reaction mixtures by GC showed only
3
h of reaction time was nearly independent of the Pd loading
in the range 0.01-1.0 mol % (entries 3, 5, and 6). Further
lowering the amount of Pd led to a distinct decrease in the yield
(
entry 7).
In contrast to the Suzuki-Miyaura cross-coupling reaction
1
1
of aryl iodides and bromides, the coupling of less expensive
but relatively unreactive aryl chlorides can be problematic and
the cross-coupled product and unreacted starting material.
12
in general requires a dedicated catalyst. To explore the activity
of Dendriphos ligands in the coupling of these substrates, we
tested the coupling of 4-nitrochlorobenzene, an activated aryl
chloride, with phenylboronic acid, yielding 4-nitrobiphenyl
(
reaction 2). The optimized conditions employed for reaction 1
were found to be ineffective for reaction 2. By changing the
solvent and the base, large increases in the catalyst performance
could be achieved (Table 4). It was found that the best base/
solvent combination was CsF in dioxane, without addition of
Subsequently, the effect of the base was tested (at 0.1 mol
Pd loading, Table 2). In aqueous MeOH, each of the bases
%
Na
activities were observed for CsF, KF, Na
triethylamine. NaOH was the base of choice for further
3
PO
4
, NaOH, and K
2
CO
3
gave good results, while lower
2
CO , Cs CO , and
3
2
3
(
12) (a) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176–
211. (b) Bedford, R. B.; Cazin, C. S. J.; Holder, D. Coord. Chem.
4
ReV. 2004, 248, 2283–2321. (c) Bellina, F.; Carpita, A.; Rossi, R.
Synthesis 2004, 2419–2440. (d) Corbet, J.; Mignani, G. Chem. ReV.
2006, 106, 2651–2710.
(
11) For the reactions run at 1.0 mol % Pd, a trace of biphenyl was observed,
formed via homocoupling of the boronic acid.
J. AM. CHEM. SOC. 9 VOL. 131, NO. 32, 2009 11409

A R T I C L E S
Snelders et al.
H
2
O. With these conditions, the quantitative yield of the cross-
Table 5. Results for Cross-Coupling of Aryl Halides with
Phenylboronic Acid Using Pd (dba) ·CHCl /1
2 3 3
coupled product was obtained within 16 h at 90 °C at a Pd
loading of 0.1 mol %. Lowering the loading from 0.1 mol % to
0
.01 mol % led to a decreased rate and yield, while an increase
to 1 mol % gave similar activity (results not shown). No other
products than the cross-coupled product were observed by
GC.
2
.2. Substrate Scope. Using the two sets of optimized
reaction conditions, cross-coupling reactions of several aryl
bromide and aryl chloride substrates with phenyl boronic acid
were then carried out at a Pd loading of 0.1 mol % (reaction
3
, Table 5). Aryl bromides could be coupled efficiently using
either NaOH in aqueous MeOH (condition I) or CsF in
dioxane (condition II). Aryl chlorides could only be coupled
using the latter combination, and higher yields were obtained
1
3
by using a slightly higher amount of ligand (L:Pd ) 4).
With these conditions, the system reached full conversion
to the cross-coupled products within 22 h with several
electronically deactivated aryl bromides (entries 1-3) and
aryl bromides containing coordinating or other functional
groups (entries 4-6). In the case of 4-bromostyrene, the
1
14
product was isolated and its identity confirmed by H NMR.
Furthermore, the sterically hindered aryl bromides 2-bromo-
toluene and 2-bromo-m-xylene could be efficiently coupled
with phenylboronic acid. The coupling reactions of these aryl
bromides with sterically hindered mesitylboronic acid proved
much more difficult; the biaryl derivative containing three
ortho-methyl groups could be synthesized in 35% yield, but
no coupling product was formed with four ortho-methyl
groups (entries 7-8). Aryl chlorides containing an electron-
withdrawing substituent at the aryl ring, as well as 2-chlo-
ropyridine, could be coupled with moderate to excellent yields
within 22 h (entries 9-13). For the nonactivated 4-chloro-
toluene, only a trace of product was obtained (entry 14). For
entries 12-14, prolonging the reaction time to 46 h or
increasing the Pd loading to 1 mol % did not significantly
improve the reaction yields.
a
Reaction Conditions: I: aryl bromide (1.0 mmol), phenylboronic
O (0.7 mL),
(0.05 mol %), 1 (0.25 mol %, L:Pd ) 2.5), reflux
acid (2.0 mmol), NaOH (2.2 mmol), MeOH (6.3 mL), H
Pd (dba) ·CHCl
2
2
3
3
temperature. II: aryl halide (1.0 mmol), phenylboronic acid (2.0 mmol),
CsF (2.2 mmol), dioxane (7.0 mL), Pd (dba) ·CHCl (0.05 mol %), 1
2
.3. Comparison of the Pd/Dendriphos System to Known
2
3
3
b
Catalytic Systems. To place the activity of the present catalytic
system in perspective, we performed the coupling reaction of
methyl 4-chlorobenzoate with phenylboronic acid (reaction 4) using
several different commercially available catalysts, using our
(0.40 mol %, L:Pd ) 4.0), 95 °C. Yields of the cross-coupled
products, determined by GC using pentadecane as internal standard;
averages of 2 independent runs. Reaction temperature: 70 °C; 0.05 mol
c
d
%
of Pd
2
(dba)
3
·CHCl
3
and 0.25 mol
%
of
1
were used. The
1
cross-coupled product was isolated and its identity confirmed by
NMR. Cross-coupling reaction of the aryl halide with mesitylboronic
acid.
H
e
(
13) This improves catalyst stability when reaction times as long as 22 h
are required. Kinetically, increasing the L:Pd ratio above 2.5 leads to
a decrease in the reaction rate during the first several hours (Figure
S2e).
experimental setup and reaction conditions. All reactions were
carried out using a Pd loading of 0.1 mol %. Where applicable,
optimal L:Pd ratios as described in literature were used. Samples
were taken at appropriate time intervals to establish the minimum
(
14) The Suzuki-Miyaura cross-coupled product was formed selectively
and in quantitative yield; no polymers or Heck coupled stilbene-
containing compounds were found.
1
1410 J. AM. CHEM. SOC. 9 VOL. 131, NO. 32, 2009

Dendriphos Ligands in Suzuki-Miyaura Cross-Coupling
A R T I C L E S
Table 6. Comparison of Pd/1 to Commercially Available Catalysts
in situ upon combination of 1 and Pd
dba
3
·CHCl , we per-
2
3
a
in Reaction 4
formed several control runs (Figure 3). These experiments were
performed using the representative substrates 4-bromotoluene
and 4-nitrochlorobenzene, using their respective optimal reaction
conditions (reactions 5 and 6, respectively).
b
Entry
Catalyst
t (h)
Yield (%)
1
2
3
Pd(OAc)
Pd(OAc)
2
2
+ Sphos (L:Pd ) 2)
0.5
0.5
>99
>99
+ CataCXium A (L:Pd ) 2)
Pd
2
(dba)
3
·CHCl
3
+
0.5 (22) 53 (99)
P(t-Bu)
Pd(OAc)
3
HBF (L:Pd ) 1.2)
4
4
5
6
7
8
9
2
+ 1 (L:Pd ) 6)
22
22
73
70
65
Pd
Pd
2
(dba)
(dba)
3
·CHCl
·CHCl
3
+ 1 (L:Pd ) 4)
+ P(o-tolyl)
2
3
3
3
(L:Pd ) 4) 22
1
5
PEPPSI
Pd(OAc)
PdCl dppf
Pd(PPh
0.5 (22) 37 (42)
2
+ PPh
3
(L:Pd ) 4)
22
22
22
6
2
1
2
1
0
3 4
)
a
Reaction conditions: methyl 4-chlorobenzoate (1.0 mmol), phenylbo-
ronic acid (2.0 mmol), CsF (2.2 mmol), dioxane (7.0 mL), catalyst (0.1
b
mol %), 95 °C. Yield of methyl 4-phenylbenzoate, determined by GC
using pentadecane as internal standard; average of 2 independent runs.
required time to reach maximum conversion for each catalytic
system. The results are shown in Table 6.
Runs in the absence of ligand, or in the presence of the
benchmark ligand PPh , each gave very low conversions under
3
identical conditions for both of these reactions. These observa-
tions indicate the beneficial effect of the use of ligand 1.
Furthermore, the use of the phosphine oxide of 1 (1-oxide) led
to rapid Pd-black formation and very low yields, indicating that
coordination of the phosphine functionality to Pd is required
for activity in this system. Finally, the addition of the quaternary
ammonium salt 3,5-bis[(benzyldimethylammonio)methyl)]benzene
dibromide (4), which is structurally analogous to 1, did not lead
to any increase in activity, either as the only additive or in
The results clearly show the superiority of the bulky,
3
1a
32d
strongly σ-donating ligands CataCXium A and S-phos
Figure 2) both used in combination with Pd(OAc) , which
(
2
gave quantitative yields within 0.5 h (entries 1 and 2). On
the other hand, conventional catalysts based on triph-
enylphosphine, as well as PdCl dppf, are totally ineffective
2
for this reaction (entries 8-10). Systems employing 1 gave
moderate yields (entries 4 and 5), ranking these systems in
the middle of this catalytic spectrum. Notably, the use of
3
combination with PPh . This shows that the activity observed
by the use of ligand 1 does not depend on the simple presence
of quaternary ammonium bromide groups.
The effect of adding poisons for ligandless Pd species to
Pd(OAc)
2
instead of Pd
2
dba
3
3
· CHCl resulted in a slightly
reaction mixtures containing Pd
2
dba
3
3
·CHCl and 1 in our
higher yield, but a higher concentration of 1 (L:Pd ) 6) was
required for optimal activity. The use of the well-known,
benchmark coupling reaction of 4-bromotoluene (reaction 5)
was investigated as well. The poisons were added to the catalytic
mixtures a few seconds after the Pd precursor had been added
to a hot mixture of the other components and compared to a
run in which no poison was added (Figure 4).
bulky ligand P(o-tolyl)
systems using 1. In the case of P(t-Bu)
3
gave an activity comparable to the
3
0a
3
,
the observed initial
activity was very high (53% yield after 0.5 h). However, some
Pd-black was formed and the activity dropped quickly.
Quantitative conversion could nevertheless be obtained within
Addition of a drop of mercury led to a gradual decrease in
activity. The initially yellow reaction mixture slowly turned
colorless, indicating that all of the Pd in solution was slowly
being absorbed by the drop of mercury. However, addition of
2
2 h (entry 3). Similar behavior was observed for the PEPPSI
3
4b
catalyst
(entry 7). However, in this case, the catalyst
1
5
became nearly inactive after 0.5 h under these conditions.
.4. Investigations into the Nature of the Active Species. To
gain insight into the nature of the active species that is formed
1
6
2
poly(4-vinylpyridine) (PVPy) (300 or 600 mol equiv of
pyridine repeat units with respect to Pd) did not have any effect
on the activity. Indeed, these mixtures stayed yellow throughout
the reaction. These observations suggest that naked Pd(0) species
might be present in solution in low concentrations and that they
can be absorbed by Hg but not by PVPy. For comparison, the
effect of adding mercury to a catalytic mixture using the
(
2 3
15) Using the base Cs CO instead of CsF (with dioxane as the solvent),
which corresponds to one of the published sets of conditions, we
obtained only a slightly higher yield (58% after 22 h) using the PEPPSI
catalyst. This result is not in line with the published results for this
catalyst, which reaches high yields within 2 h at room temperature
for similar coupling reactions. We propose that the lower observed
yield results from the lower amount of catalyst used; in the present
study we used 0.1 mol % of Pd, while the published procedures employ
3 4
benchmark catalyst Pd(PPh ) was tested under identical condi-
tions. In this case, the activity was immediately and completely
inhibited (Figure S4).
1
or 2 mol % Pd.
(
16) (a) Yu, K.; Sommer, W.; Richardson, J. M.; Weck, M.; Jones, C. W.
AdV. Synth. Catal. 2005, 347, 161–171. (b) Richardson, J. M.; Jones,
C. W. AdV. Synth. Catal. 2006, 348, 1207–1216. (c) Weck, M.; Jones,
C. W. Inorg. Chem. 2007, 6, 1865–1875. (d) Chen, J.; Vasiliev, A. N.;
Panarello, A. P.; Khinast, J. G. Appl. Catal., A 2007, 325, 76–86.
2.5. Activities of Dendriphos Ligands of Higher Generations.
The higher Dendriphos ligand generations, 2 and 3, were both
tested alongside 1 in the coupling of a selected number of
electronically different aryl halides (reaction 7). For each of
the ligand generations, a L:Pd ratio of 2.5 was used at 0.1 mol
(
17) PhB(OH)
2
is known to react in situ with hydroxide or fluoride anion
-
-
to give PhB(OH)
3
2
or PhB(OH) F , respectively: Glaser, R.; Knotts,
%
Pd loading. Kinetic profiles for the coupling reactions of
N. J. Phys. Chem. A 2006, 110, 1295–1304. Changing the concentra-
4
-nitrochlorobenzene and 4-bromotoluene with phenylboronic
tion of CsF alone did not give any change in reaction rate, indicating
-
that the formation of PhB(OH)
2
F
is very rapid.
acid are shown in Figure 5, and those for the coupling reactions
J. AM. CHEM. SOC. 9 VOL. 131, NO. 32, 2009 11411

A R T I C L E S
Snelders et al.
Figure 2. Commercially available ligands used for benchmarking of 1.
S1c, and S1d) the different ligand generations gave essentially
identical reaction rates. Furthermore, very small differences in
coupling rates were observed, even among the electronically
very different aryl bromides 4-bromonitrobenzene and 4-bro-
moanisole.
2
.6. Kinetic Investigations. To obtain insight into the origin
of the dendritic kinetic effects depicted in Figure 5, additional
kinetic investigations were carried out under identical conditions,
using 1 as ligand. Thus, the effects of increasing the concentra-
tions of either the aryl halide or that of the activated phenyl-
1
7
boronic acid on the initial reaction rate were investigated for
two different substrates, i.e., 4-chloronitrobenzene and 4-bro-
motoluene. No clear orders in the substrates could be derived
from the obtained data, but qualitative trends were observed.
Kinetic profiles for these reactions, as well as plots of the initial
reaction rate versus the substrate concentration, can be found
in Figures S2 and S3. The effect of increasing the concentration
of 1 with respect to Pd on the kinetic profile was also
investigated.
Figure 3. Control runs for investigating the nature of the active species.
In the case of 4-nitrochlorobenzene (Figure S2), increasing
the concentration of the aryl halide led to a strong, nonlinear
increase of the initial reaction rate, but no further increase was
-
1
observed beyond a concentration of 0.43 mol L . In contrast,
the concentration of the activated boronic acid did not signifi-
cantly influence the observed reaction rate. Increasing the
concentration of 1 did not influence the initial reaction rate,
but as the reaction progressed, the differences in the rates of
the individual reactions grew dramatically; a clear decrease in
rate was observed upon increasing the L:Pd ratio from 2.5 to
Figure 4. Poisoning tests for the catalytic system Pd
reaction 5.
2
dba
3
3
· CHCl /1 in
of methyl 4-chlorobenzoate, 4-nitrobromobenzene, and 4-bro-
moanisole are shown in Figure S1.
6
8
.0. No further decrease in rate was observed at a L:Pd ratio of
.0.
In the case of 4-bromotoluene (Figure S3), small positive
influences on the initial rate were found for both the concentra-
tion of the aryl halide and that of the activated boronic acid.
Increasing the concentration of 1 from L:Pd ) 2.5 to 6.0 led to
a distinct decrease in the observed rate, but no further change
was observed by increasing the concentration to L:Pd ) 8.0.
In the coupling reactions of aryl chlorides, clear rate increases
were observed by the use of ligands of higher generations. In
the case of 4-nitrochlorobenzene, this effect was readily
observed at 70 °C (Figure 5a), and increasing the temperature
led to higher rates for all the generations (Figure S1a). For
methyl 4-chlorobenzoate (Figure S1b), a reaction temperature
of 95 °C was required to obtain appreciable activity. Even
though a positive dendritic effect was observed in the initial
stages of the reaction, the highest coupling yield after 22 h for
this reaction was reached using 1 (70%). Ligands 2 and 3 gave
lower yields for the coupling reaction of methyl 4-chloroben-
zoate after 22 h (51% and 41%, respectively), indicating that
for these ligands the catalyst is less stable under the reaction
conditions used. A possible explanation for this catalyst
deactivation could be slow thermal ligand degradation in the
case of 2 and 3. For each of the aryl bromides (Figures 5b,
3. Discussion
3.1. Nature of the Active Species. The combination of
Pd
2
dba
3
·CHCl and Dendriphos ligands can achieve Suzuki-
3
Miyaura couplings of nonactivated aryl bromides as well as
activated aryl chlorides at a Pd loading of only 0.1 mol %. This
activity is dramatically higher than that of conventional systems
3
employing PPh as ligand (Figure 3, Table 6). The structure of
Dendriphos ligands incorporates not only a phosphine function
but also quaternary ammonium groups, bromide ions, and
dendritic wedges as well. Before considering the reasons for
the increased activity of Dendriphos ligands with respect to PPh
3
in terms of ligand structures, a careful investigation as to whether
the active species in this catalytic system is a homogeneous
Pd-Dendriphos coordination complex or Pd nanoparticles that
1
1412 J. AM. CHEM. SOC. 9 VOL. 131, NO. 32, 2009

Dendriphos Ligands in Suzuki-Miyaura Cross-Coupling
A R T I C L E S
Figure 5. Kinetic profiles for the coupling reactions of 4-nitrochlorobenzene (a) and 4-bromotoluene (b) with phenylboronic acid. Reaction conditions: aryl
halide (1.0 mmol), phenylboronic acid (2.0 mmol), CsF (2.2 mmol), dioxane (7.0 mL), Pd (dba) ·CHCl (0.05 mol %), 1, 2, or 3 (0.25 mol %, L:Pd ) 2.5).
Yields were determined by GC using pentadecane as internal standard and are averages of two independent runs.
2
3
3
2
4
are stabilized by Dendriphos is thus appropriate. In general, if
catalytically active metal nanoparticles are being generated in
situ from homogeneous catalyst precursors during a catalytic
reaction, observations of induction periods and sigmoidal
nonionic dendrimers have also been reported. Recently,
phosphine oxide functionalized, Fr e´ chet-type dendrons were
reported to stabilize palladium nanoparticles, which were used
25,26
as catalysts in the Suzuki-Miyaura reaction.
To investigate
1
8
kinetics are considered a “telltale sign”. The kinetic traces of
the present catalytic system show neither sigmoidal kinetics nor
induction periods (except in one case; see Figure 5a). It is widely
acknowledged that the addition of quaternary ammonium halide
salts, such as tetrabutylammonium bromide (TBAB) in high
concentrations (50-100 mol %), can improve the catalytic
efficiency in Suzuki-Miyaura couplings, and this effect is
generally attributed to stabilization of catalytically active Pd
the possibility that such stabilization effects play a role in the
present system, we employed two well-known poisoning tests.
Poly(4-vinylpyridine) (PVPy) is known to act as a selective
trap for homogeneous, ligandless Pd(0) species. Addition of
1
6
PVPy to the catalytic system Pd
2
dba
3
3
·CHCl /1 did not have
any effect on the catalytic activity. This is a strong indication
that, in the present system, the observed activity cannot be
attributed to ligandless Pd(0) species, but to a homogeneous
19-21
nanoclusters.
We investigated the possible influence of the
n
Pd-Dendriphos complex of the type Pd(0)L . Addition of
ammonium bromide groups in the architecture of 1 on the
observed activity, even though they are only present in very
low concentrations (6 equiv per ligand molecule, giving 1.5 mol
mercury led to a gradual decrease of activity. If mercury inhibits
the activity, it is concluded that either ligandless Pd(0) species
are the true active species or catalysis occurs via a cycle with
a Pd(0) intermediate. The latter is most likely the case for the
present system. For comparison, we tested the effect of adding
mercury to a catalytic reaction employing the benchmark catalyst
%
of tetraalkyl ammonium groups under our standard condi-
2
1
tions). The use of the same concentration of a structurally
analogous salt (4) did not lead to any improvement of the
activity, in either the presence or absence of PPh
3
as ligand
Pd(PPh
and complete inhibition was observed (Figure S4). It is generally
accepted that Pd(PPh in the absence of any stabilizer does
3 4
) under identical conditions. In this case, an immediate
(
Figure 3). Furthermore, using the phosphine oxide of ligand 1
gave very low conversions and led to Pd-black formation,
indicating that the palladium in solution is stabilized by the
phosphine function and not by the ammonium groups.
3 4
)
not form Pd nanoparticles in solution. It thus seems that
inhibition by Hg might not be a reliable indication for catalysis
by Pd nanoparticles for Pd-phosphine systems.
Stabilization of palladium nanoparticles, leading to catalyti-
cally active systems in C-C cross-coupling reactions, can also
be achieved by other means, such as immobilization on a solid
22
support or by in situ generation in poly(ethylene glycol) (PEG-
(
(
21) Phan, N. T. S.; Van Der Sluys, M.; Jones, C. W. AdV. Synth. Catal.
2006, 348, 609–679.
2
3
4
00). Encapsulation or stabilization of Pd nanoparticles by
22) (a) Choudary, B. M.; Madhi, S.; Chowdari, N. S.; Kantam, M. L.;
Sreedhar, B. J. Am. Chem. Soc. 2002, 124, 14127–14136. (b) Gallon,
B. J.; Kaner, R. B.; Diaconescu, P. L. Angew. Chem., Int. Ed. 2007,
46, 7251–7254.
(
(
18) Widegren, J. A.; Finke, R. G. J. Mol. Catal. A: Chem. 2003, 198,
17–341.
3
19) (a) Badone, D.; Baroni, M.; Cardamone, R.; Ielmini, A.; Guzzi, U. J.
Org. Chem. 1997, 62, 7170–7173. (b) Reetz, M. T.; De Vries, J. G.
Chem. Commun. 2004, 1559–1563. (c) Arvela, R. K.; Leadbeater,
N. E.; Sangi, M. S.; Williams, V. A.; Granados, P.; Singer, R. D. J.
Org. Chem. 2005, 70, 161–168. (d) Astruc, D.; Lu, F.; Aranzaes, J. R.
Angew. Chem., Int. Ed. 2005, 44, 7852–7872. Lys e´ n, M.; K o¨ hler, K.
Synthesis 2006, 692–698. Liu, W.; Xie, Y.; Liang, Y.; Li, J. Synthesis
(23) Han, W.; Liu, C.; Jin, Z. AdV. Synth. Catal. 2008, 350, 501–508.
(24) (a) Niu, Y.; Crooks, R. M. C. R. Chimie 2003, 6, 1049–1059. (b)
Garcia-Martinez, J. C.; Lezutekong, R.; Crooks, R. M. J. Am. Chem.
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2
006, 860–864. (e) Wu, W.; Chen, S.; Tsai, F. Tetrahedron Lett. 2006,
4
7, 9267–9270. (f) Astruc, D. Inorg. Chem. 2007, 46, 1884–1894.
(25) Wu, L.; Li, Z.; Zhang, F.; He, Y.; Fan, Q. AdV. Synth. Catal. 2008,
350, 846–862.
(g) K o¨ hler, K.; Kleist, W.; Pr o¨ ckl, S. S. Inorg. Chem. 2007, 46, 1876–
1
883.
(26) Given the specific synthesis procedure of the nanoparticles, which is
entirely different from our reaction conditions, and the difference in
molecular architecture among 1-3 and the dendrons used in that report,
it is unlikely that such Pd nanoclusters are formed in our case.
Furthermore, the phosphine oxide dendron-stabilized Pd nanoclusters
were reported to be black powders, whereas our reaction mixtures
are clear yellow solutions, which is a characteristic color of homo-
geneous Pd-P complexes.
(
20) It is worth noting that even in cases where Pd nanoclusters are believed
to be responsible for the catalytic activity in Suzuki-Miyaura and
Heck reactions, the active species are actually Pd(0) atoms that have
leached from these nanoclusters or ArPd(II)X complexes that have
leached after undergoing oxidative addition at the surface of the
nanoclusters: (a) Thathagar, M. B.; Ten Elshof, J. E.; Rothenberg, G.
Angew. Chem. 2006, 45, 2886–2890. (b) De Vries, J. G. Dalton Trans.
2
006, 421–429. (c) Gaikwad, A. V.; Holuigue, A.; Thathagar, M. B.;
Ten Elshof, J. E.; Rothenberg, G. Chem.sEur. J. 2007, 13, 6908–
913.
(27) Amatore, C.; Jutand, A. Acc. Chem. Res. 2000, 33, 314–321.
(28) (a) Saito, S.; Sakai, M.; Miyaura, N. Tetrahedron Lett. 1996, 37, 2993–
2996. (b) Shen, W. Tetrahedron Lett. 1997, 38, 5575–5578.
6
J. AM. CHEM. SOC. 9 VOL. 131, NO. 32, 2009 11413

A R T I C L E S
Snelders et al.
Figure 6. Examples of triarylphosphine ligands that have shown appreciable activity in Suzuki-Miyaura couplings of aryl chloride substrates.
4
0
40a
Finally, the presence of halide ions in solution can have
profound effects on the structure of several species that are
involved in the catalytic cycle, thereby influencing the observed
ligands such as 5,
bis(3-chlorophenyl)phenylphosphine
4
1
42
(6), and bowl-shaped phosphine ligands such as 7 (Figure
6). For these systems, the activity observed is ascribed to
facilitated dissociation of these ligands from Pd, generating the
coordinatively unsaturated and catalytically active species. In
the case of 6, this effect was tentatively ascribed to the increased
steric bulk and decreased donating ability of the ligand. In the
2
7
catalytic rate. However, as halide ions, originating from the
aryl halide substrate, are naturally released into solution in high
concentration as the reaction progresses, as a consequence of
3
5
the transmetalation step in the Suzuki-Miyaura reaction, it
is unlikely that the low added concentration of bromide ions
originating from ligands 1-3 should have a significant effect.
Indeed, no effect was observed when ammonium bromide salt
(
(
29) Tolman, C. A. Chem. ReV. 1977, 77, 313–348.
30) (a) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 1998, 37, 3387–
3
388. (b) Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000,
4
was added to a mixture employing PPh
.2. Ligand Structure of Dendriphos in Relation to Activ-
ity in Coupling Reactions of Aryl Chlorides. Conventional
catalysts such as Pd(PPh and Pd(OAc) + 2-4 equiv of PPh
3
as ligand (Figure 3).
122, 4020–4028. (c) Kirchhoff, J. H.; Netherton, M. R.; Hills, I. D.;
Fu, G. C. J. Am. Chem. Soc. 2002, 124, 13662–13663. (d) Kirchhoff,
J. H.; Dai, C.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 1945–
3
1
947. (e) Kudo, N.; Perseghini, M.; Fu, G. C. Angew. Chem., Int. Ed.
)
3 4
2
3
2006, 45, 1282–1284. (f) Fu, G. C. Acc. Chem. Res. 2008, 41, 1555–
1564.
are very effective in the coupling of aryl bromides and iodides,
but their activities in the coupling reaction of aryl chlorides are
low and they require Pd loadings as high as 3-5 mol %, to
(
31) (a) Zapf, A.; Ehrentraut, A.; Beller, M. Angew. Chem., Int. Ed. 2000,
3
9, 4153–4155. (b) Zapf, A.; Jackstell, R.; Rataboul, F.; Riermeier,
T.; Monsees, A.; Fuhrmann, C.; Shaikh, N.; Dingerdissen, U.; Beller,
M. Chem. Commun. 2004, 38–39. (c) Tewari, A.; Hein, M.; Zapf, A.;
Beller, M. Synthesis 2004, 935–941.
2
8
give moderate yields at best. The most efficient ligands for
the Suzuki-Miyaura reaction, in particular for reactions using
1
2
(32) (a) Old, D. W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1998,
aryl chlorides, are strongly σ-donating phosphines with large
1
20, 9722–9723. (b) Wolfe, J. P.; Singer, R. A.; Yang, B. H.;
2
9
cone angles, such as the trialkylphosphines employed by Fu
Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 9550–9561. (c) Walker,
S. D.; Barder, T. E.; Martinelli, J. R.; Buchwald, S. L. Angew. Chem.,
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Martinelli, J. R.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 4685–
3
0
31
et al. and Beller et al. and the o-(dialkylphosphino)biphenyl-
3
2
based ligands developed by Buchwald et al. A second class
of highly effective ligands are the N-heterocyclic carbenes
developed by Nolan et al. and Organ et al. These systems
can achieve couplings of challenging aryl chlorides using low
Pd loadings at room temperature.
4
696. (e) Billingsley, K. L.; Anderson, K. W.; Buchwald, S. L. Angew.
3
3
34
Chem., Int. Ed. 2006, 45, 3484–3488. (f) Martin, R.; Buchwald, S. L.
Acc. Chem. Res. 2008, 41, 1461–1473.
(
(
33) (a) Grasa, G. A.; Viciu, M. S.; Huang, J.; Zhang, C.; Trudell, M. L.;
Nolan, S. P. Organometallics 2002, 21, 2866–2873. (b) Navarro, O.;
Kelly, R. A., III; Nolan, S. P. J. Am. Chem. Soc. 2003, 125, 16194–
The first step in the catalytic cycle of the Suzuki-Miyaura
reaction is oxidative addition of ArX (X ) I, Br, or Cl) to
1
6195. (c) Marion, N.; Navarro, O.; Mei, L.; Stevens, E. D.; Scott,
N. M.; Nolan, S. P. J. Am. Chem. Soc. 2006, 128, 4101–4111. (d)
Navarro, O.; Marion, N.; Mei, J.; Nolan, S. P. Chem.sEur. J. 2006,
12, 5142–5148. (e) Marion, N.; Nolan, S. P. Acc. Chem. Res. 2008,
41, 1440–1449.
Pd(0)L
ArPd(II)XL
n
(L ) phosphine ligand; n ) 1 or 2), forming
35
n
(Figure 7). Theoretical studies have shown that,
in the case of aryl bromides and aryl chlorides, oxidative
addition to Pd(0)L is the energetically preferred pathway, while
34) (a) Hadei, N.; Kantchev, E. A. B.; O’Brien, C. J.; Organ, M. G. Org.
Lett. 2005, 7, 1991–1994. (b) O’Brien, C. J.; Kantchev, E. A. B.;
Valente, C.; Hadei, N.; Chass, G. A.; Lough, A.; Hopkinson, A. C.;
Organ, M. G. Chem.sEur. J. 2006, 12, 4743–4748. (c) Kantchev,
E. A. B.; O’Brien, C. J.; Organ, M. G. Aldrichimica Acta 2006, 39,
36
2
aryl iodides react with Pd(0)L . This finding is consistent with
3
7
experimental observations. In the case of aryl chlorides, the
oxidative addition can be problematic due to the strength of
the Ar-Cl bond and is considered to be the overall rate-
determining step in the catalytic cycle. The ability of a system
to stabilize Pd(0)L species, which is largely dependent on the
9
7–111. (d) Kantchev, E. A. B.; O’Brien, C. J.; Organ, M. G. Angew.
Chem., Int. Ed. 2007, 46, 2768–2813.
(35) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457–2483.
(
36) (a) Goossen, L. J.; Koley, D.; Hermann, H. L.; Thiel, W. Organo-
metallics 2005, 24, 2398–2410. (b) Ahlquist, M.; Norrby, P. O.
Organometallics 2007, 26, 550–553. (c) Lam, K. C.; Marder, T. B.;
Lin, Z. Y. Organometallics 2007, 26, 758–760. (d) Li, Z.; Fu, Y.;
Guo, Q.; Liu, L. Organometallics 2008, 27, 4043–4049.
3
8
steric properties of the ligand, thus plays a great role in
determining its efficiency in the Suzuki-Miyaura reaction,
36d,39
especially with aryl chlorides.
Dendriphos ligands are one
(
37) (a) Amatore, C.; Jutand, A. J. Organomet. Chem. 1999, 576, 254–
of the few examples of triarylphosphines that exhibit consider-
able activity in the coupling of aryl chlorides. Other cases
reported until now include ferrocene-containing triarylphosphine
2
78. (b) Barrios-Landeros, F.; Hartwig, J. F. J. Am. Chem. Soc. 2005,
27, 6944–6945. (c) Barrios-Landeros, F.; Carrow, B. P.; Hartwig,
1
J. F. J. Am. Chem. Soc. 2009, 131, 8141–8154.
1
1414 J. AM. CHEM. SOC. 9 VOL. 131, NO. 32, 2009

Dendriphos Ligands in Suzuki-Miyaura Cross-Coupling
A R T I C L E S
case of 7, the effect was ascribed to the specific bowl-shaped
geometry of the ligand. The activity that we observed for the
well-known bulky ligand P(o-tolyl) (Table 6) can be ascribed
3
to a similar effect, i.e., to the presence of the ortho-substituents
in the ligand.
Recently, triarylphosphines substituted with dendritic tetra-
6h
ethylene glycol moieties (8) were reported. Their high activity
in the Suzuki-Miyaura coupling of aryl chloride substrates was
ascribed to their large size, which excludes other large phos-
phines from the coordination sphere of the catalytic center. In
two further examples, i.e., 2-(2′,4′,6′,-triisopropylbiphenyl)-
32d
diphenylphosphine (9) and (2,3,4,5-tetraphenylphenyl)diphe-
4
3
nylphosphine (10), transient coordination of the biphenyl
1
2
moiety to Pd (with either an η or η hapticity) contributes to
the stability of the active species Pd(0)L.
These examples show that the use of a strongly σ-donating
ligand is not an absolute prerequisite for coupling of aryl
chlorides, provided that the ligand employed has a means of
stabilizing the coordinatively unsaturated and catalytically active
monophosphine palladium (Pd(0)L) species. In the case of
Dendriphos ligands 1-3, we believe that a great repulsion exists
between neighboring molecules of the dendritic hexacationic
ligands, especially when simultaneously acting as monodentate
ligand to the same metal center. The repulsion is proposed to
have a steric component due to the large size of the dendritic
ligands, as well as a Coulombic component, due to the presence
of six cationic charges in the ligand structure. Accordingly,
this interligand repulsion is expected to facilitate dissociation
of these ligands from the Pd center, allowing in situ formation
of coordinatively highly unsaturated and catalytically active
Pd(0)L species.
35
Figure 7. Mechanism for the Suzuki-Miyaura cross-coupling reaction.
chlorobenzene (Figure S2a-d). These observations indicate that
the oxidative addition is the rate-determining step, which is
corroborated by the much lower observed activity for methyl
-chlorobenzoate than for the electronically more strongly
activated 4-nitrochlorobenzene (Figure S1a,b). The kinetic
profile observed for the coupling of 4-nitrochlorobenzene (Figure
a) indicates that a short induction period exists. In this induction
period, most likely the active catalyst is formed from
Pd (dba) ·CHCl and 1. It is known that dba ligands have a
high affinity for Pd(0)-phosphine complexes and in some cases
do not readily dissociate from species of the type Pd(0)-
The data presented in Figure 5a suggest that this
process takes 5-10 min for this particular case. After this
induction period, the equilibrium between Pd(0)L + L and
2
Pd(0)L becomes operative. The decrease in observed reaction
rate upon increasing the L:Pd ratio (Figure S2e) can then be
explained by a shift of the equilibrium toward the inactive
4
4
4
5
2
3
3
3
.3. A Positive Dendritic Kinetic Effect by the Use of
Dendriphos Ligands 1-3. In the coupling reactions of aryl
halides with phenylboronic acid catalyzed by the combination
3
7a
(
dba)L
n
.
of Pd
2
(dba)
3
·CHCl with 1-3, a positive dendritic kinetic effect
3
was observed for aryl chlorides, while no significant dendritic
effect was observed for aryl bromides (Figures 5 and S1). The
combination of 1-3 with a Pd(0) source presumably leads to
2
Pd(0)L , which is in equilibrium with Pd(0)L and noncoordi-
nated L (Figure 7). With increasing generations, this equilibrium
is shifted to the side of Pd(0)L + L due to an increase in the
steric interligand repulsion, leading to a higher concentration
of Pd(0)L, the active species in the oxidative addition step. Our
kinetic investigations using ligand 1 showed a strong positive
influence of the concentration of the aryl halide, but no influence
of the activated boronic acid when the aryl halide is 4-nitro-
2
species Pd(0)L .
When the substrate is 4-bromotoluene, kinetic investigations
showed positive influences for both the aryl halide and the
activated boronic acid (Figure S3a-d), indicating that not the
oxidative addition but most likely the transmetalation is rate-
determining. This is corroborated by the observation of com-
parable reaction rates for the couplings of the activated
4-nitrobromobenzene and the deactivated 4-bromoanisole (Fig-
ure S1c,d), which should give very different rates in the
oxidative addition step. For all aryl bromides tested, all three
ligand generations gave similar rates; no dendritic effect was
observed (Figure 5b and S1c,d). A change in the rate-limiting
step does not change the position of the dissociation equilibrium
(
38) (a) Hartwig, J. F.; Paul, F. J. Am. Chem. Soc. 1995, 117, 5373–5374.
b) Galardon, E.; Ramdeehul, S.; Brown, J. M.; Cowley, A.; Hii, K. K.;
(
Jutand, A. Angew. Chem., Int. Ed. 2002, 41, 1760–1763.
(
(
39) Christmann, U.; Vilar, R. Angew. Chem., Int. Ed. 2005, 44, 366–374.
40) (a) Liu, S.; Choi, M. J.; Fu, G. C. Chem. Commun. 2001, 2408–2409.
(
6
b) Pickett, T. E.; Roca, F. X.; Richards, C. J. J. Org. Chem. 2003,
8, 2592–2599. (c) Hierso, J.; Fihri, A.; Amardeil, R.; Meunier, P.
Organometallics 2003, 22, 4490–4499. (d) Kwong, F. Y.; Chan, K. S.;
Yeung, C. H.; Chan, A. S. C. Chem. Commun. 2004, 2336–2337. (e)
Hierso, J.; Fihri, A.; Amardeil, R.; Meunier, P. Org. Lett. 2004, 6,
between Pd(0)L and Pd(0)L + L, which will still lie more to
2
the side of Pd(0)L + L with increasing ligand generations.
However, the shift in the rate-determining step away from the
oxidative addition explains why differences in the position of
this equilibrium are not reflected in the observed overall coupling
rate of aryl bromides. The decrease in rate observed at higher
L:Pd ratios (Figure S3e) can be rationalized by a transformation
of the catalyst resting state into a higher ligated form. In the
Suzuki-Miyaura reaction, the transmetalation usually occurs
3
473–3476.
(
41) Pramick, M. R.; Rosemeier, S. M.; Beranek, M. T.; Nickse, S. B.;
Stone, J. J.; Stockland, R. A., Jr.; Baldwin, S. M.; Kastner, M. E.
Organometallics 2003, 22, 523–528.
(
(
(
42) Ohta, H.; Tokunaga, M.; Obora, Y.; Iwai, T.; Iwasawa, T; Fujihara,
T.; Tsuji, Y. Org. Lett. 2007, 9, 89–92.
43) Iwasawa, T.; Komano, T.; Tajima, A.; Tokunaga, M.; Obora, Y.;
Fujihara, T.; Tsuji, Y. Organometallics 2006, 25, 4665–4669.
44) Snelders, D. J. M.; Van der Burg, C.; Lutz, M.; Spek, A. L.; Van
Koten, G.; Klein Gebbink, R. J. M. Manuscript in preparation.
J. AM. CHEM. SOC. 9 VOL. 131, NO. 32, 2009 11415

A R T I C L E S
Snelders et al.
45
via a three-coordinate Pd(II) complex ArPd(II)XL (Figure 7).
of coordinatively unsaturated and catalytically active Pd(0)L
This complex is considered to be predominantly present in its
dimeric, bromide-bridged form. It is likely that, at higher ligand
concentrations, this species, being the resting state of the catalyst,
(L ) 1, 2, 3) species with an increase in ligand generation.
Our results indicate that, in principle, a strongly σ-donating
ligand is not required for the activation of aryl chlorides,
provided that the ligand has a means of generating and, to a
certain extent, of stabilizing a Pd(0)L species. Previously
reported ligand systems have accomplished this mainly by steric
effects. The observed activity of even a relatively small ligand
as G0-Dendriphos (1) indicates that it has an effect on the
catalytic activity similar to that of a very bulky ligand. We
propose that the Coulombic interligand repulsion originating
from the six positive charges in the ligand structure plays a
role in the bulky behavior observed for this ligand system,
therefore being in part responsible for its high catalytic activity.
would transform into ArPd(II)XL (L ) 1), which has to
2
undergo dissociation of 1 before transmetalation can occur which
leads to a lower observed rate. In this case, the absence of an
induction period suggests that catalyst formation does not
significantly affect the rate in the initial stages of the reaction.
4
. Conclusion
The combination of Pd
2
(dba)
3
3
·CHCl and Dendriphos ligands
leads to a highly active catalytic system in the Suzuki-Miyaura
cross-coupling reaction. Particularly for coupling reactions of
aryl chlorides, the observed activity is uncommon for systems
employing triarylphosphine-based ligands. Importantly, the
catalytic activity observed by the use of 1 can be ascribed to a
homogeneous Pd-phosphine complex, rather than Pd nano-
clusters. In the coupling reactions of activated aryl chlorides,
an acceleration was observed by the use of ligands of higher
generation, which could be explained by a facilitated formation
Acknowledgment. This research was funded through Utrecht
University, The Netherlands. The authors thank Dr. Jim Brandts
and Dr. Johannes van Donkervoort at BASF Nederland N. V., De
Meern for many valuable discussions and for financial support.
Supporting Information Available: Experimental details and
additional kinetic plots. This material is available free of charge
via the Internet at http://pubs.acs.org.
(
45) Espinet, P.; Echavarren, A. M. Angew. Chem., Int. Ed. 2004, 43, 4704–
4
734.
JA904042H
1
1416 J. AM. CHEM. SOC. 9 VOL. 131, NO. 32, 2009