Suzuki coupling reactions in neat water as the solvent: Where in the biphasic reaction mixture do the catalytic reaction steps occur?

Article abstract of DOI:10.1002/chem.201201266

Many reports on water-compatible palladium catalysts have appeared in the recent literature. For hydrophobic substrates, mixtures with pure water are biphasic, and it is widely not regarded that the elusive locality of the catalytic process (in water, the

Full text of DOI:10.1002/chem.201201266

FULL PAPER
DOI: 10.1002/chem.201201266
Suzuki Coupling Reactions in Neat Water as the Solvent: Where in the
Biphasic Reaction Mixture Do the Catalytic Reaction Steps Occur?
Christoph Rçhlich, Andreas S. Wirth, and Klaus Kçhler*[a]
Abstract: Many reports on water-com-
patible palladium catalysts have ap-
peared in the recent literature. For hy-
drophobic substrates, mixtures with
pure water are biphasic, and it is
widely not regarded that the elusive lo-
cality of the catalytic process (in water,
the organic layer, or at the phase boun-
dary) has an important impact on the
mechanism and efficiency of the reac-
tion. In the present work, for the first
time systematic variation of reaction
parameters has been performed for
Suzuki coupling experiments with
chloro- and bromoarenes in pure
water. The investigations are not only
aimed at the factors influencing the
catalytic activity, but also at the effects
that may occur particularly in water/or-
ganic biphasic media, and on the ques-
tion as to in which of the two liquid
phases the reaction takes place. These
investigations have revealed that dilu-
tion of the base (in the aqueous layer)
and the Pd species (in the organic
layer) are detrimental to the reaction,
and that phase-transfer processes play
a major role in the overall mechanism.
A series of experiments with variation
of parameters like precatalyst hydro-
philicity, organic and water phase
volume, additives, stirring rate, base
concentration, and so forth, indicate
that for the systems under study the re-
action occurs in the organic layer. The
water phase needs to be present to dis-
solve and provide polar reactants, and
re-absorb side products. The results en-
courage to pay more regard to the
question of phase locality of coupling
reactions in water in general.
Keywords: biphasic catalysis · C–C
coupling · palladium · Suzuki reac-
tion · water
Introduction
effect has led to the new field termed “on-water chemis-
try”.[1] Aside from the ground-state destabilization of hydro-
phobic reactants in water, the accelerating effect has been
explained by the large cohesive energy density of water re-
sulting in a compression of organic reactants.[2] This hypoth-
esis has been replaced recently by the explanation that free
While for a long time water has mostly been banished from
organic synthetic protocols, it has recently become popular
again as a solvent for synthetic reactions in light of the
search for “green” chemical processes. Water is a very
cheap and the most environmentally benign solvent, as it is
abundant in nature, and nonhazardous (inflammable, non-
toxic). It also possesses a strong solvation ability especially
for polar and ionic substances. In turn, this also implies that
nonpolar substances, which represent the major part of reac-
tants and products for reactions in organic synthesis, are not
miscible with water and will cluster or separate to build a
second liquid or solid phase. Hydrophobic reaction products
can, thus, be easily separated by filtration or phase separa-
tion, while polar side products, especially saline products,
are carried away with the water phase.
ꢀ
“dangling” O H bonds at the phase boundary are able to
stabilize the transition state of some reactions, leading to in-
creased reaction rate and even altered and increased selec-
tivity.[3]
Pd-catalyzed C–C cross-coupling reactions, like, for exam-
ple, the Suzuki–Miyaura coupling of aryl halides and orga-
noboronates, represent a modern means for the versatile re-
gioselective and stereospecific synthesis of larger and com-
plex molecules from prebuilt and prefunctionalized precur-
sors. Since their discovery in the 1970s, these reactions have
found manifold applications in organic synthesis and fine
chemical production, and their development was recently
awarded with the Nobel prize. As C–C coupling reactions
include the presence of organometallic species (organopalla-
dium intermediates), exclusion of water from these reactions
seems mandatory. However, it is found that water behaves
as a poor nucleophile in C–C coupling reactions,[4] making it
suitable as a solvent or cosolvent. In fact, especially the
Suzuki–Miyaura reaction has for a long time been per-
formed under aqueous conditions or in water alone,[5,6] and
was found to benefit from the presence of water.[7]
In recent years, a surprising accelerating effect has also
been observed when reactions between water-immiscible re-
actants were performed under stirring with water. This
[a] Dr. C. Rçhlich, Dipl.-Chem. A. S. Wirth, Prof. Dr. K. Kçhler
Department of Chemistry, Catalysis Research Center
Technische Universitꢀt Mꢁnchen
Lichtenbergstr. 4, 85747 Garching (Germany)
Fax : (+49)89-289-13183
E-mail: klaus.koehler@tum.de
When nonpolar hydrophobic reactants are applied, Suzuki
reactions in water actually occur in a biphasic medium
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201201266.
Chem. Eur. J. 2012, 18, 15485 – 15494
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15485

(water + organic reactants and products). Thus, water may
not actually be a real “solvent” for this reaction, and the re-
action does not take place “in” but rather on water. This is
widely unregarded in publications about Suzuki coupling in
water or water-containing solvent mixtures; it seems to be
assumed that at least some small part of the reactant is
somehow dissolved in water and will react. In this work,
such reactions will nevertheless be regarded as reactions “in
water” or “with water as the only solvent”, to avoid confu-
sion among many different terms.
The biphasic nature of such Suzuki reaction mixtures
raises the question as to whether the actual reaction mainly
takes place in the water phase, the organic phase, or at the
phase boundary. Qualitative arguments in favor and against
any of these cases can be thought of (Table 1). The answer
The locality of the reaction also has a strong impact on
possible ways to develop and optimize catalytic systems and
reaction conditions for higher activity and efficiency in reac-
tions in pure water. All of these considerations may also
apply to aqueous solvent mixtures (water/alcohols), which
have also been widely applied for the Suzuki reaction, and
also give biphasic reaction mixtures. Nevertheless, the focus
of this work is on the use of only water.
Although there is a vast amount of available publications
on the Suzuki reaction in (pure) water, the biphasic nature
of the reaction mixture and the question of the reactionꢃs lo-
cality are widely unregarded, and a clear answer is still miss-
ing. Mostly, Pd complexes as the homogeneous catalyst have
been tailored to be water-compatible (i.e., soluble) for
higher activity.[6,8–10] Some Pd complexes have been found to
decompose under the reaction conditions, which
has been observed also for very stable precur-
Table 1. Factors affecting the locality of the catalytic process of Suzuki coupling in bi-
phasic reaction mixtures (water/organic reactants).
sors,[11,12] thereby generating the actual catalytically
active free Pd0 species, which is likely to be trans-
ferred into the organic layer for the major part. In
other words, a water-soluble precatalyst does not
necessarily lead to the active species also being dis-
solved in the water phase. This is practically never
considered in the mentioned cases. Because of bind-
ing Pd0 very strongly and therefore being part of
the active species, P ligands can be regarded as a
typical exception for this phenomenon (under mild
reaction conditions). In some work, low reaction
rates have, however, been observed for hydropho-
bic reactants in comparison to comparable hydro-
philic substrates.[13] To overcome the miscibility
“problem” detergents and co-solvents have been
Phase
water
Present species
Favorable
Unfavorable
base, phenyl
boronate, salts,
ionic Pd species
presence of boronate,
stabilization of ionic
species including saline
side products
low/no availability
of reactant,
decomposition
reactions
organic
reactant, product,
neutral and ionic
Pd species, free
excess of reactant,
no/weak solvation
of ionic species
“clustering” of
ionic species
phenyl boronic acid
phase
boundary
all
availability of
all components
diffusion limitations,
constricted mobility
as to where the reaction takes place has important conse-
quences. If the reaction takes place in the organic layer, the
reactant is the “solvent”, which influences all the manifold
and intricate processes occurring during C–C coupling catal-
ysis (side reactions, solvation of intermediates, deactivation
of Pd through agglomeration, and many more). The delicate
interplay of these processes may significantly be changed
when going from one substrate to another chemically differ-
ent substance. Moreover, the reactant “solvent” is consumed
and replaced by the (also chemically different) product as
“solvent”, having similar consequences.
On the other hand, if the reaction takes place in water,
the aqueous phase can be reused after removing the hydro-
phobic products and adding new reagents, at least until the
cumulated amount of saline side products in the water
phase stalls the catalytic activity. The products would then
also contain no or only very low amounts of Pd, making fur-
ther time- and material-consuming purification processes
unnecessary, such as, for example, for pharmaceutical prod-
ucts, the heavy metal contents of which must meet very low
law-enforced restrictions.[6] If the reaction takes place in
water, however, this also implies that the reaction rate is
limited by the low concentration of the hydrophobic reac-
tant in the aqueous layer, which has been observed in some
cases in the literature (see below).
used,[14] as well as Pd complexes or particles in conjunction
with amphiphilic, micellar polymers.[15] On the other hand,
occasionally fast reactions of hydrophobic substrates have
been observed with Pd on hydrophobic supports,[16] namely
active carbon.[17,18] Overall however, there seems to be no
clear trend as to whether hydrophilicity or lipophilicity of a
reactant, catalyst, or support is beneficial; it may depend on
the respective example.
As stated, the question as to whether the catalytic cycle
occurs in the aqueous or the organic layer is of fundamental
importance, but is widely unregarded. We have conducted
and present here experiments on the Suzuki coupling of hy-
drophobic bromo- and chloroarenes in water, by using dif-
ferent catalyst precursors, to achieve insight into the locality
of the catalytic process, and get useful information on a pos-
sible optimization of the reaction conditions. This is the first
time such systematic investigations into the details of the
phase distribution of the reactants, and their influence on
the reaction and its mechanism, have been conducted. The
experiments will be interpreted in light of the question in
which of the two liquid phases the reaction occurs. In the
present work, we hope to bring this question into the minds
of researchers working with different aspects (synthesis, cat-
alysis design, reaction mechanisms, kinetics) in this field.
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Suzuki Coupling Reactions in Neat Water as the Solvent
FULL PAPER
Results and Discussion
The experiment also demonstrates that, unsurprisingly,
water-soluble PdII compounds were more easily reduced
than hydrophobic ones. In the experiments, K2PdCl4 was re-
duced quantitatively at room temperature shortly after the
Preliminary experiments:
Distribution of reactants, catalyst, and products into the
liquid phases: In contrast to typical mechanistic investiga-
tions in the literature, it has been conclusively decided to
apply demanding substrates, such as aryl chlorides and deac-
tivated aryl bromides for the present investigations. This
should avoid misinterpretations due to the action of highly
active traces of Pd, as observed previously for aryl iodides
and activated aryl bromides.[11b] Only if it is believed to be
particularly useful (in order to verify that even activated
aryl bromides do not react under the specific conditions) ac-
tivated aryl bromides have been applied. Though a (very
small) partial solubility in the aqueous layer (intricately in-
fluenced by temperature and dissolved ionic species) cannot
be totally excluded, all introduced substrates are clearly hy-
drophobic and therefore always resulted in complete and
fast phase separation.
addition of the boronate, whereas PdACTHNGUTRENU(NG OAc)2 required heat-
ing and vigorous shaking to observe the formation of Pd
black, and even then a residual yellow color of the organic
layer indicated the presence of unreduced PdII species. Fast
reduction of PdII also implies fast agglomeration and forma-
tion of Pd black, that is, deactivation of the catalytic species.
In turn, the phase preference of the initial PdII compound
should have an influence on the catalytic result. Thus, a vari-
ety of Pd compounds, soluble either in water or the organic
layer, was applied as a precatalyst for the Suzuki reaction in
water.
Effect of precatalyst hydrophilicity: Experiments were per-
formed to investigate the influence of a Pd (pre)catalystꢃs
phase preference (i.e., solubility in water or organic com-
pounds) on the catalytic activity in the Suzuki reaction in
water. A variety of hydrophilic and lipophilic Pd compounds
were tested, including PdIIphthalocyanine (PdPc), which had
previously shown promising results in the (one-phase)
Suzuki reaction.[12] A chelate complex of 8-hydroxyquino-
Systematic variation of reaction parameters has been per-
formed for the Suzuki reaction of aryl bromides and chlo-
ACHTUNGTRENNUNG
rapidly dissolved in water under stirring, and fast and quan-
titative formation of the boronate species Na[B(Ph)(OH)3]
occurs. This species reduces free PdII to Pd0.[19] The boronate
is hydrophilic, so its concentration is high in the aqueous
layer and low in the organic layer. Therefore the reduction
of Pd occurs very fast when Pd resides in the aqueous layer,
too, or is transferred to it (see below). This can be observed
simply by adding a hydrophilic and a hydrophobic PdII com-
line-5-sulfonic acid with Pd (K2[PdACTHNGUTERNNU(G hqs)2]), the application
of which as a catalyst for Suzuki coupling reactions of bro-
moarenes in water was recently published,[10] was also in-
cluded in this study as a water-soluble counterpart to PdPc.
The precatalysts were applied in the Suzuki coupling of
4-bromotoluene or 4-chloroacetophenone in water at 658C.
As the results in Table 2 show, the water-soluble precatalysts
generally led to low yields. Better yields were obtained with
pound (e.g., PdACHTUNGTRENNUNG(OAc)2 and K2PdCl4) to a mixture
of water and xylene or bromobenzene, and adding
Na[B(Ph)(OH)3]. The formation of Pd black is ob-
served in the water layer of the solvent mixture in
these experiments. This does, however, not necessa-
rily imply that the Pd0 species remain constrained
to the water phase: if no specific ligands are applied
that stabilize Pd0 and are hydrophilic, Pd0, be it the
low-nuclear active species or Pd black, may actually
be “free to go wherever it wants”. This is even dem-
onstrated by the simple experiment discussed here,
in which the Pd black was highly capricious regard-
ing its phase preference, and ended up residing in
the aqueous layer, the organic phase, or staying at
the phase boundary, unpredictably depending on
the concentrations of each component and on
whether heating was applied. Under the reaction
conditions, a preference for the organic phase
seems to prevail.[20] Considering that Pd (pre)cata-
lysts can also decompose under the reaction condi-
tions generating the catalytically active species,[11,12]
the concept of making Pd catalysts water-soluble to
increase their potential for coupling reactions in
water cannot be taken to be generally valid.
Table 2. Yields obtained in the Suzuki coupling of different substrates in water by
using precatalysts of different phase preferences.
Precatalyst
Phase
Yield
Yield
Yield
preference[a]
4-Me-biphenyl
4-Ac-biphenyl
4-Ac-biphenyl
with excess base
[%][d]
[%][b]
[%][c]
K2PdCl4
K2PdBr4
aq.
aq.
aq.
ins./org.
org.
org.
org.
org.
8
7
19
21
0
25
18
41
9
10
10
0
60
4
80
13
6
K2[Pd
PdCl2
N
14
11
13
58
73
26
Pd
[Pd
[PdCl
PdPc
ACHTUNGTRENNUNG
N
N
CHTUNGTRENNUNG
10
[a] aq.=aqueous phase, org.=organic phase, ins.=insoluble. [b] Reaction conditions:
4-bromotoluene (3 mmol), PhB(OH)2 (3.2 mmol), Na2CO3 (3.5 mmol), “Pd”
(0.1 mol%), water (3 mL), 658C, 5 h, air. [c] Reaction conditions: 4-chloroacetophe-
none (3 mmol), PhB(OH)2 (3.2 mmol), NaOH (4.5–4.8 mmol), TBAB (1 mmol), “Pd”
(0.1 mol%), water (4 mL), 658C, 5 h, air. [d] As in [c], with 9–10 mmol of NaOH.
acac=acetylacetonate.
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K. Kçhler et al.
lipophilic precatalysts, but some of the lipophilic precatalysts
also led to low yields (e.g., Pd(OAc)2, or [PdCl2A(PPh3)2] in
talyst.[9e] This ensured comparability of the obtained results
and enabled a discussion on the effect of phase preference
of the precatalyst on the reaction outcome.
G
CHTUNGTRENNUNG
the reaction with 4-chloroacetophenone). Thus, the activity
of a precatalyst does not correlate primarily to its solubility
or phase preference. This is especially demonstrated by the
results for the coupling of 4-chloroacetophenone, in which
the addition of tetra-n-butylammonium bromide (TBAB)
transforms any of the water-soluble precatalysts into lipo-
philic ones (mainly by forming the salt TBA2ACTHUNTRGNE[UGN PdBr4]), but
still low yields are observed for water-soluble and some lipo-
philic precatalysts.
The following aspects are considered to be determining
the activity of a specific precatalyst: Firstly, as mentioned,
water-soluble precatalysts are reduced faster than lipophilic
ones, and in turn are also deactivated faster. Secondly, com-
As can be seen, PdTPP was inactive as the precatalyst,
and even in the case of highly activated 4-nitrobromoben-
zene no product formation was observed (Table 3, entry 6).
Also, in other reactions only trace amounts or no products
were observed. In contrast, PdPc was active as a precatalyst,
giving the Suzuki coupling product in good to quantitative
yields under these reaction conditions. The yields obtained
with PdPc are almost identical to the literature yields de-
rived under the same reaction conditions with a water-
soluble PdII(tetraphenylporphyrin) (see Figure 1 for its
structure).
plexes of chelating ligands (K2[PdACHTNUTRGENN(UG hqs)2], [PdAHCUTTGNREN(NNGU acac)2], PdPc)
are reduced more slowly. Thirdly, the ligand (depending on
its binding strength, chelating or monodentate nature) deter-
mines the release of Pd and, in turn, the generation of
active Pd0 species. Thereby it also determines the rate of de-
activation of the active species.
In summary, the phase preference of a precatalyst is one,
but not the determining factor for its activity. The activity is
also determined by the complexꢃs ability for Pd release
under the respective conditions (temperature regime), the
stabilization of the active species, and the prevention of de-
activation.
Comparison of PdPc and PdTPP in the Suzuki coupling of
aryl bromides: Table 3 shows the reaction results obtained
Table 3. Catalytic results for the Suzuki coupling of aryl bromides with
PdPc and PdTPP in water.[a]
Figure 1. Proposed generation equlibria for free active Pd species in the
Suzuki coupling of aryl bromides in water with Pd porphyrins and PdPc.
Entry
R
Reaction PdTPP
PdPc
Lit.
time
[h]
Conversion Yield Conversion Yield yield
ArBr [%]
[%]
ArBr [%]
[%]
[%][9e]
It has been observed in earlier work[12] that PdPc irrever-
sibly releases Pd, which becomes the active species, whereas
PdTPP reversibly releases only very low amounts of Pd and,
therefore, does not generate enough active species in the
solution. This is again reflected by its inactivity as a precata-
lyst in the Suzuki reactions described here. In contrast, a
water-soluble porphyrin from the literature report had given
rise to almost identical activity in comparison to PdPc. It
cannot be presumed that the complex stability of a Pd por-
phyrin is significantly changed by peripheral substitution
with carboxylate groups, nor that water as a surrounding
medium leads to increased release of Pd from the porphyrin.
In the latter case, PdTPP should have also been a good pre-
catalyst for the Suzuki reaction in N-methyl pyrrolidone
(NMP)/water mixtures, which has not been observed.[21] In-
stead, the observations can be explained by assuming that
any Pd that is released into the water phase will irreversibly
cross the phase boundary (Figure 1) and reside in the organ-
1
2
3
4
5
6
H
4
4
4
2
1
1
15
30
0
8[b] 77
81[b] 83
Me
MeO
CN
Ac
<1
0
84
78
83
78
n.d.
80
1
1
95
95
99
0
0
0
0
99
100
99
100
n.d.
93
NO2
[a] Reaction conditions: aryl bromide (3 mmol), K2CO3 (6 mmol),
PhB(OH)2 (4.5 mmol), precatalyst (0.1 mol%), H2O (3 mL), 1008C, air.
[b] Listed yields may be higher due to oxidative coupling of PhB(OH)2.
n.d.=not determined
in the Suzuki coupling of different aryl bromides with
PhB(OH)2 in water as the solvent. PdPc and Pd-meso-tetra-
phenylprophyrin (PdTPP), both only soluble in the organic
reactant phase, have been applied as precatalysts. The reac-
tion conditions chosen were identical to a previous report in
the literature, in which a carboxylate-substituted water-solu-
ble PdIItetraphenylporphyrin had been applied as the preca-
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Suzuki Coupling Reactions in Neat Water as the Solvent
FULL PAPER
ic phase. In turn, the porphyrin in water is depleted from
Pd, and the organic phase is continuously enriched with Pd,
in a similar manner to when PdPc is used. Since the rate-de-
termining step of the catalytic process is considered to be
the phase transfer of the boronate and the transmetallation,
which are independent from the Pd species, identical yields
are then obtained under identical reaction conditions (see
the Mechanistic Proposal section for a more detailed discus-
sion).
Effect of stirring rate: To examine the influence of the phase
transport and the interphase surface in more detail, experi-
ments were performed by applying different stirring rates.
No effect on the yields (Table 4) was found. It could be con-
Figure 2. Effect of base amount and volume of the water phase on the
yield of the Suzuki reaction in water: 4-chloroacetophenone (3 mmol),
PhB(OH)2 (3.5 mmol), TBAB (1.5 mmol), PdPc (0.1 mol%), NaOH (as
specified), water (4 mL or as specified), 1008C, 2 h, air. Reaction time
was 1 h for experiments with 9 mmol of NaOH and the different water
volumes.[23]
Table 4. Yields obtained in the Suzuki coupling at different stirring
rates.[a]
Entry
Stirring rate
[rpm]
Yield
[%]
AHCTUNGTRENNUNG
1
2
3
500
1000
1500
40
36
36
of water was necessary for the reaction to occur, as in the
absence of water only small amounts of the product were
obtained (19% yield). It should be pointed out here that the
beneficial effect of an excess or high concentration of base
is not related to the formation of phenyl boronate. From the
pKa of phenyl boronic acid (8.86),[24] one can calculate that
in all the experiments in Figure 2, >97% of phenyl boronic
acid is present as (water-soluble) sodium phenyl boronate
Na[B(Ph)(OH)3].[25]
[a] Reaction conditions: 4-bromoanisole (30 mmol), PhB(OH)2
(32 mmol), K2[PdACHTUNGTRENNUNG(hqs)2] (0.1 mol%), Na2CO3 (35 mmol), water (30 mL),
808C, 3 h, air.
cluded that all phase transport (phenyl boronate, active Pd
species, saline products) is in equilibrium as long as some
stirring is applied, and therefore this is not limiting to the
reaction rate. In addition, a reaction at the phase boundary,
which should have been enhanced by stronger stirring,
seems unlikely.
The effect of an increasing volume of the water phase was
also investigated for three other reactions: the reaction of 4-
If not stirred, all of the reaction mixtures separate to give
two distinct layers, without perturbation through boiling or
convection. Reaction mixtures that were not stirred always
led to lowered yields, which indicates a diffusion limitation
of the reaction (see Table S1 in the Supporting Informa-
tion).
chloroacetophenone with [Pd
658C, and the reaction of 4-bromoanisole with [Pd
or K2[Pd(hqs)2] at 808C (Figure 3). As the results show, the
yield eventually decreased with an increasing amount of
water in any of the experiments, when the amount of base is
kept constant. This is again explicable by a dilution of the
base being detrimental to the yield, although a minimum
amount of water also appears to be necessary for thorough
solvation of the reactants.
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
Effect of the amount of base and water phase volume: The
results for the reactions with 4-chloroacetophenone in
Table 2 also demonstrate that, in most cases, higher yields
are obtained when an excess of base is applied. This is in
line with previous observations for Suzuki couplings in pure
water by using heterogeneous catalysts.[17,18,22] The positive
effect of an excess of base was specifically investigated for
the reaction with 4-chloroacetophenone by using PdPc as
the catalyst.
Test for on-water effects: Four reactions were also performed
with D2O instead of H2O. As Table 5 shows, in comparison,
similar or even clearly increased yields were obtained when
using D2O. This is an important result, as it reveals that the
reaction does not benefit from the “on-water” effect men-
Table 5. Comparison of the yields for reactions in H2O and D2O.[23]
As Figure 2 shows, an excess (2–3 equiv) of NaOH was re-
quired for a quantitative reaction. Longer reaction times
(4 h) did not lead to significantly higher yields, so the con-
centration of NaOH seems to be a limiting factor. Accord-
ingly, when the volume of water was increased (NaOH is di-
luted), the yield decreased when low amounts of base
(about 1.1 equiv) were used. With a threefold excess of
base, this effect was no longer observed. Also, some amount
Catalyst
Aryl halide
T
Reaction Yield
Yield
[8C] time [h]
in H2O in D2O
[%]
[%]
PdPc
4-chloroacetophenone 100 0.8
74
40
58
60
96
79
62
55
[Pd
[Pd
U
4-chloroacetophenone
4-bromoanisole
65
80
80
5
3
3
K2[PdACTHNUTRGNEUNG(hqs)2] 4-bromoanisole
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K. Kçhler et al.
Figure 4. Effect of the amount of TBAB on the Suzuki reaction in water:
4-chloroacetophenone (3.0 mmol), PhB(OH)2 (3.5 mmol), TBAB (as
specified), PdPc (0.1 mol%), NaOH (9 mmol), water (4 mL), 1008C, 2 h,
air.
Figure 3. Effect of the water phase volume on the yield in the Suzuki re-
&
action in water.
=4-Chloroacetophenone (3 mmol), PhB(OH)2
(3.2 mmol), NaOH (4.8 mmol), TBAB (1.0 mmol), [PdACTHUNRGTNEUNG(acac)2]
*
(0.1 mol%), water (as specified), 658C, 5 h, air. =4-Bromoanisole
(3 mmol), PhB(OH)2 (3.2 mmol), [PdACHTNUTRGNE(UNG acac)2] (0.1 mol%), Na2CO3
~
(3.5 mmol), water (as specified), 808C, 3 h, air.
=4-Bromoanisole
(3 mmol), PhB(OH)2 (3.2 mmol), K2[PdACHTNUGTRNE(UNG hqs)2] (0.1 mol%), Na2CO3
Other additives (PEG2000, LiBr, [18]crown-6) also led to
the reaction not occurring, as did the use of other bases
(K2CO3, KOH, NaOAc, Cs2CO3) when TBAB was not pres-
ent. The reaction was also performed with 2- and 4-chloro-
benzonitrile as substrates, for which KF was used as a base
instead of NaOH to avoid saponification of the nitrile
groups. Though they are activated chlorides, and good reac-
tion results had been observed with Pd/C under these condi-
tions,[17,18] chlorobenzonitriles gave only very low conver-
sions and yields with PdPc (not quantified), probably due to
the change of base.
From these observations (Table 6), it is clear that TBAB
is not solely a phase-transfer catalyst, although it may en-
hance phase transition processes during the reaction. It
rather serves both as a catalyst stabilizer by shielding Pd
nanoparticles from further agglomeration, thereby delaying
(3.5 mmol), water (as specified), 808C, 3 h, air.[23]
tioned earlier (see the Introduction). These effects are
always lower in D2O, which is a slightly better solvent for
hydrophobic reactants than H2O,[26] and therefore causes
less destabilization. Instead of lowered yields[1] or longer re-
action times[3] in D2O, the opposite trend was observed. This
could be explained by a lower or less efficient solvation and
stabilization of the phenyl boronate in D2O, making it more
reactive or more likely to cross the phase boundary into the
organic phase.
Effect of additives: The effect of typical additives on the
Suzuki reaction was tested in the coupling of 4-chloroaceto-
phenone by using PdPc, for which the addition of a mini-
mum amount of TBAB was found to be mandatory
(Figure 4). Generally, among the tetraalkylammonium salts,
TBAB leads to the best performances in C–C coupling reac-
tions,[27] and is considered to electrosterically stabilize palla-
dium nanoparticles against agglomeration, thereby prevent-
ing premature formation of Pd black and, hence, deactiva-
tion.[11b,27–30]
TBAB has also been discussed to enhance Pd leaching
from dissolved and supported nanoparticles, and to build
stable and highly active low-nuclear bromo complexes of
Pd.[30–34] Peculiarly for C–C coupling reactions with water or
in similar biphasic mixtures, TBAB has often been stated to
be needed as a phase-transfer catalyst.[35] It is, however, not
clear as to why a phase-transfer catalyst would be needed
for reactions with aryl chlorides, whereas aryl bromides
could be effectively converted in biphasic mixtures without
additive, as demonstrated in this work. Also, some examples
of TBAB-free Suzuki reactions of aryl chlorides in water
have been reported previously.[8,36]
Table 6. Effect of different additives on the Suzuki reaction with
4-chloroacetophenone in water.[a]
Entry NaOH Additive
[mmol]
Conversion Yield
G
[%]
[%]
1
2
3
4
5
6
7
9.0
9.15
9.0
9.2
9.3
9.4
9.12
7.95
–
TBAB
TBACl
TBAFꢄ3H2O
100
32
13
99
60
2
<1
0
<1
53
71
22
100
28
6
99
46
2
<1
0
<1
51
71
22
tetra-n-heptylammonium bromide
tetra-n-octylammonium bromide
tetraphenylphosphonium chloride
tetramethylammonium bromide
tetramethylammonium hydroxide
tetramethylammonium hydroxide
tetra-n-butylammonium hydroxide
tetra-n-butylammonium hydroxide
cetyltrimethylammonium bromide
8
9[b]
10
8.67
–
9.38
11[c]
12[d]
[a] Reaction conditions: 4-chloroacetophenone (3 mmol), PhB(OH)2
(3.5 mmol), additive (1.5 mmol), PdPc (0.1 mol%), water (4 mL), 1008C,
2 h, air. [b] 3 mmol of additive were used. [c] 3.5 mmol of additive were
used. [d] 1.0 mmol of additive was used.
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Chem. Eur. J. 2012, 18, 15485 – 15494

Suzuki Coupling Reactions in Neat Water as the Solvent
FULL PAPER
the catalyst deactivation,[11b,27–30] and through the formation
of stable bromo complexes of Pd.[30–34] It also provides activi-
ty-increasing counter-ions for anionic species (palladates,
boronates[35b,38]) involved in the catalytic process.
ing the (rate-determining) step of oxidative addition in the
catalytic cycle.
Experiments were also conducted, in which the total
volume of the reaction mixtures was kept constant
(Figure 6). Water and aryl halide were added in different
Effect of organic-phase volume: If the reaction would pro-
ceed in the water phase, the hydrophobic substrate needs to
diffuse into the water layer, where it reacts with Pd and the
boronate species. The immiscibility of the substrate and
water implies that the water phase is saturated with the sub-
strate throughout the reaction. An increase of the amount
of substrate should, therefore, not influence the yield, if all
other parameters are kept constant. Experiments were, thus,
performed in which the amount of substrate, that is, the
volume of the organic layer, was varied.
Figure 5 shows the dependence of the yield (with respect
to phenylboronic acid) on the volume of the organic layer.
Figure 6. Effect of the organic phase/water phase volume ratio on the
yield in the Suzuki reaction in water, keeping the total volume constant:
&
PhB(OH)2 (3 mmol), aryl halide and water as specified. =4-Chloro-
AHCTUNGTREGaNNUN cetophenone, NaOH (9 mmol), TBAB (1.0 mmol), PdPc (0.1 mol%),
*
1008C, 2 h.
(1.0 mmol), [Pd
[Pd
moanisole, K2[Pd
=4-Chloroacetophenone, NaOH (9 mmol), TBAB
~
(acac)2] (0.1 mol%), 658C, 5 h.
=4-Bromoanisole,
!
(acac)2] (0.1 mol%), Na2CO3 (3.5 mmol), 808C, 3 h, air. =4-Bro-
(hqs)2] (0.1 mol%), Na2CO3 (6.0 mmol), 808C, 3 h, air.
ratios, to give 4 mL in total. Given the observed effects,
there would now be two opposing trends when going from
“water-rich” to “water-poor” reaction mixtures: Whereas
lower amounts of water lead to an increase of the yield (due
to the higher concentration of base and boronate), an in-
creasing organic phase volume leads to decreased yields. Ac-
cordingly, as Figure 6 shows, there is no absolutely clear
trend observable for the yield of different reactions, when
the phase volume ratio is altered. In reactions of 4-chloro-
Figure 5. Effect of the volume of the organic phase on the Suzuki reac-
tion in water. Yields are related to PhB(OH)2: black left: PhB(OH)2
(3.0 mmol), TBAB (1.0 mmol), NaOH (3.5 mmol), PdPc (0.1 mol%),
4-chloroacetophenone and water (volumes as specified), 1008C, 2 h, air;
black right: PhB(OH)2 (3.0 mmol), TBAB (1.0 mmol), NaOH
(4.7 mmol), [Pd
(volumes as specified), 658C, 5 h, air; gray left: PhB(OH)2 (3.0 mmol),
Na2CO3 (3.5 mmol), K2[Pd(hqs)2] (0.1 mol%), 4-bromoanisole and water
(volumes as specified), 808C, 3 h, air; gray right: PhB(OH)2 (3.0 mmol),
Na2CO3 (3.5 mmol), [Pd(acac)2] (0.1 mol%), 4-bromoanisole and water
ACHTUNGTRENNUNG(acac)2] (0.1 mol%), 4-chloroacetophenone and water
AHCTUNGTREGaNNUN cetophenone, the detrimental effect of an increased organic
AHCTUNGTRENNUNG
phase volume seems to prevail, as decreased yields are ob-
served for water-poor mixtures. This effect is most pro-
nounced for PdPc as a precatalyst. In contrast, reactions of
4-bromoanisole seem to give increased yields in water-poor
reaction mixtures, although the trend is less clear than for
chloroacetophenone.
AHCTUNGTRENNUNG
(volumes as specified), 808C, 3 h, air.
As it can be clearly seen, the yield generally decreased, as
the volume of the organic layer increased. This result is very
indicative of the fact that the reaction does not proceed in
the water phase! If so, the water phase would always have
been saturated with the reactant, regardless of in how much
of an excess it is present, and accordingly the yield would be
identical.
In turn, assuming that the reaction takes place in the or-
ganic layer of the reaction mixture, the inhibitive effect of
an increased volume of the organic phase could be attribut-
ed to the dilution of the active Pd species, thereby decelerat-
Immobilization of a reactant in the organic phase: To further
support the observations that the catalytic cycle takes place
inside the organic layer, a polymeric halide was introduced
as the reactant, since a polymer cannot freely dissolve into
an aqueous phase. Conversion, thus, can only occur when
the reaction occurs in the hydrophobic layer in which the
polymer is free and active. Bromo-functionalized polystyr-
ene was swollen in reactant-like organic solvents and react-
ed with phenylboronic acid in water (Table 7). As an indica-
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15491

K. Kçhler et al.
Table 7. Bromopolystyrene as reactant.[a]
with 4-chloroacetophenone. As the overall concentration of
the active species is low[12] and the oxidative addition of aryl
chlorides is likely rate-determining, the concentration of the
resulting Ar–Pd–Cl intermediate is also very low. An in-
crease of the organic phase volume is then detrimental to
the reaction due to further dilution of the active species, as
observed (Figure 5).
Entry
Organic
solvent
Br content
(blank test)
[%][b]
Br content
[%][b]
Conversion
[%][c]
1
2
chlorobenzene
4-chloroanisole
20
20
10
8
50
60
[a] Reaction conditions: bromopolystyrene (2.5 mmol “Br”), PhB(OH)2
(5.0 mmol), TBACl (1.0 mmol), [Pd(acac)2] (0.25 mol%), water (5 mL),
AHCTUNGTRENNUNG
In the aqueous phase, PhB(OH)2 and NaOH quantitative-
ly generate the boronate Na[B(Ph)(OH)3]. The presence of
a water phase is therefore mandatory to dissolve the solid
NaOH and keep the boronate species dissolved, that is, re-
active. This species has only a low tendency to cross the
phase boundary and be dissolved in the organic layer.
Through the presence of TBAB, ion exchange can occur to
give TBA[B(Ph)(OH)3], which is more likely to be transfer-
red into the organic layer, and is activated towards transme-
tallation. A similar effect has been attributed to PEG for
organic solvent (5 mL) 1008C, 24 h, air. [b] Br content determined by ele-
mental analysis. [c] Calculated: ratio of the bromide content of the
sample and of the blank test substrated from 100%.
tion of catalytic conversion, the bromide content of the pol-
ymer was compared with blank test samples (reaction with-
out Pd), which indicated 50–60% conversion. Long reaction
times and mediocre conversions are due to a reduced mobi-
lity and accessibility of the bromide functional groups in the
polymeric network. Since the halide reactant is forced to
reside in the organic layer, the catalytic cycle can only have
occurred in the organic phase.
the Suzuki reaction in a H2O–PEG–PdACTHNUTRGNEUNG
(OAc)2 system.[39]
Because of the mentioned low concentration of the
Ar–Pd–Cl species and the low concentration of the boronate
species in the organic layer, the transmetallation step should
become rate-determining as well, and activation of the boro-
nate by TBA+ is mandatory (Table 6).[35b,38] An excess of
base may also enhance this process by “salting out” the phe-
nylboronate. The phase transfer of the boronate is also en-
hanced when D2O is used instead of H2O, due to the de-
crease in stabilization by the solvent shell. This leads to a
faster reaction (Table 5). On the other hand, the presence of
fluoride ions may inhibit the phase transfer and/or the trans-
metallation step, thereby stalling the reaction, as observed
in the case of chlorobenzonitriles (see section on additives).
For the reaction of aryl bromides the addition of TBAB
was not necessary. Because of the higher reactivity of aryl
bromides towards oxidative addition, the respective concen-
tration of the Ar–Pd–Br intermediates is higher, and may be
sufficient for the reaction to work also with the very low
amounts of Na[B(Ph)(OH)3] present in the organic layer. In
other words, while both oxidative addition and transmetalla-
tion are considered to be rate-determining in the case of
aryl chlorides, for aryl bromides it may primarily be the
transmetallation step. This is also in concurrence with ob-
taining identical yields by using different macrocyclic Pd
complexes and rather similar results with different aryl hal-
ides (Table 3), if the Pd is in the organic layer and all other
reaction parameters are identical, as the availability of the
boronate depends on the reaction conditions and not the Pd
source.
Summarizing discussion:
Mechanistic proposal for the Suzuki coupling in biphasic re-
action mixtures: To explain the observed trends and effects,
a summary of processes occurring during the catalytic reac-
tion as depicted in Figure 7 is proposed, with the example of
the reaction of 4-chloroacetophenone with PdPc as a preca-
talyst. The catalytic cycle is considered to take place in the
organic layer (substrate). The reaction begins with PdPc dis-
persed in the organic layer, which generates the active Pd0
species. The active species undergoes oxidative addition
It can, however, not be ruled out that the transmetallation
step takes place at the phase boundary, either in parallel or
exclusively (Figure 7), although we consider it unlikely from
the experiments showing no difference in yield when apply-
ing different stirring rates (Table 4). Both Na– or TBA–bor-
onate species may be involved then, but the rate-enhancing
effects of TBA+ and D2O and the inhibiting effect of fluo-
ride remain similar.
Figure 7. Proposal for the processes occurring during Suzuki coupling of
4-chloroacetophenone in water by using PdPc as a precatalyst. Black
arrows indicate processes involved in the catalytic cycle, grey arrows
(quantitative) chemical reactions, dashed arrows diffusion and phase-
transfer processes.
Transmetallation generates the Pd–biaryl species, from
which the coupling product and the active species are pro-
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Suzuki Coupling Reactions in Neat Water as the Solvent
FULL PAPER
with a HP-1 column (100% dimethylpolysiloxane, bonded and cross-
linked; length: 30 m, inner diameter: 0.25 mm, film thickness: 0.25 mm)
as the stationary phase, nitrogen 5.0 (99.999 vol% purity) as the eluent
gas, and a flame-ionization detector (FID). Diethylene glycol dibutyl
ether (DEGBE) was used as an internal standard.
duced after reductive elimination. The active species enters
a new catalytic cycle or deactivation pathways, the latter
being inhibited by the presence of TBAB, as mentioned pre-
viously. The side products of the transmetallation, B(OH)3
and TBACl, are transferred back into the aqueous layer,
thereby also facilitating the transmetallation step. B(OH)3
may consume a further equivalent of NaOH to create the
corresponding water-soluble borate NaB(OH)4, a process
that may also be responsible for the necessity of an excess
of base (Table 2 and Figure 2).
Suzuki coupling of 4-chloroacetophenone in water (standard procedure):
Catalyst (0.1 mol% Pd), NaOH (4.5–9 mmol; added as pellet), phenyl-
boronic acid (3.5 mmol), TBAB (1.0 mmol), DEGBE (150–250 mg as in-
ternal standard for GC analysis), and 4-chloroacetophenone (3.0 mmol)
were introduced into a reaction tube. Water (3–4 mL) was added shortly
before the reaction tube was placed into the heating source. The reaction
was performed with vigorous stirring (800–1000 rpm) at 1008C for 2 h.
In summary, the reaction is proposed to take place in the
organic layer, while the aqueous layer has an important sup-
porting function, resulting in an efficient catalytic coupling
reaction.
Suzuki coupling of 4-bromoanisole in water (standard procedure): Cata-
lyst (0.1 mol% Pd), Na2CO3 (3.5 mmol), phenylboronic acid (3.2 mmol),
DEGBE (150 mg as internal standard for GC analysis), and 4-bromoani-
sole (3.0 mmol) were introduced into a reaction tube. Water (3 mL) was
added shortly before the reaction tube was placed into the heating
source. The reaction was performed with vigorous stirring (800–
1000 rpm) at 808C for 3 h.
Conclusion
Suzuki coupling of 4-bromoanisole in water (experiments with different
stirring rates): K2[PdACHTUNGTRNEG(UN hqs)2] (0.1 mol% Pd), Na2CO3 (35 mmol), phenyl-
boronic acid (32 mmol), DEGBE (1.60 g as internal standard for GC
analysis), and 4-bromoanisole (30 mmol) were introduced into a two-
neck-reaction tube. Water (30 mL) was added shortly before the reaction
tube was placed into the oil bath. The reaction was performed with dif-
ferent stirring rates (500, 1000, 1500 rpm) at 808C for 3 h.
Suzuki reactions in biphasic systems by using only water as
the solvent have been successfully performed in this work,
and for the first time systematic investigations have been
undertaken regarding the locality of the catalytic process. It
has been demonstrated that the phase preference of the pre-
catalyst is only one factor influencing the catalytic efficiency.
The presence of a water phase and a high concentration of
base were found to increase the yield. Among a variety of
potent phase-transfer catalysts, TBAB was found to be the
most efficient additive. An excess of the hydrophobic reac-
tant led to lowered yields.
It is suggested that the reaction occurs inside the organic
layer, while the water phase serves supporting and rate-en-
hancing purposes. With other reaction systems (reactants,
catalysts), the situation may, however, be different, as the lo-
cality of the reaction will depend on several factors: the in-
dividual miscibility of the reactants and reagents with water,
the ability of ligands to keep and stabilize Pd0 species in
water (expected for example, for sulfonated phosphane li-
gands), the pH, and the presence and effects of additives
(detergents, polymers, etc.). In light of product separation
and purification as well as catalyst reuse, a catalytic process
taking place inside the aqueous phase is preferable. With
this work, we hope to sensitize researchers in the field to
pay regard to the biphasic character of C–C coupling reac-
tion mixtures in water as the solvent. Future work to pro-
duce a broader understanding of the locality of C–C cou-
pling reactions in biphasic reaction mixtures is highly en-
couraged.
Suzuki coupling of bromopolystyrene in water (polymeric reactant reac-
tion): Bromopolystyrene (1 g; 2.5 mmol “Br”) was placed in a reaction
tube and swollen in the organic solvent (5 mL) for 12 h. Then
[PdACHTNURTGNE(GNU acac)2] (0.25 mol%), Na2CO3 (5.4 mmol), phenylboronic acid
(5.0 mmol), and tetra-n-butylammonium chloride (1.0 mmol) were intro-
duced into a reaction tube. Water (5 mL) was added shortly before the
reaction tube was placed into the oil bath. The reaction was performed
with vigorous stirring (800–1000 rpm) at 1008C for 24 h. After the reac-
tion time, the reaction vessels were dipped into a water bath for 5 min to
quench the reaction. The solvent was removed by filtration. The polymer
was purified by washing exhaustively with water and CH2Cl2.
Acknowledgements
The authors wish to thank the NanoCat graduate school of the Elitenetz-
werk Bayern for financial support.
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[35] See, for example: a) S.-H. Huang, J.-R. Chen, F.-Y. Tsai, Molecules
2010, 15, 315; b) D. Badone, M. Baroni, R. Cardamone, A. Ielmini,
U. Guzzi, J. Org. Chem. 1997, 62, 7170.
[PdACHTUNGTRENNUNG(acac)2] as the precatalyst without stirring, the organic layer of
[36] B. J. Gallon, R. W. Kojima, R. B. Kraner, P. L. Diaconescu, Angew.
Chem. 2007, 119, 7389; Angew. Chem. Int. Ed. 2007, 46, 7251.
[37] A detrimental effect of cetyltrimethylammonium bromide (CTAB)
the reaction mixture had turned black after 10 min at the reaction
temperature, while the water phase stayed colorless throughout the
reaction.
was also found for the reaction at 658C with [Pd
compared to 80% with TBAB).
ACHTUNGTERN(NGNU acac)2] (12% yield
[21] C. Rçhlich, K. Kçhler, unpublished results.
[22] S. S. Soomro, C. Rçhlich, K. Kçhler, Adv. Synth. Catal. 2011, 353,
767.
[38] N. E. Leadbeater, Chem. Commun. 2005, 2881.
[39] L. Liu, Y. Zhang, Y. Wang, J. Org. Chem. 2005, 70, 6122.
[23] After repetition of the experiments the respective yields are not
always exactly reproduced. However, the same trends in yields were
always received and can be described by a relative experimental
error D of about ꢁ3%. This establishes the validity of the observa-
tions and all general trends discussed.
Received: April 13, 2012
Published online: October 2, 2012
15494
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Chem. Eur. J. 2012, 18, 15485 – 15494