True water soluble palladium-catalyzed Heck reactions in aqueous-organic biphasic media

Article abstract of DOI:10.1016/j.tetlet.2013.03.067

A stable water soluble palladium catalyst has been demonstrated for the Heck reaction in a biphasic medium (water-non-polar organic solvent). Biphasic Heck reactions reported till now generally employ a non-polar solvent along with an aqueous polar water miscible organic solvent as the second phase. The efficiency of the Pd complex of TOTPS [Trisodium salt of tri-(ortho-tolyl) phosphine tri sulfonate] for the vinylation of different aryl iodides and olefins is demonstrated. The advantages of a co-solvent for this biphasic system have also been shown. The catalyst has been recycled efficiently retaining the activity with negligible loss of catalyst and without leaching of the Pd.

Full text of DOI:10.1016/j.tetlet.2013.03.067

Tetrahedron Letters 54 (2013) 2733–2736
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Tetrahedron Letters
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True water soluble palladium-catalyzed Heck reactions in aqueous–organic
biphasic media
⇑
,
Sangeeta Jagtap , Raj Deshpande
Chemical Engineering Division, National Chemical Laboratory, Pune, Maharashtra, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A stable water soluble palladium catalyst has been demonstrated for the Heck reaction in a biphasic med-
ium (water–non-polar organic solvent). Biphasic Heck reactions reported till now generally employ a
non-polar solvent along with an aqueous polar water miscible organic solvent as the second phase.
The efficiency of the Pd complex of TOTPS [Trisodium salt of tri-(ortho-tolyl) phosphine tri sulfonate]
for the vinylation of different aryl iodides and olefins is demonstrated. The advantages of a co-solvent
for this biphasic system have also been shown. The catalyst has been recycled efficiently retaining the
activity with negligible loss of catalyst and without leaching of the Pd.
Received 15 December 2012
Revised 12 March 2013
Accepted 16 March 2013
Available online 22 March 2013
Keywords:
Heck reaction
Aqueous biphasic catalysis
Water-soluble catalyst
C–C coupling
Ó 2013 Elsevier Ltd. All rights reserved.
The two basic problems of homogeneous catalysis are separa-
tion and recycling of the catalyst, which can be elegantly solved
by using two-phase catalysis.1 It serves the purpose of industrial
application such as easy separation of the product from the cata-
lyst and recycling of the catalyst, along with reasonable activity.
In addition, catalysis in water offers several advantages as water
is inexpensive, nontoxic, nonflammable, and readily forms biphasic
systems with a variety of organic materials. Therefore, aqueous/or-
ganic two-phase catalysis finds wide applications.2 Kuntz devel-
oped a water-soluble catalyst Rh/TPPTS,3 which served as the
starting points of aqueous-biphasic catalysis with water-soluble
catalysts. Since then, the utility of a variety of metal-catalyzed
reactions in water has been shown.2,4–17
Palladium promoted reactions in aqueous media pose major
challenges regarding the stability of palladium complex cata-
lysts.18–20 Hence the applications were mainly restricted to the
use of aqueous organic media. Until recently, very few reports have
shown that water can be added in the Heck reaction.21–25 To over-
come these problems, the studies using water were carried out in
two ways (i) where a non-aqueous biphasic medium is used,26–29
in which the biphasic system actually comprised of the organic
phase along with the ethylene glycol phase and (ii) where a homo-
geneous medium containing water is used,21,30–32 (such as water
along with acetonitrile) for the Heck reaction, although they do
not discuss methods for catalyst recycling.
Palladacycle [Pd2(P(o-Tol)3)2(l-OAc)2], discovered by Herr-
mann and Beller33 is one of the most convenient forms of palla-
dium complexes applied in homogeneous catalysis with its
unique catalytic activity. We report here a sulfonated tri o-tolyl-
phosphine that forms a stable water-soluble palladacycle catalyst
(complex 1, Fig. 1). The efficiency of this complex for Heck reac-
tions was demonstrated for a number of aryl halides, olefins, and
in the presence of different concentrations of co-solvent. The cata-
lyst was retained in the water phase with no leaching to the organ-
ic phase and was recycled efficiently with no loss in activity.
A typical problem of aqueous phase catalysis is the poor solubil-
ity of the substrates, viz. styrene and stilbene in the aqueous phase
and also the stability of the catalyst. Both these problems were
solved by taking the following measures.
The role of NaOAc (sodium acetate) in the stabilization of the
catalyst is well reported.34,35 In these works, Sheldon and co-work-
ers has suggested that the presence of NaOAc prevents the precip-
itation of Pd black. A minimum concentration of 1 mmol was
reportedly required for this purpose. Hence, in this work we used
NaOAc for the stabilization of the catalyst. Catalyst 2 prepared with
a 1:2.2 Pd:NaOAc ratio was found to be stable and did not form
metallic Pd (the synthesis of TOTPS (1) and the Pd-complex (2)
can be found in Supplementary data). In order to check whether
Pd had precipitated in the form of Pd colloidal particles, a UV spec-
trum was taken. No absorption was seen in the range of 350–
400 nm, which indicates the absence of Pd colloidal particles. This
also shows that the reaction occurs due to soluble catalytic com-
plex and not Pd metal. It was observed that preparation of the cat-
alyst in the absence of NaOAc led to precipitation of Pd, as the
catalyst formed was unstable.
⇑
Corresponding author. Tel.: +91 20 25902620; fax: +91 20 25902621.
E-mail address: sangeetajagtap@rediffmail.com (S. Jagtap).
Current address: B.G. College, Sangvi, Pune, India.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.03.067

2734
S. Jagtap, R. Deshpande / Tetrahedron Letters 54 (2013) 2733–2736
NaO3
S
The above diagnostic experiments confirmed that:
SO Na
3
SO3Na
H3C
(i) NaOAc was essential to ensure the stability of the Pd com-
plex, and prevent precipitation. The role of NaOAc was not
as a base.
(ii) Morpholine was functioning both as a base and a co-solvent.
(iii) Enhancement in the rate was substantial with morpholine as
a co-solvent.
CH3
SO3Na
P
CH2
H3
C
P
SO3Na
Pd
O
CH3
CH3
C -CH3
O
NaO3S
2
Further, detailed studies on the role of morpholine as a co-sol-
vent were conducted. The reactions were taken with varying
amounts of morpholine and the conversion of iodobenzene was
monitored (entries 2–6, Table 2).
1
2
TOTPS Ligand
[Trisodium salt of tri-(ortho-tolyl)
phosphine tri sulphonate]
Pd(acetate)2-(TOTPS)2 complex
It can be seen from the results, as the percentage of morpho-
line (as a co-solvent) in the aqueous phase increases, the rate of
reaction increases. Since morpholine in this case acts as a base as
well as a co-solvent, the concentration of morpholine was varied
in such a way that a minimum of 2% morpholine concentration
(which corresponds to the mole equivalent of the substrates) is
present as a base for all reactions and the remaining as a co-sol-
vent. A linear dependence was observed up to 14% loading of the
morpholine in the aqueous phase, beyond which no major rate
enhancement was seen. No reaction was observed in the absence
of morpholine (entry 1, Table 2), which is due to the absence of
any base.
Thus for all further screening studies 10% morpholine as a co-
solvent + base was utilized. Under these conditions analysis of
the organic phase showed no leaching and recycling of the organic
phase also showed no activity, indicating that the reaction was a
true aqueous phase reaction.
In order to ensure that the catalyst had not deactivated a few
experiments were conducted under the given reaction conditions
for varying time periods (1, 4, and 6 h) instead of taking periodic
samples.
The results in Table 3 (entries 1–3), show that there is a con-
stant increase in the formation of stilbene and iodobenzene con-
sumption with time. In this case after 6 h reaction, there was
practically no reaction. These results confirmed that the catalyst
remains active throughout the period. Hence for all the reactions,
a fixed period of 6 h was taken and no intermediate samples were
withdrawn. The turn over number (TON) was calculated at the end
of 6 h reaction (unless otherwise specified).
Figure 1.
The biphasic system was systematically tailored using the
water soluble catalyst (complex 2) in non-polar solvents such as
toluene and n-octane along with water. A significant amount of
leaching was observed (ꢀ5 ppm) when toluene was used as the or-
ganic phase. n-Octane was found to be the best option, where no
leaching of the catalyst was observed. The solubility issue was
overcome by using a co-solvent. Hartung et al.36 has mentioned
the use of DMSO as a co-solvent for the Heck reaction to improve
selectivities of non-conjugated aryl olefins in a homogeneous med-
ium. Similarly the application of co-solvents to enhance the activ-
ity is well known in the aqueous biphasic hydroformylation
reaction,37 a similar strategy was employed for improving the rates
of reaction for Heck coupling reactions.
For this study co-solvents like morpholine, NMP, and 1,4-diox-
ane (at a 10% v/v aqueous phase concentration) were used in the
presence of NaOAc as a base (already present as a stabilizer).
Although the solubility of the substrates enhanced in the presence
of NMP/1,4-dioxane co-solvent, no reaction was observed (entries
1 and 2, Table 1). This is probably due to the inability of NaOAc to
function as a base in aqueous conditions. 60% conversion of iodo-
benzene was observed, when morpholine was used as a co-solvent
(entry 3, Table 1). Since morpholine was also capable of function-
ing as a base and co-solvent, an experiment was conducted with
only stoichiometric equivalent morpholine (as base) in the reaction
medium along with NaOAc (Pd:NaOAc 1:2.2). A 20% conversion of
iodobenzene was observed after 6 h (entry 4, Table 1). This exper-
iment confirmed that morpholine could have a dual function in
aqueous biphasic Heck reactions. Analysis of morpholine in the
reaction system showed a conversion of morpholine equivalent
to the consumption of the aryl halide.
The catalyst was assessed for its activity for the Heck reaction of
various aryl halides and the results are given in Table 3 (entries 3–
6). It was seen that 4-iodoacetophenone gives faster rates than 4-
iodoanisole and iodobenzene proving that the halides with substit-
uents have more –I effect that is, a strong electron withdrawing
character, show high activity toward the vinylation. (It is well
known that electron-withdrawing substituents on the aryl halide
enhance the rate of oxidative addition of the substrate to the Pd
atom.38) Bromobenzene gave very poor activity due to the inherent
low reactivity of the bromo-substrate under the reaction
conditions.
The feasibility of using NMP/1,4-dioxane as a co-solvent was
studied in the presence of morpholine as a base but in the absence
of NaOAc. In both these cases Pd metal precipitated (entries 5 and
6, Table 1). Organic bases other than morpholine showed leaching
(about 5–15 ppm) which was confirmed by AAS studies. Many
inorganic bases showed no activity. It was observed that in the ab-
sence of morpholine no reaction takes place.
Table 1
Comparison of activity using various co-solvents and use of stabilizer for the Heck reaction in an aqueous biphasic medium
Sr. No.
Stabilizer
Co-solvent
Base
% Of co-solvent
Observation
% Conversion
TON
1
2
3
4
5
6
NaOAc
NaOAc
NaOAc
NaOAc
—
NMP
—
—
10
10
10a
2a
10
10
No reaction
No reaction
—
—
Pd metal precipitated
Pd metal precipitated
—
—
60
20
—
—
—
555
215
—
1,4-Dioxane
Morpholine
—
NMP
1,4-Dioxane
Morpholine
Morpholine
Morpholine
Morpholine
—
—
—
Reaction condition: Styrene (3.3 mmol), iodobenzene (3.0 mmol) taken in degassed n-octane (15 ml) + degassed distilled water (15 ml) along with catalyst (0.03 mmol) and
co-solvent and base (Morpholine—given in % with respect to the aqueous phase), and a stabilizer (NaOAc—1.0 mmol) (wherever used); 150 °C; 1450 rpm. (time: 6 h).
a
10% = 1.5 ml (17.2 mmol); 2% of co-solvent = 0.3 ml (3.4 mmol).

S. Jagtap, R. Deshpande / Tetrahedron Letters 54 (2013) 2733–2736
2735
Table 2
Heck reaction of olefin with iodobenzene in an aqueous biphasic medium using various concentrations of co-solvent
Sr. No.
Co-solvent
Base
% Of co-solvent
Observation
% Conversion
TON
1
2
3
4
5
6
—
—
—
0
2a
No reaction
—
—
Morpholine
Morpholine
Morpholine
Morpholine
Morpholine
—
—
—
—
—
20
39
60
80
87
215
354
555
694
738
Morpholine
Morpholine
Morpholine
Morpholine
6a
10a
14a
18a
Reaction condition: Styrene (3.3 mmol), iodobenzene (3.0 mmol) taken in degassed n-octane (15 ml) + degassed distilled water (15 ml) along with catalyst (0.03 mmol) and
co-solvent and base (Morpholine—given in % with respect to the aqueous phase) and a stabilizer (NaOAc—1.0 mmol); 150 °C; 1450 rpm. (Time: 6 h).
a
2% of co-solvent = 0.3 ml (3.4 mmol); 6% = 0.9 ml (10.3 mmol); 10% = 1.5 ml (17.2 mmol); 14% = 2.1 ml (24.0 mmol); 18% = 2.7 ml (30.9 mmol).
Table 3
Heck reaction of olefins with aryl halides in an aqueous biphasic medium
Sr. No.
Olefin
Ar-X
Time (h)
% Conversion
TON
1
2
3
4
5
6
7
8
9
Styrene
Styrene
Styrene
Styrene
Styrene
Styrene
3-NitroStyrene
4-Chlorostyrene
4-MethylStyrene
Iodobenzene
Iodobenzene
Iodobenzene
4-Iodo acetophenone
p-Iodoanisole
Bromobenzene
Iodobenzene
Iodobenzene
Iodobenzene
1
4
6
6
6
6
6
6
6
21
47
60
100
72
2
86
68
53
191
435
555
875
663
5
1008
737
544
Reaction condition: Olefin (3.3 mmol), Ar-X (3.0 mmol) taken in degassed n-octane (15 ml) + degassed distilled water (15 ml) along with catalyst (0.03 mmol) and co-solvent
(morpholine—10% of aqueous phase inclusive of 3.0 mmol as a base), and a stabilizer (NaOAc—1.0 mmol); 150 °C; 1450 rpm.
200
100
0
The Pd–TOTPS catalyst was recycled for two times to demonstrate
the feasibility of recycling, and the results are shown in Figure 2.
The catalyst gave consistent activity on recycling, with good con-
version of iodobenzene (21%, 22%, and 21%, respectively) and with
appreciable TON values (191, 200, and 186, respectively). No leach-
ing of the catalyst to the organic phase was observed during the
recycling study as confirmed by Pd analysis of the organic phase.
The organic phase was recycled to confirm the absence of catalyst
in that phase. There was no further reaction when the reaction was
conducted with the recycled organic phase along with fresh sty-
rene and iodobenzene.
The idea of using such catalyst in a biphasic system is more use-
ful through industrial point of view. The results produced here are
just to show the feasibility of the use of catalyst in a biphasic med-
ium, however proper tailoring of reaction may still improve the
Virgin
Recycle1
Recycle2
Number of recycles
Figure 2. Activity of Pd–TOTPS catalyst on recycling of the aqueous phase in an
aqueous–organic biphasic medium for the Heck reaction of styrene with iodoben-
zene. Reaction conditions: Styrene (3.3 mmol), iodobenzene (3.0 mmol) taken in
degassed n-octane (15 ml) + degassed distilled water (15 ml) along with catalyst
(0.03 mmol or recycled) and co-solvent (morpholine—10% of aqueous phase
inclusive of 3.0 mmol as a base), and a stabilizer (NaOAc—1.0 mmol); 150 °C;
1450 rpm. (time: 1 h). Selectivity of stilbene >99%.
activity and
achievable.
a high cumulative turn over number (TON) is
An aqueous biphasic medium using water and a nonpolar sol-
vent system has been demonstrated first time for the Heck reac-
tion. The reaction conditions are standardized in such a way that
there was no leaching to the organic phase. Pd–TOTPS complex cat-
alyst is found to be active for the Heck reaction, in the presence of
morpholine co-solvent. The catalyst is stable in water and could be
recycled for two times with no loss in the activity. The role of co-
solvent concentration, olefins, and aryl halides has been elucidated
in the aqueous biphasic system.
The activity of Pd–TOTPS complex catalyst was assessed for the
Heck vinylation of iodobenzene in the aqueous biphasic reaction.
Various olefins were screened for their activity. The results are pre-
sented in Table 3 (entries 3, 7–9). Among olefins, 3-nitrostyrene
was seen to be more reactive than 4-chlorostyrene, styrene, and
4-methyl styrene. This was a surprising behavior, as generally
the presence of electron withdrawing groups attached to the aro-
matic ring reduces the activity of the aryl halide compared to elec-
tron donating groups. This observation could be due to the
variation in solubility for the biphasic reaction. The reactivity of
acrylates could not be assessed, as the acrylates were found to re-
act with morpholine and form an addition product as a result of
which the Heck coupling reaction could not occur. The formation
of the addition product was confirmed by GC–MS.
Acknowledgment
S.V.J. thanks the University Grant Commission of India for PhD
fellowship.
Supplementary data
Supplementary data associated with this article can be found, in
The primary objective of developing an aqueous phase catalyst
for the Heck reaction was to facilitate catalyst recycle and recovery.
the
online
version,
at
http://dx.doi.org/10.1016/
j.tetlet.2013.03.067.

2736
S. Jagtap, R. Deshpande / Tetrahedron Letters 54 (2013) 2733–2736
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