Heck reactions in aqueous miniemulsions

Article abstract of DOI:10.1071/CH12164

Carrying out organic reactions in water-based nanoreactors represents a 'green' method for the preparation of organic compounds. This process eliminates the need for solvents, thus reducing the effect of high volumes of solvent on the environment. In this work, we demonstrate a successful Heck cross-coupling reaction, one of the most used approaches to form CC bonds using a palladium catalyst, in a miniemulsion. The miniemulsion droplet sizes were small (25 to 42nm), and the reactions resulted in high conversions of three different products with high trans stereoisomers.

Full text of DOI:10.1071/CH12164

RESEARCH FRONT
CSIRO PUBLISHING
Aust. J. Chem. 2012, 65, 1090–1094
Full Paper
http://dx.doi.org/10.1071/CH12164
Heck Reactions in Aqueous Miniemulsions
A
A
A
Hazit A. Zayas, David Valade, Zhongfan Jia,
A B
,
and Michael J. Monteiro
A
Australian Institute for Bioengineering and Nanotechnology,
University of Queensland, Brisbane, Qld 4072, Australia.
Corresponding author. Email: m.monteiro@uq.edu.au
B
Carrying out organic reactions in water-based nanoreactors represents a ‘green’ method for the preparation of organic
compounds. This process eliminates the need for solvents, thus reducing the effect of high volumes of solvent on the
environment. In this work, we demonstrate a successful Heck cross-coupling reaction, one of the most used approaches to
form C–C bonds using a palladium catalyst, in a miniemulsion. The miniemulsion droplet sizes were small (25 to 42 nm),
and the reactions resulted in high conversions of three different products with high trans stereoisomers.
Manuscript received: 22 March 2012.
Manuscript accepted: 24 April 2012.
Published online: 30 May 2012.
Introduction
Miniemulsions are formed by the high shear mixing of
surfactant, reactants, water and costabilizer that form stable
organic droplets in a continuous water phase. The costabilizer
(e.g. hexadecane) is an important ingredient that acts as a
swelling agent, and thus limits the diffusion of reagents from
the smaller droplets to the larger ones (i.e. inhibits Ostwald
ripening).[19,20] Without costabilizer, diffusion of reagents via
the action of Ostwald ripening from small to larger droplets
results in the growth of the larger droplets until they reach a
critical size of usually greater than 500 nm, become buoyant and
then rise to form a single organic phase at the top of the reaction
vessel. Miniemulsions are typically formed through high shear,
by subjecting the system to ultrasonication, homogenizer or
microfluidizer,[19,20] and have been extensively used to produce
hydrophobic polymers without the need of an organic
solvent.[19,20] The resulting nanoparticles are easy to process
due to the low viscosity medium.
The aim of this work is to carry out Heck reactions catalyzed
by a commercially available Pd complex in a miniemulsion
using the same ingredients as that for the polymerizations. We
found process conditions to produce stabilised droplets ranging
from 25 to 42 nm in diameter (DH) following the procedure by
Landfester and coworkers.[21] Three different sets of reagents
were used in miniemulsions, giving quite high conversion of
reactants to product and high trans stereoisomer formation.
Thus, in the continuing quest for green technology in chemical
processes, the miniemulsion concept is an exciting alternative to
effect inorganic[22] and organic reactions[23,24] in aqueous
media, particularly the palladium-catalyzed cross-coupling
reaction.[25]
It is well established that carrying out organic reactions in water-
based nanoreactors can have advantages over that in solution or
bulk.[1] Nanoreactors can concentrate reactants through
compartmentalization,[2] resulting in a considerable increase in
the rate of product formation. Furthermore, water provides an
environmentally friendly medium,[3] with the potential to sig-
nificantly reduce the amount of organic solvents in the synthesis
of pharmaceuticals and fine chemicals. Eliminating organic
solvents, especially volatile organic solvents (VOCs), would
also significantly reduce the cost of production as the solvents
usually constitute over 80 % of the total reaction mass.
The Heck reaction,[4] catalysed by palladium (Pd), represents
one of the most important synthetic methods for the formation of
C–C bonds in both the pharmaceutical and fine chemical
industries.[5,6] This reaction has found utility, ranging from the
synthesis of highly complex small molecules[7] to conjugated
polymers.[8] There are now many reports on the use of surfactant
and polymer micelles in water to carry out Heck reactions.[9–14]
In some cases, the Pd catalyst is captured into nanoparticles
stabilised by surfactant,[9–12] and in other cases the Pd catalyst is
bound to the micelle-forming polymer through covalently
linked ligands on the side chains.[13,14] All these methods have
been used with great success. However, there are only a few
reports of the Heck reaction being carried out in microemul-
sions[15–18] using commercially available Pd/ligand catalysts,
and there are no reports to our knowledge of Heck reactions in
miniemulsions. The advantage of micro- and miniemulsions is
the co-location of reagents and catalyst complexes in surfactant
stabilised droplets ranging in size from ,20 to 500 nm, resulting
in the potential for faster and better controlled reactions owing to
compartmentalization but also to the excellent heat transfer
through the water phase. The latter becomes important in
organic and polymer reactions that have the potential to explode
from highly exothermic reactions.
Results and Discussion
The first cross-coupling reaction, considered the gold standard
of Heck coupling, involves the coupling of styrene and
Journal compilation Ó CSIRO 2012
www.publish.csiro.au/journals/ajc

Heck Reactions in Aqueous Phase Miniemulsions
1091
Table 1. Comparison of palladium-catalyzed Heck cross-coupling reaction in miniemulsion and organic
solvents at 708C for 24 h
1 mol % Pd(PPH3)4
1 equiv. Et3N
I
ϩ
70ЊC, 24h
(E)-1,2-diphenylethene
EntryA
Solvent
Catalyst loading [mol %]
Conversion of iodobenzene [%]B (E %)C
1D
2E
3F
DMF
1
1
1
51 (83)
0 (N/A)
99 (82)
Toluene
Miniemulsion
AReactions are carried out using styrene (0.0024 mol), iodobenzene (0.0024 mol), triethylamine (0.0024 mol) and
Pd(PPh3)4 (1 mol %) at 708C for 24 h.
BDetermined by 1H NMR spectroscopy.
CDetermined by GC-MS.
DReactions carried out in 2.00 g of DMF.
EReactions carried out in 2.00 g of toluene.
FReactions carried out in 0.0450 g SDS in 2.00 g of water with 0.0600 g hexadecane as co-surfactant/hydrophobe and
reaction was run for 25 h.
(a)
(b)
(c)
(d)
Fig. 1. The Heck reaction in a miniemulsion. (a) After ultrasonication; (b) during the reaction; (c) immediately after the reaction
(24 h); and (d) left to stand for a further 1 h.
iodobenzene to produce stilbene ((E)-1,2-diphenylethene,
Table 1). In both DMF and toluene using Pd(PPh3)4 (1 mol % to
reactants), the product conversion was 51 and 0 %, respectively,
after 24 h at 708C (Table 1). In the miniemulsion approach, a
white milky solution as shown in Fig. 1a was formed using
sodium dodecylsulfate (SDS), hexadecane (costabilizer) and
water. An initial droplet diameter (DH) of 29 nm after ultra-
sonication at room temperature gave a stable miniemulsion
for over 24 h. The product precipitated out during the
reaction (Fig. 1b). At the end of the reaction and as soon as
the stirring was stopped, the product settled to the bottom of the
reaction mixture (Fig. 1c). Leaving the mixture to stand for
another hour gave a phase separation of the product from the
aqueous phase (Fig. 1d). This allowed the product to be isolated
by simply decanting the aqueous phase, and further purified by
solvent extraction and column chromatography. The conversion
of iodobenzene to product was close to 100 % (Table 1) as
monitored by 1H NMR spectrometry over 25 h (Fig. 2a).
The loss of styrene (6.7 ppm) and iodobenzene (7.7 ppm) and
the formation of a single peak from that of trans-stilbene
(or (E)-1,2-diphenylethene, 7.1 ppm) after 25 h, suggest that the
catalyst allows the reaction to reach near quantitative conversion
and with high yields of the E stereoisomer (Table 1).
The absence of any reaction in toluene was due to the poor
solubility of the catalyst in this solvent. Increasing the polarity of
the solvent to DMF increased the solubility of the catalyst and so
to the yield of product. In the miniemulsion, the catalyst was
fully soluble in the mixture of reactants, forming stable droplets
upon sonication. The complete solubilization of the commercial
catalyst allowed the miniemulsions to produce product in very
high yields. These high conversions prompted us to utilize the
same conditions for other substrates.
A reaction of 4-methoxyiodobenzene (1 equiv) and tert-
butylacrylate (1 equiv) was first attempted at a lower tempera-
ture of 508C for 24 h using 1 mol % loading of Pd(PPh3)4
(Table 2). At this milder temperature, a conversion of 63 %

1092
H. A. Zayas et al.
a
c
b
c
b
a
d
d
25h
20h
15h
e
f
e
g
c
I
f
g
b
b
d
a
c
a
d
7.6
7.4
7.2
7.0
6.8
Fig. 2. 1H NMR spectra of the Heck reaction of iodobenzene and styrene in miniemulsion at time 15, 20 and 25 h.
Table 2. Heck cross-coupling reaction of 4-methoxyiodobenzene and tert-butylacrylate in miniemulsion at different
temperatures for 24 h
O
O
1 mol % Pd(PPH3)4
1 equiv. Et3N
I
O
ϩ
O
H3CO
2.2 wt % SDS/H2O
hexadecane, 24h
H3CO
(E)-tert-butyl 3-(4-methoxyphenyl)acrylate
EntryA
DH [nm]B (PDI)C
Reaction
Catalyst
Conversion of 4-methoxyiodobenzene
[%]D (E %)E
temperature [8C]
loading [mol %]
1
2
3
4
93 (0.089)
42 (0.212)
34 (0.221)
35 (0.311)
50
50
1
2
2
2
63 (96)
81 (96)
1 (94)
40
RT
0 (NA)
AReactions are carried out using styrene (0.0024 mol), iodobenzene (0.0024 mol), triethylamine (0.0024 mol) and Pd(PPh3)4
(1 or 2 mol %) in 0.0450 g SDS in 2.00 g of water with 0.0600 g hexadecane as co-surfactant/hydrophobe for 24 h.
BHydrodynamic diameter (DH) of the miniemulsion after ultrasonication measured by DLS at 258C.
CPolydispersity index (PDI) of the particle size distribution in miniemulsion after ultrasonication measured by DLS at 258C.
DDetermined by 1H NMR spectroscopy.
EDetermined by GC-MS.
and 96 % E formation (entry 1, Table 2) was obtained as
determined by 1H NMR spectral analysis. In an effort to increase
the conversion, a 2 mol % loading of Pd(PPh3)4 was used at the
same temperature. This reaction resulted in an increase in the
conversion to 81 % (E ¼ 96 %, entry 2, Table 2). However, at
temperatures below 508C, there was little or no conversion
(entries 3 and 4, Table 2). The initial droplet diameters after
sonication at room temperature ranged between 34 and 42 nm,
which was slightly larger compared with the sizes found in
Table 1. The reason for the larger initial size of 93 nm at 1 mol %
loading is unclear, but suggests that the greater amount of
catalyst acts to further stabilize the droplets.
The Heck reaction of 4-methoxyiodobenzene with styrene
showed an increase in the conversion from 41 to 76 % when the
temperature was increased from 40 to 708C (Table 3). Over the
three temperatures used, the initial droplet sizes were similar,
ranging between 30 and 40 nm. The formation of the trans-
product was greater than 90 %. The para-methoxy group on
iodobenzene seemed to inhibit the reaction with styrene as
compared with unsubstituted iodobenzene (Table 1), whereas
its reaction with a tert-butyl acrylate (Table 2) gave a slightly
faster rate. Even though we use an inexpensive commercially
available catalyst, Pd(PPh3)4, and SDS, we obtain similar results
to those found in the literature.[10,11]

Heck Reactions in Aqueous Phase Miniemulsions
1093
Table 3. Heck cross-coupling reaction of 4-methoxyiodobenzene and styrene in miniemulsion at different
temperatures for 24 h
2 mol % Pd(PPH3)4
1 equiv. Et3N
I
ϩ
H3CO
2.2 wt % SDS/H2O
hexadecane, 24h
H3CO
(E)-1-methoxy-4-styrylbenzene
EntryA
DH [nm]B (PDI)C
Reaction
Catalyst loading
[mol %]
Conversion of 4-methoxyiodobenzene
[%]D (E %)E
temperature [8C]
1
2
3
30 (0.257)
39 (0.254)
35 (0.232)
70
50
40
2
2
2
76 (97)
74 (92)
41(90)
AReactions are carried out using styrene (0.0024 mol), iodobenzene (0.0024 mol), triethylamine (0.0024 mol) and Pd(PPh3)4
(2 mol %) in 0.0450 g SDS in 2.00 g of water with 0.0600 g hexadecane as co-surfactant/hydrophobe for 24 h.
BHydrodynamic diameter (DH) of the miniemulsion after ultrasonication measured by DLS.
CPolydispersity index (PDI) of the particle size distribution in miniemulsion after ultrasonication measured by DLS.
DDetermined by 1H NMR spectroscopy.
EDetermined by GC-MS.
Conclusion
2.4 ꢁ 10ꢀ5 mol) were mixed and added dropwise to a solution of
SDS (0.0045 g) in water (2.00 g). The mixture was stirred vig-
orously (1600 rpm) for 1 h at room temperature and ultra-
sonicated for 30 min with pulses of 50 s and pauses of 10 s at
35 % amplitude (Sonics Vibra Cell 750, 750 W, 3 mm tapered
microtip) under ice cooling. The miniemulsion was transferred
to a Schlenk tube, sealed and purged with argon for 30 min under
ice cooling and placed in an oil bath at 708C for 24 h.
In conclusion, we have successfully demonstrated the use of
miniemulsion in a palladium catalysed Heck cross-coupling
reaction of aryliodides and olefins from 40 to 708C. The catalyst
chosen was the inexpensive, commercially available Pd(PPh3)4,
resulting in high yields of product with good control of the
stereochemistry. The remarkably high stability displayed by
the miniemulsions and the excellent solubility of the catalyst in
the reagents provided proof of the successful encapsulation of
the hydrophobic reactants and catalyst in the system. This
ensured that catalysis occurred within the generated mini-
emulsion nanodroplets, resulting in high yields as compared
with the low yields found when the catalyst was poorly solvated
in either toluene or DMF. As a result, this work highlights the
potential for conducting Heck reactions in miniemulsions and
opens up the possibilities for extending this process to other
palladium-catalyzed cross-coupling reactions, including
Suzuki-Miyaura or Sonogashira reactions for organic synthesis
and polymerization reactions.
Dynamic Light Scattering (DLS)
Dynamic light scattering measurements were performed using a
Malvern Zetasizer 3000HS. A droplet from the miniemulsion
was diluted in Milli-Q water and filtered before DLS measure-
ment at 258C. The sample refractive index (RI) was set at 1.59
for polystyrene. The dispersant viscosity and RI were set to
0.89 Ns mꢀ2 and 1.33, respectively.
Nuclear Magnetic Resonance (NMR) Spectroscopy
All NMR spectra were recorded on a Bruker DRX 500 MHz
spectrometer using an external lock (CDCl3) and utilizing the
solvent peak as an internal reference.
Experimental
Materials
Gas Chromatography-Mass Spectrometry (GC-MS)
Styrene (99 %, Sigma-Aldrich), tert-butylacrylate (98 %,
Sigma-Aldrich) and iodobenzene (98 %, Sigma-Aldrich) were
passed through a column of basic alumina before use.
4-Methoxyiodobenzene (98 %, Sigma-Aldrich), Pd(PPh3)4
(99 %, Sigma-Aldrich), triethylamine (Merck), hexadecane
(99 %, Sigma-Aldrich), sodium dodecyl sulfate (ultra-pure, ICN
Biomedicals Inc.) and dichloromethane were used as received.
Milli-Q water (18.2 MO cmꢀ1) was generated using a MilliQ
Academic water purification system.
The cis : trans ratio of the products was determined by GC-MS
(Shimadzu) using a 30 m ꢁ 0.32 mm ꢁ 0.25 mm Altech column.
Conditions: injection temperature 2758C; initial temperature:
408C, 1.5 min hold time; ramp to 2758C (208C minꢀ1), 4 min
hold time.
Acknowledgement
M.J.M. acknowledges financial support from the ARC Discovery grant
(DP0987315), Z.J acknowledges the UQ Postdoctoral Research Fellowship.
Heck Cross-Coupling Reaction in Miniemulsion
References
A typical Heck cross-coupling reaction in miniemulsion was
conducted as follows: styrene (0.2500 g, 0.0024 mol), iodo-
benzene (0.4898 g, 0.0024 mol), triethylamine (0.2429 g,
0.0024 mol), hexadecane (0.0150 g) and Pd(PPh3)4 (0.0277 g,
[1] S. Tascioglu, Tetrahedron 1996, 52, 11113. doi:10.1016/0040-4020
(96)00669-2
[2] M. J. Monteiro, Macromolecules 2010, 43, 1159. doi:10.1021/
MA902348R

1094
H. A. Zayas et al.
[3] R. N. Butler, A. G. Coyne, Chem. Rev. 2010, 110, 6302. doi:10.1021/
CR100162C
[15] J. Jiang, C. Cai, J. Colloid Interface Sci. 2006, 299, 938. doi:10.1016/
J.JCIS.2006.02.035
[4] R. F. Heck, Acc. Chem. Res. 1979, 12, 146. doi:10.1021/
AR50136A006
[5] K. H. Shaughnessy, R. B. DeVasher, Curr. Org. Chem. 2005, 9, 585.
doi:10.2174/1385272053765042
[16] A. R.-B. Baruch, D. Tsvelikhovsky, M. Schwarze, R. Schomacker,
M. Fanun, J. Blum, J. Mol. Catal. Chem. 2010, 323, 65. doi:10.1016/
J.MOLCATA.2010.03.012
[17] G. Zhang, H. Zhou, J. Hu, M. Liu, Y. Kuang, Green Chem. 2009, 11,
[6] C. Torborg, M. Beller, Adv. Synth. Catal. 2009, 351, 3027.
doi:10.1002/ADSC.200900587
[7] A. de Meijere, S. Brase, J. Organomet. Chem. 1999, 576, 88.
doi:10.1016/S0022-328X(98)01087-0
[8] Z. Bao, Y. Chen, R. Cai, L. Yu, Macromolecules 1993, 26, 5281.
doi:10.1021/MA00072A002
[9] B. H. Lipshutz, B. R. Taft, Org. Lett. 2008, 10, 1329. doi:10.1021/
OL702755G
1428. doi:10.1039/B822521D
[18] D. Tsvelikhovsky, J. Blum, Eur. J. Org. Chem. 2008, 2008, 2417.
doi:10.1002/EJOC.200800028
[19] K. Landfester, Macromol. Rapid Commun. 2001, 22, 896. doi:10.1002/
1521-3927(20010801)22:12,896::AID-MARC896.3.0.CO;2-R
[20] F. J. Schork, Y. Luo, W. Smulders, J. P. Russum, A. Butte´, K. Fontenot,
in Miniemulsion Polymerization Polymer Particles 2005, p. 129
(Ed. M. Okubo) (Springer: Berlin).
[10] B. H. Lipshutz, S. Ghorai, A. R. Abela, R. Moser, T. Nishikata,
C. Duplais, A. Krasovskiy, R. D. Gaston, R. C. Gadwood, J. Org.
Chem. 2011, 76, 4379. doi:10.1021/JO101974U
[21] E.Schreiber,U. Ziener, A. Manzke, A.Plettl, P.Ziemann,K. Landfester,
Chem. Mater. 2009, 21, 1750. doi:10.1021/CM802796Y
[22] P. Dolcet, M. Casarin, C. Maccato, L. Bovo, G. Ischia, S. Gialanella,
F. Mancin, E. Tondello, S. Gross, J. Mater. Chem. 2012, 22, 1620.
[23] D. P. C. de Barros, L. P. Fonseca, J. M. S. Cabral, E. M. Aschenbrenner,
C. K. Weiss, K. Landfester, Biotechnol. Bioeng. 2010, 106, 507.
doi:10.1002/BIT.22726
[24] D. P. C. de Barros, L. P. Fonseca, J. M. S. Cabral, C. K. Weiss,
K. Landfester, Biotechnol. J.2009, 4, 674. doi:10.1002/BIOT.200800294
[25] E. Hittinger, A. Kokil, C. Weder, Angew. Chem. Int. Edit. 2004, 43,
1808. doi:10.1002/ANIE.200352863
[11] M. M. Shinde, S. S. Bhagwat, J. Dispersion Sci. Technol. 2012, 33,
117. doi:10.1080/01932691.2010.548225
[12] J. Jiang, C. Cai, J. Dispersion Sci. Technol. 2006, 27, 1137.
doi:10.1080/01932690600900251
[13] Y. M. A. Yamada, K. Takeda, H. Takahashi, S. Ikegami, Org. Lett.
2002, 4, 3371. doi:10.1021/OL0264612
[14] Y. M. A. Yamada, K. Takeda, H. Takahashi, S. Ikegami, Tetrahedron
2004, 60, 4097. doi:10.1016/J.TET.2004.02.068