Suzuki-Miyaura Micellar Cross-Coupling in Water, at Room Temperature, and under Aerobic Atmosphere

Article abstract of DOI:10.1021/acs.orglett.6b03817

Recently, oxygen-equilibrated water solutions of Kolliphor EL, a well-known surfactant, have been seen to form nanomicelles with oxygen-free cores. This has prompted the successful testing of the core environment as a green medium for palladium-catalyzed Suzuki-Miyaura cross couplings. The versatility of these conditions is endorsed by several examples, including the synthesis of relevant molecular semiconductors. The reaction medium can also be recycled, opening the way for an extremely easy and green chemistry compliant methodology.

Full text of DOI:10.1021/acs.orglett.6b03817

Letter
pubs.acs.org/OrgLett
Suzuki−Miyaura Micellar Cross-Coupling in Water, at Room
Temperature, and under Aerobic Atmosphere
Sara Mattiello, Myles Rooney, Alessandro Sanzone, Paolo Brazzo, Mauro Sassi, and Luca Beverina*
Department of Materials Science, University of Milano−Bicocca, Via R. Cozzi, 55, Milano I-20125, Italy
S
* Supporting Information
ABSTRACT: Recently, oxygen-equilibrated water solutions of Kolliphor EL, a well-known surfactant, have been seen to form
nanomicelles with oxygen-free cores. This has prompted the successful testing of the core environment as a green medium for
palladium-catalyzed Suzuki−Miyaura cross couplings. The versatility of these conditions is endorsed by several examples,
including the synthesis of relevant molecular semiconductors. The reaction medium can also be recycled, opening the way for an
extremely easy and green chemistry compliant methodology.
icellar couplings enable the use of established C−C and
C−N bond-forming strategies at room temperature in
investigation, was confirmed by means of the platinum
porphyrin luminescence method.16,17 We here show that such
micelles provide a suitable medium for the Suzuki−Miyaura
cross coupling in water at room temperature under an
oxygenated environment. We show that such a surfactant,
used directly in air, is competitive in terms of yield with other
designer surfactants described in the literature. We also show
that Kolliphor EL can be profitably exploited for the synthesis
of popular molecular semiconductors pertaining to the classes
of diarylanthracenes,18 diketopyrrolopyrroles,19−21 diarylbenzo-
thiadiazoles,22 isoindigos,23 and perylenediimides.24−27
In order to comparatively test Kolliphor EL with established
coupling promoting surfactants, we tested the method under a
set of experimental conditions generally accepted as appropriate
in the dedicated literature: room temperature, a 2 wt % solution
of the surfactant in distilled water, 0.5 M concentration of the
halide (bromide in all our reactions), [1,1′-bis(di-tert-
butylphosphino)ferrocene]dichloropalladium(II) (Pd(dtbpf)-
Cl2) 2 mol % with respect to the bromide as the catalyst,
and triethylamine (N(Et)3) as the base.8 The reaction scope is
shown with examples of cross-coupling reactions in Scheme 1.
Derivatives 2−5 have isolated yields comparable with literature
data obtained with two popular and efficient designer
surfactants, Nok and TPGS-750-M.8 Results are generally
M
water.1−3 Several examples of standard4−7 and designer8,9
surfactants have been reported in the literature to provide green
environments for popular reactions such as the Suzuki−
Miyaura, Stille, Buchwald−Hartwig, Heck, and Sonogashira
couplings. In recent years, the advantages of such approaches
have been demonstrated, such as reduction in energy
consumption and organic waste.10 It has also been demon-
strated that Pd-doped Fe nanoparticles used in connection with
the micellar environment results in an excellent route for
Suzuki−Miyaura coupling with very low palladium concen-
trations.11 Examples of nickel-catalyzed micellar reactions have
also been reported.12 New and very active phosphine ligands
afford state of the art results at very low palladium loading and
with chlorides as well as bromides.13 Micelles also provide an
ideal reaction environment for reactions other than palladium-
mediated couplings.14 In particular, the Lipshutz group recently
demonstrated that the high solubility of oxygen in organic
media, including micelles, can be very profitably exploited to
carry out the aerobic oxidation of water-insoluble arylalkynes to
β-ketosulfones under very mild conditions. Precisely because of
such high oxygen content, palladium-catalyzed micellar cross-
coupling reactions require deoxygenation of the reaction
environment. Recently, we demonstrated that the commercially
available surfactant Kolliphor EL assembles into nanomicelles
with oxygen-free cores having an average hydrodynamic
diameter of 6−7 nm.15 This unexpected property, still under
Received: December 22, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03817
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Organic Letters
Letter
Scheme 1. Micellar Couplings in Water and under
Oxygenated Environment
Table 1. Test Reaction between 3-Bromoisoquinoline and 3-
Thiopheneboronic Acid in Different Surfactants
a
a
entry
medium
run
atmosphere
time (h)
yield (%)
1
2
5
6
7
8
Kolliphor EL
Kolliphor EL
Triton X-100
Triton X-100
TPGS-750-M
TPGS-750-M
I
air
air
air
N2
air
N2
1
2
2
2
2
2
90
70
68
80
69
95
II
I
I
I
I
a
Conditions: 0.75 mmol of boronic acid, 0.5 mmol of aryl bromide,
1.5 mmol of N(Et)3, and 0.02 mmol of Pd(dtbpf)Cl2 in 1 mL of
surfactant solution at room temperature.
nitrogen-saturated water. Indeed, we were able to increase
the yield from 68 to 80% in the case of Triton X-100 and from
69 to 95% in the case of TPGS-750-M. The absolute higher
yield obtained with the latter surfactant is not surprising;
TPGS-750-M is a designer surfactant, specifically engineered to
perform cross-coupling reactions. Conversely, Kolliphor EL is
just an emulsifier, unoptimized for micellar couplings. The real
gain when using Kolliphor is the oxygen insensitivity rather
than the absolute performance (remarkable in any case).
To further substantiate this point, we carried out an
additional experiment using the oxygen-sensitive catalyst
tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4). We
prepared two identical dispersions, one with Kolliphor EL
and one with TPGS-750-M, of 10 mg of Pd(PPh3)4 in 2 mL of
2% by weight surfactant solution in water. Such dispersions,
both featuring the characteristic yellow coloration of fresh
Pd(PPh3)4, were allowed to stir at room temperature for 24 h in
a standard laboratory environment. After aging, the TPGS-750-
M dispersion darkened significantly (Figure 1). Both
dispersions were thus charged with 6-methoxynaphthalene-2-
boronic acid, 9-bromoanthracene, and N(Et)3. Figure S1 shows
the GC−MS trace of both reactions after 3 h of stirring. The
Kolliphor EL dispersion gives the expected product; conversely,
a
Aryl bromides (in red) and arylboronic acids (in black) were coupled
in 2 wt % Kolliphor EL solution in deionized water. Conditions: 0.75
mmol of boronic acid, 0.5 mmol of aryl bromide, 1.5 mmol of N(Et)3,
and 0.02 mmol of Pd(dtbpf)Cl2 in 1 mL of surfactant solution at rt
and in air. For compound 10, 0.5 mmol of 1,4-phenylbisboronic acid
and 1.5 mmol of 2-bromothiophene were used. Isolated yields and
reaction times are given.
comparable, with the relevant difference of Kolliphor reactions
being carried out under standard oxygenated environment.
Table S1 gives additional examples, including reactions
carried out with less reactive catalysts like [1,1′-bis-
(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd-
(dppf)Cl2) and palladium acetate. Whenever a thiophene
residue was present, the use of Pd(dtbpf)Cl2 gave the best
results. We carried out a comparative study on the coupling of
3-thiopheneboronic acid and 3-bromoquinoline by using two
popular micelle-forming surfactants: Triton X-100 and the
designer surfactant TPGS-750-M. Table 1 shows that under
otherwise identical conditions the reaction with Kolliphor leads
to 90% yield while the reactions with Triton X-100 and TPGS-
750-M afford the product in a more modest 68% and 69% yield,
respectively. As an extra benefit, in the case of Kolliphor, the
coupling product can be readily isolated by filtration. This
prompted us to recycle the aqueous phase for a second
consecutive reaction without adding a fresh catalyst. The
reaction behaved satisfactorily, leading to an isolated yield of
70% after 2 h.
The role of oxygen in explaining the different behavior of
Kolliphor-, Triton-, and TPGS-750-M-enhanced reactions was
further confirmed by repeating the reactions with Triton X-100
and TPGS-750-M under nitrogen atmosphere and with
Figure 1. (a) As-prepared dispersions of 10 mg of Pd(PPh3)4 in
Kolliphor EL (denoted with K) and TPGS-750-M (denoted with P).
(b) Dispersions after 24 h aging at room temperature and under
oxygenated environment.
B
DOI: 10.1021/acs.orglett.6b03817
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the TPGS-750-M reaction leads to negligible conversion,
coherent with extensive catalyst degradation.
same section, we also discuss a rationalization of such
concentration dependency, based on a previous observation
that Kolliphor micelles possess oxygen-free cores but oxy-
genated shells.15
Reaction conditions leading to diarylanthracenes were also
successfully employed for the synthesis of the organic
semiconductors shown in Scheme 3. Derivatives 16 and 17
Kolliphor EL is mostly known for being an excellent
dispersant of relatively insoluble drugs such as Taxol and its
derivatives.28 We decided to challenge its dispersion capabilities
in a series of cross-coupling reactions involving organic
semiconductors pertaining to the classes of 9,10-diarylanthra-
cenes, diketopyrrolopyrroles, diarylbenzothiadiazoles, perylene-
diimides, and isoindigos. Such compounds possess solid track
records in a variety of organic devices.29,30 The availability of an
exceedingly simple procedure for their late-stage functionaliza-
tion would be of high value for the organic materials
community. Working with such starting compounds required
further optimization of the reaction conditions.
Scheme 3. Micellar Synthesis of Selected Molecular
a
Semiconductors
Scheme 2 shows a series of reactions involving 9,10-
dibromoanthracene (DBA) and four arylboronic acids bearing
a
Scheme 2. Micellar Couplings on 9,10-Dibromoanthracene
a
Couplings of brominated precursors (in red) and arylboronic acids or
esters (in black) performed in a 2 wt % Kolliphor EL solution in
deionized water. Conditions: 0.5 mmol of bromide, 1.5 mmol of
arylboronic acid, 3.0 mmol of N(Et)3, and 0.03 mmol of Pd(dtbpf)Cl2
in 0.5 mL of surfactant solution. For compound 21, 0.5 mmol of
diphenylacetylene-4,4′-diboronic acid bis(pinacol) ester and 1.5 mmol
of bromide were used. Isolated yields and reaction times are given.
a
Couplings of 9,10-dibromoanthracene (in red) and different
arylboronic acids (in black) performed in a 2 wt % Kolliphor EL
solution in deionized water. Conditions: 0.5 mmol of bromide, 1.5
mmol of arylboronic acid, 3.0 mmol of N(Et)3, and 0.03 mmol of
Pd(dtbpf)Cl2 in 0.5 mL of surfactant solution (apart from compound
12) at room temperature and in the air. Isolated yields, after
crystallization, are given.
are known fluorescent molecules and behave in a way similar to
that of diarylanthracene compounds. These are poorly soluble
crystalline derivatives; they can be directly filtered from the
reaction medium and purified by crystallization. Derivatives 18
and 19 are examples of heavily functionalized compounds that
could interfere with the micellar structure of Kolliphor EL in
solution. Characteristics of such isoindigo derivatives made the
reaction mixture difficult to efficiently stir, as most of the
material formed an oily and sticky residue on the walls of the
reaction flask. To deal with the problem, we mechanically
shook the reaction mixture and increased the reaction time to
24 h. Derivatives 20 and 21 are examples of a coupling reaction
involving a boronic ester instead of an acid. The reactions
proved to be significantly slower, again mostly due to the high
viscosity of the reaction mixture.
different functional groups. The reaction with phenylboronic
acid was tested to optimize reaction conditions. We
consistently obtained the highest yield by increasing reaction
mixture concentrations. In particular, dilution of the reaction
mixture favored formation of the homocoupling biphenyl side
product. This process is commonly connected with oxygen
being present in the reaction mixture.31 Conversely, when
working at 1 M bromide concentration, we obtained a 95%
yield after crystallization and no isolated biphenyl.
Working under the same conditions, we isolated all other
cross-coupling products with yields between 69 and 95%. Table
S2 shows details for every reaction, including the structure and
yield of the homocoupling products (where present). In the
C
DOI: 10.1021/acs.orglett.6b03817
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Organic Letters
Letter
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graphic purification in moderate to good yields. Further
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In conclusion, we have demonstrated that Kolliphor EL, a
cheap, readily available, and well-established drug emulsifier and
surfactant, can be used with a simple room-temperature
method to access a wide variety of Suzuki−Miyaura coupling
products affording high yield in air. The scope of the reaction is
demonstrated with the coupling of a wide variety of aryl and
heteroaryl bromides with various boronic acids and esters,
including examples of well-established organic molecular
semiconductor cores. All reactions can be carried out directly
in a standard oxygenated environment in deionized water. The
reaction medium can be recycled. In the case of crystalline
compounds, the coupling products can be isolated directly by
filtration. By comparing Kolliphor EL to other designer
surfactants, we have demonstrated that Kolliphor EL alone
provides an environment suitable for efficient oxygen-
insensitive reactions. In short, we demonstrated an exceedingly
simple, economically convenient, and sustainable benchtop
protocol for efficient Suzuki−Miyaura coupling. We are
currently exploring polymerization reactions according to the
same method with very encouraging results.
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ASSOCIATED CONTENT
* Supporting Information
■
S
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(21) Ripaud, E.; Demeter, D.; Rousseau, T.; Boucard-Cetol, E.;
Allain, M.; Po, R.; Leriche, P.; Roncali, J. Dyes Pigm. 2012, 95 (1), 126.
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b03817.
(23) Stalder, R.; Puniredd, S. R.; Hansen, M. R.; Koldemir, U.;
General experimental procedures, additional examples,
and full characterization data for all compounds (PDF)
Grand, C.; Zajaczkowski, W.; Mullen, K.; Pisula, W.; Reynolds, J. R.
̈
Chem. Mater. 2016, 28 (5), 1286.
(24) Wurthner, F.; Saha-Moller, C. R.; Fimmel, B.; Ogi, S.;
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AUTHOR INFORMATION
Leowanawat, P.; Schmidt, D. Chem. Rev. 2016, 116 (3), 962.
(25) Chen, S.; Slattum, P.; Wang, C.; Zang, L. Chem. Rev. 2015, 115
(21), 11967.
(26) Hartnett, P. E.; Timalsina, A.; Matte, H. S. S. R.; Zhou, N.; Guo,
X.; Zhao, W.; Facchetti, A.; Chang, R. P. H.; Hersam, M. C.;
Wasielewski, M. R.; Marks, T. J. J. Am. Chem. Soc. 2014, 136 (46),
16345.
(27) Zhan, X.; Facchetti, A.; Barlow, S.; Marks, T. J.; Ratner, M. A.;
Wasielewski, M. R.; Marder, S. R. Adv. Mater. 2011, 23 (2), 268.
(28) Petros, R. A.; DeSimone, J. M. 2010, 1.
■
Corresponding Author
*E-mail: luca.beverina@mater.unimib.it.
ORCID
Luca Beverina: 0000-0002-6450-545X
Notes
The authors declare no competing financial interest.
(29) Lin, Y.; Li, Y.; Zhan, X. Chem. Soc. Rev. 2012, 41 (11), 4245.
ACKNOWLEDGMENTS
■
(30) Mishra, A.; Bauerle, P. Angew. Chem., Int. Ed. 2012, 51 (9),
̈
We thank Universita
̀
degli Studi Milano-Bicocca (Grant No.
2020.
2016-ATESP-0047) for financial support. L.B. and M.R. thank
the European Community’s Seventh Framework Programme
(FP7/2007-2013) under Grant Agreement No. 607232 for
financial support (THINFACE).
(31) Adamo, C.; Amatore, C.; Ciofini, I.; Jutand, A.; Lakmini, H. J.
Am. Chem. Soc. 2006, 128 (21), 6829.
(32) Lipshutz, B. H.; Gallou, F.; Handa, S. ACS Sustainable Chem.
Eng. 2016, 4 (11), 5838.
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DOI: 10.1021/acs.orglett.6b03817
Org. Lett. XXXX, XXX, XXX−XXX