Taming troublesome suzuki-miyaura reactions in water solution of surfactants by the use of lecithin: A step beyond the micellar model

Article abstract of DOI:10.1021/acs.oprd.0c00285

The use of water solutions of industrial and designer surfactants enables performing a wide variety of chemical transformations on hydrophobic precursors. Most reactions are clean, fast, and efficient with vast benefits for overall sustainability. The wid

Full text of DOI:10.1021/acs.oprd.0c00285

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Full Paper
Taming troublesome Suzuki-Miyaura reactions in water solution of
surfactants by the use of lecithin: a step beyond the micellar model
Chiara Ceriani, Erika Ghiglietti, Mauro Sassi, Sara Mattiello, and Luca Beverina
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.0c00285 • Publication Date (Web): 04 Sep 2020
Downloaded from pubs.acs.org on September 4, 2020
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Taming troublesome Suzuki-Miyaura reactions in
water solution of surfactants by the use of
lecithin: a step beyond the micellar model
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†
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∗,†
Chiara Ceriani, Erika Ghiglietti, Mauro Sassi, Sara Mattiello, and Luca
∗
,‡
Beverina
†Department of Materials Science, University of Milano-Bicocca, Via R. Cozzi, 55, Milano,
Italy.
‡Department of Materials Science, University of Milano-Bicocca and INSTM, Via R.
Cozzi, 55, Milano, Italy.
E-mail: sara.mattiello@unimib.it; luca.beverina@unimib.it
Abstract
The use of water solutions of industrial and designer surfactants enables performing
a wide variety of chemical transformation on hydrophobic precursors. Mostly reactions
are clean, fast and efficient with vast benefits for overall sustainability. The widespread
adoption of such methods is somewhat hampered by a lack of generality in the case of
troublesome substrates and scaling up. The common literature solution for such issues
is the use of small amounts of organic solvents. We here show that the use of a mixture
of L-α-lecithin and Tween 80 is a preferable solution enabling the taming of particularly
troublesome reactions, where even the cosolvent approach fails. The strong reduction
of all interface tensions characterizing such complex multiphase systems is key to the
results achieved. The protocol is general and scalable.
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Introduction
The development of improved synthetic methods offering selectivity, high yield and short
reaction times while providing moderate or no heating is a cornerstone of modern sustain-
able chemistry.1,2 Unfortunately, the need for organic solvents remains the elephant in the
room.3,4 Despite the obvious benefits, their replacement with water in homogeneous phase
reactions is troublesome as the vast majority of fine chemicals and/or precursors are water
insoluble. Literature shows that the addition of surfactants to water can drastically change
such a scenario.5–9 Several different chemical processes can be profitably performed in water
with high yield, irrespective to the solubility of reagents and products.10–14 Gathered under
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the banner of “micellar catalysis” (MC) such methods witnessed an enormous boost in scope,
generality and synthetic usefulness in the last 10 years, even at the industrial scale.15–18
Strictly speaking, MC refers to the catalytic effect on reactions performed in an homogeneous
single-phase nanodispersed medium obtained in the presence of a water based surfactant so-
lution above the critical micellar concentration (CMC).19 Under such conditions, surfactant
molecules assemble into micelles, thermodynamically stable association colloids having a
hierarchical structure consisting in a lipophilic core and a hydrophilic periphery. Micelles
formation is accompanied by a steep increase in solubility of lipophilic reagents/catalysts,
mostly localizing in the micelle core. Higher reagents concentration, co-localization and hy-
drophobic effects play a central role in the observed catalysis.19,20
However, such a prototypical micellar system is limited to low reagents loading. Concen-
−4
trations lower than 10 M, far below the saturation concentration which maintains a single
isotropic solution (maximum additive concentration, MAC), are typical of earlier kinetic
studies.21,22 The scope of surfactant enhanced reactions was later extended towards syn-
thetically useful applications. Such shift was accompanied by substantial deviations from
the aforedescribed micellar model. Formal concentrations of reactants were substantially
increased exceeding MAC and thus leading to complex multi-phase systems. As an example,
typical experimental conditions involve the use of a 1 wt% to 3 wt% water solution of the
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surfactant and 0.5 M to 1 M formal concentrations of poorly water soluble reagents resulting
in inhomogeneous mixtures as those depicted in Fig. 1.
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Figure 1: Pictures of relevant micellar reactions reported in the literature. A) Direct
arylation between N-(m-hydroxyphenyl)-N’,N’-dimethylurea and 4-iodoanisole. Copyright
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2017 American Chemical Society. B) Suzuki-Miyaura coupling between BTBT-Br and
phenylboronic acid. Reproduced from Ref.14 with permission from the Royal Society of
Chemistry. C) Amide bond formation between (S)-N-(benzyloxycarbonyl)valine and tert-
Butyl (3R,4S,5S)-3-methoxy-4-(N-methylamino)-5-methylheptanoate hydrochloride. Copy-
right 2016 American Chemical Society.23 D) Cross-metathesis reaction between 1-tert-
butyldimethylsilyloxy-2-(2-propenyl)benzene and methylvinylketone. Copyright 2014 Amer-
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ican Chemical Society.
Despite the extensive literature from the group of prof. Lipshutz and prof. Handa amongst
others23 clearly demonstrated that dealing with a complex multiphase system does not pre-
clude effective surfactant enhanced catalysis, unpredictable behavior is often encountered.25
These limits often manifest themselves as lack of reproducibility when changing the experi-
mental set-up, particularly regarding to the mixing method.11,23 The use of limited amounts
of organic solvents along with mild heating mitigates the problem but does not represent
a completely satisfactory solution: processes still rely on organic solvent and no insight
on the underlying mechanism is given.16,17,23,26 In such complex multi-phase systems the
surfactant can still form micelles or other aggregates but also lies at the phase boundary,
lowering the interfacial tension and allowing the formation of very small, kinetically sta-
ble, droplets/particles.27 Alongside with the bona fide micellar catalysis, other surfactant
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mediated processes are also at work. Boyer et al. showed that under biphasic conditions,
the catalytic effect of the surfactant can result from a combination of interfacial catalysis
(
IC) and an hybrid inverse phase transfer catalysis (IPTC).28–30 The latter involves a dual
role played by the surfactant: enhancing mass transport of reagents to the water phase and
therein promoting the micellar catalysis of the chemical step (Fig. 2). This observation
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IPTC
IC
Organic phase
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Organic phase
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Aqueous phase
Aqueous phase
Figure 2: Principles of an inverse phase transfer catalysis (IPTC) and interfacial catalysis
(IC) with a surfactant as catalyst (S, substrate; R, reactant; P, product) as described by
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highlights the fact that in complex multi-phase systems normal and inverse phase transfer
catalysis (PTC, IPTC), micellar catalysis (MC) and interface catalysis (IC) become inter-
twined phenomena. So far, the capability to form micelles of a certain dimension and aspect
ratio guided the selection of the most suitable surfactant for reactions in water environment.
Such features are critical but insufficient: the capability to maintain efficient mass transfer
through different phases during the whole chemical process is at least as important.
We here describe a different approach capable of taming capricious reactions without the
use of any organic solvent and/or heating. For this purpose, we sampled some particular
examples of troublesome coupling reactions carried out on liquid reagents having issues of
reproducibility when performed in aqueous surfactant solutions. Once recognized that the
true nature of reactions carried out with liquid reagents and limited amount of surfactant
is that of an emulsion, we selected a surfactant mixture specifically devised to better coun-
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terbalance the surface tension. In particular, we selected a mixture of two commercially
available, food-grade amphiphiles, Tween 80 and L-α-lecithin, known as efficient emulsifiers
for oil spills. Under such conditions we demonstrate that it is possible to successfully address
all reproducibility issues in terms of mixing method in a Suzuki-Miyaura (SM) coupling so
tenaciously irreproducible that not even the cosolvent method afforded satisfactory results.
We also show that such approach is general, providing excellent results for other reagents
featuring similar behavior.
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Results and discussion
We identified several SM coupling reactions showing reproducibility issues, some of which
are shown in Scheme 1 (additional examples and reactions details are listed in Table S1
of the ESI). Differences in the reaction outcome were observed upon modifications in: ves-
sel, stirrer/mixing apparatus and stirring speed. Among them, the SM coupling of (4-
bromophenyl)methyl acetate (1) with 2-thienylboronic acid (shown in heading of Table 1)
displays a particularly erratic behavior. Data in the first part of Table 1 (entries 1-8) summa-
rize the results obtained upon systematically varying the mixing setup using either a 2 wt%
solution of Kolliphor EL (K-EL) or a 2 wt% solution of the state of the art designer surfactant
TPGS-750M in water as the reaction medium. The choice of such surfactants was dictated
by their literature established performance for micellar coupling reactions.31–33 Comparison
among entries 1 to 5 clearly shows that conversion is strikingly influenced by the chosen
mixing setup, going from 15% to 80%. However, when the reaction was performed twice
using the same setup and stirring speed, consistent results were obtained (entry 4-5). In all
of the cases, leaving reactions stirring for more than 3 hours did not improve conversions.
Not even performing the reaction using the well-known TPGS-750M surfactant allowed to
obtain reproducible results (entry 6-7). Such a dependency of conversions from the mixing
method suggests that interphase mass transfer may become rate limiting once massive phase
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Et N, Pd(dppf)Cl
O
3
2 wt% K-EL in H O
2
O
S
OH
OH
2
+
B
O
O
S
O
O
rt, 3 h
80% (setup a, 800 rpm)
43% (setup a, 1000 rpm)
Br
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1b
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Et N, Pd(dppf)Cl
3
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2
S
OH
OH
+
B
S
rt, 3 h
8% (setup a)
7% (setup c)
Br
5
9
2
2b
Et N, Pd(dppf)Cl
3
2 wt% K-EL in H2O
2
N
N
S
OH
OH
+
B
S
rt, 3 h
63% (setup a)
91% (setup d)
Br
3
3b
Scheme 1: Examples of variable results obtained for SM coupling reactions of 1, 2 and
with 2-thienylboronic acid. Reaction conditions: 1 M of bromide, 1 M of boronic acid,
.5 M of NEt , 0.02 M of Pd(dppf)Cl in 2 wt% aqueous solution of Kolliphor EL, room
temperature, 3 hours. Couplings are performed on 2 mmol of bromide, and scale is unvaried
in all reactions. Setup a: 10 mL roundbottom test tube (inner diameter: 1.2 cm, height: 9
cm), cylindrical stirrer (2.5 cm length), see Figure S1-A. Setup c: 4 mL vial (inner diameter:
3
1
3
2
1
.3 cm, height: 4.4 cm), two piled round stirrers (diameter: 1.0 cm, height: 0.8 cm), see
Figure S1-C. Setup d: 4 mL vial (inner diameter: 1.3 cm, height: 4.4 cm). Reaction was
firstly homogenized using an UltraTurrax high shear mixer for 10 minutes at 5000 rpm (see
Figure S1-D), and subsequently mixed using two piled round stirrers (diameter: 1.0 cm,
height: 0.8 cm).
separation occurs during the evolution of reagents into products. This phenomena appear
as the ultimate result of the kinetic instability of the emulsion towards flocculation, coales-
cence and creaming.34 In support of this hypothesis, when we carried out the coupling using
an Ultra-Turrax homogenizer that guaranteed thorough mixing, we consistently observed
essentially quantitative conversion (entry 8).
As already mentioned, literature acknowledges that the use of moderate amount of a cosol-
vent might be an efficient strategy to tackle such mixing issues in micellar catalysis.23,26,35,36
Acetone and THF in particular are recognized as efficient cosolvents for the SM coupling.16
However, such an approach - which remains a valid and resourceful protocol to clear away
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Table 1: SM coupling of 1 with 2-thienylboronic performed with different setups and aqueous
media (reaction conditions: 1.0 M of bromide, 1.0 M of boronic acid, 1.5 M of NEt , 0.02 M
3
of Pd(dppf)Cl , room temperature, 3 hours). Setup a, c and d are described in caption of
2
Scheme 1.
S
OH
OH
1
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B
O
O
O
O
Et N, Pd(dppf)Cl
3
reaction medium
2
S
rt, 3 h
Br
1
1b
Entry
Setup
Stir. speed
(rpm)
800
1000
800
1000
1000
800
1000
1000
Reaction medium
Conv.
1
2
3
4
5
a
a
b
c
c
a
a
d
2 wt% K-EL in H O
2 wt% K-EL in H O
2 wt% K-EL in H O
2 wt% K-EL in H O
2 wt% K-EL in H O
2 wt% TPGS-750M in H O
2 wt% TPGS-750M in H O
2 wt% K-EL in H O
80%
43%
15%
65%
68%
50%
67%
94%
2
2
2
2
2
6
7
8
*
*
2
2
2
9
1
1
1
a
a
a
a
800
1000
800
(2 wt% K-EL in H O)/THF 9:1
25%
72%
70%
61%
2
0
1
2
(2 wt% K-EL in H O)/THF 9:1
2
(2 wt% K-EL in H O)/acetone 9:1
2
1000
(2 wt% K-EL in H O)/acetone 9:1
2
Setup b: 100 mL roundbottom test tube (inner diameter: 2.7 cm, height: 20 cm), cylindrical stirrer (2 cm
length), see Figure S1-B.
* Reaction was performed under N atmosphere.
2
most of the toxic organic solvents - in our case improved only modestly the behavior of the
reaction (entry 9-12) and, at the same time, does not fully honor the commitment to clear
away organic solvents.
Once recognized that the reproducibility was dependent on the kinetic stability of obtained
emulsion, we decided to approach the problem using an improved surfactant mixture able
to tackle this issue. In particular, taking inspiration from the literature pertaining self-
emulsifying systems (i.e. systems requiring very little energy to form fine emulsions),37,38
we chose to test the Tween 80/L-α-lecithin surfactants mixture. Thanks to their synergistic
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action, this food-grade amphiphiles combination already proved to be an effective and safer
alternative to toxic solvent-based dispersants for marine oil spills39–41 and also found appli-
cation in drug-delivery.42 We thus decided to test an aqueous 2 wt% Tween 80/lecithin 8:2
mixture (TL82), suitable to obtain oil-in-water emulsions, as the medium for our trouble-
some SM coupling. This particular ratio was selected in order to obtain an HLB (Hydrophilic
Lipophilic Balance) value similar to that of both Kolliphor EL (with which we already had
a vast experience) and TPGS-750-M, the standard in micellar catalysis. Also, lecithin is
not water soluble and using mixtures at a higher lecithin content would have led to poor
dispersibility in water.
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The first striking difference with prior experiments was observed during sample preparation:
a simple visual comparison, Fig. 3, highlights the superior stability of the emulsion of 1
in TL82 vs. that obtained in K-EL. While both mixtures were prepared identically and
Figure 3: Coalescence of the emulsions of 1 (1 mmol) prepared in 1 mL of a 2 wt% aqueous
solution of K-EL (left) and TL82 (right).
thoroughly mixed with the aid of an ultrasound bath, in the case of K-EL rapid coalescence
occurs and two layers separate. Conversely, a fine and stabler emulsion forms when using
TL82, meaning that the surface tension of this system is lower and droplets of organic phase
are stabilized more effectively.
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Table 2 summarizes results obtained performing the coupling reaction in both aqueous K-EL
and TL82 surfactants mixture with two different setups.
Table 2: Conversions for the SM coupling shown in Scheme 1 performed in 2 wt% aqueous
solution of K-EL or TL82. The stirring setup (10 mL roundbottom test-tube equipped with
a cylindrical stirring bar) is unvaried in all reactions.
1
1
1
1
1
1
1
1
1
1
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Entry
Surfactant
Atm.
Stirring speed
rpm)
Conversion
(Time)
(
1
2
3
4
5
K-EL
K-EL
TL82
TL82
TL82
air
air
air
air
N2
800
1000
800
1000
800
80% (3 h)
43% (3 h)
90% (1 h)
92% (1 h)
97% (1 h)
Reactions performed in TL82 do not show the reproducibility issues previously observed
with K-EL and TPGS-750M, with conversion rising to 90% in 1 hour when working under
air unregarding to the mixing setup used to perform the reaction (entry 3-4). Employing
such self-emulsifying system allows obtaining an emulsion whose features are essentially in-
dependent from the mixing method due to the reduced surface tension. The observed higher
catalytic activity is also believed to be a consequence of the formation of a finer and stable
emulsion and unhindered interphase mass transport.
Performing the reaction under inert atmosphere allowed reaching an even higher 97% conver-
sion (entry 5). This last result was expected, as environmental oxygen is a known poisoning
agent for the Pd(0) catalyst involved in the reaction.
To exclude an effect of ionic interactions between the 2-thienyl boronate and lecithin (due
to its zwitterionic nature) in the observed reaction behavior, we also performed the coupling
using a K-EL/lecithin 8:2 mixture, which does not have self-emulsifying capabilities. With
this surfactants mixture the reaction gave again unreliable results (See Table S2 in the ESI).
As the emulsifying capabilities of the TL82 mixture proved suitable to both overcome the
reproducibility issues of the chosen test coupling and to improve the reaction conversion, we
decided to test its performance on other substrates featuring similar behavior. We there-
fore performed the coupling reaction of 2-thienylboronic acid with other aryl bromides: 4-
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2
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2
2
2
2
2
2
3
3
3
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3
3
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bromoanisole (2), 3-bromoquinoline (3) and 3-bromothiophene (4). Scheme 2 summarizes
the obtained results.
S
OH
OH
B
S
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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7
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9
0
1
2
3
4
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0
1
2
3
4
5
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7
8
9
0
Pd(dppf)Cl Et N
2,
3
Br
2 wt% surfactant in H O
2
rt, 1-3 h
#
#b
Br
Br
Br
Br
S
=
O
N
4
2
3
Entry
Product
2b
2b
3b
3b
Surfactant
K-EL
TL82
K-EL
TL82
Conversion (Time)
58% (3 h)
100% (1 h)
63% (3 h)
94% (3 h)
60% (3 h)
1
2
3
4
5
6
4b
4b
K-EL
TL82
100% (1 h)
Scheme 2: Conversions obtained for the coupling reaction between 2, 3 and 4 with 2-
thienylboronic acid (1 M of bromide, 1 M of boronic acid, 1.5 M of NEt , 0.02 M of
3
Pd(dppf)Cl , room temperature) in 2 wt% surfactant solution of K-EL or TL82. Reac-
2
tions performed with TL82 surfactant were run under N atmosphere. The stirring setup
2
(10 mL roundbottom test-tube equipped with a cylindrical stirring bar, stirring speed of 800
rpm) is unvaried in all reactions.
In all of the cases, reactions performed using the K-EL surfactant did not exceed 65% conver-
sion after 3 hours. Using the TL82 surfactants mixture we obtained quantitative conversion
in the case of substrates 2 and 4 in just one hour, and 94% conversion for substrate 3 in 3
hours. As observed for substrate 1, the use of TL82 allows to obtain higher conversions in
a shorter time. Preliminary results show that the TL82 can be successfully applied in the
Sonogashira and an Heck couplings as well (see Scheme S1 of the ESI). In terms of stability
under the reaction conditions required by the various cross couplings we tested, the TL82
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mixture appears to be suitably robust (see Section 5 of the ESI). Indeed, lecithin itself is
reported to be particularly stable at high pH levels and in the absence of oxygen. Such
conditions are very similar to those we employed in our reactions.43–45
Finally, we tested the robustness towards scaling up of our protocol by performing the cou-
pling reaction of 1 with 2-thienylboronic acid on 10 g of reagents (a 14th fold increase in
the scale) in a round-bottom flask and using a mechanic stirrer, under otherwise identical
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
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4
4
4
4
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5
5
5
5
5
6
0
1
2
3
4
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7
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9
0
1
2
3
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9
0
1
2
3
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4
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0
1
2
3
4
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8
9
0
conditions to Table 2, entry 5 test. Upon the addition of NEt , the initial biphasic mixture
3
turned into an homogeneous emulsion (Figure 4), and the reaction spontaneously warmed
◦
up to 35 C over ten minutes. We achieved complete conversion within 1 h and isolated the
Figure 4: SM coupling of 1 with 2-thienylboronic on a 10 g scale. a) Reaction mixture
appearance before the addition of NEt b) Reaction mixture appearance one minute after
3
the addition of NEt c) Reaction mixture appearance one hour after the addition of NEt .
3
3
target compound in 97% yield. Lowering the catalyst amount to 1.5 mol% and 1 mol% of
Pd(dppf)Cl gave respectively a 83% and 78% conversion after 3 hours. Literature reports
2
examples of catalysts that are far more effective than the commercially available one we
selected. In particular, Liphshutz and Handa demonstrated the possibility to carry out SM
and Sonogashira reactions at ppm levels of Pd.46,47 Such a solution also represents the ideal
strategy to reduce possible palladium contamination in the product, a problem we intention-
ally did not address in this paper. We here focus only on demonstrating that TL82 mixture
enables running efficient SM coupling on otherwise troublesome substrates even in the large
scale.
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1
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2
2
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2
2
2
2
2
2
2
3
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3
3
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4
4
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4
4
4
4
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5
5
5
6
Concerned about the possible hazards connected with the exothermic behavior we observed,
we repeated the reaction three more times on the same scale, with the same setup and at
2
mol% catalyst loading. The first repetition was performed working identically, but with
a thermometer inserted in the reaction mixture (previously we monitored the temperature
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
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9
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4
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0
of the reactor’s walls by means of an IR scanner). The maximum temperature reached was
◦
5
0 C, and conversion was again quantitative after 1 h. In the second repetition we added
the base dropwise over a period of 10 minutes, while keeping the reactor immersed in a water
bath. In this case, we did not measure any appreciable raise in the temperature, yet we noted
that such a slow addition is not helpful for the homogeneity of the reaction mixture. Lumps
of sticky material formed, which were difficult to redisperse. The conversion was 72% and
the isolated yield was 68%. In the third repetition we studied the effect of the slow addition
of the catalyst. While setting up the reaction, we added the base all at once to the emulsion
of bromide and boronic acid. We noticed that just after the addition of the base and prior to
◦
the introduction of any catalyst the reaction warmed up to almost 40 C, meaning that most
of the exothermic effect is connected with the acid-base reaction of the boronic acid with the
base. This observation reduces the concerns for possible decompositions reactions leading
to runaway thermal effects. Once back at room temperature, we added the catalyst over a
period of 10 minutes. Again, we observed some demixing while doing so. The conversion
was 84% and the isolated yield was 82%. Puzzled by the partial demixing effect observed
◦
in both cases, we heated samples taken from the second and third repetition at 50 C by ex-
ternal heating, thereby restoring a homogeneous, freely stirring emulsion. Our observations
◦
suggest that reaching a temperature around 50 C in the early stage of the reaction is helpful
in maintaining a homogeneous emulsion (well in agreement with the fact that emulsions are
easier to form at high temperature).
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Conclusions
Micellar reactions carried out at formal concentrations vastly exceeding MAC are strongly
impacting the sustainability of a vast number of chemical transformations including cross-
couplings. We have faced the known issue of lack of reproducibly, particularly when changing
experimental set up and reaction scale, from a different perspective with respect to the ex-
isting literature. Whereas the general consensus to tame problematic micellar reactions
requires the use of an organic cosolvent, we focused our attention on the details of the for-
mulation state of the reaction mixture and carefully tuned the tensides cocktail accordingly.
Above MAC, micellar reactions are complex heterogeneous mixtures where micellar cataly-
sis coexists with other catalytic mechanisms like IC and IPTC. The mass transfer between
emulsion droplets, dispersed particles and micelles dominates the reaction behavior to the
point that the capability of a given surfactant to assemble into micelles of a certain shape
and/or volume has only a limited impact on the overall conversion. On the other hand, the
capability of the tensides to efficiently and rapidly emulsify the oil phase maximizing the
contact area of all interphases becomes the limiting step. Indeed, we show that the use of
a Tween 80/L-α-lecithin surfactants mixture, a system well known to readily provide finely
dispersed emulsion of the most hostile hydrophobes, leads to satisfactory results in a num-
ber of S-M couplings where other commercial and designer surfactants failed, even in the
presence of cosolvents. Even more importantly, all reactions proved to be insensible to setup
parameters like the stirring speed and reaction scale, generally heavily impacting on stan-
dard micellar protocols. Our findings clearly show that the capability of a given surfactant
to self-assemble into micelles with given characteristics does not necessarily grant success
in all reactions. Above MAC, the true nature of the reactive formulation at hand requires
balancing of interface tension between complex pseudo phases, thus favoring the selection
of high surface pressure tensides. Our approach is general, do not require the use of any
organic solvent and is based on industrially scaled, food grade surfactants.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
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9
0
1
2
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4
5
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9
0
1
2
3
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5
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8
9
0
1
2
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0
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2
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6
Experimental details
General Information. All reagents, Pd(dppf)Cl and Pd(dtbpf)Cl catalysts were bought
2
2
from Fluorochem. [Pd(π−cinnamyl)Cl] , surfactants and solvents were bought from Sigma-
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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9
0
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9
0
1
2
3
4
5
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8
9
0
Aldrich. L-α-lecithin (95%) was bought from Nutritional Biochemical Corporation. For
reactions performed under anaerobic environment, water was carefully deoxygenated before
use by bubbling N under reflux for three hours, and NEt was carefully deoxygenated by
2
3
freeze-pump-thaw degassing.
Reaction conversions were quantified by gas chromatography-mass spectroscopy (GC-MS) or
1
H NMR. For reactions performed on substrates 1, 2 and 3, composition of reaction mixtures
was quantified by quantitative GC-MS through peak integration based on response factor
method (see ESI for details). For reactions performed on other substrates, composition of
1
reaction mixtures was quantified by H NMR.
General procedure for small scale reactions. Unless when otherwise stated, reactions
were performed in a roundbottom test tube (10 mL volume, available from CEM Corpo-
ration) equipped with a cylindrical stirring bar and under standard laboratory atmosphere
(
setup a shown in figure S1A of the ESI). In a typical procedure, bromide (2 mmol), boronic
acid (2 mmol) and Pd(dppf)Cl (0.04 mmol) were weighted in the vessel and 2 mL of the
2
chosen surfactants solution was added under stirring. After 5 minutes N(Et) (3 mmol) was
3
added. The reaction mixture was stirred for 3 hours, and subsequently diluted with CH Cl ,
2
2
filtered through a pad of silica and submitted to GC-MS characterization.
Scaled-up synthesis of 1b. Reaction was performed in a 250 mL 3-necked roundbottom
flask equipped with a mechanical stirrer and a thermometer. 2-thienyl boronic acid (3.583 g,
28.00 mmol) and Pd(dppf)Cl (410 mg, 0.560 mmol) were weighted in the flask, which was
2
subsequently put under N atmosphere. Methyl-4-bromophenylacetate (6.414 g, 28.00 mmol)
2
and degassed TL82 surfactants mixture (28 mL) were subsequently added. The mixture was
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stirred at 300 rpm for 5 minutes before addition of degassed N(Et) (5.9 mL, 42 mmol). The
3
◦
reaction spontaneously warmed up to 50 C over 10 minutes. The reaction was stirred for 1
hour. Excess bromide was steam distilled from the reaction mixture by means of a Claisen
distillation apparatus. During the distillation, the volume of the reservoir was kept constant
at 100 mL by constant addition of water. The composition of both the distillate and the
mixture was monitored constantly by GC-MS. When no bromide was left in the reservoir, the
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
◦
mixture was cooled at 4 C and the precipitate thus formed was isolated by suction filtration,
washed thoroughly on the filter with water and dried till constant weight. 6.302 g, 27.1 mmol,
◦
9
6.9% (m.p. 50-51 C). The raw material was submitted to NMR characterization. Further
◦
purification was performed by evaporative distillation (water bath, 90 C, 0.02 mbar) using a
◦
standard sublimation apparatus (m.p. 54-55 C). The NMR spectra of the raw and sublimed
1
materials (Figure S2) are nearly identical. H NMR (400 Hz, CDCl ): δ [ppm] 7.57 (d, J=8.3
3
Hz, 2H), 7.30-7.26 (m, 4H), 7.07 (dd, J=5.1, 3.6 Hz, 1H), 3.71 (s, 3H), 3.64 (s, 2H).
Acknowledgement
Financial support from the Italian Ministry of University and Research (MIUR) through
grant “Dipartimenti di Eccellenza 2017 Materials For Energy” and PRIN-2017 research pro-
gramme (project “BOOSTER”) is gratefully acknowledged.
Supporting Information Available
Pictures of mixing setups. Additional reactions. E-factor of the scaled-up synthesis of 1b.
Assessment of TL82 stability under working conditions. Micrographs of the emulsion of 1
in aqueous TL82.
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