Pseudo-Solid-State Suzuki–Miyaura Reaction and the Role of Water Formed by Dehydration of Arylboronic Acids

Article abstract of DOI:10.1002/ejoc.201900410

Solvent-free reactions belong to a very attractive area of organic chemistry. The solvent-free Suzuki–Miyaura coupling is of special importance due to the problem of catalyst leaching in the presence of a solvent. This study investigates the course of reaction of solid aryl halides with arylboronic acids in the absence of a solvent and without any liquid additives. For the first time, a number of important conditions for performing a solid-state Suzuki–Miyaura reaction were analyzed in details. The results indicate a prominent role of water, which is formed as a by-product in the side reaction of arylboronic acid trimerization. Electron microscopy study revealed surprising changes occurring within the reaction mixture during the reaction and indicated the formation of spherical nano-sized particles containing the reaction product. Catalyst recycling was easily performed in the developed system and the product was isolated by sublimation, thus providing a possibility to completely avoid the use of solvents at all stages.

Full text of DOI:10.1002/ejoc.201900410

A Journal of
Accepted Article
Title: Pseudo-Solid-State Suzuki-Miyaura Reaction and the Role of
Water Formed by Dehydration of Arylboronic Acids
Authors: Evgeniy Pentsak and Valentine P. Ananikov
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900410
Link to VoR: http://dx.doi.org/10.1002/ejoc.201900410
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10.1002/ejoc.201900410
European Journal of Organic Chemistry
FULL PAPER
Pseudo-Solid-State Suzuki-Miyaura Reaction and the Role of
Water Formed by Dehydration of Arylboronic Acids
Evgeniy O. Pentsak,[a] and Valentine P. Ananikov*[a]
Abstract: Solvent-free reactions belong to a very attractive area of
organic chemistry. The solvent-free Suzuki-Miyaura coupling is of
special importance due to the problem of catalyst leaching in the
presence of a solvent. This study investigates the course of reaction
of solid aryl halides with arylboronic acids in the absence of a
solvent and without any liquid additives. For the first time, a number
of important conditions for performing a solid-state Suzuki-Miyaura
reaction were analyzed in details. The results indicate a prominent
role of water, which is formed as a by-product in the side reaction of
arylboronic acid trimerization. Electron microscopy study revealed
surprising changes occurring within the reaction mixture during the
reaction and indicated the formation of spherical nano-sized
particles containing the reaction product. Catalyst recycling was
easily performed in the developed system and the product was
isolated by sublimation, thus providing a possibility to completely
avoid the use of solvents at all stages.
irradiation[10-12]
,
which requires specific equipment and
sometimes is difficult to scale.[13] A solid-phase Pd/C-catalyzed
Suzuki-Miyaura coupling process has been reported.[14]
It should be noted that mechanistic understanding of solid-state
catalytic reaction is a challenge. The known mechanisms for
Suzuki-Miyaura coupling emphasize the crucial role of
nucleophile at the stage of transmetallation leading to production
of active boronate and/or formation of active palladium
intermediate through the ligand exchange reaction with a
base.[15]
Alkali metal carbonates are commonly used as a source of
nucleophilic species in the solvent-free Suzuki–Miyaura
reactions. The way it works under solid state conditions is yet
unknown; conventionally, carbonates of alkali metals form
nucleophilic/base species only as a result of hydrolysis, which is
hardly possible in the absence of water. Besides, the solid-
phase reaction is apparently impeded by the mass transfer
limitation factor.
The important role of water in Suzuki–Miyaura reaction has been
emphasized in many studies. Earlier, it has been reported that
water promotes Suzuki–Miyaura coupling involving carbonates
by formation of hydroxide anion.[16,17] Carrying out the reaction in
neat water reveals many interesting aspects related to the role
of water in Suzuki-Miyaura reaction, as well as a number of
mechanistic problems typical for the aqueous media. For
example, exact location of the catalytic process in multiphase
systems is an open question, along with the ways the substrates
overcome diffusion limitations and the restricted mobility over
water/organic phase boundaries. In addition, there are many
unknown aspects of the behavior of hydrophobic substrates and
the influence of the hydrophobic nature of carbon materials
(used as catalyst supports) on the course of Suzuki–Miyaura
reaction in aqueous media. Interestingly, Köhler and co-workers
have noted that hydrophobic surfaces of catalyst support can
create advantages for Suzuki–Miyaura reaction as compared to
hydrophilic oxide supports.[18] This is due to the high affinity of
lipophilic substances to the surface of carbon support, while
adhesion of water to the surface of hydrophilic supports may
impede access of reagents to catalytic sites.
Practically important is the fact that water can have an effect on
reactions in which the presence of water was not intended. For
example, the idea was expressed earlier that water can play an
important role in mechanism of Suzuki–Miyaura reaction
involving pre-formed boronates in an anhydrous medium (dry
toluene).[20] As has been noted earlier,[19] water can emerge by
dehydration of arylboronic acids that are found in equilibrium
with the initial boronates and this amount of water can dissolve
the hydrophilic components of the reaction.
Introduction
Global transition to green chemistry is associated with
increasing interest in solvent-free reactions.[1,2] Solvents used in
chemical processes represent a major source of waste. Degree
of environmental impact for a chemical process is determined
predominantly by the amount of solvents. Solid-phase organic
reactions are therefore very important as they represent an
attractive alternative to the classical organic transformations in
solution.[3] For this reason, many studies are focused on solvent-
free cross-coupling reactions.[4] Another problem that arises
when carrying out cross-coupling reactions in solution is
leaching,[5] which results in contamination of the product with the
metal traces and makes the catalyst less reusable. Thus,
efficient solvent-free cross-couplings will help to protect the
environment, as well as to reduce toxic metal contamination[6] of
fine chemicals and decrease the rates of catalyst degradation.
The majority of solvent-free reactions are conducted in the
presence of liquid reagents; otherwise, the reaction may take
place in a melt. The real solid-phase solvent-free reactions are
quite rare. A very limited number of studies describe Suzuki–
Miyaura reaction as a solid-phase synthesis (i.e. involving only
solid reagents and no solvents).[7] Such reactions are typically
carried out either in
a
ball mill[8,9] or under microwave
[a]
Dr. E.O., Pentsak
Prof. Dr. V.P., Ananikov
Zelinsky Institute of Organic Chemistry, Russian Academy of
Sciences
In this study we investigate a solvent-free Suzuki–Miyaura
reaction under conventional heating without using special
equipment (a microwave oven or a ball mill) to identify factors
responsible for the observed reactivity of solid substances. We
demonstrate that a prominent role in their reactivity is played by
side reaction of boronic acid trimerization. This side reaction
Leninsky Prospekt 47, Moscow 119991, Russia
val@ioc.ac.ru
http://AnanikovLab.ru
Supporting information for this article is given via a link at the end of
the document.
1
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10.1002/ejoc.201900410
European Journal of Organic Chemistry
FULL PAPER
proceeds with release of water, which promotes the interaction
of solid reagents. The study elucidates the possibility of carrying
out cross-coupling reactions in solid phase without the use of
solvents and liquid reagents, which remains an important
fundamental issue.
easily crumbling mass without visually detectable traces of the
liquid phase (Figure 1b). Thus, we could propose that the
reaction takes place in the solid phase. The yields reached 97 %
for 1-bromo-4-nitrobenzene and 95 % for 1-iodo-4-nitrobenzene.
In order to exclude the possibility of reaction in solution during
preparation of the samples for NMR spectroscopy, control
analyzes of the reaction mixture were carried out before the
heating. Only traces of the product were observed after 3 h
incubation of the mixture in chloroform (Figure S6). This result
indicates that the product forms as a result of heating of the dry
solid reagents with the solid catalyst and the solid base.
Results and Discussion
Reaction of solid aryl halides with phenylboronic acid in the
absence of any liquid substrates. The range of conditions for
the solid-phase Suzuki–Miyaura reaction has limitations on the
heating temperature of the reaction mixture. Boronic acids are
solid in a wide range of temperatures, but aryl halides often have
low melting points. For this reason, 1-iodo-4-nitrobenzene and 1-
bromo-4-nitrobenzene with high melting points of 171-173 °С
and 124-126 °С, respectively, have been chosen here as aryl
halides for the model reaction to allow its heating to relatively
high temperatures. Importantly, for the thorough confinement of
the reaction to belong to the solid state, melting points of the
products should also exceed the reaction temperature thereby
excluding the possibility of reaction in the molten product.
Suzuki–Miyaura coupling of the chosen aryl halides with
phenylboronic acid results in formation of 4-nitrobiphenyl with a
melting point of 111-115 °С. The reaction can therefore be
carried out at temperatures up to 100 °С without the risk of
switching to a semi-liquid state. The melting point of the mixture
of the reagents with base was measured, in order to exclude the
effect of decreased melting point for the mixture. No significant
decreases in melting points were observed in both cases, as the
mixture with 1-iodo-4-nitrobenzene melted at 170 °С, whereas
the mixture with 1-bromo-4-nitrobenzene melted at 120 °С, i.e.
melting points of the mixtures decrease by about 5 °С. The
Optimization of the reaction conditions. Optimization of the
reaction conditions was accomplished by varying the
temperature, the loading of catalyst and the substrates (see
Table S1). In the first series of experiments, the reaction of
phenylboronic acid with 1-bromo-4-nitrobenzene was carried out
at different temperatures ranging from 50 °С to 100 °С. Although
a decrease in temperature led to a decrease in conversion, at
70 °С the conversion was still good (73% in 6 h). A significant
decrease in conversion occurred when the reaction was carried
out at 50 °C (traces of product in 6 h).
Different bases were studied in the reaction (Table S2). The
highest conversion was observed in the presence of potassium
and cesium carbonates, as well as potassium hydroxide: the
conversion reached 99%, 96% and 97%, respectively (95°C,
6 h). By contrast, in the presence of sodium acetate and
potassium fluoride, the reaction almost did not proceed.
reaction was catalyzed by
a
composite of palladium
nanoparticles supported on multi-walled carbon nanotubes
(PdNPs/MWCNT) with K2CO3 as a base. The complete reaction
mixture was grinded to homogeneous powder in a ceramic
mortar; no spontaneous formation of the product was observed
during this procedure. The reaction mixture was a black loose
powder (Figure 1a).
Figure 2. Characteristic features of the solid-phase Suzuki-Miyaura reaction.
In another series of experiments, the same reaction was carried
out at 95 °С for 6 h with different loadings of the catalyst. With a
low catalyst loading of 0.01 mol%, the conversion was still very
good (77%). At the same time, unexpectedly, high catalyst
loadings led to a slight decrease in conversion (Table S1; Entry
1) probably due to the “dilution” of the solid reagents by the
supported catalyst, which is critical in the absence of a solvent
and under the impeded mass transfer conditions. No product
was formed in the absence of the catalyst. A comparison of the
two catalysts Pd/MWCNT and PdNPs supported on graphite
(Pd/graphite) was carried out. Pd/graphite was less effective
(85% conversion) as compared to Pd/MWCNT (98% conversion)
at the same conditions.
Figure 1. Initial appearance of reaction mixture after grinding in a mortar (a)
and reaction mixture after the reaction (b).
The powder was heated to 95 °С for 6 h in a closed vessel
under argon atmosphere without mixing. During the reaction, the
observable weak sintering of the mixture was accompanied by
formation of a small amount of white deposit (a mixture of the
product with the starting halide) in the upper part of the reaction
vessel. At the end, the reaction mixture was a sintered, but
A decrease in conversion was observed with upscaling the
reaction and increasing the reagent loading. This may be due to
2
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10.1002/ejoc.201900410
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difficulties in mass transfer of reagents in the absence of a
solvent (Table S3). The drop in conversion was observed at
various catalyst loadings (0.1 mol% and 1 mol%). Based on the
obtained data, the optimal ratio of reactants and catalyst was
selected: 0.25 mmol of aryl halide, 0.3 mmol each of boronic
acid and base, and 1 mol% of the catalyst.
Table 1. The influence of water on the solid-phase Suzuki-Miyaura reaction.
Entry
1
Boron reagent
Conditions[a]
Conversion, %[b]
91
Mechanistic concept of the reaction and the role of water.
Despite the use of solid reagents and prevention of the contact
with water, the solid-phase nature of the transformation itself is
questionable. A key role in the reaction between solid reagents
may be played by side processes (Figure 2), the main of which
are as follows: 1) sublimation of the starting halide or the
reaction product; 2) formation of biphenyl by homocoupling of
arylboronic acid; 3) formation of boroxine with the release of
water[19] (Scheme 1a).
The starting aryl halides, as well as the reaction product, have
high vapor pressure over solid, which contributes to their
sublimation. A thin deposit of the product and the starting aryl
halide, which is observed on the walls of the reaction vessel at
the end of the reaction, indicates the presence of aryl halide in
the vapor during the reaction. Its presence clearly enhances the
mass transfer within the system and thereby may influence the
mechanism of product formation. In addititon, sublimation of a
product can be used for solvent-free separation.[21]
Homocoupling of boronic acids to biphenyl under argon
atmosphere is inefficient, since it is an oxygen-dependent
process.[22]
80 °С
Phenylboronic acid
2
3
4
5
80 °С
95
19
2
Tolylboronic acid
preheating of
boronic acid,
80 °С
Phenylboronic acid
preheating of
boronic acid,
80 °С
Tolylboronic acid
95 °С
95 °С
0
Potassium
phenyltrifluoroborate
6
0
Potassium tetraphenylborate
7
8
addition of
95
31
water[c], 95 °С
Potassium phenyltrifluoroborate
addition of
water[c], 95 °С
Potassium tetraphenylborate
[a] Reaction conditions: 0.25 mmol 1-bromo-4-nitrobenzene, 0.3 mmol aryl borate
or aryl boronic acid, 0.5 mol% of PdNPs/C catalyst, 0.3 mmol of K2CO3 at 80 or
95 °C for 6 h. [b] Determined by 1H NMR and GC-MS of CDCl3 extract of the
mixture. [c] 25 µl of water per 150-250 mg of the mixture.
Scheme 1.
A plausible mechanism of the solid-phase Suzuki–Miyaura
process: a) trimerization of boronic acid with formation of boroxine and release
of water; b) hydrolysis of base leading to nucleophile formation; c) Pd catalytic
cycle with pathway A: the hydroxyl group formed at the previous stages acts
Most importantly, the molecular water, which forms as a by-
product of arylboronic acid trimerization, may play an essential
role in the reactivity of the solids, enhancing the mass transfer
and promoting formation of the nucleophile species (Scheme 1).
High conversion was observed under developed conditions with
phenylboronic and tolylboronic acids (Table 1; Entries 1 and 2).
However, the solid-phase Suzuki–Miyaura reaction was
suppressed upon usage of phenylboronic and tolylboronic acids
calcinated at 150 °С for elimination of water (Table 1; Entries 3
and 4). To further evaluate the importance of this water for the
efficiency of the solid-phase solvent-free Suzuki–Miyaura
process we carried out the same synthesis with non-trimerizable
borate salts instead of the boronic acid (Table 1; Entries 5 and
6). We used potassium salts, tetraphenylborate or
phenyltrifluoroborate, incapable of trimerization with the release
as
a nucleophile species in the formation of the active reagents for
transmetallation; d) Pd catalytic cycle with pathway B: the hydroxyl group
formed at the previous stages interacts with palladium complex, replaces
halide ligand, and the formed palladium complex reacts with arylboronic acid
at the transmetalation stage.
3
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10.1002/ejoc.201900410
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of water, which ensured the absence of water in the solid-phase
reaction. It turned out that under such conditions the reaction
does not proceed, but it can be induced by adding a small
amount of water (no more than 25 μl per 150-250 mg of the
mixture) to the dry reaction mixture (Table 1; Entries 7 and 8).
especially at the stage of transmetalation.[17,24,25,26] The stage of
transmetalation can proceed by two possible paths.[15,17,27] In the
case of path A, the palladium halide complex interacts with the
negatively charged nucleophilic aryltrihydroxyboronate. This
trihydroxyboronate is the product of interaction of initial
arylboronic acid with the hydroxy anion (Scheme 1c, Scheme 2,
magenta arrow). In the case of path B, the initial arylboronic acid
reacts with palladium complex, where base replaces the halide
ligand in the coordination sphere of the metal (Scheme 1d,
Scheme 2, brown arrow). The resulting palladium complex
reacts with arylboronic acid at the transmetalation stage.
Previously, it has been shown that direct interaction of halide
palladium complex with arylboronic acid may not occur.[16,17,28]
Thus, in order to carry out the transmetalation stage, it may be
necessary to have a hydroxide anion or another nucleophilic
species in the system. In our case, such a nucleophilic species
can be represented by a hydroxide anion, formed by the
interaction of water with potassium carbonate. Regardless of the
path, the organopalladium product and boric acid are produced
as a result of transmetallation stage (Scheme 2, orange arrow).
Boric acid in basic media can be converted to tetraborate with
formation of water (Scheme 2, green arrow).[29] Thus, the water
molecules leave the cycle of transformations unchanged, and no
water consumption occurs. It has also been previously reported
that hydroxide anion catalyzes the reductive elimination stage.[16]
On this basis, it can be proposed that a small amount of water is
necessary for the reaction to proceed.
The
experiments
with
tetraphenylborate
and
phenyltrifluoroborate also indicate that the vapors of halide over
the solid only insignificantly contribute to the overall reactivity. In
overall, this series of experiments (Table 1) confirmed the
principal role of water in the studied process.
Scope of the reaction. The solid-phase Suzuki–Miyaura
coupling protocol was applied to a range of arylboronic acids
substituted with various electron donating and electron
withdrawing groups (Table 2). 1-Bromo-4-nitrobenzene, contrary
to expectations, was more active than the corresponding aryl
iodide, for example, in affording 5-bromo-2-methoxy-4'-nitro-1,1'-
biphenyl and 3-chloro-4'-nitro-1,1'-biphenyl. Although some
cases of cross-coupling, in which aryl bromides give higher
yields than aryl iodides, have been described previously,[30] this
phenomenon is not trivial. It is usually assumed that the
reactivity at the oxidative addition step depends on the energy of
the R-X bond and aryl iodides should be more reactive.
Nevertheless, it is possible that other parameters, such as
crystal lattice energies of the solid aryl halide, can be more
important in the case of solid substances.
The distribution of activity among arylboronic acids
corresponded to common expectations: electron donating
substituents increased the yields, whereas an opposite influence
of electron withdrawing substituents was observed. As an
illustration, the reaction of 1-bromo-4-nitrobenzene with 2,6-
difluorophenylboronic acid yielded very small amounts of the
product, and the reaction of 1-iodo-4-nitrobenzene with 2,6-
difluorophenylboronic acid did not give a product (Table 2). The
best conversions were achieved for arylboronic acids with
methyl and methoxy substituents, e.g. for 4-tolylboronic and 2,5-
dimethoxyphenylboronic acids (Table 2). The side reaction of
arylboronic acid homocoupling was also observable, with the
yields corresponding to 1–4% of the target product.
Scheme 2. Schematic representation of water and hydroxide anion
transformations: blue arrows – water molecule formation during trimerization
arylboronic acid with formation boroxine; light blue arrows – hydrolysis of
potassium carbonate with formation of hydroxide anion; magenta arrow – the
interaction of the arylboronic acid with hydroxide anion with formation of
trihydroxyboronate anion; pink arrows - trihydroxyboronate anion can converse
back to arylboronic acid with the release of anion hydroxide; brown arrow –
halide organopalladium complex R2PdX interact with hydroxide anion with
formation complex R2PdOH; orange arrow – formation of boric acid as result of
transmetalation stage in pathway A or pathway B; green arrow - in basic
media boric acid can converse to tetraborate with formation of water
molecules. It is important to note that although the scheme considers both
paths, it is probably that only one of them makes major contribution under
certain conditions (either path A or path B).
We assume that the water formed during trimerization of aryl
boronic acid (Scheme 2, blue arrow) can play several important
roles in the course of the reaction under the described
conditions. This water is of key importance as a medium
providing diffusion, mass transfer and mobility of the interacting
hydrophilic species. In particular, the base, salts, phenyl
boronate and ionic Pd species tend to concentrate in the
aqueous phase.[23]
Water can also be considered as a source of basic nucleophilic
species: hydroxide anions generated by interaction of water with
carbonate base (Scheme 2, light blue arrow) can participate in a
variety of complex dynamic transformations (Scheme 2). Several
studies have emphasized the important role of the anionic base,
4
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10.1002/ejoc.201900410
European Journal of Organic Chemistry
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Table 2. Solid-phase Suzuki–Miyaura reaction with different reagents.[a]
Table 3. Reuse of the PdNPs/MWCNT catalyst in the solid-phase
Suzuki-Miyaura process.[a]
Cycle
Conversion, %[b]
0.1 mol% of the catalyst 0.5 mol% of the catalyst
95
1
2
3
4
5
6
7
79
80
88
86
96
97
93
Hal = I
95%[b]
Hal = Br
97%[b]
Hal = I
99%[b]
Hal = Br
100%[b]
Hal = I
Hal = Br
100%[b]
75
94
100%[b]
84
100
98
100
Hal = I
53%[b]
Hal = Br
94%[b]
Hal = I
48%[b]
Hal = Br
68%[b]
Hal = I
0[b]
Hal = Br
4%[b]
[a] Reaction conditions: 1 mmol of aryl halide, 1.2 mmol of phenylboronic acid,
1.2 mmol of K2CO3, 95 °C for 6 h. [b] Determined by GC-MS of CDCl3 extract
of the mixture.
[a] Reaction conditions: 0.25 mmol of aryl halide, 0.3 mmol of aryl boronic
acid, 0.5 mol% of PdNPs/MWCNT catalyst, 0.3 mmol of K2CO3 at 95 °C for
6 h. [b] Conversion was determined by GC-MS and NMR of CDCl3 extract of
the mixture.
All obtained conversion values were in the range from 75% to
100% for the experiment with catalyst loading of 0.1 mol% and
from 79% to 97% for the experiment with catalyst loading of
0.5 mol%. The high conversion was observed throughout the
series with a standard deviation of 9% and 8% for catalyst
loadings of 0.1 mol% and 0.5 mol%, respectively (Table 3).
Observed variation in conversion values may be explained by
the impeded mass transfer in a solvent-free system and may be
also related to mechanical mixing of solid powders. A slight
tendency towards increase in the catalyst activity upon reuse
may be explained by activation of the surface of palladium
nanoparticles during the reaction. However, microscopic
examination did not reveal noticeable changes in the
morphology of the catalyst (Figures S10-S15). The results
indicate that the PdNPs/MWCNT catalyst is stable during the
solid-phase Suzuki–Miyaura reaction and can be multiply reused
without any loss of activity.
Alternatively, the solvent-free Suzuki–Miyaura coupling under
the same conditions was attempted with aryl halides having
melting points below the reaction temperature (Table S5).
Although the reaction proceeded in the melt, the less active 4-
bromoacetophenone and 4-bromoanisole showed lower
conversions compared to high melting point aryl halides (1-
bromo-4-nitrobenzene and 1-iodo-4-nitrobenzene). Increasing
the reaction time from 6 h to 8 h resulted in slightly better
conversions, which were still lower than the conversions of the
high melting point aryl halides (1-bromo-4-nitrobenzene and 1-
iodo-4-nitrobenzene). The products of side reactions (biaryls, the
products of deboration and arylboronic acid trimerization) were
observed in various quantities (1–13%) depending on the nature
of the arylboronic acid.
As we have mentioned above, there are a number of limitations
in order to perform solid-state reactions. Thus, a strict selection
of substrates was employed (Table 2). The products scope
evaluated here confirms practical potential of the developed
methodology and is in agreement with the mechanistic findings.
Isolation of product by sublimation without using solvents.
The use of solvents at the of product isolation stage makes the
main impact to an increase in amounts of waste and, as a result,
an increase in E-factor.[31] For this reason, solvent-free reactions
are of much importance from environmental point of view if it is
possible to isolate a pure product without the use of solvents.
Isolation of a product by its sublimation from a solid reaction
mixture may be one of the possible approaches to solve this
problem. Another important aspect of this product isolation
method is elimination of the loss of palladium catalyst due to
leaching (since leaching is facilitated in the presence of
solvents).
Investigation of catalyst recycling. Recycling of the Pd-
NPs/MWCNT catalyst in the solid-phase Suzuki–Miyaura
coupling of phenylboronic acid with 1-bromo-4-nitrobenzene was
evaluated by sequential monitoring of the reaction in two parallel
series of experiments with different loadings of the catalyst
(0.1 mol% and 0.5 mol%, Table 3). All reactions were carried out
under the same conditions; after completion of each cycle in the
series, the catalyst was straightforwardly recovered from the
mixture by centrifugation.
To examine this possibility, after completion of the reaction of 1-
bromo-4-nitrobenzene with phenylboronic acid, the reaction
mixture was heated at 90 °С on a rotary evaporator under low
pressure (5 mbar). The sublimated product formed yellow
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10.1002/ejoc.201900410
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crystals that were collected in a trap. The product in an amount
of 30 mg out of a possible 82 mg was accumulated within 6 h.
To increase the efficiency of product isolation, the remaining
reaction mixture was heated to a temperature of 150 °C in an oil
bath at a pressure of 0.7 mbar, and the product was collected in
a vacuum trap (Figures S54, S55). The remaining substance
was collected in this manner for 6 h. NMR spectroscopy showed
that the crystallized product contained 10% of boroxine impurity.
Boroxine was removed by washing the resulting material with a
large amount of water or a solution of potassium carbonate.
Finally, the pure product was obtained in 98% yield.
An NMR analysis of the residual reaction mixture showed only
trace amounts of the product remaining after sublimation. The
activity of the catalyst remaining in the reaction mixture after
removal of the product by sublimation was investigated.
Substrates and base were added to this reaction mixture, from
which the product was removed by sublimation; the reaction was
carried out under similar conditions after grinding the mixture in
a mortar. Full conversion was detected after 6 h. The product
was also isolated by sublimation in an oil bath at similar
conditions (150 °C, 0.7 mbar). The amount of product
corresponding to the yield of 79% was collected in 4 h. To
isolate the remaining product, the reaction mixture was kept for
10 h under the same conditions. As a result, the total yield of the
isolated product was 92% and NMR spectroscopy showed the
absence of impurities in the isolated product. Thus, not only the
possibility of product isolation without the use of solvents was
demonstrated by sublimation, but also the possibility of catalyst
recycling by adding reagents directly to the reaction mixture
immediately after sublimation of the product.
After product isolation with sublimation, the catalyst was
examined by TEM. No significant morphological changes were
found with the size of palladium nanoparticles slightly increased
to 2-4 nm (Figures S14-S15).
Microscopic study of the solid reaction mixture. The course
of the reaction in the solid mixture should largely depend on the
uniformity of the mixing of the solid reactants in the mortar and
the homogeneity of the final mixture. To address this issue,
scanning electron microscopy (SEM) studies were carried out.
The images showed that a powder of 1-100 µm microparticles is
formed after grinding of reagents in a mortar (Figures S16, S17).
The results of Energy-dispersive X-ray spectroscopy (EDS)
studies indicate uniform distribution of the microparticles of
reagents in the reaction mixture (Figure S18). EDS mapping by
potassium signal revealed individual particles of potassium
carbonate. Since Kα signal of boron is of low intensity and it is
partially overlapped by Kα signal of carbon, it is difficult to
unambiguously determine the localization of phenylboronic
particles. Similarly, due to the overlapping of the most intense Lα
signal of bromine and Kα signal of aluminum (contained in the
microscopy sample stubs), it is difficult to identify the distribution
of bromonitrobenzene. Nevertheless, the particles of organic
substances in the secondary electron mode look darker than the
particles of K2CO3 due to the specific interaction with the
electron beam of the microscope (Figures S19, S25). Carbon
nanotubes have a characteristic morphology, so their distribution
can be easily determined in SEM images. Good surface
coverage and penetration into the organic particles volume was
typical for the Pd/MWCNT catalyst (Figures S20, S21).
Figure 3. SEM images of the spherical nanoparticles formed in the reaction
mixture (a), appearance of pores and the process of sublimation under the
influence of electron beam for 1 min (b), and an individual nanoparticle under
higher magnification showing the sublimation process directly in the
microscope chamber (c and d),
The sample obtained after completion of the reaction was also
examined by SEM. It consisted of microparticles with the size
close to the particles size of the initial reaction mixture (1-
100 µm), but their morphology was substantially different from
the initial one (Figures S26-S28, S30, S33). The particles of the
reaction mixture consisted of a bulk penetrated by carbon
nanotubes; in addition, there were inclusions of spherical
particles about 100 nm in size inside the bulk (Figures S34-S36).
In some cases, spherical particles were not included in the bulk
of larger particles and located in piles on the surface of other
particles (Figures S37-S40). Nano-sized pores in spherical
particles appeared during long-term positioning of the electron
beam (Figure 3, Figures S37-S39).
6
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10.1002/ejoc.201900410
European Journal of Organic Chemistry
FULL PAPER
Next, a sample of the reaction mixture after sublimation of the Experimental Section
product was also studied. It was found that the spherical
General Remarks. The reagents (aryl halides, boron reagents,
anhydrous bases) were obtained from commercial sources and used
after spectroscopic check (1H and 13C NMR, GC-MS). The PdNPs/C
catalysts were prepared as described previously.[32]
particles were porous after sublimation, or porous areas were
observed in the places where the spherical particles were
supposedly located (Figures S51-S53).
It can be assumed that accumulation of the product occurs
inside the detected spherical particles. Electron microscopy
provide excellent opportunity to visualize the sublimation
process from these spherical particles due to the heating of the
substance under an electron beam in a high vacuum (Figure 3).
Amazingly, the formation of pores was observed in the studied
sample directly inside the electron microscope chamber (Figure
3). In the sublimation process the evaporated product trapped
and isolated from the reaction mixture.
Catalysts and bases dried in advance at 150 °С for 8 h in vacuo were
used in all reactions. The reaction products were purified by extraction
and column chromatography; mixtures of petroleum ether with benzene
or ethyl acetate were used as eluents. After the extraction and
chromatography, the solvent was evaporated and the product was dried
in a rotary evaporator at 40 °С.
Melting points were measured by a 1101D MEL-TEMP digital melt point
apparatus.
NMR spectroscopy. The 1H NMR spectra were recorded on Bruker
DRX500, Bruker AVANCE III 400 WB and Bruker Fourier 300 HD
spectrometers. The conversions for solid-phase reactions were
determined by extraction with deuterochloroform (99.8% atom D,
stabilized with silver foil). Processing of the spectra was accomplished
with Bruker Topspin 2.1 and MestReNova (version: 6.0.2-5475) software
packages. Chemical shifts are reported in ppm relative to the solvent
resonance signal as an internal standard – CDCl3 (7.26 and 77.16 ppm
for 1H and 13C, respectively).
Conclusions
The study shows that solid arylboronic acids and aryl halides
can react in the absence of added liquids (solvents or melts).
Under optimized conditions the quantitative yields can be
achieved by conventional heating of the solid-phase reaction
mixture, and no additional mixing is required during the reaction.
We demonstrate that molecular water, which forms as a result of
arylboronic acid dehydration, is essential for the efficient solid-
phase Suzuki-Miyaura coupling. This conclusion is based on the
following findings:
1) The reaction efficiently proceeds under conditions that favor
formation of boroxine from phenylboronic acid with the release
of water, which is an expected process.
2) Pre-calcination of the initial arylboronic acid leads to a
significant reduction in the observed conversion.
3) Under studied conditions the reaction does not proceed with
potassium tetraphenylborate and potassium trifluoroborate,
while the addition of minimal amounts of water initiated the
reaction with these reagents.
4) The formation of nucleophilic species from potassium
carbonate is facilitated by the presence of water.
In the absence of side processes leading to formation of water
(and consequently to the appearance of activated nucleophilic
species) the reaction between the solid reagents is blocked.
The presence of a small amount of water in the reaction mixture
does not diminish the advantages of the solid-phase reaction,
but it might be a key factor for initiating and maintaining the
reaction. The formation of liquid promoters during the reaction
may also be an important factor in the mechanisms of other
solid-phase reactions and we may anticipate more studies in this
fascinating area in the nearest future.
In the studied Suzuki–Miyaura reaction between solid
substances, the PdNPs/MWCNT catalyst can be reused multiple
times without loss of efficiency. The absence of a liquid phase
(reagents of solvents) is an important factor to avoid metal
leaching.
Sample preparation for NMR. An aliquot of the solid reaction mixture
was suspended in 2 ml of CDCl3. The suspension was centrifuged, and
the solution was analyzed NMR spectroscopy.
Control experiment was performed to rule out the possibility of cross-
coupling reaction during the sample preparation. Solid reaction mixture
(4 mg 1-Bromo-4-nitrobenzene, 4 mg phenylboronic acid, 4 mg
potassium carbonate and 2 mg PdNPs/MWCNT) was placed in 1 mL
CDCl3. Only traces of the product were observed after 3 h keeping of the
mixture in CDCl3.
GC-MS analysis. GC-MS data were recorded on Agilent 7890B system
with an Agilent 5977A quadrupole mass analyzer using an Agilent HP-
5MS (19091s-433) column (5%-Phenyl Methyl Siloxane, 0-325 °C,
30 m×250 µm×0.25 µm) and helium grade 7.0 as
a carrier gas.
Calibration was performed automatically by PFTBA on the day of
analysis. Acquisition mode: ionization energy 70 eV, m/z scan range of
50-600 Da with
a step of 0.1, 6.7 scans/sec, transfer capillary
temperature 280 °C, source temperature 230 °C, analyzer temperature
150 °C. Chromatography mode: evaporator temperature 280 °C, injection
volume 1 µl, split ratio 1:100, isocratic mode, flow 1 ml/min; 70 °C for
2 min, 10 °C/min to 240 °C, 35 °C/min to 310 °C, 310 °C for 5 min. For
the analysis, 30 µl of the sample was diluted to 1.5 ml with CH2Cl2
(Sigma-Aldrich, HPLC, 50-150 ppm amylene).
TEM analysis. Before measurements the samples were mounted on a
3 mm copper grid with lacey carbon film and fixed in a grid holder.
Samples morphology was studied using Hitachi transmission electron
microscope (TEM). Images were acquired in bright-field TEM mode at
100 kV accelerating voltage.
SEM and EDX studies. Before the measurements the samples were
mounted on a 25 mm aluminum specimen stub and fixed by conductive
graphite adhesive tape. Sample morphology was studied under native
conditions to exclude the possible metal coating surface effects.[33] The
observations were carried out using Hitachi SU8000 field-emission
scanning electron microscope (FE-SEM). Images were acquired in
secondary electron mode at 10-30 kV accelerating voltage and at
working distance 8-10 mm. EDX studies were carried out using Oxford
Instruments X-max EDX system.
Electron
microscopy
study
suggested
that
product
formation/accumulation occurs in spherical nanoparticles with a
diameter of about 100 nm, which are capable to undergo
sublimation. Indeed, the possibility of product isolation from the
reaction mixture by sublimation was successfully demonstrated.
Avoiding solvents in cross-coupling reactions is an important
advantage to improve Green metrics and to prevent the loss of
palladium due to leaching.
7
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10.1002/ejoc.201900410
European Journal of Organic Chemistry
FULL PAPER
Control for the lack of reactivity during the grinding. 1-Bromo-4-
at 95 °С for 6 h. After that, an aliquot of the reaction mixture was
suspended in 2 ml of chloroform. The suspension was filtered, and the
solution was analyzed by GC-MS and NMR. The known products were
identified according to the published data.[34]
nitrobenzene (0.25 mmol), phenylboronic acid (0.3 mmol),
a base
(0.3 mmol) and PdNPs/MWCNT (1 mol%) were grinded thoroughly in a
ceramic mortar. An aliquot of the mixture was suspended in 2 ml of
CDCl3 and sonicated. The suspension was centrifuged or filtered after 30
min and 3 h of keeping under solvent. The solution was analyzed by GC-
MS and NMR spectroscopy.
Catalyst
recycling
study.
1-Bromo-4-nitrobenzene
(1 mmol),
phenylboronic acid (1.2 mmol), K2CO3 (1.2 mmol) and PdNPs/MWCNT
(0.1 mol% or 0.5 mol%) were mixed thoroughly in a ceramic mortar and
transferred to a screw-capped test tube. The reactions were heated at
100 °С for 6 h. After that, an aliquot of the reaction mixture was
suspended in 2 ml of chloroform. The suspension was filtered, and the
solution was analyzed by GC-MS. The solid residue was washed 5 times
with acetone and 2 times with water; the catalyst was dried in vacuo at
120 °C for 30 min and reused under the same conditions.
Control experiments in absence of the catalyst. Aryl halide (1-bromo-
4-nitrobenzene and 1-iodo-4-nitrobenzene in two separate experiments;
0.25 mmol each), phenylboronic acid (0.3 mmol), K2CO3 (0.3 mmol) were
mixed thoroughly in a ceramic mortar and transferred to a screw-capped
test tube. The reactions were heated at 90 °С for 6 h. After completion of
the reactions, the samples were analyzed by NMR spectroscopy.
Varying
the
reaction
temperature.
1-Bromo-4-nitrobenzene
Isolation of product by sublimation. The solid reaction mixture after
completion of the reaction was placed in a round bottom flask. The flask
was placed in an oil bath so that it was completely immersed in silicone
oil, and equipped with a glass trap. Then the flask with the mixture was
heated at 150 °C and a pressure of 0.7 mbar for 6-14 h. The sublimated
product was collected at the bottom of the trap in the form of yellow
crystals and characterized by GC-MS and NMR.
(0.25 mmol), phenylboronic acid (0.3 mmol), K2CO3 (0.3 mmol) and
PdNPs/C (1 mol%) were mixed thoroughly in a ceramic mortar and
transferred to a screw-capped test tube. The reaction was heated at
50 °C, 70 °C, 80 °C, 90 °C or 100 °С for 6 h. After completion of the
reaction, the sample was analyzed by NMR spectroscopy.
Varying the base for the reaction.1-Bromo-4-nitrobenzene (0.25 mmol),
phenylboronic acid (0.3 mmol), a base (0.3 mmol) and PdNPs/MWCNT
(1 mol%) were mixed thoroughly in a ceramic mortar and transferred to a
screw-capped test tube. The reaction was heated at 95 °С for 6 h. After
completion of the reaction sample was analyzed by NMR spectroscopy.
Keywords: Suzuki-Miyaura coupling • solvent-free reaction •
solid-state reaction • water • boronic acids • supported catalysts
• Pd/C catalyst • mechanistic study
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Representative reviews:
Varying the amount and type of catalyst. 1-Bromo-4-nitrobenzene
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(0.5 mol%) were mixed thoroughly in a ceramic mortar and transferred to
a screw-capped test tube. The reaction was heated at 100 °С for 6 h.
After completion of the reaction, the sample was analyzed by NMR
spectroscopy.
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Experimental scaling up of the reaction volume. 1-Bromo-4-
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scale reaction), phenylboronic acid (0.3 mmol for a standard reaction or
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bromo-4-nitrobenzene (0.25 mmol), PdNPs/C (1 mol%) and K2CO3
(0.3 mmol) and transferred to a screw-capped test tube. The reaction
was heated at 80 °С for 6 h. After completion of the reaction, the sample
was analyzed by NMR spectroscopy.
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9
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Entry for the Table of Contents
FULL PAPER
Conditions for a Suzuki-Miyaura solid-
state reaction were analyzed in
details. The results show key role of
water, which is formed as a by-
product in the side reaction of
arylboronic acid trimerization.
Key Topic: Solid-State Coupling
Evgeniy O. Pentsak, Valentine P.
Ananikov *
Page No. – Page No.
Pseudo-Solid-State Suzuki-Miyaura
Reaction and the Role of Water
Forming by Dehydration of
Arylboronic Acids
10
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