Metformin as a versatile ligand for recyclable palladium-catalyzed cross-coupling reactions in neat water

Article abstract of DOI:10.1039/C7RA01197K

We present the high catalytic activity of an in situ generated palladium(ii)/metformin complex in neat water for the Suzuki-Miyaura and Sonogashira cross-coupling reactions. These reactions were performed in pure water without any co-solvent or mass transfer agent. The palladium(ii)/metformin complex gave excellent to good yields for the Suzuki-Miyaura coupling reaction and catalyzed with a certain specificity to the aryl iodide coupling in the Sonogashira reaction. The methodology showcases a recyclability up to four catalytic runs for the Suzuki-Miyaura cross-coupling reaction, performed with only 0.5 mol% palladium loading.

Full text of DOI:10.1039/C7RA01197K

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Metformin as a versatile ligand for recyclable
palladium-catalyzed cross-coupling reactions in
Cite this: RSC Adv., 2017, 7, 21036
neat water†
*
S. Fortun, P. Beauclair and A. R. Schmitzer
We present the high catalytic activity of an in situ generated palladium(II)/metformin complex in neat
water for the Suzuki–Miyaura and Sonogashira cross-coupling reactions. These reactions were
performed in pure water without any co-solvent or mass transfer agent. The palladium(II)/metformin
complex gave excellent to good yields for the Suzuki–Miyaura coupling reaction and catalyzed with
a certain specificity to the aryl iodide coupling in the Sonogashira reaction. The methodology
showcases a recyclability up to four catalytic runs for the Suzuki–Miyaura cross-coupling reaction,
performed with only 0.5 mol% palladium loading.
Received 26th January 2017
Accepted 4th April 2017
DOI: 10.1039/c7ra01197k
rsc.li/rsc-advances
deactivation. The Suzuki–Miyaura cross-coupling reaction has
been reviewed many times in the past,4–11 but recently Ward
et al.12 showed that the current challenges to be addressed for
palladium-catalyzed coupling reactions performed in water
are the reactivity of the aryl halide, the possibility to use low
catalyst loadings, short reaction times and mild reaction
conditions (low temperature).
Introduction
Nowadays, societies are paying more attention to the envi-
ronmental impact of our life style. One of the main actual
challenges in chemistry is to develop eco-friendly processes to
lower their impact to the environment. In 1998, the 12 prin-
ciples of Green Chemistry were identied to guide chemists
through this modern vision of chemistry and they assert the
main objectives of this new branch of chemistry.1 Many
processes are considered green without applying all the 12
principles at the same time. One of these 12 principles of
Green Chemistry encourages chemists to use and develop
efficient and preferably recyclable catalytic systems, rather
than stoichiometric reactions, in order to minimize the risks
in terms of manipulation and toxicity. Metal-catalyzed cross-
coupling reactions are a powerful tool for new bond forma-
tions (carbon–carbon, nitrogen–carbon, etc.) and are widely
used in both academia2 and industry. Unfortunately they come
with a heavy price in terms of safety and sustainability, as they
are usually performed in toxic, carcinogenic and ammable
organic solvents, generally required to solubilize the organic
reactants and accelerate the reaction rates.3 To date, water
remains the greenest known solvent because of its availability,
stability, non-toxicity and non-ammability. Those properties
make coupling reactions performed in water greener, because
water is not considered as a waste. Therefore, ligands are
required to perform metal-catalyzed cross-coupling reactions
in neat water to protect the metal center from oxidation and
Since recyclability is also a major concern in green chem-
istry, a water-soluble ligand may maintain the metal in the
aqueous media and therefore may allow a simple recycling
procedure, by extracting the organic product at the end of each
catalytic cycle. Many water-soluble ligands have been explored
to favour the cross-coupling reactions in aqueous media, such
as phosphines. However, these ligands are toxic, moisture and/
or air sensitive, and produce undesired side-products.13 N-
Donor ligands are an interesting alternative for different
reasons. First, numerous easy reactions lead to nitrogen-
containing compounds with innite possibilities of design,
through the large choice of commercially available starting
materials. Also, the nitrogen atom displays different hybrid-
ization states (sp, sp2, sp3) and anionic or neutral ligand can be
envisaged for different types of interactions with a metal.
Biguanides (Fig. 1), water-soluble compounds, recently
emerged as potential ligands in terms of Green Chemistry. They
are known in medicine for their antihyperglycaemic,14 antima-
larial15 and anticancer properties16 and have been found to form
numerous complexes with bivalent transition metals.17 They
have been used as polydentate ligands, well-known to stabilize
metal nanoparticles and prevent their aggregation and/or
deactivation.18,19 Veisi et al. studied the catalytic properties of
different large and complex systems containing biguanides.
They developed versatile and recyclable functionalized meso-
porous silica molecular sieves SBA-15,20–22 biguanides-carbon
nanotubes23–25 and biguanide–chitosan26 as catalyst for cross-
´
´
´
Universite de Montreal, Departement de Chimie, 2900 Bd Edouard Monpetit CP6128
´
Succursale Centre-Ville, Montreal, H3C3J7, Canada. E-mail: ar.schmitzer@
umontreal.ca
† Electronic supplementary information (ESI) available: Suzuki–Miyaura and
Sonogashira substrates scope references. See DOI: 10.1039/c7ra01197k
21036 | RSC Adv., 2017, 7, 21036–21044
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Fig. 1 Structure of biguanides, metformin hydrochloride and its possible complexation to a transition metal [M].
coupling reactions. However, the cross-coupling reactions were the presence of a base, for a short time prior to the addition of
performed in toxic DMF (the use of carbon nanotubes not the substrates.29,30
respecting the Green Chemistry principles either) or a binary
water : ethanol mixture.
Green Chemistry is also about maximizing atom economy,
i.e. using molecules containing fewer atoms possible.
Results and discussion
Optimization of the conditions for the Suzuki–Miyaura
reaction
Commercial inexpensive metformin (Fig. 1), one of the
smallest biguanides, is highly soluble in water and was proven
to be non-toxic, since it was used as a treatment for type 2
diabetes by millions of people since 1957.27 It has previously
been shown that metformin can complex palladium(II) and
efficiently catalyze Suzuki–Miyaura reactions performed in
a water : ethanol 1 : 1 mixture with 1 mol% catalyst loading.28
However this study does not cover the recyclability, nor the
versatility aspects of the catalytic system and showed some
limitations: the Pd loading has not been optimized, two
equivalents of metformin were used and the reaction required
the use of ethanol as co-solvent.
Herein, we report the catalytic efficiency and recyclability of
a 1 : 1 metformin : Pd(OAc)2 complex in the Suzuki–Miyaura
and the Sonogashira cross-coupling reactions in neat water at
a very low catalyst loading. The catalytic species are formed in
situ to avoid the money-, time- and energy-consuming synthesis
or purication steps. This method is a green procedure, which
simply consists in mixing the metal source(s) with the ligand in
Our study began with the optimization of the reaction condi-
tions. With a loading of 2 mol% of metformin : Pd (1 : 1)
complex, complete conversion was obtained aer 15 min at
100 ꢀC (Table 1, entry 3). The time of formation of the catalytic
species was then lowered to only 15 min at 100 ꢀC (Table 1, entry
5).
The catalyst loading (Table 2) can be lowered to 0.0025
mol% without losing the efficiency of the system. Compared
to recently reported catalytic systems for the Suzuki–Miyaura
in neat water, this is a very low catalyst loading, the turnover
number (TON) and turnover frequency (TOF) are
excellent.30–33
Only one equivalent of base (as K2CO3 is dibasic) was
necessary to activate the palladium complex and the boronic
acid (Table 3 and Fig. 2).34–36 A slight excess (1.1 eq.) was used to
maintain the reaction media under basic conditions and the
metformin ligand under its deprotonated form. The tempera-
ꢀ
ture needed to be kept at 100 C to avoid a drastic decrease of
the yield (Table 3, entry 5). These optimized conditions were
tested under microwave irradiation, but only 79% yield was
obtained aer 15 min, compared to the 95% obtained with
Table 1 Formation of the catalytic species and reaction time optimi-
zation for the Suzuki–Miyaura cross-coupling reactiona
Table 2 Optimization of the catalyst loading for the Suzuki–Miyaura
cross-coupling reactiona
Formation time of the
catalytic species (min)
Reaction time
(min)
Yieldb
(%)
Entry
Pd(OAc)2
(mol%)
Metformin$HCl
(mol%)
Yieldb
(%)
TOF
1
2
3
4
5
120
120
120
120
15
120
30
15
10
15
100
94
93
61
99
Entry
TON
(sꢁ1
)
1
2
3
2
2
99
95
Traces
50
38 000
—
0.06
41.8
—
0.0025
0.001
0.0025
0.001
a
Reaction conditions: 0.02 mmol Pd(OAc)2, 0.02 mmol metformin
a
Reaction conditions: Pd(OAc)2, metformin hydrochloride, 1 mmol 40-
bromoacetophenone, 1 mmol phenylboronic acid, 2 mmol K2CO3, 5
hydrochloride,
1
mmol
40-bromoacetophenone,
1
mmol
phenylboronic acid, 2 mmol K2CO3, 5 mL distilled water, 100 ꢀC in
b
air. Non-isolated yield determined by 1H NMR.
b
mL distilled water, 100 ꢀC, 15 min, in air. Non-isolated yield
determined by 1H NMR.
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Table 3 Optimization of the amount of base and temperature for the
Suzuki–Miyaura cross-coupling reactiona
0.0025 mol% palladium loading in the absence of metformin
(Table 4, entry 1), only traces of the coupling product were
1
detected by H NMR.37,39,40
Nature of the active species of the Suzuki–Miyaura cross-
coupling reaction: the catalyst poisoning test
The nature of the catalytic species was determined by the
addition of mercury as the poisoning agent. In the case of
a heterogeneous catalyst, the addition of mercury leads to its
amalgamation on the surface of the active sites of the catalyst
and totally inhibits its catalytic activity. If the catalyst is
soluble in the reaction solvent, the addition of mercury has no
effect on the catalyst's activity. The nature of our catalytic
species was assessed by addition of 2 drops of mercury, prior
to the addition of the substrates. The yield dramatically
dropped to 3% which indicates that the catalytic species are
not water-soluble.
Entry
Base amount (eq.)
Temperature (ꢀC)
Yieldb (%)
1
2
3
4
5
2
1.1
0
0.5
1.1
100
100
100
100
90
100
98
Traces
60
14
a
Reaction conditions: 0.000025 mmol Pd(OAc)2, 0.000025 mmol
metformin hydrochloride, 1 mmol 40-bromoacetophenone, 1 mmol
phenylboronic acid, K2CO3, 5 mL distilled water, 15 min, in air.
b
1
Non-isolated yield determined by H NMR.
Substrate scope for the Suzuki–Miyaura cross-coupling
reaction
With the optimized reaction conditions in hand, the versatility
of the catalytic system was studied through a substrate scope
(Table 5). It is important to remind here that the optimized
catalyst loading was determined for the reaction between 40-
bromoacetophenone and phenylboronic acid and may not be
suitable for other substrates. The substrate scope was realized
under the optimized reaction conditions for comparison. Aryl
halides with electron-withdrawing groups and boronic acids
with electron-donating groups, especially in ortho and para
positions, are expected to favour the palladium insertion, and
therefore increase the rate of the reaction.
Fig. 2 Catalytic cycle of the Suzuki–Miyaura cross-coupling reaction.
Different aryl halides with different functional groups were
coupled to phenylboronic acid (Table 5) and a large range of
yields were obtained. Electron-decient aryl halides gave overall
excellent yields at both studied catalyst loadings (Table 5,
entries 1–6 and 16–18), while electron-rich aryl halides gave only
low to moderate yields at the optimized 0.0025 mol% Pd
loading aer 2 hours (Table 5, entries 10–13). By increasing the
catalyst loading and/or the reaction time, good to excellent
yields were obtained, showing that less reactive substrates need
a longer reaction time, such as the bulky naphtyl halides (Table
5, entries 14 and 15). In the Suzuki–Miyaura cross-coupling, aryl
iodides are supposed to give higher yields than aryl the rate-
limiting step is bromides.41 As it is not the case here, this
result suggests that the oxidative addition in the catalytic cycle,
as initially postulated by Suzuki and Miyaura.42 The water
solubility of the substrates is also an important factor and aryl
iodides are usually less soluble. Water solvation of the aryl
halide may play a role on the oxidative addition step, making it
faster in the case of aryl bromides. Moreover, at the end of the
oxidative addition, KX (X ¼ halide) is generally formed (Fig. 2).
According to the HSAB theory,43 the formation of KBr is fav-
oured compared to KI due to the nature of both the acid and the
bases.
Table 4 Control reactions of the Suzuki–Miyaura cross-coupling
reactiona
Pd(OAc)2
(mol%)
Metformin$HCl
(mol%)
Yieldb
(%)
Entry
1
2
0.0025
0
0
Traces
0
0.0025
a
Reaction conditions:
1
mmol 40-bromoacetophenone,
1
mmol
phenylboronic acid, 1.1 mmol K2CO3, 5 mL distilled water, 100 ꢀC,
15 min, in air. Non-isolated yield determined by H NMR.
b
1
conventional heating. Suzuki–Miyaura couplings usually need
higher temperatures under microwave conditions and the
optimized conditions with conventional heating are therefore
greener.37,38 Finally, the important role of the metformin as
a ligand was highlighted through a control reaction. Indeed, at
Different functionalized aryl chlorides (nitro, aldehyde,
ketone, triuoro) were used but no conversion was observed,
21038 | RSC Adv., 2017, 7, 21036–21044
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Table 5 Substrates scope of aryl halides for the Suzuki–Miyaura cross-coupling reaction catalyzed by the Metformin/Pd complex in neat watera
Isolated yield
(%)
Entry
Ar1-X
Ar2-B(OH)2
Product
1
2
39b, 77c
95
3
81
4
5
6
67
90b
46b
7
80b,c
8
97b,c
9
24b,c
10
11
12
13
42b, 77c,d
42b, 84c,d
45b, 88c,d
15b, 72c,d
14
61b,c
15
16
70c,d
99b
17
81b
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