A Bipyridine-Palladium Derivative as General Pre-Catalyst for Cross-Coupling Reactions in Deep Eutectic Solvents

Article abstract of DOI:10.1002/adsc.201900472

A versatile and DES-compatible bipyridine palladium complex has been developed as a general pre-catalyst for different cross-coupling reactions (Hiyama, Suzuki-Miyaura, Heck-Mizoroki and Sonogashira) in deep eutectic solvents. Hydrogen bond capacity of the ligand allows to keep the excellent level of results previously obtained in classical organic solvents. Palladium pre-catalyst showed a high catalytic activity for many cross-coupling reactions, demonstrating a great versatility and applicability. Also, this methodology employs sustainable solvents as a reaction medium and highlights the potential of DES as alternative solvents in organometallic catalysis. The catalyst and DES were easily and successfully recycled. The formation of PdNPs in DES has been confirmed by TEM and XPS analysis and their role as catalyst by mercury test. The dynamic coordination of bipyridine-type ligand in the palladium complex formation has been studied via UV/Vis. (Figure presented.).

Full text of DOI:10.1002/adsc.201900472

Title: A Bipyridine-Palladium Derivative as General Pre-Catalyst for
Cross-Coupling Reactions in Deep Eutectic Solvents
Authors: Beatriz Saavedra, Nerea González-Gallardo, Alessandro Meli,
and Diego Ramón
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201900472
Link to VoR: http://dx.doi.org/10.1002/adsc.201900472

10.1002/adsc.201900472
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
A Bipyridine-Palladium Derivative as General Pre-Catalyst for
Cross-Coupling Reactions in Deep Eutectic Solvents
Beatriz Saavedraa, Nerea González-Gallardoa, Alessandro Melia,b, Diego J. Ramóna*
a
Affiliation a
[Departamento de Química Orgánica and Instituto de Síntesis Orgánica (ISO), Facultad de Ciencias Universidad de
Alicante, Apdo. 99, 03080 Alicante, Spain. Email: djramon@ua.es]
Affiliation b
b
[Current adress: Universitꢀ degli Studi di Palermo, Dipartimento di Scienze Biologiche, Chimiche e Farmaceutiche,
Viale delle Scienze, Ed. 17, 90128 Palermo, Italy]
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. A versatile and DES-compatible bipyridine The catalyst and DES were easily and successfully
palladium complex has been developed as a general pre- recycled. The formation of PdNPs in DES has been
catalyst for different cross-coupling reactions (Hiyama, confirmed by TEM and XPS analysis and their role as
Suzuki-Miyaura, Heck-Mizoroki and Sonogashira) in deep catalyst by mercury test. The dynamic coordination of
eutectic solvents. Hydrogen bond capacity of the ligand bipyridine-type ligand in the palladium complex formation
allows to keep the excellent level of results previously has been studied via UV/Vis.
obtained in classical organic solvents. Palladium pre-catalyst
showed a high catalytic activity for many cross-coupling
reactions, demonstrating a great versatility and applicability.
Also, this methodology employs sustainable solvents as a
reaction medium and highlights the potential of DES as
alternative solvents in organometallic catalysis.
Keywords: Cross-coupling, Green chemistry, Hydrogen
bonds, Ligand design, Palladium.
inexpensive components. These components can
engage in reciprocal hydrogen-bonding interactions
to form an eutectic mixture that has a melting point
far lower than that of the individual components,
owing to self-association. DES are important
alternatives to volatile organic solvents, due to their
interesting properties and benefits such as low cost,
no flammability, recyclability, low vapor pressure,
ease synthetic accessibility, benign and safe nature
along with renewability and biodegradability.[3]
Introduction
Transition-metal
catalyzed
cross-coupling
reactions comprise one of the most important classes
of synthetic transformations in modern organic
chemistry, providing chemists with an exceptionally
powerful tool for the construction of carbon-carbon
(C-C) bonds including sp2-sp2 ones. These methods
have been extensively used both in academic and
industrial areas, including natural product synthesis,
material science, pharmaceutical and fine chemical
production.[1]
Although, the application of neoteric media in
metal-catalyzed reactions has undergone
a
tremendous growth in recent years,[4] only a few
catalytic systems were able to carry out cross-
coupling reactions using sustainable solvents and
there are even less reports about cross-coupling
Over the years, numerous protocols for cross-
coupling reactions have been reported. However,
most of these transformations are performed in
hazardous and toxic volatile organic solvents (VOCs). processes in DES media (Scheme 1). So, the design
The use of appropriate solvents for chemical
transformations is becoming increasingly important
for the sustainable development of the chemical
industry. Therefore, intensive research efforts have
been made to develop protocols with less ecological
footprint.[2]
and synthesis of organometallic complexes
compatible with DES (hydrogen bond interactions)
together with keeping the catalytic activities obtained
in organic solvents, is still a real challenge in order to
make this methodology useful for industry.
The first reported use of DES was described by
König and co-workers when they synthesized biaryls
using palladium-catalyzed Suzuki-Miyaura coupling
Deep eutectic solvents (DES), are generally
referred to combinations of two or three safe and
1
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10.1002/adsc.201900472
Advanced Synthesis & Catalysis
reaction in a mannitol-DMU-NH4Cl mixture.[5] A few
months later, the same group published the use of
sugar-urea-salts melts as solvent for Stille reactions,[6]
and also Heck and Sonogashira cross-coupling
reaction using sugar and L-carnitine based melts. In
all these cases, the studied scope was very limited
and each reaction needed different palladium pre-
catalyst, as well as DES.[7] Our research group
reported cationic phosphine palladium-catalyzed
cross-coupling reactions in DES media with lower
catalytic amounts, but this catalytic system was not
suitable for the Hiyama coupling reaction.[8]
Although, a pincer-type palladium catalyst was
effective for the aforementioned reaction.[9]
Recently, Capriati and co-workers published
Suzuki-Miyaura
coupling
reactions
using
aryltrifluoroborates in DES[10] and the combination of
a Suzuki cross-coupling reaction and an enzymatic
transamination in DES has been reported,[11] but none
of them were active pre-catalysts to all typical cross-
coupling processes. Nearly for each cross-coupling
reaction a different pre-catalyst is used.
Nitrogen-based ligands have received less attention
compared to phosphines or NHCs in palladium-
catalyzed cross-coupling reactions. However, the
lower cost of nitrogen-based ligands compared with
phosphines make them attractive alternative
systems.[12]
With all these precedents, and our experience in
the use of DES in other Pd-catalyzed organic
reactions,[13]
a
new amino-bipyridine-palladium
complex has been successfully applied for the first
time as a general and efficient pre-catalyst to a broad
cross-coupling reactions under heterogeneous
conditions (including Hiyama, Suzuki-Miyaura,
Heck-Mizoroki, and Sonogashira) with a great
compatibility with DES due to its intrinsic capacity of
hydrogen bond formation with the solvent.
Results and Discussion
Our investigations started with the synthesis and
characterization of the novel bipyridine-palladium
complex. Ligands 3 were synthetized following a
literature procedure, and simple metalation with
PdCl2 led to the formation of complexes 4 (Scheme
2).[14]
Scheme 2. Bipyridine-palladium catalyst synthesis.
Once we prepared and characterized the palladium
complexes (see ESI), they were tested in different
cross-coupling reactions starting by the Hiyama
reaction. Different palladium sources were evaluated
as pre-catalysts for the reaction between 4-
bromoacetophenone (5a) and trimethoxyphenylsilane
(6; Table 1). Prior to these studies we proved that the
reaction without catalyst failed (entry 1). After this
control experiment, catalyst 4a was evaluated using
Scheme 1. Previous work of cross-coupling reactions in
DES.
2
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10.1002/adsc.201900472
Advanced Synthesis & Catalysis
different catalytic amounts of complex 4a (entries 2-
under the same reaction conditions yielded only 5%
of the product (entry 7). The use of
dimethylaminobipyridine palladium complex 4b as
pre-catalyst also gave lower yield (entry 8), showing
that the presence of the free amino group in pre-
catalyst 4a enhanced its activity, probably due to its
interaction as a hydrogen donor with the DES
structure. This cooperative effect established by
hydrogen-bond network within the DES and the
ligand has been previously described by García-
Álvarez et al. in the isomerization of allylic alcohols
in DES.[15]
Once the best pre-catalytic system was stablished,
a study to find the best reaction conditions was
performed (Table 2). The reaction was performed at
different temperatures, obtaining better results at 100
oC (entries 1-2). Then, we tried a sort of bases (entries
3-8), founding out that sodium bicarbonate (2 equiv.)
provided the best yield (entry 7). The reaction
without base did not take place (entry 9). Finally,
different hydrophilic (entries 7, 10-14) and
hydrophobic (entries 15-16) eutectic mixtures and
also, pure glycerol and water (entries 17-18) were
tested as solvents, with the best results being obtained
in ChCl:glycerol (1:2; entry 7).
3) obtaining higher yield with 1 mol% of catalyst.
Table 1. Optimization of the catalyst.
Entry
Catalyst (x mol%)
Yield
(%)a)
1
2
3
4
5
6
7
-
4a (1 mol%)
4a (0.5 mol%)
0
88
75
58
30
0
PdCl2 (1 mol%)
PdCl2 (1 mol%) + 3a (1:1)
4a (1 mol%) + 3a (1:1)
(2,2'-bipyridine)dichloropalladium(II)
(1 mol%)
5
8
4b (1 mol%)
54
a)
Yield determined by GC using tridecane as the internal
standar
In order to prove the importance of the presence of
the ligand 3a, PdCl2 was employed as solely pre-
catalyst (entry 4) and in the presence of ligand 3a
(entry 5) obtaining 58 or 30% yield, respectively.
Surprisingly, pre-catalyst 4a with an excess of ligand
3a inhibited the reaction (entry 6). The amino group
of bipyridine moiety proved to be relevant as the use
of (2,2'-bipyridine)dichloropalladium(II) as catalyst
Once the optimum reaction conditions were
established, the substrate scope was studied (Table 3).
Different activated and deactivated aryl bromides
were cross-coupled with trimethoxyphenylsilane (6).
In general, very good isolated yields were obtained
for biaryls 7 regardless of the electronic nature of the
employed aryl bromide (entries 1-7).
Table 2. Optimization of the reaction conditions.
Entry
Base (x
equiv.)
Solvent
Yield (%)a)
Entry
10
Base (x
equiv.)
Solvent
Yield (%)a)
1
2
3
4
5
6
7
8
9
K2CO3
(2 equiv.)
K2CO3
(2 equiv.)
K3PO4
(2 equiv.)
Na2CO3
(2 equiv.)
NaOAc
(2 equiv.)
NaF (2
ChCl:glycerol
(1:2)
ChCl:glycerol
(1:2)
ChCl:glycerol
(1:2)
ChCl:glycerol
(1:2)
ChCl:glycerol
(1:2)
ChCl:Glycerol
(1:2)
ChCl:glycerol
(1:2)
ChCl:glycerol
(1:2)
0b)
83
70
23
68
30
88
74
0
NaHCO3
(2 equiv.)
NaHCO3
(2 equiv.)
NaHCO3
(2 equiv.)
NaHCO3
(2 equiv.)
NaHCO3
(2 equiv.)
NaHCO3
(2 equiv.)
NaHCO3
(2 equiv.)
NaHCO3
(2 equiv.)
NaHCO3
(2 equiv.)
ChCl:urea (1:2)
7
20
7
11
ChCl:ethylene
glycol (1:2)
Ph3PMeBr:glycerol
(1:2)
12
13
AcChCl:urea (1:2)
0
14
Guanidine:glycerol
(1:1)
Decanoic
acid:menthol (1:2)
Decanoic
0
15
0
equiv.)
NaHCO3
(2 equiv.)
NaHCO3
(1 equiv.)
-
16
0
acid:TBAB (2:1)
Glycerol
17
55
5
ChCl:glycerol
(1:2)
18
H2O
a) Yield determined by GC using tridecane as the internal standar b) Reaction performed at 50 oC.
3
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10.1002/adsc.201900472
Advanced Synthesis & Catalysis
4-Chloroacetophenone was also tested but the desired
product was not obtained.
Various heteroaromatic bromides were used in
good results (entries 8 and 9) and even, benzyl
bromide gave a satisfactory 89% yield (entry 10).
Different alkyl bromides (1-bromopentane and 1-
bromododecane) and allylic bromide were employed
with no results.
Table 3. Scope of the Hiyama reaction.
The Suzuki-Miyaura reaction was also evaluated
(Table 4). Preliminary optimization studies showed
o
that the optimal temperature was 100 C and the best
Entry
Ar
Product
Yield (%)a)
base was K2CO3. Different eutectic mixtures were
tested, obtaining unsatisfactory results in two
hydrophilic DES (entries 4 and 8), an hydrophobic
mixture (entry 5) and some NADES (entries 9-11).
Better yields were obtained in hydrophilic DES
ChCl:glycerol (87% yield), and ChCl:ethylene glycol
(93% yield) and, as well as, in the hydrophobic DES
decanoic acid:menthol (98% yield; entries 1, 2 and 6).
Although the best result was obtained with the
hydrophobic mixture decanoic acid:menthol (entry 2),
the purification step was more tedious due to the
presence of a large amount of menthol after the work-
up process. Also, pure ethylene glycol and water
were employed but with higher yields being obtained
in ChCl:ethylene glycol mixture (entries 13-15). The
use of PdCl2 salt as pre-catalyst (entries 16-17) or the
use of lower amounts of catalyst (entries 3, 7 and 17)
led to worse results (compare entries 7 and 17).
However using a high amount of the pre-catalyst, the
difference in activity between PdCl2 and 4a is not so
significant (compare entries 13 and 16).
1
2
3
4
5
6
7
8
9
4-(MeCO)C6H4
4-(O2N)C6H4
4-FC6H4
88b)
90c)
88
95
73
70
33
67
80
7a
7b
7c
7d
7e
7f
7g
7h
7i
Ph
4-MeC6H4
4-HOC6H4
4-MeOC6H4
3-pyridyl
3-furyl
10
CH2Ph
89
7j
a)
b)
Isolated yield after flash chromatography. Reaction
performed during 1 h. c) Reaction performed during 2 h.
Table 4. Optimization of the reaction conditions.
With the optimal conditions in hand, we explored
the scope of the reaction with a variety of aryl
bromides 5 and boronic acids 8 (Table 5). Regarding
to aryl bromides, slightly higher yields of the desired
coupled products were obtained in the presence of
electron-withdrawing groups (entries 1-3).
Entry
Catalyst
(x mol%)
Solvent
Yield
(%)a)
1
2
4a (1 mol%)
4a (1 mol%)
ChCl:glycerol (1:2)
Decanoic acid:menthol
(1:2)
Decanoic acid:menthol
(1:2)
ChCl:urea (1:2)
Decanoic acid:TBAB
(2:1)
87
98
3
62
4a
Table 5. Scope of the Suzuki-Miyaura reaction.
(0.5 mol%)
4a (1 mol%)
4a (1 mol%)
4
5
33
16
6
7
4a (1 mol%)
ChCl:ethylene glycol
(1:2)
ChCl:ethylene glycol
(1:2)
93
64
4a
(0.5 mol%)
Entry
Ar
R
Product
Yield
(%)a)
91b)
65
54
20
20
42
46
55
50
53
53
57
70
72
8
9
10
11
12
4a (1 mol%) Ph3PMeBr:glycerol (1:2)
4a (1 mol%) ChCl:oxalic acid (1:1)
4a (1 mol%) ChCl:L-tartaric acid (1:1)
0
0
0
1
2
3
4
5
6
7
8
9
4-(MeCO)C6H4
4-(O2N)C6H4
4-FC6H4
H
H
H
H
H
H
H
H
H
7a
7b
7c
7d
7k
7f
7g
7h
7l
4a (1 mol%)
4a (1 mol%)
ChCl:L-malic acid (1:1)
Decanoic acid:menthol
(1:2)
4
99b)
Ph
4-tBuC6H4
13
4a (1 mol%)
ChCl:ethylene glycol
(1:2)
91b)
4-HOC6H4
4-MeOC6H4
3-pyridyl
14
15
16
4a (1 mol%)
4a (1 mol%)
PdCl2
(1 mol%)
PdCl2
Ethylene glycol
H2O
ChCl:ethylene glycol
(1:2)
ChCl:ethylene glycol
(1:2)
88b)
89b)
85b)
2-thienyl
10
11
12
13
14
3-quinolinyl
4-(MeCO)C6H4
4-(MeCO)C6H4
4-(MeCO)C6H4
4-(MeCO)C6H4
H
7m
7n
7o
7p
7q
3-Me
4-F
4-HO
2-MeO
17
48
(0.5 mol%)
a) Yield determined by GC using tridecane as the internal
standar b) Reaction performed in 1 h.
a)
b)
Isolated yield after flash chromatography
performed in 1 h.
Reaction
4
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10.1002/adsc.201900472
Advanced Synthesis & Catalysis
Aryl bromides bearing electron-donating groups gave
low to moderate yields (entries 4-7). Heteroaromatic
bromides were tested, leading to moderate yields
(entries 8-10). Then, various boronic acids were
coupled with 4-bromoacetophenone giving moderate
to good yields (entries 11-14), with superior yields
being achieved in the case of those substrates having
electron-donating groups.
The couplings of aryl iodides with an electron-
withdrawing substituent at para-position with methyl
acrylate afforded good (entry 2) to excellent yields
(entries 1 and 3). Unactivated iodides or bearing
electron-donating substituents gave similar results
(entries 4 and 7-9) except for 2-methyl and 4-methyl
derivatives that led to slightly lower yields (entries 5
and 6).
Finally, the catalytic activity of pre-catalyst 4a in
the copper-free Sonogashira reaction was evaluated
(Table 8). To find the optimal conditions, the
Sonogashira cross-coupling between iodobenzene
(9d) and phenylacetylene (12) in DES as a model
reaction was examined. Initially, different DES were
tested (entries 1-5) and Ph3PMeBr:glycerol was
emerged as the best reaction medium (entry 5). Also,
different organic and inorganic bases were examined
(entries 6-9 and 11), obtaining the best results with
iPr2NH (entry 9) and K2CO3 (entry 11). To evaluate
which base gave better yield, higher catalytic amount
of 4a was employed (2 mol%) in longer reaction
times (entries 10 and 12); showing that the organic
base (iPr2NH) was the best (entry 10).
The Heck-Mizoroki cross-coupling reaction was
also tested (Table 6). The reaction was performed
o
using different DES as sustainable solvent at 100 C,
obtaining the best result in ChCl:ethylene glycol
mixture (entry 1). It was observed that the reaction
time could be significant reduced just by heating up
the reaction, obtaining similar yields at 120 oC
(compare entries 1 and 8).
Table 6. Optimization of the reaction conditions.
Entry
1
T
t
Solvent
Yield
(%)a)
(oC)
(h)
Table 8. Optimization of the reaction conditions.
100
24
ChCl:ethylene glycol
(1:2)
94
2
3
4
100
100
100
24
24
24
ChCl:glycerol (1:2)
ChCl:urea (1:2)
AcChCl:ethylene glycol
(1:2)
83
0
51
Entry
1
Base
t
Solvent
Yield
(%)a)
30b)
5
6
100
100
24
24
Ph3PMeBr:glycerol (1:2)
Decanoic acid:menthol
(1:2)
Decanoic acid:TBAB
(2:1)
82
0
(h)
iPr2NH
2
ChCl:ethylene glycol
(1:2)
ChCl:urea (1:2)
AcChCl:ethylene
glycol (1:2)
ChCl:glycerol (1:2)
Ph3PMeBr:glycerol
(1:2)
Ph3PMeBr:glycerol
(1:2)
Ph3PMeBr:glycerol
(1:2)
Ph3PMeBr:glycerol
(1:2)
Ph3PMeBr:glycerol
(1:2)
Ph3PMeBr:glycerol
(1:2)
7
8
100
120
24
6
0
2
3
iPr2NH
iPr2NH
2
2
33b)
20b)
ChCl:ethylene glycol
(1:2)
93
4
5
iPr2NH
iPr2NH
2
2
32b)
55b)
a) Yield determined by GC using tridecane as the internal
standard.
6
7
NaOAc
Na2CO3
K3PO4
2
2
2
2
6b)
Based on above results, we attempted the cross-
coupling reactions of various aryl iodides 9 with
methyl acrylate 10 (Table 7).
33b)
54b)
61
8
Table 7. Scope of the Heck-Mizoroki reaction.
9
iPr2NH
10
11
12
13
iPr2NH 16
80c)
68c)
71c)
84d)
K2CO3
K2CO3
5
Ph3PMeBr:glycerol
(1:2)
Ph3PMeBr:glycerol
(1:2)
Ph3PMeBr:glycerol
(1:2)
Entry
Ar
Product
Yield (%)a)
1
2
3
4
5
6
7
8
9
4-(O2N)C6H4
4-(MeCO)C6H4
4-F3CC6H4
Ph
93
67
95
90
66
79
84
86
94
11a
11b
11c
11d
11e
11f
11g
11h
11i
16
iPr2NH 16
a) Yield determined by GC using tridecane as the internal
2-MeC6H4
4-MeC6H4
2-HOC6H4
4-MeOC6H4
1-naphthyl
b)
c)
standard.
Reaction performed at 80 oC.
Reaction
performed with 4a (2 mol%). d) Reaction performed with
4a (3 mol%).
a) Isolated yield after flash chromatography.
5
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10.1002/adsc.201900472
Advanced Synthesis & Catalysis
Finally, a higher catalytic amount (3 mol%) afforded
the coupled product 13a with the best yield achieved
(84%; entry 13).
To survey the scope and versatility of catalyst 4a
in the Sonogashira reaction, diverse aryl halides 9
were coupled with terminal alkynes (12) under the
optimal reaction conditions (Table 9). Good yields
were obtained using electron-withdrawing and
electron-neutral aryl iodides (entries 1, 3, 5, 7 and 8).
Different aryl bromides were tested obtaining
moderate to good yields in the presence of electron-
withdrawing groups (entries 4 and 6) and a lower
yield with bromobenzene (entry 2). In this case, the
electronic nature of the aromatic ring had a notable
impact, obtaining lower yields with electron-donating
aryl iodides (entries 9-12). Aliphatic terminal alkynes
and heteroaryl iodides were also tested (entry 13 and
14). Ethynylcyclohexane was cross-coupled with 1-
iodo-4-nitrobenzene obtaining a moderate yield
(48%; entry 13) and surprisingly, electron rich thienyl
derivative gave a good result (entry 14).
Figure 1. Recyclability of the system.
It should be pointed out that precipitate of
palladium black was also observed during the
sequence of the reactions, which might explain the
progressive decrease of activity detected during the
recycling of the catalyst by formation of inactive
species. However, the fact that a good catalytic
activity was still detected after 3 or 5 runs suggested
that DES components played a possible stabilizing
role on the formed PdNPs.[18] To confirm this fact,
after the completion of the reaction (first cycle), the
remaining mixture was analyzed by TEM
(Transmission Electron Microscopy; Figure 2). As
expected, palladium clusters were observed with an
average of 4.16±1.10 nm diameter (Hiyama
conditions), 3.17±0.69 nm diameter (Suzuki-Miyaura
conditions), 1.81±0.40 nm diameter (Heck
conditions) and 1.66±0.33 nm diameter (Sonogashira
conditions), confirming the presence of PdNPs in all
cross-coupling reactions. These data permitted to
calculate that about 1919, 848, 156 and 118
palladium atoms constituted the average cluster,
respectively.[19]
Table 9. Scope of the Sonogashira reaction.
Entry
Ar/X
R
Product
Yield
(%)a)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Ph/I
Ph/Br
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
C6H11
Ph
84
11
90
85
91
71
83
56
29
54
15
64
48
74
13a
13a
13b
13b
13c
13c
13d
13e
13f
13g
13h
13i
13j
13k
4-(O2N)C6H4/I
4-(O2N)C6H4/Br
4-(MeCO)C6H4/I
4-(MeCO)C6H4/Br
4-F3CC6H4/I
4-FC6H4/I
2-MeC6H4/I
4-MeC6H4/I
4-MeOC6H4/I
2-H2NC6H4/I
4-(O2N)C6H4/I
2-thienyl/I
a) Isolated yield after flash chromatography.
Then, we decided to study the recyclability of our
catalytic system, which is considered to be a crucial
point for the sustainability of many industrial
processes.[16] For this purpose, after the completion of
the reactions, the mixture was extracted with 2-
MeTHF[17] (a renewable VOC solvent) to remove all
organic compounds, and the mixture of DES and
catalyst was reused under the same reaction
conditions. The catalyst remained active and could be
efficiently recycled up to 5 consecutive cycles in
Hiyama and Suzuki reactions. In the case of Heck
and Sonogashira reactions, the catalyst could be
recycled only 3 consecutive cycles (Figure 1).
Figure 2. TEM images of PdNPs after the first cycle of the
Hiyama (A), Suzuki-Miyaura (B), Heck (C) and
Sonogashira (D) reactions.
6
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10.1002/adsc.201900472
Advanced Synthesis & Catalysis
XPS (X-ray Photoelectron Spectroscopy) analysis
tritiation showed the formation of an initial complex
with a palladium atom coordinated with two ligands,
probably by the more donating nitrogen atoms (NH2
moiety: A in Figure 5).
was performed to confirm the oxidation state of the
catalyst after the catalytic reactions (Figure 3). This
analysis showed that part of the initial palladium(II)
was reduced to palladium(0).
FIT
3d 3/2 Pd (Catalyst 4a)
3d 5/2 Pd (Catalyst 4a)
A
FIT
B
3d 3/2 Pd (Catalyst 4a)
3d 3/2 Pd(0)
3d 5/2 Pd (Catalyst 4a)
3d 3/2 Pd(0)
Figure 4. Molar ratio = 1:2 (metal:ligand) obtained by
UV/Vis tritiation studies at 224 nm and 222.8 nm.
Figure 3. A) XPS of pre-catalyst 4a before the reaction, B)
XPS of palladium catalyst after the reaction.
The mercury test was performed in order to check
if the generated nanoparticles catalyzed the reaction.
The reaction was set up under Hiyama standard
conditions and Hg (2.5 equiv.) was added, observing
only a 2% of conversion of desired product 7a. Also,
kinetic studies were performed for all cross-coupling
reactions observing an induction period with low
catalyst loadings in all cases. During this initial
period, palladium nanoparticles were not observed by
TEM images (see ESI). Only, the nanoparticles
isolated from the first Hiyama cycle, after aqueous
work-up and centrifugation of the aqueous mixture,
were used in a second cycle with fresh solvent and
reagents obtaining a slightly decrease in the yield (7a,
56%). These results seem to indicate that catalyst 4a
Figure 5. Different coordination of palladium with ligand
3a.
Then, this initial complex evolves towards the
thermodynamic complex formed by coordination
with the two nitrogen atoms of the bipyridine unit (C),
probably through an intermediate complex involving
the coordination with the amino pyridine subunit of
the ligand (Figure 5, coordination B).
plays
a
pre-catalyst role and palladium(0)
nanoparticles might be the real catalyst for the
reaction, and they are generated in the reaction
medium.
To obtain more information about the formation of
complex 4a, an UV/Vis study of the evolution of the
coordination of the ligand 3a (5·10-5 M in
acetonitrile) to palladium salt [Pd(MeCN)2Cl2 2.6·10-
Experimental UV/Vis tritiation studies in
acetonitrile at different wavelengths revealed that
palladium was initially coordinated by two bipyridine
ligands 3a (Figure 4 and ESI). Surprisingly,
characterization analysis of the crude mixture of pre-
catalyst 4a synthetized with an excess of ligand 3a,
showed only the presence of one ligand by one
palladium atom (see ESI: Complex NMR analysis).
Therefore, we began to suspect that the UV/Vis
4
M in acetonitrile] with the time was carried out,
showing that the initial complex (t = 0 min) is
changing and the final shape (t = 6 h) is in
consonance with the spectrum of the previously
synthetized and isolated complex 4a (2.5·10-4 M in
acetonitrile; Figure 6).
7
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10.1002/adsc.201900472
Advanced Synthesis & Catalysis
Experimental Section
Ligand 3a without Pd
0 min
1 h
General. Solvents and reagents were used as obtained
from commercial sources and without purification. 1H
NMR (300 MHz) spectra were recorded on Bruker AC-300
NMR spectrometers respectively in proton coupled mode.
13C NMR (75.5 MHz) spectra were recorded on Bruker
AC-300 NMR spectrometers respectively in proton
decoupled mode at 20 °C; chemical shifts are given in δ
(parts per million) and coupling constants (J) in Hertz.
Low-resolution mass spectra (EI) were obtained at 70 eV
on an Agilent Technologies GC/MS-5973N spectrometer
or Agilent 5973 Network spectrometer with Direct
Insertion Probe (73DIP-1), giving fragment ions in m/z
with relative intensities (%) in parentheses. Infrared
spectra were measured on a Jasco FT/IR-4100 Fourier
Transform Infrared Spectometer. Melting points were
obtained with a Reichert Thermovar apparatus. XPS
analyses were carried out on a VG-Microtech Mutilab.
TEM images were obtained on a JEOL, model JEM-2010
equipped with an X-ray detector OXFORD INCA Energy
TEM 100 for microanalysis (EDS). The chromatographic
analyses (GC) were determined with a Younglin 6100
instrument equipped with a flame ionization detector and
30 m HP-5 capillary column (0.25 mm diam, 0.33 mm film
thickness), using nitrogen (2 mL/min) as a carrier gas,
Tinjector = 270 ºC, Tcolumn = 60 ºC (3 min) and 60-270 ºC (15
ºC/min), P = 12 psi. Thin layer chromatography (TLC) was
carried out on Schleicher & Schuell F1400/LS 254 plates
coated with a 0.2 mm layer of silica gel; detection by
UV254 light. Column chromatography was performed using
silica gel 60 of 40-63 mesh. UV-Vis spectra were recorded
in a SHIMAZDU UV-1603 apparatus.
2 h
3 h
4 h
6 h
Complex 4a
Complex 4a + Ligand 3a (1 equiv.)
Ligand 3a without Pd
General Procedure of Hiyama reaction. To a solution of
aryl halide (0.5 mmol), sodium bicarbonate (1 mmol),
catalyst 4a (0.005 mmol) in 1 mL of DES, 0.75 mmol of
organosilane was added and the resulting mixture was
stirred at 100 °C for 16 h. The mixture was quenched with
water and extracted with EtOAc (3 × 5 mL). The combined
organic phases were dried over MgSO4, followed by
evaporation under reduced pressure to remove the solvent.
Products were usually purified by chromatography on
silica gel (hexane/ethyl acetate) and/or distillation to give
the corresponding products.
Figure 6. Evolution of palladium coordination with ligand
3a.
Conclusion
A novel and versatile pre-catalyst has been
successfully applied for the first time to common
cross-coupling reactions usually performed in toxic
dipolar aprotic solvents (Hiyama, Suzuki-Miyaura,
Heck-Mizoroki and Sonogashira), in environmentally
friendly eutectic mixtures. It is important to note that:
(i) the same palladium pre-catalyst is able to catalyze
a broad number of cross-coupling reactions, keeping
the excellent results obtained in hazardous organic
solvents, (ii) the reactions proceed in DES under
aerobic conditions, and (iii) the use of DES as a
reaction medium allows the catalyst recycling (up to
3 or 5 consecutive times depending on the cross-
coupling reaction) without loss of catalytic activity.
Different studies showed the dynamic behaviour of
palladium complexes as well as its role as pre-
catalyst, with nanoparticles of palladium(0) seeming
to be the real catalyst. All these results highlight the
broad potential of DES as substituents for hazardous
organic solvents in any type of cross-coupling
reaction, just by choosing the correct pre-catalyst,
making organic synthesis more sustainable and
reducing its negative impact on the environment.
General Procedure of Suzuki-Miyaura reaction. To a
solution of aryl halide (0.5 mmol), potassium carbonate
(0.75 mmol), catalyst 4a (0.005 mmol) in 2 mL of DES,
0.55 mmol of boronic acid was added and the resulting
mixture was stirred at 100 °C for 4 h. The mixture was
quenched with water and extracted with EtOAc (3 × 5 mL).
The combined organic phases were dried over MgSO4,
followed by evaporation under reduced pressure to remove
the solvent. Products were usually purified by
chromatography on silica gel (hexane/ethyl acetate) and/or
distillation to give the corresponding products.
General Procedure of Heck-Mizoroki reaction. To a
solution of aryl halide (0.5 mmol), sodium acetate (0.75
mmol), catalyst 4a (0.005 mmol) in 1 mL of DES, 0.60
mmol of methyl acrylate was added and the resulting
mixture was stirred at 120 °C for 6 h. The mixture was
quenched with water and extracted with EtOAc (3 × 5 mL).
The combined organic phases were dried over MgSO4,
followed by evaporation under reduced pressure to remove
the solvent. Products were usually purified by
chromatography on silica gel (hexane/ethyl acetate) and/or
distillation to give the corresponding products.
General Procedure of Sonogashira reaction. To a
solution of aryl halide (0.5 mmol), diisopropyl amine (1
mmol), catalyst 4a (0.015 mmol) in 2 mL of DES, 0.60
mmol of phenylacetylene was added and the resulting
mixture was stirred at 60 °C for 16 h. The mixture was
quenched with water and extracted with EtOAc (3 × 5 mL).
The combined organic phases were dried over MgSO4,
followed by evaporation under reduced pressure to remove
8
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10.1002/adsc.201900472
Advanced Synthesis & Catalysis
the solvent. Products were usually purified by
chromatography on silica gel (hexane/ethyl acetate) and/or
distillation to give the corresponding products.
[5] G. Imperato, S. Höger, D. Lenoir, B. König, Green
Chem. 2006, 8, 1051-1055.
[6] G. Imperato, R. Vasold, B. König, Adv. Synth. Catal.
2006, 348, 2243-2247.
General procedure for the preparation of DESs. A
mixture of hydrogen-bond donor and hydrogen-bond
acceptor, with the previously specified molar ratio, was
added in a round bottom flask under an inert atmosphere.
The mixture was stirred for 60 minutes in a T range
between 65 and 80 °C obtaining the corresponding DES.
[7] F. Ilgen, B. König, Green Chem. 2009, 11, 848-854.
[8] X. Marset, A. Khoshnood, L. Sotorrios, E. Gómez-
Bengoa, D. A. Alonso, D. J. Ramón, ChemCatChem
2017, 9, 1269-1275.
General Procedure for Recycling Experiments. The
reaction was performed according to the general procedure.
Once the reaction was completed, the reaction mixture was
cooled to room temperature, and 2-MeTHF (3 x 3 mL) was
added to the reaction vessel. The biphasic mixture was
stirred for 5 min, and the upper phase (VOC-phase, mainly
unreacted organic reagents and products) was separated by
decantation and analyzed by GC using tridecane as the
internal standard. The eutectic mixture with the remaining
PdNPs (bottom phase) was dried under vacuum and was
charged again with fresh reagents and base, repeating the
process.
[9] X. Marset, S. De Gea, G. Guillena, D. J. Ramón, ACS
Sustainable Chem. Eng. 2018, 6, 5743-5748.
[10] G. Dilauro, S. M. Garcia, D. Tagarelli, P. Vitale, F. M.
Perna, V. Capriati, ChemSusChem 2018, 11, 3495-3501.
[11] J. Paris, A. Telzerow, N. Ríos-Lombardía, K. Steiner,
H. Schwab, F. Morís, H. Gröger, J. González-Sabín,
ACS Sustainable Chem. Eng. 2019, 7, 5486−5493.
Acknowledgements
[12] a) W.-Y. Wu, S.-N. Chen, F.-Y. Tsai, Tetrahedron
Lett. 2006, 47, 9267-9270; b) S.-N. Chen, W.-Y. Wu,
F.-Y. Tsai, Tetrahedron 2008, 64, 8164-8168; c) S.-H.
Huang, J.-R. Chen, F.-Y. Tsai, Molecules 2010, 15, 315.
This work was supported by the University of Alicante (VIGROB-
316) and the Spanish Ministerio de Economia, Industria y
Competitividad (CTQ2015-66624-P, PGC2018-096616-B-100).
BS thanks Generalitat Valenciana (ACIF/2017/211) for a
fellowship.
[13] B. Saavedra, J. M. Pérez, M. J. Rodríguez-Álvarez, J.
García-Álvarez, D. J. Ramón, Green Chem. 2018, 20,
2151-2157.
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10.1002/adsc.201900472
Advanced Synthesis & Catalysis
UPDATE
A Bipyridine-Palladium Derivative as General Pre-
Catalyst for Cross-Coupling Reactions in Deep
Eutectic Solvents
Adv. Synth. Catal. Year, Volume, Page – Page
Beatriz Saavedraa, Nerea González-Gallardoa,
Alessandro Melia,b, Diego J. Ramóna*
10
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