Palladium Supported on Silk Fibroin for Suzuki–Miyaura Cross-Coupling Reactions

Article abstract of DOI:10.1002/ejoc.202001120

Silk fibroin supported Pd (Pd/SF) has been prepared and used as catalyst in Suzuki–Miyaura cross-coupling reactions in water/ethanol (4:1 v/v) mixture. The reactions proceed rapidly with aryl iodides and boronic acids with different electronic properties using low metal loading (0.38 mol-%). Pd/SF exhibits better recyclability compared to other biopolymer-supported Pd catalysts, up to nineteen cycles without loss of activity.

Full text of DOI:10.1002/ejoc.202001120

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Palladium supported on silk fibroin for Suzuki-Miyaura cross-
coupling reactions
Authors: Giorgio Rizzo, Gianluigi Albano, Marco Lo Presti, Antonella
Milella, Fiorenzo G. Omenetto, and Gianluca M. Farinola
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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the VoR from the journal website shown below when it is published
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202001120
Link to VoR: https://doi.org/10.1002/ejoc.202001120
01/2020

10.1002/ejoc.202001120
European Journal of Organic Chemistry
COMMUNICATION
Palladium supported on silk fibroin for Suzuki-Miyaura cross-
coupling reactions
Giorgio Rizzo,[a] Gianluigi Albano,[a] Marco Lo Presti,[b] Antonella Milella,[a] Fiorenzo G. Omenetto,[b] and
Gianluca M. Farinola*[a]
Dedicated to Professor Franco Cozzi on the occasion of his 70th birthday
[a]
[b]
Mr. G. Rizzo, Dr. G. Albano, Dr. A. Milella, Prof. G. M. Farinola
Dipartimento di Chimica
Università degli Studi di Bari “Aldo Moro”
Via Edoardo Orabona 4, 70126 Bari, Italy
E-mail: gianlucamaria.farinola@uniba.it
http://www.chimica.uniba.it
Dr. M. Lo Presti, Prof. F. G. Omenetto
Silklab, Department of Biomedical Engineering
Tufts University
4 Colby Street, Medford, Massachusetts 02155, USA
Supporting information for this article is given via a link at the end of the document.
Abstract: Silk fibroin supported Pd (Pd/SF) has been prepared and
used as catalyst in Suzuki-Miyaura cross-coupling reactions in
water/ethanol 4:1 v/v mixture. The reactions proceed rapidly with aryl
iodides and boronic acids with different electronic properties using
low metal loading (0.38 mol%). Pd/SF exhibits better recyclability
compared to other biopolymer-supported Pd catalysts, up to nineteen
cycles without loss of activity.
as wide possibility of doping[16] and good biocompatibility.[17]
Moreover, chemical modification of SF offers unprecedented
opportunities to obtain materials for applications in
environmentally sustainable technological devices.[18]
Interestingly, degummed SF fibers are among the first
investigated supports for Pd catalysts: in 1956, Akabori et al.
developed a silk fibroin-supported palladium catalyst (Pd/SF),[19]
which was extensively studied in the asymmetric reduction of
alkenes, exploiting the chirality induction by the SF support.[20]
After over 40 years, Pd/SF has been rediscovered as versatile
catalyst for chemoselective hydrogenation of alkenes, alkynes,
azides and nitro groups,[21] and more recently for Heck reactions.[22]
However, the true potential of Pd catalysts supported on SF fibers
is still almost unexplored, especially in cross-coupling chemistry.
We have recently contributed to the development of sustainable
methodologies based on Pd‐catalyzed cross-coupling reactions.[23]
Following these studies and our interest in developing new
protocols for the Suzuki-Miyaura and related reactions,[24] in the
present work we report a new and easy route to SF supported Pd,
which is tested as a catalyst for the Suzuki-Miyaura cross-coupling.
Reactions performed in water/ethanol mixture and under
atmospheric conditions were found to proceed rapidly with low
metal loading (0.38 mol%). More importantly, compared to all
other biopolymer-supported palladium catalysts for the Suzuki-
Miyaura coupling, the Pd/SF reported here shows superior
recyclability (up to 19 cycles without loss of catalytic activity) and a
mainly heterogeneous mechanism.
For the preparation of the Pd/SF catalyst, degummed SF was
soaked for 15 minutes in a boiling aqueous solution of PdCl2 (6
mM), affording Pd(II)-impregnated fibers. In previous literature
procedures, the subsequent reduction step of Pd(II) to Pd(0) was
performed using hydrogen at high pressure as the reducing
agent[19-20] or methanol as both the reductant and the solvent.[21a-d]
We propose an alternative route to Pd/SF, based on the
synergistic effect of sodium ascorbate (NaAsc) and sodium
borohydride (NaBH4). Although preliminary reduction tests
performed with only NaAsc or NaBH4 were unsuccessful, good
results were obtained when the two reagents were used in
sequence. In the optimized procedure Pd(II)-SF complex was first
Among the Palladium-catalyzed cross-coupling reactions, the
Suzuki-Miyaura reaction is definitely one of the first choices for
generating Csp2–Csp2 bonds.[1] In recent years, it has been
extensively used for the synthesis of many core structural motifs
for pharmaceuticals, agrochemicals[2] and molecular materials.[3]
Most of Suzuki-Miyaura reactions are performed in organic
solvents using phosphine ligand-based homogeneous Pd
catalysts,[4] which are very efficient but cannot be easily recovered
and reused, and often require complex purification procedures to
isolate the final products free from metal and ligand contaminants.
A different approach consists of the use of Pd coated nanosystems[5]
or Pd species immobilized on solid supports, which has the
advantage of easy separation from the reaction mixture and good
recyclability.[6] Palladium supported on various inorganic, organic
and hybrid matrices has been successfully tested in Suzuki-
Miyaura coupling reactions. Although there are examples of
reactions in aqueous conditions,[7] most of them are performed in
organic solvents.[8] The growing interest in environmentally friendly
experimental conditions has recently boosted studies on Suzuki-
Miyaura protocols involving Pd catalysts supported on natural
biopolymers, such as cellulose,[9] chitosan,[10] alginate,[11] wool.[12]
However, some issues still remain with these systems, in particular
the need of high catalytic loading, often accompanied by severe
metal leaching.
Silk fibroin (SF), commonly available from cocoons of
domesticated silkworm (Bombyx mori), is a protein biopolymer
with increasing interest for its applications, including those in
material science.[13] Due to its structure, consisting of hydrophobic
crystalline β-sheet units alternated to hydrophilic disordered
regions,[14] SF shows mechanical stiffness and strength,[15] as well
1
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10.1002/ejoc.202001120
European Journal of Organic Chemistry
COMMUNICATION
treated at 60 °C with NaAsc (10 equiv. with respect to PdCl2) in
H2O for 24 h, then with additional aqueous NaAsc (10 equiv.) for
further 10 h at 60 °C, and finally with NaBH4 (10 equiv.) in ethanol
at room temperature for 48 h.
XPS analysis was performed to determine the amount of
palladium loading on the SF fibers. The Pd atomic concentration
was found to be 0.7±0.1%. Furthermore, from the curve-fitting of
Pd3d spectrum (Figure S1 in Supporting Information) it was
possible to obtain information on the Pd oxidation state. The Pd3d
spectrum consists of a doublet (Pd5/2-Pd3/2) due to spin-orbit
splitting and each component of the doublet involves two peaks
assigned to Pd(0) and Pd(II), with area percentages of 70 % and
30 %, respectively.
h (Table 1, entry 10): the result was not surprising, since the
beneficial role of ethanol in Suzuki-Miyaura reaction has been
already reported.[26] In particular, the minimum amount of ethanol
for quantitative yield after 1 h was found H2O/EtOH 4:1 v/v mixture
(Table 1, entry 11). Starting from these conditions, we
investigated the effect of reduced palladium loading (Table 1,
entries 13-15): interestingly, 99% yield in 1 h was observed
reducing the amount of catalyst down to 0.38 mol% (Table 1,
entry 14). Finally, shorter reaction time (Table 1, entry 16) and
lower temperature (Table 1, entry 17) were tested, but lower
yields were found.
Table 1. Pd/SF-catalyzed Suzuki-Miyaura coupling: optimization of the reaction
conditions.
Pd loading
(mmol %)
T
(°C)
t
Yield[b]
(%)
Entry[a]
Base
Solvent
(h)
1[c]
2[d]
3
-
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
NaOH
NaAc
H2O
H2O
75
75
75
50
25
75
75
75
75
75
75
75
75
75
75
75
50
24
6
0
1.50
1.50
1.50
1.50
1.50
1.50
1.50
1.50
1.50
1.50
1.50
0.75
0.38
0.19
0.38
0.38
76
99
66
22
84
17
81
50
99
99
91
99
99
67
93
78
H2O
6
4
H2O
6
5
H2O
6
6
H2O
6
7
H2O
6
8
Cs2CO3
Li2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
H2O
6
Figure 1. Scanning Electron Microscopy (SEM) images of degummed SF (a),
Pd(II)-SF complex (b), freshly prepared Pd/SF (c) and Pd/SF after 25 cycles of
Suzuki-Miyaura coupling (d) at the same magnification (scale bar = 20 μm).
9
H2O
6
10
11
12
13
14
15
16
17
H2O/EtOH (1:1)
H2O/EtOH (4:1)
H2O/EtOH (5:1)
H2O/EtOH (4:1)
H2O/EtOH (4:1)
H2O/EtOH (4:1)
H2O/EtOH (4:1)
H2O/EtOH (4:1)
1
1
Scanning Electron Microscopy (SEM) images of the starting
degummed SF (Figure 1a), Pd(II)-SF complex (Figure 1b) and
final Pd/SF (Figure 1c) do not show Pd clusters bigger than 1 nm
(which is the detection limit of SEM instrument). Interestingly, the
Pd/SF structure is quite similar to that of starting SF: the fibers
integrity is preserved, although their smoothness and straightness
seem to be reduced, and the fibers’ diameters are slightly
changed: degummed SF fibers are 9.9±0.5 µm in diameter, whilst
treatment with Pd cause a small increase of fiber dimensions, with
Pd(II)-SF 12.0±0.6 µm and Pd/SF 12.6±0.8 µm.
1
1
1
1
0.5
1
[a] All reactions were carried with 0.11 mmol of p-iodoanisole (1a), 0.16 mmol
of phenylboronic acid (2a), 0.16 mmol of base, 2.5 mL of solvent, under
atmospheric conditions. [b] Yields were estimated by GC-MS analysis on the
crude product. [c] Reaction performed with degummed SF as catalyst instead
of Pd/SF. [d] Reaction performed with Pd(II)-SF complex as catalyst instead of
Pd/SF.
p-Iodoanisole (1a) and phenylboronic acid (2a) were chosen as
model reactants to investigate the catalytic performance of Pd/SF
in the Suzuki-Miyaura coupling reaction. (Table 1).
A reference experiment was performed at 75 °C in H2O using
K2CO3 as the base and degummed SF as the catalyst: as
expected, in the absence of Pd no cross-coupling product was
observed, even after 24 h (Table 1, entry 1). The reaction under
the same conditions but in the presence of Pd/SF (using 1.50
mol% of palladium) showed quantitative yield after 6 h affording 4-
methoxy-1,1'-biphenyl (3aa) (Table 1, entry 3). It is worth
emphasizing that the intermediate Pd(II)-SF complex also exhibits
some catalytic activity, although less efficient than Pd/SF catalyst
under the same conditions (76% yield, Table 1, entry 2). Actually,
this result is not surprising: the lower catalytic activity of Pd(II)-SF
could be explained by hypothesizing the need of a preliminary
Pd(II) → Pd(0) reduction step, due to the presence of an excess of
boronic acid.[25] A decrease in yield was observed at lower
temperature (Table 1, entries 4-5) and by changing the base
(Table 1, entries 6-9). The introduction of ethanol as co-solvent
led to a neat increase of the reaction rate, with a 99% yield after 1
With the optimized experimental conditions in hand (i.e. Pd
loading 0.38 mol%, K2CO3, H2O/EtOH 4:1 v/v, 75 °C, 1 h, Table 1,
entry 14), we investigated the substrate scope of Pd/SF catalyst in
the Suzuki-Miyaura cross-coupling reaction (Table 2).
First, we tested the protocol in the coupling of (hetero)aryl iodides
with different stereo-electronic properties (1a-s) and phenylboronic
acid (2a). The Pd/SF catalyst worked very efficiently with aryl
iodides bearing both electron donating (1c-h) and electron
withdrawing groups (1i-o), giving in most cases quantitative yield
in only 1 h. Lower yields observed for iodotoluenes 1e-g can be
attributed to their low solubility in water. The Suzuki-Miyaura
protocol was successfully extended to polycyclic and heterocyclic
aromatic iodides (1p-s), requiring in some cases longer reaction
times (6 h) to get quantitative yield. We then investigated the
coupling of p-iodoanisole (1a) with some (hetero)aryl boronic acids
(2b-j): Pd/SF showed a broad versatility, although in general
2
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10.1002/ejoc.202001120
European Journal of Organic Chemistry
COMMUNICATION
electron-rich substrates (2b-d) worked better than those with
electron-poor functional groups (2f-h). 4- Mercaptophenylboronic
acid (2e) did not react, likely because sulfur atoms poisoned the
Pd catalyst.[20b]
were performed between phenylboronic acid (2a) and aryl iodides
with different stereo-electronic properties (i.e., p-iodoanisole (1a),
iodobenzene (1b), o-iodoanisole (1d), 4’-iodoacetophenone (1j), 4-
iodoaniline (1o) and 2-iodothiofene (1s)). These tests were carried
out under the same optimized conditions using 2.2 mmol of aryl
iodide and 3.2 mmol of 2a, i.e., 20 times larger than the scale of
model reaction. Interestingly, isolated yields of pure products were
found in fully agreement with those estimated by GC-MS analysis
for the corresponding small scale tests.
Moreover, we also applied our protocol in the three-step synthesis
of compound 8 (Scheme 1), a key intermediate for the synthesis
of Conivaptan hydrochloride, which is an arginine vasopressin
antagonist.[27] First, 2-iodobenzaldehyde (4) was oxidized to the
corresponding acid 5 using KMnO4; then, the Suzuki-Miyaura step
was performed with the Pd/SF catalysed optimized protocol,
giving [1,1'-biphenyl]-2-carboxylic acid (6) very rapidly (1 h) and in
good yields (84%) after column chromatography purification. The
final amide 8 was obtained (91% yield) from 6 via conversion into
the corresponding acyl chloride and following one-pot reaction
with amine 7.
We also tested the applicability of Pd/SF in the coupling of aryl
bromides and chlorides. Under the same experimental conditions,
reaction of 4-anisylboronic acid (2b) with bromobenzene (1t) was
complete in 1 h, while in the case of chlorobenzene (1u) longer
reaction times (24 h) are required and a significant amount of 4,4'-
dimethoxy-1,1'-biphenyl (deriving from the homocoupling of 2b)
by-product was obtained. However, compared to all other
biopolymer-supported Pd catalysts applied in the Suzuki-Miyaura
coupling to date, which were found not effective towards aryl
chlorides,[12] this preliminary result confirms the high catalytic
activity of Pd/SF and represents a very interesting starting point
for future investigations.
Table 2. Substrate scope of the Pd/SF-catalyzed Suzuki-Miyaura coupling.[a]
Scheme 1. Synthesis of 4-[(biphenyl-2-ylcarbonyl)amino]benzoic acid (8), key
intermediate of the AVP antagonist conivaptan hydrochloride, involving our
Pd/SF catalysed Suzuki-Miyaura protocol.
An interesting property of Pd/SF catalyst is its high recyclability in
Suzuki-Miyaura cross-coupling, investigated by repeating 25 times
the reaction of 1a and 2a, recharging the same Pd/SF batch with
fresh reagents (Figure 2). Pd/SF showed reduced yield (70%) in
the second cycle, but catalytic activity was totally recovered from
the third cycle and maintained until the nineteenth cycle, with
yields always close to 100%. The decrease of efficiency in the
second run was already observed for SF supported Pd catalysts,
and it was attributed to a conformational rearrangement of SF in
the reaction medium during the first cycle, thus making deposited
palladium less accessible in the second cycle; then, the gradual
relaxation of SF fibers in the following cycles makes palladium more
available again, resulting in a complete recovery of the catalytic
activity.[20b] However, it is worth emphasizing that Pd/SF showed
an exceptionally high recyclability (up to 19 cycles) which is much
higher than all the other biopolymer-supported palladium catalysts
applied to the Suzuki-Miyaura coupling reported to date.[9-12]
Interestingly, SEM images of Pd/SF after the 25th cycle (Figure
1d) showed that the structure of silk fibers remained almost
unaltered, while EDS analysis of the same sample revealed that
the amount of Pd loading has not changed. Consecutive use of
the catalyst caused a narrowing of the fibers down to 10.1±1.0 µm
diameter.
[a] Reactions were carried with 0.11 mmol of aryl halide 1, 0.16 mmol of arylboronic
acid 2, 0.16 mmol of K2CO3, 0.38 mol% of Pd/SF, 2.5 mL of H2O/EtOH (4:1), for
1 h under atmospheric conditions. Yields were estimated by GC-MS analysis on
the crude product. [b] Yield after 6 h. [c] Yield after 24 h.
In order to confirm the efficiency and versatility of Pd/SF catalysed
Suzuki-Miyaura protocol in organic synthesis, scale-up experiments
3
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10.1002/ejoc.202001120
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In conclusion, we have developed a new protocol for the
preparation of Pd/SF catalyst, which was characterized by XPS
and SEM analysis and then tested in the Suzuki-Miyaura coupling.
Compared to all the other biopolymer-supported palladium
catalysts reported to date, Pd/SF was found more active and
highly reusable. Our protocol represents a fast, scalable, versatile
and cheap access to biaryl compounds. The potential in organic
synthesis of this method appears interesting, and further
investigations on the substrate scope extension (i.e., aryl
chlorides) and application in the synthesis of atropisomeric
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Figure 2. Recycling tests of Pd/SF promoted Suzuki-Miyaura coupling,
performed under the optimized conditions (0.11 mmol of 1a, 0.16 mmol of 2a,
0.16 mmol of K2CO3, 0.38 mol% of Pd/SF, 2.5 mL of H2O/EtOH (4:1), for 1 h
under atmospheric conditions). Yields of 3aa product were estimated by GC-MS
analysis on the crude product.
Acknowledgements
Dr. Antonio Palermo and Dr. Adriano Boghetich are gratefully
acknowledged for NMR and SEM-EDS analyses, respectively.
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Keywords: biopolymers • cross-coupling • palladium catalyst •
silk fibroin • Suzuki-Miyaura
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10.1002/ejoc.202001120
European Journal of Organic Chemistry
COMMUNICATION
Table of Contents
Palladium Catalysis
Silk fibroin-supported Pd catalyst (Pd/SF) has been prepared and tested in the Suzuki-Miyaura coupling, showing better activity, wide
substrate scope and high recyclability compared to other biopolymer-supported palladium catalysts.
Institute and researcher Twitter usernames:
Università degli Studi di Bari “Aldo Moro”: @unibait
Silklab, Department of Biomedical Engineering: @The_SilkLab
Gianluigi Albano: @GianluigiAlbano
Marco Lo Presti: @MarcoLoPresti16
Fiorenzo G. Omenetto: @fio99re
Gianluca M. Farinola: @GMFarinola
6
This article is protected by copyright. All rights reserved.