Si-Gly-CD-PdNPs as a hybrid heterogeneous catalyst for environmentally friendly continuous flow Sonogashira cross-coupling

Article abstract of DOI:10.1039/d1gc02490f

We have reported a waste-minimized protocol for the Sonogashira cross-coupling exploiting the safe use of a CPME/water azeotropic mixture and the utilization of a heterogeneous hybrid palladium catalyst supported onto a silica/β-cyclodextrin matrix in con

Full text of DOI:10.1039/d1gc02490f

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Si-Gly-CD-PdNPs as a hybrid heterogeneous
catalyst for environmentally friendly continuous
Cite this: DOI: 10.1039/d1gc02490f
flow Sonogashira cross-coupling†
Francesco Ferlin, ‡a Daniele Sciosci,‡a Federica Valentini,a Janet Menzio,b
a
Giancarlo Cravotto, b Katia Martina b and Luigi Vaccaro
*
We have reported a waste-minimized protocol for the Sonogashira cross-coupling exploiting the safe use
of a CPME/water azeotropic mixture and the utilization of a heterogeneous hybrid palladium catalyst sup-
ported onto a silica/β-cyclodextrin matrix in continuous flow. The use of the aq CPME azeotrope has
proven to be crucial to enhance the catalyst performance including very low metal leaching. In addition,
we have also completed the flow protocol by setting a downstream in-line liquid/liquid separation that
allows the continuous recovery and reuse of the CPME fraction leading to consistent waste reduction.
Finally, E-factor distribution and safety/hazard analysis have been performed highlighting the chemical
and environmental efficiency of our protocol.
Received 13th July 2021,
Accepted 11th August 2021
DOI: 10.1039/d1gc02490f
rsc.li/greenchem
compounds with the possibility of easily removal and reuse of
the metal-based catalytic systems is highly desirable.
Introduction
Since its first appearance in the literature, the Sonogashira
Since the 90s, hybrid catalytic systems, that consist of both
cross-coupling reaction1 has been playing a pivotal role in inorganic and organic components, have been employed in a
organic synthesis. The formation of a new C–C bond between wide range of reactions.5 Hybrid catalysts combine hetero-
an acetylenic compound and an aromatic or aliphatic halide, geneous and homogeneous advantages with the key possibility
in a fast and economical way, allows for the synthesis of to tune the hybrid materials making them suitable for
several target compounds, i.e. active pharmaceutical ingredi- different catalytic pathways and conditions.6
ents as well as optoelectronic materials, with excellent yields.2
The preparation of organic–inorganic hybrid systems can
While the typical first discovered Sonogashira coupling is be approached in two ways. The first, and most used, consists
based on the use of a copper co-catalyst,1c an effective, and of a grafting procedure which is accomplished by physical
nowadays interesting as more sustainable, copper-free adsorption. However, in this case, a non-homogeneous dis-
approach was immediately disclosed by Cassar and Heck.1a,b persion of the organic layer can be observed.7 The second
Currently, still considering sustainability issues, copper-free approach is based on the selective covalent grafting between
Sonogashira coupling (or the Cassar/Heck reaction) is desir- the organic and the inorganic components and it represents a
ably performed using recoverable catalytic palladium systems. valid alternative to preserve the structure, morphology and
Accordingly, the demand for newly developed heterogeneous porosity of the support material.8
catalysts for cross-coupling3 and in general for metal catalysed
The most explored supports are mesoporous materials,9
C–C bond formation processes4 is in continuous growth.3 polymers,10 nanostructures11 and metal organic frameworks
Indeed, a more sustainable approach to prepare the desired (MOFs),12 while, the organic moiety can be a small molecule,
or an oligomer and represent the anchored ligand.
β-Cyclodextrins (β-CDs) can be efficiently used as ligand/stabil-
izers for metal nanoparticles.13 Due to their ability to host and
aLaboratory of Green S.O.C. – Dipartimento di Chimica, biologia e Biotecnologie,
Università degli Studi di Perugia, Via Elce di Sotto 8, 06123 – Perugia, Italy.
E-mail: luigi.vaccaro@unipg.it; http://greensoc.chm.unipg.it/
bDipartimento di Scienza e Tecnologia del Farmaco, University of Turin,
Via P. Giuria 9, 10125 Turin, Italy
stabilize metal ions and salts, CDs have been widely exploited
for the preparation of hybrid organic–inorganic heterogeneous
catalytic systems.14
Although, different heterogeneous catalysts and techno-
logies have been developed to increase the efficiency of the
Sonogashira reaction,15 the use of continuous flow method-
ologies is relatively less explored.16 When using a hybrid cata-
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
d1gc02490f
‡These authors contributed equally.
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lytic system the use of flow conditions becomes of crucial
utility where improved stability and recoverability of the solid
Results and discussion
catalyst can be achieved.17,18 In this regard, also the solvent Our investigation began with the design and the preparation
selection plays a pivotal role in the efficiency of the whole strat- of a hybrid organic–inorganic support for supporting palla-
egy. Indeed, as demonstrated, it is possible to minimize metal dium nanoparticles (Pd NPs). Silica SIPERNAT 320 (Evonik)
leaching from a heterogeneous catalyst and expand its stability was employed as an inorganic support, having moderate
and use by a careful choice of the most appropriate solvent or adsorption capacity and a BET specific surface area (SSA) of
solvent mixture.19
164 m2 g−1
Former studies showed that the Si-Gly-Und-CD support
.
In this context, low-coordinating reaction media or azeotro-
pic mixtures can be the preferred choice. Moreover, the latter proved efficient and homogeneous impregnation of small Pd
can also be in certain cases recyclable leading to a dramatic NPs exhibiting excellent activity.14g It was demonstrated that
minimization of waste.20
an amino alcoholic spacer and the β-CD derivative effectively
In this contribution, after comparing a large number of immobilize and stabilize Pd NPs thanks to the chelating and
potentially green and efficient reaction media, we focused our inclusive properties making both groups elemental for Pd
attention on the aqueous cyclopentyl methyl ether (CPME) anchoring. Its preparation started with derivatizing silica with
azeotrope. This medium proved to be crucial in influencing 3-glycidoxypropyltrimethoxysilane (GPMS), which was then
the catalytic performance of the hybrid Si-Gly-CD-PdNPsβ-CD reacted with 10-undecynil-1-amine (Und) to obtain an alkyl
heterogeneous catalyst. Indeed, taking advantage of the hydro- hydroxyl amino spacer prior to anchoring β-CD through a Cu-
philic nature of β-CD ligands, an easier access to the active catalyzed azide–alkyne cycloaddition with 6I-monoazido-6I-
catalytic sites occurs. Moreover, the presence of CPME and deoxy-β-CD (Scheme 2).21
water allowed to solubilize both the reagents and the halide
Aiming at simplifying the already established system (Si-
salts stoichiometrically produced during the process and Gly-Und-CD) in terms of synthetic steps, two different hybrid
leading to a homogeneous reaction mixture that can be pro- supports were also designed: a Si-Gly derivative was grafted
cessed in flow. Finally, we have also completed the protocol with 6I-amino-6I-deoxy-β-CD which opened the epoxide ring
by combining a downstream in-line liquid/liquid continuous reducing the length of the hydroxyl amino spacer (Si-Gly-CD);
separation that allowed to efficiently recover and reuse the afterwards a third support was achieved consisting of β-CD
CPME fraction facilitating the work-up and minimizing waste- directly bound to silica previously converted to silica chloride
generation (Scheme 1).
using thionyl chloride, followed by nucleophilic substitution
with 6I amino-6I-deoxy-β-CD (Si-NH-CD) (Scheme 2).
As reported in previous studies,14e the beneficial effect of
ultrasound (US) irradiation was exploited to maximize the
grafting of GPMS and the synergic effect of combined MW and
US irradiation was used when the Si-Gly derivative was reacted
with 6I-amino-6I-deoxy-β-CD21 achieving an efficient grafting of
β-CD in 4 h at 100 °C. The reaction in the absence of enabling
technologies required 16 h to reach the same results.
The synthesized silica derivatives were characterized by
infrared spectroscopy (IR) and the grafting efficacy was
measured from the percentage weight loss by thermo-
gravimetric analysis (TGA) performed in the selected tempera-
Scheme 1 Features of Si-Gly-CD-PdNPs and βCD catalysed
Sonogashira reaction in continuous flow.
Scheme 2 Synthetic routes to solid supported CDs Si-Gly-Und-CD; Si-Gly; Si-NH-CD.
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ture range from 150 °C to 800 °C to negate the influence of sol-
vents in the yield measure.
The infrared spectrum of hybrid Si-βCD supports (see ESI†)
shows the fingerprint modes of CD between 1500 and
Different batches of directly grafted Si-NH-CD were pre- 1250 cm−1 (δCH and δOH bending modes). The intense CH/
pared and despite the fact that the Si–Cl intermediate was CH2 stretching modes (νCH/CH2) at 2928 and 2856 cm−1 prove
always titrated before the reaction with β-CD we observed a the presence of an alkyl chain in Si-Gly-CD and in Si-Gly-Und
limit in reproducibility. TGA analysis showed a constant CD. The broad absorption between 3000 and 3750 cm−1 is
decomposition of the sample, therefore we could not evidence related to –OH groups from the CD rings and Si–OH groups
any degradation step. Differently, as showed in Fig. 1, the first from the silica surface (see ESI†). The νNH band at 1660 cm−1
derivative peak temperature of Si-Gly-Und-CD was detected at can be seen and the IR spectrum of Si-Gly-Und-CD showed
309 °C while the second was at 549 °C and a comparable trend also a band at 1630 with a shoulder that corresponds to the
was evidenced for Si-Gly-CD that starts the first thermal degra- triazolyl group ring vibrations.
dation at 319 °C while a second was detected at 489 °C. The
results collected from different preparations of Si-Gly-Und-CD the Pd(OAc)2 precursor in ethanol with heating at reflux.
and Si-Gly-CD demonstrated a good reproducibility of grafting From the inductively coupled plasma (ICP) analyses carried
PdNPs were immobilized on the supports by reduction of
efficiency. As described in Table 1 the efficiency of grafting was out on the catalysts, palladium loading data were obtained
measured on the basis of weight loss by TGA by comparison of (Table 2). The results showed that all the Si-CD supports load
different synthetic steps. The amount of loaded β-CD Pd NPs efficiently.
measured was from 57 to 130 µmol g−1 in the three derivatives.
All three catalysts were preliminary tested in a C–C Heck
The quantification of grafted β-CD with unchanged inclus- coupling reaction to evaluate if comparable catalytic activities
ive properties was evaluated by loss of UV absorbance at could be observed. As previously optimized, styrene may
553 nm of phenolphthalein (Php) when included in the β-CD efficiently react with iodo-benzene in the presence of 0.5 mol%
cavity after the treatment of a Php water solution with a Pd NPs supported on Si-Gly-Und-CD at 120 °C in MW for
weighed amount of β-CD-silica.14f The high specificity of this 1 h.14g The reaction gave successfully >99% on conversion with
titration highlights only the CDs available for the formation of both Si-Gly-Und and Si-Gly-CD supported Pd nanocatalysts.
the complex and we could observe differences when a spacer is 82% conversion was observed with Si-NH-CD (see ESI†).
used to maintain the inclusive capacity of cyclodextrin, there- Although it enables comparable Pd adsorption this support
fore Si-Gly-Und-CD showed from the titration with PhP a com- showed limit in preparation reproducibility and lower syn-
parable loading with respect to the TGA.
thetic activity therefore it was discarded. Since the Si-Gly-
CD-PdNPs showed comparable reactivity, stability, and a
reliable and simplified synthesis when compared to the Si-Gly-
Und derivative, it was selected for tests carried out in this
work. Surprisingly we observed that the inclusive capacity of
CD does not affect the loading capacity of the Pd NPs and
their catalytic activity.
TEM images of the catalysts Si-Gly-CD-PdNPs are shown in
Fig. 2. The solid supported catalyst consists of uniform
(mainly spheroidal) particles with a diameter range of 2–8 nm
(Fig. 2, particle distribution). Surprisingly by comparison with
the Si-Gly-Und-CD-PdNPs14g already studied, we could observe
that smaller Pd particles were present on Si-Gly-CD but with a
comparable uniformity of distribution.
With the catalyst in hand, we started to test the catalytic
performance in the model Sonogashira coupling between iodo-
benzene 1a and phenylacetylene 2a in the presence of DABCO
as a base. We screened environmentally friendly reaction
media, different common petrol-based solvents, and their
combination with water for the preliminary selection of the
best reaction conditions (Table 3).
Fig. 1 TGA profiles of silica and organic-inorganic silica derivatives
(a) Silica, (b) Si-NH-CD, (c) Si-Gly-CD, (d) Si-Gly-Und-CD.
Table 1 Loading quantification of grafted silica derivatives
Support
Loading % w/w
Loading µmol g−1
6.373a
275a
Table 2 PdNP loading (% w/w) from ICP analysis
Si-Gly
Si-Gly-CD
Si-Gly-Und-CD
Si-NH-CD
6.39b–1.94c
17.2b–9.3c
6.9b–0.75c
57b–17c
130b–83c
70b–7c
Catalyst
Loading % w/w
Si-Gly-Und-CD-PdNPs
2
1.8
2.2
a Gly amount measured by TGA. b β-CD grafting measured by TGA. Si-Gly-CD-PdNPs
c β-CD grafting measured by PhP titration.
Si-CD-PdNPs
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CH3CN is used as a solvent 70% of product 3a was obtained
(Table 3, entry 6) while, in the CH3CN/water azeotropic
mixture the conversion increased up to 85% (Table 3, entry 7).
The same increase was observed also for CPME (Table 3, entry
13) and CPME/water heterogeneous azeotropic mixtures
(Table 3, entry 14) leading to 97% conversion of product 3a
with high isolated yield, further confirming the benefit related
to the presence of water.
With the optimized reaction conditions, we proceeded to
test the stability and durability of our catalyst in the selected
reaction medium CPME/water azeotrope (Table 4).
As expected, the catalyst showed very promising results in
terms of recyclability allowing to be reused for three represen-
tative consecutive runs without loss in catalytic efficiency, and
up to five runs with negligible differences. Moreover, the cata-
lyst was further stressed by performing recycling experiments
at half conversion (Fig. 3) showing good durability.22
Fig. 2 TEM images of Si-Gly-CD Pd NPs. Pd particle size distribution is
also reported.
Table 3 Screening of reaction media for Sonogashira cross-coupling of
1aa
With these promising results under batch conditions, we
began to plan the assembly of our flow system. We packed the
Si-Gly-CD-PdNP catalyst inside a stainless-steel reactor and we
installed it into a thermostated box. The system has been
designed by using two channels for the delivery of the reactant
through the catalyst column (Fig. 4).
Entry
Medium
Cb [%]
Table 4 Catalyst recycling and reuse under batch conditionsa
1
2
3
4
DMF
90
92
88
70
DMF/water (6 : 1)
DMF/water (2 : 1)
NMP
5
6
NMP/water (2 : 1)
CH3CN
73
70
7
8
9
10
11
12
13
14
15
16
CH3CN/water az.
Propylene carbonate
Ethylene carbonate
GVL
GVL/water (2 : 1)
2-Me-THF
CPME
CPME/water az.
Water
85
87
89
90
92
87
Run
Cb [%]
Leachingc (%)
1
2
3
4
5
97 (94)
97 (94)
97 (94)
95 (91)
88 (85)
0.94
0.86
0.86
0.84
0.82
85
97 (94)c
74
Water + SDS
88
a Reaction conditions: 1a (1 mmol), 2a (1.5 mmol), DABCO (1.2 eq.), Si-
Gly-CD-PdNPs (5 mol%), CPME/water az (1 mL, 1 M), 85 °C, 16 h.
b GLC conversion has been determined using samples of the pure com-
pound as reference standards; the remaining materials are 1a and 2a.
c Determined with MP-AES, as percentage from the initial content of
the fresh catalyst.
a Reaction conditions: 1a (1 mmol), 2a (1.5 mmol), base (1.2 eq.), Si-
Gly-CD-PdNPs (5 mol%), solvent (1 mL, 1 M), 85 °C, 16 h. b GLC con-
version has been determined using samples of the pure compound as
reference standards; the remaining materials are 1a and 2a. c Isolated
yield is given in parenthesis.
The catalyst showed good performance in almost all the
reaction media tested. The enhancement of the catalytic
activity is interesting when a mixture of solvent/water was
employed. This behaviour is attributable to the hybrid nature
of our Si-Gly-CD-PdNP catalyst. Indeed, the presence of β-CDs
makes the hybrid heterogeneous system water-friendly. It is
worth noting that the benefits achieved from the presence of
water are strictly related to its ratio with the organic solvent
(see for example Table 3 entries 1–3).
Moreover, when the organic solvent and water form an
azeotropic mixture, homogeneous or heterogeneous, the
Fig. 3 Catalyst recycles at t1/2 under batch conditions. Reaction con-
ditions: 1a (1 mmol), 2a (1.5 mmol), catalyst (5 mol%), DABCO (1.2 eq.),
improvement in catalytic activity is remarkable. When pure solvent (1 mL, 1 M), 7 h.
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Fig. 4 Continuous flow system for the Sonogashira reaction.
The channel A was charged with a CPME solution of 1a and
2a (0.5 M and 0.75 M respectively) while channel B with a 3.25
M aqueous solution of DABCO and kept at 40 °C. The flow
rates of the two channels have been regulated in order to have
the exact azeotropic ratio of CPME/water inside the reactor (see
the ESI† for further details).
Further optimizations of the other flow parameters were
conducted to achieve a stable and durable conversion over the
time (Table 5). When 100–250 BPRs were used, poor conver-
sion was obtained associated with a low residence time
(Table 5, entries 3 and 4), while, increasing the residence time
to 35–50 minutes resulted in good to excellent conversions to
product 3a (Table 5, entries 5–7).
Scheme 3 Scope of Sonogashira in flow. Isolated yields are reported.
At the output of the reactor, a liquid/liquid membrane
separator was installed for the separation of the reaction
mixture in the two pure components. These features allow us
to also optimize the work-up procedure. Indeed, by the evapor-
ation and recovery of the CPME we were also able to reuse it
continuously, while the aqueous DABCO-I solution represents
the sole waste of the reaction.
With the optimized continuous-flow set-up we started to
explore the scope of the Sonogashira reaction achieving high
yields for all the substrates screened (Scheme 3).
yields (90–98%). Moreover, our continuous flow set-up showed
good performance also when iodo-heterocycles (1g–h) were
coupled with phenylacetylene 2a and deactivated alkyne 2c.
By employing the designed flow set-up, we were able to
efficiently convert 20 mmol of the differently substituted iodo-
arene, heterocycles and phenylacetylenes with only 0.06 mmol
palladium (350 mg of Si-Gly-CD-PdNP catalyst) proving the
catalyst stability and durability. Under these conditions, and
after 10 h of continuous operation, the catalyst showed a TON
Both electron withdrawing and electron donating groups on
the iodoarene are well tolerated as well as electron donating
group in the acetylenic compound leading to excellent isolated
value of 333 and a TOF of 33 h−1
.
In addition, the palladium leaching was continuously
monitored during the flow operation (Fig. 5). The value
recorded was extremely low in the first 5 h of flow procedure
with an additional reduction over the next hours. TEM images
of the used catalyst Si-Gly-used CD-PdNPs (see the ESI†) show
that Pd NPs formed some nanoparticle agglomerates with a
slightly increase in the particle size.
Table 5 Optimization of flow parameters
Channel A
(mL min−1
Channel B
(mL min−1
BPR
(psi)
Residence
time
Ca
[%]
Entry
)
)
1
2
3
4
5
6
7
0.840
0.420
0.420
0.420
0.168
0.084
0.084
0.160
0.080
0.080
0.080
0.032
0.016
0.016
500
500
250
100
500
500
250
10 min
20 min
7 min
9
48
3
5 min
3
35 min
50 min
40 min
60
99
93
a GLC conversion has been determined using samples of the pure com-
pound as reference standards; the remaining materials are 1a and 2a.
Fig. 5 Leaching of metal in solution.
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Fig. 6 XRD patterns measured on samples listed in Table 1: (a) Si-Gly-
CD-PdNPs; (b) Si-CD -PdNPs; (c) Si-Gly-Und-CD-PdNPs and (d) Si-Gly-
CD-PdNPs after usage.
Scheme 4 Scope of Sonogashira in flow using aryl-bromide. Isolated
yields are reported.
XRD patterns of the fresh catalysts (Fig. 6, pattern a, b and
c) and of the catalyst used in the flow procedure (Fig. 6,
pattern d) prove that Pd NPs exist on the Pd/Si-CD. As shown
in Fig. 6, the typical diffused scattering of the amorphous SiO2
support gave the strongest peak in the XRD pattern (21.868).
The other peaks are indexed as the (111), (2 0 0), (2 2 0), and (3
11) planes of the Pd NPs (cubic phase, JCPDS 46-1043). With
respect to standard references, a slight shift in the 2θ values
was observed, for all peaks, and we can assume that a small
increase in crystallite θ spacing happens as a consequence of
the particle nano size.
In order to evaluate the efficiency of the catalyst utilized in
the newly developed flow reactor, we have also tested more
challenging aryl-bromides as substrates. Under identical con-
ditions in flow aryl-bromide 4a and 4b gave high isolated yield
of the corresponding coupling products. We therefore also
finalized our study in the synthesis of API intermediates 3o
and 3p obtained by coupling 6-Br-nicotinaldehyde 4c and 6-Br-
nicotinic acid 4d with trimethylsilylacetylene 2d (Scheme 4).
Compound 3p is obtained with an E-factor of 2.27, and it is
the key intermediate that by already reported procedures,23
after desilylation and coupling with 6-halo-4,4-dimethyl-
thiochromane allows to obtain the API tazarotene. Finally, in
order to evaluate the sustainability improvement of our proto-
col, we focused our attention on a comprehensive and general
assessment of the environmental features. Initially we calcu-
lated the mass-dependent metrics (E-factor) for the whole pro-
cedure and for other representative similar flow processes
(Fig. 7). Due to the CPME recovery and reuse, the E-factor
value associated with our flow set-up is extremely low (2.12).
Aiming at the identification of the major contributions to
the very low E-factor values,24 we observed that the mixture
concentration and the auxiliary material strongly affected the
waste production (see the ESI† for further details).
Fig. 7 E-Factor distribution analysis.
In addition, to gain more insight, we analysed different
green metrics in terms of the vector magnitude ratio by adopt-
ing the radial polygon analysis (Fig. 8).25
Fig. 8 Environmental and safety analyses based on radial polygons.
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In these analyses we also have included the determination
of the benign index (BI) and the safety hazard index (SHI)
associated with the waste material.
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mainly influenced the environmental profile exploited by our
flow assisted Sonogashira reaction. In addition, the BI and SHI
highly benefit from the use of CPME as an environmentally
friendly solvent and DABCO as the base, which has a higher
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Conclusions
In conclusion, here we reported a flow-assisted Sonogashira
cross-coupling reaction catalysed by a Si-Gly-CD-PdNP hybrid
catalyst. The catalytic efficiency was improved by exploiting the
hydrophilicity of the β-CD ligand allowing the utilization of a
CPME/water azeotropic mixture. The selected reaction medium
and flow technology led to a dramatic minimization of metal
leaching in solution, improving catalyst stability and
durability.
Moreover, the synergy between the recovery of CPME and
the packed-bed flow technology allows us to achieve great
improvement in terms of waste reduction. The designed meth-
odology allowed the continuous flow production of 20 mmol
of differently substituted compounds with only 0.06 mmol
palladium.
The environmental features were also evaluated based on
the green-metrics and by considering the safety hazard and
the benign index associated with the waste material.
Conflicts of interest
There are no conflicts to declare.
7 B. Lei, B. Li, H. Zhang, L. Zhang and W. Li, J. Phys. Chem.
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Acknowledgements
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The Università degli Studi di Perugia and MIUR are acknowl-
edged for financial support to the project AMIS, through the
program “Dipartimenti di Eccellenza
University of Turin is acknowledged for the financial support
(ricerca locale 2020). We thank M. C. Valsania (Mayita) from
the Microscopy Laboratory of the NIS Centre and Prof
G. Berlier for their precious help.
– 2018–2022”. The
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