Immobilized palladium nanoparticles on potassium zirconium phosphate as an efficient recoverable heterogeneous catalyst for a clean Heck reaction in flow

Article abstract of DOI:10.1016/j.molcata.2015.02.012

Palladium nanoparticles on layered potassium α-zirconium phosphate (PdNP/α-ZrPK) with high palladium loading (10.6 wt%) have been prepared and used as catalyst in low amount (0.1 mol% of Pd) in the Heck reaction of methyl acrylate and styrene with a series of aryl iodides in CH₃CN/H₂O azeotrope as a green medium. The procedure has been optimized under flow conditions obtaining an extremely low waste production (E-factor) and allowing to isolate the final product with very low residual palladium content without any purification step.

Full text of DOI:10.1016/j.molcata.2015.02.012

Accepted Manuscript
Title: Immobilized palladium nanoparticles on potassium
zirconium phosphate as an efficient recoverable heterogeneous
catalyst for a clean Heck reaction in flow
Author: Chiara Petrucci Matteo Cappelletti Oriana Piermatti
Morena Nocchetti Monica Pica Ferdinando Pizzo Luigi
Vaccaro
PII:
S1381-1169(15)00060-6
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.molcata.2015.02.012
MOLCAA 9428
To appear in:
Journal of Molecular Catalysis A: Chemical
Received date:
Revised date:
Accepted date:
3-12-2014
10-2-2015
11-2-2015
Please cite this article as: Chiara Petrucci, Matteo Cappelletti, Oriana Piermatti,
Morena Nocchetti, Monica Pica, Ferdinando Pizzo, Luigi Vaccaro, Immobilized
palladium nanoparticles on potassium zirconium phosphate as an efficient recoverable
heterogeneous catalyst for a clean Heck reaction in flow, Journal of Molecular Catalysis
A: Chemical http://dx.doi.org/10.1016/j.molcata.2015.02.012
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Immobilized palladium nanoparticles on potassium zirconium phosphate
as an efficient recoverable heterogeneous catalyst for a clean Heck
reaction in flow
a
Chiara Petrucci , Matteo Cappellettia, Oriana Piermatti*a, Morena Nocchettib, Monica
Picab, Ferdinando Pizzoa, Luigi Vaccaro*a,
aLaboratory of Green Synthetic Organic Chemistry, CEMIN - Dipartimento di Chimica
Biologia e Biotecnologie, Università di Perugia, Via Elce di Sotto, 8; Perugia, Italy
b
Dipartimento di Scienze Farmaceutiche, Università di Perugia, Via Fabretti; Perugia,
Italy
Fax: (+) 390755855560; E-mail: oriana.piermatti@unipg.it; luigi.vaccaro@unipg.it
Highlights
 Palladium nanoparticles on layered potassium -zirconium phosphate have been
prepared
 PdNP/α-ZrPK was used as catalyst in the Heck reaction to prepare 16 different
products
 CH3CN/H2O azeotrope has been used as a green and recoverable reaction medium
 The use of the flow technology reduce the waste produced
 The waste produced was measured using green metric E-factor
Abstract: Palladium nanoparticles on layered potassium -zirconium phosphate (PdNP/α-
ZrPK) with high palladium loading (10.6 wt%) have been prepared and used as catalyst in
low amount (0.1 mol% of Pd) in the Heck reaction of methyl acrylate and styrene with a
series of aryl iodides in CH3CN/H2O azeotrope as a green medium. The procedure has
been optimized under flow conditions obtaining an extremely low waste production (E-
factor) and allowing to isolate the final product with very low residual palladium content
without any purification step.
1

Keywords: Heck reaction, heterogeneous catalysis, palladium nanoparticles, recoverable
reaction media, flow chemistry.
2

1. Introduction
Heck reaction is one of the most powerful and widely used methods to couple alkenes
with aryl halides [1-3]. The resulting products have found extensive applications as
intermediates in the preparation of materials [4-8], natural products and bioactive
compounds [9-14].
Problems associated with separation and recovery of homogeneous palladium catalysts
represent major limit in the industrial and synthetic applications of Heck reaction.
This latter aspect, together with the high cost of metal catalysts and their known toxic
effects, have led to an increased interest in immobilizing metal catalysts onto solid
supports [2,15-17]. In fact, recoverable and reusable heterogeneous catalysts may
significantly help to minimize waste production contributing to the development of
sustainable chemical processes [18-21].
A variety of organic and inorganic supports have been explored to develop efficient
heterogenous palladium sources [2,3,17,22]. Recently, supported metal palladium
nanoparticles (PdNPs) with a high surface to volume ratio have attracted a great deal of
attention as stable and recoverable ligand-free catalysts. [23-28].
It has been recently reported that palladium nanoparticles immobilized on various supports
have been employed in the Heck reaction [29-33]. However the stability and reactivity of
these catalytic systems are highly dependent on the support used for the immobilization.
Therefore, the search for new efficient supports for catalytically active palladium
nanoparticles is a wide ongoing area of research.
Tetravalent metal phosphates and phosphonates featuring a layered structure are attracting
supports for metal nanoparticles because of their chemical and thermal stability [34] and
high versatility [35-42]. In addition, since they are insoluble in water and organic solvents,
they can be easily recovered by simple filtration or centrifugation and efficiently reused
[35-51]. Layered zirconium hydrogen phosphate with an -type structure (-Zr(HPO4)2H2O)
is a well known material, consisting of layers made of planes of zirconium atoms bonded
to monohydrogen phosphate groups, on both sides of each plane. Several monovalent and
divalent cations are able to exchange the -ZrP protons, thus providing a variety of ionic
groups on the layer surface. It was found that the presence of cations, such as Na+ and K+,
3

in the ion exchange sites of the support, improves the catalytic properties for metallic
silver particles [52]. As a matter of fact, these cations turned out to stabilize the silver
catalyst, by blocking the exchange sites for the Ag+ ions, thus hindering their back
diffusion [52]. Therefore, layered potassium -zirconium phosphate -Zr(KPO4)2 (hereafter -
ZrPK) is a promising support for the immobilization and stabilization of palladium
nanoparticles.
Recently, we have been involved in the development of novel solid catalysts to be used in
benign reaction media for the definition of environmentally-efficient processes [43-48,53-
57]. In this contribution we report the preparation of PdNPs supported on layered
potassium -zirconium phosphate as catalyst for the Heck cross-coupling reaction.
The main goal of this study is the preparation of highly-performing heterogeneous Pd
catalysts able to be used efficiently in sustainable reaction media, in order to develop an
environmentally friendly method for the Heck reaction.
As a matter of fact, Heck reaction is usually carried out in aprotic polar solvent such us
N,N’-dimethylformamide (DMF) and N-methylpyrrolidone (NMP), which are among the
most undesirable media, because of their toxicity and difficult disposal [58-59].
In this contribution we have investigated the use of the prepared catalytic material in the
azeotropic mixture CH3CN/H2O 84% as a safer and easily recoverable reaction medium,
alternative to conventional dipolar aprotic media. In fact, in coupling processes such as
Heck reaction, the need of combined organic/aqueous media is common to reach highest
efficiency. We are investigating, at this purpose, the use of aqueous azeotropes which is
truly interesting because, while they combine the properties of organic and aqueous media,
they also have the potential of being recovered at the end of the reaction and reused
without increasing the amount of waste. Moreover, in this case acetonitrile is an
acceptable solvent, recommended as alternative to DMF or NMP [58-59].
To the best of our knowledge, this is the first example of the use of layered α-ZrPK as
palladium support in acetonitrile/water azeotrope.
The base has a fundamental role in the Heck reaction mechanism, since it regenerates the
active Pd species in the last step of the catalytic cycle. Although, homogeneous bases such
as triethylamine (TEA) are generally used, thus work up procedures are needed to isolate
the pure products.
4

In view of waste minimization, we were able to avoid wasteful work up procedures using
a polystyrene-supported base (PS-TEA), removable by simple filtration.
In addition, the use of flow technology may offer several advantages as compared to
traditional batch reactor. Flow reactors have proved to be efficient tools to optimize the
recovery and reuse of the catalyst, minimize waste and in particular the amount of organic
solvent needed to isolate the final products.[60]
After optimization of the reaction in batch conditions, we applied the flow technology for
the development of sustainable protocol for Heck reaction.
2. Experimental Section
2.1. General remarks.
1
All chemicals were purchased and used without any further purification. H-NMR, and
13C-NMR spectra were recorded at 400 MHz and 100.6 MHz, respectively, on a Bruker
DRX-ADVANCE 400 MHz in CDCl3 using TMS as the internal standard.
Zr and Pd analyses were performed on a ICP Varian Liberty inductively coupled plasma-
optical emission spectrometry (ICP-OES) with axial injection. C, H, N Elemental Analyses
(EA) were performed on a Fisons EA1108CHN.
X-ray diffraction patterns (XRPD) of powders were collected with a Philips X'Pert PRO
MPD diffractometer operating at 40 kV and 40 mA, with a step size 0.03341 and step
scan 40 s, using Cu Kα radiation and an X'Celerator detector.
Transmission electron microscopy (TEM) analysis was carried out by a Philips 208
transmission electron microscope, operating at an accelerating voltage of 100 kV.
Powders were rapidly diluted in ethanol, then supported on copper grids (200 mesh)
precoated with Formvar carbon films, and quickly dried.
GLC analyses were performed by using Hewlett-Packard HP 5890A equipped with a
capillary column DB-35MS (30 m, 0.53 mm), a FID detector and hydrogen as gas carrier.
GC-EIMS analyses were carried out by using a Hewlett-Packard HP 6890N Network GC
system/5975 Mass Selective Detector equipped with an electron impact ionizer at 70 eV.
Thin layer chromatography analyses were performed with silica gel on aluminum plates
(silica gel 60 F254, Fluka). Column chromatography purification was performed with
silica gel (230–400 mesh) eluting with hexane or mixture hexane/ethyl acetate (98:2
5

to70:30). Melting points were measured on a Büchi 510.
Flow procedures were performed using a Jasco PU-2080 HPLC pump, a Omnifit glass
column as reservoir and a Supelco HPLC column blank as the base/catalyst column. All
the equipment was connected using 1⁄16’ OD PTFE tubing and stainless steel 1/16
ODx0.02 ID capillary tubing and Hamilton HPV Plug Valves. The system was placed in a
ventilated Plexiglas box equipped with a electrical resistance heating.
Diethylaminomethyl-polystyrene (PS-TEA) was prepared by reacting Merrifield resin
(200-400 mesh, 4.4 mmol/g Cl loading, 2% cross-linked with divinylbenzene) with
diethylamine (2.5 equiv) in toluene at 100 °C for 24 hours. The resin was then washed
with a 0.5 M solution of diethylamine in toluene, then toluene, dichloromethane, water and
acetone to remove the excess amine, then dried under vacuum. The loading of amine is
calculated by C, H, N elemental analysis (EA) on the element Nitrogen, which is not
contained in the purified and fully dried polimeric support. Solid NMR analyse also
confirm the absence of free amine.
Compounds 3a [61], 3b [61], 3c [61], 3d [62], 3e [61], 3f [63], 3g [62], 3h [61], 6a [61],
6b [64], 6c [61], 6d [65], 6e [61], 6f [66], 6g [65], 6h [66] are known.
2.2 Preparation of α-Zr(KPO4)2, (α-ZrPK)
α-ZrPK was obtained by titration with KOH 0.1M in KCl 0.1M of α-Zr(HPO4)2·H2O,
prepared according to Alberti et al. method [67]. To a suspension of α-Zr(HPO4)2·H2O (2
g, 6.64 mmol) in KCl 0.1M (300 mL), KOH 0.1M (133 mL) was added slowly, under
stirring, keeping the pH below 9. The titration is complete in about three days (the
complete potassium exchange is verified by XRPD analysis). The obtained α-ZrPK was
separated from aqueous medium by centrifugation, washed with water (3 x 100 mL) and
finally dried at 80 °C for 24 hours (2.2 g).
2.3 Preparation of PdNP/α-ZrPK
To a suspension of α-ZrPK (0.5 g) in ethanol (25 mL), palladium acetate (0.112 g, 0.5
mmol) was added and the mixture stirred at 50 °C for 20 h. Then, the obtained dark solid
material was separated by centrifugation, washed with ethanol (2x10 mL) and dried at 50
°C for 24 h (0.46 g). The PdNP/α-ZrPK catalyst was characterized by using ICP-OES,
6

XRPD and TEM techniques.
2.4 Determination of Pd content
A weighed amount of the PdNP/α-ZrPK catalyst was first treated with concentrated HF in
order to dissolve α-ZrPK, then with aqua regia to digest the Pd species, and the obtained
solution was diluted with deionized water and analyzed by ICP-OES. The Pd content was
determined to be 1 mmol/g, which is equal to 10.6 wt% Pd loading.
2.5 General procedure for the Heck reaction under batch conditions
To a solution of the aryl iodide 1a-h (1 mmol) and the alkene 2 or 5 (1.2 mmol) in
CH3CN/H2O az. (1 M, 1 mL), triethylamine (TEA, 1.2 mmol) and catalyst PdNP/α-ZrPK
(0.1 mol%, 1 mg) were added. The reaction mixture was stirred at 120 °C for 3 h with
methyl acrylate (2) and for 4 h with styrene (5); the conversion of the aryl iodide 1a-h was
monitored by GLC analyses. The reaction mixture was diluted with water (2 mL) and
extracted with ethyl acetate (3 x 3 mL). The combined organic layers were dried with
sodium sulfate and evaporated under reduced pressure.
2.6 General procedure for recovery and reuse of PdNP/α-ZrPK in the Heck reaction
under batch conditions.
To a solution of iodobenzene (1a, 6 mmol) and methyl acrylate (2, 7.2 mmol) in
CH3CN/H2O az. (1 M, 6 mL), triethylamine (7.2 mmol) and catalyst PdNP/α-ZrPK (0.1
mol%, 6 mg) were added. The reaction mixture was stirred at 120 °C for 3 h; the
conversion of the iodobenzene (1a) was monitored by GLC analyses. The solid catalyst
was separated by centrifugation and then washed with CH3CN/H2O az. (2 x 1mL), dried
at 50 °C for 3 h and reused in a successive cycle. The product was isolated after extraction
with ethyl acetate.
2.7 General procedure for the Heck reaction in presence of PS-TEA under batch
conditions
To a solution of iodobenzene (1a, 1 mmol) and methyl acrylate (2, 1.2 mmol) in
CH3CN/H2O az. (1 M, 1 mL), diethylaminomethyl-polystyrene (PS-TEA, 3.84 mmol/g,
7

1.2 equiv, 0.312 g) and catalyst PdNP/α-ZrPK (0.1 mol%, 1 mg) were added. The
reaction mixture was stirred at 120 °C for 3h; the conversion of the iodobenzene (1a) was
monitored by GLC analyses. The heterogeneous base and catalyst were separated by
filtration and the product 3a isolated by distillation of the azeotrope.
2.8 Heck reaction of iodobenzene (1a) and methyl acrylate (2) under flow conditions.
A pre-mixed mixture of iodobenzene (1a) (50 mmol, 5.60 mL) and methyl acrylate (2) (60
mmol, 5.40 mL) in CH3CN/H2O az. (50 mL) was charged into a glass column functioning
as a reservoir. Diethylaminomethyl-polystyrene (3.84 mmol/g, 75 mmol, 19.5 g) and the
catalyst PdNP/α-ZrPK (0.1 mol%, 50 mg) were mixed and dispersed in 1 mm diameter
solid glass beads and charged in a stainless steel HPLC column; the equipment was
connected, by using the appropriate valves, to a pump and installed into a thermostated
box. The reaction mixture was continuously pumped (flow rate 2.0 mL/min) through the
base - catalyst column at 130 °C until complete conversion of reactants to methyl
cinnamate (3a) was achieved (the reaction was monitored by GLC). At this stage, the
pump was left to run in order to recover the reaction mixture into the reservoir. To
completely recover the product and clean the reactor, CH3CN/H2O azeotrope (3 x 25 mL
at a 2 mL/min) was cyclically pumped through the base - catalyst column for 15 min (each
fraction) and then collected into the reservoir to isolate the product in 89 % yield, after
removal and recovery of the azeotrope (95% of which was recovered) via distillation.
E-Factor Calculations for the preparation of PdNP/α-ZrPK
E-factor = [0.5 g (α-ZrPK) + 19.72 g (ethanol) + 0.112 g (Pd(OAc)2) + 15.78 g (ethanol
wash) – 0.460 g (PdNP/α-ZrPK)]/0.460 g (PdNP/α-ZrPK) = 77.5.
Representative Batch reaction with TEA
E-factor for Heck reaction of iodobenzene (1a) (1 mmol) and methyl acrylate (2) (1.2
mmol) (98% isolated yield): E-factor = [0.204 g (iodobenzene (1a)) + 0.103 g (methyl
acrylate (2)) + 0.121 g (TEA) + 0.818g (1 mL CH3CN/H2O 84:16) + 2 g (water) + 8.1 g
(ethyl acetate) – 0.159 g (methyl cinnamate (3a))]/0.159 g (methyl cinnamate (3a)) =
70.4. (catalyst was not considered due to its recovery and recycle)
8

Representative E-Factor Calculations for the Batch reaction with PS-TEA
E-factor for Heck reaction of iodobenzene (1a) (1 mmol) and methyl acrylate (2) (1.2
mmol) (96% isolated yield): E-factor = [0.204 g (iodobenzene (1a)) + 0.103 g (methyl
acrylate (2)) + 0.312 g (PS-TEA) + 0.001 g (PdNP/α-ZrPK) + 0.818g (1 mL CH3CN/H2O
84:16) – 0.155 g (methyl cinnamate (3a))]/0.155 g (methyl cinnamate (3a)) = 8.3.
Representative E-Factor Calculations for the reaction in flow at 120 °C
E-factor for Heck reaction of iodobenzene (1a) (50 mmol) and methyl acrylate (2) (60
mmol) (89 % isolated yield): E-factor = [10.20 g (iodobenzene (1a)) + 5.40 g (methyl
acrylate (2)) + 102.25 g (medium) + 19.5 g (PS-TEA) + 0.050 g (catalyst) – 7.20 g
(methyl cinnamate (3a)) – 97.15 g (95% recovered medium)]/7.20 g (methyl cinnamate
(3a)) = 4.6.
3. Results and Discussion
3.1. Catalyst preparation and characterization
The layered potassium -zirconium phosphate (α-ZrPK), has been easily prepared by
titration with 2 equiv. of KOH of a suspension of -zirconium hydrogen phosphate, α-Zr
(HPO4)2·H2O, in a 1 M solution of KCl [67]. The solid was separated by centrifugation,
washed with water and dried at 80 °C for 24 h.
We decided to prepare the heterogeneous palladium catalyst by the immobilization of
palladium nanoparticles (PdNPs) on α-ZrPK using the method of alcohol reduction of
palladium acetate [24,29]. To a suspension of α-ZrPK in EtOH, palladium acetate (1
mmol for 1 g of support) was added and the mixture stirred at 50 °C for 20 h. The
PdNP/α-ZrPK was separated by centrifugation, washed with ethanol and dried at 50 °C
for 24 h.
The PdNP/α-ZrPK was characterized by using ICP-OES, XPRD and TEM techniques.
Figure 1 shows two representative TEM micrographs of PdNP/α-ZrPK before the
catalytic tests. The surface of the α-ZrPK platelets is decorated with the PdNPs, which
show an almost spherical morphology, and a relatively good monodispersity. The PdNPs
size range from 5 to 20 nm.
9

Fig. 1. TEM micrographs of PdNP/α-ZrPK at different magnification.
The XRPD of the catalyst (Figure 2) shows the typical (002) reflection of anhydrous α-
ZrPK (2θ = 10°), suggesting that the interlayer region did not undergo significant
modifications during the preparation of the catalyst. Additional reflections in the range 35-
70° 2 were assigned to the (111), (200) and (220) crystalline planes of the typical cubic
phase of metallic palladium (JCPDS #05-06-81). The average size of the palladium
crystalline domains was determined by using the Debye-Scherrer formula [68], from the
(111) X-ray line broadening, corrected for the instrumental broadening, by using LaB6 as
an external peak profile standard. The average crystalline domain size of the PdNPs on α-
ZrPK is estimated to be about 9 nm, in good agreement with the data obtained from TEM
analysis.
10

Fig. 2 XRPD spectra of PdNP/α-ZrPK catalyst.
A Pd content of 1 mmol/g (10.6 wt%) was determined by ICP-OES analysis. It should be
noticed that this high palladium loading value is very useful in view of larger scale
protocols, allowing the use of minimal quantities of catalytic material.
3.2. Catalytic activity
We started our investigation testing the catalytic activity of PdNP/α-ZrPK in the Heck
reaction between iodobenzene (1a) e methyl acrylate (2) in CH3CN/H2O azeotrope (Table
1).
Table 1
Optimization of reaction conditions in the Heck coupling of iodobenzene (1a) and methyl
acrylate (2).
11

Entry a Base
T (°C)
70
t (h)
24
24
3
Conv %b
66
Pd (ppm)c
1
2
3
4
5
TEA
n.d
24
34
8
TEA
90
>99
TEA
120
90
>99d
>99
PS-TEA
PS-TEA
24
3
120
>99
6
a Reaction conditions: 1a (1.0 mmol), 2 (1.2 mmol), base (1.2 mmol), catalyst (0.1 mol%),
b
CH3CN/H2O az. (84%, 1 M, 1 mL). Conversion of 1a to 3a is measured by GLC
c
analyses, the remaining material is unreacted 1a. Determined by ICP-OES analysis of
d
crude reaction product. In presence of 0.01, 0.05 and 0.08 mol% of Pd the conversion of
1a to 3a, after 3h at 120°C, was 32, 86 and 98%, respectively.
In the presence of triethylamine (TEA) as the base, at 70 °C the conversion after 24 h is
only 66% (Table 1, entry 1). Increasing the reaction temperature up to 90 °C the reaction
was complete after 24 h (Table 1, entry 2). The time required to reach complete
conversion of 1a decreased to 3 h when the reaction was performed at 120 °C (Table 1,
entry 3). Decreasing the amount of Pd from 0.1 to 0.01 mol%, the conversion of 1a to 3a,
after 3 h at 120°C, strongly decreased to 32% (Table 1, entry 3). The ICP-OES analyses
of crude products, obtained by standard work-up procedure (filtration, extraction with
ethyl acetate, evaporation of solvent under reduced pressure), revealed the presence of
palladium.
It is known that Heck reaction may proceed through a “release and catch” mechanism
[21,61,69-75] and that common dipolar aprotic media and some organic bases strongly
12

bind the soluble palladium species, facilitating its dissolution from the support and
consequently the leaching into the products [76-78]. On this regard, it should be
considered that, although the palladium amount exceeded the allowed upper limit value
[79], the percentage of Pd leaching was less than 4.5%, with respect to the initial amount
in the PdNP/α-ZrPK catalyst.
It should be noticed that, besides the Pd leaching is often limited at higher temperatures
[74,80], in this case an increase in the reaction temperature from 90 to 120 °C had a
minimal influence on the palladium contamination of the products (Table 1, entry 3 vs 2).
This may be due to the complexing ability of the homogenous TEA [76-78].
In order to simplify the work-up procedure, but also reduce the leaching, we investigated
the use of a heterogeneous base, namely diethylaminomethyl-polystyrene (PS-TEA) which
can be removed by simple filtration of the reaction mixture, therefore making possible the
isolation of the final product after the distillation of the azeotropic reaction medium. As
aforementioned, a homogeneous tertiary amine is generally used for its fundamental role in
regenerating the active palladium species [81], with the consequent formation of the
corresponding ammonium salt. Therefore, purification steps such as extraction or column
chromatography are normally needed to remove the salt, leading to the production of a
great amount of waste. Indeed, the resulting Environmental Factor (E-Factor) values (kg
of waste / kg of isolated desired product) in academic literature protocols are generally
very high [82,83].
As shown in Table 1, when the reaction was performed in the presence of PS-TEA, the
catalytic activity was unchanged while the Pd leaching greatly decreased (Table 1, entries
4 and 5). Indeed, at 120 °C (Table 1, entry 5) the Pd content in the product is only 6 ppm,
very close to the allowed limit value [79]. It is reasonable to suppose that the polystyrene-
bonded amino groups can act as capping agents for the PdNPs, as a result the Pd leaching
is noticeably reduced [84-87].
At this point, in order to evaluate the robustness of the prepared catalyst and thus its
recovery and reuse, recycle tests were performed in batch, for the reaction with
homogeneous TEA. In fact, when PS-TEA is used in batch, it is not possible to separate
the catalytic material from the heterogeneous base at the end of the reaction.
For each cycle, the catalyst is recovered by centrifugation, washed with CH3CN azeotrope
13

and reused in the next cycle (Table 2). The solid catalyst was used six times without loss
of activity achieving a TON of ca. 6000 and a TOF of ca. 333 h-1. Conversion after 1 h of
reaction time was also evaluated and a consistent conversion of 1a to 3a of ca. 36% was
observed in all the cycles. The ICP-OES analyses of crude products confirmed that the
palladium leaching was relatively high in the first cycle, but it decreased in the successive
cycle suggesting a stabilization of the PdNP/α-ZrPK catalyst.
In Figure 3 the TEM images of PdNP/α-ZrPK after six cycles are shown. The PdNPs still
have a spherical morphology with a good monodispersity, but the particles size range
increased from 5-20 nm of the starting material (Figure 1) to 15-60 nm after six cycles.
The little increase of particles size doesn’t affect the catalytic activity but gives an
increased stability to the immobilized palladium nanoparticles.
Table 2
Recycling test of PdNP/α-ZrPK in the Heck reaction between iodobenzene (1a) and
methyl acrylate (2) in CH3CN/H2O az.
Runa
Conv %b
>99
Yield (%)c
Pd (ppm)d
1
2
3
4
5
6
96
98
97
98
97
96
34
25
11
14
15
16
>99
>99
>99
>99
>99
a
First cycle: 1a (6.0 mmol), 2 (7.2 mmol), TEA (7.2 mmol), catalyst (0.1 mol%),
14

CH3CN/H2O az. (84%, 1 M, 6 mL), 120 °C, 3 h. Successive cycles: the reagents and
b
medium quantities were calculated on the basis of the amount of recovered catalyst.
Conversion of 1a to 3a is measured by GLC analyses, the remaining material is unreacted
c
d
1a. Yield of isolated product. Determined by ICP-OES analysis of crude reaction
product.
Fig. 3. TEM micrographs of PdNP/α-ZrPK after six cycles.
To confirm the efficiency of PdNP/α-ZrPK in the Heck reaction, we extended the coupling
to several aryl iodides (1a-h) with methyl acrylate (2) (Table 3) and styrene (5) (Table 4).
The reactions of the aryl iodides (1a-h) with methyl acrylate (2) (Table 3) were carried at
120 °C for 3 h, in presence of 0.1 mol% of PdNP/α-ZrPK, obtaining from high to
quantitative conversions of 1 and excellent yields of isolated products 3a-h. For 4-nitro-
iodobenzene (1b), 2’-iodoacetophenone (1f) and 2-iodothiophene (1h) we observed the
formation of the corresponding homocoupling products: the biphenyls 4b, 4f and 4h and
therefore the products 3b, 3f and 3h were purified by column chromatography (Table 3,
15

entries 2, 6 and 8).
Table 3
Heck reaction between aryl iodide 1a-h and methyl acrylate (2).
Entrya
Product
3a
R
Conv (%)b
>99
>99
99
Yield (%)c
98
3/4
1
2
3
4
5
6
7
8
H
100
95:5
100
100
100
93:7
100
84:16
4-NO2
4-COCH3
4-CH3
4-OCH3
2-COCH3
2-CH3
92d
3b
99
3c
>99
>99
99
96
3d
99
3e
90d
3f
94
89d
3g
>99
71d
3h
a
Reaction conditions: aryl iodide 1a-h (1.0 mmol), 2 (1.2 mmol), TEA (1.2 mmol),
b
catalyst (0.1 mol%), CH3CN/H2O az. (84%, 1 M, 1 mL), 120 °C, 3 h. Conversion of 1
1
to 3 and 3/4 ratio are measured by GLC and H-NMR analyses, the remaining material is
unreacted 1. c Yield of isolated products 3. dAfter column chromatography purification.
When styrene (5) was used with iodobenzene (1a), longer reaction time was needed to
achieve quantitative conversion (Table 4, entries 1-2). Therefore, a reaction time of 4 h
was adopted in the reactions between the aryl iodides 1a-h and styrene (5) (Table 4,
16

entries 2-9). In all cases we observed the formation of the gem-products 7a-h and for 2’-
iodoacetophenone (1f) and 2-iodothiophene (1h) we observed also the formation of the
corresponding homocoupling products, namely the biphenyls 4f and 4h (Table 4, entries 7
and 9).
Table 4
Heck reaction between aryl iodides 1a-h and styrene (5).
Entrya
Product
6a
R
Conv (%)b
Yield (%)c
6/7/4 b
1d
2
3
4
5
6
7
8
9
H
98
>99
96
98
95
90
94
70
99
88:12:0
86:14:0
95:5:0
91
92
95
97
94
88
73
67
92
H
6a
4-NO2
4-COCH3
4-CH3
4-OCH3
2-COCH3
2-CH3
6b
94:6:0
6c
86:14:0
84:16:0
74:7:19
89:11:0
85:10:5
6d
6e
6f
6g
6h
a
Reaction conditions: aryl iodide 1a-h (1.0 mmol), 5 (1.2 mmol), TEA (1.2 mmol),
b
catalyst (0.1 mol%), CH3CN/H2O az. (84%, 1 M, 1 mL), 120 °C, 4 h. Conversion of 1
17

to 6 and 6/7/4 ratio are measured by GLC and 1H-NMR analyses, the remaining material is
unreacted 1. c Yield of isolated products (6+7) d Reaction time 3 h.
According to our project, we have also defined a flow procedure to optimize the efficiency
of the process and simplify the isolation of the pure products, while minimizing the waste
production.
In order to study the catalytic behavior of the prepared catalyst, PdNP/-ZrPK, under flow
conditions, the Heck reaction between iodobenzene (1a) and methyl acrylate (2) was
selected as representative model process using CH3CN/H2O azeotrope as medium and the
heterogeneous PS-TEA as base.
We realized the flow protocol by charging a mixture of the catalyst PdNP/-ZrPK and the
supported base PS-TEA (1.5 equiv) in a stainless-steel HPLC column, while the reactants
solution was charged in another glass column, acting as the reservoir (Scheme 1).
Scheme 1. Schematic flow reactor for the representative preparation of 3a.
18

All the equipment was connected, by using the appropriate valves, to a pump and installed
into a thermostated box (not shown in Scheme 1 for clarity). After setting the temperature
at 120 °C, the reaction mixture was cyclically pumped through the columns at a 2.0
mL/min flow rate for the time required to obtain quantitative conversion of 1a to 3a (8
hours, monitored by GLC).
The column containing the PS-TEA and catalyst was then cyclically washed with
acetonitrile/water azeotrope (0.5 mL/mmol, 3 times at 2 mL/min) to clean all the
equipment and completely recover the product 3a. Finally, the product was isolated in
high purity after distillation of the medium at ambient pressure, without any further
purification step, in 89 % yield. The ICP analyses revealed a Pd content of ca. 6 ppm.
The CH3CN aqueous azeotrope distilled off after reaction complexion, was recovered
with a high purity (GLC analysis), totally comparable to the starting azeotropic mixture,
thus being reusable without affecting the reaction yield.
To evaluate the waste minimization we calculated the E-Factor value for both the batch
and the flow protocol. The reaction performed in batch using TEA as the base featured an
E-Factor value of 70.4, mainly affected by the need of extraction work-up. Using PS-TEA
under flow conditions on a larger scale (50 mmol) we were able to reduce this value to
4.6, since no purification steps were required and the reaction medium was recovered.
Performing the reaction in cyclic flow conditions we were able to exploit the
aforementioned "release and catch" mechanism [21,61,69-75], in which the supported
palladium nanoparticles serve as reservoir for active Pd species that are dissolved from the
solid catalyst and can move through the flow apparatus. The soluble Pd species are then
effectively scavenged by the support after reaction completion, as proved by the low level
of residual Pd in the products. Alternatively, direct flow conditions furnished unreacted
product with increased palladium content.
4. Conclusion
In this contribution we reported the preparation of an efficient and recyclable catalyst for
the Heck cross-coupling reaction, based on palladium nanoparticles supported on layered
potassium -zirconium phosphate. The catalytic material features a high palladium loading
19

(1 mmol/g), allowing its use in minimal quantity, moreover it proved to be recoverable and
recyclable.
We successfully used a promising recoverable medium, i.e. the acetonitrile/water
azeotrope, which can be an effective alternative to highly toxic dipolar aprotic solvent,
such as DMF, commonly used in Heck cross-coupling reaction.
A great reduction of the waste produced was given by the combined use of a recoverable
medium and a heterogeneous base, which was removed from the reaction mixture by
simple filtration, avoiding wasteful work up procedures.
Finally, the flow technology has proved to be an alternative efficient stirring method, able
to preserve the physical integrity and activity of the heterogeneous catalyst and contribute
to waste minimization. Indeed with the flow approach we were able to noticeably simplify
the experimental procedures and to achieve an E-Factor reduction from 70.4 to 4.6.
Acnowledgements
We gratefully acknowledge the Università degli Studi di Perugia, and the Ministero
dell’Istruzione, dell’Università e della Ricerca (MIUR) for the financial support.
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