Heterogenization of Pd-NHC complexes onto a silica support and their application in Suzuki-Miyaura coupling under batch and continuous flow conditions

Article abstract of DOI:10.1039/c4cy00829d

The heterogenisation of a new family of Pd-NHC complexes is reported via a straightforward and efficient synthetic procedure. These silica-immobilised materials were successfully applied as catalysts in the Suzuki-Miyaura coupling of aryl chlorides and bromides under mild conditions. The materials exhibited improved stability when the catalytic reaction was run under anhydrous conditions and could be recycled up to five times without significant loss of activity. When the reaction was run within a continuous flow microreactor, these catalysts showed good activity after at least two hours on stream.

Full text of DOI:10.1039/c4cy00829d

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Heterogenization of Pd–NHC complexes
onto a silica support and their application
in Suzuki–Miyaura coupling under batch
and continuous flow conditions†
Cite this: DOI: 10.1039/c4cy00829d
Alberto Martínez,a Jamin L. Krinsky,a Itziar Peñafiel,a Sergio Castillón,b
c
c
a
a
*
*
Konstantin Loponov, Alexei Lapkin, Cyril Godard and Carmen Claver
The heterogenisation of a new family of Pd–NHC complexes is reported via a straightforward and efficient
synthetic procedure. These silica-immobilised materials were successfully applied as catalysts in the
Suzuki–Miyaura coupling of aryl chlorides and bromides under mild conditions. The materials exhibited
improved stability when the catalytic reaction was run under anhydrous conditions and could be recycled
up to five times without significant loss of activity. When the reaction was run within a continuous flow
microreactor, these catalysts showed good activity after at least two hours on stream.
Received 27th June 2014,
Accepted 10th August 2014
DOI: 10.1039/c4cy00829d
www.rsc.org/catalysis
have shown high activity and long-term reusability. In these
systems, the use of silica supports has proven effective due
Introduction
In the last decade, continuous flow operation has emerged as
a powerful tool for chemical synthesis, enabling more effi-
cient transformations in the fine chemicals industrial sector.1
Indeed, continuous flow systems were shown to provide effi-
cient mass transport and mixing2 and to improve heat trans-
fer compared to batch systems, resulting in faster and safer
reactions with enhanced product yields.3,4 Furthermore, the
combination of improved dynamics and kinetic characteris-
tics of flow chemistry with the use of recyclable catalytic
materials represents an innovative synthetic methodology that
perfectly fits the current need for more environmentally
friendly procedures for transformations catalysed by precious
metals such as the Pd-catalysed Suzuki–Miyaura coupling.
A desirable strategy would be to fully exploit the features
of a specifically designed catalyst in conjunction with mod-
ern flow techniques to define useful and practical procedures
for the recovery and reuse of the catalysts while obtaining the
desired product with minimal cost in terms of time and
waste.5 Among the reported catalysts designed for this pur-
pose, many supported molecular6 or particulate7 catalysts
to their thermal and chemical stability as well as their
rigid yet porous structure devoid of swelling properties, a
characteristic that makes them compatible with a wide range
of solvents.
Pd-catalysed cross-coupling reactions are currently
regarded as one of the most important methods for the
construction of carbon–carbon bonds.8–10 The application of
flow chemistry to these transformations is particularly
challenging due to the formation of salts during the reac-
tions, which often leads to rapid clogging of tubular reactors.
However, recently several examples of successful metal-
catalysed C–C cross coupling reactions under flow conditions
have been reported11 employing a broad range of solid sup-
ports such as monolithic systems,7,12–18 thin films of palla-
dium nanoparticles,19 Pd/C20 and ionic liquids.21
In the Suzuki–Miyaura process, several methodologies
have been reported for the preparation of catalysts under
flow conditions. These include immobilisation of a catalyst
on a membrane at the centre of a microchannel,22–24 the use
of a fluorous-tagged palladium complex25 or the immobili-
sation of palladium particles on the surface of unfunctionalised
and functionalised silica-coated magnetic nanoparticles.26,27
Alternatively, microwave-assisted continuous-flow processes
have been described for this reaction.28,29 Organ used capil-
laries coated with a thin film of palladium,19,30 and Ley
and co-workers filled a U-shaped glass tube with the encap-
sulated catalyst PdEnCat™.31,32 Kirschning and co-workers
also reported the use of a homogenous Pd catalyst attached
directly through coordination of the metal centre to a
a Department of Physical and Inorganic Chemistry, Universitat Rovira i Virgili,
C/ Marcel li Domingo s/n, Campus Sescelades, 43007, Tarragona, Spain.
E-mail: cyril.godard@urv.cat; Fax: (+34) 977 559563
b Department of Analytical and Organic Chemistry, Universitat Rovira i Virgili,
C/ Marcel li Domingo s/n, Campus Sescelades, 43007, Tarragona, Spain
c Department of Chemical Engineering and Biotechnology, University of Cambridge,
New Museum Site, Cambridge CB2 3RA, UK
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4cy00829d
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polymeric support, namely polyvinylpyridine.12 This system
was found to operate via a so-called “release and catch” path-
way where the active Pd species is initially released from the
support and re-deposited onto the support after the reaction.
Excellent results were obtained with this system using a
0.2 mol% catalyst, employing isopropyl alcohol as the solvent
and potassium tert-pentoxide as the base. Under flow con-
ditions up to 94% yield could be achieved after 20 hours
on stream using aryl chlorides as substrates.
Following this approach, the anchoring can be performed
via substitution at the para position of one or both aryl rings
of the ligand. Lu and co-workers reported the introduction of
an allyl moiety at this position which was subsequently
functionalised via thiol–ene methodology and anchored
onto an MCM-41 support.52 This supported carbene system
was successfully applied in the chemical fixation of carbon
dioxide to form cyclic carbonates.
Inspired by the work of Nolan and co-workers, who
recently described that para-alkoxy functionalized NHCs
provide more active Pd catalysts than their unfunctionalised
counterparts in the Buchwald–Hartwig C–N coupling,53 we
reported a synthetic strategy for the anchoring of Pd–NHC
catalysts via an alkoxy-functionalized ligand.54 Here, we
report the synthesis and characterisation of heterogenized
Pd–NHC complexes onto amorphous silica via covalent
attachment and their application in the Suzuki–Miyaura
coupling reaction of aryl chlorides and bromides under batch
and continuous flow conditions.
Under batch conditions, soluble Pd catalysts bearing bulky
N-heterocyclic carbene (NHC) ligands have proven to be
extremely effective for the Suzuki–Miyaura reaction.33,34 Steri-
cally congested NHC ligands are electronically and sterically
stabilised and their electron-rich character makes them
attractive ligands for a wide range of catalytic transforma-
tions. Furthermore, they are resistant to air oxidation and
bind very strongly with soft metal centres, which is essential
if one is to avoid metal leaching during the catalytic process.
Over the last decade, the immobilisation of NHC-based sys-
tems has been reported for various types of supports such as
polymers, dendrimers, clays and silica.35–40 Various strategies
were reported for the anchoring of N-heterocyclic carbenes.
In most cases, NHC moieties are covalently attached to the
support using alkylic linkers bonded to one or both nitro-
gen atoms of the imidazolylidene ring (see Scheme 1,
complexes 1 and 2, respectively).41–47 These methods usually
exhibit advantages in terms of synthetic procedures but
they reduce the steric profile of the ligands and hence the
performance of the corresponding catalysts. Alternatively,
linkers have been attached to the carbon backbone of the
NHC ligands, thus avoiding such an alteration but resulting
in the need for complex synthetic methods (see Scheme 1,
complexes 3 and 4).48–51
Results and discussion
The synthetic procedure for the preparation of the imi-
dazolium pre-ligands 2a/2b was recently reported by our
group and is summarised in Scheme 2.54 This methodology
includes the introduction of alkenyl groups through
etherification and subsequent photoinitiated thiol–ene addi-
tion of mercaptopropyl(triethoxy)silane for the incorporation
of triethoxysilyl groups. Using this synthetic route, the two-
tethered imidazolium salts 2a/2b were obtained selectively
using two equivalents of the thiol. A mixture of one- and two-
An interesting alternative for the heterogenisation of such
systems involves the introduction of functionality at the
N-aryl moieties, as shown in Scheme 1 (complexes 5 and 6).
Scheme 1 Reported strategies for anchoring NHC-based catalysts
onto solid supports.
Scheme
2 Retrosynthetic scheme for the preparation of the
imidazolium pre-ligands 2a, 2b and 3a, 3b.54
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tethered imidazolium salts 3a/3b and 2a/2b in a ca. 2 : 1 ratio
was also obtained when one equivalent of the thiol was used
(Scheme 2). While such a mixture of products is not
ideal, the preparation of this material afforded a facile
method for testing the effect of the ligand's anchoring mode
on the resulting catalyst's activity.
These ligand precursors were then used in the synthesis
of the corresponding heterogenised catalysts. The species
2a/2b bearing triethoxysilyl groups were first coordinated to
Pd to form complexes 4a/4b by reaction with [Pd(acac)2] in
1,2-DCE at 75 °C for 48 h prior to their immobilization onto
silica (see Scheme 3).
During the synthesis, the complexes 4 were not isolated
and the crude reaction mixtures containing 4a/4b were
used directly for immobilisation onto silica gel, yielding
4a@SiO2/4b@SiO2 after heating the Pd–NHC/silica mix-
tures at 75 °C for 24 h. To confirm that the formation of
complexes 4 was completed the reaction was monitored
by 1H NMR spectroscopy which proved the clean, near-
quantitative formation of the desired Pd complex under
these conditions (see details in ESI).†
to cap the remaining accessible hydroxyl groups of the
silica surface. The materials obtained are herein labeled
4@SiO2+TMS and 5@SiO2+TMS.
The Pd content of these materials was found to range
between 1.7 and 2.6 wt% according to ICP analysis and the
results of elemental analysis of 4a@SiO2/4b@SiO2 indicated
that the immobilised species are 1 : 1 NHC–Pd complexes.
To further probe the composition of these materials, a sam-
ple of 1b was prepared, incorporating a 13C label at the C2 posi-
tion by using 13C-enriched paraformaldehyde during the
imidazolium-formation step. This modification enabled the
electronic environment at the ligand C2 (carbene donor) posi-
tion to be easily tracked by 13C NMR spectroscopy during the
immobilisation and post-immobilisation modification steps.
Fig. 1 depicts the 13C{1H} NMR spectra of 1b, 4b, and 5b as well
as the CP-MAS NMR spectra of the silica-immobilised 5b@SiO2
and the post-immobilisation modified 5b@SiO2+TMS.
No significant difference in the chemical shift of C2 was
observed between the spectrum of the precursor 1b (Fig. 1, i)
and that of the product of the thiol–ene reaction 2b
(Fig. 1, ii), indicating that the imidazolium C2 carbon's
electronic environment is not affected by the introduction of
the silyl groups. Upon treatment with Pd, the carbon signal
shifted downfield to 160 ppm with the formation of the
Pd-coordinated imidazol-ylidene species 5b (Fig. 1, iii). The
CP-MAS NMR spectrum of the silica-immobilised 5b@SiO2
(Fig. 1, iv) showed a strong, broad signal at a similar chemi-
cal shift, confirming that most of the immobilised ligand is
coordinated to Pd. Finally, in the spectrum of the
5b@SiO2+TMS species (Fig. 1, v) the signals arising from the
incorporation of SiMe3 groups in the final material were
detected at ca. 0 ppm (Fig. 1, v, labeled b). These results
clearly show that at least the majority of the Pd–NHC
complexes had been successfully anchored to the silica sup-
port without catalyst degradation.
Further optimisation showed that the entire synthetic
sequence, from thiol addition to alkenyloxy-imidazolium
chlorides
1 and then to immobilization of Pd–NHC
complexes 4 and 5 onto silica (3 steps), could be performed
as a sequential one-pot reaction as shown in Scheme 4.
This methodology was also used for the preparation of
the 5a@SiO2/5b@SiO2 materials by reacting 1a/1b with a
single equivalent of the thiol reagent. This procedure
afforded a mixture of one- and two-tethered imidazolium pre-
ligands in a ca. 2 : 1 ratio, estimated by quantifying the
amount of unreacted [Pd(1)(acac)Cl] remaining in solution
after the immobilisation procedure.
Finally, the samples of the immobilised catalysts 4@SiO2
and 5@SiO2 were treated with excess MeOSiMe3 in order
Scheme
3 Two-tethered silica gel-bound Pd–NHC complexes
4a@SiO2/4b@SiO2.
Fig. 1 13C{1H} NMR spectra of 13C2-labeled 5b@SiO2+TMS and
synthetic precursors: i) imidazolium pre-ligand 1b; ii) triethoxysilyl-
functionalised imidazolium pre-ligand 2b; iii) Pd-coordinated
imidazolylidene 5b; iv) silica-immobilised Pd-imidazolylidene 5b@SiO2;
v) post-immobilisation modified Pd-imidazolylidene (5b@SiO2+TMS). a.
The imidazolium/ylidene C2 carbon. b. The peak corresponding to sur-
face SiMe3 groups.
Scheme 4 Three-step one-pot sequence used for the synthesis of the
one-tethered enriched mixture 5a@SiO2/5b@SiO2.
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Performance of the new silica-supported NHC–Pd complexes
in the Suzuki–Miyaura reaction
catalyst decomposition under these conditions. Indeed, when
a series of recyclability tests were performed under these con-
ditions, a rapid decrease in activity was observed after the
first cycle and no conversion was achieved after the third
cycle (see the ESI).†
Activity and recyclability under batch conditions. The
silica-immobilised Pd complexes described above were tested
in the Suzuki–Miyaura reaction of 4-methoxyphenylboronic
acid and 1-bromo-2,4-dimethylbenzene. First, the reaction
conditions (temperature, solvent base and catalyst loading)
were optimised (see the ESI).† The optimal reaction condi-
tions for these catalysts included a biphasic toluene–water
mixture as solvent and Cs2CO3 or K3PO4 as base at a tempera-
ture of 60 °C. Under these conditions, activity comparison of
the different catalyst formulations was performed (Table 1).
Only low to moderate yields were achieved when catalysts
bearing methyl substitution at the ligand's aromatic rings
(labelled “a”) were used (Table 1, entries 1 and 2). Catalysts
featuring isopropyl substituents showed higher activity,
furnishing the biaryl product in 85% yield (Table 1, entry 4).
It is also noteworthy that catalysts containing single anchor-
ing of the Pd–NHC complexes proved more active than those
where only double anchoring is present (entry 5 vs. 4, 3).
Finally, post-immobilisation modification by capping the
silica surface with SiMe3 groups had a very important benefi-
cial effect on activity, enabling much faster reactions at
reduced catalyst loading (Table 1, entry 7 vs. 5).
The most active catalyst formulation (5b@SiO2+TMS)
was used to briefly explore the substrate scope achievable
with this system; for full details, see the ESI.† ortho-Substituted
coupling partners, activated bromides and chlorides and
also heteroaromatic bromides and chlorides furnished the
desired biaryl products in over 80% yield, except for the
more challenging heteroaromatic halides for which only
50% and 45% yields were obtained in the case of 2-bromo-
and 2-chloropyridine, respectively.
To investigate the origin of such unexpected decomposi-
tion/deactivation, the soluble complex [Pd(1b)(acac)Cl)] (6b)
was used as the precatalyst in the Suzuki–Miyaura coupling
under the same reaction conditions used for their supported
analogues. The formation of a black precipitate that was
observed shortly after the reaction was brought to tempera-
ture indicated that catalyst decomposition also occurred in
this case, ruling out a deleterious interaction between the
metallic centre and the support. It was therefore thought that
the use of water as co-solvent in the reaction medium might
be detrimental to the stability of these catalysts and new
experiments were carried out to investigate their activity and
stability under anhydrous reaction conditions.
Several NHC–Pd based heterogenised catalysts have
been reported that can operate in nonaqueous solvents. A
variety of systems using anhydrous solvent/base such as
57
58
iPrOH/t-BuOK,55,56 DMF/Cs2CO3 or xylene/K2CO3 have
been used in the coupling of arylboronic acids with aryl and
benzyl bromides and chlorides. In our case, further optimisa-
tion indicated that under anhydrous conditions these cata-
lysts worked best in toluene using cesium carbonate as a
base at a reaction temperature of 80 °C.
The recyclability of the one-tethered 5b@SiO2+TMS
and the two-tethered 4b@SiO2+TMS catalysts was exam-
ined in the coupling of 1-bromo-2,4-dimethylbenzene with
4-methoxyphenylboronic acid under these alternative condi-
tions. The results are shown in Fig. 2.
However, darkening of the reaction mixtures was observed
in all cases, indicating the formation of Pd black and hence
As previously observed under aqueous biphasic condi-
tions, higher activity was achieved using the single tethered
5b@SiO2+TMS in the first run, yielding 95% biaryl product
after 12 h. In the next run a large drop in catalyst activity
Table 1 Comparison of activity of the silica-supported catalysts in a
model Suzuki–Miyaura reaction
Entrya
Catalyst
Mol% Pd
Time (h)
Yieldb (%)
1
2
4a@SiO2
5a@SiO2
1.5
1.5
20
20
40
35
3
4
5
4b@SiO2
4b@SiO2
5b@SiO2
1.0
2.0
1.5
5, 20
20
20
34, 58
85
85
6
7
8
4b@SiO2+TMS
5b@SiO2+TMS
5b@SiO2+TMS
2.0
1.0
2.0
5
5
5
87
88
>95
a
Conditions: 0.5 mmol of ArBr, 0.6 mmol of ArB(OH)2, 1.0 mmol of
b
Fig. 2 Performance of the supported catalysts 4b@SiO2+TMS and
5b@SiO2+TMS under anhydrous conditions.
Cs2CO3, 1.5 mL of MePh, 0.75 mL of H2O, 60 °C. By GC-FID,
average of two runs.
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occurred and the coupling product was only obtained in
ca. 40% yield. These moderate yields were maintained in the
following two cycles before the conversion dropped gradually
over the next two runs, resulting in only 3% conversion in
the sixth cycle. On the other hand, double tethered
4b@SiO2+TMS, although outperformed in the first cycle by
the one-side attached analogue, proved more robust and
achieved yields in the 50–60% yield range over the next four
cycles before eventually showing signs of degradation after
the sixth reuse. No visible formation of precipitated palla-
dium was observed in any case under these conditions and
the potential leaching of Pd during each run was measured
by ICP measurement (Fig. S2 in the ESI.†). However, no
relevant amount of Pd could be detected.
Substrate scope under batch conditions. Since the
5b@SiO2+TMS catalyst was found to be reasonably stable
in recycling under the conditions outlined above, this system
was chosen for evaluation in the Suzuki–Miyaura coupling
of sterically hindered and heteroaryl bromides and
chlorides. The results are summarized in Table 2. Using
ortho-tolylboronic acid, excellent yields were obtained with
1-bromo-2,4-dimethylbenzene and 2-bromopyridine sub-
strates (entries 1 and 2). However, a lower yield was achieved
in the transformation of 2-chloropyridine using the same
coupling partner (entry 3), indicating that the C–X bond
activation might be rate limiting under these reaction
conditions. Using 4-methoxyphenylboronic acid as the
coupling partner, high to excellent yields were also obtained
with 1-bromo-2,4-dimethylbenzene and 4-bromo- and
4-chlorobenzonitrile (entries 5–7), although 2-bromopyridine
afforded a much lower product yield (entry 4). These results
show that under these conditions the ortho-substitution in
both coupling partners and the use of substrates containing
heteroatoms were tolerated and provided efficient transforma-
tions using the catalytic system 5b@SiO2+TMS.
Evaluation of the performance of the new catalysts under
continuous flow conditions
Next, performance of the silica-supported 4b@SiO2+TMS
and 5b@SiO2+TMS was assessed under continuous flow
operation. Dry methanol was used as a solvent because
it offered the best compromise between the catalyst activity
and the solubility of the reactants and by-product salts
(Fig. 3a, experiments 1 and 2); for comparison, wet acetonitrile
was also used as a solvent. Two solutions with different
chemical compositions were used in the packed bed flow
reactor and the catalyst and the corresponding amounts of
Pd in the catalytic bed (see the ESI).†
Table 2 The Suzuki–Miyaura substrate scope of the silica-supported cat-
alyst (5b@SiO2+TMS) under anhydrous conditionsa
Entry
1
ArB(OH)2
Ar'X
Isolated yield (%)
82
2
3
90
43
Fig. 3 Experiments 1 and 2 took place in dry MeOH under anhydrous
4
5
55
91
conditions. For both experiments solution
I was 0.2 M in the
corresponding ArBr and solution II was 0.4 M in base ( Cs2CO3) and
0.2 M in boronic acid. Experiment 3 was carried out in wet acetonitrile,
solution I was 1 M in the ArBr and solution II was 2 M in base (K3PO4) and
1 M in boronic acid. (a) Conversion of the ArBr to the Suzuki coupling
product vs. time on stream. (b) TOF vs. time on stream. Experiment
numbers correspond to Table S3†; lines are given as guides to the eyes.
C0 = 0.1 M in the reactor; u1 = u2 = 0.15 mL min−1 in both experiments.
GC conversion; mesitylene was used as the internal standard.
6
7
92
83
a
Conditions: 1 mmol of ArX, 1.2 mmol of ArB(OH)2, 2.0 mmol of
Cs2CO3, 4 mL of toluene anh., 80 °C, 12 h.
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Different reaction parameters were used in the flow tests.
were characterized by ICP, elemental analysis, and solid
state 13C and 29Si NMR. These catalysts were active in the
Suzuki–Miyaura reaction of aryl chlorides and bromides
bearing sterically hindered substituents. The stability of
these catalysts improved under anhydrous conditions
and the coupling of 1-bromo-2,4-dimethylbenzene with
4-methoxyphenylboronic acid was carried out five successive
times by simply filtering and washing the catalyst. Finally,
4b@SiO2+TMS and 5b@SiO2+TMS catalysts were evaluated
under continuous flow operation. Moderate conversions
were achieved at a relatively short residence time of 3.5 min
and conversion was stable for two hours in flow, confirming
the increased robustness of these systems under anhydrous
reaction conditions.
For all the experiments, the temperature inside the flow reac-
tor was set at 65 °C, the total flow rate was 0.30 mL min−1
and the residence time was 3.5 min for experiments 1 and 2
and 1.9 min for experiment 3.
The flow experimental conditions clearly show the trend
of catalyst activation–deactivation under the reaction condi-
tions. In all three experiments we observed an initial incuba-
tion period, which could indicate the possible generation of
palladium nanoclusters, although no decomposition was
apparent during the experiments.59 Full conversion of the
bromide substrate was achieved with the 5b@SiO2+TMS cata-
lyst after 40 min time-on-stream (see Fig. 3a, empty circles).
Then, as also observed under batch conditions, conversion
dropped to ca. 40–50%, and this level of activity was
maintained over the following 90 min.
Experimental section
The 4b@SiO2+TMS catalyst also showed an incubation
period after which the mixture that came out of the reactor
reached a maximum conversion of 70% after 10 min on
stream. In this case a smaller drop in conversion occurred
compared with the single tethered catalyst, and conversion
remained stable at 40–50% after two hours under continuous
flow. When a biphasic aqueous–organic mixture was used
(experiment 3, Fig. 3b), higher initial activities (expressed as
turnover frequency, TOF) were achieved, followed by a
decrease of 80% in catalytic activity after 45 minutes in flow,
dropping from 10 to 2 s−1. Traces of the deboronation
by-product as well as an unidentified by-product (possibly
arising from homo-coupling) were observed for both cata-
lysts. However, the selectivity of the ArBr substrate towards
the Suzuki coupling product was found to be 93–96%. The
color of the supported catalysts changed from the initial
yellow to dark orange-brown over time. However, no visible
Pd black was observed in the outlet flow.
The observed concentration vs. time-on-stream trends for
several experiments show fluctuations in concentrations.
These are correlated with periodic increases in the pressure
drop within the packed catalyst bed caused by salt formation
and its removal from the packed bed with the flow. The
estimated residence time in the single-phase experiments
is 3.5 min, resulting in 50–60% conversion. The consid-
erably faster reaction in flow compared to batch conditions is
due to the high ratio of catalyst to reactant in the packed-
bed microreactor. Despite the observed fluctuations the
overall conversion was relatively stable over ca. 90 min
on stream.
General considerations
Reactions were carried out using standard bench-top tech-
niques unless the use of a Schlenk flask is specified, in which
case inert atmosphere techniques were used. Where stirring
of the reaction mixture is indicated, magnetic stirring using a
Teflon-coated stir bar is employed throughout. Commercially
supplied compounds were used without further purification.
Dry solvents were prepared by distillation from CaH2/NaH
or P2O5 or collected from an MBraun SPS800 solvent purifica-
tion system. Photochemical reactions were performed using a
Philips HPL-N 125 W high-pressure mercury lamp which can
be purchased at most commercial lighting stores. Solution
NMR spectra were obtained at the Servei de Recursos
Científics i Tècnics (SRCT) of the URV using a 400 MHz
Varian Mercury VX400 spectrometer and calibrated to the
residual solvent peaks. CP-MAS spectra were recorded at the
Servei de Ressonància Magnètica Nuclear (SeRMN), Universitat
Autònoma de Barcelona on a 400 MHz spectrometer at a 12 kHz
rotation speed (and calibrated to an external adamantane
standard). Chemical shifts in the 1H and 13C{1H} NMR spectra
are reported relative to TMS. ICP analyses were conducted at
the SCRT using an ICP-OES Spectro Arcos instrument. Sam-
ples were digested in concentrated HNO3 under microwave
irradiation before being diluted for analysis. HR-MS (ESI-TOF)
analyses were also performed at the SCRT on an Agilent
Time-of-Flight 6210 spectrometer. GC-MS and GS-FID analy-
ses were conducted on Shimadzu GC-MS-QP2010 and Agilent
6850 instruments, respectively, fitted with HP-5 capillary
columns. Elemental analyses were performed at the Centro
de Microanálisis Elemental de la Universidad Complutense
de Madrid or at the Unitat d'Anàlisi Química i Estructural-
Serveis Tècnics de Recerca, Universitat de Girona. Aside
from solvents, reagents obtained from commercial sources
were used without further purification. Silica used for catalyst
immobilization was 60 mesh chromatography-grade
(purchased from SDS), dried for 1 h at 80 °C and 10−3 mbar
prior to use. [Pd(acac)2]60 was prepared according to litera-
ture procedures. Preparative procedures for the imidazolium
salt ligands and precatalysts 1a/1b, 2a/2b and 3a/3b,
Conclusions
In the present work, the synthesis and characterisation of
a new family of silica-immobilised Pd–NHC precatalysts
are reported, following a highly modular synthesis of the
functionalised ligands recently reported by our group. The
introduction of trialkoxysilyl groups to the imidazolium
architecture allowed the covalent attachment of the Pd
complexes onto the silica support. These supported catalysts
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characterization data for all compounds and computational
details can be found in the ESI.†
with copious amounts of CH2Cl2. The recovered yield of
4b@SiO2 was 2.5 g. Pd content determined by ICP: 1.76 wt%
(0.165 mmol g−1). Anal. calcd. for C50H80ClN2O6PdS2Si2@SiO2
based on Pd loading: C, 9.91; H, 1.33; N, 0.46; S, 1.06. Found:
C, 8.87; H, 1.94; N, 0.58; S, 0.97.
Synthesis of supported catalysts
One-pot procedure for the preparation of [Pd(2a)(acac)
One-pot procedure for the preparation of [Pd(3a)(acac)
Cl@SiO2] (4a@SiO2).
A
flame-dried Schlenk flask was
Cl@SiO2] (5a@SiO2). A flame-dried Schlenk flask was
charged with 1a (200 mg, 0.441 mmol, 1.0 equiv.),
3-mercaptopropyl(triethoxy)silane (270 μL, 1.064 mmol, 2.4
equiv.) and DMPA (22 mg, 0.09 mmol, 0.20 equiv.), followed
by freshly dried EtOH (1.5 mL). The reaction mixture was
then stirred at room temperature and irradiated with a
125 W high-pressure mercury lamp (8 cm separation between
the bulb and the flask) for 24 h. The solvent was removed
under reduced pressure, and the residue was re-dissolved in
CH2Cl2 and evaporated again in order to fully remove EtOH.
Then the crude product was washed three times with hexane
(3 mL). Next, [Pd(acac)2] (134 mg, 0.441 mmol, 1.0 equiv.)
was added along with 1,2-DCE (5 mL). After the reaction
mixture was heated at 75 °C with stirring for 2 days and then
allowed to cool, it was slowly transferred via a cannula to
another Schlenk flask containing a stirred (400 rpm) suspen-
sion of previously dried 60 mesh silica (2.0 g) in 1,2-DCE
(5 mL). This suspension was stirred at 250 rpm for 30 min at
ambient temperature, then the temperature was increased to
75 °C and stirring was continued for 24 h. During this time
the yellow color of the supernatant was transferred to the
silica. Finally, the material was hot-filtered and washed with
copious amounts of CH2Cl2. The recovered yield of 4a@SiO2
was 2.36 g. Pd content determined by ICP: 2.65 wt%
(0.249 mmol g−1). Anal. calcd. for C42H64ClN2O6PdS2Si2@SiO2
based on Pd loading: C, 12.5; H, 1.61; N, 0.70; S, 1.60. Found:
C, 9.55; H, 1.93; N, 0.67; S, 1.18.
One-pot procedure for the preparation of [Pd(2b)(acac)
Cl@SiO2] (4b@SiO2). A flame-dried Schlenk flask was
charged with 1b (213 mg, 0.377 mmol, 1.0 equiv.),
3-mercaptopropyl(triethoxy)silane (228 μL, 0.905 mmol,
2.4 equiv.) and DMPA (19 mg, 0.08 mmol, 0.20 equiv.),
followed by freshly dried EtOH (1.5 mL). The reaction
mixture was then stirred at room temperature and irradiated
with a 125 W high-pressure mercury lamp (8 cm separation
between the bulb and the flask) for 24 h. The solvent was
removed under reduced pressure, and the residue was
re-dissolved in CH2Cl2 and evaporated again in order to fully
remove EtOH. Then the crude product was washed three
times with hexane (3 mL). Next, [Pd(acac)2] (115 mg,
0.377 mmol, 1.0 equiv.) was added along with 1,2-DCE (5 mL).
After the reaction mixture was heated at 75 °C with stirring for
2 days and then allowed to cool, it was slowly transferred via a
cannula to another Schlenk flask containing a stirred (400
rpm) suspension of previously dried 60 mesh silica (1.71 g) in
1,2-DCE (3 mL). This suspension was stirred at 250 rpm for 30
min at ambient temperature, then the temperature was
increased to 75 °C and stirring was continued for 24 h. During
this time the yellow color of the supernatant was transferred
to the silica. Finally, the material was hot-filtered and washed
charged with 1a (1.00 g, 2.21 mmol, 1.0 equiv.),
3-mercaptopropyl(triethoxy)silane (560 μL, 2.21 mmol,
1.0 equiv.) and DMPA (56 mg, 0.221 mmol, 0.10 equiv.),
followed by freshly dried EtOH (40 mL). The reaction mixture
was then stirred at room temperature and irradiated with a
125 W high-pressure mercury lamp (8 cm separation between
the bulb and the flask) for 2 days. The solvent was removed
under reduced pressure, and the residue was re-dissolved in
CH2Cl2 and evaporated again in order to fully remove the
EtOH. Then the crude product was washed three times
with hexane (3 mL). Next, [Pd(acac)2] (673 mg, 2.21 mmol,
1.0 equiv.) was added along with 1,2-DCE (15 mL). After
the reaction mixture was heated at 75 °C with stirring for
2 days and then allowed to cool, it was slowly transferred
via a cannula to another Schlenk flask containing a stirred
(400 rpm) suspension of previously dried 60 mesh silica
(7.30 g) in 1,2-DCE (20 mL). This suspension was stirred at
250 rpm for 30 min, then the temperature was increased
to 75 °C and stirring was continued for 24 h. Finally, the
material was hot-filtered and washed with copious amounts
of CH2Cl2. The recovered yield of 5a@SiO2 was 8.66 g. Pd
content determined by ICP: 2.53 wt% (0.238 mmol g−1).
One-pot procedure for the preparation of [Pd(3b)(acac)
Cl@SiO2] (5b@SiO2). A flame-dried Schlenk flask was
charged with 1b (875 mg, 1.54 mmol, 1.0 equiv.),
3-mercaptopropyl(triethoxy)silane (390 μL, 1.54 mmol,
1.0 equiv.) and DMPA (50 mg, 0.20 mmol, 0.13 equiv.),
followed by freshly dried EtOH (40 mL). The reaction mix-
ture was then stirred at room temperature and irradiated
with a 125 W high-pressure mercury lamp (8 cm separation
between the bulb and the flask) for 2 days. The solvent
was removed under reduced pressure, and the residue
was re-dissolved in CH2Cl2 and evaporated again in order
to fully remove the EtOH. Then the crude product was
washed three times with hexane (3 mL). Next, [Pd(acac)2]
(469 mg, 1.54 mmol, 1.0 equiv.) was added along with
1,2-DCE (20 mL). After the reaction mixture was heated at
75 °C with stirring for 2 days and then allowed to cool, it
was slowly transferred via a cannula to another Schlenk flask
containing a stirred (400 rpm) suspension of previously dried
60 mesh silica (5.10 g) in 1,2-DCE (10 mL). This suspension
was stirred at 250 rpm for 30 min at ambient temperature,
then the temperature was increased to 75 °C and stirring was
continued for 24 h. Finally, the material was hot-filtered and
washed with copious amounts of CH2Cl2. The recovered yield of
5b@SiO2 was 6.14 g. Pd content determined by ICP: 2.50 wt%
(0.237 mmol g−1). 13C{1H} CP-MAS and 29Si{1H} MAS NMR
spectra of a C2 13C-labeled sample of 5b@SiO2 are included
in the NMR spectra section of the ESI.†
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End-capping treatment of silica-supported materials to
runs. Purified by column chromatography using n-hexane as
the eluant. H NMR (400 MHz, CDCl3): δ 7.26–7.19 (m, 3H),
1
obtain 4b@SiO2+TMS, 5a@SiO2+TMS and 5b@SiO2+TMS.
A Schlenk flask was charged with the appropriate supported
Pd complex (1.00 g) and flushed with N2. The solid was
suspended in toluene (3 mL) and then stirred at 400 rpm
while MeOSiMe3 (1.5 mL) was added dropwise via a syringe.
After fastening the flask's stopper securely and closing the N2
inlet, the reaction mixture was heated at 60 °C with stirring
(150 rpm) overnight. Upon cooling, the product material
was collected by filtration and washed with copious amounts
of CH2Cl2. Note: the synthesis of 5b@SiO2+TMS was also
carried out on a 3 g scale. 4b@SiO2+TMS: yield = 980 mg; Pd
content determined by ICP: 1.67 wt% (0.157 mmol g−1).
5a@SiO2+TMS: yield = 990 mg; Pd content determined by
ICP: 1.97 wt% (0.185 mmol g−1). 5b@SiO2+TMS: yield = 1.00 g;
Pd content determined by ICP: 1.73 wt% (0.163 mmol g−1).
13C{1H} CP-MAS and 29Si{1H} MAS NMR spectra of a C2
13C-labeled sample of 5b@SiO2+TMS are included in the NMR
spectra section of the ESI.†
General procedure for catalytic Suzuki–Miyaura reaction
runs. A small Schlenk flask or a 5 mL screw topped vial was
charged with the catalyst, base, boronic acid and the aryl
halide (if solid). The flask or the vial was capped with a
septum and flushed with N2, and then the aryl halide was
added using a microsyringe if liquid. The solvent was added
using a syringe (4 mL of organic solvent or 1.5 mL of organic
solvent and 0.75 mL of water) and, in the case of the Schlenk
flask runs, the septum was replaced with a glass stopper. The
reaction mixture was then stirred at 400 rpm and heated at
the indicated temperature. After the indicated reaction time,
the vessel was cooled in an ice bath. Next, the organic
fraction was filtered through a small plug of silica. In the
case of the biphasic aqueous runs, the aqueous layer was
then extracted with toluene (2 × 0.5 mL) and the extracts
were filtered through the same silica plug. The silica plug
was then washed with toluene (1 mL). The product mixture
was analyzed by GC-FID at this stage, and then it was evapo-
rated under reduced pressure and purified by silica gel chro-
matography using hexane/EtOAc as the eluent.
7.11–7.09 (m, 2H), 7.04 (br d, J = 7.6 Hz, 1H), 7.00 (d, J =
7.6 Hz, 1H), 2.37 (s, 3H), 2.06 (s, 3H), 2.03 (s, 3H). MS (EI):
m/z = 196 (M+), 181, 165, 152. NMR and MS peaks match
literature values.62
2-(2-methylphenyl)pyridine. The reagents 2-bromopyridine
(96 μL, 1.0 mmol, 1.0 equiv.), 2-methylphenylboronic acid
(164 mg, 1.2 mmol, 1.2 equiv.), Cs2CO3 (652 mg, 1.0 mmol,
2.0 equiv.), (5b@SiO2+TMS) (30 mg, 0.01 equiv.) were used as
described in the general procedure for catalytic SM reaction
runs. Purified by column chromatography using 10 : 1
n-hexane/EtOAc as the eluant. 1H NMR (400 MHz, CDCl3):
δ 8.71 (d d d, J1 = 4.9 Hz, J2 = 1.8 Hz, J3 = 0.9 Hz, 1H), 7.78
(d d d, J1 = 7.7 Hz, J2 = 7.7 Hz, J3 = 1.8 Hz, 1H), 7.43 (d d d,
J1 = 7.8 Hz, J2 = 1.1 Hz, J3 = 1.0 Hz, 1H), 7.41–7.39 (m, 1H),
7.32–7.26 (m, 4H), 2.03 (s, 3H). HR-MS: m/z = 170.1000, calcd.
for C12H12N [M–H+]: 170.0966.
2-(4-methoxyphenyl)pyridine. The reagents 2-bromopyridine
(96 μL, 1.0 mmol, 1.0 equiv.), 4-methoxyphenylboronic acid
(182 mg, 1.2 mmol, 1.2 equiv.), Cs2CO3 (652 mg, 1.0 mmol,
2.0 equiv.), (5b@SiO2+TMS) (30 mg, 0.01 equiv.) were used as
described in the general procedure for catalytic SM reaction
runs. Purified by column chromatography using 10 : 1 n-hexane/
EtOAc as the eluant. 1H NMR (400 MHz, CDCl3): δ 8.65 (d d d,
J1 = 4.9 Hz, J2 = 1.8 Hz, J3 = 1.0 Hz, 1H), 7.95 (d, J = 9.0 Hz,
2H), 7.75–7.66 (m, 2H), 7.18 (d d d, J1 = 7.2 Hz, J2 = 4.9 Hz,
J3 = 1.3 Hz, 1H), 7.00 (d, J = 9.0 Hz, 2H), 3.87 (s, 3H). HR-MS:
m/z = 186.0889, calcd. for C12H12NO [M–H+]: 186.0915.
General procedure for recycling of the silica-supported cat-
alysts. In the cases where catalyst recycling was performed,
an internal standard (undecane) was added after cooling the
reaction mixture in an ice bath; the supported catalyst was
separated from the organic phase by decantation, filtration
and washing with toluene (2 × 1 mL), which combined with
the organic phase. The supported catalyst was then succes-
sively washed with water, EtOH and Et2O, then dried under
vacuum and directly reused in the next cycle.
Experimental procedure for continuous flow tests. The
catalytic activity and stability of the catalysts 4b@SiO2 and
5b@SiO2 were studied under flow conditions using a
Vapourtec system with an R2 pump module and an R4
reactor module. The rig is shown schematically in Fig. 4.
Two feed solutions were deoxygenated by bubbling N2 for
1 h prior to reactions and then were pumped by two HPLC
pumps into the T-connection (PTFE, 0.5 mm through holes,
Upchurch Scientific) via PFA tubing (1.6 mm in OD, 1.2 mm
in ID) at equal flow rates (u1 = u2 = 0.15 mL min−1). The
Coupling products obtained by S.M. reactions
4-methoxy-2′,4′-dimethylbiphenyl. The reagents 4-bromo-m-
xylene (136 μL, 1.0 mmol, 1.0 equiv.), 4-methoxyphenylboronic
acid (182 mg, 1.2 mmol, 1.2 equiv.), Cs2CO3 (652 mg,
2.0 mmol, 2.0 equiv.), (5b@SiO2+TMS) (60 mg, 0.01 equiv.)
were used as described in the general procedure for catalytic
SM reaction runs. Purified by column chromatography using
25:1 n-hexane/EtOAc as the eluant. 1H NMR (400 MHz, CDCl3):
δ 7.24 (d, J = 8.8 Hz, 2H), 7.12 (d, J = 7.7 Hz, 1H), 7.09 (s, 1H),
7.05 (d, J = 7.7 Hz, 1H), 6.94 (d, J = 8.8 Hz, 2H), 3.85 (s, 3H),
2.36 (s, 3H), 2.25 (s, 3H). NMR data match literature values.61
MS (EI): m/z = 212 (H+), 197, 181.
2,4-dimethyl-2′-methylbiphenyl. The reagents 4-bromo-m-
xylene (136 μL, 1.0 mmol, 1.0 equiv.), 2-methylphenylboronic
acid (164 mg, 1.2 mmol, 1.2 equiv.), Cs2CO3 (652 mg, 2.0 mmol,
2.0 equiv.), (5b@SiO2+TMS) (60 mg, 0.01 equiv.) were used as
described in the general procedure for catalytic SM reaction
Fig. 4 Scheme of a Vapourtec reactor.
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Paper
merged flow was then introduced to the inlet of the packed-
bed column assembly (borosilicate glass with PTFE end
pieces, 6.6 mm in ID × 100 mm in length, OmniFit).
12 K. Mennecke and A. Kirschning, Synthesis, 2008, 20, 3267–3272.
13 A. Gömann, J. A. Deverell, K. F. Munting, R. C. Jones,
T. Rodemann, C. A. J. Canty, J. A. Smith and R. M. Guijt,
Tetrahedron, 2009, 65, 1450–1454.
The column was packed with a catalyst and has a catalytic
bed length of 2.3 cm, which corresponds to a packed bed vol-
ume of 0.787 mL. The measured amount of the catalyst was
diluted with QuadraSil AP (Johnson Matthey) spherical silica
beads. The void volume in the catalytic bed in the approxima-
tion of random close packing of ideal spheres is 0.295 mL
(the void fraction is about 0.375, neglecting the porosity of
the support). The mean residence times in the packed bed
were found to be 3.5 and 1.9 minutes in the cases of the sin-
gle phase and biphasic aqueous–organic flow, respectively
(calculated from the residence time distribution curves mea-
sured for the QuadraSil AP using a standard tracer tech-
nique). For the loadings of the catalysts used in this study
this void corresponds to an initial molar ratio of Ar–Br : Pd ≈ 2.1
in the reactor in the case of the biphasic aqueous–organic
flow or 0.4 in the case of the single phase conditions.
The catalytic loadings in the reactor are still quite high even
if we assume the porosity of the support to be about 60%
(ArBr : Pd ≈ 4.2 or 0.9 for the biphasic and single phase
conditions, respectively).
14 R. C. Jones, A. J. Canty, J. A. Smith, R. M. Guijt,
T. Rodemann, J. A. Smith and V.-A. Tolhurst, Tetrahedron,
2009, 65, 7474–7481.
15 K. Mennecke and A. Kirschning, Beilstein J. Org. Chem.,
2009, 5, 21.
16 U. Kunz, A. Kirschning, H.-L. Wen, W. Sodolenko, R. Cecilia,
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17 N. Karbass, V. Sans, E. García-Verdugo, M. I. Burguete and
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18 N. Nikbin, M. Ladlow and S. V. Ley, Org. Process Res. Dev.,
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23 Y. M. A. Yamada, T. Watanabe, K. Torii and Y. Uozumi,
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Acknowledgements
The authors are grateful to the 7th Framework Program
(NMP2-LA-2010-246461; SYNFLOW) and the Spanish Ministerio
de Economía y Competitividad (CTQ2010-14938/BQU, and a
Ramon y Cajal fellowship to C. Godard) for financial support.
24 Y. M. A. Yamada, T. Watanabe, T. Beppu, N. Fukuyama,
K. Torii and Y. Uozumi, Chem.
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