This is the peer reviewed version of the following article: ChemSusChem 2015, 8, 123 – 130, which has
been published in final form http://onlinelibrary.wiley.com/doi/10.1002/cssc.201402858/abstract	
  
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Highly Functionalized Biaryls via Suzuki–Miyaura Cross-Coupling
Catalyzed by Pd@MOF under Batch and Continuous Flow
Regimes
Vlad Pascanu,[a] Peter R. Hansen,[b] Antonio Bermejo Gómez,[a] Carles Ayats,[c] Ana
E. Platero-Prats,[a, d] Magnus J. Johansson,[e] Miquel A. Pericàs,[c, f] and Belén MartínMatute*[a]
[a] V. Pascanu, Dr. A. Bermejo Gómez, Dr. A. E. Platero-Prats, Prof. B. Martín-Matute. Department of
Organic Chemistry and Berzelii Center EXSELENT Arrhenius Laboratory. Stockholm University.
Stockholm, 106 91 (Sweden). E-mail: belen@organ.su.se [b] P. R. Hansen. RIA IMed, Medicinal
Chemistry, Innovative Medicines Unit AstraZeneca R&D, Mólndal, 431 83 (Sweden) [c] Dr. C. Ayats,
Prof. Miquel A. Pericàs. Institute of Chemical Research of Catalonia Av. Països Catalans, 16, Tarragona,
43007 (Spain) [d] Dr. A. E. Platero-Prats. Department of Materials and Environmental Chemistry
Arrhenius Laboratory, Stockholm University, Stockholm, 106 91 (Sweden) [e] Dr. M. J. Johansson.
CVMD IMed, Medicinal Chemistry, Innovative Medicines Unit AstraZeneca R&D, Mölndal, 431 83
(Sweden) [f] Prof. Miquel A. Pericàs. Department of Organic Chemistry University of Barcelona, 08028
Barcelona (Spain)

Abstract: A diverse set of more than 40 highly functionalized biaryls was
synthesized successfully through the Suzuki–Miyaura crosscoupling reaction
catalyzed by Pd nanoparticles supported in a functionalized mesoporous MOF (8
wt% Pd@MIL-101(Cr)-NH2). This could be achieved under some of the mildest
conditions reported to date and a strong control over the leaching of metallic species
could be maintained, despite the presence of diverse functional groups and/or
several heteroatoms. Some of the targeted molecules are important intermediates in
the synthesis of pharmaceuticals and we clearly exemplify the versatility of this
catalytic system, which affords better yields than currently existing commercial
procedures. Most importantly, Pd@MIL-101-NH2 was packed in a micro-flow reactor,
which represents the first report of metallic nanoparticles supported on MOFs
employed in flow chemistry for catalytic applications. A small library of 11 isolated
compounds was created in a continuous experiment without replacing the catalyst,
demonstrating the potential of the catalyst for large-scale applications.
At the center of the rapidly evolving green revolution in chemistry,[1] catalysis plays a
pivotal role.[2] Without catalytic processes, it would be unconceivable to aim for a
sustainable chemical industry.[3] When it comes to organometallic catalysis, special
attention is dedicated to the recycling of metallic species.[4] Aside from the obvious
health hazards associated with exposure to heavy metals, resources of palladium or
ruthenium are scarce and likely to become increasingly expensive in the future.[5]
Solid supports facilitate the recovery of these species and have been used for the
immobilization of catalysts as either discrete species[6] or nanometer-scale metal
clusters.[7]
Still, a common limitation in heterogeneous transformations is the narrow substrate
scope, which often addresses model substrates that do not reflect the challenges of
practical applications. Relevant substrates with multiple heteroatoms and competing
functional groups are more challenging, so they should be addressed when new
heterogeneous catalysts are developed.

Metal–organic frameworks (MOFs),[8] porous crystalline materials with extremely high
surface areas, have the potential to fill in this area because they are highly versatile
compared to other materials.[9] Since their properties can easily be modulated,[10] they
could be applied in advanced organic processes such as tandem and cascade
reactions.[11]
Microscale flow chemistry[12] has diffused slowly into academic laboratories,
provoking synthetic chemists to face issues traditionally reserved for process
chemists and engineers to deal with.[13] The symbiosis between heterogeneous
catalysis and flow chemistry became a natural direction of progress in the field,
leading to a new generation of packed-bed microreactors.[14] Surprisingly, despite all
recent reports on MOF-type catalysts, they have not yet been developed into flow
applications. To the best of our knowledge, Galarneau and co-workers[15] were the
only ones so far to develop a successful catalytic process at the intersection of flow
chemistry and MOFs, using Cu-HKUST-1.[16]
Herein, we report the synthesis of heteroatom-functionalized biaryls through Suzuki–
Miyaura cross-couplings catalyzed by Pd nanoparticles supported on MIL-101-NH2[17]
under very mild reaction conditions. The coupling products are potential building
blocks of biologically active molecules. Besides a significant expansion of the
substrate scope, we discuss in detail some of the particularities of performing this
reaction under heterogeneous conditions. We also show the first example of a
nanocatalyst supported on a MOF and employed in a packed-bed micro-flow reactor.
Pd@MIL-101-NH2 displays good stability under a continuous flow regime, with
barely detectable levels of leached metallic species.
A summary of relevant homogeneous Pd catalysts for difficult Suzuki–Miyaura crosscouplings and a comparison of our catalyst with recently developed heterogeneous
systems are included in the Supporting Information (Section I). Although the majority
of aryl chlorides are still out of reach, the Pd nanocatalyst reported herein has the
highest activity amongst the existing heterogeneous systems for this type of
applications.

Results and Discussion
We started by investigating the coupling of boronic acids [1,Y=(OH)2] or pinacolate
esters (1, Y= pinacolate = pin) with heteroaryl iodides (2a–f) using K2CO3 as base (2
equiv) in a mixture of H2O/EtOH (1:1) as solvent and a catalyst loading of only 1
mol% Pd (Scheme 1a). The material of choice was 8 wt% Pd@MIL-101-NH2, which
we recently reported to have the optimal amount of palladium impregnated in MIL101-NH2 for this type of applications.[18, 19] The large majority of these functionalized
(hetero)aromatic iodides reacted in excellent yields at mild temperatures (20 or 50
ºC) and in very short reaction times (0.5–4 h), leading to the facile synthesis of 3a–f
despite the presence of one or several heteroatoms. Even hindered aryl iodides (2b)
and lengthy substrates (2f) afforded the coupling products 3b and 3f, important
building blocks in the synthesis of pharmaceutically active intermediates,[20] in high
yields (85% and 82 %, respectively) after short reaction times (1 and 4 h,
respectively). We then proceeded to the coupling of less reactive aryl bromides (2g–
2m) while also testing the reactivity of different types of boronates (Scheme 1b). A
quantitative yield was obtained in the synthesis of 3g from p-anisylboronic acid (R =
OCH3, BY = B(OH)2), even when the catalyst loading was decreased 10 times (0.1
mol% Pd), as well as from the analogous trifluoroborate and MIDA (Nmethyliminodiacetic acid) ester. The latter, more complex MIDA-boronate gave to our
delight an excellent yield, however showed no rate enhancement relative to the other
boron derivatives and was therefore not considered further. The same product, 3g,
was also obtained in less than 30 min at 20 ºC when ethyl 4-bromobenzoate (2g)
was replaced with the corresponding triflate. 2-Bromobenzonitrile (2h) could also be
coupled with p-tolylboronic acid at ambient temperature in only 30 min, affording a

quantitative yield of 3h, an intermediate in the synthesis of the cardiovascular drug
Valsartan.[21]

Scheme 1. Couplings of (hetero)aromatic aryl iodides and bromides. [a] Unless otherwise
noted, 0.1 mmol of aryl halide and 1.1 equiv of transmetallating agent were used. Conversion
determined by LC-MS. Isolated yields in parenthesis. [b] 80% conversion in 4 h from 2bromothiophene. [c] 0.1 mol% Pd was used. [d] Equimolar amounts of boronic acid were
used (1.02 equiv) [e] Low isolated yield due to the hydrolysis of the ester. Pin = pinacolate.
MIDA = N-methyliminodiacetate.

Methyl 5-bromo-1H-pyrrole-2-carboxylate (2k), 6-bromoindole (2l), and 3bromoquinoline (2m) were all well tolerated reaction partners despite their
coordinating properties and the bulky nature of 2l and 2m, and afforded 3k–3m in
good-to excellent yields. The catalytic system displayed very good compatibility
under microwave (MW) irradiation conditions (Scheme 1 b, 3j), as further exemplified
in the following sections, which helped to speed up the reaction significantly. The
extent to which functional groups can exert a steric hindrance was further examined
in more detail (Scheme 2). In the series of trifluoromethylphenylboronic acids
(Scheme 2 a), the ortho substituted starting material completely inhibited the reaction
even at 50 ºC (Scheme 2 a, 4c). In contrast, the para and meta analogues afforded
4a–b in excellent yields. This surprising interference prompted us to examine other
ortho-substituted phenylboronic acids. When a less bulky chloride replaced the
trifluoromethyl functionality at the ortho position, the reactivity returned to normal and
4d could be obtained in a very good yield. Furthermore, a range of other hindered
products were synthesized and isolated successfully (4e–g) proving a good tolerance
of our catalyst to different ortho substituents (i.e.; OMe, CH2OH and OH). However,
2-formylphenylboronic acid (4h) reacted at a slightly reduced rate, while the omethylcarboxylate function (4i), inhibited the reaction. This set of experiments
indicates that formation of the desired products is suppressed when the boronic acid
contains electron-withdrawing groups in addition to bulky ortho substituents.

Scheme 2. Influence of steric effects. [a] 0.1 mmol of aryl halide and 1.1 equiv of
transmetallating agent were used. Conversion determined by LC–MS. Isolated yields in
parenthesis.

This effect proved to be less pronounced when the bulky, electro-withdrawing
functionality was switched to the aryl halide (Scheme 2 b). In this case, methyl oiodobenzoate reacted with (5-formylfuran-2-yl)boronic acid using slightly harsher
conditions than the meta and para ethyl analogues. Consequently, although a
significant rate deceleration is observed, this problem can be, in most cases,
circumvented at higher temperatures and the catalyst is capable to return an
excellent conversion.
Even though the catalytic tests performed so far were rewarding, superior results
were obtained when the heterocyclic moiety was located on the boron
transmetallating partners. As a general trend, it was observed that this arrangement
of reactive groups (boron located on the more functionalized fragment) leads to a
better tolerance towards multiple coordinating heteroatoms. A large variety of
interesting (hetero)aromatic or vinylboronic acids (6a–6n) were coupled with aryl
iodides (Scheme 3a, 7a–j) and aryl bromides (Scheme 3b, 7k–n) and afforded
biaryls 8a–j and 8k–n, respectively, encountering very little difficulties. Notably, 8c
and 8d, containing a sophisticated motif present in patented antagonists of P2X
purinergic receptors,[22] reached full conversion at low temperatures in 30 min and in
2 h, respectively. It was especially interesting to observe that a complex aryl halide
such as 7d could be easily coupled with isoprene-2-yl boronic acid pinacolate ester
(6d), which contains a vinylic substituent. Furthermore, boronic acids of pyridines,
indoles, furans and thiophenes were well tolerated. The use of MW irradiation was
proven once again to be highly effective and led to the isolation of 8e and the
sterically hindered 8f in excellent yields, after merely 10 min of reaction time. More
sophisticated products like 8m and 8n could also be synthesized and successfully
isolated in very good yields from the corresponding aryl bromides at 50 ºC.
In our efforts to determine the tolerance limit that Pd@MIL-101-NH2 has for complex
substrates, it was found that certain classes of heterocycles do not react readily.
Halides of pyrazoles, indazoles and benzimidazoles stood out as very challenging

substrates. Their poisoning effect was recently discussed in detail by Buchwald and
co-workers,[23] who provided evidence for the formation of bridged Pd complexes,
which inhibit the Suzuki coupling. A strong influence over the outcome was also
attributed to the pKa values of the heterocycles employed. In this context, it was
interesting to examine the inhibitory properties of these substrates. In a robustness
assessment, as proposed by Glorius et al.,[24] when this type of heterocycles
(benzimidazole or 1-methylimidazole) were used as additives in the cross-coupling of
two standard substrates, the reaction was completely suppressed and no product
formation could be detected (Scheme 4). In contrast, when indole was used as an
additive, almost no inhibition could be detected.

Scheme 3. Couplings of (hetero)aromatic boronic acids. [a] Unless otherwise noted, 0.1
mmol of aryl halide and 1.1 equiv of transmetallating agent were used. Conversion
determined by LC-MS. Isolated yields in parenthesis. [b] Using isoprene-2-yl boronic acid
pinacolate ester. [c] Using 2-bromofuran.

Scheme 4. Inhibitory effects of heterocycles. [a] 0.1 mmol scale. 1.2 equiv of transmetallating
agent and 1 equiv of additive were used. Composition of the reaction mixture after 30 min
determined by 1H NMR spectroscopy using 1,2,4,5-tetrachloro-3-nitrobenzene as internal
standard. Pin = pinacolate.

Gratifyingly, this problem was partially bypassed using the heterocycles as
transmetallating agents under mild conventional heating (Scheme 5, 9a and b) or

MW irradiation conditions. This strategy enabled the synthesis of several aryl
substituted pyrazoles and oxazoles in good to excellent yields (9a–d).

Scheme 5. Coupling of pyrazole and oxazole derived boronic acids. [a] Unless otherwise
noted, 0.1 mmol of aryl halide and 1.1 equiv of transmetallating agent were used. Conversion
determined by LC–MS. Isolated yields in parenthesis [b] 50% conversion at 50 ºC,
conventional heating. Pin = pinacolate.

Although previous reports provide limited evidence that catalysis can occur on the
surface of the nanoparticles and inside the pores,[25] homogeneous contributions from
leached metallic species must be considered, while the debate on the true nature of
the active Pd species is still fiercely active.[26] We consider the character of the
dominant mechanism (heterogeneous or homogeneous) to be strongly dependent on
the reaction conditions but these two possible pathways can operate
simultaneously.[24b] Taking advantage of the good scavenging properties of the MOF,
products free of contamination can still be obtained.
Several reactions presented above were repeated in order to assess the extent of Pd
leaching and to investigate its dependence on the nature of the substrates and the
reaction conditions. When model substrates with no heteroatoms were used, the Pd
content in solution after filtration of the catalyst was in most cases below the
detection limit of the inductively coupled plasma–optical emission spectrometry (ICPOES) method (<0.1 ppm). Our attempts to measure precise kinetic profiles of the
reaction over several runs were hampered by the insufficient solubility of the starting
materials in the solvents mixture and the precipitation of the biaryl product at high
concentrations. However, even when the catalyst loading was decreased to 0.1
mol%, the reaction between p-bromobenzaldehyde and phenylboronic acid was
completed in less than 10 min, over at least 5 recycling runs. The rate in this case
was mainly influenced by the rate of solvation of the aryl halide. After repeated
recycling runs, some Pd agglomeration becomes evident under TEM.[18] These
results suggest that even if Pd leaching occurs, the redeposition process is extremely
efficient and products completely free of contamination can be obtained.
However, when one N atom is present in the aryl halide, leached Pd can be detected
in very small amounts (2.8–5.0 ppm) which appear to also be dependent on the
reaction time and temperature (Scheme 1 and 6, 3i, 3l and 3m). At elevated
temperatures and under MW irradiation (Scheme 3 and 6, 8e), even higher levels of

Pd can be detected (12–14 ppm), although the MOF keeps the leaching at very
reasonable levels for such drastic conditions. The only case where the leaching of Pd
was severe was that of pyrazole (Scheme 5 and 6, 9c). 51 ppm of Pd were detected
after 10 min at 80 ºC under MW irradiation, conditions which were required to
achieve a complete conversion. When the same set of substrates were reacted for 1
h at 30 ºC, the level of Pd in solution was measured to be only 5.9 ppm but no
desired product was observed. This indicates that the presence of a second N atom
in the substrate affects the stability of the nanoparticles even more than the harsh
conditions employed.

Scheme 6. Pd leaching measured for various N-containing substrates.

In order to further demonstrate the applicability of our catalyst, the Pd loading was
decreased to 0.01 mol% and 1-(4’-bromophenyl) ethanone was reacted in a 7.5gram-scale using only an equimolar amount of p-tolylboronic acid as transmetallating
agent (Scheme 7). The conversion was measured at regular intervals by LC–MS and
determined to be complete after 280 min. A simple extraction with EtOAc led to the
isolation of the desired biaryl (10) in 99% yield (turnover number TON = 10000) with
remarkable purity as proven by the 1H NMR spectrum of the crude mixture (Figure
S6). Without further purification, 4-(4’-methylphenyl) acetophenone (10) was reacted
for 3 h with commercially available alloxan hydrate to obtain compound 11 in a 96%
yield after just filtration and washing with water, with no need for chromatographic
purification or recrystallization (Scheme 7). This is a drastic improvement on the
previously reported synthesis of 11 by Nicolotti et al.[27] (50% overall yield), which has
been proposed as an inhibitor for matrix metalloproteinases involved in inflammatory
diseases.

Scheme 7. Synthesis of MMP inhibitor 11.

Encouraged by the results presented above and the facile recyclability of this catalyst
under batch conditions, previously demonstrated by our group,[18] we proceeded to
investigate the behavior of Pd@MIL-101-NH2 under continuous-flow conditions.[28]
The catalyst was packed in an Omnifit glass column (d = 10 mm; 70 mm max
adjustable bed height). For evaluating its performance under flow conditions, an
“endurance test” was set up. Thus, 350 mg of catalyst (7.29 wt% Pd@MIL-101-NH2)
was packed as described in the Supporting Information. A vigorously stirred mixture
of starting materials (10 mmol of p-bromobenzaldehyde,12 mmol of phenylboronic
acid pinacolate ester, and 20 mmol of K2CO3, in a mixture of 30 mL H2O and 120 mL
EtOH) was passed through the column at an optimized flow rate of 75 µLmin-1. After
stabilization of the system, regularly collected samples were analyzed by 1H NMR
spectroscopy for measuring the conversion and by ICP-OES for determining the level
of leached metallic species. The catalyst displayed a remarkable stability for a
considerable period of 54 h, during which the aryl halide was fully converted to the
desired product, at a turnover frequency of 1.25 h-1 (0.91 h-1 calculated from isolated
yield), with no formation of by-products and barely detectable levels of metallic
species in solution (max. 0.2 ppm of Pd and max. 0.1 ppm of Cr; see Table S1).
After 66 h, it was observed that the outflowing solution had turned from colorless to
strongly yellow. This correlated with increased leaching (up to 1.2 ppm of Pd and 0.2
ppm of Cr) while significant amounts of dehalogenated by-product (benzaldehyde)
were detected. The experiment was stopped after 70 h and the catalyst was
recovered, washed and dried. The XRPD analysis showed a complete amorphization
of the recycled material (Figure S4 a). The increased leaching and loss of selectivity
are not surprising considering that after the amorphization of the framework, Pd
nanoparticles are no longer protected by the MOF pores. In this case, they will
agglomerate, forming conglomerates of uncontrolled size and morphology, with
inferior catalytic properties.
Satisfied with the determined stability timeframe, we planned to synthesize a small
library of more challenging compounds in a single continuous flow experiment. This
is an interesting application of flow processes with immobilized catalytic systems in
pharmaceutical research. In this manner, focused libraries of drug candidates or drug
intermediates can be readily prepared in a sequential procedure, free of
contamination by the metal catalyst, through a process easily amenable to
automation.[29]

Mixtures of similar concentration (0.3 mmol of aryl halide in 6 mL of solvent, see the
Supporting Information) were prepared and passed through an identically packed
catalyst column at a reduced flow rate of 50 µLmin-1 (see the Supporting Information
for detailed procedure). To our delight, 11 coupling products (Scheme 8, 14a–l),
several of which were known to be problematic, could be synthesized before catalytic
activity of the system was compromised.
By running the reaction under non-equilibrium conditions specific to continuous flow
regimes, some slightly lower yields were obtained compared to batch reactions. Also
a minor decrease in activity and selectivity is gradually observed as the column starts
to degrade under the stress produced by passing more bulky and heteroaromatic
substrates. However, it is not until the 12th product that the operation of the flow
column becomes unproductive.[30] As previously observed, a yellow coloration of the
outflowing solution started to mark the steep decline in catalytic activity. The
recovered catalyst was found to be partially crystalline (Figure S4 b) with a remaining
Pd content of 6.81 wt% (initially 7.29 wt%).

Scheme 8. Synthesis of a mini-library of coupling products in one continuous flow

experiment. [a] Products listed in the order they were synthesized. Left: Isolated yields
1
reported. Right: by-products determined by H NMR spectroscopy from crude reaction
mixtures. [b] Outflowing solution slightly yellow. [c] Outflowing solution strongly yellow. [d]
Product not isolated. Pin = pinacolate.

Conclusions
We propose a robust heterogeneous catalytic system for the Suzuki–Miyaura crosscoupling reaction. The system consists of palladium nanoparticles immobilized on the
metal–organic framework MIL-101-NH2, and employs some of the mildest reaction
conditions reported to date. Its applicability is demonstrated in the synthesis of a
large number of diverse heteroaromatic and highly functionalized biaryls (more than
40 examples). The substrate scope includes motifs frequently encountered in drug
molecules and we illustrate the potential to improve existing synthetic routes for
commercially relevant products. By adapting this system to operation under
continuous flow, we have developed what will hopefully become the first in a rich
family of catalysts based on metallic nanoparticles supported on MOFs and applied
in packed-bed flow reactors.
After successfully synthesizing a small library of 11 isolated products in a single
experiment, we are confident that the set up exemplified in this work demonstrates
the potential of Pd@MIL-101-NH2 to be employed in automated processes under a
continuous-flow regime. Fulfilling the main directives of green chemistry through
catalysis, efficiency, selectivity and recyclability, we hope that the arguments
presented in this report make Pd@MIL-101-NH2 an attractive solution for large scale
applications.

Experimental Section
General procedure for the Suzuki–Miyaura cross-coupling reactions
8 wt% Pd@MIL-101-NH2 was prepared according to the reported procedure.[18]
Unless otherwise stated, in a 20 mL regular vial or Biotage microwave vial, the
arylboronic acid (0.83 mmol), the aryl halide (0.158 g, 0.75 mmol), K2CO3 (0.207 g,
1.5 mmol), and 8 wt% Pd@MIL-101Cr-NH2 (10 mg, 7.5 µmol, 1 mol% Pd) were
added together with a magnetic stirring bar. EtOH (5 mL) and H2O (5 mL) were
added. The mixture was stirred in a sealed vial at the given temperature under
conventional heating or microwave irradiation. The compound was extracted with
EtOAc or CH2Cl2 (5 mL), the organic phase was separated and the volatile solvents
were evaporated to yield the crude product. The product was purified by flash
chromatography (see the Supporting Information).
Procedure for experiments under flow regime
For the mini-library experiment, 12 mixtures of starting materials were prepared:
consisting of aryl halide (0.3 mmol), boronic acid/ ester (0.45 mmol) and K2CO3 (0.6
mmol) in a mixture of H2O (1.5 mL) and EtOH (4.5 mL). Due to the low solubility of
some of the chemicals, the reaction mixture was stirred vigorously during the loading
process. Increasing the excess of transmetallating reagent to 1.5 equiv helped to
minimize the formation of dehalogenation by-products. Each freshly prepared mixture
was passed through the column at 50 µLmin-1 corresponding to a residence time of
35–40 min. The column was then flushed with a clean solvent mixture (H2O/EtOH,
1:3 v/v) at the same flow rate for 1 h and at 500 µLmin-1 for another 30 min. The
outflowing solution was checked by TLC to verify that no residual product is left in the
column before switching the inlet needle to the next reaction mixture. For each run,

the outflowing solution was collected together with the flushing solvent and extracted
with EtOAc. The organic phase was separated, the volatiles were evaporated and
the residue was purified by column chromatography (see the Supporting
Information).

Acknowledgements
This project was supported by the Swedish Governmental Agency for Innovation
Systems (VINNOVA) and AstraZeneca through the Berzelii Center EXSELENT, by
the Swedish Research Council (VR) through a project grant to B.M.-M and for the
MATsynCELL project through the Röntgen Ångström Cluster, and by the Knut and
Alice Wallenberg Foundation (Catalysis in selective organic synthesis). The work on
flow chemistry was funded by MINECO (grant CTQ2012-38594-C02-01), DEC (grant
2009SGR623) and the ICIQ Foundation. ICIQ authors also thank EU-ITN network
Mag(net)icFun (PITN-GA-2012-290248) for financial support. B.M.-M. was supported
by VINNOVA through a VINNMER grant. V.P. is grateful to the EU-ITN network
Mag(net)icFun (PITN-GA-2012-290248) for a secondment at ICIQ. C.A. thanks
MICINN for a Juan de la Cierva postdoctoral fellowship.
Keywords: flow chemistry · heterocycles · MOF catalysis · suzuki-miyaura
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[30] Although agglomeration of Pd upon MOF collapse has been described after
multiple recycling runs under batch,[18] we had not seen yellow colouring in the
solutions during the recycling experiments. On the contrary, under the continuous
flow regime, the MOF suffers from more severe decomposition probably due to the
higher pressure in this system.