Direct α-arylation of ketones efficiently catalyzed by Cu-MOF-74

Article abstract of DOI:10.1016/j.cattod.2019.09.033

The activity and reusability of Cu-MOF-74 as heterogeneous catalyst were studied in the Cu-catalyzed C[sbnd]C cross-coupling reaction of 4-iodotoluene (4-IT) with acetylacetone (AcAc) to direct synthesis of α-aryl-ketones. Cu-MOF-74 is characterized by having unsaturated copper sites into its highly porous metal-organic framework that can play a crucial role in catalytic applications. The influence of critical reaction variables such as solvent, reaction temperature, AcAc/4-IT ratio, catalyst concentration and basic agent (type and concentration) were evaluated. High conversions were achieved at 140 °C, 5 mol % of catalyst, AcAc/4-IT ratio of 2:1, DMF as solvent and 1.5 equivalent of Cs₂CO₃ base. The C-arylation between 4-IT and AcAc proceeded only in the presence of Cu-MOF-74 material, being very low the transformation in absence of the solid catalyst. Cu-MOF-74 material displayed a remarkable structural stability, regarding its XRD patterns and solid recovery degree after several reaction cycles, which was also complemented by the negligible amount of copper leached in the reaction media. This catalyst showed promising results in comparison to other homogeneous and heterogeneous Cu-based catalysts. This work evidences the great potential of MOF materials as heterogeneous catalysts in fine chemistry applications.

Full text of DOI:10.1016/j.cattod.2019.09.033

Journal Pre-proof
Direct ␣-arylation of ketones eeficiently catalyzed by Cu-MOF-74
P. Leo, G. Orcajo, D. Briones, F. Mart´ınez, G. Calleja
PII:
S0920-5861(19)30530-9
DOI:
https://doi.org/10.1016/j.cattod.2019.09.033
CATTOD 12485
Reference:
To appear in:
Catalysis Today
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Revised Date:
Accepted Date:
1 July 2019
8 September 2019
18 September 2019
Please cite this article as: Leo P, Orcajo G, Briones D, Mart´ınez F, Calleja G, Direct
␣-arylation of ketones eeficiently catalyzed by Cu-MOF-74, Catalysis Today (2019),
doi: https://doi.org/10.1016/j.cattod.2019.09.033
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DIRECT α-ARYLATION OF KETONES EEFICIENTLY
CATALYZED BY Cu-MOF-74
P. Leoa, G. Orcajob*, D. Brionesa, F. Martíneza, G. Callejab
a
Department of Chemical and Environmental Technology, Rey Juan Carlos University, Calle
Tulipán s/n, 28933 Móstoles, Spain.
b
Department of Chemical, Energy and Mechanical Technology, Rey Juan Carlos University,
Calle Tulipán s/n, 28933 Móstoles, Spain.
*Corresponding author: Tlf: +34 91 488 76 01, FAX: +34 91 488 70 68
E-mail address: gisela.orcajo@urjc.es
Graphical abstract

Highlights
 Cu-MOF-74 catalyst showed efficient performance in a C-arylation reaction.
 Cu-MOF-74 catalytically surpassed other homogeneous and heterogeneous Cu-
catalysts.
 Cu-MOF-74 was stable and reusable during several reaction cycles.
Abstract
The activity and reusability of Cu-MOF-74 as heterogeneous catalyst were studied in the
Cu-catalyzed C-C cross-coupling reaction of 4-iodotoluene (4-IT) with acetylacetone
(AcAc) to direct synthesis of α-aryl-ketones. Cu-MOF-74 is characterized by having
unsaturated copper sites into its highly porous metal-organic framework that can play a

crucial role in catalytic applications. The influence of critical reaction variables such as
solvent, reaction temperature, AcAc/4-IT ratio, catalyst concentration and basic agent
(type and concentration) were evaluated. High conversions were achieved at 140 ºC, 5
mol % of catalyst, AcAc/4-IT ratio of 2:1, DMF as solvent and 1.5 equivalent of Cs2CO3
base. The C-arylation between 4-IT and AcAc proceeded only in the presence of Cu-
MOF-74 material, being very low the transformation in absence of the solid catalyst. Cu-
MOF-74 material displayed a remarkable structural stability, regarding its XRD patterns
and solid recovery degree after several reaction cycles, which was also complemented by
the negligible amount of copper leached in the reaction media. This catalyst showed
promising results in comparison to other homogeneous and heterogeneous Cu-based
catalysts. This work evidences the great potential of MOF materials as heterogeneous
catalysts in fine chemistry applications.
Keywords: MOF; heterogeneous catalyst; recyclable Cu-MOF-74; α-aryl-ketones
1. Introduction
α-aryl ketones constitute an important class of organic molecules, since are crucial
intermediates [1] and final products in the synthesis of natural products and
pharmaceutical compounds [2] and accordingly their synthesis has gained attention
during the last years. Buchwald and Hartwig pioneered the palladium-catalyzed arylation

of several carbonyl compounds using aryl halides as electrophiles. In this process, an
enolate is generated from a ketone and base in the presence of an aryl halide, and a
palladium catalyst couples this enolate with the aryl halide [3, 4]. Despite the promising
results obtained in those works, the high cost and relatively low availability of palladium,
encouraged to explore other cheaper alternatives like homogeneous copper-based
catalytic systems for synthesizing aryl carbonyls molecules [5, 6]. Besides, nowadays
there is a strong incentive to replace homogeneous processes by green and efficient
heterogeneous processes for economic and environmental reasons. In heterogeneous
systems, not only the separation of the catalyst but also the reaction products also becomes
easier, allowing the catalyst to be reused in consecutive reaction cycles [7]. Up to date,
few works has been addressed to the use of Cu-based heterogeneous catalysts in this kind
of reactions, two examples of them are CuO-nanoparticles and another one testing the
MOF-199 material (also called HKUST-1) [8, 9].
Metal-organic framework (MOF) materials are porous crystalline solids with specific
surface areas surpassing activated carbons and zeolites, composed of metal-containing
nodes connected by organic linkers through coordination chemical bonds [10]. Recently,
MOFs are being extensively tested in different catalytic system for a wide range of acid-
base and redox reactions [11 - 14]. The most stimulating features of MOF materials for
catalytic applications are their high surface area, tunable pore size, scaffold flexibility,
and particularly, the great diversity of structural metallic and organic functional sites [15].
From the best of our knowledge, the only work where a copper-based MOF is used for
this kind of C-C coupling reaction is the one reported by Phan and co-workers who tested
HKUST-1 in the coupling of aryl iodides with acetylacetone to form α-aryl ketones as
principal products [8].

The family of MOF-74 materials are quite interesting since they are robust, enough
porous (~1000 m2/g), with one of the highest concentration of metal sites per volume
among MOF materials, and can be prepared with Zn, Ni, Co, Mg, Mn and Cu [16, 17].
They provide non-coordinated metal sites after removing the synthesis solvent, leading
to the so-called Open Metal Sites (OMS). This fact is of a valuable interest for catalytic
applications offering active sites for accessible substrates. Particularly, Cu-MOF-74 was
developed in our research group [17] and it could be a good candidate to catalyze C-C
cross-coupling reactions. This Cu-MOF-74 material was previously tested in the C-O
coupling reaction of phenol with 4-nitrobenzaldehyde, exhibiting a remarkable catalytic
activity and structural stability under consecutive reaction cycles [18].
For those reasons, in the present work, the Cu-MOF-74 material was studied as a
heterogeneous catalyst for C-arylation reaction of acetylacetone and 4-iodotoluene. The
influence of different variables such as reaction temperature, solvent, catalyst
concentration and the type and concentration of base will be evaluated in order to
determine the best reaction conditions for the synthesis of α-aryl ketones using a
recoverable and reusable catalyst.
2. Experimental
2.1. Catalysts preparation
Cu-MOF-74 was solvothermally synthesized basically following the procedure
previously published [17], in which a mixture of 2.2g of 2,5 dihydroxyterephthalic acid
(H2dhtp, 11.2 mmol, Aldrich) and trihydrated copper nitrate(II) (5.9 g, 24.6 mmol,
Aldrich) were dissolved in 250 mL solution of N,N-dimethylformamide (DMF) and 2-
propanol (20:1 (v/v)) using a 500 mL screw cap bottle. Then, the resultant solution was
placed in an oven at 80 °C during 18 h. Thereafter, it was cooled down to room

temperature and the reddish needle-shaped crystals were separated from the mother liquor
by vacuum filtration. Afterwards, the solid was washed with DMF and immersed in 100
mL of methanol for four 4 days, renewing it by fresh methanol every 24 h. Prior to the
catalytic runs, the solid material was dried at 150 °C under vacuum (10−3 bar) for 5 h and
stored under inert atmosphere. For comparison purposes, other heterogeneous catalysts
such as copper oxide (CuO) or copper-containing MOF materials -URJC-1 (Universidad
Rey Juan Carlos) and HKUST-1 (Hong Kong University of Science and Technology)-
and homogeneous coper salts (CuCl2 and Cu(NO3)2) were used. URJC-1 was synthesized
in our laboratory according to the procedure described in the literature [19]. The other
materials (CuO y HKUST-1) and copper salts were purchased to Sigma-Aldrich.
2.2. Catalyst characterization
X-ray powder diffraction (XRD) patterns were acquired on a PHILIPS X‘PERT
diffractometer using Cu Kα radiation. The data were recorded from 5 to 50° (2Ө) with a
resolution of 0.01º. Scanning electron microscopy (SEM) micrographs were obtained on
a PHILIPS XL30 ESEM electronic microscope operating at 200 kV. Nitrogen
adsorption–desorption isotherms at −196 °C were measured using an AutoSorb
equipment (Quantachrome Instruments). The specific surface area was calculated by
using the Brunauer–Emmett–Teller (BET) model [20]. The pore volume and diameter
were estimated by non-local DFT calculations, assuming a kernel model of N2 at
-196 °C on carbon (cylindrical pores, NLDFT equilibrium model) [21]. Simultaneous
thermogravimetry and derivative thermogravimetric analyses (TGA/DTG) were carried
out under nitrogen atmosphere with an N2 flow of 100 mL min−1 at a heating rate of
5 °C/min up to 700 °C, using a TA Instruments SDT 2860 apparatus.
2.3. Reaction procedure

Cu-MOF-74 material was tested in the C-arylation cross coupling reaction of
acetylacetone (AcAc) and 4-iodotoluene (4-IT) to form 4-methylphenylacetone
(4-MPAc; [1]) as a principal product and 3-phenyl-2,4-pentanodione (3-PP; [2]) as
byproduct. A schematic view of this particular reaction (reactants, products and catalyst)
is depicted in Scheme 1. All the catalytic experiments were carried out in a round bottom
flask placed in a silicone bath under N2 atmosphere. The influence of temperature, molar
ratio between substrates (AcAc/4-IT), catalyst concentration, type of solvent, type of base
and base concentration was evaluated, starting with the conditions found in literature [8].
The required amounts of substrates (AcAc and 4-IT) were added to 12 mL of DMF. The
base and Cu-MOF-74 catalyst concentrations were adjusted according to molar ratios of
base/AcAc and Cu/4-IT, respectively. The reaction was monitored by withdrawing
aliquots from the reaction medium at different times ranging from 0 to 300 min. All
reactants and products concentrations in the reaction were quantified by gas
chromatography, using a GC-3900 Varian chromatograph equipped with a CPSIL 8 CB
capillary column (30 m × 0.25 mm, film thickness 0.25 µm) and a flame ionization
detector (FID). The injector and FID temperature were set to 300ºC and the oven
temperature program starts a 80ºC to further heating until 300ºC at 40°C/min-1 and then
it was kept at 300ºC during 0.6 min. Hexadecane was used as internal standard and all
samples were analyzed by duplicate.

4-MPAc
4-IT
Cu-MOF-74
AcAc
3-PP
Scheme 1. C-C cross-
coupling reaction of acetylacetone with 4-iodotoluene.
3. Results and discussion
3.1 Characterization of Cu-MOF-74
The most relevant characterization data of the Cu-MOF74 synthesized by solvothermal
method is depicted in Figure 1. Powder X-ray diffraction (PXRD) pattern revealed the
location and intensity of the main reflections of the MOF-74 phase [22], discarding the
presence of secondary crystalline phases when comparing with the simulated pattern from
the crystallographic data (Figure 1a). SEM micrographs of the as-synthesized material
revealed the expected large needle-shaped crystals with a size of 20 µm that have been
previously reported for this Cu-MOF-74 material [17] (Figure 1b). Elemental analysis by
using ICP-OES indicated a copper loading of 6.1 mmol/g, which is quite close to the
theoretical content from the molecular structure (6.2 mmol/g). The porosity of the
material was measured by nitrogen adsorption at -196 ºC (Figure 1c). The basically type
I adsorption/desorption isotherm revealed a permanent microporosity with a BET specific

surface area around 1126 m2/g, a pore volume of 0.57 cm3/g and an average pore diameter
of ca. 10 Å. Thermogravimetric analysis (TGA) under N2 atmosphere evidenced a
significant loss of weight at ca. 100 ºC which was attributed to the methanol used for the
removal of original DMF solvent. The decomposition of the structural organic ligand at
ca. 370 °C, evidences a remarkable thermal stability (Figure 1d).
Figure 1. Catalyst characterization of Cu-MOF-74: a) PXRD patterns; b) SEM images
c) Nitrogen adsorption-desorption isotherms at -196 °C (inset of micropore size
distribution curve generated by NL-DFT method), and d) TGA at inert atmosphere.
3.2. Catalytic study
Influence of temperature
The influence of the temperature on the C-arylation cross-coupling reaction of
4-iodotoluene (4-IT) and acetylacetone (AcAc) to form α-aryl ketones was evaluated at

80, 100, 120 and 140 °C (Figure 2). These reactions were carried out in DMF as solvent,
an AcAc/4-IT molar ratio of 3:1, 1.5 equivalents of Cs2CO3 as base and 10 mol % of
catalyst, which are similar conditions to those published by Phan et al. [8]. The increase
of temperature improved the catalytic performance of Cu-MOF-74 material. A
remarkable 72 % of 4-iodotoluene (4-IT) conversion and 57 % of 4-methylphenylacetone
(4-MPAC) yield were achieved in only 30 min at 140 ºC. For longer reaction times until
6 h, a moderate increase of both, 4-IT conversion and 4-MPAC yield, was obtained
(almost 90 % of conversion and product yield). It must be also pointed out that the
increase of temperature evidenced a significant enhancement of the 4-MPAC yield. In
this Ullmann coupling reaction, other side by-products such as, 3-phenyl-2,4-
pentanodione (3-PP) can appear. Thus, the increase of temperature seems to prompt the
breakdown of acetylacetone to react with the toluene-based intermediates, increasing the
4-MPAC yield.
80 °C
100 °C
120 °C
140 °C
100
80
60
40
20
0
100
80
60
40
20
0
2 h
4 h
0.5 h
6 h
Figure 2. Influence of temperature on the catalytic performance of Cu-MOF-74. Normal
columns indicate 4-IT conversion; fill columns indicate 4-MPAC product yield.

In order to evaluate the contribution of homogeneous catalysis from possible leached
copper species of Cu-MOF-74, an additional experiment at 140 ºC was carried out, that
is shown in Figure 3. For that purpose, the solid catalyst was separated after the first 30
minutes from the reaction medium by hot filtration, and the reaction continued up to 6
hours (catalyst removal). The figure shows the comparison of 4-IT conversion profiles of
this experiment with the typical experiment keeping the solid Cu-MOF-74 catalyst for the
complete reaction time of 6 hours (with catalyst). The active role of the solid Cu-MOF-
74 in the C-arylation cross-coupling reaction is clearly proven when comparing both
profiles. No further conversion of 4-IT was detected once the solid catalyst was removed
from the reaction mixture, which demonstrates a null contribution of homogeneous
catalysis by plausible copper leaching. Moreover, ICP-OES analyses revealed that copper
species were not detected in the reaction medium.
With catalyst
Catalyst removal
100
80
60
40
20
0
0
1
2
3
4
5
6
Time (hours)
Figure 3. Evaluation of homogeneous catalytic contribution of Cu-MOF-74 for C-
arylation cross-coupling reaction of AcAc and 4-IT.
Influence of catalyst concentration

In order to assess the influence of the catalyst concentration over the reaction evolution,
the reaction was carried out in DMF at 140 °C, AcAc/4-IT molar ratio of 3:1, one and
half equivalents of Cs2CO3 as base and catalyst concentrations of 0, 2.5, 5, 7.5, 10 mol %
(Figure 4), regarding the copper/4-iodotoluene molar ratio.
Blank
2.5%
5%
7.5%
10%
100
80
60
40
20
0
100
80
60
40
20
0
0.5 h
4 h
6 h
2 h
Figure 4. Influence of the Cu-MOF-74 concentration on the reaction performance.
Normal columns indicate 4-IT conversion; fill columns indicate 4-MPAC product yield.
A low 4-IT conversion of ca. 20% and poor 4-MPAC yield were achieved after 6 hours
of reaction in absence of the solid catalyst. The presence of Cu-MOF-74 catalyst provided
a remarkable initial rate for the initial 30 min of reaction, with values of 4-IT conversion
ranging from ca. 60% (for 2.5 mol % of catalyst) to 72 (from 5 to 10 mol % of catalyst).
It is remarkable that higher concentrations of catalyst than 5 mol % in the reaction
medium do not improve the 4-IT conversion. Similar behavior was observed for the
results of the 4-MPAC yield with values around 55-57% at 30 minutes and 86-90 % after
6 hours of reaction for catalyst concentrations between 5 and 10 mol %. It should be noted
that the commonly used copper concentration for this kind of reactions in homogeneous
systems is around 10% [23], occasionally reporting up to 20 % [24, 25]. Regarding the

only heterogeneous catalysts tested to date, HKUST-1 material and CuO nanoparticles
[8, 9], a concentration of 10 mol % was employed, which is the double to that required in
the case of Cu MOF-74. In this work, Cu-MOF-74 catalyst achieved 4-IT conversions of
around 90 % and 4-MPAC yields close to 90 % after 6 hours of reaction with only 5 mol
% of copper with respect to 4-iodotoluene substrate.
Influence of solvent
The effect of the solvent can be decisive in coupling Ullmann-type reactions due to its
impact on the reaction mechanism and solubility of reactants and products [26]. It has
been observed that the polarity of the solvent is the critical parameter and it can be
measured by their dielectric constant. Therefore, the C-arylation reaction of 4-iodotoluene
with acetylacetone was carried out in different common solvents as dimethyl sulfoxide
(DMSO), N,N-dimethylformamide (DMF), nitrobenzene, N-Methyl-2-pyrrolidone
(NMP) and toluene , with different dielectric constants of 47, 37, 35, 32 and 2.4,
respectively. For the rest of variables the AcAc/4-IT molar ratio was kept at 3:1, 1.5
equivalents of Cs2CO3 as base and 5 molar % of catalyst concentration. As shown in
Figure 5, a poor performance was evidenced for the solvent with the lowest dielectric
constant (toluene), obtaining only 20 % of 4-IT conversion after 6 h of reaction. Under
the same conditions, nitrobenzene led to a much higher conversion (78 %), although still
lower than the 91 % conversion attained with DMF. This is not surprising since the
reaction intermediate is a carbanion that would have greater stability in polar solvents [9].
So, these results are in good agreement with previous works found in literature using
other homogeneous and heterogeneous catalysts such as copper iodide and CuO
nanoparticles, respectively [8, 9, 27]. Both NMP and DMSO were found to be unsuitable
for this reaction using Cu-MOF-74 catalyst, since the MOF structure collapsed in these

solvents at 140 °C. Special attention is paid to the results obtained for nitrobenzene
referred to the high conversion values but very low yields, evidencing a poor selectivity
towards 4-MPAC product, which denotes possible low solubility of the products in
nitrobenzene. In order to confirm this assumption, an extra experiment was done by
adding the product 4-methylphenylacetone in nitrobenzene at 140 °C and vigorous
stirring during 20 min. The results evidenced that the product was not dissolved. Apart
from the importance of the solubility of reactants and products in the solvent, it has been
reported that polar solvents favor the formation of ionic complexes, suggesting that ionic
forms promote the halogen atom transfer of aryl chlorides for the formation of α-aryl
ketones [28].
Toluene
Nitrobenzene
DMF
100
80
60
40
20
0
100
80
60
40
20
0
6 h
4 h
0.5 h
2 h
Figure 5. Influence of the solvent reaction on the catalytic performance of Cu-MOF-74.
Normal columns indicate 4-IT conversion; fill columns indicate 4-MPAC product yield.
Influence of acetylacetone /4-iodotoluene molar ratio
The influence of the reactants ratio in the cross-coupling reaction was also investigated
for AcAc/4-IT molar ratio of 1:1, 2:1, 3:1 and 4:1 (Figure 6). These reactions were carried

out at 140 °C with DMF and one and half equivalents of Cs2CO3 as base in the presence
of 5 mol % of Cu-MOF-74 catalyst.
AcAc/4-IT Molar ratio
1:1
2:1
3:1
4:1
100
80
60
40
20
0
100
80
60
40
20
0
6 h
0.5 h
2 h
4 h
Figure 6. Influence of AcAc/4-IT molar ratio on catalytic performance of Cu-MOF-74.
Normal columns indicate 4-IT conversion; fill columns indicate 4-MPAC product yield.
Equimolar conditions of reactants allow reaching a conversion from 62 to 75% after 6
hours and a 4-MPAC yield from 32 to 51 %, which suggests a fast kinetic reaction during
the first 30 min, and then, evolving slower until reaching the chemical equilibrium at 6
hours. It is also evidenced the enhancement of 4-IT conversion when acetylacetone is
increased up to AcAc/4-IT of 2:1, attaining 89 % of 4-IT conversion and 82 % of 4-
MPAC yield after 6 hours of reaction. From AcAc/4-IT molar ratio of 2:1 to 4:1, the
enhancement in the catalytic activity is not significant. It must be noted that similar results
were reported using other copper-based MOF material, being the optimal AcAc/4-IT
molar ratio of 2:1 [8]. This result can be explained by the role of acetylacetone in
increasing the formation of the copper intermediate that leads to the product without
carbon-carbon cleavage [9], but limited by the stoichiometry of this reaction.
Influence of base

The influence of the base nature on the catalytic activity of Cu-MOF-74 was also studied.
In order to accelerate the transmetalation step in the catalytic mechanism, different bases
have been used in transition-metal catalyzed reactions [26, 29, 30, 31]. In this work, some
easy-available and inexpensive bases have been selected to be evaluated like Cs2CO3,
K2CO3, Na2CO3, K3PO4, Na3PO4 in the performance of the reaction using one and half
equivalent of base, AcAc/4-IT molar ratio 2:1, DMF, 140 °C and 5 molar % of catalyst.
The results are shown in Figure 7.
No base
K3PO4
Na3PO4
K2CO3
Na2CO3
Cs2CO3
100
80
60
40
20
0
100
80
60
40
20
0
0.5 h
2 h
4 h
6 h
Figure 7. Influence of the base agent on catalytic performance of Cu-MOF-74. Normal
columns indicate 4-IT conversion; fill columns indicate 4-MPAC product yield.
Insignificant 4-IT conversion of 12% was achieved in absence of base after 6 hours of
reaction time, meanwhile higher values of conversion and yield were obtained when the
base was added to the reaction media. The catalytic activity of Cu-MOF-74 is quite
influenced by the type of anion of the used salt (carbonate or phosphate) and its counter-
cation. Carbonates evidenced a better catalytic performance than phosphates for the same
counter-cation. The higher kinetic diameter of phosphate anions is probably affecting the
catalytic process of deprotonation of the acetylacetone inside the porous structure of Cu-

MOF-74. Additionally, the use of cesium with a lower electronegativity (0.7) than
potassium (0.8) or sodium (0.9), marks an enhancement of the catalytic performance of
Cu-MOF-74. This fact suggests that higher electronegativity promotes stronger affinity
to deprotonated anions, consequently hindering the transmetallation step for the
formation of α-aryl ketones compound [18].
Since the most suitable base was Cs2CO3, its concentration was also studied by varying
the base equivalents from 0.5 to 2 equivalents. Figure 8 shows the 4-IT conversion and
4-MPAC yield for four catalytic experiments of 0.5, 1, 1.5 and 2 equivalents, using DMF
at 140 °C, AcAc/4-IT molar ratio of 2:1 and 5 molar % of catalyst.
0.5 equiv
1 equiv
1.5 equiv
2 equiv
100
80
60
40
20
0
100
80
60
40
20
0
2 h
4 h
6 h
0.5 h
Figure 8. Influence of Cs2CO3 concentration on catalytic performance of Cu-MOF-74.
Normal columns indicate 4-IT conversion; fill columns indicate 4-MPAC product yield.
The increase of the Cs2CO3 concentration from 0.5 to 1 equivalent enhances the catalytic
activity of Cu-MOF-74, especially in terms of 4-MPAC yield. However, the increase
beyond 1.5 equivalents does not produce further improvement, revealing that one and half
equivalents are enough to promote an efficient deprotonation of the acetylacetone
substrate.

3.3 Comparison with other Cu-catalyst
The catalytic performance of Cu-MOF-74 in the cross-coupling reaction of acetylacetone
with 4-iodotoluene was also compared with other Cu-based heterogeneous (CuO, URJC-
1 and HKUST-1) and homogeneous (CuCl and Cu(NO3)2 salts) catalysts. It is important
to note that CuO is a common heterogeneous catalyst used in this kind of reactions and it
has also a similar chemical nature than the inorganic clusters of the Cu-MOF-74 material.
The catalyst concentration was always set to copper contents of 5 mol %. The experiments
were carried out using DMF at 140°C, AcAc/4-IT molar ratio of 2:1 and 1.5 equivalents
of Cs2CO3 as base. As it is displayed in Figure 9, the Cu-MOF-74 catalyst exhibited the
best catalytic performance, in terms of 4-IT conversion and 4-MPAC yield, among all
tested copper catalysts, particularly from 2h of reaction times.
CuO
URJC-1
CuCl2
CuNO3
HKUST-1
Cu-MOF-74
100
80
60
40
20
0
100
80
60
40
20
0
4 h
0.5 h
2 h
6 h
Figure 9. Catalytic performance for different Cu-based catalysts in the C-arylation cross
coupling reaction of 4-iodotoluene and acetylacetone.
The homogeneous catalytic systems based on CuCl2 and Cu(NO3)2 salts show high 4-IT
conversions after 6 hours of reaction (ca. 75 % and 81 %, respectively), but in general,
they are worse than the results of heterogeneous catalysts. This could be attributed to

-
possible negative effects of Cl- and NO3 anions in the C-arylation cross-coupling
reaction. This was confirmed by additional experiments performed with extra amount
-
(1.39 mg/mL) of Cl- and NO3 , provided by potassium-based salts. These experiments
showed a significant decrease in 4-IT conversion to 59% and 68% for CuCl and
Cu(NO3)2, respectively, after 6h of reaction, demonstrating the strong interference of the
anions in the reaction course.
Concerning the results obtained for heterogeneous Cu catalysts, CuO showed the worst
performance in terms of 4-IT conversion. The three MOF materials tested (Cu-MOF-74,
URJC-1 and HKUST-1) are characterized by porous materials with unsaturated copper
sites, which would favor the interaction with the reaction species. The 4-IT conversions
of these three materials were very similar along the different reaction times; however,
important differences in the 4-MPAC yield were observed. URJC-1 showed a significant
lower yield to 4-MPAC respect to the other two MOFs. The selectivity to specific
products, and consequently their reaction yields, can be controlled by the size and
interconnection of the porous system. However, the molecular size of reactants and
products (3-6 Å) are small enough to diffuse well into the porous structure of the three
materials, with pore size distributions centered at 15 Å for URJC-1 and 10 Å for both Cu-
MOF-74 and HKUST-1 materials. The URJC-1 material evidences a lower surface area
of 408 m2/g as compared to Cu-MOF-74 and HKUST-1 materials with values of 1126
m2/g and 1008 m2/g, respectively. Additionally, the structural and compositional
crystalline unit of URJC-1 is completely different to the other two carboxylated-MOF
materials. The copper ions in the URJC-1 material is connected to five nitrogen atoms
belonging to tetrazole and imidazole rings of the ligand and one oxygen of the DMF
solvent (CuN5O) [19]. On the other hand, Cu-MOF-74 and HKUST-1 materials are
carboxylated-MOF materials with copper clusters connected to the oxygen atoms of

carboxylated groups of the ligand [17, 32]. Thus, the different specific surface area of
URJC-1 material and the nature of the copper-active sites seem to affect significantly the
4-MAPC yield. Regarding Cu-MOF-74 and HKUST-1 materials, the Cu-MOF-74
material displays a slight enhancement of the 4-IT conversion and 4-MPAC yield. The
catalyst activity of carboxylated MOF materials such as Ni-MOF-74, MIL-100(Al),
Cu3(BTC)2(HO2)3 and UiO-66 have been also proven in other C-C coupling reactions [33,
34].
3.4. Reuse of Cu-MOF-74
An important issue of chemical processes based on organic reactions from the
environmental point of view, is the reusability of the catalyst in several reaction cycles.
Therefore, the recyclability of the catalyst was also studied in the C-arylation cross-
coupling reaction for four successive catalytic runs. Prior to each catalytic run, the catalyst
was recovered and washed with methanol several times and dried at 150ºC for 18 h. The
4-IT conversion and the XRD patterns of the catalyst after the four reaction cycles are
shown in the Figure 10a and Figure 10b, respectively. The catalytic performance was
above 84 % for the four cycles although a very slight decrease of activity was observed
in the last cycle (Figure 10a). The XRD patterns of the catalyst after each cycle evidenced
the maintenance of the crystalline phase of Cu-MOF-74 (Figure 10b), demonstrating the
robustness of the MOF structure. Likewise, the copper leaching in the reaction medium
was negligible and the catalyst recovery after each cycle was above 98 %. These results
demonstrate the remarkable structure stability of the MOF material under the studied
conditions. Thus, the slight catalyst deactivation could be attributed to possible
chemisorbed by-products along the reaction cycles, that are not effectively removed
through the regeneration process.

a)
b)
100
100
80
60
40
20
0
4° cycle
3° cycle
80
60
40
20
0
2° cycle
1° cycle
As-synthesized
1° Cycle
2° Cycle
3° Cycle
4° Cycle
5
10
15
20
25
30
35
40
45
50
2 (°)
Figure 10. (a) Catalytic activity of Cu-MOF-74 catalyst after several reaction cycles.
Normal columns indicate 4-IT conversion; fill columns indicate 4-MPAC product yield.
(b) XRD patterns of Cu-MOF-74 catalyst after several reaction cycles.
4. Conclusions
The activity of Cu-MOF-74 and the influence of different critical variables on the
performance of C-arylation of 4-IT and AcAc has been proven. This C-arylation reaction
only proceeds in the presence of Cu-MOF-74 heterogeneous catalyst, discarding copper
leaching from the MOF structure. The increase of temperature promoted a higher 4-
MPAC yield and the solvent polarity played an important role in the catalytic performance
of Cu-MOF-74. The optimal conditions using this catalyst were 4-IT:AcAc ratio of 1:2,
DMF as solvent and Cs2CO3 base. A catalyst concentration of 5 mol % allowed a high 4-
iodotoluene conversion (ca. 90%) with a 4-methylphenylacetone product yield of 83%
after 6 hours of reaction at 140 °C. The catalytic activity of Cu-MOF-74 was higher than
those shown by homogeneous (CuCl and Cu(NO3)2) and heterogeneous (CuO, URJC-
1HKUST-1) Cu-based catalysts in terms of 4-IT conversion and 4-MPAC product yield.
Finally, the catalyst was stable and reusable during several reaction cycles. This work

evidences the enormous potential of MOF materials as heterogeneous catalysts for many
applications, particularly in fine chemistry.
ACKNOWLEDMENTS
The authors wish to thank Spanish Ministry of Science and Innovation for the financial
support to the CICYT Projects (CTQ2015-64526-P and PGC2018-099296-B-I00).
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