Enhanced Catalytic Properties of Carbon supported Zirconia and Sulfated Zirconia for the Green Synthesis of Benzodiazepines

Article abstract of DOI:10.1002/cctc.201801274

This work reports for the first time a new series of promising porous catalytic carbon materials, functionalized with Lewis and Br?nsted acid sites useful in the green synthesis of 2,3-dihydro-1H-1,5-benzodiazepine – nitrogen heterocyclic compounds. Benzodiazepines and derivatives are fine chemicals exhibiting interesting therapeutic properties. Carbon materials have been barely investigated in the synthesis of this type of compounds. Two commercial carbon materials were selected exhibiting different textural properties: i) Norit RX3 (N) as microporous sample and ii) mesoporous xerogel (X), both used as supports of ZrO₂ (Zr) and ZrO₂/SO₄^2? (SZr). The supported SZr led to higher conversion values and selectivities to the target benzodiazepine. Both chemical and textural properties influenced significantly the catalytic performance. Particularly relevant are the results concerning the non-sulfated samples, NZr and XZr, that were able to catalyze the reaction leading to the target benzodiazepine with high selectivity (up to 80 %; 2 h). These results indicated an important role of the carbon own surface functional groups, avoiding the use of H₂SO₄. Even very low amounts of SZr supported on carbon reveal high activity and selectivity. Therefore, the carbon materials herein reported can be considered an efficient and sustainable alternative bifunctional catalysts for the benzodiazepine synthesis.

Full text of DOI:10.1002/cctc.201801274

Accepted Article
Title: Enhanced catalytic properties of carbons supported zirconia
(Zr) and sulfated zirconia (SZr) in the green synthesis of
benzodiazepines
Authors: Marina Godino-Ojer, Leticia Milla-Diez, Ines Matos, Carlos J.
Durán-Valle, Maria Bernardo, Isabel M. Fonseca, and Elena
Perez-Mayoral
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the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
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To be cited as: ChemCatChem 10.1002/cctc.201801274
Link to VoR: http://dx.doi.org/10.1002/cctc.201801274
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ChemCatChem
10.1002/cctc.201801274
FULL PAPER
Enhanced catalytic properties of carbons supported zirconia (Zr)
and sulfated zirconia (SZr) in the green synthesis of
benzodiazepines
[
a]
[a]
[b]
[c]
[b]
[b]
M. Godino-Ojer, L. Milla-Diez, I. Matos, C. J. Durán-Valle, M. Bernardo, I. M. Fonseca* and E.
[
a]
Pérez Mayoral*
Abstract: This work reports for the first time a new series of
promising porous catalytic carbon materials, functionalized with
Lewis and Brönsted acid sites useful in the green synthesis of 2,3-
dihydro-1H-1,5-benzodiazepine - nitrogen heterocyclic compounds.
Benzodiazepines and derivatives are fine chemicals exhibiting
interesting therapeutic properties. Carbon materials have been
barely investigated in the synthesis of this type of compounds.
Two commercial carbon materials were selected exhibiting different
textural properties: i) Norit RX3 (N) as microporous sample and ii)
in acid or basic media, low corrosion capability, hydrophobic
character, easy recovery from the reaction mixture and also their
biocompatibility, which make them excellent candidates as
supports of choice for catalytic purposes. Interestingly, the
chemical surface and textural properties of carbon materials are
important issues in catalysis, since catalytic activity is depending
on the nature and concentration of active sites distributed over
the carbon surface as well as the porosity and pore size
distribution. The hydrophobicity provided by the carbon materials
often comprises the appropriate environment for catalyzing
some interesting organic transformations. In this sense, we
suspect and recently demonstrated, by using computational
methods, the involvement of the carbon surface, through -
stacking interactions with reagents containing benzene rings, for
the synthesis of relevant nitrogen heterocycles via the
2
mesoporous xerogel (X), both used as supports of ZrO (Zr) and
2-
4
ZrO
2
/SO
(SZr).
The supported SZr led to higher conversion values and selectivities
to the target benzodiazepine. Both chemical and textural properties
influenced significantly the catalytic performance.
Particularly relevant are the results concerning the non-sulfated
samples, NZr and XZr, that were able to catalyse the reaction
leading to the target benzodiazepine with high selectivity (up to 80%;
2h). These results indicated an important role of the carbon own
surface functional groups, avoiding the use of H SO . Even very low
2
4
[2-4]
Friedländer reaction.
amounts of SZr supported on carbon reveal high activity and
selectivity. Therefore, the carbon materials herein reported can be
considered as efficient and sustainable alternative bifunctional
catalysts for the benzodiazepine synthesis.
Carbon-supported metal catalysts have been extensively
explored in the synthesis of valuable products, some of them
[
5]
exhibiting relevant pharmacological properties. Very recently
the authors have published for the first time different
nanocarbons consisting of carbon aerogels doped with zero-
valent transition metals efficiently catalyzing the synthesis of
[6,7]
quinolines and related compounds.
Introduction
In continuation with ongoing investigations the authors seek to
develop new series of bifunctional carbon catalysts incorporating
Lewis or/and Brönsted acid sites by modifying the carbon
surface with zirconia (Zr) or sulfated zirconia (SZr) able to
catalyze the formation of benzodiazepines. SZr and its modified
Carbons are considered low cost materials able to act as
catalysts or even as supports of active sites meeting the
specifications for much more green and sustainable chemical
[1]
synthesis.
Carbon-based
materials
show
unique
[8]
forms are recognized as highly acid catalysts, even stronger
characteristics, among them high thermal and chemical stability,
[9]
than traditional H-zeolites, frequently explored in the synthesis
of a huge number of interesting organic transformations some
[
10,11]
of them with industrial applications.
[
[
a]
b]
Ms L. Milla-Díez, Dr. M. Godino-Ojer, Dr. E. Pérez-Mayoral
Departamento de Química Inorgánica y Química Técnica
Universidad Nacional de Educación a Distancia, UNED
Paseo Senda del Rey 9, Facultad de Ciencias
Benzodiazepines are considered as relevant nitrogen
heterocyclic systems and their importance is related to diverse
pharmacological
activities:
anti-inflammatory,
antiviral,
28040-Madrid (Spain)
analgesic, anti-microbial, sedative, hypnotic, anti-depressive,
anti-tumor, anti-HIV, and also effective on cardiovascular
E-mail: eperez@ccia.uned.es
Dr. I. Matos, Dr. M. Bernardo, Dr. I. Fonseca
LAQV/REQUIMTE, Departamento de Química,
Faculdade de Ciências e Tecnologia
Universidade Nova de Lisboa
[12]
disorders etc.
Different homogeneous catalysts, mainly
consisting of metal transition salts, and also heterogeneous
ones, operating under a great variety of reaction conditions
have been applied in the synthesis of benzodiazepines from o-
2829-516 Caparica (Portugal)
[
c]
Dr. C. Duran-Valle
[
13]
Departamento de Química Orgánica e Inorgánica
Universidad de Extremadura
Avda de Elvas, s/n
phenylendiamine and ketones
Among the most important
heterogeneous catalytic systems, it can be cited: zeolites, Al-
[14]
[15]
MCM-41 and Cu(BDC),
H-MCM-22,
SiO
2
[21]
supporting
E-06006 Badajoz (Spain)
[16]
[17]
[18-20]
H
2
SO
4
and HClO
4
,
clays
and even SZ.
Supporting information for this article is given via a link at the end of
the document.
The goal of this paper is, therefore, to perform a comparative
study of Zr and SZr catalytic properties with those found for
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ChemCatChem
10.1002/cctc.201801274
FULL PAPER
supported carbon with Zr and SZr. It is reasonable to assume
that the combination of porous structure of different carbon
supports with the highly acidic character of SZr could make
these solids interesting catalysts for the green synthesis of 2,3-
dihydro-1H-1,5-benzodiazepines as an important type of
bioactive compounds. Although Zr, particularly its modified form
SZr, has been extensively used in industrial reactions, only a
few examples of Zr and SZr supported on carbons have been
recently reported.
All samples derived from Norit-RX3 are mainly microporous
samples (pore radius, R < 10 Å), barely showing mesopores in
the range of 10 to 250 Å pore radius. Thus, the N adsorption-
2
desorption isotherms shape are of type I, exhibiting a H4 type
hysteresis loop, typical of micro-mesoporous materials. In
general, the surface area and pore volume dramatically
decrease by the presence of Zr, as expected. However, the pore
radius mode calculated by DA method notably increases with
the presence of Zr. This feature can be attributed to blockage of
the narrowest pores (micropores) by Zr. Thus, the remaining
micropores are those with higher width.
Zr and SZr showed a lower SBET, with similar micro- and
macroporous volume. SZr did not show the presence of
Results and Discussion
mesopores. The N
2
adsorption–desorption isotherms of the
Synthesis and characterization of the supported Zr
xerogel type carbons also reveal the mesoporous nature of
these materials presenting a type IV isotherm with a type H3
hysteresis loop, typical of materials with mesoporosity. The
introduction of Zr strongly influenced the textural parameters
with a sharp decrease of surface area and porous volume
indicating the possible blockage of pores. The Eads (Table 1)
values, obtained from DR method, for each type of carbon (N or
X), followed an inverse trend with microporous radius. Therefore,
the narrow pores can lead to adsorption on both sides of the
pore, increasing adsorption energy.
catalysts. Firstly, the Zr and SZr control samples were prepared.
Zr was synthetized from ZrCl
4
by treatment with aqueous
ammonia solution according to the experimental procedure
[
22]
reported by Scurrell,
H SO .
2 4
which was subsequently sulfated using
[23]
The synthesis of carbon supported Zr and SZr
samples was achieved by adapting this experimental protocol
but in the presence of the corresponding carbon material. The
carbon supports of our choice were two commercial activated
carbons, Norit-RX3(N) and a pure carbon xerogel (X). The
obtained carbon supported Zr samples were finally sulfated
Figure 1 depicts the macropore size distribution obtained by Hg
porosimetry for Norit-based materials. In general, the supported
NZr produces a decrease of mesopore volume, Vmeso, but also
an increase of macropore volume, Vmacro due to the oxide
2 4
using two different concentrated H SO solutions. Thus, two
series of supported carbons were obtained, denoted as NZr and
XZr and the corresponding sulfated samples as NZr-S1, NZr-S2
and XZr-S1, XZr-S2 where N and X are Norit-RX3 and xerogel,
structure. In contrast, treatment of NZr with concentrated H
solution leading to NZr-S1 sample, originated an increase of
meso and a decrease of Vmacro. This circumstance is probably
due to the partial solubilization of Zr in the reaction medium. In
the case of NZr-S2 sample, it was observed an increase in
macroporosity and almost a total disappearance of mesoporosity
2 4
SO
respectively, Zr is zirconia and S stand for the used H
solutions, concentrated (S1) and diluted (S2).
2 4
SO
V
The surface and bulk properties of the catalysts were studied by
adsorption-desorption, mercury porosimetry, elemental
N
2
analysis, WDXRF, XPS, thermogravimetry, XRD and SEM-EDS.
The textural parameters of the investigated carbon materials
changed significantly after modification of the carbon support
(
Table 1). Regarding the xerogel materials, it can be observed a
small decrease on the surface area and on the micro- and
mesopore volumes in the supported carbons.
(
Table 1).
Table 1. Textural parameters obtained from N
2
adsorption-desorption isotherms and Hg Porosimetry for carbon materials and Zr-supported carbon materials.
[
a]
[b]
[b]
[c]
micro DR
[c]
[c]
ads
[d]
micro DA
[d]
moda
[e]
[e]
-1
Sample
S
BET
S
DFT
2
V
p
V
R
E
V
R
V
meso
V
macro
2
-1
-1
3
-1
3
-1
-1
3 -1
3
-1
3
(
m g )
(m g )
(cm g )
(cm g )
(nm)
(kJmol )
(cm g )
(nm)
(cm g )
(cm g )
3
48
11
234
0.33
0.14
0.94
13.85
0.19
0.83
0.15
0.47
Zr
3
232
0.28
0.13
0.86
15.02
0.17
0.79
0.00
0.54
SZr
N-RX3
NZr
1587
888
1247
952
595
555
445
1288
707
984
737
492
460
367
0.73
0.44
0.56
0.46
0.47
0.39
0.35
0.72
0.35
0.54
0.41
0.24
0.22
0.17
1.1
11.96
18.25
14.83
14.63
26.04
25.07
24.18
0.80
0.44
0.57
0.47
0.24
0.19
0.18
0.23
0.71
0.75
0.73
1.37
1.36
1.40
0.10
0.04
0.11
0.00
0.24
0.21
0.18
0.46
1.76
0.51
1.15
0.02
0.08
0.06
0.71
0.87
0.89
1.40
1.41
1.42
NZr-S1
NZr-S2
X
XZr-S1
XZr-S2
[
a] SBET = Apparent surface area (BET method). [b] SDFT = Surface area (Density functional theory, DFT, method), Vp = pore volume (DFT method), [c] Vmicro DR
=
micropore volume (Dubinin-Radushkevich, DR, method), R = micropore radius (DR method), Eads = N adsorption energy into micropores (DR method). [d] Vmicro
2
DA = micropore volume (Dubinin-Astakhov, DA, method), Rmoda = micropore radius(DA method) [e] Vmeso , Vmacro = meso -macropore volume, by Hg porosimetry
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ChemCatChem
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FULL PAPER
Table 2. Composition (expressed on wt%) of the Zr-supported Norit-RX3 carbon materials.
[
a]
[a]
[a]
[a]
[a]
[a]
[b]
[b]
[b]
[b]
[b]
[c]
[c]
[d]
Sample
C 1s
O 1s
N 1s
Si 2p
Zr 3d
S 2p
C
H
N
S
O
Zr
S
Zr
NZr
46.71
82.68
43.12
15.47
10.60
18.60
0.35
0.65
0.22
1.09
3.28
0.00
34.90
1.56
0.00
0.82
2.17
81.62
71.97
74.03
2.54
3.03
3.75
0.71
0.47
0.49
0.40
0.84
2.27
14.73
23.69
19.47
25.61
1.11
0.37
1.04
1.00
n.d.
0.68
NZr-S1
NZr-S2
35.89
22.34
24.80
Determined by [a] XPS [b] elemental analysis, ash free basis [c]WDXRF [d] ICP-AES; n.d. – not determined
NZr and NZr-S2. NZr-S1 sample presented a considerable lower
amount of Zr, which means that the treatment of NZr with diluted
Norit-RX3
NZr
NZr-S1
NZr-S2
2
1
1
0
0
,0
,5
,0
,5
,0
2 4
H SO solution is the most efficient method to maximize sulfated
Zr over the carbon surface. The use of concentrated acid
promoted the leaching of the Zr, thus remaining only a small
amount, probably located inside the pores. Similar results were
observed for the xerogel type carbons. The samples with higher
pores volumes retained higher amounts of zirconium. In fact,
XPS analysis was unable to detect any zirconium in the surface
of sample XZr-S1 (Table 3), confirming that the remaining
0
,00
0,01
0,10
1,00
10,00
100,00 1 000,00
Pore width (mm)
2 4
zirconium after H SO treatment is located inside the pores. The
0
0
0
0
0
0
,25
XPS analysis of XZr-S2 xerogel sample did not detect as much
Zr as seen by WDXRF, probably due to sample heterogeneity.
However, values determined by ICP were closer to the ones
detected by XPS.
,20
,15
,10
,05
,00
NZr
NZr-S1
NZr-S2
NZr
NZr-S1
NZr-S2
5000
4000
3000
2000
1000
0
500
400
300
200
100
0
0
,00
0,10
10,00
1 000,00
Pore width (mm)
2
00 195 190 185 180 175 170
155
160
165
B.E (eV)
170
175
180
B.E. (eV)
Figure 1. Macropore size distribution obtained by Hg porosimetry for Norit-
RX3, NZr, NZr-S1 and NZr-S2 samples.
Figure 2. XPS spectra of Zr 3d (left) and S 2p (right) binding for the NZr and
NZr-S catalysts.
In order to determine the chemical composition, the samples
were characterized by elemental analysis, WDXRF and XPS. In
the case of samples prepared from Norit-RX3, it can be
observed from Table 2 that the S content was notably increased
for those submitted to the acid treatment. The sulfur groups are
preferentially bound to the Zr surface being higher for the
sample NZr-S2, as expected. The increased H% loading from
NZr to NZr-S2 may also indicate the small size of graphene
sheets especially for the NZr-S2. In the same context, the
WDXRF analysis demonstrated that the NZr and NZr-S2
samples showed high Zr loadings. The acid treatment using
The presence of S and O was also detected for samples NZr-S1
and NZr-S2, although in different %. Obviously, the samples
containing Zr showed higher O% due to the presence of ZrO
2
over the carbon surface but also to the oxygenated functional
groups generated by the acid treatment (Table 2). Surface
analyses of Zr3d and S2p over the catalysts are shown in Figure
2
. XPS spectra for the N-Zr and NZr-S samples showed the
presence of the typical doublet with binding energies (BE) of
83.68 (Zr3d5/2) and 185.7 eV (3d3/2) indicating the presence of
1
Zr, also observed for NZr-S1 although at lower BE probably
because of small amount of Zr supported over the carbon
surface. XPS spectra of S2p binding of NZr-S1 and NZr-S2
samples demonstrated the presence of sulfur. Small differences
in BE values were observed which could be attributed to the
presence of sulfate groups in Zirconia for NZr-S2 sample and of
diluted H
2 4
SO solution have barely influenced the Zr content 
25.61 and 22.34 expressed in wt. % for NZr and NZr-S2,
respectively . However, the NZr-S1 sample just showed 1.11%
of Zr loading. The same behavior was observed for the xerogel
carbons. Even though the amount of Zr in samples XZr (10.2
wt%) and XZr-S2 (7.6 wt%) is very high, after treatment with
concentrated acid, XZr-S1 presents a very low content of
zirconium (0.3 wt%). Due to the higher microporosity of the Norit
based samples, NZr-S1 was able to retain in its structure a
higher amount of SZr compared to sample XZr-S1 (Table 3).
Complementarily, the surface composition of the Norit based
samples was also analyzed by XPS (Table 2 and Figure 2). And
it was confirmed the higher loadings of zirconium for samples
3
–SO H functions anchored on the carbon surface for NZr-S1
catalyst.
All these results are in good agreement with the textural
properties of these materials which are strongly affected by the
presence of Zr. It is important to note that samples NZr and NZr-
S2 present similar textural properties. For the xerogel carbon,
the sample XZrS1 almost recovered the surface area of the
parent carbon.
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ChemCatChem
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FULL PAPER
Table 3. Composition (expressed on wt%) of the Zr-supported xerogel carbon materials.
[
a]
[a]
[a]
[b]
[b]
[b]
[b]
[b]
[c]
[c]
[d]
Sample
XZr-S1
XZr-S2
C 1s
O 1s
Zr 3d
C
H
N
S
O
Zr
S
Zr
89.10
80.40
10.90
13.64
n.d.
86.47
62.17
1.65
1.27
0.09
0.12
0.19
0.81
11.79
35.63
0.90
0.01
1.08
0.33
7.60
5.97
39.72
Determined by [a] XPS [b] elemental analysis [c] WDXRF [d] ICP; n.d. – not detected
Scheme 1. Synthesis of benzodiazepine 1 from o-phenylendiamine 2 and acetone 3 at 50 °C.
The samples were also characterized by XRD (Figure 3). The
XRD patterns confirmed the low crystallinity of ZrO when
compared to SZr. Sample SZr was submitted to thermal
treatment and its mainly composed by tetragonal SZr. The
Norit carbon has a more sponge like appearance with clear
surface porosity, while the xerogel carbon appears as cleaner
surface with sharp edges. The SEM images of the samples with
higher amount of Zr (XZr-S2 and NZr-S2) clearly show a
heterogeneous distribution of the Zr, indicating that these
catalysts are in fact a composite of carbon and zirconia. The
excess amount of zirconium source used in the synthesis
2
2
amorphous ZrO was also observed in XZr-S2 sample whereas
XZr-S1 showed the absence of diffraction lines corresponding to
Zr. These results are in good agreement with those above
mentioned.
2
allowed not only the introduction of ZrO inside the pores, but
also its precipitation on the external surface and in the
surroundings of the carbon. Several EDS scans in different
areas of the sample, confirmed the presence of carbon and of Zr
throughout the samples. Even in samples NZr-S1 and XZr-S1
with lower amount of Zr, the EDS analysis over a carbon particle
detected the presence of zirconium confirming the incorporation
inside the material (complementary material, fig 1). The
2 4
treatment with concentrated H SO removed all the outer Zr
species of the sample, leaving only a small amount of SZr inside
the pores of the carbon, as detected by EDS. These results are
in agreement with the drastic changes observed in the textural
properties and composition of the different carbons.
Figure 5 shows NH
Since the treatment of the catalyst NZr with sulfuric acid can
also modify the support, the NH -TPD profile of the carbon
3
-TPD profiles of NZr and NZr-S2 samples.
3
support when treated with sulfuric acid is also presented, N-S.
The results evidence the presence of different strength acid sites
in the catalysts due to the modifications performed. The carbon
support only presents weaker acid sites (dash line) responsible
for the peaks at lower temperature, up to 350 ºC. The presence
of zirconium oxide corresponded to an intensification of groups
of medium strength (marked with *). The catalysts NZr-S2
presents new stronger acid sites (500-650 ºC) as a result of the
sulfated zirconia.
Figure 3. XRD patterns for Zr, SZr, XZr-S1 and XZr-S2 samples.
Figure 4 presents the SEM images of SZr supported in carbons.
The two carbons present a clear difference in morphology. The
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ChemCatChem
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FULL PAPER
XZr-S1
XZr-S2
NZr-S1
NZr-S2
Figure 4. SEM Images of samples NZr-S1, NZr-S2, XZr-S1 and XZr-S2
NZr-S2
NZr
N-S
However, we surprisingly observed some interesting findings
2
,5
1
(
Figure 6). The reaction in the presence of both Zr and SZr
1
0
catalysts, at 50 °C, using similar catalyst amount than that
supported on carbon surface, produced high conversion values
after only 15 min of reaction time (up to 70%). An analysis of the
*
#
1
H NMR spectra of the crude, when the reaction was achieved in
,5
0
the presence of Zr, demonstrated the almost exclusive presence
of a new product whose structure was assigned to compound 4b
by the presence of two signals in the aromatic region, at  6.41
and 6.24 ppm as multiplets, and a singlet at 1.49 ppm
corresponding to methyl groups. Interestingly intermediate
1
00
200
300
400
500
600
Temperature (ºC)
[
20]
Figure 5. NH
3
-TPD profiles of Norit carbon catalysts.
compound 4a was not detected.
Remarkably, only after 120 min of reaction time, the formation of
the benzodiazepine 1 in almost 3% of yield was observed. This
intermediate compound was also observed when the reaction
was carried out in the presence of SZr. The selectivity to
compound 1 increased with the reaction time. These results
strongly suggest that the first step of the reaction consisting of
imination reaction between reagents followed by formation of
compound 4b, is mainly catalyzed by Lewis acid sites. Whereas
the second imination and subsequent electrocyclization are
probably promoted by Brönsted acid sites functions that can also
Table 4 summarises the amount obtained for the different
strength acid sites by deconvolution of the TPD profiles.
Table 4. Deconvolution peaks of NH
3
-TPD profiles
150-250 ºC 250-350 ºC
350-500 ºC
500-650 ºC
Sample
N-S
NZr
mmolNH3 adsorved / gCat
0.028
0.102
0.027
0.257
0.348
0.094
0.327
0.238
0.864
-
0.133
0.519
NZr-S2
.
[25]
be present in the SZr sample
Catalytic performance. The catalysts were tested in the
synthesis of benzodiazepines 1 from o-phenylendiamine 2 and
acetone 3 at 50 °C (Scheme 1). Initially, the reaction was carried
out in the presence of non-supported Zr and SZr, as already
On the other hand, we also investigated the catalytic behavior of
the commercial sample Norit-RX3, leading to 55% of conversion
with increased selectivity values to 1 (85%) after 1h of reaction
time.
[
21, 24]
reported by Reddy and col.
The authors prepared, isolated
Having these results in mind, the authors think that the
combination of porous structure of the different carbon supports
together with the high acid character of SZr, could make these
and purified by column chromatography on silica gel several
benzodiazepines from o-phenylendiamine
2 and different
substituted ketones, under ambient conditions.
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ChemCatChem
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FULL PAPER
solids interesting catalysts for the green synthesis of 2,3-
dihydro-1H-1,5-benzodiazepines. Although SZr has been
extensively used in different organic transformations, as far as
we know, only a few examples of carbon supported Zr and SZr
allowing the involvement of the carbon in the process. On the
other side, the NZr-S1 catalyst is mainly a microporous sample
exhibiting high surface area, in contrast to NZr-S2 sample
showing lower Vmicro and higher Vmacro
influencing the reaction selectivity.
, both parameters
[
26-28]
have been recently reported.
Among them Zr-supported on
carbon nanotubes has been reported for the ketonization of
Remarkably the formation of benzodiazepine 1, with selectivities
up to 40% (15 min) becoming 80 and almost 90%, during
prolonged reaction times, even in the presence of NZr was
observed. This suggests that the Bronsted acid sites present in
the carbon surface are the ones involved in the second step of
the reaction. This result is especially relevant since allows the
eco-friendly synthesis of benzodiazepines avoiding the use of
H SO
Therefore, since these SZr-supported catalysts contain two or
more catalytic active sites involved in cascade reactions, the
carbon materials herein reported can be considered as
bifunctional or multifunctional carbon-based catalysts able to
efficiently catalyze the synthesis of benzodiazepines.
[29]
acetic acid. In this sense, we tested the carbon supported Zr
and SZr in the reaction under study. As can be observed from
Figure 7, conversion values of 2 were up to 80%, after the first
15 min of reaction time, when operating in the presence of the N
catalysts.
These results are particularly relevant if analyzing the
selectivities to benzodiazepine 1. It was observed that the best
selectivities to 1 were obtained in the presence of NZr-S1 and
NZr-S2 samples, as expected. The presence of Zr, -SO H
3
functions and carbon support, all of them probably involved in
2
4.
the catalytic reaction, improved significantly the selectivity to 1.
Zr-S
Zr
In order to explore the influence of the textural properties of the
catalysts in the reaction, we also investigated the catalytic
behavior of the analogous catalysts based on commercial
carbon xerogel. In Figure 7, it is shown the conversion values of
reagent 2 in the presence of XZr, and also XZr-S1 and XZr-S2.
The conversion values decreased from XZr to XZr-S2 while the
selectivity to product 1 follows the inverse trend.
Comparing N and X samples, conversion and selectivity values
were maintained in the presence of both supported Zr samples.
However, when using carbon supported Zr and SZr catalysts the
composition and porosity notably affected the catalytic
performance. In the case of using NZr-S catalysts, the
oxygenated functions over the carbon surface and the highest
1
00
80
60
40
20
0
0
30
60
Zr-S Zr
90
120
1
00
V
micro and SBET in NZr-S1 favored the reaction and increased the
8
6
4
2
0
0
0
0
0
selectivity to product 1, probably due to a confinement effect. In
contrast, among XZr-S samples, XZr-S2 catalyst with higher
loading of SZr exhibited lower conversion values but the best
selectivity to 1, probably due to lower porosity in comparison
with XZr-S1 sample.
Additionally, in order to explore the stability of the catalysts in
the reaction medium, the reaction under study was carried out in
the presence of XZr-S1 which was subsequently removed from
the reaction mixture after 15 min of reaction time. It was
observed that total conversion values vs time were maintained in
comparison to those for reaction in the presence of XZr-S1
catalyst. However, selectivity to benzodiazepine 1 decreased
whereas selectivity to 4b increased from 43 to 60 % after 2h of
reaction time, traces of intermediate compounds 4a and 5 were
also detected (Scheme 1). These results strongly suggest that
no leaching of the catalytic species occurred and the observed
reactivity can be attributed to the reaction in absence of any
catalyst. It is noteworthy that the blank experiment under the
same experimental conditions gave 34% of total conversion and
selectivity to 1 of 5%, during 2h of reaction time.
1
5
30
60
120
Time (min)
Figure 6. Synthesis of benzodiazepine 1 from o-phenylendiamine 2 and
acetone 3, at 50 °C, catalysed by Zr or SZr.
Thus, the benzodiazepine 1 was obtained with 80% of selectivity
in only 30 min of reaction time in the presence of NZr-S1
catalyst. Whereas the reaction catalyzed by NZr-S2 sample led
to compound 1, with selectivity slightly lower. It is important to
note that the benzodiazepine
quantitative yields in the presence of both catalysts after 2 or 3h
of reaction time.
The selectivity and activity differences of the catalysts can thus
be attributed to their different chemical composition and textural
properties. NZr-S1 sample showed lower Zr and S contents but
also comprising higher carbon porous surface, whereas NZr-S2
consists of higher Zr and S loadings (Table 2).
1 was obtained in almost
These results strongly suggest that there is an optimum
concentration of SZr able to efficiently catalyze the reaction
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FULL PAPER
NZr
NZr-S1
NZr-S2
N-Zr
NZr-S1
NZr-S2
1
00
100
80
60
40
20
0
8
6
4
2
0
0
0
0
0
0
30
60
XZr
90
120
150
180
15
30
60
120
180
XZrS1
XZr-S2
XZr
XZr-S1
XZr-S2
1
00
100
80
60
40
20
0
80
60
40
20
0
0
30
60
90
120
150
180
1
5
30
60
Time (min)
120
180
Time (min)
from o-phenylendiamine
Figure 7. Synthesis of benzodiazepine
1
2
and acetone 3, at 50 ºC, catalyzed by Zr or SZr-supported carbons.
Table 5. Catalytic performance of the previously reported catalysts in the
Finally, the reaction was explored using other different carbonyl
synthesis of benzodiazepine 1
components such as cyclohexanone 6a and ethyl acetoacetate
Reaction
conditions
Time
(h)
2
Conversion
6b in the presence of XZr-S1 (Scheme 2).
Catalyst
[a]
Ref.
(%)
42
93
1
mmol / 2 mmol /
00 mg, 323 K
HY
14
1
4
Al-MCM-41
Cu(BDC)
6
6
69
48
14
14
1
3
5
40
60
90
2
mmol / 56 mmol /
00 mg, 329 K
Bentonite
K-10 Mont
18
1
1
.0 mmol / 2.5 mmol
300 mg, rt
1.0 mmol / 2.2 mmol
50mg, rt
mmol / 2.5 mmol in
6
5
89
77
19a
19b
/
2+
Zn -Mont
/
1
H-MCM-42
acetonitrile / 100 mg,
rt
1
87
15
Scheme 2. Synthesis of benzodiazepine 7 from o-phenylendiamine 2 and
other carbonyl compounds 6 catalyzed by XZrS1, at 50 °C, under solvent-free
conditions.
1
mmol / 2.5 mmol /
0 mg, rt
HClO
4
-SiO
2
1
92
97
17
21
5
2−
4
SO
/ZrO
2
No details, rt
2-3
1
mmol / 10 mmol /
1 (30
min)
96 (93,
S=80)
This
work
NZr-S1
Thus, when using 6a it was observed the exclusive formation of
the corresponding benzodiazepine 7 in 76%, after 3h of reaction
time, as unique reaction product, and in good agreement with
data previously reported using other catalytic systems (Figure 8)
100mg, 323 K
[
a] o-Phenylendiamine / acetone / Catalyst. S = selectivity.
Table
5 shows some heterogeneous catalysts, reaction
[
14]
conditions and catalytic performances reported in the literature
for the synthesis of benzodiazepine 1. It can be observed that
when using the methodology described in this work it is possible
to obtain a conversion value of 93% with high selectivity to
benzodiazepine 1, in only 30 min of reaction time, under solvent-
free conditions.
; in this case, the lower conversion values are attributed to the
steric hindrance of the corresponding carbonyl compound
regarding to acetone 3. On the other hand, the reaction in the
presence of ethyl acetoacetate 6b led to the total transformation
of o-phenylendiamine 2 yielding a mixture of the intermediate 8,
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ChemCatChem
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resulting of the imination reaction between reagents and
subsequent tautomerization, and of
solutions. It is also confirmed the involvement of the carbon
support in the reaction under study. In this sense, the
combination of porous structure of carbon supports together with
the acid character of supported Zr or SZr allows a much more
sustainable synthesis of benzodiazepine 1, affording high
activity and selectivity while using an environmentally friendly
catalyst. These new catalysts are even much more efficient than
2-methylbenzoimidazole 9 (compounds 8/9 ratio = 77:23 after
15 min of reaction time), instead of the corresponding
benzodiazepine. At this regard, Figure 8 depicts the evolution of
the reaction in which compound 8 is transformed into 9. These
results are in accordance with those previously reported where
the authors described the synthesis of 2-methylbenzoimidazole
from o-phenylendiamine 2 and ethyl acetoacetate 6b upon
[
9].
zeolites or mesoporous silica catalysts
One of the most relevant results is the high catalytic
performance of carbons with low Zr loading, confirming the
combination of material properties between carbon and Zr.
In summary, the Zr and SZr-supported carbon catalysts herein
reported were found to be multifunctional carbon-based
catalysts involved in the synthesis of benzodiazepines. The
observed reactivity opens the doors to explore other interesting
cascade reactions for the synthesis of relevant heterocyclic
systems.
[
30]
microwave irradiation in water
salts at 85 °C.
or promoted by ammonium
[
31]
7
9
1
00
80
60
40
20
0
Experimental Section
The selected carbon materials were two commercial carbons, i) Norit
RX3 (NORIT Nederland B.V.) and ii) mesoporous carbon (Xerolutions
S.L.). All reagents and solvents were purchased from Sigma-Aldrich.
0
30
60
90
120
150
180
Time (min)
1.
Synthesis of catalysts
Figure 8. Synthesis of benzodiazepine 7 from o-phenylendiamine (2) and
cyclohexanone (6a) (blue) and 2-methylbenzimidazole (9) from o-
phenylendiamine (2) and ethyl acetoacetate (6b) (green) catalyzed by XZrS1,
at 50 °C, under solvent-free conditions.
4
1.1. Synthesis of Zr and SZr. A solution of ZrCl (1 g) in of water (10
mL) was treated with ammonia until pH = 10. The solid was then filtered,
washed with abundant water and dried at 110 ºC. SZr was prepared from
2 4
Zr (1 g) and H SO 0.5M (15 mL) and the mixture was stirred, at room
temperature, during 30 min. The solid was filtered, washed with abundant
water and calcined at 600 ºC during 4 h.
Conclusions
This work reports for the first time a new series of promising
porous catalytic carbon materials, functionalized with Lewis and
Brönsted acid centers, useful in the green synthesis of 2,3-
dihydro-1H-1,5-benzodiazepine from o-phenylendiamine and
ketones. Although SZr has been widely used in interesting
1
4
.2. Synthesis of Zr-supported carbons. To a solution of ZrCl (1 g) in
water (100 mL) the corresponding carbon material (1 g) was added and
the reaction mixture was stirred during 1 h. Subsequently the suspension
was treated with ammonia until pH = 10 and stirred during 1h. The solid
was then filtered, washed with abundant water and dried at 110 ºC.
organic transformations, only
a few examples of carbon
supported Zr and SZr have been recently reported. NZr, XZr and
the corresponding sulfated catalysts led to high conversions and
selectivity values to compound 1 in comparison with non-
supported Zr and SZr.
1
.3. Synthesis of SZr-supported carbons. Method A: A suspension of
the corresponding Zr-supported carbon was treated with commercial
[32]
H
2
SO
4
(98%) (15 mL)
and the reaction mixture was stirred during 90
min. The solid was then filtered, washed with abundant water and dried
Remarkably, our results demonstrated that while the non-
supported Zr sample catalyzes the first steps of the reaction,
comprising the monoimination reaction between reagents and
subsequent intramolecular cyclization, leading to the 2,3-
dihydrobenzimidazole 4b, the Brönsted acid sites in the non-
supported SZr promote the second imination and
electrocyclization reactions resulting in benzodiazepine 1.
However, the investigated reaction in the presence of Zr or SZr-
supported on carbon catalysts yielded the compound
benzodiazepine 1 with increased selectivity even at short
reaction times.
at 110 ºC during 12h. Method B: A suspension of the corresponding Zr-
2 4
supported carbon was treated with H SO 0.5 M (15 mL) and the reaction
mixture was stirred during 30 min. The solid was then filtered, washed
with abundant water and dried at 110 ºC during 12h.
Then, two different series of carbon materials were prepared: i) NZr, NZr-
S1 and NZr-S2; ii) XZr, XZr-S1 and XZr-S2 where N = Norit-RX3, X =
2
-
xerogel, Zr = ZrO
2
, Zr-S1 = SO
4
/ZrO
2
synthetized by using the method
2-
A and Zr-S2 = SO /ZrO synthetized by using the method B.
4 2
An especially relevant result is the formation of product 1, with
good conversions and selectivity, in the presence of the
supported catalysts, NZr and XZr, avoiding the use of H SO
2 4
2
.
Characterization of the catalysts. The materials under study
were characterized by: a) N adsorption--desorption isotherms at 77K
2
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10.1002/cctc.201801274
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Keywords: zirconia and sulphated zirconia carbon catalysts •
multifunctional carbon catalysts • cascade reactions •
benzodiazepines
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FULL PAPER
This work reports a new series of
porous catalytic carbon materials,
functionalized with Lewis and
M. Godino-Ojer, L. Milla-Diez, I. Matos,
C. J. Durán-Valle, M. Bernardo, I. M.
Fonseca* and E. Pérez Mayoral*
Brönsted acid centers, active in the
green synthesis of 2,3-dihydro-1H-1,5-
benzodiazepine. The studies
demonstrated that both the carbon
porous structure and acid site types
are involved in the reaction. The
texture and composition of the
Page No. – Page No.
Enhanced catalytic properties of
carbons supported zirconia (Zr) and
sulfated zirconia (SZr) in the green
synthesis of benzodiazepines
investigated carbon materials strongly
influenced the catalytic performance.
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