Remarkable Acceleration of Benzimidazole Synthesis and Cyanosilylation Reactions in a Supramolecular Solid Catalyst

Article abstract of DOI:10.1002/cctc.201601407

A solid metal–organic catalyst with hydrophobic pockets and Lewis acid centers strongly accelerates the reaction rate for organic reactions. This is exemplified for the cyanosilylation of ketones and for the synthesis of benzimidazoles, for which very hig

Full text of DOI:10.1002/cctc.201601407

Accepted Article
Title: Remarkable Acceleration of Benzimidazoles Synthesis and
Cyanosilylation Reaction in a Supramolecular Solid Catalyst
Authors: Avelino Corma, PILAR GARCIA, and SERGIO ROJAS
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Remarkable Acceleration of Benzimidazoles Synthesis and
Cyanosilylation Reaction in a Supramolecular Solid Catalyst
Sergio Rojas-Buzo,[a] Pilar García-García,*[a] Avelino Corma*[a, b]
Dedication ((optional))
Abstract: A solid metal-organic catalyst with hydrophobic pockets
and Lewis acid centers strongly accelerates the reaction rate for
organic reactions. This is exemplified for the cyanosilylation of
ketones and for the synthesis of benzimidazoles in where very high
selectivities are obtained. The solid can be recovered and reused
and its behavior approaches to a functional enzyme mimic.
synthesis of spirooxiindoles products and asymmetric
organocatalytic Michael-type reactions. Key in the design of
that solid catalyst was the employment of the organic spacer
4-heptylbenzoic acid with only one carboxylate group that
interacts with the inorganic metallic nodes ([AlO6]), and also
contains one hydrocarbonated tail that structurally favor the
formation of lamellar and mesoscopic phases, while
additionally resulting in the formation of hydrophobic pockets
that probed crucial in the catalytic experiments. Here we
report the remarkable ability of Al-ITQ-HB for the rate
acceleration in the cyanosilylation reaction of ketones and
also for the selective synthesis of benzimidazole compounds,
while showing with this study that challenges a) to d) have
been met.
As part of our ongoing project devoted towards the development
of practical synthesis of molecules of interest in fine chemistry
under a clean and green reaction profile, we have explored the
possibility of synthesizing 2-substituted benzimidazoles by
means of our supramolecular catalytic approach.
The benzimidazole core is an important pharmacophore in
modern drug discovery. It is an integral part of various clinical
medicines.[10] Benzimidazole derivatives exhibit significant
activity in several therapeutic areas[11]. Additionally, they are
Introduction
Stabilization and activation of molecules in supramolecular cage
compounds is recently attracting considerable attention in the
Host-Guest chemistry.[1] The pursuit of catalysts mimicking
enzyme activity is a main goal for the sake of the development
of green and sustainable synthetic chemical procedures.
Scientists have identify the dual role of enzymes in promoting
reactions via active site performance together with many elusive
and cumulative non-covalent bond interactions, resulting in
excellent catalytic systems promoting the biochemical
transformations in aqueous systems and under very mild
reactions conditions. In this scenario, chemists have developed
several synthetic host-guest systems that copy these
remarkable properties such as cyclodextrins,[2] cucurbiturils,[3]
structural
subunits
of
many
functional
materials.
calixarenes,[4] carcerands,[5] zeolites[6] and self-assembled
Polybenzimidazoles[12] are
a
class of high-performance
7]
hosts.[1,
Far from the achievements already accomplished,
polymers which have been receiving increasing interest during
the last years due to their high potential in fuel-cell technology
and a number of other applications such as catalysis. Such
importance from pharmacological, industrial and synthetic points
of view has led to the development of several methods for the
preparation of benzimidazole derivatives.
several challenges remain such as a) the development and
engineering of larger and more sophisticated host structures that
can incorporate several reaction components, b) the utilization of
systems that provide selectivity levels approaching those
observed in natural enzymes,[8] c) the use of truly catalytic
systems wherein catalytic turnover is possible and is not
inhibited by product binding[8] and d) the possibility of a
supramolecular host catalysts that could be recycled and reused.
In this regard, we have recently developed a novel metal-
organic hybrid supramolecular material, Al-ITQ-HB,[9] that
exhibits excellent abilities in mimicking enzyme-type
catalysis.[9a] Namely, rate acceleration was demonstrated in
several reactions such as Knoevenagel condensation,
There are two general methods for the synthesis of 2-substituted
benzimidazoles. The traditional method involves the
condensation of o-phenylenediamines and carboxylic acids or
their derivatives (nitriles, imidates or orthoesters) under harsh
dehydration conditions.[13] These procedures often require strong
acidic conditions such as polyphosphoric acid or other mineral
acids[14] sometimes combined with high temperatures (i.e.
polyphosphoric acid, 180ºC) or the use of microwave irradiation.
Another way to prepare these targets, and probably the most
popular one, involves a two-step procedure with the dehydrative
Schiff’s base formation followed by oxidative cyclization in the
same pot, using o-diaminoarenes and aldehydes as starting
materials. The reported procedures for the latter protocol involve
a wide spectrum of reagents such as In(OTf)3,[15] Sc(OTf)3,[16]
Yb(OTf)3,[17] Sm(OTf)3,[18] WOx/ZrO2,[19] H2O2/HCl.[20] Various
[a]
[b]
S. Rojas-Buzo, Dra. P. García-García, Prof. A. Corma.
Instituto de Tecnología Química, UPV-CSIC, Universitat Politècnica
de València-Consejo Superior de Investigaciones Científicas.
Avenida de los Naranjos s/n 46022 Valencia, Spain.
E-mail: pgargar@itq.upv.es, acorma@itq.upv.es.
Prof. A. Corma
King Fahd University of Petroleum and Minerals, P. O. Box 989,
Dhahran 31261, Saudi Arabia
oxidative
reagents
such
as
nitrobenzene,[21]
1,4-
benzoquinone,[22]
DDQ,[23]
tetracyanoethylene,[24]
benzofuroxan,[25] MnO2,[26] Pb(OAc)4,[27] Oxone,[28] NaHSO3,[29]
I2,[30] sulfamic acid,[31] IBD,[32] H2O2/HCl[20] and Na2S2O5 have
[33]
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
been employed. However, many of these methods have some
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10.1002/cctc.201601407
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drawbacks such as air sensitive catalysts, the requirements of a
stoichiometric or excess amount of oxidants, low yields, high
reaction temperature, long reaction times, tedious work-up
procedures and the occurrence of several side-reactions.
Therefore, the search continues for a better catalyst for the
synthesis of benzimidazoles in terms of operational simplicity,
reusability, economic viability and greater selectivity.
phenylenediamine 1a were used in a 1:1 ratio along with Al-
ITQ-HB (30 mol% loading), and the transformation was
carried out in the presence of oxygen atmosphere (O2
balloon, i.e. 1 bar approximately).
Table 1. Synthesis of benzimidazole 4a using p-NO2-benzaldehyde and o-
phenylenediamine and molecular oxygen as green oxidant.[a]
.
In this paper, we report a practical, facile, and selective
synthesis
of
2-arylbenzimidazoles
starting
from
o-
phenylenediamines and aromatic aldehydes in ACN:H2O in the
presence of catalytic amounts of Al-ITQ-HB at ambient
temperature and with molecular oxygen as the sole “green”
oxidant.
Results and Discussion
Synthesis of benzimidazoles
Recently prepared in our group, Al-ITQ-HB is a metal-organic
hybrid material synthesized by the solvothermal reaction of
aluminum
chloride
and
p-heptylbenzoic
acid
in
dimethylformamide.[9a] The solid thus obtained and owing to the
specific organic linker utilized is formed by lamellar structural
subdomains with octahedral aluminum units (AlO6) separated by
the hydrocarbonated tails perpendicularly located to inorganic
nodes. Al-ITQ-HB presents a very weak Lewis acidity, as
observed by CO adsorption at low temperature (100 K)
monitored by FTIR spectroscopy. It also contains hydrophobic
pockets, as created by the hydrocarbonated tails. The pore-size
distribution is around 20-25 Å, showcasing the mesoscopic
nature of Al-ITQ-HB solid. Al-ITQ-HB has been applied as an
Entry
1
Additive (X mol%)
--
3a [b]
4a [b]
5a [b]
39
0
0
effective catalyst that enhances the rate of
a variety of
2
0
96
94
7
0
condensation reactions such as Knoevenagel condensation of
aromatic aldehydes with Meldrum’s acid and the synthesis of
spirooxiindol products as well as several enantioselective
organocatalytic Michel-type reactions.
Al-ITQ-HB (30)
3[c]
4
0
0
Al-ITQ-HB (6)
81
29
48
57
74
0
10
0
MIL-53 (Al) (30)
In a continuing effort to better understand the enzyme-like
behavior of the hybrid Al-ITQ-HB and explore its application as
catalyst for organic synthesis, we sought to investigate the ability
in the synthesis of 2-substituted benzimidazoles from o-
phenylenediamines and aldehydes (Table 1). This synthetic
procedure involves essentially two steps. Initially, Schiff’s base
3a is formed in a dehydration step. In the second step, imine 3a
cyclizes oxidatively to the product 4a. Selectivity becomes an
issue to consider in the procedure since 1,2-disubstituted
benzimidazole 5a could also be formed by reaction of 3a with
another molecule of the starting aldehyde 2a. Indeed, micellar
conditions have been successfully utilized for the construction of
benzimidazoles in the presence of sodium dodecyl sulfate (SDS)
as catalyst.[34] This mildly basic surface-active compound affords
predominantly 1,2-disubstituted benzimidazoles of type 5a.
Nonetheless, acidic surfactant, dodecylbenzenesulfonic acid
(DBSA) with the aid of the additional presence of I2,[35] is
reported to yield preferably 2-substituted benzimidazoles of type
4a.
5
56
43
41
0
4-heptylbenzoic acid (30)
4-heptylbenzoic acid (15)
4-heptylbenzoic acid (1)
Na 4-heptylbenzoate (30)
AlCl3·6H2O (30)
6
0
7
0
8
0
9
93
3
AlCl3·6H2O (30) + 4-heptylbenzoic acid
(30)
10
11
0
0
88
81
6
14
Al(NO3)3 9H2O (30)
Al(OH)(OAc)2 (30)
Al-MCM-41 (30)
12
13
14
85
18
15
7
0
0
0
0
81
Al-MCM-41 cal (30)
[a] Reaction conditions: o-phenylendiamine 1 (0.1 mmol), aldehyde 2 (0.1
mmol) and additive (X mol%) in ACN:H2O 1:1 (0.25 M) at room temperature
under O2 atmosphere for 6 hours. [b] % Yield determined by 1H NMR using
trimethoxybenzene as external standard. [c] 24 hours
We started our work with a focus on optimizing the reaction
conditions.
p-NO2-Benzaldehyde
2a
and
o-
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catalytic activity was also tested for the benzimidazole synthesis
(Table 1, Entry 12) that was obtained in a low yield of 7%, once
again evidencing the critical role of the hydrophobic property of
our supramolecular host solid. To complement this study, we
also tested the activity of siliceous based heterogeneous
mesoporous catalysts. Therefore, Al-MCM 41 with a Si:Al ratio
of 15 was employed. This material was tested in the calcined
version (Table 1, Entry 14), as well as with the inclusion of the
cetyltrimethylammonium bromide that it is employed in its
synthesis (Table 1, Entry 13) and could possibly form
hydrophobic pockets itself inside the siliceous material. While
the latter did not afford the desired product 4a, a good yield of
81% was obtained when using the calcined Al-MCM 41. These
results reveal the importance of easy accessibility to active sites
in the catalytic procedure. Whereas calcined Al-MCM 41
presents a free mesoporous scaffold in where reactants and
formed products can easily diffuse, the presence of
cetyltrimethylammonium bromide would clog the pores and
channels hindering transport of molecules to the active sites and
therefore resulted in a non-appropriate catalytic material.
First trials pointed out the influence of the solvent election in
the reaction yield and selectivity towards 3a, 4a or 5a. 1,2-
Disubstituted benzimidazole 5a was not formed in any of the
solvents tested as determined by 1H NMR of the crude
reaction mixture. We found out that ACN was the solvent that
affords benzimidazole 4a in higher yield (see Supporting
Information for optimization details). Combination with H2O
resulted beneficial, and the desired product 4a was formed in
94% yield under very mild reaction conditions (neutral, room
temperature) in the presence of 6 mol% of Al-ITQ-HB, as the
product easily diffuse through the mesoporous channels
liberating the host to embrace another pair of reacting
components (Table 1, Entry 3). Control experiment without
catalyst showed barely formation of benzimidazole product
4a (Table 1, Entry 1). With the aim to determine whether
hydrophobic pockets in Al-ITQ-HB play a role in the catalytic
procedure, the activity of the metal-organic framework MIL-
53 (Al) was also tested for the synthesis of benzimidazole 4a.
MIL-53 (Al) is a 3D framework built up of infinite trans chains
of corner-sharing AlO4(OH)2 octahedra. The chains are
interconnected by the 1,4-benzenedicarboxylate groups
creating 1D rhombic-shaped tunnels.[36] MIL-53 (Al) also
presents Lewis acidity as observed by CO adsorption at low
temperature (100 K) monitored by FTIR spectroscopy[9a] and
its ability in sorption of several gases such as O2 among
others have been reported.[37] We found out that MIL-53 (Al)
affords benzimidazole product 4a in low yield of 7% (Table 1,
Entry 4) under otherwise identical reaction conditions. This
experiment reveals the special features of Al-ITQ-HB such
as the lamellar structural subdomain and the hydrophobic
characteristic that could be harnessed for interesting
applications such as heterogeneous catalysis.
It was found that 4-heptylbenzoic acid also promotes the
transformation, a fact that was expected since we can find
several reports in the literature that claim that acidic catalysts
favor formation of 2-substituted benzimidazoles.[20, 35] However,
we observed that 4-heptylbenzoic acid was not selective in the
transformation resulting in mixtures of products, imine 3a and
benzimidazole 4a, in varied proportions depending on the
amount of acid catalyst employed (Table 1, Entries 5-7). Micellar
catalysis was also tested by using sodium 4-heptylbenzoate
under otherwise similar conditions that resulted in no formation
of the benzimidazole product 4a, and only imine 3a was
detected by 1H NMR of the crude reaction mixture (Table 1,
Entry 8). This study was completed with the testing of several
aluminum Lewis acidic catalysts.[38] Under the reaction
conditions employed here, we found that AlCl3·6H2O itself or in
combination with 4-heptylbenzoic acid also promote the
transformation, and benzimidazole 4a is formed in 93 and 88%
yield along with low amounts of derivative 5a (Table 1, Entries 9
and 10) that was not detected when using the supramolecular
host catalyst Al-ITQ-HB. Al(NO3)3·9H2O also promotes the
transformation, although subproduct 5a was formed in larger
amount of 14% yield (Table 1, Entry 11). Al(OH)(OAc)2 appears
similar to the structural building unit in Al-ITQ-HB and therefore
As to the mechanism, we speculated that the benzimidazole
synthesis proceeds via activation of the aldehyde substrate by
the weak Lewis acidic site in the solid (Scheme 1). The diamine
then attacks the aldehyde activated by the aluminum center,
resulting in the formation of Schiff’s base 3a in a dehydration
step. This transformation is always inclined toward the product
3a since the water molecule is ejected out of the hydrophobic
core as soon as it is formed. In the second step, imine 3a
(activated by the Lewis
acidic site)
cyclizes
to
dihydrobenzimidazole A that gets oxidized to the product 4a by
the dissolved oxygen in the solvent. The weak Lewis acidity
combined with the O2 sorption capacity of this type of solids[37]
should favor this oxidative cyclization step.
The reaction was followed over time (Scheme 2) by using 1H
NMR spectroscopy analysis. We observe that in the presence of
Al-ITQ-HB, starting materials are fully converted within the first
20 minutes, to form the Schiff’s base product 3a that afterwards
cyclizes oxidatively to the benzimidazole 4a with O2 as oxidant.
The hydrophobic core of the solid along with the weak Lewis
acidity facilitates the fast conversion of the starting materials to
the initially formed 3a product. The efficient binding of the two
substrates to the hydrophobic pocket circumvents the entropic
cost of the bimolecular reaction and the condensation reaction
seems to be facilitated as the water molecule is ejected out of
the hydrophobic core as soon as it is formed. Intramolecular
cyclization then occurs to form dihydrobenzimidazol A, while
oxidation to 4a appeared straightforward since intermediate A
(Scheme 1) was not detected at any stage by 1H NMR
spectroscopy analysis. Product 3a is also formed in the control
experiment (no additive used) although at much lower pace
achieving a conversion of 39% in the same reaction time (6
hours) while benzimidazole 4a is not detected in this case
(Scheme 2). After 24 hours, the control experiment shows full
conversion to products 3a and 4a in 89 and 9% yield,
respectively (data shown in the Supporting Information).
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Scheme 1. Synthesis of benzimidazoles using o-diaminoarenes and aldehydes. Plausible mechanistic pathway.
100
80
60
40
20
0
100
80
60
40
20
0
Al-ITQ-HB
no additive
4a (Al-ITQ-HB)
3a (Al-ITQ-HB)
4a (no additive)
3a (no additive)
0
1
2
3
4
5
6
0
1
2
3
4
5
6
Time / h
Time / h
Scheme 2. Kinetic study of the synthesis of 2-substituted benzimidazole 4a using Al-ITQ-HB and control experiment.
The oxidative cyclization step was studied separately and
product 3a was independently prepared and isolated and treated
under oxygen atmosphere in ACN:H2O in the presence of a
variety of additives (Table 2). Superiority of Al-ITQ-HB was also
evident in this reaction step. While desired product 4a was not
formed in the absence of additives after 24 hours, Al-ITQ-HB (30
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mol%) affords full conversion to benzimidazole 4a in 24 hours
reaction time. The particular features of our supramolecular host
are evidenced since the related MIL-53 (Al) and Al(OH)(OAc)2
allow product formation in lower yield (14 and 31%, respectively).
The Brønsted acid 4-heptylbenzoic acid also catalyzed the
transformation although at lower pace when compared to Al-
ITQ-HB (Table 2, Entry 5). Furthermore, the use of the
surfactant sodium 4-heptylbenzoate (as a related structural unit
in Al-ITQ-HB) under otherwise identical conditions (ACN:H2O)
was not successful in this case in the oxidative cyclization of
imine 3a (Table 2, Entry 6). We believe that O2 sorption ability
along with the hydrophobic characteristics of Al-ITQ-HB facilitate
the encounter of this two reagents and promote the
transformation. Weak Lewis acids in the solid may also play a
role, since we observe that in the one-pot procedure (Table 1,
Entry 2) the benzimidazole 4a is formed in lower reaction time of
6 hours, while 24 hours were required to achieve full conversion
when 3a was used as starting material in the cyclization step
(Table 2, Entry 2).
and selectivity (Table 3, entries 1-4). Similarly, no distinct
substituent effect was observed on the yields of 2-substituted
Table 3. Selective synthesis of 2-arylbenzimidazoles in the presence of Al-
ITQ-HB catalyst.[a]
To test the generality and versatility of this method, a series of
aromatic aldehydes 2 was treated with various o-diaminoarenes
1 under optimal reaction conditions. The developed process was
found to be excellent in terms of yield and selectivity resulting in
a variety of 2-substituted benzimidazoles 4 in very high yield
(Table 3). Apparently, the position of the substituents in the
benzaldehyde ring did not have great influence on the reactivity
Table 2. Oxidative cyclization reaction of Shiff’s base 3a to benzimidazole
4a by molecular oxygen as “green” oxidant.[a]
Entry
Additive (X mol%)
--
4a [b]
0
1
2
3
4
5
6
Al-ITQ-HB (30)
95
14
31
36
0
MIL-53 (Al) (30)
Al(OH)(OAc)2 (30)
4-heptylbenzoic acid (30)
Na 4-heptylbenzoate (30)
[a] Reaction conditions: o-phenylendiamine 1 (0.1 mmol), aldehyde 2 (0.1
mmol) and catalyst (30 mol%) in ACN:H2O 1:1 (0.25 M) at room temperature
under O2 atmosphere for 6 hours. [b] 18 hours. [c] 12 hours. [d] 16 hours. [e] 24
hours.
[a] Reaction conditions: imine 3a (0.1 mmol), and additive (X mol%) in
ACN:H2O 1:1 (0.25 M) at room temperature under O2 atmosphere for 24
hours. [b]
external standard.
%
Yield determined by 1H NMR using trimethoxybenzene as
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benzimidazoles 4 by varying substituents in the o-diaminoarene
component (Table 3, entries 5-6). Aromatic aldehydes with
electron donating groups while reacting with diminished
selectivity, afford the benzimidazole product in good yields
(Table 3, entries 7-8)
Another important aspect of heterogeneous catalysis concerns
the stability of the catalyst during recycling runs. This is certainly
an advantage with respect to homogeneous catalysis. In our
case, the supramolecular catalyst Al-ITQ-HB, could be
recovered by simple centrifugation or filtration and can be
reused for further repeating runs (Supporting Information). A
slight deterioration of the catalytic activity was observed, while
good yields of the benzimidazole product 4a (93% and 91% in
runs 2 and 3, respectively) were achieved by allowing longer
reaction time (24 h). PXRD showed that the recycled Al-ITQ-HB
maintain its mesoscopic nature after use being observable the
low angle diffraction band (Supporting Information).
versatility and potential of host Al-ITQ-HB should be expanded.
We focused our attention to the cyanosilylation reaction of
carbonyl compounds with trialkylsilyl cyanide since it is an
important reaction in organic synthesis for producing
cyanohydrin derivatives, which can be transformed into a variety
of building blocks, including α-hydroxy acids, α-hydroxy ketones
and β-amino alcohols.[39]
Indeed, many of the newly developed porous MOFs with open
metal sites are tested as Lewis acid catalysts in the
cyanosilylation of benzaldehydes using trimethylsilylcyanide
(TMSCN).[38] However, fewer reports account on the more
difficult cyanosilylation of alkyl aldehydes and ketones, for which
yields are normally lower than those of the cyanosilylation of
benzaldehydes due to the lower activity and also steric
hindrance in the case of ketones. Certainly, only
a few
heterogeneous catalysts have shown good conversions when
ketones were used as substrates.[40] Regarding to metal-organic
materials,[41] Table 4 shows a compilation of results attained in
the cyanosilylation reaction of acetophenone as a model ketone
substrate catalyzed by metal-organic solids. As observed, typical
catalyst loadings ranges from 2 to 5 mol% and sometimes
Cyanosilylation reaction
Encouraged by the excellent results and owing to the facility of
Al-ITQ-HB in activating carbonyl compound derivatives in
condensation reactions with o-phenylendiamines as shown
above and with Meldrum’s acid or malononitrile as reported
previously,[9a] we wonder whether such carbonyl activation could
be achieved in other non-condensation reactions and therefore
relatively
high
temperature
(80ºC),
relatively
high
TMSCN:ketone ratio (up to 4) or the use of ultrasound is
necessary to achieve efficient conversion for this particular
Table 4. Cyanosilylation reaction of acetophenone: a compilation of all reported procedures using metal-organic solids as heterogeneous
catalysts
Y [%][a]
TOF [h-1] [b]
Ref
TMSCN:
t [h]
TON[b]
Catalyst
Catalyst
loading
[mol%]
solvent, T
ketone ratio
[41a]
[41b]
[41c]
[41d]
[41e]
[41f]
Mn3[(Mn4Cl)3(BTT)8(CH3OH)10 2
]
11
2
1.5 : 1
2.0 : 1
1.5 : 1
1.1 : 1
1.1 : 1
2.0 : 1
2.0 : 1
CH2Cl2, r.t.
24
28
80
39
99
99
91
61
2.5
40
0.1
1.7
19
Sc2(squarate)3
THF, 40ºC
24
1
[In2(dpa)3(1,10-phen)2]·H2O
[In4(OH)4(hfipbb)4(4,4’-bipy)]
[In8(OH)6(popha)5(H2O)4]·3H2O
[Nd(btc)(H2O)]·(H2O)0.5DMF
Er-DADQ
2.5
2.5
5
solvent free, 80ºC
solvent free, 80ºC
solvent free, r.t.
solvent free, r.t.
16
48
16
18
3
40
140[c]
1.3
1.1
8
20
4.5
2.5
20
[41g]
solvent free, r.t.
ultrasound
24
[Ba(H2LOMe
) ]
0.5
2
4.0 : 1
1.2 : 1
1.2 : 1
solvent free, r.t.
2
3
8
100
99
50
99
25
[41h]
Al-ITQ-HB
Al-ITQ-HB
1
solvent free, r.t.
solvent free, r.t.
57[d]
56[d]
this work
this work
0.5
97
194
[a] Y = Yield. [b] Values calculated from the data reported in the reference. [c] Data reported in the reference. [d] Calculated at initial reaction rate
as moles of product formed per hour and per mole of Lewis acidic active site. H3BTT = 1,3,5-benzenetristetrazol-5-yl; H2dpa = diphenic acid;
1,10-phen = 1,10-phenantroline; H2hfipbb = 4,4’-hexaflurorisopropylidene bis(benzoic acid); 4,4’-bipy = 4,4’-bipyridine; H3popha = 5-(4-carboxy-2-
nitrophenoxy)isophthalic acid. H3BTC = 1,3,5-benzenetricarboxylic acid. H2DADQ = N,N’-dibenzoic acid-2,3-diaminoquinoxaline. H4LOMe = 5,5’-
(2,3,6,7-tetramethoxyanthracene-9,10-diyl)diisophthalic acid.
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substrate. We will show herein that Al-ITQ-HB is the most
efficient metal-organic solid catalyst, as far as we know, for the
cyanosilylation reaction of acetophenone. Low catalyst loading
of 0.5 mol% could be used to promote efficiently the
transformation under very mild reactions conditions in short
reaction time.
We used acetophenone as
a model ketone substrate to
investigate the effect of hydrophobic Al-ITQ-HB on the
cyanosilylation reaction. Our experiments employed a 1:1.2
molar ratio of acetophenone and trimethylsilylcyanide (TMSCN)
at ambient temperature and under solvent free conditions. It
should be noted that no thermal pre-treatment was necessary in
order to activate the hybrid metal-organic solid, or to remove
adsorbed solvent species, and Al-ITQ-HB was used directly in
the catalytic reaction. As shown in Scheme 3, a loading of as
low as 0.5 mol% was sufficient in promoting the reaction
efficiently, while in the absence of Al-ITQ-HB, the desired
product was not formed.
100
80
60
40
20
0
Al-ITQ-HB (1.0 mol%)
Al-ITQ-HB (0.5 mol%)
Al-ITQ-HB (0.1 mol%)
Al-ITQ2 (0.5 mol%)
HB (0.5 mol%)
MIL-53 (Al) (0.5 mol%)
Al(OH)(OAc)2 (0.5 mol%)
0
1
2
3
4
5
6
7
8
Once again, the particular features of Al-ITQ-HB probed crucial
in the catalytic procedure, since the related MOF MIL-53 (Al)
with similar Lewis acidic sites, did not promote the
transformation under otherwise equal conditions (solvent free
conditions using 1:1.2 molar ratio of acetophenone and
trimethylsilylcyanide at ambient temperature). The hydrophobic
cavity of Al-ITQ-HB appears to play a significant role in the
reaction because the individual components[38] Al(OH)(OAc)2 or
4-heptylbenzoic acid did not promote the transformation
substantially (Scheme 3).
Time / h
Scheme 3. Cyanosilylation reaction of acetophenone with trimethylsilylcyanide
When using a solid catalyst two points become important issues
to be considered. The first one is the possibility that some active
sites migrate from the solid to the liquid phase and that those
leached species would become responsible for a significant
extent of the catalytic activity. To rule out the contribution of
homogeneous catalysis in the results shown in Scheme 3, the
reaction was carried out in the presence of the solid Al-ITQ-HB
for 1 h and, at that point, the catalyst was filtered off. The liquid
filtrate was then allowed to react, but no significant conversion
was observed after 7 hours under the presented reaction
conditions (Supporting Information). This clearly indicates that
no active species were present in the liquid phase and it is a true
heterogeneously catalyzed procedure. The second point is the
deactivation and reusability of Al-ITQ-HB. It should be noted that
while most supramolecular systems and Lewis acids are difficult
to recover or they decompose or deactivate in the presence of
protic solvents or water, Al-ITQ-HB is stable both in water and
organic solvents and could be easily recovered and reused for at
least 8 runs without loss of yield of product. Thus, after the first
run, which gave the corresponding cyanosilyl ether in 98% yield
after 2 hours when using 2 mol% loading of Al-ITQ-HB, the
catalyst was filtered and washed with MeOH and dried in
vacuum for two hours before submitting it to the next run. The
resulting recovered catalyst was weighed and the next reaction
was run using amounts of reactants to maintain the same
substrate/catalyst ratio (Scheme 4). The average chemical yield
for 8 consecutive runs was 97% that account for a TON of 388,
which clearly demonstrates the practical recyclability of this
catalyst. Furthermore, the low-angle XRD pattern of the
100
90
80
70
60
50
40
30
20
10
0
1
2
3
4
5
6
7
8
Run
Scheme 4. Recyclability of Al-ITQ-HB for the cyanosilylation of acetophenone
using TMSCN.
mesoscopic hybrid material, Al-ITQ-HB was measured after the
8th run and the trace resulted similar to that of the as synthesized
material (Supporting Information). Further characterization of the
reutilized material was performed (Supporting Information) such
as FTIR spectroscopy analysis and termogravimetrical analysis
and the data showcase the chemical stability of Al-ITQ-HB under
the reaction conditions.
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10.1002/cctc.201601407
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mol% to achieve efficiently the desired TMS-cyanhydrine
product.
Conclusions
In summary, Al-ITQ-HB, which can be prepared by one single
operation from commercially available and cheap starting
materials, efficiently catalyzes the synthesis of benzimidazoles
and the cyanosilylation reaction of carbonyl compounds. The
catalyst shows chemical stability and could be recovered and
reused for several reaction cycles without loss of reactivity.
These results clearly exhibit the promising abilities of
supramolecular metal-organic Al-ITQ-HB as catalyst in organic
synthesis, especially for fine chemicals synthesis. The effective
combination of both the weak Lewis acids and the hydrophobic
pockets in the solid can be responsible for the excellent catalytic
activity.
100
80
60
40
20
0
Benzaldehyde (9)
2-acetonapthone (7)
Acetophenone (6)
2-acetylanthracene (8)
0
2
4
6
8
Time / h
Experimental Section
General Procedure for the synthesis of benzimidazoles.
Al-ITQ-HB (8.0 mg, 0.03 mmol, 30 mol%) was placed in a 2 mL glass
vessel. Diamine (0.1 mmol) and aldehyde (0.1 mmol) were then added.
The vessel was sealed and purged with O2 balloon (1 atm). Acetonitrile
(0.2 mL) and water (0.2 mL) were then added and the mixture was left to
stir vigorously at room temperature for the corresponding time. The
reaction mixture was then extracted with ethyl acetate. Solvent was later
removed under reduced pressure and the crude product was purified by
column chromatography using hexane/ethyl acetate as eluent.
100
80
60
40
20
0
Benzaldehyde (9) 0,5 mol %
Benzaldehyde (9) 0,05 mol %
General Procedure for the cyanosilylation of ketones.
The mesoscopic hybrid material, Al-ITQ-HB (0.025 mmol, 0.5 mol%) was
placed in a 10 mL glass vessel. Ketone (5.08 mmol), TMSCN (6.10
mmol) and dodecane (0.43 mmol) were then added. The mixture was left
to stir vigorously at room temperature. Yield was determined by analysis
by gas chromatography of aliquots taken from the reaction mixture at
different times.
0
1
2
3
4
Time / h
Scheme 5. Cyanosilylation reaction of ketones and bezaldehyde with
trimethylsilylcyanide at room temperature in the presence of Al-ITQ-HB
catalyst (0.5 mol%) under solvent-free reaction conditions.
Acknowledgements ((optional))
The scope in the cyanosilylation reaction was assayed for
several ketones of increased size to establish whether the solid
could display a size exclusion effect (Scheme 5). Indeed, while
2-acetonapthone 7 gave the corresponding TMS-cyanohydrine
product with a reaction rate slightly higher than acetophenone 6
(Scheme 5), we observed that 2-acetylanthracene hardly forms
the desired product under the same reaction conditions (0.5
mol% of Al-ITQ-HB was used). However, the observed different
behavior have to be also attributed to the inherent distinct
reactivity of the substrates. Performance with aldehydes was
also evaluated by using the model substrate benzaldehyde. As
expected, reaction rate was much higher than for ketones
(Scheme 5) and catalyst loading could be reduced to even 0.05
This work was funded by the Generalitat Valenciana (Prometeo).
The Severo Ochoa program (SEV-2012-0267) is thankfully
acknowledged. S. R-B acknowledges a PhD fellowship from the
Generalitat Valenciana.
Keywords: supramolecular catalyst • metal-organic catalyst •
enzyme mimic • benzimidazole • cyanosilylation
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A metal-organic hybrid material
catalyzes the cyanosilylation reaction
of ketones and the synthesis of
benzimidazoles. The catalytic
reactions require both the
supramolecular microenvironment
catalyst and the Lewis acidity
operating in concert to achieve
Sergio Rojas-Buzo, Pilar García-
García,* Avelino Corma*
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efficient turnover number/frequency.
The supramolecular catalyst acts as
functional enzyme mimic and the
catalytic solid could be recycled and
reused.
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