Mesoporous silica supported ytterbium as catalyst for synthesis of 1,2-disubstituted benzimidazoles and 2-substituted benzimidazoles

Article abstract of DOI:10.1002/aoc.4507

The benzimidazole ring is an important pharmacophore in contemporary drug discovery. Thus, effort to identifying new compounds containing benzimidazole scaffolds have gained much attention in recent years. In the present study, MCM-41 type mesoporous silica with large pore (l-MSN) supported ytterbium was successfully prepared by wet impregnation method. Among rare earth metal salts, ytterbium triflate has already been widely investigated as a catalyst in organic synthesis but less toxic ytterbium oxide has yet to be explored. Relatively high abundance and low cost of ytterbium with respect to many catalytically active metals (e.g. Pd, Au, Ru, Ir, Pt) offer an opportunity to develop sustainable catalysts for organic conversions. The catalyst has been characterized by various techniques including nitrogen adsorption, FT-IR, TEM, SEM, EDX technique and elemental mapping. The obtained materials exhibit high surface area and a narrow distribution of mesoporosity. The catalytic performance of the Yb@l–MSNs was tested by synthesis of 1,2-disubstituted benzimidazoles and 2-substituted benzimidazoles through the coupling of aldehydes with o-phenylenediamine. The catalyst resulted in excellent yields in short reaction times and the reaction showed tolerance toward both electron-donating and electron-withdrawing functional groups at room temperature. A particularly interesting finding was the solvent selectivity of this reaction; namely, 1,2-disubstituted benzimidazoles generated as major product in water-ethanol, while the 2-substituted benzimidazoles was generated exclusively in non-polar solvents like toluene.

Full text of DOI:10.1002/aoc.4507

Received: 22 March 2018
DOI: 10.1002/aoc.4507
Revised: 31 May 2018
Accepted: 15 June 2018
F U L L P A P E R
Mesoporous silica supported ytterbium as catalyst for
synthesis of 1,2‐disubstituted benzimidazoles and
2‐substituted benzimidazoles
Partha Kumar Samanta1 | Rumeli Banerjee1 | Ryan M. Richards2
| Papu Biswas1
1 Department of Chemistry, Indian
The benzimidazole ring is an important pharmacophore in contemporary drug
discovery. Thus, effort to identifying new compounds containing benzimid-
azole scaffolds have gained much attention in recent years. In the present
study, MCM‐41 type mesoporous silica with large pore (l‐MSN) supported
ytterbium was successfully prepared by wet impregnation method. Among rare
earth metal salts, ytterbium triflate has already been widely investigated as a
catalyst in organic synthesis but less toxic ytterbium oxide has yet to be
explored. Relatively high abundance and low cost of ytterbium with respect
to many catalytically active metals (e.g. Pd, Au, Ru, Ir, Pt) offer an opportunity
to develop sustainable catalysts for organic conversions. The catalyst has been
characterized by various techniques including nitrogen adsorption, FT‐IR,
TEM, SEM, EDX technique and elemental mapping. The obtained materials
exhibit high surface area and a narrow distribution of mesoporosity. The
catalytic performance of the Yb@l–MSNs was tested by synthesis of 1,2‐disub-
stituted benzimidazoles and 2‐substituted benzimidazoles through the coupling
of aldehydes with o‐phenylenediamine. The catalyst resulted in excellent
yields in short reaction times and the reaction showed tolerance toward both
electron‐donating and electron‐withdrawing functional groups at room
temperature. A particularly interesting finding was the solvent selectivity of
this reaction; namely, 1,2‐disubstituted benzimidazoles generated as major
product in water‐ethanol, while the 2‐substituted benzimidazoles was
generated exclusively in non‐polar solvents like toluene.
Institute of Engineering Science and
Technology, Shibpur, Howrah 711 103,
West Bengal, India
2 Department of Chemistry, Colorado
School of Mines, Golden, CO 80401, USA
Correspondence
Papu Biswas, Department of Chemistry,
Indian Institute of Engineering Science
and Technology, Shibpur, Howrah 711
103, West Bengal, India.
Email: papubiswas_besus@yahoo.com;
pb.besu.chem@gmail.com
Funding information
CSIR India, Grant/Award Number:
01(2459)/11/EMR‐II dated 16/05/2011;
DST‐Inspire Fellowship, Grant/Award
Number: IF160999
KEYWORDS
1,2‐disubstituted benzimidazoles, 2‐substituted benzimidazoles, heterogeneous catalyst, mesoporous
silica, solvent dependent synthesis, ytterbium loading
1 | INTRODUCTION
structural unit.[1] The benzimidazole moiety is
isostructural to the purine bases and found in a variety
Among benzofused nitrogen‐containing heterocyclic
compounds, the benzimidazole scaffold is an important
core unit in drug discovery due to the broad range of
biological activities exhibited by compounds bearing this
of natural products.[2] Commercially available medicines
having a benzimidazole ring comprise proton‐pump
inhibitors (omeprazole, esomeprazole, lansoprazole,
rabeprazole), direct thrombin inhibitor dabigatran, AT1
Appl Organometal Chem. 2018;e4507.
wileyonlinelibrary.com/journal/aoc
© 2018 John Wiley & Sons, Ltd.
1 of 13
https://doi.org/10.1002/aoc.4507

2 of 13
SAMANTA ET AL.
receptor antagonists (candesartan, telmisartan), H1
receptor antagonist mizolastin, anthelmintic agent for
the management of veterinary heart failure pimobendan,
chemotherapeutic drug to treat chronic lymphocytic
leukemia bendamustine etc. Moreover benzimidazole‐
quinolinonebased potent EGFR‐3 inhibitor, Dovitini is
currently in phase‐III clinical trials for the treatment of
metastatic renal cell cancer.[3] Benzimidazole derivatives
also exhibit biological activities such as antimicrobial,[4]
antioxidant,[5] anti‐leishimanial,[6] antitubercular,[7] anti-
fungal[8] and activity against several viruses[9] and human
cytomegalovirus (HCMV). In addition, benzimidazole
based structural frameworks are explored as electron‐
transporting hosts for phosphorescent organic light‐emit-
ting diodes (PHOLEDs).[10] Thus, owing to the vast
importance of benzimidazole moiety in pharmaceutical
industries, synthesis of benzimidazoles are therefore of
continuing interest.
Generally, direct one‐pot condensation of 1,2‐
diaminoarenes with aldehydes followed by oxidative
cyclization is the most straightforward approach to pre-
pare benzimidazoles.[11] The other common procedures
include condensation of 1,2‐diaminoarenes with carbox-
ylic acids,[12] carboxylic acid derivatives and nitriles
under dehydrating conditions.[13] Though the reported
protocols are quite efficient, many of those have several
limitations such as use of perilous organic solvents,
require elevated temperature and costly reagents.
Moreover, one of the major drawbacks of these protocols
are that they show poor selectivity towards N‐1 substitu-
tion, which results in the formation of 1,2‐disubstituted
benzimidazole as a side product along with 2‐substituted
benzimidazole (Scheme 1).
different mesoporous silica materials, MCM–41 have
attracted much attention as adsorbents and catalysts due
to their remarkably high surface area, large pore volume,
uniform pore structure, and tailored pore size up.[16] Dif-
ferent metal incorporated or loaded MCM–41 materials
have been studied focussing on their application as cata-
lysts and adsorbents. Despite these advances, the efficacy
of this material in fine chemical synthesis is not well
explored due to its poor intrinsic activity as well as lower
pore diameter. Lin and his co‐worker reported a MCM–
41type MSN (l‐MSN) material with a large pore diameter
to study uptake and release profiles of cytochrome c.[17]
Very recently, Trewyn et al. have studied activity of re‐
associated concanavalin A released from l‐MSN.[18] The
high surface area and large pore diameter of l‐MSN could
be attractive for supported metal catalysts.
Moreover, in organic chemistry, solvent‐selective
reactions offer unique synthetic methodology.[19]
Combining the same reactants in different solvents selec-
tively generates different products.[19] Thus, solvent can
be considered as one of the most important stimuli that
can direct the course of reactions from one product to
another. Considering the importance of benzimidazole
moiety in pharmaceutical industries, heterogeneous
catalytic activity of ytterbium loaded mesoporous silica
has been explored here for the solvent selective synthesis
of 1,2‐disubstituted benzimidazole and 2‐substituted
benzimidazole. To the best of our knowledge, single
catalyst furnishing both 1, 2‐disubstituted benzimidazole
and 2‐substituted benzimidazole selectively in different
solvents under similar reaction conditions is not known
so far.
As a part of our current research in this area,[14] we
report here a MCM‐41 type mesoporous silica‐supported
ytterbium catalyzed synthesis of regio‐defined 1,2‐disub-
stituted benzimidazole and 2‐substituted benzimidazole
(Scheme 1). During the last two decades, ytterbium
triflate has been found as unique Lewis acid that has
exhibited high catalytic activity in many organic reac-
tions, including Michael, aldol, Friedel‐Crafts, Mannich,
Diels‐Alder, Povarov reactions, imino ene reaction
etc.[15] Other ytterbium salts or ytterbium oxides have
not been investigated so far. This motivates us to explore
the opportunity of making a less hazardous MCM–41
type mesoporous silica loaded with ytterbium possessing
high surface area and large pore diameter. Among
2 | EXPERIMENTAL
2.1 | Materials and methods
Cetyl trimethyl ammonium bromide (CTAB, 99%),
tetraethyl orthosilicate (TEOS, 99%) and ytterbium nitrate
pentahydrate (99.9%) were purchased from Sigma‐
Aldrich. All chemicals were used as received without
any purification. All solvents were of analytical grade
and distilled before use. Large pore MCM‐41 type meso-
porous silica with (l‐MSN) was synthesized via the
method of Slowing et al.[17,18] using CTAB and mesitylene
as template and pore‐expanding agent, respectively.
SCHEME 1 Competitive formation of
1,2‐disubstituted and 2‐substituted
benzimidazoles

SAMANTA ET AL.
3 of 13
methanol, and dried under vacuum at 100 °C for 12 h.
The synthesized material (1.0 gm) was stirred in a mix-
ture of methanol (100 ml) and concentrated hydrochloric
acid (0.75 ml) at 50 °C for 6 h to remove the structure‐
templating CTAB and mesitylene molecules. The tem-
plate‐removed product was then filtered and dried under
vacuum at ambient temperature for 12 h.
2.2 | Characterization techniques
Nitrogen adsorption–desorption isotherms of the samples
were measured at liquid nitrogen temperature with a
Micromeritics Tristar 3020 surface area and porosity ana-
lyzer. The samples were degassed under nitrogen flow at
373 K for 6 h. The surface areas were calculated by the
Brunauer–Emmett–Teller (BET) method and the pore
size distribution were calculated by the Barrett–Joyner–
Halenda (BJH) method.
Scanning Electron Microscopy (SEM) was performed
using a JEOL JSM 7610F instrument. The samples were
dispersed on a conductive carbon tape and analyzed
using an accelerating voltage of 15 kV. EDS and particle
mapping were performed using an Oxford Instruments
X‐MaxN 50 X‐ray detector attached with the aforemen-
tioned SEM instrument.
Transmission Electron Microscopy (TEM) imaging was
done on a Philips FEI CM 200 transmission electron
microscope operated at 200 kV. TEM samples were pre-
pared by sonicated the samples in ethanol for 15 min. 2
μL of this suspension was drop‐casted onto carbon‐
coated, 300 mesh copper grids.
2.4 | Catalyst synthesis
A series of ytterbium‐containing l‐MSN samples with
spherical morphology were synthesized in the following
manner. Yb (NO3)3·5H2O was completely dissolved in
10 ml ethanol and 0.5 g of l‐MSN was suspended in Yb
(NO3)3·5H2O/ethanol solution. The suspension was left
to dry in air at 30 °C with constant stirring. The solid
obtained was then calcined in air at 550 °C for 5 h. The
synthesized catalysts are referred to as Xm‐Yb, where
Xm represents the amount of ytterbium precursor added
in mmol during the synthesis.
Ytterbium content in the samples were measured
using a Perkin Elmer inductively coupled plasma atomic
emission spectrometer (ICP‐AES) model NexION 300Q.
5 mg of catalyst was dissolved in 10 mL aliquot of
500 mL solution prepared from mixing 50 μL of 36% HF
and 500 μL of aqua regia.
2.5 | General experimental procedure for
the synthesis of 1, 2‐disubstituted
benzimidazole
A mixture of aldehyde (2 mmol), o‐phenylenediamine
(1 mmol) and catalyst (15 mg) was taken in a single neck
round bottom flask in water/ethanol (2:1, 5 ml). The reac-
tion mixture was stirred for 1 h. The progress of the reac-
tion was monitored by TLC. After completion of the
reaction, the catalyst was recovered by centrifugation
and solvent was evaporated at reduced pressure. The
product was purified by column chromatography using
ethyl acetate and hexane (30:70) mixture as eluent.
1H NMR spectra were recorded on a Bruker Avance
III 300, 400 and 500 MHz NMR spectrometer. NMR spec-
tra were recorded at room temperature with CDCl3 or
1
DMSO‐d6 as the solvent. Chemical shifts (δ) of H NMR
spectra are reported in ppm relative to residual solvent
signals (CHCl3 in CDCl3: δ = 7.26 ppm, DMSO in
DMSO‐d6: δ = 2.50 ppm); data are reported as br = broad,
s = singlet, d = doublet, t = triplet, q = quartet, m = mul-
tiplet; J values are given in Hz.
FT‐IR spectra were recorded using KBr disks with
JASCO FTIR‐460 Plus spectrophotometers.
2.6 | General experimental procedure for
the synthesis of 2‐substituted
benzimidazole
2.3 | Synthesis of mesoporous silica
nanoparticle with large pores (l‐MSN)
A mixture of aldehyde (1 mmol), o‐phenylenediamine
(1 mmol) and catalyst (15 mg) in toluene (5 ml) was
taken in a round bottom flask. The reaction mixture
was stirred for 1 h. The progress of the reaction was
monitored by TLC. After completion of the reaction,
the catalyst was separated by centrifugation and solvent
was evaporated at reduced pressure. The product was
purified by column chromatography using ethyl acetate
and hexane (30:70) mixture as eluent to obtain the
desired product.
Cetyltrimethylammonium bromide (CTAB, 1.0 g,
2.7 mmol) was dissolved in 480 ml water and 3.5 ml of
2 M NaOH in aqueous medium was added to it followed
by mesitylene (5.87 gm, 48.8 mmol). The mixture was
stirred vigorously at 80 °C for 2 h and then tetraethyl
orthosilicate (4.56 gm, 21.9 mmol) was added to the solu-
tion dropwise. The reaction was heated to 80 °C with vig-
orous stirring and continued for another 2 h. The white
precipitate was isolated by filtration, washed with

4 of 13
SAMANTA ET AL.
exhibits a double plateau shape which can be attributed
to the heterogeneous pore expansion and the results are
consistent with previously reported pore expanded meso-
porous silica.[17] Barrett–Joyner–Halenda (BJH) pore size
distributions data show (Table 1) narrow pore size distri-
bution with peak at 5.6 nm. The BJH pore size distribu-
tions of l‐MSN shows only one peak unlike two peaks
reported previously (Figure 2b). As shown in Figure 1a,
ytterbium loaded samples show only one hysteresis loop
(H2 type) in the 0.4 to 0.75 P/P0 range. The surface area
and pore volume gradually decreased with the increase
in ytterbium loading. This may be due to the blocking of
pores of parent l–MSN by ytterbium ions. Accordingly,
the pore volume decreases with increases in ytterbium
loading (Table 1). The synthesized catalysts exhibit a
narrow pore size distribution at around 4.6 nm, which
are slightly reduced in comparison to parent l‐MSN.
As shown in Figure 2, l‐MSN, 0.75 m‐Yb and 1.0 m‐
Yb were characterized by low angle XRD. The diffraction
pattern of l‐MSN exhibits a sharp peak for d100 plane as
well two low intensity peaks for d110 and d200 planes of
hexagonally ordered pores common to MCM‐41 type
materials.[20] In the ytterbium loaded samples, most
intense d100 diffraction is observed clearly, but higher
peaks are broadened and not clearly observed. In high
angle X‐ray diffraction pattern of 0.75 m‐Yb, no charac-
teristics peak for Yb2O3 is observed (Figure S1) indicat-
ing the uniform dispersion of ytterbium in the silica
matrix.
3 | RESULTS AND DISCUSSION
3.1 | Characterization of Catalyst
The MSN with large pores has been synthesized by
adding mesitylene as a pore‐expanding agent to a CTAB‐
templated base‐catalyzed condensation reaction of silicate
as reported previously.[17,18] The catalysts were obtained by
impregnating the l‐MSN support in the ethanolic solution
of Yb (NO3)3·5H2O, followed by calcination.
The nitrogen adsorption–desorption isotherm and BJH
pore size distribution determined for l–MSN and l–MSN
supported ytterbium catalysts are displayed in Figure 1
and textural characteristics are summarized in Table 1.
The samples exhibited type IV adsorption–desorption
isotherm, which is characteristic of mesoporous materials.
The parent l–MSN support was characterized by a rela-
tively high surface area and pore volume of 743 m2 g−1
and 1.18 cm3 g−1, respectively (Figure 1a). The isotherm
Figure 3 presents the scanning electron micrographs
of parent l‐MSN and 0.75 m‐Yb. Micrographs of l‐MSN
and 0.75 m‐Yb are showing spherical particles and the
size of these particles is in a range from 0.3 to 0.8 μm.
The energy dispersive X‐ray (EDX) spectroscopy of
0.75 m‐Yb shows the presence of Yb (Figure S2). The
ytterbium dispersion was measured by EDS mapping of
the catalyst sample (Figure 4). The result shows that
ytterbium is homogeneously dispersed throughout the
surface of the silica support. TEM micrograph of the
0.75 m‐Yb obtained is shown in Figure 5. The image
clearly displays spherical nature and the radial porosity
of the silica frame. Figure S3 exhibit FT–IR of
0.75 m‐Yb. The exact metal loading of these MSN
catalysts was analyzed by ICP‐OES technique and the
results were summarized in Table 1. The measured load-
ing is very close to the amount introduced.
3.2 | Synthesis 1,2‐disubstituted
benzimidazoles and 2‐substituted
benzimidazoles
FIGURE 1 (a) Nitrogen adsorption and desorption isotherm
(closed symbol: adsorption and open symbol: desorption) and (b)
BJH pore size distribution of catalysts
Initial optimization of the reaction conditions for the
synthesis of substituted benzimidazoles, were performed

SAMANTA ET AL.
5 of 13
TABLE 1 Summary of physical properties of supported catalysts
Amount of Yb (NO3)3·5H2Oa
SBET
Pore volume
(cm3 g−1 b
Entry
Catalyst
(mmol)
(gm)
(m2 g−1 b
)
WBJH (nm)b
)
Yb/Sic
1
2
3
4
l‐MSN
‐
‐
743
537
365
275
5.6
4.8
4.6
4.3
1.18
0.81
0.63
0.34
‐
0.5 m‐Yb
0.75 m‐Yb
1.0 m‐Yb
0.5
0.75
1.0
0.22
0.34
0.45
0.061
0.091
0.12
aAmount of Yb (NO3)3·5H2O used per 0.5 gm of l‐MSN.
bSpecific surface area (SBET) and mean pore diameter (WBJH) were obtained from nitrogen sorption analysis. The specific surface area was calculated by BET
method and the mean pore diameter was calculated by BJH method.
cThe molar ratio of Yb/Si determined by ICP‐AES analysis.
temperature. The conversion percentage increased with
the increase in ytterbium loading from 14 wt% to
17 wt%. With further increase in ytterbium loading,
the percentage of conversion diminished. It seems that,
with 17 wt% ytterbium loading there is monolayer
coverage of Yb2O3 on the support. But with increased
ytterbium percentage there is excess loading of metal
and some pores of l‐MSN are blocked. Poor yield was
obtained with unmodified solid support l‐MSN. No
product is obtained when the reaction was carried out
without any catalyst.
Then the effect of solvent on the reaction was
evaluated thoroughly using 0.75 m‐Yb as the catalyst. It
is evident from Table 3 that polar solvents like ethanol,
methanol, DMF and DMSO (entries 1–4) exhibit
high conversion with very good selectivity towards 1,2‐
disubstituted benzimidazole whereas water shows poor
conversion rate with excellent selectivity towards 1, 2‐
FIGURE 2 Low angle XRD of l‐MSN, 0.75 m‐Yb and 1.0 m‐Yb
disubstituted benzimidazole (entry 5). When the reaction
with 4‐methylbenzaldehyde as a model substrate in pres-
ence of o‐phenylenediamine in ethanol using ytterbium
containing l‐MSN as catalysts (Table 2). In a typical
experiment, a mixture of o‐phenylenediamine (1 mmol)
and 4‐methylbenzaldehyde (1 mmol) in 5 ml solvent
was reacted in presence of 15 mg catalyst for 1 h at room
was performed in ethanol/water (2:1) mixture, 92%
conversion obtained with excellent selectivity towards 1,
2‐disubstituted benzimidazole (entry 9). Other solvents
such as acetonitrile, THF exhibits a poor conversion rate
as well as selectivity (entries 6, 7). Interestingly, toluene
demonstrates 95% conversion with absolute selectivity
FIGURE 3 Scanning electron microscope images of (a) l‐MSN and (b) 0.75 m‐Yb

6 of 13
SAMANTA ET AL.
FIGURE 4 EDS mapping of 0.75 m‐Yb used to measure dispersion of active species within the catalyst
TABLE 2 Comparison of catalytic performance of catalysts on
benzimidazole synthesisa
Entry
Catalyst
Conversion (%)b
1
2
3
4
5
0.5 m‐Yb
0.75 m‐Yb
1.0 m‐Yb
l‐MSN
70
90
85
30
None
Trace
aReaction condition is detailed in the experimental section.
bPercent conversion of o‐phenylenediamine.
for 2‐substituted benzimidazole (entry 8). There was no
noticeable increase in the yield on prolonging the time
span or increasing the metal loading (entries 10–13).
Lower conversions were obtained when Yb (NO3)3·5H2O,
YbCl3·6H2O and ytterbium oxide powder were used
(entries 14–16). Ytterbium loaded l‐MSN (0.75 m‐Yb)
was better suited to afford 1,2‐disubstituted benzimid-
azoles in ethanol/water (2:1) mixture at room tempera-
ture. Whereas toluene emerged as the best choice
FIGURE 5 TEM image of ytterbium containing porous silica
sphere of 0.75 m‐Yb

SAMANTA ET AL.
7 of 13
TABLE 3 Optimization of reaction conditions for the synthesis of 1,2‐disubstituted benzimidazoles and 2‐substituted benzimidazolesa
Selectivity (%)c
Catalyst
Amount (mg)
Time
(h)
Entry
Solvent
Catalyst
Conversion(%)b
3a
4aa
1
ethanol
0.75 m‐Yb
0.75 m‐Yb
0.75 m‐Yb
0.75 m‐Yb
0.75 m‐Yb
0.75 m‐Yb
0.75 m‐Yb
0.75 m‐Yb
0.75 m‐Yb
0.75 m‐Yb
0.75 m‐Yb
0.75 m‐Yb
0.75 m‐Yb
Yb (NO3)3·6H2O
YbCl3·6H2O
Yb2O3
15
15
15
15
15
15
15
15
15
15
15
20
10
15
15
15
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
2.0
4.0
1.0
1.0
4.0
4.0
5.0
90
65
82
90
40
43
34
95
92
90
92
90
82
65
63
56
75
60
70
80
90
55
60
0
25
40
30
20
10
45
40
100
10
10
10
10
10
10
10
10
2
DMF
3
DMSO
4
methanol
water
5
6
ACN
7
THF
8
toluene
9
EtOH/H2O
EtOH/H2O
EtOH/H2O
EtOH/H2O
EtOH/H2O
EtOH/H2O
EtOH/H2O
EtOH/H2O
90
90
90
90
90
90
90
90
10
11
12
13
14
15
16
aReaction conditions: 1a (1.0 mmol), 2a (2 mmol), catalyst in solvent (5 ml), room temperature.
bPercent conversion of o‐phenylenediamine.
cIsolated yield.
amongst other solvents to obtain 2‐substituted benzimid-
azoles utilizing 0.75 m‐Yb as catalyst.
The scope of the catalyst was broadened successfully to
the synthesis of 2‐substituted benzimidazoles in toluene.
The optimised protocol was 1, 2‐phenylenediamine
(1 mmol) and aldehyde (1 mmol) in the presence of
15 mg catalyst in toluene at 25 °C. The electronic effect of
substituent groups on the yield of reaction was thoroughly
examined and is shown in Scheme 3. Aldehydes bearing
electron withdrawing as well as electron donating groups
(Scheme 3, 4aa, 4 ac–4aj) produced very good to excellent
yield (78─95%) under the optimal reaction conditions. The
presence of both electron withdrawing and donating
groups does not affect the yield of the reaction consider-
ably. Inactivated aliphatic aldehyde also shows good
yield (Scheme 3, 4al). 2‐Pyridine aldehyde and 1,2‐
dihydroanthracene‐9‐carbaldehyde also furnished moder-
ate yield (Scheme 3, 4ak and 4 am). 1,2‐Phenylenediamine
having electron donating groups (Scheme 3, 4bb–4db) also
gave very good yield whereas diamine with electron
withdrawing furnished much inferior yield.
To examine the versatility of this reaction, a series of
aromatic aldehydes were introduced to the optimal
reaction conditions (Scheme 2). By using ethanol/water
(2:1) as solvent at room temperature, 1,2‐disubstituted
benzimidazoles were obtained in excellent yields. Most
aromatic aldehydes bearing both electron‐donating and
electron‐withdrawing groups in the para‐position were
well resilience under the same reaction condition
affording high yields (Scheme 2, 3b–3g). Aromatic
aldehydes having substitution on ortho‐position furnished
moderate yield due to steric hindrance (Scheme 2, 3h–3j).
Heteroaromatic thiophene‐2‐carbaldehyde, 2‐pyridyl
benzaldehyde and 3‐pyridyl benzaldehyde (Schme 2,
3 k–3 m) were also furnished corresponding 1,2‐disubsti-
tuted benzimidazoles in decent yields. To the contrary,
the reaction of aliphatic aldehydes needed extended
reaction time to achieve moderate yields.

8 of 13
SAMANTA ET AL.
SCHEME 2 Substrates scope in 1,2‐disubstituted benzimidazole formation
To test the recyclability of the catalyst, a reaction
with 4‐methylbenzaldehyde and o‐phenylenediamine
was performed in the presence of 0.75 m‐Yb in
ethanol/water (2:1). Figure 6 shows the recyclability of
the l‐MSN catalyst for five cycles. Both conversion and
yield were maintained as >90% in the first three cycles

SAMANTA ET AL.
9 of 13
SCHEME 3 Substrates scope in 2‐substituted benzimidazole formation
and then started decreasing during the fourth run and
dropped significantly for the next cycle. The reused
catalyst (after five cycles) was also characterized by
BET and TEM after five consecutive runs. The results
demonstrated that the catalyst suffered no observable
changes in mesoporosity (Figure 7a), although pore
volume and BET surface area reduces to 0.22 cc g−1
and 140 m2 g−1, respectively (Figure 7b), pore diameter
remained unchanged. The reduction in pore volume
can be attributed to blocking of the pore channels by
reaction species in the mixture. To prove the blocking
of pore channel, the reused catalyst after five cycle was
calcined at 550 °C and BET surface area of the calcined
sample was measured. BET surface area and pore
volume (Figure 7c) of the calcined sample were found
to be 0.55 cc g−1 and 326 m2 g−1. These values are very
close to the BET surface area and pore volume of catalyst
0.75 m‐Yb (Table 1).
In addition, leaching of metal ion has been a concern
for metal catalysts incorporated in mesoporous
silica. To discard the contribution of homogeneous
catalysis, the reaction with 4‐methylbenzaldehyde and
o‐phenylenediamine was conducted in the presence of
0.75 m‐Yb in ethanol/water (2:1) for 30 min to obtain a
yield of 68%. The solid catalyst was removed by filtration
and the filtrate was then transferred to another vessel.

10 of 13
SAMANTA ET AL.
FIGURE 6 Reusable profiles of the 0.75 m‐Yb catalyst for
the synthesis of 1‐(4‐methylbenzyl)‐2‐(p‐tolyl)‐1Hbenzo[d]
imidazole (3a)
Stirring of the catalyst‐free solution was continued for
additional 1 h at room temperature, but no further reac-
tion took place. The reaction solution was then subjected
to ICP‐AES analysis and no metal ion were detected
within the detection limit.
In order to examine the efficiency of 0.75 m‐Yb, we
compared the results for the synthesis of 1,2‐disubstituted
benzimidazoles and 2‐substituted benzimidazoles in the
presence of this catalyst with few heterogeneous
catalysts[11v,21] reported so far in the literature (Table 4).
As evident from Table 4, these catalysts furnished either
1‐benzyl‐2‐phenyl‐1H‐benzo [d] imidazole or 2‐phenyl‐
1H‐benzo [d]imidazole.
To rationalize the role of solvent on selectivity
control, we move toward the mechanism of the Yb
incorporated mesoporous silica catalyzed synthesis of
1,2‐disubstituted benzimidazole and 2‐substituted benz-
imidazole. Scheme 4 illustrates a plausible reaction path-
way for this reaction. The Yb3+, is assumed to accelerate
the nucleophilic attack by o‐phenylenediamine. Solvents
with low polarity such as toluene facilitate the formation
of monoimine (5), whereas in highly protic polar solvent
such as ethanol/water mixture, bisimine (6) is formed.
Cyclization of monoimine (5) followed by oxidative dehy-
drogenation by air leads to 2‐substituted benzimidazole.
The higher polarity and hydrogen bonding ability of
ethanol/water mixture facilitate it to act as effective
electrophilic co‐activating agents for bisimine formation
and stabilizes bisimine through formation of hydrogen
bonding. 1,2‐Disubstituted imidazoles formed by intra-
molecular nucleophilic attack in bisimine (6) followed
by a 1,3‐hydride shift.
FIGURE 7 (a) TEM and (b) BET isotherms of the reused 0.75 m‐
Yb after five runs of the 1‐(4‐ ethylbenzyl)2‐(p‐tolyl)‐1H‐benzo [d]
imidazole synthesis (3a) and (c) BET isotherms of the five times
reused 0.75 m‐Yb after calcination

SAMANTA ET AL.
11 of 13
TABLE 4 Comparison of results for 0.75 m‐Yb with heterogeneous catalysts for the synthesis of 1‐benzyl‐2‐phenyl‐1H‐benzo [d] imidazole
or 2‐phenyl‐1H‐benzo [d]imidazole
Entry
Catalyst
Solvent
Temperature (°C)
Time (min)
Product
Yielda (%)
Ref.
[11v]
1
Nano indium oxide
EtOH/H2O
(2:1)
60
120
89
[21a]
2
N,N‐Dimethylaniline/
EtOH
75
240
69
graphite,
[21a]
3
4
p‐Toluensufonic acid/
graphite
Solvent free
75
40
60
Mixture (1:2.9)b
89c
80
0.75 m‐Yb
EtOH/H2O
(2:1)
RTd
This work
5
0.75 m‐Yb
Toluene
RT
60
95
This work
aIsolated yield.
bBoth 1‐benzyl‐2‐phenyl‐1H‐benzo [d] imidazole (66%) and 2‐phenyl‐1H‐benzo [d] imidazole (23%).
cTotal yield.
dRoom temperature.
SCHEME 4 Mechanism for formation
of 1,2‐disubstituted benzimidazole and 2‐
substituted benzimidazole
temperature. The condensation of diamine with aldehyde
in the presence of ytterbium loaded catalyst was found to
be solvent selective, generating 1,2‐disubstituted
benzimidazoles in water/ethanol medium (2:1) and 2‐
substituted benzimidazoles exclusively in toluene. Thus,
the present study offers a simple procedure for the
selective synthesis of 1,2‐disubstituted benzimidazoles
4 | CONCLUSIONS
A series of ytterbium loaded mesoporous silica nanoparti-
cles (Xm‐Yb) as catalysts for synthesis of substituted
benzimidazoles have been synthesized through wet
impregnation methods. It has been shown that catalysts
prepared by this approach exhibit homogeneous distribu-
tions of ytterbium within the mesoporous catalyst
support. Synthesized catalysts have been found to be
efficient for the synthesis of substituted benzimidazoles
by the condensation of diamine with aldehyde at room
and 2‐substituted benzimidazoles promoted by
a
reusable, non‐toxic and environmentally benign mesopo-
rous silica supported ytterbium catalyst (0.75 m‐Yb).
Moreover, the methodology reported here are highly

12 of 13
SAMANTA ET AL.
H. Melief, K. Kumar, S. E. Knudson, R. A. Slayden, I. Ojima,
Bioorg. Med. Chem. 2014, 22, 2602.
chemoselective, requiring short reaction time, can be
performed at room temperature and exhibit a wide
functional group tolerance. We believe the current proto-
col using 0.75 m‐Yb will find widespread applications in
academic laboratories and industry.
[8] B. Fang, C. H. Zhou, X. C. Rao, Eur. J. Med. Chem. 2010, 45,
4388.
[9] (a) A. R. Porcari, R. V. Devivar, L. S. Kucera, J. C. Drach, L. B.
Townsend, J. Med. Chem. 1998, 41, 1252; (b) T. Roth, M. L.
Morningstar, P. L. Boyer, S. H. Hughes, R. W. Buckheitjr, C.
J. Michejda, J. Med. Chem. 1997, 40, 4199; (c) M. T. Migawa,
J. L. Girardet, J. A. Walker, G. W. Koszalka, S. D. Chamberlain,
J. C. Drach, L. B. Townsend, J. Med. Chem. 1998, 41, 1242; (d) I.
Tamm, P. B. Sehgal, Adv. Virus Res. 1978, 22, 187; (e) I. Tamm,
Science 1957, 126, 1235; (f) R. Zou, K. R. Ayres, J. C. Drach, L.
B. Townsend, J. Med. Chem. 1996, 39, 3477; (g) Y. ‐F. Li, G. ‐F.
Wang, P. ‐L. He, W. ‐G. Huang, F. ‐H. Zhu, H.‐Y. Gao, W.
Tang, Y. Luo, C.‐L. Feng, L.‐P. Shi, Y.‐D. Ren, W. Lu, J.‐P.
Zuo, J. Med. Chem. 2006, 49, 4790; (h) S. Hirashima, T. Suzuki,
T. Ishida, S. Noji, S. Yata, I. Ando, M. Komatsu, S. Ikeda, H.
Hashimoto, J. Med. Chem. 2006, 49, 4721; (i) S. Hirashima, T.
Oka, K. Ikegashira, S. Noji, H. Yamanaka, Y. Hara, H. Goto,
R. Mizojiri, Y. Niwa, T. Noguchi, I. Ando, S. Ikeda, H. Hashi-
moto, Bioorg. Med. Chem. Lett. 2007, 17, 3181.
ACKNOWLEDGMENTS
PKS is indebted to UGC‐India for JRF (ID‐131818). P.B.
acknowledges CSIR‐India for the Project (Sanction letter
no. 01 (2459)/11/EMR‐II dated 16/05/2011). RB acknowl-
edges DST, India for DST‐Inspire Fellowship (IF160999).
ORCID
Ryan M. Richards http://orcid.org/0000-0001-8792-3964
Papu Biswas http://orcid.org/0000-0002-7697-849X
REFERENCES
[1] M. E. Welsch, S. A. Snyder, B. R. Stockwell, Curr. Opin. Chem.
Biol. 2010, 14, 347.
[10] J.‐J. Huang, M.‐K. Leung, T.‐L. Chiu, Y.‐T. Chuang, P. T. Chou,
Y.‐H. Hung, Org. Lett. 2014, 16, 5398.
[2] (a) Y. Bansal, O. Silakari, Bioorg. Med. Chem. 2012, 20, 6208; (b)
X. ‐J. Fang, P. Jeyakkumar, S. R. Avula, Q. Zhou, C. ‐H. Zhou,
Bioorg. Med. Chem. Lett. 2016, 26, 2584; (c) A. Kamal, M. P. N.
Rao, P. Swapna, V. Srinivasulu, C. Bagul, A. B. Shaik, K.
Mullagiri, J. Kovvuri, V. S. Reddy, K. Vidyasagar, N. Nagesh,
Org. Biomol. Chem. 2014, 12, 2370.
[11] (a) M. M. Heravi, S. Sadjadi, H. A. Oskooie, R. H. Shoar, F. F.
Bamoharram, Catal. Commun. 2008, 9, 504; (b) A. B. Allouma,
K. Bougrinb, M. Soufiaoui, Tetrahedron Lett. 2003, 44, 5935; (c)
K. Bahrami, M. M. Khodaei, I. Kavianinia, Synthesis 2007, 4,
547; (d) P. Gogoi, D. Konwar, Tetrahedron Lett. 2006, 47, 79;
(e) S. Lin, L. Yang, Tetrahedron Lett. 2005, 46, 4315; (f) D. Saha,
A. Saha, B. C. Ranu, Green Chem. 2009, 11, 733; (g) B. Das, H.
Holla, Y. Srinivas, Tetrahedron Lett. 2007, 48, 61; (h) Z. ‐H.
Zhang, L. Yin, Y. ‐M. Wang, Catal. Commun. 2007, 8, 1126;
(i) S. Hashem, H. S. Mona, M. Fatemeh, Can. J. Chem. 2008,
86, 1044; (j) A. Kumar, R. A. Maurya, P. Ahmad, J. Comb.
Chem. 2009, 11, 198; (k) H. Sharghi, M. Aberi, M. M.
Doroodmand, Adv. Synth. Catal. 2008, 350, 2380; (l) A. T.
Khan, T. Parvin, L. H. Choudhury, Synth. Commun. 2009, 39,
2339; (m) D. K. Maiti, S. Halder, P. Pandit, N. Chatterjee, J.
D. De, N. Pramanik, Y. Saima, A. Patra, P. K. Maiti, J. Org.
Chem. 2009, 74, 8086; (n) R. Ruiz, A. Corma, M. J. Sabater, Tet-
rahedron 2010, 66, 730; (o) M. A. Chari, D. Shobha, S. M. J.
Zaidi, B. V. S. Reddy, A. Vinu, Tetrahedron Lett. 2010, 51,
5195; (p) M. A. Chari, D. Shobha, T. Sasaki, Tetrahedron Lett.
2011, 52, 5575; (q) H. Jin, X. Xu, J. Gao, J. Zhong, Y. Wang,
Adv. Synth. Catal. 2010, 352, 347; (r) S. M. Inamdar, V. K. More,
S. K. Mandal, Tetrahedron Lett. 2013, 54, 579; (s) R. Chebolu, D.
N. Kommi, D. Kumar, N. Bollineni, A. K. Chakraborti, J. Org.
Chem. 2012, 77, 10158; (t) K. Bahrami, M. M. Khodaei, A.
Nejati, Green Chem. 2010, 12, 1237; (u) D. N. Kommi, P. S.
Jadhavar, D. Kumar, A. K. Chakraborti, Green Chem. 2013,
15, 798; (v) S. Santra, A. Majee, A. Hajra, Tetrahedron Lett.
2012, 53, 1974; (w) M.‐G. Shen, C. Cai, J. Fluor. Chem. 2007,
128, 232; (x) L.‐J. Zhang, J. Xia, Y.‐Q. Zhou, H. Wang, S.‐W.
Wang, Synth. Comm. 2012, 42, 328.
[3] P. A. Renhowe, S. Pecchi, C. M. Shafer, T. D. Machajewski, E.
M. Jazan, C. Taylor, W. Antonios‐McCrea, C. M. McBride, K.
Frazier, M. Wiesmann, G. R. Lapointe, P. H. Feucht, R. L.
Warne, C. C. Heise, D. Menezes, K. Aardalen, H. Ye, M. He,
V. Le, J. Vora, J. M. Jansen, M. E. Wernette‐Hammond, A. L.
Harris, J. Med. Chem. 2009, 52, 278.
[4] (a) F. Hernandez‐Luis, A. Hernandez‐Campos, R. Castillo, G.
Navarrete‐Vazquez, O. Soria‐Arteche, M. Hernandez‐
Hernandez, L. Yepez‐Mulia, Eur. J. Med. Chem. 2010, 45,
3135; (b) A. M. Khalil, M. A. Berghot, M. A. Gouda, Eur. J.
Med. Chem. 2010, 45, 1552; (c) H. Goker, D. W. Boykin, S.
Yildiz, Bioorg. Med. Chem. 2005, 13, 1707; (d) S. Braun, A.
Botzki, S. Salmen, C. Textor, G. Bernhardt, S. Dove, A.
Buschauer, Eur. J. Med. Chem. 2011, 46, 4419.
[5] (a) A. T. Mavrova, D. Yancheva, N. Anastassova, K. Anichina, J.
Zvezdanovic, A. Djordjevic, D. Markovic, A. Smelcerovic,
Bioorg. Med. Chem. 2015, 23, 6317; (b) G. A. Holloway, J. B.
Baell, A. H. Fairlamb, P. M. Novello, J. P. Parisot, J. Richardson,
K. G. Watson, I. P. Street, Bioorg. Med. Chem. Lett. 2007, 17,
1422.
[6] S. K. Tipparaju, S. Joyasawal, M. Pieroni, M. Kaiser, R. Brun,
A. P. Kozikowski, J. Med. Chem. 2008, 51, 7344.
[7] (a) P. S. Hameed, A. Raichurkar, P. Madhavapeddi, S.
Menasinakai, S. Sharma, P. Kaur, R. Nandishaiah, V. Panduga,
J. Reddy, V. K. Sambandamurthy, D. Sriram, ACS Med. Chem.
Lett. 2014, 5, 820; (b) B. Park, D. Awasthi, S. R. Chowdhury, E.
[12] (a) X. Wen, J. El Bakali, R. Deprez‐Poulain, B. Deprez, Tetrahe-
dron Lett. 2012, 53, 2440; (b) D. Hein, R. J. Alheim, J. Leavitt,
J. Am. Chem. Soc. 1957, 79, 427; (c) M. Phillips, J. Chem. Soc.

SAMANTA ET AL.
13 of 13
1928, 0, 2393; (d) D. Rambabu, P. R. K. Murthi, B. Dulla, M. V.
B. Rao, M. Pal, Synth. Commun. 2013, 43, 3083.
[18] G. V. Deodhar, M. L. Adams, S. Joardar, M. Joglekar, M.
Davidson, W. C. Smith, M. Mettler, S. A. Toler, F. K. Davies,
S. K. R. Williams, B. G. Trewyn, Langmuir 2018, 34, 228.
[13] (a) V. K. Tandon, M. Kumar, Tetrahedron Lett. 2004, 45, 4185;
(b) Y. K. Bommegowda, G. S. Lingaraju, S. Thamas, K. S. V.
Kumar, C. S. P. Kumara, K. S. Rangappa, M. P. Sadashiva, Tet-
rahedron Lett. 2013, 54, 2693; (c) J. L. Pinder, R. E. Davis, J.‐D.
Charrier, Tetrahedron Lett. 2014, 55, 4853; (d) N. Dubois, D.
Glynn, T. McInally, B. Rhodes, S. Woodward, D. J. Irvine, C.
Dodds, Tetrahedron 2013, 69, 9890.
[19] (a) T. Poon, J. Sivaguru, R. Franz, S. Jockusch, C. Martinez, I.
Washington, W. Adam, Y. Inoue, N. J. Turro, J. Am. Chem.
Soc. 2004, 126, 10498; (b) N. H. Nguyen, M. E. Levere, J. Kulis,
M. J. Monteiro, V. Percec, Macromolecules 2012, 45, 4606; (c)
C.‐G. Wang, A. Goto, J. Am. Chem. Soc. 2017, 139, 10551.
[20] C. T. Kresge, M. E. Leonowicz, W. J. J. C. Vartuli, J. S. Beck,
Nature 1992, 359, 710.
[14] (a) S. Das, S. Samanta, S. K. Maji, P. K. Samanta, A. K. Dutta,
B. Adhikary, P. Biswas, Tetrahedron Lett. 2013, 54, 1090; (b)
S. Samanta, S. Das, P. Biswas, J. Org. Chem. 2013, 78, 11184.
[21] (a) H. Sharghi, O. Asemani, S. M. H. Tabaei, J. Heterocyclic
Chem. 2008, 45, 1293; (b) M. Curini, F. Epifano, F. Montanari,
O. Rosati, S. Taccone, Synlett 2004, 10, 1832.
[15] (a) M. Curini, F. Epifano, F. Montanari, O. Rosati, S. Taccone,
Synlett 2004, 10, 1832; (b) L.‐J. Zhang, H.‐L. Lu, Z.‐W. Wu, Y.‐S.
Huang, Curr. Org. Chem. 2013, 23, 2906; (c) I. M. de Oliveira, S.
S. N. Vasconcelos, C. S. Barbeiro, T. C. Correra, A. Shamim, D.
C. Pimenta, I. Caracelli, J. Z. Schpector, H. A. Stefani, F.
Manarin, New J. Chem. 2017, 41, 9884.
SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of the
article.
[16] (a) P. Hongmanorom, A. Luengnaruemitchai, N. Chollacoop,
Y. Yoshimura, Energy Fuel 2017, 31, 8202; (b) S. Loganathan,
A. K. Ghoshal, Chem. Eng. J. 2017, 308, 827; (c) R. Sanz, G.
Calleja, A. Arencibia, E. S. Sanz‐Pérez, Micro. Meso. Mat.
2015, 209, 165; (d) M. Sasidharan, Y. Kiyozumi, N. K. Mal, M.
Paul, P. R. Rajamohanan, A. Bhaumik, Micro. Meso. Mat.
2009, 126, 234; (e) A. Bhaumik, T. Tatsumi, J. Catal. 2000,
189, 31.
How to cite this article: Samanta PK, Banerjee
R, Richards RM, Biswas P. Mesoporous silica
supported ytterbium as catalyst for synthesis of 1,2‐
disubstituted benzimidazoles and 2‐substituted
benzimidazoles. Appl Organometal Chem. 2018;
e4507. https://doi.org/10.1002/aoc.4507
[17] I. I. Slowing, B. G. Trewyn, V. S.‐Y. Lin, J. Am. Chem. Soc. 2007,
129, 8845.