Synergetic catalytic effect of ionic liquids and ZnO nanoparticles on the selective synthesis of 1,2-disubstituted benzimidazoles using a ball-milling technique

Article abstract of DOI:10.1039/c5gc00536a

A solvent-free selective green synthesis of 1,2-disubstituted benzimidazoles was developed using a ball-milling technique. Recyclable ionic liquid-coated ZnO-nanoparticles (ZnO-NPs, catalyst 5) were employed as a catalyst, which produced high yields, turn

Full text of DOI:10.1039/c5gc00536a

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DOI: 10.1039/C5GC00536A
Synergetic catalytic effect of ionic liquids and ZnO nanoparticles on
the selective synthesis of 1,2-disubstituted benzimidazoles using a ball-
milling technique
Hemant Sharma,a Navneet Kaur,b Narinder Singh,a,* and Doo Ok Jangc,*
aDepartment of Chemistry, Indian Institute of Technology Ropar, Rupnagar, Punjab140001, India
bCentre for Nanoscience & Nanotechnology, Panjab University, Chandigarh, Panjab 160014, India
cDepartment of Chemistry, Yonsei University, Wonju 220-710, Korea
nsingh@iitrpr.ac.in; dojang@yonsei.ac.kr
Abstract: A solvent-free selective green synthesis of 1,2-disubstituted benzimidazoles was developed using a
ball-milling technique. Recyclable ionic liquid-coated ZnO-nanoparticles (ZnO-NPs, catalyst 5) was employed
as a catalyst, which produced high yields, turnover number and turnover frequency because of synergetic
catalytic properties of ionic liquid and ZnO-NPs. The present method successfully employed the synthesis of
various 1,2-disubstituted benzimidazole derivatives in excellent yields with high selectivity. The reaction could
also be performed at a multi-gram scale with the same efficiency. A high eco-scale score and low E-factor
emphasize the ecofriendly nature of the present method.
Keywords: benzimidazole, ball-milling, ZnO-nanoparticle, ionic liquid, catalyst
Introduction
Benzimidazole derivatives are extensively employed in the pharmacological industry due to their broad
biological functions.1-4 Recently, benzimidazole derivatives have been involved in the treatment of ischemia-
reperfusion injury,5 hypertension6 and obesity.7 Benzimidazole derivatives also show potential activities toward
HIV,4 human cytomegalovirus (HCMV),4 herpes (HSV-1) 8 and influenza.9
For the synthesis of benzimidazole derivatives, condensation of o-phenylenediamines with carboxylic
acids is the most widely employed strategy, but it requires harsh dehydrating conditions.10,11 Other approaches,
such as the rhodium-catalyzed hydroformylation of N-alkenyl phenylenediamines,12 reductive cyclization
reaction of o-nitroaniline with aldehydes,13 palladium-catalyzed tandem carbonylation–cyclization reaction of
o-phenylenediamines,14 and palladium-catalyzed tandem dehydration-coupling reaction of 2-bromoaniline,15
have been reported. A major limitation of these methodologies is forming a mixture of 2-substituted and 1,2-
disubstituted benzimidazoles because of the low selectivity in terms of the N-1 substitution. Although a few
1

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methods have been reported that selectively synthesized 1,2-disubstituted benzimidazolesDaOsI: 1a0.1m03a9j/Co5rGpC0ro05d3u6Act,
they suffer from long reaction times, use of toxic catalysts and a long work-up process.16-19
Ball milling is an attractive mechanical technique for solvent-free synthesis, which avoids the use of
harmful solvents and toxic wastes.20 This technique has found many applications in the field of synthetic
organic chemistry such as asymmetric aldol reactions,21,22 Baylis–Hillman reactions,23 protection of diamines,24
oxidations,25,26 reductions,27 condensations,28,29 Wittig reactions,30 asymmetric Michael addition reactions,31
transition metal-catalyzed coupling reactions,32a-c click reaction,32d,e and synthesis of pyrimidines,32f indoles,32g
and pyrans.32h
Ionic liquids (ILs) gain considerable attention as they are possible environmentally benign catalysts.
They offer significant properties like a wide liquid range, negligible vapor pressure, high catalytic activity, good
thermal stability and adjustable physical and chemical properties that make them novel and green catalysts. 33,34
Various types of reactions using ILs as a catalyst have been reported, including alkylation, nitration,
Diels−Alder reactions, Michael addition and esterification of carboxylic acids with increasing overall yields and
reduction in reaction times.35-39 Immobilization of ILs on the surface of solid materials provides more efficient
protocols in terms of product separation and catalyst recovery.40,41 Organic polymers, inorganic materials and
magnetic nanoparticles have been employed as the supports.42,43 In this context, we report recyclable IL-coated
ZnO-nanoparticles (ZnO-NPs) for the selective synthesis of 1,2-disubstituted benzimidazoles using a ball-
milling technique.
Results and discussion
1-Ethyl-3-methylimidazolium bromide (1) and 1-methyl-3-carboxymethylimidazole bromide (2) were
immobilized on the surface of ZnO-NPs by in situ capping ILs on the surface of ZnO-NPs 3 using a sol-gel
method to produce compounds 4 and 5, respectively. The modified ZnO-NPs 4 and 5 have different sizes and
morphologies that were confirmed by dynamic light scattering (DLS) and scanning electron microscopy (SEM)
analyses (Figures S1 and S2). ILs act as an organic template or a structure-directing agent that governs the
growth of ZnO-NPs in a particular direction.44 The wurtzite-type structure of ZnO-NPs was confirmed by
powder X-ray diffraction (PXRD) studies (Figure S3). The structure of catalyst 4 represents the coating of
ligand 1 on the surface of ZnO-NPs. In the case of catalyst 5, the presence of carboxylic acid group on the
surface of ZnO-NPs was confirmed by IR spectra of catalyst 5, showing the peak at 3448 cm-1 corresponding to
–OH of carboxylic acid group (Figure S4).
For a model study, o-phenylenediamine and 4-hydroxy-3-nitrobenzaldehyde were chosen as model
compounds. Reactions of o-phenylenediamine with 4-hydroxy-3-nitrobenzaldehyde were performed in the
presence of different catalysts 1-5 at room temperature. A mixture of o-phenylenediamine with 4-hydroxy-3-
nitrobenzaldehyde in the presence of a 0.2 mol% catalyst was milled in a tungsten carbide milling jar without
2

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1
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solvent for 22 min at 600 rpm under argon. The progress of the reaction was monitored by H NMR and TLC.
DOI: 10.1039/C5GC00536A
The results are summarized in Table 1. ILs 1 and 2 gave moderate overall chemical yields of products 6 and 7
(Table 1, Entries 1 and 2). Catalyst 2 showed a higher selectivity for 1,2-disubstituted benzimidazole i.e.
compound 6, compared with compound 7. Very similar results were observed with catalysts 3 and 4 with
moderate overall yields with low selectivities (Entries 3 and 4). Catalyst 5 afforded only compound 6 without
detecting compound 7 with an excellent yield (Entry 5). A control experiment was performed without catalyst,
resulting in a low overall yield of products with an inversion of selectivity (Entry 6). These results confirm the
catalytic effect on the efficiency and selectivity of the reaction. The high selectivity of catalyst 5 was attributed
to the synergetic catalytic effect of IL 2 and ZnO-NPs 3. ZnO-NPs have a high affinity for COOH, OH and
C=N groups,45-48a and ILs act as a structure-directing agent. Thus, a 3D network is formed between ZnO-NPs 3
and IL 2.44 IL 1 does not form a 3D network with ZnO-NPs 3 because of the absence of a linker group such as
COOH.
Figure 1. Structure of catalysts 1-5.
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DOI: 10.1039/C5GC00536A
Table 1. Screening catalysts for the reaction of o-phenylenediamine with 4-hydroxy-3-nitrobenzaldehyde.a
entry
catalyst
product 6 product 7 overall yield selectivity
(%)b
(%)b
(6+7) (%)
(6/(6+7))
1
2
3
4
5
6
1
2
3
4
5
-
35
52
47
38
97
14
22
14
19
33
0
57
66
66
71
97
53
0.61
0.78
0.71
0.53
1
39
0.26
aReaction conditions: o-phenylenediamine (9.2 mmol), 4-hydroxy-3-nitrobenzaldehyde (18.5 mmol), catalyst
(0.2 mol%), 600 rpm, 20 milling balls (5 mm) in a milling jar (80 mL) at room temperature under argon.
bIsolated yield with column chromatography on silica gel.
The effect of the catalyst loading on the product yield and the catalytic activity like the turnover number
(TON) and turnover frequency (TOF) was investigated by varying catalyst 5 from 0.01 to 1.0 mol%. The results
are presented in Figure 2. The results show that the product yield, TON and TOF increase with increasing
amount of catalyst up to 0.2 mol%. A linear relation of the product yields, TON and TOF was observed with up
to 0.2 mol% catalyst. A further increase in the amount of catalyst led to a small decrease in terms of the product
yield and catalytic efficiency.
The reaction parameters, including milling times, ball to powder ratio, milling speeds and molar ratios of
aldehyde and amine were screened. The results are summarized in Table 2. The progress of the reaction was
1
monitored by recording the H NMR spectra of the reaction mixture at regular intervals. It is essential to stop
the reaction at an appropriate time to obtain product 6 in high yield (Entries 1-7). The highest yield of product 6
was obtained in 22 min at a milling speed of 600 rpm (Entry 4). The longer milling time decreased the yield of
product 6 (Entries 5-7). The milling speed also influenced the reaction efficiency. It took 120 min for
completion of the reaction at lower speed (100 rpm) than at 600 rpm (Entries 8-10). Milling at a speed (800 rpm)
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faster than 600 rpm generated side products and made the overall yield of product 6 decrease (Entry 11). The
DOI: 10.1039/C5GC00536A
molar ratio of aldehyde and amine was also important in attaining a high yield of product 6. The high yields of
product 6 with complete selectivities were obtained when the ratios of aldehyde and amine were 2:1. The use of
the equimolar ratio of aldehyde and amine afforded product 6 as a major product along with product 7 (Entry
12).
1
Figure 2. Relationship of the catalyst loading with the product yields calculated from the integration of H
NMR peaks, TON and TOF.
Table 2. Optimization of ball-milling conditions for the reaction of o-phenylenediamine with 4-hydroxy-3-
nitrobenzaldehyde.a
entry
time (min)
speed (rpm)
yield of 6 (%)b
1
2
3
4
5
6
7
8
5
12
17
22
30
45
120
22
45
120
22
600
600
600
600
600
600
600
100
100
100
800
600
35
69
88
97
91
86
83
52
73
87
83
39c
9
10
11
12
22
5

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a
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DOI: 10.1039/C5GC00536A
Reaction conditions: o-phenylenediamine (9.2 mmol), 4-hydroxy-3-nitrobenzaldehyde (18.5 mmol), catalyst 5
(0.2 mol%), 20 milling balls (5 mm) in a milling jar (80 mL) at room temperature under argon. bThe yield of 6
1
c
was calculated from the comparison of integration of the H NMR peaks. A 1:1 molar ratio of o-
phenylenediamine and 4-hydroxy-3-nitrobenzaldehyde was used.
To monitor the temperature during ball milling, a reaction was performed in a particular milling jar. The
milling jar had a special lid and transmitter. Temperature was monitored using EASY GTM software, observing
that the temperature increased as the milling time increased as shown in Table S1. Maximum temperature at 22
min (the time required to complete the reaction) was 30.0 ºC. It shows that the milling temperature is not much
far from room temperature. Ball to powder ratio is also an important parameter, significantly influencing the
yields of reaction. The productivity of milling process is proportional to weight ratio because of increase in
number of collision per unit time.48b The increase in collision frequency results in an increase in milling
temperature.48b To avoid the excessive heating, a range of ratio of ball to powder (from 20:3 to 20:4) was
employed in the present methodology with maximum temperature of 30 ºC. Further increase in ball to powder
ratio increased the yield of reaction with a small extent, but the temperature of milling process increased much.
Optimization of the ratio of ball to powder for each product is presented in Table S2.
With optimal reaction conditions, we investigated the scope and limitations of this methodology by
varying aldehydes. The results are presented in Table 3. The interesting feature of this methodology is that the
yields of the 1,2-disubstituted benzimidazole derivatives are independent of the structure of the aldehydes.
Aldehydes with an electron-withdrawing group and with an electron-donating group afforded excellent yields of
1,2-disubstiuted benzimidazole derivatives. Another promising feature of the present methodology is that the
products were obtained after washing with water followed by a small amount of methanol for quick drying.
These advantages distinguished the present methodology from previously reported methods, which required a
large amount of organic solvents and time-consuming tedious purification processes.
Table 3. Synthesis of various 1,2-disubstiuted benzimidazole derivatives under solvent-free, ball milling reaction
conditions.a,b
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DOI: 10.1039/C5GC00536A
aReaction conditions: o-phenylenediamine (9.2 mmol), aldehyde (18.5 mmol), catalyst 5 (0.2 mol%), 600 rpm,
20 milling balls (5 mm) in a milling jar (80 mL) for 22 min at room temperature under argon. bIsolated yield.
A plausible mechanism for the reaction was proposed to probe the role of catalyst 5 on selectivity
control. Two different pathways were previously suggested as shown in Scheme 1: (i) a sequence of bisimine
formation, cyclization and rearrangement (Path a)19, 20a, 49-52 and (ii) a sequence of monoaldimine formation and
cyclization, followed by immonium rearrangement (Path b).53 Control experiments were performed to
differentiate Paths a and b. A reaction was performed in the presence of a radical scavenger, 2,2,6,6-
tetramethylpiperidinyloxy (TEMPO), affording no 1,2-substituted benzimidazole product. This implies that the
reaction proceeds via radical intermediates. With further studies, bisimine intermediate II was successfully
isolated and confirmed by spectroscopic data. A reaction of o-phenylenediamine with salicyaldehyde-d1 was
performed, resulting in the formation of a fully deuterium-labeled product at the N-benzyl position. This is
consistent with the process occurring via a 1,3-hydrogen shift. Based on these observations, a plausible
mechanism is suggested as shown as Path a in Scheme 1.
As stated earlier, ZnO-NPs have a high affinity for an imine-linkage. Ball-milling led to an increase in
surface energy and the number of surface defects.20a The mechanical energy generated by a milling process
promotes the transition of an electron from the valence band to the conduction band.20a,54,55 The imine
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intermediate accepts an electron from the conduction band, resulting in an anionic radical III, which is
DOI: 10.1039/C5GC00536A
immediately converted into another radical species IV.56 This intermediate undergoes a 1,3-hydrogen shift,
producing the final product.
Scheme 1. A plausible mechanism for the catalytic synthesis of 1,2-substituted benzimidazole derivatives.
Scalability is an important aspect for pharmacological industries. To examine the scalability of the
present methodology, a reaction of o-phenylenediamine with salicylaldehyde was performed at the 80 mmol-
scale with catalyst 5 (0.2 mol%) when the rest of the reaction conditions remained the same. The corresponding
1,2-disubstituted derivative 10 was obtained at a 90% isolated yield as shown in Scheme 2. The catalytic cycle
was one of the main factors in estimating the overall cost of the products. To examine the recyclability of
catalyst 5, a reaction of o-phenylenediamine and salicylaldehyde was performed. At the end of the reaction, the
crude product was washed with a mixture of methanol-acetone (1:1, v/v) and the catalyst precipitated. The
catalyst was washed with methanol three times. Catalyst 5 could be recycled six times without loss of the
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catalytic reactivity. In the seventh run, the catalytic activity decreased, producing a 64% yield of product 10 due
DOI: 10.1039/C5GC00536A
to changes in the morphology and size of catalyst 5 confirmed by SEM images and DLS studies (Figure S5).
Scheme 2. Scalability of the reaction to the multi-gram scale.
To fulfill the pharmacological need of benzimidazole derivatives, a direct one-pot green synthesis with a
high purity is highly in demand. The eco-scale and E-factor are the most widely accepted measures of the
environmental impact of the chemical processes.57-59 The eco-scale is a parameter to compare the safety,
economic and ecological features of the chemical process performed at a laboratory scale. It includes yield, cost,
safety, conditions and ease of purification. The advantage of this tool is to compare the safety, economic and
ecological features of the chemical reaction. The E-factor is defined as the mass ratio of waste to the desired
product, including chemical yield, all reagents, solvent losses, all process aids and even the energy required as
this generates waste in the form of carbon dioxide.60 The reaction with a high E-factor produces a more negative
environmental impact. The greenness of the present methodology was monitored by calculating the eco-scale
score and the E-factor. For comparison with literature, a reaction of o-phenylenediamine and salicylaldehyde
was chosen as a model reaction. The calculated environmental parameters (eco-scale score and E-factor in
Tables S3 and S4) were compared with literature methods. The values are summarized in Table 4. The present
methodology scored a high eco-scale value with a low E-factor. The method reported by Chebolu et. al. comes
in second place in the eco-scale score but it has a high E-factor. Only the present method provides a good
combination of the eco-scale score and E-factor, which advocates a clean and green synthetic route for the
synthesis of 1,2-disubstituted benzimidazole derivatives. Moreover, a high yield, short reaction time,
recyclability of the catalyst and ease of the purification make the present methodology more desirable than
others.
Table 4. Comparison of the syntheses reported in literature with the present methodologya
group
solvent
catalyst
temp time
yield
(%)
purification
ecoscale E-
scoreb
factor
column chromatography 60
ref
(oC)
rt
(h)
Chebolu CF3CH2
-
0.5
94
1.37
0.46
16
17
et. al.c
Shelkar
et. al.
OH
H2O
CeO2
rt
0.5
82
liquid-liquid
extraction/column
14
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chromatography
filtration or EtOH
recrystallization
liquid-liquid
extraction/filtration or
EtOH recrystallization
liquid-liquid
extraction/column
chromatography
liquid-liquid
extraction/column
chromatography
filtration/column
chromatography
Wan et. H2O
al.
TMSCl
SDS
85
rt
8
85
98
5D9OI: 10.1039/C51G.C1020536A 18
Bahrami H2O
0.3
55
49
52
41
0.55
28.3
0.30
19
49
50
et. al. c
Varala
CHCl3
L-proline
rt
rt
5
95
et. al. c
Oskooie no
Fe(ClO4)3
0.16 90
et. al. c
solvent
Jacob et. no
SiO2/ZnCl2 rt
0.3
15
0.3
72
78
94
1.19
4.5
52
61
-
al. c
solvent
Paul et.
al.
no
solvent
Fe2(SO4)3-
silicate
ZnO-NPs
90
rt
column chromatography 43
Present
Work
no
solvent
washing with H2O and
MeOH
65
0.17
aThe reaction of o-phenylenediamine with salicylaldehyde was selected for the comparison. bThe eco-scale
score was calculated using a literature method.57 For safety, chemicals having hazard code (B, C, Xn, Xi and O)
c
were assigned 5 penalty points for each. The reaction of o-phenylenediamine with benzaldehyde was chosen
for comparison.
Conclusions
A novel green synthetic route was developed for the facile synthesis of 1,2-disubstitiuted benzimidazole
derivatives using IL-coated ZnO-NPs as a catalyst under solvent-free conditions via a ball-mill technique. The
reaction was proven to be a radical reaction with a 1,3-hydrogen shift. The present methodology has a high eco-
scale and a low E-factor, which indicates greenness of the reaction. The ease of purification, solvent-free
conditions, recyclability of the catalyst and scalability to a multi-gram scale make the reaction an economical
and environmentally benign route for the selective synthesis of 1,2-disubsitiuted benzimidazoles on the
industrial scale.
Experimental Section
General
All chemicals and solvents were purchased from Sigma Aldrich and used as received without purification. A
planetary ball mill made of Fritsch “Pulverisette 7 premium line” (Fritsch GmbH, Idar-oberstein, Germany) was
employed. The reaction was performed in tungsten carbide grinding cups (80 mL) and milled with tungsten
carbide balls (20×5 mm). To ensure the purity of the reaction, all vessel and balls were cleaned several times
with acetone followed by aqua regia. 1H (400 MHz) and 13C (100 MHz) NMR spectra were recorded on a JNM-
ECS400 JEOL spectrophotometer in DMSO-d6 solvent. The splitting patterns were indicated as s (singlet), bs
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(broad singlet), d (doublet), dd (doublet of doublet), t (triplet), and m (multiplet). The PDAONI: 1a0l.y10t3i9c/aCl5GXC0’0P5E36RAT
PRO diffractometer was employed for analysis of the crystal structure of ZnO powder, operated at 45 KV, 40
mA using Ni-filtered Cu Kα radiation with a scan speed of 10º/min for 2θ in a range from 10 to 100. The sample
was air-dried and divided into fine powder for XRD analysis. A uniform layer was spread on a zero background
sample holder. The morphology of the nanoparticles was studied using scanning electron microscopy (SEM,
JEOL JSM-6610LV) at a voltage of 15 KV. A dilute solution of ZnO (100 µM) in ethanol was placed on carbon
tape and dried at room temperature under a vacuum. The Metrohm Microtrac Ultra Nanotrac Particle Size
Analyzer (Dynamic Light Scattering) was used to measure the hydrodynamic diameter of ZnO particles using a
DMSO/water (5:5, v/v) system as the dispersion medium.
Synthesis of ionic liquid and catalysts. 1-Ethyl-3-methylimidazolium bromide (1) was purchased from
Sigma Aldrich and 1-methyl-3-carboxymethylimidazole bromide (2) was prepared using a literature method.62
A sol-gel method was employed for the synthesis of ZnO nanoparticles. The ILs 1 or 2 was coated through in-
situ addition during the synthesis of ZnO nanoparticles and produced catalysts 4 or 5, respectively. Zn(ClO4)2
(595 mg, 2 mmol) and NaOH (120 mg, 3 mmol) was dissolved in 30 mL methanol along with the respective IL
(7 mmol). The resultant solution was heated to reflux for 2 h. Filtration produced a white product. The presence
of a wurtzite-type structure for ZnO-NPs was confirmed by PXRD. SEM and DLS studies were performed to
examine the morphology and size of the ZnO-NPs.
General procedure for the synthesis of 1,2-disubstituted benzimidazoles. A tungsten carbide
grinding beaker (80 mL) and milling balls (20 × 5 mm) were set as a reaction chamber. For each reaction,
particular aldehyde (18.5 mmol) and o-phenylenediamine (9.2 mmol) along with 0.2 mol% (4.0 mg) of the
catalyst 5 were milled for 22 min at 600 rpm at room temperature under argon. The product was purified by
washing with water followed by two washes with methanol for quick drying at room temperature.
4-(1-(4-Hydroxy-3-nitrobenzyl)-1H-benzo[d]imidazol-2-yl)-2-nitrophenol (6):63a 1H NMR (400 MHz,
DMSO-d6) δ 11.05 (s, 2H, -OH), 8.13 (s, 1H, Ar), 7.85 (d, J = 8.6 Hz, 1H, Ar), 7.68 (dd, J = 5.4, 3.2 Hz, 1H,
Ar), 7.51- 7.57 (m, 2H, Ar), 7.20 – 7.24 (m, 3H, Ar), 7.09 (d, J = 8.6 Hz, 1H, Ar), 7.00 (d, J = 8.5 Hz, 1H, Ar),
13
5.53 (s, 2H, -CH2); C NMR (100 MHz, DMSO-d6) δ 154.0, 153.1, 151.1, 139.3, 136.7, 136.4, 135.4, 134.3,
129.1, 126.2, 125.9, 125.5, 124.5, 123.0, 120.1, 119.2, 116.0, 112.3, 49.6. Anal. Calcd for C20H14N4O6: C, 59.12;
H, 3.47; N, 13.79. Found: C, 59.71; H, 3.28; N, 14.03.
1-Benzyl-2-phenyl-1H-benzo[d]imidazole (8):63b 1H NMR (400 MHz, DMSO-d6) δ 7.63 (dd, J = 7.3,
1.5 Hz, 4H, Ar), 7.36–7.24 (m, 4H, Ar), 7.21 (d, J = 4.5 Hz, 5H, Ar), 7.16–7.12 (m, 1H, Ar), 5.18 (s, 2H, -CH2);
13C NMR (100 MHz, DMSO-d6) δ 153.7, 142.2, 137.0, 136.7, 132.9, 129.4, 129.0, 128.8, 128.5, 128.0, 126.6,
124.5, 123.0, 120.1, 112.31, 48.4. Anal. Calcd for C20H16N2: C, 84.48; H, 5.67; N, 9.85. Found: C, 84.79; H,
5.43; N, 9.77.
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4-(1-(4-Hydroxybenzyl)-1H-benzo[d]imidazol-2-yl)phenol (9):63b 1H NMR (400DMOI:H10z.1,03D9/MC5GSCO00-5d366)A δ
9.99 (s, 1H, -OH), 9.38 (s, 1H, -OH), 7.62 (dd, J = 6.4, 2.3 Hz, 1H, Ar), 7.53 (d, J = 8.6 Hz, 2H, Ar), 7.40 (dd, J
= 6.4, 2.3 Hz, 1H, Ar), 7.20–7.15 (m, 2H, Ar), 6.88 (d, J = 8.6 Hz, 2H, Ar), 6.80 (d, J = 8.5 Hz, 2H, Ar), 6.62 (d,
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13
J = 8.5 Hz, 2H, Ar), 5.38 (s, 2H, -CH2); C NMR (100 MHz, DMSO-d6) δ 162.6, 155.4, 153.1, 139.2, 138.5,
136.7, 131.5, 124.5, 123.0, 121.7, 118.5, 115.8, 114.5, 114.0, 112.3, 49.6. Anal. Calcd for C20H16N2O2: C, 75.93;
H, 5.10; N, 8.86. Found: C, 76.11; H, 5.32; N, 8.73.
2-(1-(2-Hydroxybenzyl)-1H-benzo[d]imidazol-2-yl)phenol (10):63b 1H NMR (400 MHz, DMSO-d6) δ
13.18 (s, 1H, -OH), 11.06 (s, 1H, -OH), 7.67 (d, J = 8.0 Hz, 1H, Ar), 7.19–7.25 (m, 2H, Ar), 6.99 (t, J = 8.0 Hz,
3H, Ar), 6.85 (t, J = 8.0 Hz, 1H, Ar), 6.77 (d, J = 8.0 Hz, 1H, Ar), 6.66 (d, J = 8.0 Hz, 1H, Ar), 6.57 (t, J = 8.0
Hz, 1H, Ar), 6.48 (t, J = 8.0 Hz, 1H, Ar), 6.30 (d, J = 8.0 Hz, 1H, Ar), 5.35 (s, 2H, -CH2); 13C NMR (100 MHz,
DMSO-d6) δ 158.3, 157.1, 151.8, 139.2, 136.7, 130.6, 130.4, 129.1, 128.5, 125.3, 124.5, 123.0, 121.4, 120.1,
119.7, 118.6, 117.4, 112.8, 112.3, 44.3. Anal. Calcd for C20H16N2O2: C, 75.93; H, 5.10; N, 8.86. Found: C,
75.84; H, 5.01; N, 8.97.
3-(1-(3-Hydroxybenzyl)-1H-benzo[d]imidazol-2-yl)phenol (11):63b 1H NMR (400 MHz, DMSO-d6) δ
9.71 (s, 1H, -OH), 9.35 (s, 1H, -OH), 7.67 (dd, J = 6.5, 2.2 Hz, 1H, Ar), 7.34 (dd, J = 6.3, 2.0 Hz, 1H, Ar), 7.27
(t, J = 7.9 Hz, 1H, Ar), 7.21–7.17 (m, 2H, Ar), 7.12–7.09 (m, 1H, Ar), 7.05 (t, J = 7.9 Hz, 2H, Ar), 6.88 (dd, J =
8.0, 2.1 Hz, 1H, Ar), 6.58 (dd, J = 8.0, 1.9 Hz, 1H, Ar), 6.43 (d, J = 7.6 Hz, 1H, Ar), 6.33 (s, 1H, Ar), 5.43 (s,
13
2H, -CH2); C NMR (100 MHz, DMSO-d6) δ 158.2, 158.1, 153.8, 143.1, 138.9, 136.4, 131.7, 130.4, 123.13,
122.7, 120.0, 119.7, 117.4, 117.1, 116.5, 115.0, 113.2, 111.6, 47.9. Anal. Calcd for C20H16N2O2: C, 75.93; H,
5.10; N, 8.86. Found: C, 76.07; H, 5.21; N, 8.94.
1
4-(1-(3,4-Dihydroxybenzyl)-1H-benzo[d]imidazol-2-yl)benzene-1,2-diol (12): H NMR (400 MHz,
DMSO-d6) δ 9.37 (s, 1H, -OH), 9.19 (s, 1H, -OH), 8.82 (s, 1H, -OH), 8.78 (s, 1H, -OH), 7.59 (d, J = 7.2 Hz, 1H,
Ar), 7.29 (d, J = 7.4 Hz, 1H, Ar), 7.19–7.07 (m, 3H, Ar), 6.94 (d, J = 9.7 Hz, 1H, Ar), 6.79 (d, J = 8.2 Hz, 1H,
13
Ar), 6.60 (d, J = 8.0 Hz, 1H, Ar), 6.35 (s, 1H, Ar), 6.30 (d, J = 7.8 Hz, 1H, Ar), 5.30 (s, 2H, -CH2); C NMR
(100 MHz, DMSO-d6) δ 152.1, 146.1, 144.4, 144.2, 139.2, 136.7, 127.6, 124.5, 124.2, 123.0, 121.7, 120.4,
120.1, 116.59, 116.2, 116.0, 114.5, 112.3, 49.6. Anal. Calcd for C20H16N2O4: C, 68.96; H, 4.63; N, 8.04. Found:
C, 69.12; H, 4.69; N, 7.98.
1
3-(1-(2,3-Dihydroxybenzyl)-1H-benzo[d]imidazol-2-yl)benzene-1,2-diol (13): H NMR (400 MHz,
DMSO-d6) δ 15.58 (s, 2H, -OH), 9.56 (s, 2H, -OH), 8.45 (d, J = 8.4 Hz, 1H, Ar), 7.90 (d, J = 9.1 Hz, 1H, Ar),
7.78 (d, J = 8.0 Hz, 1H, Ar), 7.50 (ddd, J = 8.4, 6.9, 1.3 Hz, 1H, Ar), 7.42 (dd, J = 7.9, 1.2 Hz, 1H, Ar), 7.35–
7.29 (m, 1H, Ar), 7.07–6.96 (m, 2H, Ar), 6.80 (dd, J = 8.0, 1.3 Hz, 1H, Ar), 6.67 (td, J = 7.9, 1.3 Hz, 1H, Ar),
13
5.03 (s, 2H, -CH2); C NMR (100 MHz, DMSO-d6) δ 149.7, 148.7, 146.9, 145.6, 144.0, 139.2, 136.7, 126.1,
124.50, 123.0, 122.5, 121.6, 120.7, 120.1, 118.4, 114.6, 113.7, 112.3, 44.0. Anal. Calcd for C20H16N2O4: C,
68.96; H, 4.63; N, 8.04. Found: C, 68.84; H, 4.73; N, 8.11.
12

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2-(1-(2-Hydroxy-5-nitrobenzyl)-1H-benzo[d]imidazol-2-yl)-4-nitrophenol (14): H NMR (400 MHz,
DOI: 10.1039/C5GC00536A
DMSO-d6) δ 14.17 (s, 2H, -OH), 9.17 (s, 2H, Ar), 8.75 (d, J = 2.9 Hz, 2H, Ar), 8.23 (dd, J = 9.3, 2.9 Hz, 2H,
13
Ar), 7.58 (dd, J = 6.0, 3.3 Hz, 2H, Ar), 7.47 (dd, J = 5.9, 3.4 Hz, 2H, Ar), 5.37 (s, 2H, CH2); C NMR (100
MHz, DMSO-d6) δ 163.1, 162.4, 150.0, 140.2, 139.7, 139.2, 136.7, 126.3, 125.5, 124.5, 124.1, 123.1, 120.7,
120.1, 118.7, 115.7, 112.3, 45.2. Anal. Calcd for C20H14N4O6: C, 59.12; H, 3.47; N, 13.79. Found: C, 59.21; H,
3.41; N, 13.77.
2-(Pyridin-2-yl)-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazole (15):16 1H NMR (400 MHz, CDCl3) δ
8.58-8.55 (2H, Ar), 8.47–8.41 (m, 2H, Ar), 7.86–7.80 (m, 2H, Ar), 7.47 (td, J = 7.7, 1.7 Hz, 1H, Ar), 7.37–7.32
(m, 2H, Ar), 7.31–7.26 (m, 3H, Ar), 7.14–7.10 (m, 1H, Ar), 6.88 (d, J = 8.0 Hz, 1H, Ar), 6.28 (s, 2H, -CH2); 13C
NMR (100 MHz, CDCl3) δ 157.5, 150.4, 147.0, 149.3, 148.8, 142.8, 137.4, 137.0, 124.7, 124.0, 123.8, 123.1,
122.4, 121.7, 121.0, 120.2, 110.9, 51.2. Anal. Calcd for C18H14N4: C, 75.50; H, 4.93; N, 19.57. Found: C, 75.62;
H, 5.02; N, 19.72.
2-(Thiophen-2-yl)-1-(thiophen-2-ylmethyl)-1H-benzo[d]imidazole (16):63b 1H NMR (400 MHz,
DMSO-d6) δ 7.80–7.76 (m, 2H, Ar), 7.69 (dd, J = 5.9, 2.1 Hz, 3H, Ar), 7.56 (d, J = 7.7 Hz, 1H, Ar), 7.45 (d, J =
7.2 Hz, 1H, Ar), 7.36 (dd, J = 5.1, 1.1 Hz, 1H, Ar), 6.99 (d, J = 4.0 Hz, 1H, Ar), 6.93–6.89 (m, 1H, Ar), 5.90 (s,
13
2H, -CH2); C NMR (100 MHz, DMSO-d6) δ 147.5, 142.9, 139.9, 130. 2, 129.3, 129.0, 128.8, 128.4, 127.6,
127.2, 126.5, 123.5, 123.1, 119.5, 111.4, 43.6. Anal. Calcd for C16H12N2S2: C, 64.83; H, 4.08; N, 9.45. Found:
C, 64.79; H, 4.12; N, 9.51.
2,2’-((1E,1’E)-(1,2-Phenylenebis(azanylylidene))bis(methanylylidene))diphenol (II):63b 1H NMR
(400 MHz, DMSO-d6) δ 12.91 (s, 2H, OH), 8.90 (s, 2H, CH=N)), 7.62 (d, 2H, J = 8.0 Hz, Ar), 7.44–7.35 (m,
6H, Ar), 6.95–6.91 (m, 4H, Ar).
Acknowledgements
This work was supported by ISIRD grant from IIT Ropar.
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DOI: 10.1039/C5GC00536A
Graphical Abstract
Synergetic catalytic effect of ionic liquids and ZnO nanoparticles on the
selective synthesis of 1,2-disubstituted benzimidazoles using a ball-milling
technique
Hemant Sharma, Navneet Kaur, Narinder Singh,* and Doo Ok Jang*
A solvent-free selective synthesis of 1,2-disubstituted benzimidazoles was developed in the
present of recyclable ionic liquid-coated ZnO-nanoparticles using a ball-milling technique.