Ionic Liquid

[cmmim][HSO4]

Catalyzed One Pot

Synthesis of

Triaryl Imidazoles

Chapter 5

Department of Chemistry, Sardar Patel University Page | 164

5.1. INTRODUCTION

Imidazole moiety is an important substructure in a number of molecules which exhibit as

array of biological and pharmacological activities. The imidazole ring system is an

important constituent of numerous natural products and medicinally important

compounds. In 1858, a scientist Heinrich Debus [1] for the first time reported a

multicomponent synthesis of imidazole from glyoxal, formaldehyde and ammonia. Later

in 1882, Radiziszewski and Japp independently reported a classical method to obtain 2, 4,

5-triphenyl imidazoles 4 by condensing 1, 2 dicarbonyl compounds 1 with different

aldehydes 2 and ammonia 3 in acidic medium [2,3]. Thr method was modified by

Weidenhagen in 1935[4]. Therefore, this reaction is generally known as the Radziszewski

reaction. Occasionally, it is also called the Radziszewski synthesis, Weidenhagen

Synthesis or Debus-Radziszewski imidazole synthesis.

Among different substituted imidazoles, 2,4,5-trisubstituted imidazoles derivatives

surmount much more attraction of chemist because of excellent biological activities.

Many drug like Omeprazole [5] a proton pump inhibitor, flumazenil [6]. A platelet

coagulation drug in animal and human beings, trifenagrel [7], is a 2,4,5- trisubstituted

aryl-1 H-imidazole derivatives. The effectiveness of the 2,4,5-trisubstituted aryl

imidazoles is substrate dependent; the use of more highly functionalized or sterically

hindered aldehydes severely reduced yields. Afterwards, several new modified

procedures were reported over the past two centuries for the synthesis of these biological

important scaffolds starting from banzil/benzoin, aldehydes and ammonium acetate. The

discovery and development of new catalytical reaction conditions have lead to general

methods for the direct preparation of 2,4,5- triaryl imidazole derivatives in high yield by

development of novel strategies. The detail reports are summarized below.

Chapter 5

Department of Chemistry, Sardar Patel University Page | 165

5.2 RECENT LITERATURE SURVEY

Although there is no general mechanism for Radziszewski synthesis of 2,4,5-triaryl

imidazoles in the cited literature, it is plausible that ammonia (or primary amine) reacts

with a α-dicarbonyl compound to form α-diimine, which then condenses with an

aldehydes to give 2,4,5-tri substituted imidazole derivatives. In the meantime, it is also

possible to form an oxazole as the by-product from this multicomponent condensation.

O

O

NH3O

NH2O

H

O

NHHO

H

-H2O

O

NH

NH3-H2O

NH

NH

HR

O

N

NH

R

OHH

N

NH2

R

NN

R OH

H

-H2O

N

H2N

R

N OH

R

NH

NO

NH2

H

R

-NH3

NO

ROxazole (By product)

Substituted Imidazole

Scheme 5.2 Mechanistic Pathway

HHN

NH

R

O

OH

H

Due to great biological importance, many synthetic strategies have been developed for

the synthesis of substituted imidazoles. Recently, numbers of articles are cited in

literature in which HY-zeolites/Silica gel, ZnCl4, NiCl2, NiCl2·2H2O, Iodine, Sodium

bisulfate, p-TSA, InCl3·3H2O, excess H2SO4, Alum, and PEG supported ionic liquids

have been employed as the catalyst for the synthesis of 2,4,5-triaryl-1H-imidazoles

Chapter 5

Department of Chemistry, Sardar Patel University Page | 166

starting from an aldehydes, a benzil, and ammonium acetate. Some recently reported

methods for the preparation of substituted imidazole derivatives are summarized below.

Sarshar, S. et. al. [8] recently reported the synthesis of highly substituted imidazoles

libraries on solid support using an aldehydes, an amine and a 1,2-dione in presence of

ammonium acetate. The synthesis was accomplished by attaching the aldehyde or amine

component to wang resin via ester or ether linkage. Claiborne, C. F. et. al. [9] carried out

a synthesis of tri and tetra substituted imidazoles under neutral condition by taking N-(2-

oxo)-amides with neat ammonium trifluoroacetate.

Balalaie, S. and Arabanian, A. [10] reported four-component condensation of benzil,

aromatic aldehydes, primary amines and ammonium acetate catalyzed by zeolite HY and

silica gel without any solvent under microwave irradiation leading to tetrasubstituted

imidazoles in high yields and purity. Balalaie, S. et. al. [11] reported a Zeolite HY and

silica gel as an efficient catalyst for the three-component condensation of benzil,

benzaldehyde derivatives, and ammonium acetate under solvent-free conditions and

microwave irradiation. Balalaie, S. et. al. [12] again reported one-pot, three-component

condensation of benzil, benzonitrile derivatives and primary amines on the surface of

silica gel under solvent-free conditions and microwave irradiation for the synthesis of

tetrasubstituted imidazoles in high yields.

Usyatinsky, A. Y. et. al. [13] carried out solvent-free microwave assisted synthesis of

2,4,5-substituted and 1,2,4,5-substituted imidazoles by condensation of 1,2-dicarbonyl

compound with aldehydes and amine using acidic alumina impregnated with ammonium

acetate as the solid support.

Frantz, D. E. et. al. [14] reported a one-pot synthesis of substituted imidazoles. The

cornerstone of this methodology involves the thiazolium-catalyzed addition of an

aldehyde to an acyl imine to generate the corresponding α-ketoamide in situ followed by

ring closure to the imidazole in a one-pot sequence. The extension of this methodology

was the one-pot synthesis of substituted oxazoles and thiazoles.

Sparks, R. B. and Combs, A. P. [15] reported a synthesis of 2,4,5-triaryl-imidazoles

directly from the keto-oxime in moderate to good yields via cyclization to the N-

hydroxyimidazole and an unprecedented in situ thermal reduction of the N-O bond upon

microwave irradiation at 200°C for 20 min. Wolkenberg, S. E. et. al. [16] reported a

simple, high-yielding synthesis of 2,4,5-trisubstituted imidazoles from 1,2-diketones and

Chapter 5

Department of Chemistry, Sardar Patel University Page | 167

aldehydes in the presence of NH4OAc. Under microwave irradiation, alkyl-, aryl-, and

heteroaryl-substituted imidazoles were formed in yields ranging from 80 to 99%.

Kidwai, M. et. al. [17] carried out the synthesis of 2,4,5-triaryl-1H-imidazoles under

microwave irradiation. The solvent free microwave assisted method seemed to be

convenient for the synthesis of 2,4,5-triaryl-1H-imidazoles. Kidwai, M. et. al. [18] also

reported elemental iodine as an efficient catalyst for the synthesis of 2,4,5-

triarylimidazoles in excellent yields via condensation of benzoin, ammonium acetate, and

aromatic aldehydes. This was a simple, one-pot, high yielding technique using cheap,

non-toxic iodine in catalytic amounts.

Siddiqui, S. A. et al. [19] reported an improved and rapid one-pot synthesis of 2,4,5-

triaryl imidazoles in a room temperature ionic liquid, which did not need any added

catalyst. The one-pot methodology resulted in excellent isolated yields in short reaction

times was characterized by simple work up procedures and efficient recovery and

recycling of the ionic liquid, which acted as a promoter. Sharma, G. V. M. et al. [20]

carried out the rapid synthesis of 2,4,5-trisubstituted and 1,2,4,5-tetrasubstituted

imidazoles in high yields using ZrCl4 as an efficient catalyst at room temperature. The

reaction required longer reaction time at room temperature depending upon the nature of

different aldehydes taken.

Wang, L. –M. et. al. [21] reported Ytterbium triflate as an efficient catalyst for the

synthesis of 2,4,5-triaryl-1H-imidazoles derivatives via three-component coupling

reactions of benzil, aldehydes and ammonium acetate under mild conditions. The process

presented was operationally simple, environmentally benign and had excellent yield.

Furthermore, the catalyst could be recovered conveniently and reused for at least three

reaction cycles without any loss of activity. Heravi, M. M. et. al. [22] carried out a

synthesis of 2,4,5-triaryl-1H-imidazoles in the presence of catalytic amount of

NiCl2·6H2O supported onto acidic alumina.

Mohammadi, M. M. et. al. [23] carried out the synthesis of trisubstituted imidazoles in

high yields in the presence of potassium aluminum sulfate (alum) as a non-toxic,

reusable, inexpensive and easily available reagent at 70oC. Sangshetti, J. N. et. al. [24]

reported synthesis of 2,4,5-Triaryl-1H-imidazoles from benzoin or benzil, ammonium

acetate, and aromatic or heteroaromatic aldehydes in the presence of sodium bisulfite as

the catalyst. The presented protocol offered significant improvements for the synthesis of

Chapter 5

Department of Chemistry, Sardar Patel University Page | 168

2,4,5-triaryl-1H-imidazoles with regard to yield of products, simplicity in operation, and

cost of catalyst.

Shitole, N. V. et. al. [25] used L-Proline as an efficient organocatalyst for one-pot

synthesis of 2,4,5-triaryl substituted imidazole by the reaction of an aldehyde, a benzil

and an ammonium acetate. The short reaction time and excellent yields made this

protocol practical and economically attractive. Wang, R. et. al. [26] used Yttrium(III)

trifluoroacetate as an efficient catalyst for reaction of benzil, aldehydes, and ammonium

acetate under mild and solvent-free conditions to afford the corresponding 2,4,5-

triarylimidazoles in high yields and short reaction time. The catalyst Yttrium(III)

trifluoroacetate could be recovered conveniently and reused several times in the reaction

without significant loss of catalytic activity.

Fong, D. et. al. [27] reported a novel recyclable temperature-dependant phase-separation

catalytic system comprised of PEG1000-based functional dicationic acidic ionic liquid

and propylene glycol monomethyl ether in the synthesis of 2,4,5-trisubstituted imidazoles

via one-pot three-component condensation with various aldehydes, benzil and ammonium

acetate in reasonable to good yield of 81–95%. The reaction was accomplished

homogeneously at 70oC and the product was separated from the catalyst system by

liquid/liquid phasic-separation at room-temperature.

Nagargoje, D. et. al. [28] carried out a one pot, three-component condensation of

benzoin/benzil, an aldehyde, and ammonium acetate using diethyl bromophosphate as a

mild oxidant for the synthesis of trisubstituted imidazole compounds. Under ultrasound

irradiation, a smooth condensation occurred to get the 2,4,5-triaryl-1H-imidazole

compounds in good to excellent yields.

Chapter 5

Department of Chemistry, Sardar Patel University Page | 169

5.3 OBJECTIVES

The objectives of the present work

1. To carry out ionic liquid mediated synthesis of 2,4,5-triaryl-1H-imidazoles in

order to search for a novel mild and efficient procedure.

2. To carry out study on effect of ionic liquid and solvent on reaction under different

energy sources.

3. To carry out spectroscopic characterization of synthesized 2,4,5-triaryl-1H-

imidazoles.

The work carried out to meet the said objective is described in the following sections.

The synthesis of 2,4,5-triaryl-1H-imidazoles using conventional energy sources and

microwave irradiation are correspondingly covered in section 5a and 5b. The

spectroscopic characterization is dealt with in section 5c with spectral data of all

synthesized 2,4,5-triaryl-1H-imidazoles, some selected spectra are also put on view in the

same section.

Chapter 5

Department of Chemistry, Sardar Patel University Page | 170

5.4 RESULT AND DISCUSSION

The synthesis of 2,4,5-triaryl-1H-imidazoles 4 (Scheme 5.4a.1) was carried out by one-

pot reaction of benzil 1, various aldehydes 2 and ammonium acetate 3 in presence of

carboxy functionalized ionic liquid [cmmim][HSO4] under conventional thermal heating

and under microwave irradiation in absence of any added catalyst. The most optimum

reaction condition and the role of ionic liquid to accelerate the reaction are discussed in

this section.

5.4.1 Reaction optimization under conventional method

Table 5.1 Optimization for the synthesis of 2,4,5-triaryl-1H-imidazole in

[cmmim][HSO4] for the model reaction of 4a

Entry CatalystAmmount of

Catalyst (mg)Solvent Temp.(

oC)

Time

(h)

Yield

(%)

1 [cmmim][HSO4] 400 - 70oC 4 34

2 [cmmim][HSO4] 100 EtOH Reflux 3 58

3 [cmmim][HSO4] 200 EtOH Reflux 3 78

4 [cmmim][HSO4] 300 EtOH Reflux 1.5 92

5 [cmmim][HSO4] 400 EtOH Reflux 1.5 89

6 No catalyst 0 EtOH Reflux 6 -

aAll the reactions were monitored to completion using TLC

bYield after crystallization of 4a.

Chapter 5

Department of Chemistry, Sardar Patel University Page | 171

Table 5.2 Effect of solvent on the synthesis of 2,4,5-triaryl-1H-imidazoles using 300

mg [cmmim][HSO4] as a catalyst for preparation of 4a.

Entry Solvent Temp. (oC) Time (h)a Yield (%)b

1 EtOH Reflux 1.5 91

2 MeOH Reflux 1.5 88

3 H2O Reflux 3 76

4 CH2Cl2 Reflux 3 60

5 CH3CN Reflux 3 65

aAll the reactions were monitored to completion using TLC

bYield after crystallization of 4a.

By taking carboxy functionalized ionic liquid, [cmmim][HSO4] as the catalyst, the one-

pot condensation of benzil (10 mmol), benzaldehyde (10 mmol) and ammonium acetate

(25 mmol) in ethanol was carried out. When reaction was carried out alone in carboxy

functionalized ionic liquid [cmmim][HSO4] (400 mg), the reaction proceeded with

comparatively low yield (Entry 1, Table 5.1). This may be due to low solvation capacity

of ionic liquid and hence reaction becomes non-homogeneous. The use of ethanol along

with ionic liquid increased the yield of the reaction. As the amount of ionic liquid

increased, the yield was increased up to 91% using 300 mg of [cmmim][HSO4] (Entry 4,

Table 5.1). It was noticed that there was no any significant change observed in reaction

time and yield by increasing the amount of ionic liquid [cmmim][HSO4] beyond 300 mg.

Same reaction was carried out by taking 400 mg ionic liquid in presence of ethanol as co-

solvent but no significant change in yield was observed (Entry 5, Table 5.1). No

significant formation of the product was observed, when reaction was carried out by

taking ethanol as the only solvent without ionic liquid (Entry 6, Table 5.1). Optimization

of the reaction condition was continued by employing 300 mg [cmmim][HSO4] in a

variety of solvent (Table 5.2). Ionic liquid [cmmim][HSO4] (300 mg) in ethanol was

found to be best optimization reaction condition for the formation of 2,4,5-triaryl-1H-

imidazoles.

Chapter 5

Department of Chemistry, Sardar Patel University Page | 172

5.4.1.1 Reaction characterization data for the synthesis of 2,4,5-triaryl-1H-

imidazoles

Based on above optimization, a number of 2,4,5-triaryl-1H-imidazoles were successfully

synthesized using 300 mg IL in ethanol at refluxing temperature from a variety of

aldehydes. It was noticed that aldehydes having electron donating/withdrawing

substituents reacted in short reaction time to afford the 2,4,5-triaryl-1H-imimdazoles in

very good to excellent yields. The various aldehydes employed and the characteristic data

for them are shown in Table 5.4a.3.

Table 5.3 Characteristic data for all synthesized 2,4,5-triaryl-1H-imidazoles

derivatives varying aldehydes

Compound RReaction time

a

(h) Yield (%)b

4a C6H5 1.5 91

4b 4-NO2C6H4 2.5 89

4c 4-Cl C6H4 2 91

4d 4-OCH3 C6H4 1.5 90

4e 4-OH C6H4 1.5 93

4f 4-OH-3-OCH3 C6H3 2 89

4g 4-F C6H4 2 90

4h 2-Cl C6H4 2 90

4i 3-NO2 C6H4 2.5 88

4j 2-NO2 C6H4 2.5 88aAll the reaction were run till the completion as indicated by TLC

b isolated yield after crystallization

All the reactions were monitored by TLC and proceeded till the completion of the

reaction as indicated by TLC. All the synthesized 2,4,5-triaryl-1H-imidazoles were

homogeneous on TLC and pure enough for further practical use. However, all the

Chapter 5

Department of Chemistry, Sardar Patel University Page | 173

synthesized compounds were crystallized from hot ethanol and the % yield was

calculated after crystallization step. All the compounds were characterized by melting

point,1H NMR,

13C NMR spectral techniques. Additional conformation for the structures

is also obtained by IR, 13C NMR (APT) and mass spectroscopic studies for the

representative samples from the series. All the data were in agreement with the

compounds cited in the literature.

5.4.1.2 Mechanism

The IL, [cmmim][HSO4] promotes the reaction due to its inherent Bronsted acidity. The –

COOH proton of [cmmim][HSO4] is capable of bonding with carbonyl oxygen of benzil

as well as an aldehyde. The capacity of IL to form the bond with substrate may push the

reaction in forward direction. Based on this, the plausible mechanism for the reaction is

given as under (Scheme 5.4).

Chapter 5

Department of Chemistry, Sardar Patel University Page | 174

5.4.1.3 Experimental

All the aromatic aldehydes, benzil, ammonium acetate and solvents were of loboratory

grade and used as obtained without further purification. The reactions were performed in

50 ml round bottom flask equipped with a refluxing condenser and magnetic stirrer in a

preheated oil bath.

5.4.1.3.1. General procedure for the synthesis of 2,4,5-triaryl-1H-imidazoles

A mixture containing benzil (10 mmol), substituted aldehydes (10 mmol), ammonium

acetate (25 mmol) and [cmmim][HSO4] (30 mg) in ethanol was refluxed in a 50 ml

capacity round bottom flask. After completion of the reaction (as indicated by TLC) the

reaction mixture was diluted with water (10 ml). The solid separated was filtered through

a sintered funnel under suction, washed with water (5x3 ml) and then crystallized from

hot ethanol to afford 2,4,5-triaryl-1H-imidazoles. The aqueous filtrate was heated at 80oC

under reduced pressure (10 mm Hg) for 5 h to leave behind the IL in neat complete

recovery, pure enough to use in next run without further purification. The recovered ionic

liquid was found to be equally effective for at least four runs in the synthesis of 4a.

5.4.1.3.2 Recovery of Ionic liquid

The activity of recycled ionic liquid was studied in the model reaction of benzil,

benzaldehyde, and ammonium acetate to afford 4a. After filtration of solid product,

aqueous layer was subjected to vacuo at 80°C under reduced pressure (10 mm of Hg) for

5 h to leave behind the ionic Liquid. This recovered IL was reused in the next run without

any further purification by charging with the same substrate. As shown in Figure 5.1 the

recovered ionic liqud can be reused at least four times without significant decrease in the

yields.

Chapter 5

Department of Chemistry, Sardar Patel University Page | 175

1 2 3 4

0

20

40

60

80

898990909091 9191

%Yield

Reaction cycle

Conventional

Microwave irradiation

91

Figure 5.1 Recyclability of [cmmim][HSO4] in model reaction of benzaldehyde, benzil

and ammonium acetate to afford 4a.

Chapter 5

Department of Chemistry, Sardar Patel University Page | 176

5.4.2 Reaction optimization under microwave irradiation

The literature survey reveals that many catalysts have been employed for the synthesis of

2,4,5-triaryl imidazoles but the potentiality of microwave/ionic liquid (MW/ILs)

synergetic couple uniquely for the synthesis of substituted imidazoles has not been

explored much. Keeping in mind the literature reports, we tried the combined use of ionic

liquid and organic solvent for the synthesis of 2,4,5-triaryl-1H-imidazoles under

microwave irradiation.

Initially, the reaction of benzil (10 mmol), benzaldehyde (10 mmol), and

ammonium acetate (25 mmol) was carried out by using 300 mg [cmmim][HSO4] in

ethanol as reaction promoter with respect to different power levels of MW set-up. The

optimization data with respect to power level of microwave are given in Table 5.4.

Table 5.4 Data representing the optimization of reaction condition for synthesis of

2,4,5-triaryl-1H-imidazoles under microwave set up

Entry

Power

levels in

Watt

Reaction

time

(min)a

%

YieldPurity of product

1 140 8.0 0 Reaction not proceeded

2 210 7.0 25

Contained some impurity along with

starting materials

3 240 7.0 25

4 280 7.0 37

5 350 6.0 70

6 420 5.0 93Fine purity

7 450 5.0 92

8 490 4.0 73Impure with degraded product, more loss

of yield9 560 4.0 69

10 700 4.0 58

aAll the reactions were run till the end as indicated by TLC.

From the series of experiments for the optimization of power level in microwave,

it was found that an increase in the power level of microwave above 450 watt the product

was found to be impure with degraded products. Thus, it was found that the reaction at

Chapter 5

Department of Chemistry, Sardar Patel University Page | 177

power level 6 (420 Watt) provided 2,4,5-triaryl-1H-imidazoles in good yield with high

purity. This power level was chosen for further studies to synthesize imidazoles to be

covered under the present study.

5.4.2.1 Characteristic data showing the synthesis of synthesized 2,4,5-triaryl-1H-

imidazoles under microwave irradiations

All the aldehydes have proceeded in short reaction times under MW irradiation to afford

2,4.5-triaryl-1H-imidazoles in excellent yields. MW/ILs induced protocol showed the

ability to tolerate various aldehydes containing both electron donating and electron

withdrawing substituents. Characteristic data for all the synthesized 2,4,5-triaryl-1H-

imidazoles are given in Table 5.5.

Table 5.5 Characteristic data for the synthesized 2,4,5-triaryl-1H-imidazoles under

MW irradiation

Compound RReaction timea

(min) Yield (%)b

4a C6H5 5.0 93

4b 4-NO2C6H4 6.5 90

4c 4-Cl C6H4 6.0 92

4d 4-OCH3 C6H4 5.5 93

4e 4-OH C6H4 5.0 94

4f 4-OH-3-OCH3 C6H3 6.0 91

4g 4-F C6H4 5.5 92

4h 2-Cl C6H4 5.5 92

4i 3-NO2 C6H4 6.5 90

4j 2-NO2 C6H4 6.5 88aAll the reaction were run till the completion as indicated by TLC

bIsolated yield after crystallization

Chapter 5

Department of Chemistry, Sardar Patel University Page | 178

5.4.2.2 Mechanism

The mechanistic pathway for the reaction is expected to be same as given in section

5.4.1.2 of this chapter.

5.4.2.3 Experimental

All the chemicals were of laboratory grade and used as obtained without any further

purification. The reactions were performed in scientific microwave system (Catalyst

system ‘CATA-R’ 700 W).

5.4.2.3.1 General procedure for the synthesis of 2,4,5-triaryl-1H-imidazoles

derivatives

A mixture containing benzil (10 mmol), aldehyde (10 mmol), ammonium acetate (25

mmol), and [cmmim][HSO4] (30 mg) in ethanol was charged in a 50 ml round bottom

flask. The mixture was stirred with magnetic stirrer for few seconds to ensure reaction to

become homogeneous. Then, reaction mixture was subjected to microwave irradiation at

60% power level (CATA-R, 700 W) for appropriate time. After completion of the

reaction (as indicated by TLC) the reaction mixture was diluted with water (10 ml). The

solid separated was filtered through a sintered funnel under suction, washed with water

(5x3 ml) and then crystallized from hot ethanol to afford 2,4,5-triaryl-1H-imidazoles. The

aqueous layer was subjected to vacuo at 80oC under reduced pressure (10 mm of Hg) for

5 h to leave behind the Ionic Liquid, pure enough to use in next run without further

purification. The recovered ionic liquid was found to be equally effective for at least four

cycles in the synthesis of 4a.

5.4.2.3.2 Recyclability of ionic liquid

In this study, the recyclability of carboxy functionalized [cmmim][HSO4] ionic liquid has

been investigated by using model reaction of benzil, benzaldehyde, and ammonium

acetate to afford 4a. Since the product is insoluble in water, it was easily filtered after

reaction mixture was diluted with water. After filtration, the aqueous layer was subjected

to vacuo at 80oC under reduced pressure (10 mm of Hg) for 5 h to leave behind the Ionic

Liquid. Recovered ionic liquid was subjected to next run of the reaction by charging with

Chapter 5

Department of Chemistry, Sardar Patel University Page | 179

the model reactants. As shown in Figure 5.1, the reaction can be repeated for at least four

times without any further purification of recovered ionic liquid to yield the targeted

compound with almost comparable efficiency.

5.5 CONCLUSION

In conclusion, the conventional method is an easy and general method for the synthesis of

2,4,5-triaryl-1H-imidazoles via one-pot condensation reaction between benzil, aldehyde

and ammonium acetate in presence of catalytic amount of ionic liquid. This method

worked under mild reaction condition, produced compounds in good yields and with

nearly complete recovery of ionic liquid. The activity of ionic liquid persisted for next

four runs with same efficiency with the model reaction. The synergic effect of

microwave-ionic liquid couple provides an easy and green route to synthesize 2,4,5-

triaryl-1H-imidazoles. The milder reaction conditions, absence of additional catalyst,

high reaction rates, excellent yields, easy work up procedures and MW-IL strategy make

this procedure more advantageous over the conventional acid/base catalyzed thermal

processes and its environment friendly with minimal or no waste.

Chapter 5

Department of Chemistry, Sardar Patel University Page | 180

5.6 CHARACTERIZATION

All the compounds were characterized by 1H NMR and 13C NMR (APT) techniques.

Additional confirmation was obtained by IR and mass spectrometry of some

representative compounds. 1H NMR and 13C NMR (APT) were recorded on BRUKER

AVANCE 400 MHz instrument using CDCl3 as a solvent. GC-MS data were recorded on

Perkin Elmer, Autosystem XL GC+. FT IR spectra were recorded on Shimadzu FT-IR-

S8401 spectrophotometer using KBr. The representative spectra are included at the end

of the section for perusal.1H NMR spectra for compound 4d and 4e are given in Figures

5.2 and 5.7 respectively. 13C NMR spectra for same compounds are described in Figures

5.3 and 5.8 respectively.13C NMR (APT) spectra for same compounds are described in

Figures 5.4 and 5.9 respectively. The mass spectra of same compounds are shown in

Figures 5.5 and 5.10 respectively. The infrared spectra for 4d and 4e are given in Figures

5.6 and 5.11 respectively. The other parameters like solubility and melting points were

checked by the standard methods and compared with the reported one if available from

the literature.

The1H NMR data is interpreted in terms of number of protons, splitting pattern and their

relative δ values. The 13C NMR APT experiments are also conducted for the additional

conformation of the structures. Addition conformation for the structures is also obtained

by mass spectrometric and by infrared spectroscopic studies for the representative

samples from the series. The molecular structures and characterization data for all

synthesized 2,4,5-triaryl-1H-imidazoles are given below in tabular form.

Chapter 5

Department of Chemistry, Sardar Patel University Page | 181

Spectral Data: 4a

2,4,5-triphenyl-1H-imidazole (4a)

Molecular Formula C21H16N2

Molecular Weight (gm/mol) 296.37

Melting Point (oC) 274-276

1H NMR (400 MHz, DMSO-d6) : δ = 7.46–8.18 (m, 15H), 12.61 (s, 1H) 13C NMR (400 MHz, DMSO-d6) : δ = 122.1, 127.2, 128.5, 129.1, 136.5

Spectral Data: 4b

2-(4-nitrophenyl)-4,5-diphenyl-1H-imidazole (4b)

Molecular Formula C21H15N3O2

Molecular Weight (gm/mol) 341.36

Melting Point (oC) 231-233

1H NMR (400 MHz, DMSO-d6) : δ = 7.25–7.57 (m, 10H), 7.78 (d, J=9 Hz, 2H), 8.50 (d,

J=9 Hz, 2H), 12.59 (s, 1H)

13C NMR : δ = 122.7, 124.2 127.3, 127.6, 132.8, 146.7, 160.8

Spectral Data: 4c

2-(4-chlorophenyl)-4,5-diphenyl-1H-imidazole

(4c)

Molecular Formula C21H15ClN2

Molecular Weight (gm/mol) 330.81

Melting Point (oC) 262

1H NMR (400 MHz, DMSO-d6) : δ = 7.47-7.55 (m, 10H), 7.62-7.64 (d, J=8 Hz, 2H),

8.04-8.06 (d, J=8.1 Hz, 2H), 12.47 (s, 1H)

13C NMR (400 MHz, DMSO-d6) : δ = 126.90, 127.89, 128.43, 131.71, 134.23, 135.81,

161.52

Chapter 5

Department of Chemistry, Sardar Patel University Page | 182

Spectral Data: 4d

2-(4-methoxyphenyl)-4,5-diphenyl-1H-imidazole

(4d)

Molecular Formula C22H18N2O

Molecular Weight (gm/mol) 326.39

Melting Point (oC) 234-236

1H NMR (400 MHz, DMSO-d6) : δ = 3.85 (s, 3H), 7.03-7.06 (d, J= 8 Hz, 2H), 7.23-7.52

(m, 10H), 8.01-8.04 (d, J= 8 Hz, 2H), 12.52 (s, 1H)

13C NMR (400 MHz, DMSO-d6) : δ = 55.16, 114.05, 123.09, 126.39, 126.66, 127.02,

127.37, 131.24, 135.26, 136.73, 145.59, 159.38

13C NMR (APT) : Up Peaks: 123.09, 145.59, 135.26, 136.73 159.38

Down Peaks: 55.16, 114.05, 126.39, 126.66, 127.02, 127.37, 131.24

IR (KBr): 1216, 1636, 2465, 2893, 3428

MS Data: m/z = 326 [M+]

Spectral Data: 4e

2-(4-hydroxyphenyl)-4,5-diphenyl-1H-imidazole

(4e)

Molecular Formula C21H16N2O

Molecular Weight (gm/mol) 312.36

Melting Point (oC) 198

1H NMR (400 MHz, DMSO-d6) : δ = 4.12 (s, 1H), 6.84-6.87 (d, J= 8 Hz, 2H), 7.18-7.55

(m, 10H), 7.89-7.92 (d, J= 8 Hz, 2H), 12.42 (s, 1H)

13C NMR (400 MHz, DMSO-d6) : δ = 115.37, 121.59, 127.00, 127.48,131.26, 136.55,

144.7, 159.2

13C NMR (APT): Up Peaks: 121.59, 131.26, 136.55, 144.70, 159.20

Down Peaks: 115.37, 127.00, 127.48, 128.57

IR (KBr): 1216, 1638, 2465, 2998, 3432, 3596

MS Data: m/z = 312 [M+]

Chapter 5

Department of Chemistry, Sardar Patel University Page | 183

Spectral Data: 4f

2-(4-hydroxy-3- methoxyphenyl)-4,5-diphenyl-

1H-imidazole (4f)

Molecular Formula C22H18N2O2

Molecular Weight (gm/mol) 342.39

Melting Point (oC) 191

1H NMR (400 MHz, DMSO-d6) : δ = 3.85 (s, 3H), 6.90–6.96 (d, J= 8.2 Hz, 1H), 7.21–

7.29 (m, 5H), 7.32–7.37 (d, J= 8.1 Hz, 1H), 7.48–7.50 (m, 5H), 7.65–7.72 (d, J=8 Hz,

1H), 12.52 (s, 1H)

13C NMR (400 MHz, DMSO-d6) : δ = 55.1, 108.5, 114.6, 118.1, 121.1, 126.2, 127.3,

127.5, 132.3, 146.3, 146.8

Spectral Data: 4g

2-(4-fluorophenyl)-4,5-diphenyl-1H-imidazole (4g)

Molecular Formula C21H15FN2

Molecular Weight (gm/mol) 314.36

Melting Point (oC) 313-315

1H NMR (400 MHz, DMSO-d6): δ = 7.43-7.52 (m, 10H), 7.59-7.64 (d, J=8 Hz, 2H),

7.98-8.00 (d, J=8.1 Hz, 2H), 12.49 (s, 1H)

13C NMR (400 MHz, DMSO-d6) : δ = 114.32, 127.45, 128.43, 131.21, 135.74, 147.87,

159.20

Spectral Data: 4h

2-(2-chlorophenyl)-4,5-diphenyl-1H-imidazole (4h)

Molecular Formula C21H15ClN2

Molecular Weight (gm/mol) 330.81

Melting Point (oC) 270-271

1H NMR (400 MHz, DMSO-d6): δ = 7.37–7.47 (m, 10H), 7.55–7.59 (dd, J=9 Hz, 1H),

7.67–7.69 (d, J=8 Hz, 2H), 8.12–8.15 (dd, J=8.79 Hz, 1H), 12.5 (s, 1H)

13C NMR (400 MHz, DMSO-d6) : δ = 125.4, 125.6, 126.5, 126.9, 127.2, 128.4, 128.6,

128.8, 129.6, 130.1, 130.5, 142.2

Chapter 5

Department of Chemistry, Sardar Patel University Page | 184

Spectral Data: 4i

2-(3-nitrophenyl)-4,5-diphenyl-1H-imidazole (4i)

Molecular Formula C21H15N3O2

Molecular Weight (gm/mol) 341.36

Melting Point (oC)

1H NMR (400 MHz, DMSO-d6): δ = 7.62-7.68 (m, 10H), 7.79-7.82(dd, J=7.9 Hz, 1H),

8.34-8.37 (dd, J=7.9 Hz), 8.62-8.69 (d, 2H), 12.58 (s,1H)

13C NMR (400 MHz, DMSO-d6) : δ = 123.54, 127.54, 129.43, 131.67, 133.98, 136.34,

146.65, 160.03

Spectral Data: 4j

2-(2-nitrophenyl)-4,5-diphenyl-1H-imidazole (4j)

Molecular Formula C21H15N3O2

Molecular Weight (gm/mol) 341.36

Melting Point (oC)

1H NMR (400 MHz, DMSO-d6): δ = 7.60-7.67 (m, 10H), 7.74-7.76 (t, J=7.9 Hz, 1H),

7.95-8.08 (d, 3H), 12.61 (s, 1H)

13C NMR (400 MHz, DMSO-d6) : δ = 123.21, 126.51, 127.52, 129.32, 133.25, 135.23,

138.20, 147.14, 150.55

Chapter 5

Department of Chemistry, Sardar Patel University Page | 185

Figure 5.21H NMR spectrum of compound 4d

Figure 5.313C NMR spectrum of compound 4d

Chapter 5

Department of Chemistry, Sardar Patel University Page | 186

Figure 5.413C NMR (APT) spectrum of compound 4d

Figure 5.5 Mass spectrum of compound 4d

Chapter 5

Department of Chemistry, Sardar Patel University Page | 187

Figure 5.6 Infrared spectrum of compound 4d

Figure 5.71H NMR spectrum of compound 4e

Chapter 5

Department of Chemistry, Sardar Patel University Page | 188

Figure 5.813C NMR spectrum of compound 4e

Figure 5.913C NMR (APT) spectrum of compound 4e

Chapter 5

Department of Chemistry, Sardar Patel University Page | 189

Figure 5.10 Mass spectrum of compound 4e

Figure 5.11 IR spectrum of compound 4e

Chapter 5

Department of Chemistry, Sardar Patel University Page | 190

5.7 REFERENCES

1. Debus, H., Ueber die Einwirkung des Ammoniaks auf Glyoxal. Annalen der

Chemie und Pharmacie 1858, 107 (2), 199–208.

2. Radziszewski, B., Chem. Ber., 1882, 15, 1493.

3. Japp, F. R.; Robinson, H. H., Chem. Ber., 1882, 15, 1268.

4. (a) Weidenhagen, E., Chem. Ber., 1935, 68, 1953. (b) Weidenhagen, E., Chem.

Ber., 1937, 70, 570.

5. Tangiwara, Y.; Aoyama, N.; Kita, T.; Shirakawa, K.; Komada, F.; Kasuga, M.K.,

Clin. Pharmacol. Ther., 1999, 66, 528.

6. Hunkeler, W.; Mohler, H.; Pieri, L.; Polc, P.; Bonetti, E.; Cumin, R.; Schaffner,

R., Nature 1981, 290, 514.

7. Abrahams, S.; Hazen, R.; Batson, A.; Phillips, A., J. Pharmacol. Exp. Ther.,

1989, 249, 359.

8. Sarshar, S.; Siev, D.; Mjalli, A. M. M., Imidazole libraries on solid support.

Tetrahedron Letters 1996, 37 (6), 835-838.

9. Claiborne, C. F.; Liverton, N. J.; Nguyen, K. T., An efficient synthesis of

tetrasubstituted imidazoles from N-(2-Oxo)-amides. Tetrahedron Letters 1998, 39

(49), 8939-8942.

10. Balalaie, S.; Arabanian, A., One-pot synthesis of tetrasubstituted imidazoles

catalyzed by zeolite HY and silica gel under microwave irradiation. Green

Chemistry 2000, 2 (6), 274-276.

11. Balalaie, S.; Arabanian, A.; Hashtroudi, M. S., Zeolite HY and Silica Gel as New

and Efficient Heterogenous Catalysts for the Synthesis of Triarylimidazoles under

Microwave Irradiation. Monatshefte für Chemie / Chemical Monthly 2000, 131

(9), 945-948.

12. Balalaie, S.; Hashemi, M. M.; Akhbari, M., A novel one-pot synthesis of

tetrasubstituted imidazoles under solvent-free conditions and microwave

irradiation. Tetrahedron Letters 2003, 44 (8), 1709-1711.

13. Usyatinsky, A. Y.; Khmelnitsky, Y. L., Microwave-assisted synthesis of

substituted imidazoles on a solid support under solvent-free conditions.

Tetrahedron Letters 2000, 41 (26), 5031-5034.

Chapter 5

Department of Chemistry, Sardar Patel University Page | 191

14. Frantz, D. E.; Morency, L.; Soheili, A.; Murry, J. A.; Grabowski, E. J. J.; Tillyer,

R. D., Synthesis of Substituted Imidazoles via Organocatalysis. Organic Letters

2004, 6 (5), 843-846.

15. Sparks, R. B.; Combs, A. P., Microwave-Assisted Synthesis of 2,4,5-Triaryl-

imidazole; A Novel Thermally Induced N-Hydroxyimidazole N−O Bond

Cleavage. Organic Letters 2004, 6 (14), 2473-2475.

16. Wolkenberg, S. E.; Wisnoski, D. D.; Leister, W. H.; Wang, Y.; Zhao, Z.;

Lindsley, C. W., Efficient Synthesis of Imidazoles from Aldehydes and 1,2-

Diketones Using Microwave Irradiation. Organic Letters 2004, 6 (9), 1453-1456.

17. Kidwai, M.; Saxena, S.; Ruby; Rastogi, S., An efficient synthesis of 2,4,5-

trisubstituted and 1,2,4,5-tetrasubstituted-1H-imidazoles. Bulletin of the Korean

Chemical Society 2005, 26 (12), 2051-2053.

18. Kidwai, M.; Mothsra, P.; Bansal, V.; Goyal, R., Efficient Elemental Iodine

Catalyzed One-Pot Synthesis of 2,4,5-Triarylimidazoles. Monatshefte für Chemie

/ Chemical Monthly 2006, 137 (9), 1189-1194.

19. Siddiqui, S. A.; Narkhede, U. C.; Palimkar, S. S.; Daniel, T.; Lahoti, R. J.;

Srinivasan, K. V., Room temperature ionic liquid promoted improved and rapid

synthesis of 2,4,5-triaryl imidazoles from aryl aldehydes and 1,2-diketones or α-

hydroxyketone. Tetrahedron 2005, 61 (14), 3539-3546.

20. Sharma, G. V. M.; Jyothi, Y.; Lakshmi, P. S., Efficient room-temperature

synthesis of tri- and tetrasubstituted imidazoles catalyzed by ZrCl4. Synthetic

Communications 2006, 36 (20), 2991-3000.

21. Wang, L.-M.; Wang, Y.-H.; Tian, H.; Yao, Y.-F.; Shao, J.-H.; Liu, B., Ytterbium

triflate as an efficient catalyst for one-pot synthesis of substituted imidazoles

through three-component condensation of benzil, aldehydes and ammonium

acetate. Journal of Fluorine Chemistry 2006, 127 (12), 1570-1573.

22. Heravi, M. M.; Bakhtiari, K.; Oskooie, H. A.; Taheri, S., Synthesis of 2,4,5-

triaryl-imidazoles catalyzed by NiCl2·6H2O under heterogeneous system. Journal

of Molecular Catalysis A: Chemical 2007, 263 (1–2), 279-281.

23. Mohammadi, A. A.; Mivechi, M.; Kefayati, H., Potassium aluminum sulfate

(alum): an efficient catalyst for the one-pot synthesis of trisubstituted imidazoles.

Monatshefte für Chemie / Chemical Monthly 2008, 139 (8), 935-937.

Chapter 5

Department of Chemistry, Sardar Patel University Page | 192

24. Sangshetti, J. N.; Kokare, N. D.; Kotharkar, S. A.; Shinde, D. B., Sodium

Bisulfite as an Efficient and Inexpensive Catalyst for the One-pot Synthesis of

2,4,5-Triaryl-1<i>H</i>-imidazoles from Benzil or Benzoin and

Aromatic Aldehydes. Monatshefte für Chemie / Chemical Monthly 2008, 139 (2),

125-127.

25. Shitole, N. V.; Shelke, K. F.; Sonar, S. S.; Sadaphal, S. A.; Shingate, B. B.;

Shingare, M. S., L-Proline as an Efficient Catalyst for the Synthesis of 2,4,5-

Triaryl-1H-Imidazoles. Bulletin of the Korean Chemical Society 2009, 30 (9),

1963-1966.

26. Wang, R. X.; Liu, C. S.; Luo, G. X., A convenient synthesis of 2,4,5-

triarylimidazoles catalyzed by Y(TFA)(3). Green Chemistry Letters and Reviews

2010, 3 (2), 101-104.

27. Fang, D.; Yang, J.; Jiao, C., Thermal-regulated PEG1000-based ionic liquid/PM

for one-pot three-component synthesis of 2,4,5-trisubstituted imidazoles.

Catalysis Science & Technology 2011, 1 (2), 243-245.

28. Nagargoje, D.; Mandhane, P.; Shingote, S.; Badadhe, P.; Gill, C., Ultrasound

assisted one pot synthesis of imidazole derivatives using diethyl bromophosphate

as an oxidant. Ultrasonics Sonochemistry 2012, 19 (1), 94-96.