Chapter II

Page 25

Preparation and characterization of alumina, zirconia, manganese oxide

modified alumina and zirconia catalyst and there catalytic activity in

the synthesis of Benzimidazoles and Benzodiazepines

Chapter II

Page 26

Introduction

Benzimidazole (I) and benzodiazepine (II) are organic heterocyclic structural units found

in many pharmaceutical agents which exhibit a wide range of biological applications [1].

N

NH

R

Substituted benzimidazole

NH

N

R1

R

R

Substituted benzodiazepine

I II

Benzimidazoles

Various pharmacophores of N-1 substituted and 2-substituted benzimidazole

derivatives are employed as subunits of biologically important molecules[2, 3]. These

derivatives are structural isosteres of naturally occurring nucleotides, which allow them

to interact easily with the biophores [4]. Biological activities of benzimidazole

derivatives includes antimicrobial [5], anticancer [6], anti-inflammatory [7], antiviral [8],

antiparasitic [9], antiprotozoal [10], antihelminitics [11], protein kinase inhibitors [12]

and H+/K

+ ATPase inhibitors [13].

Polyfunctionality of 2-aminobenzimidazole molecule synthesized from the cyclic

guanidine moiety has made it a building block for the further synthesis of a large number

of derivatives of pharmacological interest [14], for instance in vivo and in vitro growth

inhibition activity against various strains of bacteria, fungi and yeast. Benzimidazoles

also exhibit significant activity against several viruses including HIV [15], herpes (HSV-

1) [16], influenza [17] and human cytomegalovirus (HCMV) [18].

Benzimidazoles and their derivatives are generally prepared starting from o-

phenylenediamine (OPDA) with a carboxylic acid and its derivative [19-21], orthoesters

[22, 23] in the presence of a strong acid such as p-TsOH and silica supported fluoroboric

acid at elevated temperature. Several other protocols have also been introduced in which

aldehydes [24], acid chloride [25], o-dinitrobenzene [26], (CH3)2NCH=NCH=N(CH3)2Cl,

Chapter II

Page 27

Gold’s reagent[27] and 2-nitroanilines [28] are used as one of the starting materials for

the synthesis of benzimidazoles. Brain and Steer have developed a new procedure for the

preparation of benzimidazole derivatives by palladium-catalyzed aryl-amination

chemistry [29].A solvent free synthesis of benzimidazoles under microwave irradiation

using Yb(OTf)3 [30] has been reported by Wang. et al. KSFclay [31], PPA [32], metal

halide supported alumina [33] and solid support [34, 35] have been used as catalysts in

the preparation of a number of substituted benzimidazoles. It is also evident from the

literature that not only different catalysts were investigated to activate the reactants in the

synthesis of benzimidazole derivatives but also the effect of variation of experimental

conditions has been studied.

Benzodiazepines

Benzodiazepines are another important class of organic heterocyclic compounds which

findapplications in medicinal chemistry. They are used astranquilizers [36], anti-anxiety

agents [37], anti-inflammatory agents [38], anticonvulsants and hypnotics [39, 40].

Benzodiazepines are valuable synthons used for the preparation of other fused ring

compounds such as triazolo- [41], oxadiazolo- [42], oxazino- [43] or furano-

benzodiazepines [44]. Benzodiazepine derivatives find commercial applications as dyes

for acrylic fibers and photography [45, 46].

Due to wide range of pharmacological activities, industrial and synthetic applications of

benzodiazepines and its derivatives, their synthesis has received good attention of

synthetic organic chemists;as a result several methods for their preparation have been

reported in the literature. These include condensation of o-phenylenediamines with

unsaturated carbonyl compounds [47]. These reactions have been carried out in the

presence of different kind of homogeneous and heterogeneous Lewis acid catalysts which

are either supported or unsupported.

The following are a few reports in which unsupported homogeneous catalysts were used

in the synthesis of benzodiazepines: Herbert and Suschitzky have synthesized

benzodiazepines using ketones in presence of BF3-OEt2 [48]. The applications of ionic

Chapter II

Page 28

liquid [49], Yb-(OTf)3 [50], Silver complex in CH3OH [51], ionicliquid (1-butyl-3-

methylimidazolium bromide) ([bmim]Br) [52] as homogeneous catalysts have also been

reported.

Unsupported heterogeneous catalysts such as MCM-41 [53], Amberlyst-15 [54],

heteropoly acids [55] and supported heterogeneous catalysts such as polyphosphoric acid

supported on SiO2 [56], POCl3 supported on MgO [57] and CeCl3·7H2O/NaI supported

on silica gel [58] are found to be good catalysts in the synthesis of

benzodiazepines.Microwave induced synthesis of benzodiazepines in the presence of

acetic acid [59], and Al2O3/P2O5 [60] have also been reported.

The homogeneous catalysts in general have been found to be selective, however the main

disadvantages of using these catalysts seems to be the separation and reusability of the

catalyst. Many times these methodologies are suitable only under certain synthetic

conditions. There also exist drawbacks such as long reaction time, use of environmentally

unfriendly reagents and high boiling solvents like dimethyl formamide (DMF) and

dimethyl sulfoxide (DMSO). However when heterogeneous catalysts were used, not only

the selectivity and yield of the product were good but also the catalysts could be easily

separated from the reaction mixture and reused, thus making the process environmentally

benign and economical. There is a scope for further development of a mild, efficient,

greener solid acid catalysts which can be easily recovered and reused from the reaction

mixture and thus overcome some of the above mentioned disadvantages. It is further

evident from the literature that no attempt has been made to correlate the catalytic activity

of the heterogeneous solid acid catalysts and their textural properties. In light of the

above, herein we have made an attempt to:

Prepare alumina, zirconia, manganese oxide supported alumina and manganese

oxide supported zirconia materials by simple precipitation-impregnation

technique. The selected materials are inexpensive, non-toxic and environmentally

benign.

Chapter II

Page 29

Characterize the materials for their textural properties such as crystallinity,

surface area, pore size, pore volume, surface acidty and surface morphology by

suitable techniques, inorder to correlate the catalytic activity with their textural

properties.

Determine the catalytic activity of the material under different reaction conditions

in the synthesis of pharmacologically important derivatives of benzimidazoles and

benzodiazepines.

Author’s work

The experimental work carried out involves the following three sections. These are

1. Preparation of catalysts

2. Characterization of the catalyst

3. Catalytic activity determination.

Each of the above sections follows a presentation of the results and discussions.

2.1 Preparation of the catalyst

In the present work alumina and zirconia were prepared from commercial aluminum

hydroxide and zirconium hydroxide. Manganese oxide supported on alumina and

manganese oxide supported on zirconia was prepared by simple precipitation-

impregnation method.The procedure followed and conditions are described below.

2.1.1 Preparation of alumina support

Commercial aluminium hydroxide Al(OH)3 (Across, Belgium. 99%pure) was used to

obtain alumina support. A required amount of aluminium hydroxide was transferred into

a silica crucible and dried at 120oC. A part of it taken in a silica crucible was placed in an

electric muffle furnace at 450oC for 5 h. These samples were stored in air tight containers

separately and used for further studies. Thus obtained alumina samples were abbreviated

as Al2O3-120 and Al2O3-450, where the numbers indicate the heat treatment

temperatures.

Chapter II

Page 30

2.1.2 Preparation of manganese oxide supported on alumina.

Manganese (5%) in the form of its oxide supported on alumina was prepared by simple

precipitation-impregnation method using manganese sulphate as a precursor. In a typical

procedure for the preparation of manganese oxide supported on alumina containing 5%of

manganese, 30.87 g of aluminum hydroxide (Al(OH)3) powder (Across chemicals,

Belgium, 99%pure) was suspended in 2 L of distilled water and mixed with 3.84 g of

manganese sulfate (MnSO4. H2O, Merck). The suspension thus obtained was heated to 70

oC on a heating Remi make Rota Mantle. The hot solution was stirred for 1 h and liquor

ammonia (28%aqueous NH3) was added slowly using a burette with stirring to precipitate

manganese as its hydroxide (pH 9).

The thick brown precipitate thus obtained was stirred for 2 h at 70oC to get a

homogeneous mixture which was left overnight undisturbed at room temperature. The

supernatant liquid was decanted and the solid was separated by filtration using Buchner

funnel fitted with Whatmann-1filter paper. The solid was washed with deionized water

until the washings were free from sulfate ions as confirmed by barium chloride test. The

solid wasdried in an air oven at 120oC for 12 h followed by calcination at 450

oC for 5 h

in a muffle furnace.The material dried at 120oC was abbreviated as Mn/Al2O3-120,

whereas the one calcined at 450oC was abbreviated as Mn/Al2O3-450.

2.1.3 Preparation of zirconia support.

Commercial zirconium hydroxide, Zr(OH)4 (Sigma Aldrich, 99.99% pure, India)

was used to obtain zirconia support. A certain amount of zirconium hydroxide was

transferred into silica crucible and dried at 120oC and a part of it taken in a silica crucible

was placed in an electric muffle furnace at 450oC for 5 h. these samples were stored in

airtight containers separately and used for further studies. These zirconia materials were

abbreviated as ZrO2-120 and ZrO2-450, where the numbers indicate the heat treatment

temperatures.

Chapter II

Page 31

2.1.4. Preparation of manganese oxide supported on zirconia

Manganese (5%) in the form of its oxide supported on zirconia was prepared by

simple precipitation-impregnation method using manganese sulphate as a precursor. In a

typical procedure for the preparation of manganese oxide supported on zirconia

containing 5% of manganese, 29.65 g of zirconium hydroxide [Zr(OH)4] powder (Sigma

Aldrich, 99.99% pure, India) was suspended in 2 L of distilled water and mixed with 3.84

g of manganese sulfate (MnSO4. H2O, Merck). The suspension thus obtained was heated

to 70oC on a heating Remi make Rota Mantle. The hot solution was stirred for 1 h and

liquor ammonia (28%aqueous NH3) was added slowly using a burette with stirring to

precipitate manganese as its hydroxide (pH 9).

Thus obtained thick brown precipitate was stirred for 2 h at 70oC to get a homogeneous

mixture which was left overnight undisturbed at room temperature. The supernatant

liquid was decanted and the solid was separated by filtration using Buchner funnel fitted

with Whatmann-1 filter paper. The solid was washed with deionized water until the

washings were free from sulfate ions as confirmed by barium chloride test. The solid was

dried in an air oven at 120oC overnight followed by calcination at 450

oC for 5 h in a

muffle furnace. The material dried at 120oC was abbreviated as Mn/ZrO2-120, whereas

the one calcined at 450oC was abbreviated as Mn/ZrO2-450.

2.2 Characterization of the catalysts

All the catalytic materials as prepared in the previous sections were thoroughly

characterized for their surface and bulk properties by appropriate techniques as indicated

below:

The exact percentage composition of manganese by Inductively Coupled Plasma-

Optical Emission Spectrometer (ICP-OES),

Crystallinity by Powder X-ray diffraction (PXRD).

Functional group analysis by Fourier Transform Infrared spectrophotometry (FT-

IR).

Specific surface area, pore size and pore volume by N2 adsorption method.

Brunauer-Emmett-Teller (BET) method.

Chapter II

Page 32

Quality and quantity of surface acid sites by Temperature programmed desorption

of ammonia (TPD-NH3) and n-butyl amine back titration method.

Thermal stability by Thermo gravimetric analysis (TGA)

Surface morphology by scanning electron microscopy (SEM) and transmission

electron microscopy (TEM).

The experimental procedures used in the above characterization techniques have been

briefly described in the following sections.

2.2.1 Inductively Coupled Plasma-Optical Emission Spectrometer (ICP-OES)

Quantity of manganese present in alumina and zirconia based catalysts was

estimated by ICP OES analysis technique using Thermo-iCAP 6000 Series instrument.

The operation conditions are mentioned as shown in Table 2.1. The standards ranging

from 20-140 ppm were prepared by digesting the catalyst material at pH 1-2 using nitric

acid (HNO3) and this solution was filtered through 0.45µ (micron) membrane filter and

used for further analysis by the instrument.

Table 2.1.Operating conditions of ICP-OES instrumental analysis

Auxiliary Flow (l/min) 0.5

RF power (W) 1200

Nebulization Pressure (psi) on

Speed peristaltic pump - Flush pump rate and Analysis pumprate

(rpm)

50

Speed peristaltic pump - Analysis pump rate (rpm) 50

Pump stabilization time (sec) 5

Integration Time in the UV and visible 15 - 10

Chapter II

Page 33

2.2.2. Powder X-ray diffraction (PXRD)

In order to ascertain crystalline/amorphous nature of the materials, their Powder

X-ray diffraction patterns were recorded on a Panalytical Xpert pro X-ray diffractometer

using Cu Kα radiation (λ=0.154 nm) a graphite crystal monochromator. Diffractograms

were obtained in the 2θ range from 5o to 70

o at 40 KV with a scanning rate of 2

o min

-1.

2.2.3 Fourier Transform Infrared spectrophotometry (FT-IR)

The characteristic bond vibrational frequencies of supports and supported

catalysts, as well as any anions of the precursor salts occluded into the catalysts during

their preparations, were identified by recording their FT-IR spectra as KBr pellets, with 4

cm-1

resolution using a Nicolet IR200 FT-IR Spectrophotometer in the range 400-4000

cm-1

.

2.2.4 Specific surface area, pore size and pore volume by N2 adsorption method.

Brunauer-Emmett-Teller (BET) method

The specific surface area, pore diameter and pore volume were evaluated by a

Micromeritics TriStar 3000 instrument. In this analysis the samples were degassed at 523

K for 5 h before the measurement. A calculated amount of sample was taken in a U

shaped tube. The sample was cooled to room temperature and then bought to 77 K using

liquid nitrogen as coolant. The sample was saturated with nitrogen when it is physically

adsorbed on the sample at the temperature of 77 k. The amount of nitrogen adsorbed was

recorded using a detector from which surface area is calculated. The pore volume and

pore size distributions were estimated at a relative pressure p/po and N2 adsorption

desorption isotherm using BJH model respectively.

2.2.5 Temperature programmed desorption of ammonia (TPD-NH3)

The TPD-NH3is a powerful technique used to determine total number of acidic

sites (total acidity) and the strength of acidic sites present on catalyst surfaces. The later

is temperature dependent. In a typical Temperature Programmed Desorption of ammonia

(TPD-NH3) experiment, 0.1 g of the catalyst was pretreated in He gas at 300 oC for 2 h

and cooled to room temperature. The adsorption studies were conducted at 100 oC by

Chapter II

Page 34

passing He gas containing 5% of NH3 over the catalyst. The catalyst surface was then

flushed with He gas for 2 h to flush of the physisorbed NH3. The catalyst with adsorbed

ammonia is then heated in the temperature range 50-700 oC. The amount of NH3desorbed

was calculated from the peak area of the already calibrated TCD signal.

2.2.6 n-butyl amine back titration method.

The total surface acidity of the material can be estimated by this method. About 0.5 g of

the catalyst was suspended in 25 ml of dry benzene solution of 0.05 M n-butyl amine.

The mixture was left for 24 h. during this period all the acid sites on the surface of the

solid get neutralized. The unreacted n-butyl amine was estimated by titrating against 0.05

M HCl using bromothymol blue as an indicator. The surface acidity of the solid catalyst

was calculated from the decrease in concentration of n-butyl amine. The calculation of

total acidity is as follows:

Molarity of n-butyl amine before the catalyst = x mole/L

Molarity of n-butyl amine after treating with the catalyst = y mole/L

Weight of the catalyst = W g.

The surface acidity of the catalyst = ( )

= m mol/g of the catalyst.

2.2.7 Thermo gravimetric analysis (TGA)

The percentage of weight loss at particular temperature and also the phase transitions

taking place during thermal treatment of the materials is given by TGA technique.

Thermo gravimetric analysis was carried out using a Mettle-teledo 851e TGA/SDTA

India private limited system driven by star e7.1 software. About 300 mg of the catalyst

sample was taken in an alumina crucible and heated in the TG balance at the rate of

5oC/min till 700

oCin the presence of 50 ml/min O2 gas. The temperature was plotted on

Chapter II

Page 35

abscissa and weight was plotted as ordinate and from the plot at different temperatures

the weight loss of the sample was measured.

2.2.8 Scanning electron microscopy (SEM)

The catalyst particle morphology was investigated by field-emission scanning electron

microscopy. SEM (Jeol JSM-7500F microscope operating at 20 kV at a working distance

of 8 mm).The sample for SEM analysis was prepared by physically adsorbing a thin layer

of the sample on an aluminum stud and subsequent coating of the sample with an electro

active material. SEM gives a 3D image of the catalyst at lower resolution and give

information on the surface topography on the average atomic number in the scattered

area.

2.2.9 Transmission electron microscopy (TEM)

TEM is a powerful method for investigating the morphology of supported metal catalysts.

TEM provides direct images of the catalyst's microstructure, enabling accurate particle

size distributions to be determined. In addition to the above it also provides information

about the deposition of the supported particles.

Samples for TEM were prepared by dispersion in ethanol for 10 min in an ultrasonic

bath. A drop of the sample was deposited on a holey carbon-coated copper grid and

allowed to dry before imaging. The sample was observed using a Philips Tecnai 10

electron microscope operated at 80 kV.

2.3 Catalytic activity studies

The catalytic activity of alumina, zirconia, manganese oxide supported alumina and

manganese oxide supported zirconia was investigated in a condensation reaction between

OPDA and an aldehyde or a ketone (Scheme 2.1).

Chapter II

Page 36

+

aetophenone

Ethanol, 80 oC

NH2

NH2

+O

H C6H5Ethanol, 80

oC

N

NH

C6H5

benzaldehyde

O

H5C6CH3

NH2

NH2

o-phenylenediamine

o-phenylenediamine

0.2 g catalyst

NH

N

CH3

C6H5

C6H5

0.2 g catalyst

1,5 substituted benzodiazepine

2-substituted benzodiazepine

Scheme 2.1 Synthesis of benzodiazepines and benzimidazoles from OPDA and an

aldehyde/ketone.

The catalytic activity studies were carried out in a 100 ml RB flask fitted with a water

cooled condenser on a heating rota mantle. In a typical procedure a mixture of OPDA (1

mmol), benzaldehyde (1 mmol) or acetophenone (2.2 mmol), ethanol (5 ml) and the

catalyst (0.2 g) taken in a 100 ml RB flask was heated to 80oC. The progress of the

reaction was monitored periodically by analyzing the reaction mixture by thin layer

chromatography technique (TLC) using a mixture of petroleum ether and ethyl acetate in

8:2 ratio as an eleuent. After completion of the reaction as indicated by the absence of

any reactant peak in TLC plate, the reaction mixture was diluted with 10 ml of ethanol

and filtered to recover the solid catalyst. The recovered catalyst was further washed with

acetone to remove any adsorbed organic molecule on the surface of the catalyst. The

filtrate was poured into a beaker containing crushed ice and stirred well for 10 min using

a glass rod. The precipitate obtained was separated by filtration from ice cold water, dried

and further purified by column chromatography using silica gel [100-200 mesh] with

petroleum ether and ethyl acetate as solvent. The solvent from the collected fractions

containing the pure product was removed using rota evaporator.

Chapter II

Page 37

2.4 Characterization of products

The melting points of the products were recorded in open capillary tube and were

uncorrected. The pure products were further analyzed by IR, GC-MS and1H NMR

techniques. Infrared spectra were recorded as KBr pellets of the samples using Nicolet

Model Impact 400D FT-IR Spectrometer with 4 cm-1

resolution from 4000 to 400 cm-1

.

The mass spectra were recorded on GC-MS Shimadzu QP 5000, GC-17A instrument. 1H

NMR spectrum was obtained in DMSO at 300 MHz using Bruker Avance NMR

spectrometer. 1H NMR Spectra was referenced to tetramethylsilane (TMS). Multiplicity

is indicated using the following abbreviations: s (singlet), d (doublet), dd (double

doublet), t (triplet), m (multiplet).

2.5 Results and discussion

The results obtained from various characterization techniques and catalytic activity

studies and a detailed discussions on these results are presented in the following sections.

2.5.1 Inductively Coupled Plasma-Optical Emission Spectrometer (ICP-OES)

The amount of manganese present in Mn/Al2O3-450 and Mn/ZrO2-450 was estimated by

ICP OES analysis technique. The exact percentages of manganese present were found to

be 4.32 and 4.77 respectively in Mn/Al2O3-450 and Mn/ZrO2-450. The results indicate

near quantitative precipitation of the manganese ions and also indicate that there is no

significant loss of manganese species upon calcinations of the catalyst at 450oC. The ICP

OES analysis of the catalysts recycled from catalytic activity studies was also performed.

It was observed that the leaching of manganese in alumina catalyst was very significant

after each cycle as the percentage of manganese dropped after each cycle, whereas in

Mn/ZrO2-450 catalyst leaching of manganese was very less compared to alumina

catalyst. The results obtained are as shown in the Table 2.2. The results indicate the

difference in the tenacity with which manganese species are associated with alumina and

zirconia supports.

Chapter II

Page 38

Table 2.2 The % of manganese present in alumina and zirconia catalyst before and after

first and second run.

Catalyst Mn % actual Mn % after first cycle Mn % after second cycle

Mn/Al2O3-450 4.32 4.03 3.72

Mn/ZrO2-450 4.77 4.65 4.43

2.5.2 Fourier Transform infrared spectroscopy (FT-IR)

Initially the FT-IR spectra of the precursors of alumina and zirconia supports i.e

aluminum hydroxide and zirconium hydroxide dried at 120oC were recorded for

reference and these spectra are provided Figure 2.1.

In the IR spectra of Al2O3-120 and ZrO2-120 are given in Figure 2.1. The -OH stretching

vibrational band of Al2O3-120 in the frequency range around 3500 cm-1

are sharp in

nature. This indicates the OH groups in this sample are relatively free and not formed

extensive hydrogen bonding. The Al-O bond stretching vibrations at 1050 and 751 cm-1

and bending vibrations at 596 cm-1 are also evident from the spectrum. These bands are

attributed to six-coordinated Al3+

ions [61]. The -OH stretching vibrational band of ZrO2-

120 around 3400 cm-1

is very broad, which indicates the presence of extensive hydrogen

bonded hydroxyl group and bending vibrational bands were observed in the region 1600

cm-1

and the absorption bands at 514-523 cm-1

correspond to Zr-O vibrations.

The IR spectra of Al2O3-450 and ZrO2-450 are shown in Figure 2.2. The -OH stretching

vibrational band around 3500 cm-1

in the IR spectra Al2O3-450 is very broad indicating

hydrogen bonded OH bonds. Further the bands corresponding to Al-O stretching and

bending vibrations are significantly altered indicating a possible change in the

arrangement of constituent atoms of the support. In case of ZrO2-450 no significant

change was observed upon calcinations. The broad hydroxyl stretching band in zirconia

also indicates the existence of surface water and interstitial water at 3650 cm-1

-3000 cm-1

[62].

Chapter II

Page 39

Manganese oxide is associated with alumina and zirconia support calcined at 450oC is

given in Figure 2.2. Mn/Al2O3-450 sample exhibited in its IR spectra a broad band with

decreased intensity of -OH bond stretching. Mn/Al2O3-450 and Mn/ZrO2-450 exhibited

bands in the region 1385-1377 cm-1

due to stretching vibrations of S=O bonds which are

ascribed to the presence of highly covalent sulfates [63]. These bands are not exhibited

by Al2O3-450 and ZrO2-450 samples. It may be inferred that the SO42-

ions were

incorporated into Mn/Al2O3-450 and Mn/ZrO2-450 catalysts during their synthesis.

4000 3500 3000 2500 2000 1500 1000 500

30

40

50

6040

50

60

Aluminum hydroxide

Tra

nsm

itta

nce

(%

)

Wave length (cm

-1)

Zirconium hydroxide

Figure2.1 FTIR spectra of pure aluminum hydroxide, Al(OH)3 and Zirconium hydroxide,

Zr(OH)4 heated at 120oC overnight.

Chapter II

Page 40

4000 3500 3000 2500 2000 1500 1000 500

(Al2O

2- 450)

Wavelength (Cm-1)

Tra

nsm

itta

nce

(%

)

(Mn/Al2O

2- 450)

(Mn/ZrO2- 450)

(ZrO2- 450)

Figure 2.2 FT-IR spectra of Al2O3-450, Mn/Al2O3-450, ZrO2-450 and Mn/ZrO2-450.

2.5.3 Powder X-ray diffraction pattern (PXRD)

PXRD patterns of Al2O3-120 and ZrO2-120 are given in Figure 2.3. The sharp diffraction

pattern of Al2O3-120 indicates its high crystalline nature. The diffraction patterns Al2O3-

120 reveal that it is present in Gibbsite phase [64]. This is known to be the most

crystalline phase of alumina. ZrO2-120 exhibited a broad X-ray diffraction patterns which

show its amorphous nature.

Calcination of Al2O3-120 and ZrO2-120 at 450oC induce phase transition in both the

samples. The PXRD patterns of Al2O3-450 and ZrO2-450 are given in Figure 2.4. The

Gibbsite alumina has changed to Boehmite phase. The diffraction peaks of Al2O3-450 at

2θ=14.54o, 28.31

o, 38.34

o, 49.03

o, 49.37

o, 55.35

o corresponding to the (020), (120),

(140), (031), (051) and (200) crystal planes respectively, corroborate the Boehmite phase

of alumina [65, 66]. Amorphous zirconia (ZrO2-120) turned crystalline upon calcinations

at 450oC and ZrO2-450 exhibited diffraction peaks at 2θ=28.14

o, 30.34

o, 31.52

o, 35.24

o,

Chapter II

Page 41

50.46o and 60.22

o corresponding to (111), (002), (022), (113) [67, 68] representing

tetragonal and monoclinic phases.

Upon manganese oxide deposition on both alumina and zirconia, phase changes are

observed. Mn/Al2O3-450 exhibited diffraction patterns at 2θ=32.67o and 36.14

o

corresponding to the Hausmannite Mn3O4 phase [69] in addition to the Boehmite phase

of alumina. The intensity of the peaks corresponding to Mn3O4 phase was very weak.

This is probably due low concentration of manganese present. W. Wang et.al have

reported that the appearance of crystalline Mn3O4 becomes predominant on Al2O3 support

only when the manganese loading reaches higher than 20% [70]. It is to be noted that in

the present investigation the percentage of manganese in Mn/Al2O3-450 is less than 5%.

In Mn/ZrO2-450 the diffraction peaks due to monoclinic phase (2θ=28.14o and 31.52

o)

have disappeared and peaks corresponding to tetragonal phase (2θ=30.34o, 35.24

o, 50.46

o

and 60.22o) were retained.

The tetragonal phase is known to be metastable and catalytically active. Several attempts

have been made to stabilize the tetragonal phase by pre and post synthesis modifications

[71]. It is reported that incorporation of SO42-

ions, WO3, MoO3, CeO2 [72-75] not only

stabilizes the tetragonal phase but also increases the acidity of zirconia and hence its

catalytic activity. We have noticed in the present studies that in the case of Mn/ZrO2-450

the intensity of the diffraction peaks corresponding to the tetragonal phase have increased

where as those of monoclinic phase have disappeared. The stabilization of catalytically

active tetragonal phase is attributed to the decrease in the particle size of zirconia [76].

Chapter II

Page 42

10 20 30 40 50 60 70

0

20

40

60

80

100

120

140

0

500

1000

1500

2000

2500

3000

3500

Zirconium hydroxide

2 (Degree)

Rel

ati

ve

inte

nsi

ty (

a.u

)

Aluminum hydroxide

Figure 2.3 PXRD patterns of aluminum hydroxide and Zirconium hydroxide heated at

120 oC overnight.

10 20 30 40 50 60 70

ZrO2-450

Inte

nsi

ty (

a.u

)

Mn/ZrO2-450

Al2O

3-450

2 (Degree)

Mn/Al2O

3-450

Figure 2.4 PXRD patterns of Al2O3-450, Mn/Al2O3-450, ZrO2-450 and Mn/ZrO2-450 .

Chapter II

Page 43

2.5.4 BET specific surface area, pore size and pore volume

The BET surface area, pore size and pore volumes of all the catalysts are given in the

Table.2.3. Al2O3-120 sample had very low BET surface area (1.38 m2/g) [64].

Whereas ZrO2-120 was relatively very high (174.26 m2/g), this is in agreement with

the crystalline nature of the former and amorphous nature of the later sample. Upon

calcination, the surface area of Al2O3-120 has increased where as that of ZrO2-120

has decreased significantly. This is in concurrence with the change in their PXRD

patterns.

The surface area of Mn/Al2O3-450 (209.67m2/g) was higher than Al2O3-120 but less

than Al2O3-450 (262.81m2/g). Whereas, the surface area of Mn/ZrO2-450 (92.37

m2/g) was lower than ZrO2-120 but more than ZrO2-450 (61.39 m

2/g). Thus the effect

of addition of manganese oxide on the surface area of alumina was different from that

of zirconia. Similar observations were made by Einaga, H etal, [77] and Qiang Zhao

[78]. It is reported that the presence of manganese oxide on zirconia strongly interacts

with zirconia which reduces surface diffusion and sintering. This results in

stabilization of tetragonal phase of zirconia and an increase in its surface area. Parida

et al., have made similar observation when molybdovanadophosphoric acid was

deposited on zirconia [79].

Table 2.3 BET surface area,Pore size and Pore volume of all the catalysts.

Catalyst BET surface area (m2/g) Pore size (Ǻ) Pore volume (cm

3/g)

Al2O3-120 1.38 147.7 0.0051

Al2O3-450 262.81 36.5 0.240

Mn/Al2O3-450 209.67 44.9 0.235

ZrO2-120 174.26 24.9 0.108

ZrO2-450 61.39 36.7 0.052

Mn/ZrO2-450 92.37 34.9 0.061

Chapter II

Page 44

2.5.5 Temperature programmed desorption of ammonia (TPD-NH3) analysis

Graphical representation of the amount of ammonia (mmolg-1

) desorbed from the surface

of Al2O3-450, Mn/Al2O3-450, ZrO2-450 and Mn/ZrO2-450 when subjected to heat

treatment in the temperature range 50oC to 700

oC are given in the Figure 2.5. Desorption

peak in the range 50-250oC accounts for weak acid sites, 250-350

oC for moderate strong

acid sites and above 350oC to strong acid sites present on the surface of the catalysts [80,

81].

The NH3 desorption on Al2O3-450 catalyst showed a strong peak around 400-600oC

indicating the presence of strong acid sites. The width of the peak indicates that the

distribution of acid site strength is very narrow. Similar observations were made in the

case of Mn/Al2O3-450. It is to be noted from the area under the peak that Al2O3-450

possessed higher concentration of weak acid sites compared to Mn/Al2O3-450.ZrO2-450

and Mn/ZrO2-450 exhibited the TPD-NH3 profiles characteristic of the presence of the

acid sites with a wide range of distribution of their strength. The area under the

desorption curves indicated that Mn/ZrO2-450 had higher concentration of acid sites than

ZrO2-450. Thus, incorporation of manganese oxide increased the strength and

concentration of acid sites in Mn/ZrO2-450. Further zirconia catalysts exhibited higher

concentrations of acid sites especially in the moderate to intermediate strong region than

the alumina catalysts.

Chapter II

Page 45

Figure 2.5 TPD-NH3 profile of various catalysts Al2O3-450 (a), Mn/Al2O3-450 (b), ZrO2-

450 (c) and Mn/ZrO2-450 (d).

2.5.6 Scanning electron microscopy (SEM)

SEM images of Al2O3-450, ZrO2-450, Mn/Al2O3-450 and Mn/ZrO2-450 samples are

shown in the Figure 2.6. Morphologies of Mn/Al2O3-450 and Mn/ZrO2-450 samples were

distinctly different from those of Al2O3-450 and ZrO2-450. In the case of Al2O3-450 the

large particles converted into a powder like texture whereas powder like ZrO2-450

developed into tubular like particles upon incorporation of manganese oxide. Thus the

influence of manganese oxide on the textural properties of zirconia in particular is

noteworthy, if one is interested in the preparation of nano rods of zirconium oxide under

uncomplicated conditions.

Chapter II

Page 46

Figure 2.6 SEM images of Al2O3-450 (a), ZrO2-450 (b), Mn/Al2O3-450 (c) and Mn/ZrO2-

450 (d) catalysts.

2.5.7 Transmission electron microscopy (TEM)

TEM images of Al2O3-450, ZrO2-450, Mn/Al2O3-450 and Mn/ZrO2-450 samples are

shown in Figure 2.7. It was interesting to observe that the big crystalline like particles of

alumina changed to powder like material on deposition of manganese oxide. It is also

noteworthy that powder like material of zirconia developed into rod like structures. TEM

images shows that the rods of Mn/ZrO2-450 have a diameter of 30 nm. These

morphological changes observed due to the incorporation of manganese into alumina and

zirconia has been found to have a significant effect on their catalytic properties as

described in the subsequent sections. This change in morphology is related to the higher

surface area of Mn/ZrO2 compared to ZrO2.

Chapter II

Page 47

Figure 2.7 TEM images of Al2O3-450 (a), ZrO2-450 (b), Mn/Al2O3-450 (c) and Mn/ZrO2-

450 (d) catalysts.

2.6 Catalytic activity studies

The results and discussions pertaining to the catalytic activity studies of all the catalysts

in the synthesis of substituted benzimidazoles and benzodiazepines, described in the

previous sections have been discussed in the following sections.

2.6.1 Catalytic activity and surface acidity of the catalysts

Catalytic activity of all the catalysts prepared and characterized as described in the

previous section was investigated in the synthesis of benzimidazoles and benzodiazepines

starting from OPDA and an aldehyde/ketone. This synthetic reaction is activated by an

acid catalyst. It is also mentioned in section (2.6.5) that all the catalysts investigated in

the present studies possessed acid sites with different strength and concentrations. The

following trends were observed in catalytic activity of the materials with respect to

isolated yield of the product in the synthesis of benzimidazoles and benzodiazepines.

Chapter II

Page 48

Alumina catalysts:Mn/Al2O3-450 > Al2O3-450 > Mn/Al2O3-120 > Al2O3-120

Zirconia catalysts:Mn/ZrO2-450 > Mn/ZrO2-120 > ZrO2-450 > ZrO2-120

The percentage yields of the isolated products in the condensation reaction between

OPDA and benzaldehyde/acetophenone conducted in the presence of solid acid

catalysts are given in the Table 2.4.The%yield of the isolated product was in the

range 30 to 95. When the reaction was carried out in the absence of the catalyst the

product yield was significantly very low (< 10%).

It is interesting to note that the catalytic activity order is same as that of total surface

acidity order. This signifies the importance of surface acidity in activating a

condensation reaction between OPDA and an aldehyde or a ketone.

Zirconia based catalysts exhibited higher surface acidity and hence catalytic activity

than the alumina based catalysts. The materials calcined at 450oC showed higher

catalytic activity than those dried at 120oC. Further the catalysts containing

manganese oxide performed better as catalysts than the pure supports. These

observations imply an increase in the surface acidity upon calcinations and

incorporation of manganese oxide. The increase in acidity may be attributed not only

to the increase but also to the generation of new Lewis acid sites on the surface of

supports. Transition metals are known to increase the Lewis acidity of the solid acids

such as metal oxides, zeolites, clays etc. [82]

Further, taking into account, the variation of other textural properties of the catalyst

on calcinations and incorporation of manganese oxide, it is worthwhile to mention

here that synergistic effects of the following parameters contribute to the overall

increase in the catalytic activity of the solid catalysts.

Enhancement of the intrinsic surface acid sites concentration of the supports on

calcination.

Contribution to the additional acidity by the presence of manganese oxide on the

solid supports

Stabilization of catalytically active tetragonal phase of zirconia on calcination in

the presence of manganese oxide.

Chapter II

Page 49

Table 2.4 Effect of catalyst, their acidity on the% yield of the product.

Catalyst Surface acidity (m.mol/g) Yield (%)*

benzimidazole benzodiazepine

Al2O3-120 0.75 30 30

Mn/Al2O3-120 1.00 67 60

Al2O3-450 1.01 52 35

Mn/Al2O3-450 1.25 90 85

ZrO2-120 0.50 34 47

Mn/ZrO2-120 1.50 70 74

ZrO2-450 1.25 65 70

Mn/ZrO2-450 1.70 95 93

*Isolated yield.

It is evident from the above discussions that Mn/ZrO2-450 exhibited highest catalytic

activity in terms of isolated yield and selectivity of the product. Hence further

optimization reactions were carried out to check the effect of the nature of the

solvent, reaction temperature, amount of the catalyst, generality of the catalyst in the

presence of Mn/ZrO2-450 as the catalyst.

2.6.2 Effect of Solvent and temperature

The percentage of isolated yields of benzimidazoles and benzodiazepines from the

reactions conducted in the presence of different solvents using Mn/ZrO2-450 as the

catalyst is shown in Figure 2.8(a). The high boiling solvents such as

dimethylsulphoxide (DMSO) and dimethylformamide (DMF) resulted in low yield of

the product and also presented handling problems. Acetonitrile and chloroform also

Chapter II

Page 50

resulted in lower yields. When water was used as a solvent, isolation of the products

from reaction mixture was found to be tedious. Though methanol when used as a

solvent did not pose any problem, it is not a preferred solvent because of its toxic

nature. Ethanol was found to be the best solvent for this reaction due to the following

advantages: low cost, easy work-up of the reaction mixture and good isolated yield of

the products. Hence for further studies in synthesis of substituted benzimidazoles and

benzodiazepines ethanol was used as a solvent.

The results of the experiments conducted at different temperatures are shown in

Figure 2.8 (b). When the reaction was conducted at room temperature the yield was

only 25%to 30%. However the percentage conversion of OPDA was found to

increase with good selectivity with an increase in the temperature up to 80oC, above

which the conversion of OPDA remained constant while the selectivity towards the

expected product decreased.

50

55

60

65

70

75

80

85

90

95

100

Ethan

ol

Meth

anol

Wat

er

Chloro

form

Aceto

nitrile

DM

F

DMSO

Solvents

% y

ield

Benzimidazole

Benzodiazepine

(a)

Chapter II

Page 51

Figure 2.8.Effect of (a) Solvents and (b) Temperature on the % of isolated yield of

benzimidazoles and benzodiazepines in the presence of Mn/ZrO2-450catalyst.

2.6.3 Effect of the amount and reusability of the catalyst

The condensation reactions were conducted using ethanol as the solvent at 80oC

using different amounts of Mn/ZrO2-450 catalyst in the range 0.05 to 1 g. The best

yield of the reaction product was obtained with 0.2 g of the catalyst. Higher amounts

of the catalyst did not improve the yield. The catalyst could be easily recovered by

simple filtration of the reaction mixture, followed by washing with acetone and

drying in oven at 120oC for 2 h. Recovery of the catalytic activity of the zirconia

based catalysts was better than alumina based catalysts. Zirconia catalysts could be

reused upto 5 cycles without any significant loss in catalyst efficiency (Table 2.5).

0

20

40

60

80

100

120

25 30 40 50 60 70 80 90 100

Temperature (oC)

% y

ield

Benzimidazole

Benzodiazepine

(b)

Chapter II

Page 52

Table 2.5 Recyclability of Mn/ZrO2-450 catalyst on the % yield of the products.

Entry No of cycles Yield (%)*

benzimidazolea benzodiazepine

b

a 1 95 93

b 2 90 85

c 3 88 83

d 4 87 75

*Isolated yield.

aReaction conditions: OPDA (1 mmol), aldehyde (1 mmol), 0.2 g Mn/ZrO2-450

catalyst, 5 ml ethanol.

bReaction condition: OPDA (1 mmol), ketone (2.2 mmol), 0.2 g Mn/ZrO2-450

catalyst, 5 ml ethanol.

2.6.4 Generality of the catalytic activity of Mn/ZrO2-450 catalyst

The activity of Mn/ZrO2-450 catalyst was investigated for its general application in

the condensation reaction of OPDA with other substituted aldehydes and ketones. All

the reactions were conducted using ethanol as the solvent at 80oC. The results in

terms of the isolated yield of the expected product with various substituted aldehydes

and ketones are presented in the Table 2.6 and Table 2.7 respectively. It is

noteworthy that an excellent yield of the expected product could be obtained within

1-2 h of the reaction time. Isolated products were analyzed by MP, IR, GC-MS and

1HNMR techniques. The condensation of OPDA with aldehydes was more efficient

than the ketones in terms of the duration of the reaction. Thus Mn/ZrO2-450 is a good

general catalyst to activate the condensation reaction between OPDA and

aldehyde/ketone for the synthesis of derivatives of benzimidazoles and

benzodiazepines in excellent yield and selectivity.

Chapter II

Page 53

Table 2.6 Condensation of OPDA with various substituted aldehydes in presence of

Mn/ZrO2-450 catalyst.

Entry Diamine Aldehyde Product Time

(min)

Yield

(%)

1

Benzaldehyde

60

95

2

2-Methyl

butyraldehyde

90

87

3

2-Ethylbutyraldehyde

90

90

4

4-Fluorobenzaldehyde

45

91

5

4-Chlorobenzaldehyde

45

85

6

Cinnamicaldehyde

35

92

7

Anisaldehyde

45

93

8

4-Cyanobenzaldehyde

45

90

NH2

NH2

N

NH

NH2

NH2

N

NH

CH3

CH3

NH2

NH2

N

NH

CH3

CH3

NH2

NH2

N

NH

F

NH2

NH2

N

NH

Cl

NH2

NH2

N

NH

Ph

NH2

NH2

N

NH

Ph O CH3

NH2

NH2

N

NH

CN

Chapter II

Page 54

Table 2.7 Condensation of OPDA with various substituted ketones in presence of

Mn/ZrO2-450 catalyst.

Entry Diamine Ketone Product Time (min) Yield (%)

1

Acetone

45

93

2

2-butanone

60

87

3

3-pentanone

90

92

4

Cyclopentanone

90

85

5

Cyclohexanone

90

85

6

Cycloheptanone

90

92

7

Acetophenone

60

90

8

4-nitro-

acetophenone

60

87

NH2

NH2

CH3NH

NCH3

CH3

NH2

NH2

CH3NH

N

CH3

CH3

NH2

NH2

EtNH

NEt

Et

CH3

NH2

NH2

NH

N

NH2

NH2

NH

N

NH2

NH2

NH

N

NH2

NH2

PhNH

N

CH3

Ph

NH2

NH2

4-NO2 Ph

NH

N

CH3

4-NO2 Ph

Chapter II

Page 55

The spectral data of some representative products

Entry 1 in Table 2.6

2-phenyl–1H–benzimidazole: Pale yellow solid. M.P 293-296 ºC; IR (KBr) 3042,

1440, 1403, 1271, 971 cm-1

. Ms: m/z=193(M+).

1HNMR (300 Hz, DMSO),

δH:7.22(m,2H), 7.48(m, 5H), 7.58(s, IH), 8.04(d, 2H,Ј=1.6Hz).

Entry 5 in table 2.6

2-(4-chlorophenyl)-1H-benzimidazole: pale yellow solid. M.P 291-293 ºC; IR (KBr)

3039, 1449, 1400, 1275, 961 cm-1

. Ms: m/z=228(M+).

1HNMR (300 Hz, DMSO), δH:

7.10(m, 2H), 7.6(d,2H,Ј=8.4Hz), 7.3(m, 2H), 8.2(d,2H,Ј=8.7Hz), 8.04(d,

2H,Ј=1.6Hz).

Entry 7 in Table 2.6

2-(4-methoxyphenyl)-1H-benzimidazole: yellow solid. M.P 225–226 ºC; IR (KBr)

3478, 2985, 1625, 1537, 1341, 1127, 1038, 835cm-1

. Ms: m/z=224(M+).

1HNMR

(300 Hz, DMSO), δH:8.00 – 8.08 (m, 2H), 7.20–7.60 (m, 6H), 3.52 (m, 3H).

Entry 1 in Table 2.7

2-methyl-2, 4-diphenyl-2,3–dihydro–1H-1,5-benzodiazepine: yellow solid. M.P 150-

152 ºC. IR (KBr) 3351, 1647, 1593 cm-1

. Ms: m/z=188 (M+).

1HNMR (300 Hz,

DMSO), δH: 1.73(s, 3H), 2.95(d, 2H, Ј =0.17Hz), 3.12 (d, 2H, Ј=0.17Hz), 3.38(br,

1H), 6.80-7.72(m, 14 H).

Entry 3 in Table 2.7

2,2,4,-triethyl-3-methyl-2,3-dihydro–1H-1,5-benzodiazepine: Yellow solid; M.P 143–

145 ºC; IR (KBr) 3324, 1637, 1582 cm-1

. Ms: m/z=245 (M+).

1HNMR (300 Hz,

DMSO), δH: 0.78-1.75(m, 14H), 2.63 (m, 2H), 3.13 (q, 1H, Ј=7.0Hz), 3.69 (br, 1H),

6.71-7.48 (m, 4H).

Chapter II

Page 56

Entry 7 in table 2.7

2-methyl-2,4-diphenyl-2-3-dihydro–1H-1,5-benzodiazepine: Yellow solid; M.P 149-

151 ºC; IR (KBr) 3349, 1643, 1593 cm-1

. Ms: m/z=313 (M+).

1HNMR (300 Hz,

DMSO), δH: 1.72 (s, 3H), 2.95 (d, 2H, J=0.17Hz), 3.68 (br, 1H), 6.93-7.79 (m, 14H).

2.6.5 Comparison of catalytic activity of Mn/ZrO2-450 catalyst with other reported

catalysts:

The superiority of the present method over reported methods was noticed by comparing

our results with those reported in the literature (Table 2.8). The reaction of OPDA with

an aldehyde or a ketone in presence of Mn/ZrO2-450catalyst was selected as the model

reaction and the comparison was made in terms of reaction temperature, and isolated

yield of the product. Some of the other reported methods require longer duration of the

reaction and the isolated yield is less compared to Mn/ZrO2-450 catalyst. The present

methodology progresses in the presence of an ecofriendly solvent ethanol at 80oC for 1 h.

The reaction distinctly requires shorter reaction time and the catalyst can be recycled

without significant loss in its activity for 4 cycles.

Table 2.8 Comparison of catalytic activity of MnZrO2-450 catalyst with other reported

catalysts.

Catalyst Solvent RT B1 B2 Reference

5% MnZrO2 Ethanol 1 85-95 - this work

Lewis acid catalysts Ethanol 1-14 5-93 - 83

Heteropoly acids Acetic acid 3 50-97 - 84

Amberlite IR-120 Ethanol/water 1.45-6.5 70-95 - 85

Chapter II

Page 57

PAS CH2Cl2 2 90 - 86

5% MnZrO2 Ethanol 1 - 85-93 this work

MCM-41 Ethanol 8 - 50-60 87

Ag3PW12O40 Solvent free 3-7 - 72-90 88

NbCl5 n-hexane 3-6 - 85-95 89

SbCl3-Al2O3 Solvent free 3-4 - 83-90 90

NOTE: RT. Reaction time (h), B1. Benzimidazoles yield (%),B2. Benzodiazepines yield

(%). PAS: Polyanilinesulphate.

Conclusion:

The catalytic activity of alumina, zirconia, and manganese oxide supported on alumina

and zirconia was determined in the condensation reaction between OPDA and

benzaldehyde/acetophenone for the synthesis of Benzimidazoles and Benzodiazepines.

The catalytic activity is dependent on the amount of surface acid sites of the catalyst. The

surface acid sites concentration on the supports increases on calcinations. Presence of

manganese oxide on the solid supports contributes to the additional acidity of the acidity.

Mild reaction conditions, easy work up and high yields along with reusability of the

catalyst make MnZrO2-450 a valuable alternative to the existing catalysts in the literature.

Chapter II

Page 58

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