Organic synthesis

Study and Synthesis of imidazole derivative

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 Table of Content

1. Introduction of imidazole
2. Biological importance
3. Physical Properties
4. Chemical properties
4.1. Aromaticity
4.2. Resonance
4.3. Tautomerism
4.4. Hydrogen bonding
4.5. Amphoteric
4.6. Characteristic reaction of imidazole

5. Medicinal use of imidazole derivatives

6. Synthesis of Imidazole
7. Triphenyl Imidazole
7.1. Introduction
7.2. Pharmacological importance
7.3. Laboratory Synthesis of Triphenyl Imidazole
7.4. Identification of compound
7.5. Application

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 Introduction

 Imidazole was first reported in 1858 by the German chemist Heinrich Debus
from Glyoxal and ammonia and named as Glyoxaline.

 The name "imidazole" was coined in 1887 by the German chemist Arthur
Rudolf Hantzsch (1857-1935).

Arthur Rudolf Heinrich Debus

(1824-1916)
Hantzsch

 Imidazole is a heterocyclic aromatic organic compound.

 It is further classified as an alkaloid. Imidazole refers to the parent
compound C3H4N2.
 Whereas imidazole’s are a class of heterocycles with similar ring structure
but varying substituents. This ring system is present in important biological
building blocks such as histidine, and the related hormone histamine.
 Imidazole can act as a base and as a weak acid. Imidazole exists in two
tautomeric forms with the hydrogen atom moving between the two nitrogen’s.

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 Biological Importance
Imidazole nucleus forms the main structure of some well-known components of
human organisms, that is, the amino acid histidine, vitamin b-12, a components of
DNA base structure and purines, histamine, and biotin.

• It is also present in the structure of many natural or synthetic drug

molecules
• In short, this ring system is present in important biological building blocks,
such as histidine and the related hormone histamine.
• Imidazole -containing drugs have a broaden scop in remedying various
dispositions in clinical medicine, such as antifungal drugs e.g.,
Clotrimazole, antiulcer drugs, cimetidine etc. and antimicrobial
nitroimidazoles, e.g., metronidazole, ornidazole etc.

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 metronidazole

Physical Properties

 Molecular formula: C3H4N2

 Appetence: white crystals
 Color: white
 Odor: ammonia like
 Molar mass: 68.08 gm
 Density: 1.01g/ml at 20C
 Melting point: 88-91C
 Boiling point: 256C
 Ph: 9.5-11.0
 RF value: 1.4801
 Flashpoint: 145c
 Solubility: soluble in ether, chloroform, pyridine, benzene. Insoluble in
water and petroleum ether

Chemical Properties

4.1. Aromaticity
 Imidazole have 3C and 2N, all are sp2 hybridized.
 sp2 hybridization is planner, it makes a planner imidazole ring structure.
 Each ring atoms also contains unhybridized p orbital that is
perpendicular to the plane of ƥ bones (plane of ring).

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  The total no. of non-bonding e- are 6 (3 of three C,1 from one N and 2 of
other N).
 The resonance of 6 e- follows the Hückel’s rule.

4.2.Resonance

4.3. Tautomerism
 Imidazole with a ring N-hydrogen are subject to tautomerism.
 4-methylimidazole equilibrium with 5-methylimidazole.

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 4.4. Hydrogen bonding

4.5. Amphoteric nature

 Imidazole is amphoteric in nature
 That means it can function as both acid and base
 As an acid, the Pka of imidazole is 14.5, making it less acidic them
carboxylic acids, phenols, and imides, but slightly acidic than alcohols.
 As a base, the Pka of the conjugate acid is approximately 7, making
imidazole approximately sixty time more basic then pyridine

4.6. Characteristic reaction of imidazole:

1. Electrophilic substitution
Imidazole is more susceptible to electrophilic attack than pyrazole.
Electrophilic aromatic substitution of imidazole involves through the
intermediate formation of ion.

Electrophilic substitution at 4 or 5 position in imidazole is favored due to

formation of highly stable resonance hybrid.

The attack at 2-position involves a canonical form with highly unfavored

nitrogen at3-position.in case, position 4 & 5 are blocked, substitution takes
place in position -2

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 a. Nitration: imidazole undergoes nitration with nitric acid and sulphuric
acid.

b. Sulphonation: it goes under sulphonation with disulfuric acid at 100C

c. Halogenation

i. Bromination: brominated with bromine in chloroform

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 ii. iodination: imidazole is iodinated with iodine in alkaline condition

2.alkylation:

The amino hydrogen atom of imidazole can be replaced by alkyl groups on

reaction with alkyl halide. n-alkyl imidazole’s isomerize on passing through red
hot tube to 2-alkyllimidazole.

3.coup ling
reaction

Coupling of imidazole with diazonium salts take place in the 2-position.

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 4. ring opening reaction:

Benzoyl chloride in the presence of sodium hydroxide opens the imidazole

ring.

5. oxidation and reduction:

Imidazole is extremely stable to oxidizing and reducing agents, but

hydrogen peroxide opens the nucleus to form oxide

Medical uses of imidazole

Metronidazole:

Metronidazole is used in the treatment of bacterial indications and

parasitic indications. It is used in infections of the brain, reproductive system,
gastrointestinal tract, vagina , skin and other area of the body

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 metronidazole

Tolazoline:

Tolazoline is a non-selective alpha-adrenergic receptor antagonist.it is a

vasodilator that is used to treat spams of peripheral blood vessels.

Methimazole:

Methimazole is used to trat hyperthyroidic, a condition that occurs when

the thyroid gland produce too much thyroid hormone.

Clotrimazole:

Clotrimazole is a topical broad-spectrum antifungal agent used for the

treatment of a wide variety of dermatophyte infections and candidiasis.

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 Synthesis of Imidazole

 There are no rally general ways of synthesizing imidazole and it is

invariable necessary to consider a number of divergent whenever a
synthesis is contemplated.

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 TRIPHENYL IMIDAZOLE (imidazole derivatives)

 INTRODUCTION

STRUCTURE: -

TRIPHENYL IMIDAZOL

Imidazole’s are probably the most well-known heterocycle which in

common and important feature of a verity product and medicinal
agent.

The compound C21H16N2 has been known since 1877. Although the crystal
structure of 36 derivatives of lophine are known, the structure of parent
compound has remained unknown until now.

The three phenyl rings bonded to the imidazole core are not coplanar with the
latter, with dihedral angles of 21.4 (3), 24.7 (3), and 39.0 (3) °, respectively,
between the phenyl ring planes in the 2-, 4- and 5-positions of the imidazole
ring. The molecules are packed in layers running perpendicular to the b axis.
There are acceptor and donor atoms for hydrogen bonds.

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 Synthesis of novel 2, 4, 5-triphenylimidazole derivatives seems to be main
focus of the medicinal research because compounds containing triphenyl
imidazole moiety provides a number of needful biological activities such as
analgesic and anti-inflammatory activities

Azole ring in place of abstractable hydrogen in 2, 4, 5-triphenylimidazole ring

potent antibacterial and anti-inflammatory activity.

Pharmacological importance
On the basis of various literature surveys Imidazole derivatives shows various
pharmacological activities:

 Anti-fungal and Anti-bacterial activity

 Anti-inflammatory activity and analgesic activity
 Anti-tubercular activity
 Anti-depressant activity
 Anti-cancer activity
 Anti-viral activity
 Antileishmanial activity
 Anti-arthritic activity
 Anti-angiogenesis

 Method of triphenyl imidazole preparation

1) Conventional heating: burugale swati

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 1,2-diphenylethane-1,2-dione 2,4,5-triphenyl-1H
imidazole

2) Catalyst used: NANA V. SHITOLE

3) Radiszewski synthesis: -

Laboratory Synthesis of triphenyl imidazole:-

 Aim: Synthesis of 2,4,5-triphenyl-1H-imidazole

 Chemical required: benzil, benzaldehyde, ammonium acetate, glacial
acetic acid, ammonium hydroxide
 Apparatus: RBF, oil bath, water condenser, beaker, glass funnel.

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  Principle: -Triphenyl imidazole prepared by debus Radziszewski
imidazole reaction used to synthesis of imidazole from Di carbonyl, an
aldehyde and ammonia.

Procedure: -

Benzil (25mmol), benzaldehyde (25mmol) and ammonium acetate

(130mmol) was dissolved in 100ml ethanoic acid (100%) in 250ml round
bottom flask containing a magnetic stirrer bar and was heated at the
mixture to reflux in oil bath for 1hr with stirring. After this time the
mixture was cooled to room temperature and was filtered to remove
precipitate which may be present. 500ml of water was added to filtrate
and collected the precipitate by filtration with suction. Filtrate was
neutralized with Ammonium Hydroxide and second crop of solid was
collected. The two crop of solid was combined and recrystallized from
aqueous ethanol.

Identification of triphenyl imidazole

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 Properties of triphenyl imidazole:

1. Colour: - yellow white

2. Melting point: 274-278C

3. Boling point: 427.96c

4. Solubility: soluble in methanol, in soluble in water

5. Lassaigne test:

Take a small piece of sodium metal in a glass fusion tube and heat till red-hot
add a little of the substance. Slowly heat this fusion tube till red-hot and drop
into an evaporating dish containing about 10ml of distilled water. in this way
make use of 2-3 fusion tube. Boil the solution for 5 min. now filter the solution
and use the filtrate for detection of element. The filtrate is known as
Lassaigne’s filtrate
Now take little portion of L.F. in test tube with freshly prepared feso 4 solution.
heat and cool the mixture and add little portion of dilute h 2so4 and add fecl3
solution at last. Blue colouration is observed
therefore
NITROGEN is present in compound.

6. TLC test - observed one spot in the mixture of hexane and ethyl acetate
(2:1)

Spectral data: Infra-red spectroscopy:

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 100 80
Transmittance [%]
60 40
20

3426.05

3080.33
3062.24
3037.70
2987.48
2967.12
2924.89
2853.26
2783.48
2730.06
2643.13
2540.10

2360.49
2341.61

1950.35
1883.07
1806.83

1676.34
1660.89
1594.97
1503.65
1488.37
1460.80
1408.71
1397.87
1324.21
1211.63
1175.27
1071.62
1027.98
966.60
916.02
876.15
766.02
734.44
697.33
643.19
605.33
510.56
458.17
3500 3000 2500 2000 1500 1000 500
Wavenumber cm-1

C:\FTIR DATA\MEAS\MEAS\MEAS\2,4,5 Triphenyl Imidazole BSc. Sem 6 16 03 23.0 2,4,5 Triphenyl Imidazole BSc. Sem 6 16 03 23 Instrument
16/03/2023
type and / or accessory

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Type of vibration Observance value

AR c-h stretching 3037,3062,3080 cm-1

C=C aromatic starching vibrations 1503,1594 cm-1

N-H stretching vibrations 3426.05 cm-1

N-H bending vibrations 1594,1660,1676 cm-1

Alkane starching vibrations 2987,2967,2924,2853 cm-1

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  Mass spectra of 2,4,5 Triphenyl imidazole :

BASE PEAK= 296

M. Wt. of Tri phenyl imidazole is 296 g/mol
Applications:
2, 4, 5-Triphenyl imidazole is used in the synthesis of fluorescent diarylethene
and nanowires of 2, 4, 5-triphenyl imidazole, which finds application as single
wire active optical waveguide and optically driven ultraviolet lasers.
It is mostly used in pharmaceutical industries as a base moiety.

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