“SYNTHESIS OF 5 ,7 PHENYL (PARA

CHLOROPHENYL)-1,2,4-TRIAZOLO-[3,2-b]-
PYRIMIDINE-6,6- CARBONITRILE”

A Dissertation submitted to the

Department of Chemistry, Arya Vidyapeeth College
For the partial fulfilment of the requirements for
the award of the degree of
Master of science in Chemistry
Under Gauhati University

SUBMITTED BY
MEGHA SAHA
M.Sc. 4th SEMESTER
ROLL NO: PCHE220011
REGISTRATION NO:19103701
UNDER THE SUPERVISION OF
DR. SUSANTA KUMAR BORTHAKUR
DEPARTMENT OF CHEMISTRY
ARYA VIDYAPEETH COLLEGE, AUTONOMOUS
 Dr.Susanta Kumar Borthakur
Assistant Professor
Departmentof Chemistry
Arya Vidyapeeth College
Guwahati-781016, Assam, India

Date:

CERTIFICATE

This is to declare that the contents of this report titled “SYNTHESIS OF 5 ,7 PHENYL (PARA
CHLOROPHENYL)-1,2,4-TRIAZOLO-[3,2-b]-PYRIMIDINE-6,6- CARBONITRILE”,
submitted by Miss MEGHA SAHA, a student of MSc. 4th Semester, Roll No. PCHE220011 and
Registration No. 19103701, is a project dissertation carried out solely under my supervision. She
puts her sincere effort and has shown a great deal of enthusiasm, her conduct was excellent.

Dr.Susanta Kumar Borthakur

Assistant Professor
Department of Chemistry
Arya Vidyapeeth College AUTONOMOUS
DECLARATION

I, MEGHA SAHA, hereby declare that the subject matter of the project report entitled
“SYNTHESIS OF 5 ,7 PHENYL (PARA CHLOROPHENYL)-1,2,4-TRIAZOLO-[3,2-b]-
PYRIMIDINE-6,-6-carbonitrileis the record of original research work carried out by me at the
Department of Chemistry, Arya Vidyapeeth College, Guwahati, Assam under the supervision of
Dr.Susanta Kumar Borthakur,Assistant Professor, Department of Chemistry, Arya Vidyapeeth
College, and it has not been previously submitted for a degree or diploma in any University or
Institution of higher education.
To the best of my knowledge and belief, this project report contains no materials written by another
person except where due reference is made within the project report itself.
As a general practice of writing scientific reports, due acknowledgement has been made to all the
authors whose works have been discussed in this survey and unintentional omission, if any, is highly
regretted.

Date:

Place: Guwahati MEGHA SAHA

MSc. 4th Semester

Roll. No: PCHE220011

Department Of Chemistry

Arya Vidyapeeth College

ACKNOWLEDGEMENT

Firstly, I would like to express my gratitude to my guide Dr.Susanta KumarBorthakur, Assistant

professor, Department of Chemistry, Arya Vidyapeeth College, Guwahati for his inspiring and
invaluable guidance throughout the period of my project work. He was a constant source of guidance
and supervision without which this project report would not have been possible.
I offer my humble thanks to Prof. Dr.Pankaj Kalita Head of the Department of Chemistry, Arya
Vidyapeeth College, Guwahati for providing all the necessary departmental facilities necessary for
this work.
I express my gratefulness to Dr. Pradip Kr. Bhattacharya, Principal, Arya Vidyapeeth College,
Guwahati for allowing me to carry this project work.
I am also thankful to all the other Faculty and Staff members of our department for their kind
cooperation and help during my work.
Lastly, I would like to express my deep appreciation towards my lab mate for helping me through
every difficulty in laboratory work of the project.

Date: MEGHA SAHA

Place: Guwahati MSc. 4th Semester
ABSTRACT

From last few decades the majority of chemist developed a interest on heterocyclic
compound,heterocyclic compound contain largest varied family of organic compounds including of
al derivatives and their uses in pharma , chemical industries.
Heterocycles are important structural components in medicinal chemistry and are typically found in
high concentrations in biomolecules such as enzymes, vitamins, natural products and biologically
active components such as anti-fungal, anti-cancer, anti-oxidant, anti-inflammatory and herbicidal
agents.
Heterocyclic compounds are one of the vital class of organic compounds which are used in many
biological field due to its activeness.Biological molecule including DNA,RNA,vitamins,hemoglobin
and many more have heterocyclic compound as major skeleton.
The aim of this work is to synthesized 5 ,7 PHENYL (PARA CHLOROPHENYL)-1,2,4-
TRIAZOLO-[3,2-b]-PYRIMIDINE-6,6- CARBONITRILE by the reaction between para-chloro
benzyldehyde and arylidene malononitrile in the presence of 1,4 dioxane which acts as a catalyst.
The structure of the synthesized compound will be illustrated on the basis of physical analysis and
spectroscopic data like IR and 1H NMR. Since the synthesized compound contain pyrimidine ring
which is biologically active. The motive of the synthesizing this compound is that the formation of
highly biologically active compound which contribute their activities toward medicinal chemistry.
CONTENT
TOPICSPage no.

1. INTRODUCTION1- 8

2.SYNTHESIS AND EXPERIMENTAL8- 12

PROCEDURE

2.1.SCHEME 1: Method for synthesis of

arylidene malononitrile derivatives
2.2.SCHEME-2: SYNTHESIS OF 5 ,7 PHENYL (PARA CHLOROPHENYL)-1,2,4-TRIAZOLO-
[3,2-b]-PYRIMIDINE-6,6- CARBONITRILE”
3. SPECTRAL ANALYSIS12- 13
3.1.Analysis of IR spectra of 5 ,7 PHENYL (PARA CHLOROPHENYL)-1,2,4-TRIAZOLO-[3,2-b]-
PYRIMIDINE-6,6- CARBONITRILE”
3.2.Analysis of NMR spectra of 5 ,7 PHENYL (PARA CHLOROPHENYL)-1,2,4-TRIAZOLO-[3,2-
b]-PYRIMIDINE-6,6- CARBONITRILE”

4. RESULT AND DISCUSSION14

5. CONCLUSION14
6. REFERANCES15-17
 1

1.INTRODUCTION
Globalisation, combined with constant biosphere contamination and mass migration processes,
increased the impact on human health and mental peace, resulting in an increase in morbidity ranging
from heart diseases to various types of cancers. In this regard, there is a need of innovative, effective,
selectively acting and low toxic medications for such diseases. In recent research in the area of
medicinal chemistryit should be noted that over 90 % of drugs currently in use have heterocyclic
compounds as their active ingredients, and the study of their mechanism of various drug activity will
allow to elucidate the specific biochemical processes. The rational design of new chemical entities
with varied physical, chemical and biological features by fusing two active compounds is more
effective strategy for drug development than each active heterocyclic molecule. [1]
Tuberculosis(TB) is a major health problem approximately world’s one third population infected with

Mycobacterium tuberculosis.There is an urgent need for novel antitubercular agent with low toxicity lower side

effects, rapid action . Advantageously, antitubercular drugs with heterocyclic ring which are effective against these

resistant strains,have entered clinical trials in recent years.

The biological activities of heterocyclic compounds include those that areantifungal, anti-
inflammatory, antibacterial, antioxidant, anticonvulsant, antiallergic, antidiabetic, enzyme inhibitors,
herbicidal activity, anti-HIV, anticancer activity, anticonvulsant, antidepressant, and anti-cancer. The
synthesis of heterocyclic compound is currently of critical importance to the scientific community.

1.1 HETEROCYCLIC COMPOUND

The most prevalent heteroatoms are nitrogen, oxygen, and sulphur but heterocyclic rings including
additional hetero atoms are also well known. Heterocyclic compounds are cyclic organic molecules
that contain at least one hetero atom. Heterocyclic compounds are regarded as one of the essential
types of organic chemicals that are used in various biological fields.There are lots of heterocyclic
compounds which have application in many common diseases such as triazine derivatives have been
used as antimicrobial herbicides, urinary antiseptics and anti-inflammatory agents.Benzimidazoles
derivatives have been reports to possess wide range of biological activities such as antibacterial,
antifungal, antiviral, and anthelmintic. [2] [3]
Heterocyclic compounds are widely present in natural products,biological, pharmaceutical molecules.The organic,

pharmaceutical chemist make an effort to construct those heterocyclic frameworks through developing versatile and

efficient synthetic stratergies.The direct C-H functionalization via radical pathway has emerged as a promising

approach towards heterocycles. Heterocyclic compounds such as

furan,indoles,quionolines,isoquionolines,benzofurans have successfully synthesised by C-H functionalization via the

radical pathway.
 2

The application of heterocycles can be beneficial for changing solubility. The ability of biologically
active substances to form hydrogen bonds, polarity,and exhibit lipophilicity allows medications or
drug candidates to have their ADME characteristic optimised. Many heterocyclic lead compounds,
on the other hand, were obtained from natural sources and their structures were later simplified and
changed by medicinal chemists. Thus, heterocycles are essential for medicinal chemists since they
allow for their expansion of the chemical species that can acts as potential drugs and the
improvement of drug development programmes.[3]Heterocycles are frequently found in large percent
in biomolecules such as enzyme, vitamins, natural products and biologically active compound
including antifungal, anti-inflammatory,antibacterial, antioxidant, anticonvulsant, antiallergic,
antidiabetic, enzyme inhibitors, herbicidal activity, anti-HIV, anticancer activity, insecticidal
agents.heterocycles have been discovered to have a key structural role in medical chemistry. In
general, the physical and chemical properties of heterocyclic compounds are best understood by
comparing them with ordinary organic compounds that do not contain heteroatoms.[2][4]

IMPORTANCE OF HETEROCYCLIC COMPUND

Heterocyclic chemistry deals with heterocyclic compunds which constitute about sixty-five percent of

organic chemistry literature. Heterocyclic compunds are widely distributed in nature and essential to life;

they play a vital role in the metabolism of all living cells.Genetic material DNA is also composed of

heterocyclic bases- pyrimidines and purines.A large number of heterocyclic compunds, both synthetic

and natural,are pharmacological active and are in clinic use . Heterocyclic compunds have an wide range

of application: they are predominant among the type of compunds used as pharmaceuticals2,as

agrochemicals and as veterinary products.They also find applications as sensitizers, developers,

antioxidants,as corrosion inhibitors,as copolymers,dyestuff3.They are used as vehicles in the synthesis

of other organic compounds.

Fig 1: Some five and six membered heterocyclic compounds

 3

DIELS-ALDER
The Diels-Alder reaction is one of the most common and important methods for the
construction of six-membered ring system1-6. The introduction to heterosubstituents
on the regiochemistry of the cycloaddition, and permits further transformations which
take advantage of the relationship between the hetero-substituents and the newly
formed carbon -carbon double bond; the use of such dienes in the Diels-Alder reaction
has recently been an area of great synthetic activity. Diels-Alder reactions of
heteroaromatic compunds and of vinyl-heteroaromatic compunds have recently been
the subject of a comprehensive review9 and therefore are not discussed extensively.

The theoretical rationalizations and predictions of mechanisms of cycloadditions are

significant achievements of Woodward and Hoffmann. (5) While dienes and alkenes
generally react in a [4 + 2] (Diels–Alder) (6) fashion via a concerted pathway, (7,8)
halogenated dienes and alkenes often lead to (2 + 2) adducts by diradical mechanisms.

41 years after its discovery,the Diels-Alder reaction remains one of the key reactions
in organic synthesis The relatively recent use of the hetero-substituent diens described
in this review has opened up a new range of possible application to natural product
synthesis.
 4

1.2 TRIAZOLE
Triazoles are part of family of five membered heterocycles that has attracted a sustainable and
increasing interest among the scientific community, notably due to their wide applications in
pharmaceutical,1 agricultural2 and material sciences fields. 3 Among them the 1,2,4 triazoles result
from a precise arrangement of the three nitrogen atoms and the two carbon atoms which confer
unique properties combining different weak interactions, a characteristic basicity and several
coordination modes.1,2 1,2,4 –Triazoles are key scaffold in a large number of molecular architecture
that display antibacterial, antifungal, antitubercular, antioxidant, antitumor, analgesic, anti-
inflamatory or pesticidal activities.3-12 The ability of install various substituents on all the nitrogen
and carbon atoms of the skeleton is therefore of crucial importance to modulate these properties and
contributes to the use of triazoles for a broad panel of applications.

Fig: 1,2,3-triazole Fig: 1,2,4-triazole

BIOLOGICAL ACTIVITY OF TRIAZOLE

1.3 IMPORTANCE OF 1,2,4-TRIAZOLE AND ITS DERIVATIVES

Derivatives of 1,2,4- Triazoles and pyrimidines are of current interest in view of broad spectrum
biological activity exhibited by these compounds as drugs[1]. Substituted triazoles are reported to act
as bactericides, pesticides, and potential fungicides[2]. Pyrimidines have been reported to possess
fungicidal [3,4], atherosclerotics, and muscle cell growth inhibitor[5] activity. Substituted
triazolopyrimidines have been also reported to be anticancer agents[6] and also act as potential
antiasthma agents[7]. A variety of 1,2,4-triazole derivatives have been described as having biological
activities including antidepressive, anti-inflamatory, antibacterial, antifungal, and insecticidal
properties [9]. 1,2,4- Triazolopyrimidine has been shown to be a good inhibitor of CAMP PDE and
to be 100 times more effective than theophylline in protecting laboratory animals from histamine
induced bronchospasm[8].
 5

1.4 PYRIMIDINE
Pyrimidine is a class of organic compounds of the heterocyclic series characterised by a ring
structure composed of four carbon atoms and two nitrogen atoms with uracil, cytosine and thymine
being the basal structures of ribose- containing nucleosides, or deoxyribose containing
deoxynucleosides and their corresponding ribonucleotides or deoxynucleotide. Genetic defects
involving enzymes essential for pyrimidine nucleotide metabolism have provided new insights into
the viral physiological functions of these molecules in addition to nucleic acid synthesis. [33-36] The
biological and pharmacological effects of pyrimidine and its derivatives include anticonvulsant,
antibacterial, antifungal, antiviral and anticancer characteristics. The versatility of pyrimidine in
synthetic chemistry has made it possible to create a wide range of structurally diverse derivatives,
including analogues derived from the substitution of the aryl ring and derivation of the pyrimidine
nitrogen and C2/C4/C5/C6 carbon positions.[32] Pyrimidine and its various derivatives as
antimicrobial agents. In the current studies it’s found that more than 200 pyrimidine as antimicrobial
agents with different mono, di, tri, and tetra substituted classes along with in vitro antimicrobial
activities of pyrimidines derivatives. [37-39]

Fig 5:Pyrimidine

TRIAZOLOPYRIMIDINE
Infectious diseases have emerged as an important clinical threat accounting for 20 % of worldwide mortality
[1–3]. Antimicrobial resistance (AMR) is considered one of the main public health threats of the current
century [4]. UK Government argued that AMR could kill ten million people by 2050 [5,6]. On the other hand,
viral infections account for 70 % of worldwide mortality [1]. Viruses have been responsible for a large number
of deaths in recent years, including the most recent SARSCoV-2 outbreak [7]. Due to a lack of or restricted
treatment options for many infections, as well as drug resistance, the hunt for novel antimicrobial and
antiviral drugs is crucial. This highlights the need to develop new drugs that can be utilized as antimicrobial
and antiviral therapies as well as combating resistant strains. Literature reports exhibited that the ring system
of thiouracil carbonitrile represented a remarkable motif in the design and synthesis of novel series of
chemotherapeutic molecules with promising pharmacological activities [8–11]. One of the most promising
bioorganics that could be accessed from thiouracil is triazolopyrimidine whose ring could be built from the
thiouracil through different methods generating a lead structural feature of many active compounds with
diversified pharmacology efficacy. In fact, the various forms and potent efficacy of triazolopyrimidine made
them the prime choice of many researchers all over the world. The triazolopyrimidine structures have evoked
the interest of researchers to develop novel compounds with anticancer, anti-inflammatory, antibacterial,
antifungal, anti-viral, antiAlzheimer, and anti-malarial properties in a variety of biochemical systems [12].
 6

1.5 ARYLIDENE MALONONITRILE AND ITS BIOLOGICAL ACTIVITY

The arylidene malononitiles are versatile intermediates for synthesis of a large number of
biologically important heterocyclic molecules.[24] Arylidene malononitrile is used in the
pharmaceutical industry, pharmacology, biotechnology, speciality chemical, perfumes and for
fluorescence-based assays to determine methane and is manufactured using polluting routes. All
synthesized catalysts were evaluated in Knoevenagel condensation of aromatic benzaldehyde with
malononitrile to give arylidene malononitrile. [40-42]There are various method for preparing arylidene
malononitrile and we picked up the simplest method, where an aromatic aldehyde (10mmol),
malononitrile (10mmol) and K2CO3 (1mmol) were added in a mortar and ground rapidlywith a pestle
at RT for a specific period of time. Then the mixture was washed with water, filtered and dried. [25]
(scheme 1)
Malononitriles are highly reactive compounds. The reactive methylene group is actively used in
condensation reactions as a nucleophile in the preparation of carbo and heterocyclic products. This
property makes them important chemical in medical, industrial and agricultural applications. Its
biological activities such as causing an increase of nucleoproteins in cells, regulating RNA synthesis
in neurons and nerve tissues, promoting nerve tissue regeneration, neurotransmitter acetylcholine
biosynthesis, antithyroid effects. All malononitrile derivatives are found to be of potential CA
inhibitors. The benzylidene malononitrile derivatives were tested against two gram- negative and
gram- positive microorganisms.[43-44]

CN
C C
CN
R

Fig 6:Arylidene malononitrile

Where R = H, P- OCH3, P-NO2, P-N(CH3)2 etc.
 7

LITERATURE REVIEW OF ARYLIDENE MALONONITRILE

Some national and international status:
EskandarKolvariet al.2022 The synthesis of 2-amino-4H-pyrans from aromatic aldehyde,
malononitrile and ethyl acetoacetate and 2-benzylidene malononitriles from aromatic aldehyde and
malononitrile through the Knoevenagel condensation reaction in an aqueous medium at 80 °C and 50
°C respectively by using basil seed (Ocimumbasilicum) as a cheap, natural, and biodegradable
efficient catalyst.[45]

Zhenggang Lan et al. 2012The photoinduced nonadiabatic decay dynamics of 2-[4-

(dimethylamino)benzylidene]malononitrile (DMN) in the gas phase are explored using surface
hopping simulations at the semiempirical OM2/MRCl level. In the nonadiabatic dynamics of DMN,
the twisting around the C7=C8 double bond act as the driving coordinate toward the lowest energy
s0/s1 conical intersection, which mediates the internal conversion to the electronic ground state. [56]

Shantaram Kamath et al. 2003Studied that both docking and 3D QSAR analyses have been
employed to explore the binding modes of benzylidene malononitrile tyrphostins at ATP sites of
EGFR and HER-2 kinases and to gain insights into possible factors contributing to selectivity of
benzylidene malononitriles as of EGFR or HER-2 kinase activity.[47]

2. SYNTHESIS AND EXPERIMENTAL PROCEDURE

2.1SCHEME 1: Fast method for synthesis of arylidene malononitrile derivatives
R
R CN
O CN K2CO3
C H2C C C
CN RT H CN
H

A
romatic Malononitrile Arylidene malononitrile
Benzaldehyde

Where R = H, P-OCH3, P-NO2

Fig 8: SCHEME 1- Synthesis of arylidene malononitrile

EXPERIMENTAL PROCEDURE:
 8

An aromatic aldehyde (10mmol), malononitrile (10mmol) and K 2CO3 (1mmol) were added in a
mortar and ground rapidly with a pestle at RT for a specific period of time. Then the mixture was
washed with water, filtered and dried.[49]

Synthesis of para Nitro benzylidine malononitrile

EXPERIMENTAL PROCEDURE:

An para Nitro benzyldehyde (10mmol), malononitrile (10mmol) and K CO (1mmol) were added in a mortar and ground rapidly
2 3
with a pestle at RT for a specific period of time. Then the mixture was washed with water, filtered and dried.

1 Physical data (scheme 1)

Serial no Aromatic Arylidene Percentage Melting

benzaldehydes malononitriles yield point
(°C)
H

CHO CN
1 C C
CN
97 83-85

H3CO

CHO CN
C C
CN
95 114-118
2
OCH3

O2N

CHO CN
C C
CN
92 159-162
3
NO2
 9

Fig 9: (4-nitrobenzylidene) Fig 10: (4-methoxybenzylidene) Fig 11: Benzylidene

2.2 SCHEME-2:Synthesis of 5,7 phenyl( para chlorophenyl)-1,2,4- triazolo-[3,2-b]-pyrimidine-

6,6-carbonitrile

Fig12: SCHEME-Synthesis of 5,7 phenyl( para chlorophenyl)-1,2,4- triazolo-[3,2-b]-pyrimidine-6,6-

carbonitrile
 10

EXPERIMENTAL PROCEDURE:
In the typical experiment, in a round bottom flask a solution of 1.35g of para chloro benzyldehyde
(0.001 mol) and 0.84g (0.001 mol) of 2-amino-1,3-triazole in 20ml of 1,4- Dioxane were refluxed for
12 hours. The progress of the reaction was being monitored by taking TLC (UV active) at subsequent
intervals of time. Successful spots on the TLC plates confirmed about the formation of the product.
The solvent that was used for TLC was petroleum ether and ethyl acetate taken in the ratio 8:2.

Fig 14: TLC plates for monitoring the reaction progress on reflux

The synthesized product of 5 ,7 PHENYL (PARA CHLOROPHENYL)-1,2,4-TRIAZOLO-[3,2-b]-

PYRIMIDINE-6,6- CARBONITRILE” was then separated from the reaction mixture with the help
of the column chromatography using petroleum ether as a solvent and silica as the stationary phase.
Here also monitoring the separation process by taking TLC (UV active) at subsequent interval of
time. Likewise, in comparison to the reflux´s TLC plates to confirmed the separation of the product.
The solvent that was used for TLC was petroleum ether and ethyl acetate taken in the ratio 8:2.
 11

Fig 15: Separation process of 5,7 phenyl( para chlorophenyl)-1,2,4- triazolo-[3,2-

b]-pyrimidine-6,6-carbonitrile using column chromatography

Fig 16: TLC plates for monitoring the separation process

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