a dissertation submitted in partial fulfillment of the ... and characterization of...

Synthesis and characterization of aspirin-thiourea derivatives and their antibacterial

activity

Choi Ching Liang

35741

A dissertation submitted in partial fulfillment of the requirement for the degree of Bachelor

of Science (Hons.)

Supervisor: Assoc. Prof. Dr. Zainab Ngaini

Resource Chemistry

Department of Chemistry

Faculty of Resource Science and Technology

Universiti Malaysia Sarawak

2015

II

Acknowledgement

First of all, I would like to thank to my supervisor, Assc. Prof. Dr. Zainab Ngaini,

her for giving me the opportunity to have this research title for my final year project. Her

patience guidance and generous help give me a lot of support in completing this thesis.

Without her advice, I would face a lot of difficulty to complete this research.

I am also grateful to all the master and PhD students in the organic laboratory. I am

extremely thankful to them for sharing their experience and giving suggestion to help me

solve the difficulty in my research.

I take this opportunity to express gratitude to all the technical staff and laboratory

assistant for their proficient assistance and providing the laboratory facilities for analysis. I

would also like to thank to my fellow friends for supporting me during this research.

Last but not least, I also thank to my parents and family members who always give

their fully support to me, encourage me in my study. In addition, my sense of gratitude to

one and all, who direct or indirectly lent their hand in this venture.


III

Declaration

In this dissertation, there is no part of work has been submitted in report of an application

for another degree of qualification of this or any other university or institution of higher

learning. I declare that this project is the work of my own excluded of the references

document that have been acknowledged.

(CHOI CHING LIANG)

DATE

Resource Chemistry Programme



University Malaysia Sarawak

IV

Table of Contents

Acknowledgement .................................................................................................................... II

Declaration............................................................................................................................... III

Table of Contents .................................................................................................................... IV

List of Abbreviations .............................................................................................................. VII

List of Schemes .................................................................................................................... VIII

List of Figures .......................................................................................................................... IX

List of Tables ........................................................................................................................... XI

Abstract ...................................................................................................................................... 1

1.0 Introduction ......................................................................................................................... 2

1.1 Background ...................................................................................................................... 2

1.2 Problem Statement ........................................................................................................... 4

1.3 Objectives ........................................................................................................................ 4

2.0 Literature Review ................................................................................................................ 5

2.1 Aspirin ............................................................................................................................. 5

2.2 Biological Activity of Aspirin Derivatives ...................................................................... 6

2.2.1 Antithrombotic Activity ........................................................................................... 6

2.2.2 Antibacterial Activity .............................................................................................. 7

2.3 Thiourea ........................................................................................................................... 7

2.4 Synthesis of Thiourea Derivative Compound .................................................................. 8

2.5 Application of Thiourea Derivative ............................................................................... 10

2.5.1 Biological Properties .............................................................................................. 10

2.6 Liquid Crystal ................................................................................................................ 11

2.7 Thiourea as Liquid Crystal ............................................................................................ 12

3.0 Material and Method ......................................................................................................... 13

3.1 Material .......................................................................................................................... 13

3.2 Instrument for Characterization ..................................................................................... 13

V

3.3 General Procedure for Synthesis of Aspirin-thiourea Derivatives ................................ 13

3.3.1 Preparation of Precursor 10 ................................................................................... 13

3.3.2 Synthesis of Intermediate 11 ................................................................................. 14

3.3.3 Synthesis of Thiourea Derivatives 12 ................................................................... 14

3.4 Methods ......................................................................................................................... 15

3.4.1 Synthesis of N-(4-hexoxyphenyl)acetamide (13) .................................................. 15

3.4.2 Synthesis of N-(4-decoxyphenyl)acetamide (14) .................................................. 16

3.4.3 Synthesis of N-(4-dodecoxyphenyl)acetamide (15) .............................................. 17

3.4.4 Synthesis of N-(4-tetradecoxyphenyl)acetamide (16) ........................................... 18

3.4.5 Synthesis of 4-hexoxyaniline (17) ......................................................................... 19

3.4.6 Synthesis of 4-decoxyaniline (18) ......................................................................... 20

3.4.7 Synthesis of 4-dodecoxyaniline (19) ..................................................................... 21

3.4.8 Synthesis of 4-tetradecoxyaniline (20) .................................................................. 22

3.4.9 Synthesis of [2-[(4-hexoxyphenyl)carbamothioylcarbamoyl]phenyl] acetate

(21) ........................................................................................................................ 23

3.4.10 Synthesis of [2-[(4-decoxyphenyl)carbamothioylcarbamoyl]phenyl] acetate

(22) ........................................................................................................................ 24

3.4.11 Synthesis of [2-[(4-dodecoxyphenyl)carbamothioylcarbamoyl]phenyl]

acetate (23)…........................................................................................................ 25

3.4.12 Synthesis of [2-[(4-tetradecoxyphenyl)carbamothioylcarbamoyl]phenyl]

acetate (24)…........................................................................................................ 26

3.5 Antibacterial Screening .................................................................................................. 27

3.5.1 Bacterial Suspension .............................................................................................. 27

3.5.2 Disc-diffusion Method ........................................................................................... 27

4.0 Results and Discussion ...................................................................................................... 28

4.1 Synthesis of N-(4-hexoxyphenyl)acetamide (13) .......................................................... 28

4.2 Synthesis of N-(4-decoxyphenyl)acetamide (14) .......................................................... 31

4.3 Synthesis of N-(4-dodecoxyphenyl)acetamide (15) ...................................................... 34

VI

4.4 Synthesis of N-(4-tetradecoxyphenyl)acetamide (16) ................................................... 38

4.5 Synthesis of 4-hexoxyaniline (17) ................................................................................. 41

4.6 Synthesis of 4-decoxyaniline (18) ................................................................................. 45

4.7 Synthesis of 4-dodecoxyaniline (19) ............................................................................. 48

4.8 Synthesis of 4-tetradecoxyaniline (20) .......................................................................... 51

4.9 Synthesis of [2-[(4-hexoxyphenyl)carbamothioylcarbamoyl]phenyl] acetate (21) ....... 55

4.10 Synthesis of [2-[(4-decoxyphenyl)carbamothioylcarbamoyl]phenyl] acetate (22) ..... 59

4.11 Synthesis of [2-[(4-dodecoxyphenyl)carbamothioylcarbamoyl]phenyl]acetate (23) .. 63

4.12 Synthesis of [2-[(4-tetradecoxyphenyl)carbamothioylcarbamoyl]phenyl] acetate (24)67

4.13 Antibacterial Activity .................................................................................................. 72

5.0 Conclusion and Recommendations ................................................................................... 75

6.0 References ......................................................................................................................... 76

VII

List of Abbreviations

Fourier Transform Infrared Spectroscopy FTIR

13C Nuclear Magnetic Resonance

13C-NMR

1H NMR Nuclear Magnetic Resonance

1H-NMR

Thin Layer Chromatography TLC

Escherichia coli E.coli

Dimethyl sulfoxide DMSO

Dichloromethane DCM

Centimeter cm

Part per million ppm

Millimeter mm

VIII

List of Schemes

Scheme 2.1: Synthesis of Aspirin 6

Scheme 2.2: Synthesis of 1-Phenyl-3-(3-methyl-2-oxo-3H-benzoxazole-6-yl)

thiourea 1 8

Scheme 2.3: Synthesis of 1-phenyl -3-benzoyl-2- thiourea 2 9

Scheme 2.4: Synthesis of 4-alkoxy-N[(4alkoxyphenyl)carbamothioyl]benzamide 3 9

Scheme 3.1: Synthesis of the Precursor 10 13

Scheme 3.2: Synthesis of Intermediate 11 14

Scheme 3.3: Synthesis of the Thiourea Derivatives 12 14

Scheme 4.1: Synthesis of Compound 13 28




Scheme 4.5: Synthesis ofCompoundCompound17 41








IX

List of Figures

Figure 1.1: Aspirin 2

Figure 1.2: Thiourea 2

Figure 2.1: Structure of Ca-ASP 6

Figure 2.2: Thiourea Derivatives 4 and 5 with Antibacterial Activity 10

Figure 2.3: Thiourea Derivatives 6 and 7 with Antibacterial Activity 11

Figure 2.4: Liquid Crystal Compounds 11

Figure 2.5: Thiourea Derivatives 8 with Liquid Crystal Properties 12

Figure 2.6: Thiourea Derivatives 9 with Liquid Crystal Properties 12

Figure 4.1: FT-IR Spectrum for Compound 13 29

Figure 4.2: 1H-NMR Spectrum for Compound 13 30

Figure 4.3: 13

C-NMR Spectrum for Compound 13 31



Figure 4.6: 13




Figure 4.9: 13




Figure 4.12: 13




Figure 4.15: 13



X


Figure 4.18: 13




Figure 4.21: 13




Figure 4.24: 13




Figure 4.27: 13




Figure 4.30: 13




Figure 4.33: 13




Figure 4.36: 13


Figure 4.37: Antibacterial Test Using Disc-diffusion Plate Method 74

XI

List of Table

Table 4.1: Inhibition Activity and Its Zone of Inhibition of the Compounds 73

1

Synthesis and characterization of aspirin-thiourea derivatives and their antibacterial activity

CHOI CHING LIANG



University Malaysia Sarawak

Abstract

Thiourea and its derivatives have been actively studied in recent years mostly in their

biological activities. This study focused on the synthesis and characterization of aspirin-

thiourea derivatives. The syntheses have been done via the reaction of acetylsalicyloyl

chloride with series of amines. The long chains of amine formed by using 4-hydroxyl

acetanilide and a series of bromoalkane have been synthesized. The synthesis aspirin-

thiourea derivatives were characterized by Fourier transform infrared spectroscopy (FTIR), 13

C nuclear magnetic resonance (NMR) and 1H NMR spectroscopy. The antibacterial

properties of the synthesized compound were determined by disc diffusion method against

Escherichia Coli (E.coli). However, the newly synthesized aspirin-thiourea derivatives

show intermediate antibacterial activity against E.coli. The effect of the structure of the

compounds on antibacterial activity is discussed.

Keyword: Thiourea, acetylsalicyloyl chloride, 4-hydroxyl acetanilide, antibacterial

properties

Abstrak

Thiourea dan derivatifnya telah dikaji secara aktif terutamanya mengenai aktiviti biologi.

Kajian ini memberi tumpuan terhadap sintesis dan pencirian aspirin-thiourea. Sintesis ini

telah dilakukan melalui reaksi klorida acetylsalicycloyl dan siri aniline. Rantaian

pangjang amina telah dihasilkan dengan menggunakan acetanilide 4-hidroksil dan siri

bromaalkana. Strucktur derivatif thiourea yang berjaya dihasilkan dikenalpasti

menggunakan FTIR, 13

C NMR dan 1H NMR. Ciri-ciri anti-bakteria kompaun pula

ditentukan dengan ujian disk-diffussion menggunakan Escherichia Coli (E.coli).

Walaubagaimanapun, aspirin-thiourea yang berjaya dihasilkan menunjukkan aktiviti anti-

bakteria yang sederhana. Oleh itu, pengaruh struktur kompound terhadap aktiviti anti-

bakteria telah dibincangkan.

Kata Kunci: Tiourea, klorida acetylsalicyloyl, acetanilide 4-hidroksil, aktiviti anti-bakteria

2

1.0 Introduction

1.1 Background

Aspirin (Figure 1.1) or acetylsalicylic acid is widely used to reduce the minor aches

and pains as well as fever reducer. Aspirin is a salicylate drug which has been use as

analgesic and anti-inflammatory in medical field. Aspirin use in the primary prevention of

cardiovascular disease and cancer in the prophylactic use (Sutcliffe et al., 2013).

Figure 1.1 : Aspirin

Thiourea (Figure 1.2) is a white crystalline solid with the functional group of amino,

imino and thiol. Thiourea is also called as thiocarbamide or sulfourea with the formula of

CH4N2S.

Figure 1.2: Thiourea

Thiourea derivatives have been actively investigated for their biological activites.

Thiourea derivatives compound have been synthesized using aniline and benzoyl

isothiocyanate in dry benzene (Alkherraz et al,. 2014).

Thiourea derivatives are widely used in many biological activities such as antiviral

(Kossakowski and Struga, 2006), antimicrobial (Josepharajan et al., 2005), anticancer,

anticonvulsion, analgesic and HDL-elevating properties(Yahyazadeh & ghasemi, 2003).

3

Other than that, thiourea plays an important role in the enantioselective synthesis such as

Aza-Henry reactions, Michael addition and nitro-Mannich reaction (Saeed et al., 2010).

In this study, new aspirin-thiourea derivatives were synthesized by incorporation of

long alkyl chain amine into aspirin-thiourea. The synthesized compound was characterized

using Fourier transform infrared spectroscopy (FTIR), 13

C nuclear magnetic resonance

(NMR) and 1H-NMR spectroscopy. The antibacterial activity of the aspirin-thiourea

derivatives had been determined by disk diffusion method.

4

1.2 Problem Statement

Various types of thiourea derivatives have been studied for their biological properties and

many studied reported that thiourea derivatives exhibits pharmaceutical activity such as

antibacterial activity, antitumor activity. The increase in the lipophilicity of the alkyl chain

of the compound will affect the antibacterial activity (Ngaini et al., 2012). Besides that,

aspirin has been found to use as antipyetic, anti-coagulate and as pain reliever. Therefore,

the incorporating of the aspirin and thiourea with long alkyl chain can enhance the

pharmaceutical effect. The main purpose of this project is to prepare new aspirin-thiourea

derivatives with long alkyl chain and study on their antibacterial activity.

1.3 Objectives

1. To synthesize aspirin-thiourea derivatives with long alky chain by reacting with

different long alkyl chain amine with appropriate thiocyanate group.

2. To characterize the synthesized tris-thiourea derivatives using Fourier transform

infrared spectroscopy (FTIR), 13

C nuclear magnetic resonance (NMR) and 1H-NMR

spectroscopy.

3. To study the antibacterial activity of the aspirin-thiourea derivatives against E.coli.

5

2.0 Literature Review

2.1 Aspirin

Aspirin or acetylsalicylic acid is widely used to reduce the minor aches and pains as well

as fever reducer. Aspirin is a salicylate drug which has been use as analgesic and anti-

inflammatory in medical field.

Salicin was obtained by Maclagan from the common white willow to act as fever

reducer, pain killer and inflammation of rheumatic fever in 1874 (Vane & Botting, 2003).

Aspirin was discovery to be able to prolong life due to it can use to treat and decrease the

risk of many diseases. For example, Aspirin use in the primary prevention of

cardiovascular disease and cancer in the prophylactic use (Sutcliffe et al., 2013).

A research to investigate the anti-inflammatory and analgesic activities of aspirin

and combination of aspirin with nifedipine shows that aspirin alone has better anti-

inflammatory effect and analgesic than aspirin-nefedipine combination but aspirin-

nefedipine found to have potentiate the anto-nociceptive action of aspirin (Patowary, 2007).

Aspirin not only shows it anti-inflammatory effect, aspirin also use for inhibition of

prostaglandin synthesis by cyclooxygenase and decrease the platelets activity by inhibiting

thromboxane A2 synthesis (Buczko et al., 2003).

Aspirin can be prepared by the esterification of the 2-hydroxy benzoic acid and

ethanoic anhydride (scheme 2.1). The reaction takes place easily in acidic condition but

several compounds were form in the reaction other than the aspirin product. All the

apparatus must be keep in dry to prevent the ethanoic anhydride form back ethanoic acid

and the product form is purified by recrystallization (Lewis, 2003).

6

Scheme 2.1: Synthesis of Aspirin

2.2 Biological Activities of Aspirin Derivatives

The research in aspirin derivatives have been carried out widely and the

modification of the aspirin were reported show various biological activities such as

antithrombotic, antiplatelet, anticancer (Zheng et al.,2007) and antibacterial (Al-Bakri et

al., 2009).

2.2.1 Antithrombotic Activity

Zhen et al. (2014) reported that the modification of the aspirin with nano-

hydroxyapatite (Figure 2.1) shows the similar antithrombotic activity as aspirin but without

the side effect associate with aspirin. The side effect of the aspirin, gastric damage inflicted

by the aspirin derivatives was much lesser than the aspirin. This is because the free

carbonyl group of the aspirin has been converted into salt forms which decrease the

reactivity.

Ca10(PO4)6

Figure 2.1: Structure of Ca-ASP

7

2.2.2 Antibacterial Activity

Lawal et al. (2006) reported that the synthesis of aspirin and paracetamol with

metal complexes shows that the aspirin derivatives exhibit strong inhibition to the Bacillus

subtilis and it show higher activity than the original aspirin. Lawal et al. (2006) found that

the addition of the cobalt and ferum metal with chlorine ligands shows the highest

antibacterial activity to inhibits Bacillus subtilis.

Balamani et al. (2009) reported that the syntheses of peptide derivatives of aspirin

have greatly increased the antibacterial activity. Balamani et al. (2009) found that the

addition of the methionine amide shows the highest antibacterial activity to E.coli . This is

due to the sulphur contain in the methionine group possess strong inhibition activity to the

E.coli .

2.3 Thiourea

Thiourea shows white or almost colorless crystal at room temperature and is a

diamide of thiocarbonic acid at room temperature (Akron, 2009; Hazardous Substances

Data Bank, 2009). Under normal temperature and pressures, thiourea is very stable (Akron,

2009).

Thiourea do not has a sharp melting point as it rearrangement to ammonium

thiocyanate (NH4SCN) occurs at the temperature above 130ºC (Mertschenk and Beck,

1995). Thiourea is soluble in water, which is 13g/litre at 20°C, polar protic and aprotic

organic solvent but insoluble in non-polar solvents (Hazardous Substances Data Bank,

2009).

There are many of applications of thiourea such as for producing and modifying

textile and dyeing auxiliaries, in the production of pharmaceuticals (thiouracils, tetramisole,

8

sulfathiazoles and cephalosporins), image reproduction, and industrial cleaning agents and

as an isomerization catalyst in the conversion of fumaric and maleic acid (Mertschenk &

Beck, 1995).

Other than that, thiourea normally use in the production of thiourea dioxide for

textile and wool processing, in ore leaching, in diazo papers and act as a catalyst in the

synthesis of fumaric acid (Mertschenk & Beck, 1995).

2.4 Synthesis of Thiourea Derivative Compounds

In the research on new synthesis thiourea derivatives, 1-phenyl-3-(3-methyl-2-oxo-

3H-benzoxazole-6-yl)thiourea 1 are prepared by substituted isocyanate or isothiocyanate

derivative into the solution of 6-amino-3-methyl-2(3H)-benzoxazolone or 6-amino-5-

chloro-3-methyl-2(3H)-benzoxazolone compounds in THF at room temperature. The yield

of product formed was 92% as shown as scheme 2.1 (Gulkok et al., 2012).

R1=-H,-Cl

(CH2)n

1

R2=-H,-Cl,-OCH3

(CH2)n

X

X= S,O

X

n=0,1,2

Scheme 2.2: Synthesis of 1-Phenyl-3-(3-methyl-2-oxo-3H-benzoxazole-6-yl)thiourea 1

Alkherraz et al. (2014) reported that synthesis the thiourea by using aniline and

benzoyl isothiocyanate in dry benzene as shown as scheme 2.3. It was reported 1-phenyl -

3-benzoyl-2- thiourea 2 was synthesized with the yield of 75%. The 75% yield of the

thiourea 2 was less than the thiourea 1 which used different starting material and solvent

which were 6-amino-3-methyl-2(3H)-benzoxazolone and Tetrahydrofuran, THF to yield

92% of the thiourea 1.

9

2

KNCS

Scheme 2.3: Synthesis of 1-phenyl -3-benzoyl-2- thiourea 2

Another example of synthesis thiourea is shown in scheme 2.4. 4-dodecoxy-N-[(4-

dodecoxyphenyl)carbamothioyl]benzamide 3 was successfully synthesized by the reaction

of 4-Alkyloxybenzoylisothiocyanate with 4-alkyloxyanilines in benzene. The yield of the

product was 40-50% (Seshadri, 2005). The yield of the thiourea 3 was less than the

thiourea 2 that yield 75% with the starting material anilines and benzoyl isothiocyanate

(Alkherraz et al., 2014).

R= O-C8H17,O-C10H21,O-C12H25,O-C16H33,O-C18H373

R RR' R'

Scheme 2.4: Synthesis of 4-alkoxy-N[(4alkoxyphenyl)carbamothioyl]benzamide 3

From the method of synthesis thiourea mention above, isothiocyanate or

thiocyanate is one of the important materials for the forming of aromatic thiourea

derivative compound (Gulkok et al., 2012; Alkherraz, 2014; Seshadri, 2005). Other than

that, different types of solvents are use to recrystalline the product such as a mixture of

heptanes and dichloromethane (Seshadri, 2005) and ethanol (Alkherraz, 2014).

10

2.5 Application of Thiourea Derivatives

2.5.1 Biological Properties

Thiourea derivatives are very important that contribute in biological activities.

Thiourea derivatives involve in many biological activities such as antiviral (Kossakowski

& Struga, 2006) , antimicrobial (Josepharajan et al., 2005) , anticancer, anticonvulsion,

analgesic and HDL-elevating properties(Yahyazadeh & ghasemi, 2003).

Kaymakcioglu et al. (2013) reported that new synthesis thiourea derivative 1-{4-

[(4-Amino-5-thioxo-4,5-dihydro-1H-1,2,4-triazole-3-yl)methyl]phenyl}-3-(2,4,6-

trichlorophenyl)-thiourea 4 and 1-{4-[(4-amino-5-thioxo-4,5-dihydro-1H-1,2,4-triazole-3-

yl)methyl]phenyl}-3-(4-(trifluoromethyl)phenyl)thiourea 5 were most active against

Phomopsis obscurans and P. viticola. The presence of the 2,4,6-trichloro and 4-

trifluoromethyl group on the phenyl thiourea ring inhibit the growth of the Phomopsis

obscurans and P. viticola (Kaymakcioglu et al., 2013).

4 5

Figure 2.2: Thiourea Derivatives 4 and 5 with Antibacterial Activity

Other than that, Gulkok et al. (2012) reported that 1-Phenyl-3-(5-chloro-3-methyl-

2-oxo-3H-benzoxazole-6-yl)thiourea 6 and 1-Benzyl-3-(5-chloro-3-methyl-2-oxo-3H-

benzoxazole-6-yl)thiourea 7 exhibit good antibacterial activity against E.coli with a MIC

value of 32 μg/mL. The presence of chloro substituent in the compound at the 5 position

allowed the compound exhibit high activity against E.coli.

11

6 7 Figure 2.3: Thiourea Derivatives 6 and 7 with Antibacterial Activity

2.6 Liquid Crystal

Liquid crystal is an intermediate between liquid and the crystal state of matter. It

will show some properties of liquid as well as a crystalline (Kalakonda, 2013). Most of the

molecule exhibit liquid crystalline properties when the molecule has anisotropic shape or

the molecule have flat segment. For example molecules that contain benzene ring shown in

Figure 2.4 (Kalakonda, 2013).

R = -CnH2n+1; n=1 , -OCnH2n+1; n=1, -COO-, X = - -, - O-, -CH CH-R'= -R, -C , -Cl, -Br

XR R

Figure 2.4: Liquid Crystal Compounds

Apreutesei et al. (2006) stated that liquid crystals compound that optical

birefringence and fluidity must be thermally stable in the mesophases domain. The thermal

stability for the compound is very important especially when the clearing point is near to

the decomposition temperature. Therefore, the primary important for designing new liquid

crystal compound is to attach mesogenic units which are thermally stable even at elevated

temperature (Apreutesei et al., 2006).

12

2.7 Thiourea as Liquid Crystal

In the research done by Seshadri et al. (2005), it was reported that thiourea

derivative which name N-[(4-dodecoxyphenyl)carbamothioyl]-4-hexadecoxy-benzamide 8

and [4-[(4-dodecoxybenzoyl)carbamothioylamino]phenyl] 4-dodecoxybenzoate 9 exhibit

liquid crystal properties. It was believed due to the extra unit of the molecule by the

benzoyl group increase the additional nematic phase (Seshadri et al., 2005). The compound

with liquid crystal properties shows higher melting and chearing transition temperature

with a high order Sm and wide range of thermal stability (Tomma, 2010).

Figure 2.5: Thiourea Derivatives 8 with Liquid Crystal Properties

Figure 2.6: Thiourea Derivatives 9 with Liquid Crystal Properties

13

3.0 Materials and Methods

3.1 Materials

4-hydroxyl acetanilide used in this study was received from Acros Organics and others

chemical and reagent used for the synthesis were received from Merck KGaA. Those

chemical are 4-hydroxyl acetanilide, potassium carbonate, a series of bromoalkane, 2%

sodium hydroxide and acetylsalicyloyl chloride. All the solvents use for synthesis and

recrystallization was reagent graded. Distilled acetone, ethanol, petroleum ether,

dichloromethane and ethyl acetate are the solvents used in this study.

3.2 Instrument for Characterization

Perkin Elmer 1605 Fourier transform infrared spectrophotometer in KBr disk was use to

determined the infrared spectrum. 1H-NMR and

13C-NMR spectrum was recorded in JEOL

ECA 500 at 500 MHz with DMSO-D6 and CDCl3-D1 as reference.

3.3 General Procedure for Synthesis of Aspirin-Thiourea Derivatives

3.3.1 Preparation of Precursor 10

10

heated

reflux

R1= C6H13Br,C10H21Br,C12H25Br,C14H29Br

i) R1

ii) 2%NaOH

R1

Scheme 3.1: Synthesis of the Precursor 10

4-hydroxyl acetanilide was heated at reflux for 48h with a series of bromoalkane in

the presence of potassium carbonate in acetone to give off white colour solution and white

precipitate. The mixture was allowed to cool at room temperature and dried. The white

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