Synthesis and Characterization of New Phthalimides linked ... and... · Synthesis and...

Ministry of Higher Education and Scientific Research University of Baghdad College of Science Department of Chemistry

Synthesis and Characterization of New Phthalimides linked to

Schiff ’s Bases

A thesis Submitted to the College of Science University of Baghdad

in Partial Fulfillment of the Requirements for the Degree of Master of

Science in Chemistry

By

Marwa Shawqi Abd Al-Razzak (B.Sc. 2008)

Supervised by

Dr. Ahlam Marouf Al-Azzawi

1433 2012

بسم اهللا الرحمن الرحيم

بقدرها فـاحتمل اء ماء فسالت أودية أنزل من السم

ل زبدا رابيـا ومما يوقدون عليه في النـار ابتغاء السيـله كذلك يضرب الله الحق حلية أو متـاع زبد مثـ

والبـاطل فـأما الزبد فيذهب جفـاء وأما ما ينفع النـاس )١٧(فيمكث في األرض كذلك يضرب الله األمثـال

صدق اهللا العظيم

}الرعد{ سورة » ١٧ةاآلي «

Advisor Certification

I certify that this thesis was prepared under my supervision in the University of

Baghdad College of Science, as a partial requirement for the degree of Master of

Science in Chemistry.

Signature :

Advisor : Dr. Ahlam Marouf Al-Azzawi

Date :

In view of the available recommendation , I forward this thesis for debate by the

examining committee .

Signature :

Name : Dr. Mohammad Rifat Ahamad

Head of Chemistry Department

College of Science

Baghdad University

Date :

Examination committee

We , the examining committee , certify that we have read this thesis and

examined the student in its contents and that , in our opinion , it is adequate

with " " standing as a thesis for the degree of Master of Science

in Chemistry .

Signature : Signature :

Name : Name :

Date : Date :

Chairman Member

Signature :

Name :

Date :

Member

Signature :

Name : Dr. Ahlam Marouf Al-Azzawi

Date :

Supervisor

Approved by the University Committee on Graduate Studies.

Signature :

Name : Prof. Dr. Saleh Mahdi Ali

Dean of the College of Science.

Date :

إلى من نهلت منه العلم وأمدني بنبع الحياة وعلمني سبل العطاء،إلى من يبذل نفسه

إلى القلب الدافئ وحياته من اجلي ، ..............................الغالي)....................................(والدي .................

ولكن الربيع يعود وهي لن ر الربيع في فصول ألسنه،من مرت بحياتي مرو إلى

إلى من أيقظت في نفسي قوى الصبر،إلى من رحلت عن الدنيا وتركت قلبي , تعود يكسره الشوق لها ..........................هللا)....(أمي رحمها .........................................

فأشد بهم أزري وأقوي بهم ، اة واللذين أعطوني الدعم والقوه دائماأملي في الحي إلى

عزيمتي. .........................)...........حفظهم هللا ..........................................(إخوتي

ت جميله رسمت بين مرافئ لوحاإلى من نقشوا محبتهم على جدران قلبي ،فكانوا

ا وجماال مع مرور األيامتشع بريق الوجدان

.............)....................عذراء,شيماء,حنان(..........................................

إلى البراعم الصغيره ...…………يسر) ,ايه,هاله,علي,عمار,ابراهيم,(ساره……………………

ACKNOWLEDGMENTS

First of all , It is with great pleasure that I place my deep sense

of gratitude and heartfelt thanks to my supervisor Dr. Ahlam Marouf

Al-Azzawi for her immense guidance , Kind support , Constant

encouragement throughout the progress of the dissertation work , I wish

her a long life with best health.

My sky high respect with great thanks to Dr. Mohammad Rifat

Ahamad the Head of Chemistry Department , for providing the facilities

which helped in accomplishing .

I sincerely express my gratitude to University of Baghdad , College of

Science, Chemistry Department who helped me in various stages to

complete my project work successfully.

It would not have been possible to realise this work without the

friendly help and advice of several people.

Finally , my sincerest appreciation goes to my beloved family for their

endless love , patience , and having the fortitude to stay by my side during

these years .

Marwa

2012

i

CONTENTS

Subject Page List of Contents i List of Tables iv List of Figures v Abstract vii CHAPTER ONE : INTRODUCTION 1.1. Schiffs base 1 1.2. Synthesis of Schiffs bases 2 1.3. Applications of Schiffs bases 8 1.4. Cyclic imides 9 1.5. Methods for synthesis of cyclic imides 10 1.5.1. Dehydration of amic acids by using dehydrating agents 10 1.5.2. Thermal Dehydration 11 1.5.3. Gabriel Type Synthesis 11 1.5.4. Diels-Alder Adducts 12 1.6. Other methods used in preparation of cyclic imides 12 1.7. Biological Activity of Cyclic Imides 18 Aim of the Work 22

ii

CHAPTER TWO : EXPERIMENTAL 2.1. Instruments and Chemicals 24 2.1.1. Instruments 24 2.1.2. Chemicals 24 2.2. Part One 25 2.2.1. Preparation of N-phenyl phthalamic acid [1] 26 2.2.2. Preparation of N-phenyl phthalimide [2] 26 2.2.3. Preparation of 4-(N-phthalimidyl) phenyl sulfonyl chloride [3] 26 2.2.4. Preparation of 4-(N-phthalimidyl)phenyl sulfonyl hydrazine [4] 27 2.2.5. Preparation of Schiffs Bases [5-18] 27 2.3. Part Two 27 2.3.1. Preparation of 4-(4'-(N-phthalimidyl) phenyl sulfonate acetophenone) [19] 28

2.3.2. Preparation of 4-(4'-N-phthalimidyl) phenyl sulfonate methyl benzylidene (Schiffs bases) [20-26] 28

2.4. Part Three 29 2.4.1. Preparation of-(4-(4'-N-phthalimidyl) phenyl sulfonate benzaldehyde) [27] 29

2.4.2. Preparation of 4-(4'-(N-phthalimidyl) phenyl sulfonate benzylidene (Schiffs bases) [28-33] 29

2.5. Part Four 30 2.5.1. Preparation of phthalimide potassium salt 30 2.5.2. Preparation of N-(4-phenyl phenacyl) phthalimide [34] 30 2.5.3. Preparation of Schiffs bases [35-40] 31

iii

CHAPTER THREE : RESULTS AND DISCUSSION 3.1. Part One 32 3.1.1. N-phenyl phthalamic acid [1] 32 3.1.2. N-phenyl phthalimide [2] 33 3.1.3. 4-(N-phthalimidyl) phenyl sulfonyl chloride [3] 35 3.1.4. 4-(N-phthalimidyl) phenyl sulfonyl hydrazine [4] 36 3.1.5. N-[4-(N-phthalimidyl) phenylsulfonamido] benzylidene [5-18] 38 3.2. Part Two 61 3.2.1. 4-[4'-(N-phthalimidyl) phenyl sulfonate] acetophenone [19] 61 3.2.2. 4-[4'-(N-phthalimidyl) phenyl sulfonate] methyl benzylidene [20-26] 62

3.3. Part Three 76 3.3.1. 4-[4'-(N-phthalimidyl) phenyl sulfonate] benzaldehyde [27] 76 3.3.2. 4-[4'-(N-phthalimidyl) phenyl sulfonate] benzylidene [28-33] 77 3.4. Part Four 91 3.4.1. N-(4-phenyl phenacyl) phthalimide [34] 91 3.4.2. N-phthalimidyl-4-phenyl (substituted benzylidene) methane [35-40] 92

Biological Activity 104 Suggestions for Future Work 105 References 106

iv

LIST OF TABLES

Table No. Title Page

3-1 Physical properties of compounds [1-4] 41

3-2 Physical properties of Schiffs bases [5-18] 42

3-3 Spectral data of compounds [1-4] 44

3-4 Spectral data of Schiffs bases [5-18] 44





3-9

Physical properties of compounds [35-40]

95

3-10

Spectral data of compounds [35-40]

96

v

LIST OF FIGURES

Fig. No. Title Page

1 FT-IR spectrum for compound [1] 46







8 1H-NMR spectrum of compound [1] 53

9 13C-NMR spectrum of compound [1] 54













vi




















vii

Abstract

The present work involved synthesis of new phthalimides linked to

Schiffs bases through different strategies. The work was divided into four

main parts:

1. The first part involved synthesis of phthalimides linked to Schiff bases

through phenyl sulfonamido group [5-18] Scheme(1). Performing this part include the following steps:

a. Synthesis of N-phenyl phthalamic acid [1] via reaction of phthalic

anhydride with aniline.

b. Dehydration of the synthesized phthalamic acid by acetic anhydride

and anhydrous sodium acetate as dehydrating agent producing N-

phenyl phthalimide [2].

c. The synthesized N-phenyl phthalimide was introduced in

chlorosulfonation reaction producing phthalimidyl phenyl

sulfonyl chloride [3].

d. Phthalimidyl phenyl sulfonyl chloride was treated with hydrazine

hydrate producing phthalimidyl phenyl sulfonyl hydrazine [4].

e. Reaction of compound [4] with different aromatic aldehydes and

ketones producing the target compounds [5-18].

2. The second part involved synthesis of new phthalimides linked to Schiffs

bases through phenyl sulfonate moiety [20-26] Scheme(2).

Performing this part involved the following steps:

a. Synthesis of phthalimidyl phenyl sulfonate acetophenone [19] via

reaction of the synthesized phthalimidyl phenyl sulfonyl chloride

with 4-hydroxy acetophenone.

viii

b. Reaction of compound [19] with different primary aromatic amines

producing the desired compounds [20-26].

3. The third part involved synthesis of new phthalimides linked to Schiffs

bases through phenyl sulfonate moiety [28-33]Scheme(3).

This part involved the following steps:

a. Synthesis of phthalimidyl phenyl sulfonate benzaldehyde [27] via

reaction of the synthesized phthalimidyl phenyl sulfonyl chloride

with 4-hydroxy benzaldehyde.


producing the desired compounds [28-33].

4. The fourth part involved synthesis of new phthalimides linked to Schiffs

bases through methylene group [35-40].

Performing this part includes the following steps:

a. Synthesis of N-[4-phenyl phenacyl] phthalimide [34] via reaction of

phthalimide potassium salt with 4-phenyl phenacyl bromide.


producing the desired compounds [35-40] Scheme(4).

All the synthesized compounds were characterized by FT-IR

spectroscopy and 1H-NMR , 13C-NMR spectra for some of them.

5. Antibacterial activity for some of the synthesized imides were evaluated

against two types of bacteria and the results showed that most of them

have a good antibacterial activity.

ix

CO

CO

OCONH

+

NH2

AcetoneCOOH

CN

CO

O

CN

CO

O

SO2 N=CNHR

R'

Ac2O / NaOAc -H2Oreflux

CN

CO

O

SO2Cl

CN

CO

O

SO2NHNH2

HSO3Cl

reflux 6 hrs. Hydrazine hydrate

reflux 6 hrs. Aromatic aldehydes or ketones

N-phenyl phthalamic acid [1]

N-phenyl phthalimide [2]4-(N-phthalimidyl) phenyl sulfonyl chloride [3]

4-(N-phthalimidyl) phenyl sulphonyl hydrazine [4]

N-[4-(N-phthalimidyl) phenyl sulfonamido] substituted imine [5-18]

R = (o and p-nitro phenyl) , OCH3 (o , m ,and p-hydroxy phenyl) ,

Cl

CH3

,

R = H , CH3 , ph'

Scheme (1)

,NH

O,

, , ,

x

CN

CO

O

S

O

O

Cl

CN

CO

O

+

Chlorosulfonic acid

Cl S

O

O

OH

CN

CO

O

S

O

O

O C

O

CH3

CN

CO

O

S

O

O

O C RN

CH3

[20-26]

4-(N-phthalimidyl) phenyl sulfonyl chloride [3]

4-hydroxy acetophenone

4-[4-(N-phthalimidyl) phenyl sulfonate] acetophenone [19]'

4-[4-(N-phthalimidyl) phenyl sulfonate] methyl benzylidene'

R =

CH3N

S ,

, ,

H3C O2NCl ,

Cl

Cl

NO2

,

Scheme (2)

Different primary aromatic amines

CH3

N-phenyl phthalimide [2]

xi

CN

CO

O

S

O

O

Cl

CN

CO

O

+

Chlorosulfonic acid

Cl S

O

O

OH

CN

CO

O

S

O

O

O C

O

H

CN

CO

O

S

O

O

O C RN

H

[28-33]

4-hydroxy benzaldehyde

4-[4-(N-phthalimidyl) phenyl sulfonate] benzaldehyde [27]'

4-[4-(N-phthalimidyl) phenyl sulfonate] benzylidene'

R =

CH3 ,

, ,

H3C O2NCl

Cl

Cl NO2 ,

Scheme (3)


N-phenyl phthalimide [2]

4-(N-phthalimidyl) phenyl sulfonyl chloride [3]

xii

CN

CO

O

CH2

CN

CO

O

C

O

H KOH (alcoholic)

CN K

CO

O

CN

CO

O

CH2 C

NR

4-phenyl phenacyl bromide

N-(4-phenyl phenacyl) phthalimide [34]

[35-40]

N-phthalimidyl-4-phenyl benzylidene methane

R =

CH3 ,

, ,

HO

Cl

NO2

,

Scheme (4)


OHBr

unsubstituted Phthalimide phthalimide potassium salt

Chapter One Introduction

1

sbase sʼSchiff -1-1

A Schiffs base is a type of chemical compounds containing carbon-

nitrogen double bond in which nitrogen atom connected to aryl or

alkyl group,these compounds were named after Hugo Schiff (1) since their

synthesis was first reported by Schiff , they have the following general

structure.

The role of R3 group is to stabilize the iminic Schiffs base.

Structurally a Schiffs base (also known as imine or azomethine) is a

nitrogen analogue of an aldehyde or ketone in which the carbonyl group

(C=O) has been replaced by an imine or azomethine group.

Schiffs bases of aliphatic aldehydes are unstable and readily

polymerizable while those of aromatic aldehydes having an effective

conjugation system are more stable(2).

The most common method for preparation of Schiffs bases involved

acid-catalyzed condensation reaction of an amine and aldehyde or ketone

under refluxing conditions(3,4).

The first step in this reaction involved nucleophilic addition which

leads to the formation of unstable carbinol amine intermediate which loses

a molecule of water in the second step forming the corresponding imine.

R2

R1C=O + R3NH2 C N R3

R1

R2

O H

HC N

R1

R2

OH H

R3R2

R1C=NR3 H2O+

Carbinol amineintermediate

NN==CC

CC==NN RR33RR22

RR11(( RR11 ,, RR22 ,, RR33 aarree aarryyll oorr aallkkyyll ggrroouuppss ))


2

bases s Schiff of Synthesis -2-1

The first preparation of imines was reported in the 19th century by

Schiffs (1864). Since then a variety of methods for the synthesis of imines

have been described(5).

The classical synthesis reported by Schiffs involves condensation of

carbonyl compound with an amine under azeotropic distillation(6),

molecular sieves are then used to remove the formed water. In 1990s an in

situ method for water elimination was developed using dehydrating

solvents such as tetramethylorthosilicate or trimethylorthoformate(7,8).

In 2004,Chakraborti et al.(9) demonstrated that the efficiency of these

methods is dependent on the use of highly electrophilic carbonyl

compounds and strongly nucleophilic amines.

They proposed use of substances that function as Bronsted-Lowry or

Lewis acids to activate the (C=O) of aldehydes , catalyze the nucleophilic

attack by amines and eliminate water as the final step.

Examples of the used Bronsted-Lowry or Lewis acids include :

ZnCl2, alumina, TiCl4, H2SO4, CH3COOH and HCl(10-15).

In the 12 past years a number of innovations and new techniques

have been reported, including solvent-free/ clay/microwave irradiation,

solid-state synthesis, water suspension medium, NaHSO4-SiO2/ microwave/

solvent-free and solvent-free/CaO/microwave(1٦-1۹).

Among these innovations microwave irradiation has been extensively

used due to its operational simplicity, enhanced reaction rates and

selectivity(۲۰).

In 2001 Roman and Andrei(۲۱) synthesized twenty new Schiffs bases

with a potential biological activity resulted from the acid-catalyzed

condensation of orthophenolic aldehydes with several aromatic and hetero

aromatic amines in ethanol.


3

Yang et.al(22) performed a microwave-assisted preparation of a series

of Schiffs bases via efficient condensation of salicylaldehyde and aryl

amines without solvent.

In this method microwave irradiation plays an important role for

promoting condensation reaction of aldehyde and amine thus reaction is

performed within (0.5min.-4mins.).

On the other hand eight new Schiffs bases [2a-h] were prepared in

excellent yields via the condensation of different aromatic amines

and azoaldehyde [1] 2-hydroxy-3-methoxy-5-(4-methoxyphenylazo)

benzaldehyde in dry dichlolromethane in the presence of anhydrous

MgSO4(23).

OHCHOR3

R2R1

ArNH2H2SO4 (Catalyst)

reflux+

OHCH=N ArR3

R2R1

R1 , R2 , R3 = H, Br, I

CH3

CH3

Cl

Cl

Cl

Cl

Cl

CO2CH3

CO2CH3

CO2CH3

, ,

,

Ar =

OOHH

CCHHOO++

OOHH

CCHH==NN

NNHH22NN

RRMMiiccrroowwaavvee NN RR

RR == --CCHH33 ,, --BBrr


4

Treatment of two moles of azoaldehyde [1] with one mole of 4,4'-

diaminodiphenyl ether in refluxing absolute ethanol gave in excellent

yields the two novel compounds [3a-b].

The new ten Schiffs bases [2a-h] and [3a-b] showed different

antibacterial activities on testing against five types of bacteria.

Also several Schiffs bases [5a-d] were synthesized by Baluja et al.(24)

via condensation of sulfanilamide [4] with aromatic aldehydes.

SSOO22NNHH22

NNHH22

CCHHOO

RR11

RR22

++

SSOO22NNHH22

NN==CCHH RR11

RR22

[[44]] [[55aa--dd]]

55aa :: RR11 == --HH ,, RR22 == --HH55bb :: RR11 == --OOCCHH33

,, RR22 == --HH55cc :: RR11 == --SSCCHH33 ,, RR22 == --HH55dd :: RR11 == --OOCCHH33 ,, RR22 == --OOHH

CH3O N=N

OCH3

OH

CHO

ArNH2+ CH3O N=N

OCH3

OH

CH=N Ar

Ar =

CH2

OH CH3

H3C H3CO OCH3

OCH3

[1] [2a-h]

, , ,

, , ,

MgSO4

CCHH33OO NN==NN

OOCCHH33

OOHH

CCHHOO

++ XX NNHH22HH22NN

((XX == OO ,, SSOO22))

CCHH33OO NN==NN

OOCCHH33

OOHH

CC==NN XX NN==CC

OOCCHH33HHOO

CCHH33OO

NN==NN

33aa XX == OO33bb XX == SSOO22


5

The same team synthesized several Schiffs bases [7a-d] via refluxing

5-ethyl resacetophenone [6] with aniline derivatives in methanol in the

presence of anhydrous ZnCl2.

These Schiffs bases [5a-d] and [7a-d] showed good antimicrobial

activity against different types of bacteria and fungi.

Since coumarin derivatives are of great interest due to their role in

natural and synthetic organic chemistry and many coumarin containing

products exhibit biological activity, coumarins containing a Schiffs base

are expected to have enhanced biological activities, so according to this

satyanarayana and coworkers(25) synthesized a series of new Schiffs bases

containing coumarin moiety by the condensation of aryl/hetero aromatic

aldehydes with 2-[(4-methyl-2-oxo-2H-chromen-7-yl)oxy]acetohydrazide

[8] under conventional and microwave conditions.

The synthesized compounds have been screened for antimicrobial

activity.

Non classical methods including water based reaction, microwave

and grindstone chemistry were used by Naqvi(26) and coworkers for the

preparation of Schiffs bases [10a-f] from 3-chloro-4-fluoroaniline and

several benzaldehydes.

++

RR11

RR22

NNHH22RR33

ZZnnCCll22 ((aannhh))CCOOCCHH33

OOHHHHOO

HH55CC22 CC==NN

OOHHHHOO

HH55CC22

CCHH33

RR11

RR22RR33

[[77aa--dd]][[66]]

77aa :: RR11 == --NNOO22 ,, RR22 == --HH ,, RR33 == --HH 77bb :: RR11 == --CCHH33 ,, RR22 == --HH ,, RR33 == --CCHH3377cc :: RR11 == --HH ,, RR22 == --NNOO22 ,, RR33 == --HH77dd :: RR11 == --HH ,, RR22 == --CCHH33 ,, RR33 == --HH

CC

OOOO

HH22NN--HHNNOO OO

CCHH33

HHNNOO OO

CCHH33

NNRR

[[88]] [[99aa--ff ]]

CC

OOOO

++

CCHHOO

RR == --HH ,, --NNOO22 ,, --CCll ,, --OOHH ,, --OOCCHH33 ,, --NN((CCHH33))22

RR


6

The key raw materials were allowed to react in water, under

microwave irradiation and grindstone.

These methodologies constitute an energy efficient and

environmentally benign greener chemistry version of the classical

condensation reactions for Schiffs bases formation(27,28).

Water has been proved here as a suitable (green solvent) for the

synthesis of Schiffs bases and increase in %yield is in following order =

Method C < Method B < Method A

(grindstone) < (Microwave) < (Water based synthesis)

S. Kumar et al.(28) synthesized ten Schiffs bases of sulfonamides by

condensing 4-aminobenzene sulfonamide with different aromatic aldehydes

in the presence of glacial acetic acid and ethanol at (50-60)°C.

The antimicrobial activity of these compounds were examined

against different Gram-positive, Gram-negative bacteria and fungal strains.

The presence of azomethine and sulfonamide functional group is

responsible for antimicrobial activity.

On the other hand G. Kumar et al.(29) synthesized new Schiffs base via

mixing a warm dilute ethanolic solution of thiocarbohydrazide with

2-amino-4-ethyl-5-hydroxy benzaldehyde under reflux for 2hrs.

+R

Cl

FCH=NCHO

R

NH2

ClF

method A , Band C

[10a-f]Schiff bases

R = 3,4-Di OCH3 , 2-Cl , 4-Cl , 2-OH , 4-OH , 3-NO2

SO2NH2

NH2

+

SO2NH2

N=CH

C2H5OH / HOAC glacialreflux (5-6) hrs

CHO

R = -H , -Cl , -OH , -N(CH3)2 , OCH3 , NO2 , -(OCH3)3

R


7

Complex of Cr, Mn and Fe with this Schiffs base were prepared .The

Schiffs base ligand and their complexes were tested for their antimicrobial

against many types of bacteria and fungi. The Cr(III) Complex showed the

best antimicrobial activity but the ligand alone was found to be active

against the fungus trichoderma reesei.

Yang and Sun(30) prepared Schiffs base [9] 4-methyl-N-(3,4,5-

trimethoxy benzylidene)benzene amine by three different ways.

The first one involved introducing a mixture of p-toluidine, 3,4,5-

trimethoxy benzaldehyde, neutral alumina and dichloromethane into

microwave oven irradiated for 4 mins.

While in the second way a solution of the two mentioned reactants in

benzene was heated in reflux until no water appear then removing solvent

in vaco.

The third method involved addition of anhydrous MgSO4 to a

solution of trimethoxy benzaldehyde and p-toluidine in dichloromethane

followed by stirring for 2hrs. at room temperature. Comparison the results

of the three methods shown in Table (1-1) indicated that microwave

method is the most convenient one since it affords higher yields in shorter

reaction time, clean and cheap.

NH2

CH3

+

CHO

OCH3

H3CO

HC=N

OCH3OCH3

H3CO

CH3

[9]

OCH3

+CHOHO

H5C2 NH2

H2NNH

S

NH

NH2

HN

S

NH

CH=N N=CHHO

H5C2 NH2

OH

H2N C2H5

2 Reflux


8

bases sʼSchiff Applications of -3-1

The chemistry of the carbon-nitrogen double bond plays a vital role in

the progress of chemistry science(31).

Schiffs bases have been widely used in many fields e.g.

biological(32-34), inorganic(35,36), analytical(37,38) drug synthesis and as

bidentate ligand in the field of coordination chemistry.

The Schiffs base complexes have been used in catalytic reactions and

also have been used as fine chemicals and medical substrates(39,40).

Schiffs bases form a significant class of compounds in medicinal and

pharmaceutical chemistry(41-44) with several biological applications that

include antibacterial(45-61), antifungal(62-68), antimalarial(69), anticancer(70-74),

antitubercular(75) , anti-inflammatory(76) , antimicrobial(70) , antiviral(46),

antitumor(78,79) and herbicidal(80) activities.

Also Schiffs bases are important class of ligands due to their synthetic

flexibility, their selectivity and sensitivity towards the central metal

atom(81-83).

The imine group present in such compounds has been shown to be

critical to their biological activities(84).

Anticancer activities of three Schiffs bases N-(1-phenyl-2-hydroxy-2-

phenyl ethyledine)-2,4-dinitro phenyl hydrazine (PDH), N-(1-phenyl-2-

hydroxy-2-phenyl ethyledine)-2-hydroxy phenyl imine (PHP) and N-(2-

hydroxy benzylidine)-2-hydroxy phenyl imine (HHP) against Ehrlich

Way Reaction condition Time Yield(%)

1 Microwave irradiation 4 min. 85

2 Reflux Over 7 hr 72

3 Room temperature stirring 4 hr 75

Table (1-1)


9

ascities carcinoma (EAC) cells in Swiss albino mice have been studied(85).

These compounds enhanced life span, reduced average tumor weight

and inhibited tumor cell growth of EAC cell bearing mice.

Cyclic imides -4-1

Cyclic imides such as maleimide [10], succinimde [11], phthalimide

[12], glutarimide [13], and citraconimide [14] are cyclic organic

compounds, their molecules contain an imide ring and the general structure

(-CO-N(R)-CO-)(86).

These cyclic imides are an important functionality which have been

found to maintain significant biological activity(87,88).

O

O

N R

O

O

N R

O

O

N R

O

O

N R

O

O

N R

H3C

[10] [12]

[13] [14]

[11]

CC==NNHHCC

NNHH--

OO22NN

NNOO22 CC==NN

HHOO

OOHH

CCHH==NN

HHOO

HHHHPP

PPDDHH PPHHPP

OOHH HHCC OOHH


10

Methods for synthesis of cyclic imides -5-1 Synthesis of cyclic imides may be performed by many methods

including agentsdehydrating of amic acids by using ydration Deh -1-5-1

The most common method used for preparation of cyclic imides

involved dehydration of amic acids by using different dehydrating agents.

Amic acids are organic compounds containing both carboxyl and

amide groups in their molecules and can be prepared easily with excellent

yields via reaction of cyclic anhydrides with different aliphatic or aromatic

amines(89-95).

Treatment of amic acids with suitable dehydrating agents lead to

dehydration and cyclization producing the corresponding cyclic imides as

shown in Scheme (1-1).

The most important dehydrating agents used in dehydrating of amic

acids to the corresponding imides include:

1-Acetic anhydride with anhydrous sodium acetate(96-104).

2-Thionyl chloride(105-107).

3-Acetyl chloride with triethyl amine(108,109).

4-Phosphorus trichloride(110,111).

5-Phosphorus pentaoxide(112).

C

O

C

O

O + RNH2

COOH

CONHR

Suitable dehydrating agentC

O

C

O

N R

Scheme (1-1)


11

ydrationhThermal De -2-5-1

This method has been used for preparation of imides whenever

dehydration agents failed to do so(113,114).

Al-Azzawi(115) applied this method successfully in the preparation of

several N-substituted citraconimides in high yields (85-90%).

Also Al-Azzawi and Al-Obaidi(116) performed synthesis of several N-

(hydroxy phenyl)phthalimides by depending on fusion method. Moreover

Al-Azzawi and Ali(117-120) synthesized a series of N-(hydroxy phenyl)

maleimides and N-(hydroxy phenyl) citracoimides in high yields and purity

by application of this method.

Gabriel Type Synthesis -3-5-1

This method involved treatment of potassium salt of unsubstituted

succinimide and phthalimide with different alkyl halides producing the

corresponding N-substituted imides(121).

C

O

C

O

NH + KOHC

O

C

O

N K

Br(CH2)2OHC

O

C

O

N OH(CH2)2 + KBr

Scheme (1-2)

COOHR

CONH

OH

C

O

C

O

NFusion

R

OH

COOH

CONH

OH

Fusion C

O

C

O

N

OH

(R = H or CH3)


12

AdductsAlder -Diels -4-5-1

Maleimide and substituted maleimides can be prepared by heating

maleic anhydride with cyclopentadiene to form Diels-Alder adduct [15]

which was then converted to imide [15] by reaction with amine.

Heating of [16] would produce N-substituted maleimide(122) as

shown in Scheme (1-3)

lic imidescher methods used in preparation of cyOt -6-1

The development of simple, relatively mild, efficient and practical

method for the synthesis of N-alkyl and N-arylphthalimides and

succinimides was reported by Langade(123).

This method was performed by using (10 mol%) sulphamic acid

catalyst. Thus a series of N-substituted phthalimides and succinimides were

prepared via reaction of phthalic and succinic anhydride with primary

amines in acetic acid in the presence of (10%) sulphamic acid at (110 °C)

for appropriate time.

C

O

C

O

O+C

O

C

O

OC

O

C

O

N RRNH2

C

O

C

O

N R+

Scheme (1-3)

[15] [16]


13

On the other hand N-(4-nitro-2-phenoxy phenyl)methane sulfonamide

or nimesulide [17] a preferential cyclo oxygenase-2(COX-2) inhibitor is

one of the well known non-steroidal anti-inflammatory drugs that has been

utilized to treat pain and other inflammatory diseases.

Reduction of the nitro group in [17] afforded the required amine [18] .

Treatment of [18] with a variety of cyclic anhydrides in refluxing glacial

acetic acid in the presence of sodium acetate afforded a series of novel

nimesulide-based cyclic imides [19-24] as shown in Scheme (1-4).

Some of the synthesized imides showed anti-inflammatory activities

when tested in rats(124).

The prepared new imides and reaction conditions are shown in Table

(1-2) .

O

NO2

NHSO2CH3

O

NHSO2CH3

NH2

CO

CO

O

Sn / HCl90 C , 3h.o O

NHSO2CH3

Cyclic anhydrides

[17] [18]N

CO

C OImides [19-24]

Scheme (1-4)

C

O

C

O

O

C

O

C

O

O

or Sulphamic acid

C

O

C

O

N

C

O

C

O

or

N

+

NH2

R = -H , 4-Cl , 4-NO2 , 3-OH , 4-CH3 , 4-OCH3

R

R

R


14

The unsubstituted cyclic imide is an important functionality which

has been found to maintain significant biological activity(125-129).

A series of un substituted cyclic imides were prepared from cyclic

anhydrides, hydroxylamine hydrochloride and 4-N,N-dimethyl amino

pyridine (DMAP) base catalyst under microwave irradiation(130).

This novel microwave synthesis produced high yields of the

unsubstituted cyclic imides as shown in Table (1-3).

Comp. No.

Cyclic anhydrides

Cyclic imides Reaction

conditions Yield(%)

19

110-120 ºC

10 min 73

20

110-120 ºC

15 min 65

21

110-120 ºC

15 min 65

22

110-120 ºC

15 min 65

23

110-120 ºC

20 min 65

24

110-120 ºC

20 min 75

Table (1-2)

CC

OO

CC

OO

OOCC

OO

CC

OO

NN HH++ NNHH22OOHH..HHCCllDDMMAAPP

MMiiccrroo wwaavveeiirrrraaddaattiioonn

Reaction conditions for preparation of imides (19-24)

CC

OO

CCOO

OOCC

OO

CCOO

NN NNHHSSOO22CCHH33

OOPPhh

CC

OO

CCOO

OO

NNOO22

CC

OO

CCOO

NN NNHHSSOO22CCHH33

OOPPhhNNOO22

CC

OO

CCOO

OOOO22NN OO22NN

CC

OO

CCOO

NN NNHHSSOO22CCHH33

OOPPhh

CC

OO

CCOO

OOCC

OO

CCOO

NN NNHHSSOO22CCHH33

OOPPhh

CC

OO

CCOO

OOCC

OO

CCOO

NN NNHHSSOO22CCHH33

OOPPhh

CC

OO

CCOO

OO NN NNHHSSOO22CCHH33

OOPPhh

CC

OO

CCOO


15

On the other hand Mogilaiah and Sakram(131) reported a practical and

efficient method for the synthesis of 1,8-naphthyridinyl phthalimides.

Treatment of 2-amino-3-aryl-1,8-naphthyridines [25a-g]with phthalic

anhydride in the presence of catalytic amount of DMF in absence of

solvent under microwave irradiation afforded the corresponding N-(3-aryl-

1,8-naphthyridin-2-yl) phthalimides [26a-g] Scheme (1-5) in excellent

yields (92-98%) with short reaction time (3-4 min). The reaction is simple,

clean, rapid and efficient.

Also a series of phthalimides possessing N-phenoxyalkyl moiety

substituted at position 3 or 4 of the phenyl ring [27-35] was synthesized

and evaluated for anticonvulsant activity(132).

Imides Time(min) Yield(%)

2.68 97

1.82 96

1.57 84

Table (1-۳): Synthesis of unsubstituted imides using NH2OH and DMAP

NN

Ar

NH2

+ C

O

C

O

O DMFM.W

C

O

C

O

NNN

Ar

[26a-g][25a-g]

a , Ar = C6H5 e , Ar = p-ClC6H4b , Ar = p-CH3OC6H4 f , Ar = p-BrC6H4c , Ar = o-ClC6H4 g , Ar = p-NO2C6H4 d , Ar = m-ClC6H4

Scheme (1-5)

CC

OO

CCOO

NN HH

CC

OO

CCOO

NN HH

CC

OO

CCOO

NN HH


16

Synthesis of these imides [27-35] performed by alkylation of

potassium phthalimide with appropriate phenoxyalkylbromide in the

presence of K2CO3 and triethylbenzylammonium chloride (TEBA) in

acetone as shown in Scheme (1-6).

Phenoxyalkyl bromides used in the synthesis of compounds [68-76]

were prepared from reaction between the phenols and an excess of 1,2-

dibromoethane or 1,3-dibromopropane.

Comp. No.

R Comp. No.

R

27

32

28

33

29

34

30

35

31

R

OH (CH2)n BrBr+

(n = 2 , 3)

' R

O

'

Br(CH2)n (R = Br)

(n = 2 , 3)

C

O

C

O

N K + R Br K2CO3 , TEBAacetone , 6 h reflux

C

O

C

O

N R

Scheme (1-6)

OO CC((CCHH33))33((CCHH22))22 OO

OOCCHH33

OO CCll((CCHH22))22 OO CCll

OO CCHH33((CCHH22))22 OO CC((CCHH33))33

OO

CCll

OO

OOCCHH33

OO

CCFF33


17

Moreover a new series of 2-(1,3-dioxo-2,3-dihydro-1H-2-isoindolyl)

ethyl-2-hydroxy-2-(substituted phenyl) acetates [39a-e] have been

synthesized from the combination of N-(2-hydroxy ethyl)phthalimide [36]

and substituted mandelic acids [38a-e] which resulted in both anti-

inflammatory and antimicrobial activities(133).

Among the compounds tested for anti-inflammatory activity

compounds [39b] and [39e] showed significant activity and compound

[39b] showed potent antibacterial and antifungal activity.

[36] + [38a-e] DCCDioxaneR.T. 18 hr

C

O

C

O

N

OH

ROC

O

OH

[39a-d]

C

O

C

O

N

OH

OC

O

OH

[39e]Scheme (1-7)

C

O

C

O

O +NH2 OH

Et3NToluene

reflux , 4 hr

C

O

C

O

NOH

[36]

OH

R+

CHO

COOH

NaOH(0-5 oC)

OH

COOH

HOR

[35a-d] [38a-d]

OH

+ CHO

COOH

NaOH(0-5 oC)

HO

OH

COOH

[35e] [38e]

R = H , CH3 , Cl , OCH3


18

Biological Activity of Cyclic Imides -7-1

N-substituted cyclic imides represent an important class of bioactive

molecules that show a wide range of pharmacological activities such as

anti-inflammatory, anxiolytic, antifungal , antiviral , antibacterial, analgesic

and antitumor properties(134-142).

Beside these biological effects some phthalimide derivatives

constitute an important class of compounds possessing diverse type of

biological properties including antimicrobial(143), antimalarial(143),

antihypertensive(144), antiviral(145) and herbicides(146,147) activity.

Also N-phenylphthalimide and its derivatives have been widely

reported to possess beneficial pharmacological effects , they have

been shown to be anticonvulsant(148,149), anti-inflammatory and

hypolipidemic(150,151).

In addition tetrachlorophthalimide has been reported to possess

potent hypoglycemic activity(152-154).

A series of sixteen N-phenylphthalimide derivatives [40-55] was

synthesized by the reaction between phthalic anhydride and different

amines in acetic acid at reflux temperature(155).

The α-glucosidase inhibitory activity of these compounds [40-55] in

microbial and mammalian enzymes was evaluated and the results showed

that N-phenylphthalimide substituted at position 3 of the benzene ring with

NO2 group showed moderate α-glucosidase inhibitory activity, while the

presence of NO2 group at the 2- and 4-positions resulted in the most active

α-glucosidase inhibitor among N-phenylphthalimide derivatives.

CC

OO

CCOO

NN

RR11 RR22

RR33


19

Also a series of new cyclic imides [56a-b] and [57a-b] with a carbazole

skeleton and a basic side chain at the imide nitrogen were tested in vitro for

tumor cell-growth inhibition(156).

The results showed that compound [56a] is a superior as compared to

[56b] the latter lacking the second methyl group at the aromatic scaffold.

Comp. No. R1 R2 R3

40 H H H

41 NO2 H H

42 H NO2 H

43 H H NO2

44 NO2 H NO2

45 NH2 H H

46 H NH2 H

47 H H NH2

48 NH2 H NH2

49 H Cl H

50 H H Cl

51 Cl H Cl

52 H Br H

53 H OH H

54 NO2 H Cl

55 Cl H NO2

Table (1-4)


20

Likewise when [57a] is compared to its methoxy derivative [57b] the

latter structural modification is clearly beneficial.

On the other hand a series of N-substitutedmaleimides linked to

benzothiazole moiety [58a-j] were synthesized by Al-Azzawi and

Mehdi(157), via reaction of maleic anhydride with different substituted-2-

aminobenzothiazoles producing benzothiazol-2-yl maleamic acids followed

by dehydration with acetic anhydride and sodium acetate Scheme (1-8).

Antimicrobial activity study of the synthesized maleimides [58a-j]

against Staphylococcus aureus, Klebsiella pneumonia and Candida

albicans showed that many of the prepared maleimides have good

antimicrobial activity.

Also Al-Azzawi and Hassan(158) synthesized a series of citraconimides

linked to benzothiazole moiety [59a-k], Scheme (1-9) studying their

antimicrobial activity against Staphylococcus aureus, Streptococcus

pyogenes, E.Coli, Pseudomonas aeruginosa and Candida albicans, most

of the tested citraconimides showed good antibacterial and antifungal

activities.

C

O

N

N

C

O

H

N(C2H5)2

56a R = CH356b R = H

C

O

N

N

C

O

57a R = H57b R = CH3O

R

CH3

CH3

N(C2H5)2

R


21

Moreover Al-Azzawi and Al-Amerri(159) synthesized a series of

phthalimides [60-64] and succinimides [65-69] linked to 1,3,4-oxadiazole

moiety , the new imides showed good antibacterial activity against

Staphylococcus aureus and E. Coli bacteria.

C

O

C

O

NO

NN

R

C

O

C

O

NO

NN

R

[60-64] [65-49]

(R = 2-OH , H , 4-Cl , 4-OCH3 , 2-NO2)

S

NR

NH2

C

O

C

O

O+S

NR

N C

O

HOOC

H

R = H , 6-CH3 , 6-Cl , 6-NO2 , 4,6-dichloro , 4,6-di CH3 , 6-OCH3 , 4-NO2-6-Cl , 6-COOH , 4-Cl-6-NO2

S

NRC

O

C

O

N

[58a-j]

Ac2O

S

NR

NH2

C

O

C

O

O+S

NR

N C

O

HOOC

H

H3C

CH3

Ac2O / NaOAcor Fusion

S

NRC

O

C

O

N

[59a-k]

CH3

R = 6-CH3 , 6-Cl , 6-NO2 , 6-COOH , 4,6-dichloro , 6-OCH3 , 4,6-di CH3 , 6-COOH-7-OH , 6-NHCO3 , 4-NO2-6-Cl , 4-Cl-6-NO2

Scheme (1-9)

NaOAc

Scheme (1-8)


22

Aim of the Work

Since both phthalimides and Schiffs bases exhibited wide range of

biological activities and have wide spectrum of biological applications the

target of this work involved synthesis of new phthalimides linked to Schiffs

bases by using different strategies involving the following parts:

Part One

This part involved synthesis of phthalimides linked to Schiffs base

through phenyl sulfonamido group.

These new imides were synthesized via preparation of N-phenyl

phthalamic acid which introduced subsequently in dehydration reaction

producing N-phenyl phthalimide and this was treated with chloro sulfonic

acid producing phthalimidyl phenyl sulfonyl chloride which in turn was

treated with hydrazine hydrate producing phthalimidyl sulfonyl hydrazine

which represent the main synthones introduced in reaction with different

aldehydes and ketones to afford the desired new phthalimides.

Part Two

This part involved synthesis of new phthalimides linked to Schiffs

base through phenyl sulfonate moiety via reaction of phthalimidyl sulfonyl

chloride with 4-hydroxy acetophenone producing phthalimidyl phenyl

sulfonate acetophenone which in turn introduced in reaction with different

primary aromatic amines producing the desired new phthalimides.

Part Three


base through phenyl sulfonate moiety via reaction of phthalimidyl sulfonyl

chloride with 4-hydroxy benzaldehyde producing phthalimidyl phenyl

sulfonate benzaldehyde which in turn introduced in reaction with different

primary aromatic amines producing the desired imides.


23

Part Four


base through methylene group via reaction of 4-phenyl phenacyl bromide

with phthalimide potassium salt producing N-(4-phenyl phenacyl)

phthalimide which in turn introduced in reaction with different primary

aromatic amines to afford the desired imides.

Chapter Two Experimental

24

2-1- Instruments and Chemicals

2-1-1- Instruments 1. Melting points were determined on Gallenkamp capillary melting point

apparatus.

2. FT-IR spectra were recorded using KBr discs on SHIMADZU FT-IR-

8400 Fourier Transform Infrared Spectrophotometer, in college of

science, Baghdad University and on SHIMADZU FT-IR-prestige-21

Fourier Transform Infrared Spectrophotometer,in Ibn-Sina Company.

3. 1H-NMR and 13C-NMR spectra were recorded on near magnetic

resonance Bruker, Ultrasheild 300 MHZ in Jordan, using tetra methyl

silane as internal standard and DMSO-d6 as solvents.

2-1-2- Chemicals Chemicals used in this work were purchased from BDH, Merck and

Fluka companies and involved the following:

No. Chemical Compounds

1 Phthalic anhydride

2 Acetic anhydride

3 Different primary aromatic amines

4 Ethanol(abs.)

5 Acetic acid (glacial)

6 Anhydrous sodium acetate

7 Chlorosulfonic acid

8 Acetone

9 Hydrazine hydrate

10 Different aromatic aldehydes and ketones


25

The experimental chapter in this work involved the following parts:

2-2- Part One

This part involved synthesis of phthalimides linked to Schiffs bases

through sulfonamido group.

Performing this target involved the following steps:

1. Synthesis of N-phenyl phthalamic acid.

2. Dehydration of the prepared N-phenyl phthalamic acid producing

N-phenyl phthalimide.

3. Chlorosulfonation of the prepared phthalimide producing

4-(N-phthalimidyl) phenyl sulfonyl chloride.

4. Treatment of phthalimidyl phenyl sulfonyl chloride with hydrazine

hydrate producing the corresponding sulfonyl hydrazine.

5. Introducing of sulfonyl hydrazine in reaction with different aromatic

aldehydes and ketones producing the desirable new phthalimide.

No. Chemical Compounds

11 Ethanol

12 Methanol

13 Hydrochloric acid

14 4-phenyl phenacyl bromide

15 Unsubstituted Phthalimide

16 Potassium hydroxide

17 Sodium hydroxide

18 Sodium bicarbonate

19 Cyclo hexane

20 Dioxane


26

2-2-1- Preparation of N-phenyl phthalamic acid [1] To a solution of (0.01 mol, 1.48 g) of phthalic anhydride in 25 mL of

acetone, (0.01 mol, 1mL) of aniline was added drop wise with stirring and

cooling(120,160,161,).

Stirring was continued for two hours at room temperature the resulted

precipitate was filtered, dried, recrystallized from ethanol.

The physical properties of compound [1] are listed in Table (3-1).

2-2-2- Preparation of N-phenyl phthalimide [2] A mixture of (0.01 mol, 2.41 g) of N-phenyl phthalamic acid in 25 mL of

acetic anhydride and (5 %) by weight of anhydrous sodium acetate was

refluxed for two hours with stirring(158,162).

The resulted homogenous solution was cooled to room temperature and

pouring into crushed ice, compound [2] was obtained filtered, dried,

recrystallized from acetone.


2-2-3- Preparation of 4-(N-phthalimidyl) phenyl sulfonyl chloride [3]

Chlorosulfonic acid (4 mL) was added drop wise to (0.01 mol, 2.23 g)

of N-phenyl phthalimide during two hours with stirring and keeping

temperature at 0 oC(162).

Stirring was continued for ten hours at room temperature then the

resulted mixture was poured into crushed ice carefully with stirring.

The obtained precipitate was filtered, dried, recrystallized from acetone.



27

2-2-4- Preparation of 4-(N-phthalimidyl)phenyl sulfonyl hydrazine [4]

To a solution of (0.01 mol, 3.22 g) of compound [3] in 5 mL of absolute

ethanol, (0.01 mol) of hydrazine hydrate was added drop wise with stirring

and keeping temperature at 0 oC.

The resulted mixture was refluxed for six hours then cooled to room

temperature then pouring on crushed ice with stirring(163).

The resulted precipitate was filtered, washed with cold water, dried and

finally recrystallized from ethanol.


2-2-5- Preparation of Schiffs Bases [5-18] A mixture of 4-(N-phthalimidyl) phenyl sulfonyl hydrazine (0.01 mol,

3.17 g), aromatic aldehyde or ketone (0.01 mol) and (2-3) drops of glacial

acetic acid in absolute ethanol (20 mL) was refluxed for six hours(164).

After cooling the obtained precipitate was filtered then washed with

cold ethanol, dried and recrystallized from a suitable solvent.

Physical properties of compounds [5-18] are listed in Table (3-2).

2-3- Part Two

This part involved synthesis of new phthalimides linked to Schiffs bases

through phenyl sulfonate moiety.


1. Reaction of 4-(N-phthalimidyl) phenyl sulfonyl chloride with 4-

hydroxy acetophenone producing 4-(4'-(N-phthalimidyl) phenyl

sulfonate) acetophenone.

2. Introducing of the prepared phthalimidyl sulfonate acetophenone in

reaction with different primary aromatic amines producing the desirable

new imides.


28

2-3-1- Preparation of 4-(4'-(N-phthalimidyl) phenyl sulfonate)

acetophenone [19] In a three-necked flask equipped with a stirrer and thermometer a

mixture of (2.04 g, 0.015 mol) of 4-hydroxy acetophenone and (3 mL) of

pyridine was placed.

The flask was surrounded by a bath sufficiently cold to lower the

thermometer of the mixture to 10 oC(164).

4-(N-phthalimidyl)phenyl sulfonyl chloride (0.01 mol, 3.22 g) was

added in portions during 20 minutes with continuous stirring.

The mixture was refluxed for two hours on a water bath then cooled to

room temperature then the reaction mixture was poured into cold water with

stirring until the resulted oily layer solidified.

The solid product was filtered, washed with cold dilute HCl solution

followed by dilute NaHCO3 solution then with distilled water , dried,

recrystallized from ethanol to give pale brown crystals in 70% yield and

m.p.(152-154)oC.

FT-IR: 1739, 1720 cm-1 n(C=O) imide, 1674 cm-1 n(C=O) ketone,1593

cm-1 n(C=C) aromatic , 1361 cm-1 and 1176 cm-1 n(SO2) sulfonate.

2-3-2- Preparation of 4-(4'-N-phthalimidyl) phenyl sulfonate methyl

benzylidene (Schiffs base) [20-26] In a suitable round bottomed flask (0.01 mol, 4.21 g) of compound [19]

was dissolved in 20 mL of absolute ethanol then (0.01 mol) of primary

aromatic amine was added followed by addition of (2-3) drops of glacial

acetic acid with stirring.

The mixture was refluxed for four hours then cooled to room

temperature and the obtained precipitate was filtered, dried and purified by


29

recrystallization from a suitable solvent.

The physical properties of Schiffs bases [20-26] are listed in Table (3-5).

2-4- Part Three This part involved synthesis of new phthalimides linked to Schiffs bases

through sulfonate moiety.

Performing this target involved the following steps: 1. Reaction of 4-(N-phthalimidyl) phenyl sulfonyl chloride with

benzaldehyde producing 4-(4'-(N-phthalimidyl) phenyl sulfonate)

benzaldehyde. 2. Introducing of the prepared phthalimidyl sulfonate benzaldehyde in

reaction with different primary aromatic amines producing the desirable

new imides.

2-4-1- Preparation of 4-(4'-N-phthalimidyl) phenyl sulfonate

benzaldehyde [27] The titled compound [27] was prepared by following the same

procedure used in the preparation of compound [19] except using of

4-hydroxy benzaldehyde instead of 4-hydroxy acetophenone, recrystallized

from ethanol to give pale brown crystals in 72% yield and m.p.(176-178)oC.

FT-IR: 1741 and 1718 cm-1 n(C=O) imide, 1699 cm-1 n(C=O) aldehyde,

1593 cm-1 n(C=C) aromatic and 1360, 1186 cm-1 n(SO2) sulfonate.

2-4-2- Preparation of 4-(4'-N-phthalimidyl) phenyl sulfonate

benzylidene (Schiffs bases) [28-33] The titled compounds were prepared by following the same procedure

used in the synthesis of compounds [20-26] except using of compound [27] as

starting material instead of compound [19].

The physical properties of compounds [28-33] are listed in Table (3-7).


30

2-5- Part Four

This part involved synthesis of new phthalimides linked to Schiffs bases

through methylene (-CH2-).


1. Preparation of phthalimide potassium salt.

2. Reaction of phthalimide potassium salt with 4-phenyl phenacyl bromide

producing N-(4-phenyl phenacyl) phthalimide.

3. Introducing N-(4-phenyl phenacyl) phthalimide in reaction with

different primary aromatic amines producing the desirable imides.

2-5-1- Preparation of phthalimide potassium salt Phthalimide (0.01 mol, 1.47 g) was dissolved in 20 mL of absolute

ethanol then was heated in a water bath.

The obtained clear solution was added to alcoholic potassium

hydroxide solution [(0.01 mol) KOH in 25 mL absolute ethanol] with

continuous stirring and cooling, then the obtained precipitate was

filtered and dried.

2-5-2- Preparation of N-(4-phenyl phenacyl) phthalimide [34] In a suitable round bottomed flask (0.01 mol, 2.75 g) of 4-phenyl

phenacyl bromide was dissolved in 25 mL of absolute ethanol then (0.01 mol,

1.85 g) of phthalimide potassium salt was added gradually with stirring(164).

The resulted mixture was refluxed for six hours with continuous stirring

then was cooled to room temperature and the formed precipitate was filtered,

washed with distilled water and dried.

The solid product was recrystallized from ethanol producing reddish

brown crystals in 65% yield and m.p.(106-108)oC.


31

FT-IR: 1774 and 1716 cm-1 n(C=O) imide, 1689 cm-1 n(C=O) ketone,

1600 cm-1 n(C=C) aromatic and 1392 cm-1 n(C-N) imide.

2-5-3- Preparation of Schiffs Bases [35-40] A mixture of (0.01 mol, 3.41 g) of N-(4-phenyl phenacyl) phthalimide,

(0.01 mol) of primary aromatic amine in 25 mL of absolute ethanol and (2-3)

drops of glacial acetic acid was refluxed for six hours with stirring.

The resulted mixture was cooled to room temperature and the

precipitate was obtained, filtered, dried, recrystallized from a suitable solvent.

The Physical properties of the prepared Schiffs bases [35-40] are listed

in Table (3-9).

Chapter Three Results and Discussion

۳۲

Results and Discussion

Among the bicyclic nitrogen heterocycles phthalimides are an

interesting class of compounds with a large range of applications.

Recently phthalimide and some of its derivatives have provide to

have important biological effects similar or even higher than known

pharmacological molecules and so their biological activity is being

a subject of biomedical research(143-151).

Schiffs bases belong to a widely used group intermediates important

for production of specially chemicals like pharmaceuticals or rubber

additives and also have uses in many fields including analytical, inorganic,

medicinal and polymer chemistry(32-38).

According to all these mentioned facts the target of the present work

has been directed toward building of new molecules containing these two

active moieties (phthalimide and Schiffs base) via applying different

strategies, involving the following parts:-

3-1-Part One

3-1-1- N-phenyl phthalamic acid [1] Compound [1] was prepared via reaction of equimolar amounts of

phthalic anhydride and aniline in acetone.

The reaction was carried out(159) via nucleophilic attack of amino

group of aniline on carbonyl group in phthalic anhydride as shown in

Scheme (3-1).


۳۳


FT-IR spectra of compound [1] showed strong absorption bands at

3325 cm-1 and at 3136 cm-1 due to n(O-H) carboxylic and n(N-H) amide.

Other absorption bands appeared at 1720 cm-1, 1643 cm-1 and 1600

cm-1 due to n(C=O) carboxylic, n(C=O) amide and n(C=C) aromatic

respectively(165).

1H-NMR spectrum of this compound showed signals at δ= (7.04-

7.89) ppm due to aromatic protons and (N-H) proton and a clear signal at

δ= 10.33 ppm due to (O-H) carboxylic proton while 13C-NMR spectrum of

the same compound showed signals at δ= (119.9-140) ppm, 167.8 ppm

and 167.92 ppm due to aromatic ring carbons, (C=O) amide and (C=O)

carboxyl respectively(166).

3-1-2- N-phenyl phthalimide [2] Compound [2] was prepared via dehydration of the prepared

N-phenyl phthalamic acid using acetic anhydride and anhydrous sodium

acetate as dehydrating agent.

Mechanism(159) steps of dehydration reaction are shown in Scheme

(3-2).

CCOO

CC

OO

OO

++....HH22NN

AAcceettoonneeCC

OO

NN

CCOO

OOHH

HH

NNHHCC

OO

CCOO

OOHH

SScchheemmee ((33--11))


۳٤

The physical properties of compound [2] are listed in Table (3-1) and

its structure was confirmed by FT-IR, 1H-NMR and 13C-NMR spectral

data. Thus FT-IR spectrum of compound [2] showed disappearance of

n(O-H) and n(N-H)absorption bands proving success of dehydration

reaction and appearance of two bands at 1735 cm-1 and 1708 cm-1 for

asym. and sym. n(C=O) imide , absorption bands of n(C=C) aromatic

and n(C-N) imide appeared at 1593 cm-1 and 1384 cm-1 respectively.

1H-NMR spectrum of compound [2] showed disappearance of

(O-H) carboxyl proton signal and appearance of two multiplet signals at

CC

CCOO

OO

NNHH

OOHH

++ CCHH33CCOOOO NNaa

CC

CCOO

OO

NNHH

OO NNaa

++ CCHH33CCOOOOHH

CC

CCOO

OO

NNHH

OO NNaaCC

OOCCOO

OOCCHH33

CCHH33

++CC

CCOO

OO

NNHH

OO CC OO CC CCHH33

OOOO NNaa

CC

CCOO

OO

NNHH

OO CC CCHH33

OO

....++ CCHH33CCOOOO NNaa

CC

CCOO

NN

OO CC CCHH33

OOOO

HH

CCNN

CC

OO

OO

++ CCHH33CCOOOOHH


HH33CC


۳٥

δ= (7.44-7.56) ppm and (7.89-7.97) ppm of two aromatic rings protons. 13C-NMR spectrum of the same compound showed signals at

δ= (123.8-135.1) ppm and δ= 167.4 due to aromatic ring carbons and

(C=O) imide respectively.

3-1-3- 4-(N-phthalimidyl) phenyl sulfonyl chloride [3]

The titled compound was prepared via treatment of N-phenyl

phthalimide with chlorosulfonic acid at 0 oC.

Mechanism(157) of this reaction involved electrophilic attack by

chlorosulfonic acid on para position of phenyl ring in phthalimide as

described in Scheme (3-3).

CCll SS

OO

OO

OOHH

CCNN

CC

OO

OO

++

CCll SS

OO

OO

OOHH

CCNN

CC

OO

OO

HH

CCNN

CC

OO

OO

HH

CCll SS

OO

OO

CCNN

CC

OO

OO

CCll SS

OO

OO

OOHH

OOHH22

CCNN

CC

OO

OO

CCll SS

OO

OO


--HH22OO


۳٦


FT-IR spectrum of compound [3] showed absorption bands at 1743

cm-1 and 1720 cm-1 due to asym. and sym. n(C=O) imide, also two clear

absorption bands appeared at 1365 cm-1 and 1188 cm-1 due to asym. and

sym. n(SO2) respectively.

Other absorption bands appeared at 1585 cm-1 and 1300 cm-1 due to

n(C=C) aromatic and n(C-N) imide respectively.

Compound[3] was identified also by application of Lassaigne test(164),

thus the positive results obtained in both tests for sulfur and chlorine gave

another proofs for structure of compound [3].

3-1-4- 4-(N-phthalimidyl) phenyl sulfonyl hydrazine [4]

Compound [4] was prepared via treatment of phthalimidyl phenyl

sulfonyl chloride with hydrazine hydrate.

The mechanism(157) of this nucleophilic substitution reaction was

performed by nucleophilic attack of amino group of hydrazine compound

on sulfur atom in compound [3] followed by elimination of (HCl) molecule

as described in Scheme (3-4).


۳۷

The physical properties of compound [4] are listed in Table (3-1) and

its structure was confirmed by FT-IR, 1H-NMR and 13C-NMR spectral

data.

FT-IR spectrum of compound [4] showed two strong absorption bands at

3359 cm-1 and 3265 cm-1 to (-NH-NH2) group and this is an excellent proof

for the success of hydrazine compound formation.

Other absorption bands appeared at 1718 cm-1, 1710 cm-1, 1595 cm-1,

1390 cm-1, 1338 cm-1 and 1170 cm-1 due to asym. n(C=O) imide, sym.

n(C=O) imide, n(C=C) aromatic, asym. n(SO2), n(C-N) imide and sym.

n(SO2) respectively.

CCNN

CC

OO

OO

SS

OO

OO

CCll ++ HH22NN NNHH22

....

CCNN

CC

OO

OO

SS

OO

OO

NN NNHH22

CCll

HH HH

--HHCCll

CCNN

CC

OO

OO

SS

OO

OO

NNHHNNHH22



۳۸

1H-NMR spectrum of this compound showed signals at δ= (3.5

and 3.8) ppm due to (NH2) and (NH) of hydrazine moiety while

signals of aromatic protons appeared at δ= (7.39-7.99) ppm. 13C-NMR spectrum of compound [4] showed signals at

δ= (124-137.9) ppm and 167 ppm due to carbons of aromatic ring and

(C=O) imide respectively.

Details of FT-IR spectral data of compounds [1-4] are listed in Table (3-3).

3-1-5- N-[4-(N-phthalimidyl)phenylsulfonamido]benzylidene[5-18]

The final step in this part involved introducing of compound [4]

phthalimidyl sulfonyl hydrazine in condensation reaction with different

aromatic aldehydes and ketones to afford the desirable phthalimides linked

to Schiffs base through phenyl sulfonamide group.

The first step in condensation reaction between the hydrazine

compound and carbonyl compounds involved nucleophilic addition(167) of

hydrazine compound to carbonyl group producing [I] which eliminate

water molecule in step two to afford the desirable Schiffs base [II] as

shown in Scheme (3-5).


۳۹

Physical properties of compounds [5-18] are listed in Table (3-2)

and their structures are confirmed by FT-IR, 1H-NMR and 13C-NMR

spectral data.

CC

OO

RR RR''11-- CC

OOHH

RR RR'' CC

OOHH

RR RR ''

22--CC

NNCC

OO

OO

SS

OO

OO

NNHHNNHH22

....CC

OOHH

RR RR''

CC

NN

CC

OO

OO

SSOO22 CCNNHH RRRR''

OOHH

NN

HH

HH

CC

NN

CC

OO

OO

SSOO22 CCNNHH RR

RR''

OOHH22

NN

HH


CC

NN

CC

OO

OO

SSOO22 NN==CCNNHHRR

RR''

[[II]]

[[IIII]]

--HH22OO

((RR == HH oorr ddiiff ffeerreenntt aallkkyyll oorr aarryyll ggrroouuppss))((RR == ddiiffffeerreenntt aallkkyyll oorr aarryyll ggrroouuppss))''

HH22OO

CCHH33CCOOOOHH // HHPPrroottoonnaattiioonn

CCHH33CCOOOO++

CCHH33CCOOOO

CCHH33CCOOOOHH

PPrroottoonnaattiioonnCCHH33CCOOOOHH // HH

CCHH33CCOOOO

CCHH33CCOOOOHH

++


٤۰

FT-IR spectra of compounds [5-18] showed disappearance of the two

characteristic absorption bands at 3359 and 3265 cm-1 due to (-NH-NH2)

group in hydrazine compound [4] and appearance of new clear absorption

band at (1608-1658) cm-1 due to n(C=N) imine.

These two points are excellent proofs for the success of Schiff base

formation(168).

Besides FT-IR spectra of compounds [5-18] showed clear absorption

bands at (1735-1743) cm-1 and (1706-1720) cm-1 due to asym. and sym.

n(C=O) imide.

Other absorptions appeared at (1573-1604) cm-1, (1373-1388) cm-1,

(1157-1170)cm-1 and (1315-1348) cm-1 due to n(C=C) aromatic, asym.

n(SO2), sym. n(SO2) and n(C-N) imide respectively.

Moreover FT-IR spectra of Schiff bases [6,8,12,15] showed clear

absorption band at (3429-3479) cm-1 n(O-H) phenolic, while compound [7]

showed two absorption bands at (1234 and 1126) cm-1 n(C-O-C) ether and

finally compound [14] showed strong absorption band at 1091 cm-1 due to

n(C-Cl).

All details of FT-IR spectral data of compounds [5-18] are listed in

Table (3-4).

1H-NMR spectrum of compound [5] showed signal at δ= 1.4 ppm

belong to (CH3) protons, multiplet signals at δ= (7.39-8.34) ppm due to

aromatic protons and signal at δ= 8.97 ppm due to imine (-CH=N-) proton.

13C-NMR spectrum of compound [5] showed signals at δ= 24.97

ppm, (123.8-134.4) ppm, 135.3 ppm and 159.1 ppm due to (CH3) group,

aromatic ring carbons, (C=N) imine and (C=O) imide respectively.


due to (OCH3) protons and four multiplet signals at δ= (6.89-7.96) ppm

due to aromatic protons.


٤۱

13C-NMR spectrum of compound [7] showed signal at δ= 57 ppm

due to (OCH3) group and signals at δ= (123.9-127.1) ppm, 135.1 ppm and

168 ppm due to aromatic carbons, (C=N) imine and (C=O) imide

respectively.

Comp. No. Compound structure Color Melting

Points °C Yield

% Recrystallization

Solvent

1 CONH

COOH

White 170-172 88 Ethanol

2 C

NCO

O

Off white 204-205 85 Acetone

3 C

NCO

O

SO2Cl

Brown 200 dec. 72 Acetone

٤ C

NCO

O

SO2NHNH2

White 210 dec. 95 Ethanol

Table (3-1): Physical properties of compounds [1-4]


٤۲

Table (3-2): Physical properties of Schiffs bases [5-18]

Comp. No. Compound structure Color

Melting Points

°C

Yield %

Recrystallization Solvent

5 C

NCO

O

SO2 N=CNH

CH3H

Pale yellow 119-120 85 Acetone

6 C

NCO

O

SO2 N=CNHH

OH

Orange 168-170 87 Acetone

7 CN

CO

O

SO2 N=CNH OCH3

Off white 192-193 81 Ethanol

8 C

NCO

O

SO2 N=CNHH

HO

Deep yellow 196-198 54 Acetone

9 C

NCO

O

SO2 N=CNHCH3



٤۳


Melting Points

°C

Yield %


10 C

NCO

O

SO2 N=CNH

O2N

H


11 CN

CO

O

SO2 N=CNH

Off white 200 dec. 72 Acetone

12 C

NCO

O

SO2 N=CNH OHCH3


13 C

NCO

O

SO2 N=CNHH

NO2

Pale yellow 130-132 91 Ethanol

14 C

NCO

O

SO2 N=CNHH

Cl

White 226 dec. 77 Ethanol

15 C

NCO

O

SO2 N=CNH

OHH

Off white 135-136 83 Acetone

16 C

NCO

O

SO2 N=CNH NO2

CH3

Pale yellow > 220 93 Ethanol

17 C

NCO

O

SO2 N=CNHH

White 187-188 90 Acetone

18

Yellow 198 dec 86 Ethanol NN HH

OOCC

NNCC

OO

OO

SSOO22 NNNNHH


٤٤

Table (3-3): Spectral data of compounds [1-4]

Comp. No. Compound structure

FTIR spectral data cm-1

n(O-H) carboxylic

n(N-H) amide

n(C-H) aromatic

n(C=O) carboxylic

n(C=O) amide

n(C=C) aromatic

1 CONH

COOH

3325 3136 3062 1720 1643 1600

2 C

NCO

O

n(C-H) aromatic n(C=O) imide n(C=C)

aromatic n(C-N) imide

3074 1735 1708 1593 1384

3 C

NCO

O

SO2Cl

n(C-H) aromatic

n(C=O) imide

n(C=C) aromatic

n(SO2) asym.

n(SO2) sym. n(C-N) imide

3101 1743 1720 1585 1365 1188 1300

4 C

NCO

O

SO2NHNH2

n(-NH NH2) hydrazine

n(C-H) aromatic

n(C=O) imide

n(C=C) aromatic

n(SO2) asym.

n(SO2) sym.

n(C-N) imide

3359 3265 3097 1743

1718 1595 1390 1170 1338

Table (3-4): Spectral data of Schiffs bases [5-18]



n(N-H) amide

n(C=O) imide

n(C=N) imine

n(C=C) aromatic

n(SO2) asym.

n(SO2) sym.

n(C-N) imide others

5 C

NCO

O

SO2 N=CNH

CH3H

3221 1739 1712 1627 1589 1373 1165 1338 -

6 C

NCO

O

SO2 N=CNHH

OH

3221 1739 1716 1608 1589 1373 1165 1338

n(O-H) Phenolic

3340

7 CN

CO

O

SO2 N=CNH OCH3

3417 1743 1716 1651 1597 1377 1168 1315

n(C-O-C) 1234 1126


٤٥

8 C

NCO

O

SO2 N=CNHH

HO

3221 1739 1716 1616 1589 1377 1165 1338

n(O-H) Phenolic

3479

9 C

NCO

O

SO2 N=CNHCH3

3043 1716 1624 1573 1388 1157 1330 -

10 CN

CO

O

SO2 N=CNH

O2N

H

3030 1741 1706 1610 1595 1386 1166 1340

n(NO2) 1498

11 CN

CO

O

SO2 N=CNH

3151 1735 1716 1654 1593 1377 1168 1319 -

12 C

NCO

O

SO2 N=CNH OHCH3

3209 1739 1716 1627 1604 1377 1168 1342

n(O-H) Phenolic

3460

13 C

NCO

O

SO2 N=CNHH

NO2

3221 1739 1716 1651 1589 1373 1165 1338

n(NO2) 1496

14 C

NCO

O

SO2 N=CNHH

Cl

3377 1741 1716 1625 1595 1375 1170 1330 n(C-Cl)

1091

15 C

NCO

O

SO2 N=CNH

OHH

3221 1739 1716 1627 1589 1373 1165 1338

n(O-H) Phenolic

3429

16 C

NCO

O

SO2 N=CNH NO2

CH3

3232 1740 1716 1658 1593 1373 1165 1342

n(NO2) 1469 1300

17 C

NCO

O

SO2 N=CNHH

3147 1741 1720 1625 1593 1375 1170 1338 -

18 N H

OCN

CO

O

SO2 NNH

3400 1741 1718 1620 1593 1380 1170 1348

n(C=O) Amide 1701

46

% T

Wave number ( cm-1 )

Fig. No. ( 1 ) : FT-IR spectrum for compound [ 1 ]

CCOONNHH

CCOOOOHH

47

% T


Fig. No. ( 2 ) : FT- IR spectrum for compound [ 2 ]

CCNN

CC

OO

OO

48

% T



CCNN

CC

OO

OO

SSOO22CCll

49

% T



CCNN

CC

OO

OO

SSOO22NNHHNNHH22

50

% T



CCNN

CC

OO

OO

SSOO22 NN==CCNNHH

CCHH33HH

51

% T



CCNN

CC

OO

OO

SSOO22 NN==CCNNHHHH

OOHH

52

% T



CCNN

CC

OO

OO

SSOO22 NN==CCNNHHHH

NNOO22

53

] 1 [ compound for spectrum NMR-H1 : ) 8 ( No. Fig.

CCOONNHH

CCOOOOHH

54

] 1 [ compound for mpectrus NMR-C13 : ) 9 ( No. Fig.

CCOONNHH

CCOOOOHH

55


CCNN

CC

OO

OO

56

] 2 [ compound rfo spectrum NMR-C13 : ) 11 ( No. Fig.

CCNN

CC

OO

OO

57


CCNN

CC

OO

OO

SSOO22NNHHNNHH22

58

] 4 [ compound for spectrum NMR-C13 : ) 31 ( No. Fig.

CCNN

CC

OO

OO

SSOO22NNHHNNHH22

59


CCNN

CC

OO

OO

SSOO22 NN==CCNNHH

CCHH33HH

60

] 5 [ compound for spectrum MRN-C13 : ) 51 ( No. Fig.

CCNN

CC

OO

OO

SSOO22 NN==CCNNHH

CCHH33HH


٦۱

3-2-Part Two

3-2-1- 4-[4'-(N-phthalimidyl) phenyl sulfonate] acetophenone [19]

The titled compound [19] was prepared via reaction between

4-(N-phthalimidyl) phenyl sulfonyl chloride [3] and 4-hydroxy

acetophenone.

This reaction represent esterfication between acid chloride

(compound [3]) and substituted phenol (4-hydroxy acetophenone) and the

mechanism(167) was suggested via nucleophilic attack of phenolic hydroxyl

group on sulfur atom in acid chloride followed by elimination of (HCl)

molecule as described in Scheme (3-6).

CCNN

CC

OO

OO

SS

OO

OO

CCNN

CC

OO

OO

SS

OO

OO

OO CC

OO

CCHH33

CCNN

CC

OO

OO

SS

OO

OO

OO CC

OO

CCHH33

++ HHOO CC

OO

CCHH33CCll

PPyyrriiddiinnee

....

HH

CCll

--HHCCll

[[1199]]SScchheemmee ((33--66))


٦۲

Compound [19] was recrystallized from ethanol and was obtained as

pale brown crystals in 70% yield with melting point (152-154)oC.

The major FT-IR absorptions in FT-IR spectrum of compound [19]

include absorption bands at 1739 cm-1 and 1720 cm-1 due to asym. and

sym. n(C=O) imide, bands at 1674 cm-1, 1593 cm-1, 1361 cm-1 and 1176

cm-1 due to n(C=O) ketone, n(C=C) aromatic, asym. n(SO2) and sym.

n(SO2) respectively.

1H-NMR spectrum of compound [19] showed signal at

δ= 2.569 ppm (CH3) group protons and multiplet signals at

(δ= 7.28-8.13) ppm due to aromatic protons, while 13C-NMR spectrum

of the same compound showed signal at δ= 27.2 ppm due to (CH3) group.

Signals at δ= (122.6-153) ppm due to aromatic ring carbons , signal

at δ= 166.8 ppm due to (C=O) imide and signal at δ= 198 ppm due to

(C=O) ketone.

Chemical test for compound [19] gave positive results in both

(Iodoform test) and general test for carbonyl compounds(169) and these are

good additional proofs for success of compound [19] formation.

3-2-2- 4-[4'-(N-phthalimidyl) phenyl sulfonate] methyl benzylidene [20-26]

The titled Schiffs bases [20-26] were prepared via condensation

reaction of compound [19] with different primary aromatic amines.

Mechanism(167) of this reaction involved nucleophilic attack of

primary amine on carbonyl group in compound [19] producing addition

product [I] which subsequently eliminated water molecule producing the

desirable compound as shown in Scheme (3-7).


٦۳

CN

CO

O

S

O

O

O C

O

CH3

[19]

CN

CO

O

S

O

O

O C

OH

CN

CO

O

S

O

O

O C

OH

1-

RNH2

..

CN

CO

O

S

O

O

O C

OH

CN

CO

O

S

O

O

O C

OH

NR

H

H

CN

CO

O

S

O

O

O C

CH3

N

HOH

R

[I]

CN

C

O

O

S

O

O

O C

CH3

N

OH2

R

H

-H2O

H2OC

NCO

O

S

O

O

O C

CH3

N R

[20-26]

2-

Scheme (3-7)

+ +

CH3COOH / H Protonation


CH3COOH

CH3COOH

CH3COO

CH3COO

CH3COO+

+

CH3

CH3

CH3

CH3

R =

CH3N

S ,

, ,

H3C O2N

Cl ,

Cl

Cl

NO2

,CH3


٦٤


FT-IR spectra of compounds [20-26] showed disappearance of

absorption band at 1674 cm-1 which due to n(C=O) ketone and appearance

of clear strong absorption band at (1681-1690) cm-1 due to n(C=N) imine.

FT-IR spectra of compounds [20-26] showed bands at

(1725-1743) cm-1, (1710-1726) cm-1, (1593-1595) cm-1, (1361-1385) cm-1

and (1176-1199) cm-1 due to asym. n(C=O) imide, sym. n(C=O) imide,

n(C=C) aromatic, asym. n(SO2) and sym. n(SO2) respectively.

All details of FT-IR spectral data of compounds [20-26] are listed in

Table (3-6).

1H-NMR spectrum of compound [21] showed two signals at

δ= 2.35 ppm and δ= 2.56 ppm due to two (CH3) groups, while signals at

δ=(7.28-8.12) ppm are due to aromatic ring protons.

13C-NMR spectrum of the same compound showed signal at

δ= 27.21 ppm due to (CH3) group and signals at δ= (122.5-138.2) ppm

due to aromatic ring carbons and signals at δ= 152.6 ppm and

δ=166.8 ppm are due to (C=N) imine and (C=O) imide respectively.

1H-NMR spectrum of compound [24] showed signals at δ= 2.54

ppm and δ= 2.56 ppm due to two (CH3) groups, while signals at δ= (7.28-

8.12) ppm are due to aromatic ring protons.

13C-NMR spectrum of compound [24] showed signal at δ= 27.2

ppm due to (CH3) groups and signals at δ= (122-135) ppm due to

aromatic ring carbons and signals at δ= 153 ppm and δ= 166 ppm due to

(C=N) imine and (C=O) imide respectively.


٦٥


Melting Points

°C

Yield %


20 C

NCO

O

SO2 OCH3

C=N

Pale brown 155-156 72 Ethanol

21 C

NCO

O

SO2 OCH3

C=N

H3C


22 C

NCO

O

SO2 OCH3

C=N

NO2


23 C

NCO

O

SO2 OCH3

C=N Cl

Cl

Pale brown 172-173 90 Ethanol

24 C

NCO

O

SO2 OCH3

C=N CH3


25 C

NCO

O

SO2 OCH3

C=N Cl

NO2


26 S

N

CH3CN

CO

O

SO2 OCH3

C=N

Pale brown 167-168 77 Cyclo hexane



٦٦




n(C-H) aromatic

n(C=O) imide

n(C=N) imine

n(C=C) aromatic

n(SO2) asym.

n(SO2) sym.

n(C-N) imide others

20 C

NCO

O

SO2 OCH3

C=N

3109 1739 1720 1685 1593 1373 1180 1300 -

21 C

NCO

O

SO2 OCH3

C=N

H3C

3062 1740 1720 1685 1593 1373 1176 1296 -

22 C

NCO

O

SO2 OCH3

C=N

NO2

3100 1743 1722 1683 1593 1385 1182 1300

n(NO2) 1496 1355

23 C

NCO

O

SO2 OCH3

C=N Cl

Cl

3100 1739 1726 1687 1593 1369 1182 1355 n(C-Cl)

1078

24 C

NCO

O

SO2 OCH3

C=N CH3

3109 1743 1720 1685 1593 1373 1199 1300 -

25 C

NCO

O

SO2 OCH3

C=N Cl

NO2

3080 1725 1710 1690 1595 1372 1185 1300

n(NO2) 1490 1350

n(C-Cl) 1090

26 S

N

CH3CN

CO

O

SO2 OCH3

C=N

3109 1737 1720 1685 1593 1373 1199 1300 n(C-S)

609

67

% T



CCNN

CC

OO

OO

SSOO22 OO CC

OOCCHH33

68

% T



CCNN

CC

OO

OO

SSOO22 OO

CCHH33CC==NN CCHH33

69

% T



SS

NN

CCHH33CCNN

CC

OO

OO

SSOO22 OO

CCHH33CC==NN

70


CCNN

CC

OO

OO

SSOO22 OO CC

OOCCHH33

71


CCNN

CC

OO

OO

SSOO22 OO CC

OOCCHH33

72


CCNN

CC

OO

OO

SSOO22 OOCCHH33

CC==NN

HH33CC

73

] 21 [ compound for mspectru NMR-C13 : ) 22 ( No. Fig.

CCNN

CC

OO

OO

SSOO22 OOCCHH33

CC==NN

HH33CC

74


CCNN

CC

OO

OO

SSOO22 OO

CCHH33CC==NN CCHH33

75


CCNN

CC

OO

OO

SSOO22 OO

CCHH33CC==NN CCHH33


۷٦

3-3-Part Three

3-3-1- 4-[4'-(N-phthalimidyl) phenyl sulfonate] benzaldehyde [27]

Compound [27] was prepared via reaction between 4-(N-

phthalimidyl) phenyl sulfonyl chloride [3] and 4-hydroxy benzaldehyde. Mechanism(167) of reaction involved nucleophilic attack of phenolic

hydroxyl group on sulfur atom in compound [3] followed by elimination of

(HCl) molecule producing the desirable imides as described in Scheme

(3-8).

Compound [27] was recrystallized from ethanol and gave pale brown

crystals in 72% yield with melting point (176-178)oC. FT-IR spectrum of compound [27] showed absorption bands at 1741

cm-1 and 1718 cm-1 asym n(C=O) and sym. n(C=O) imide and a clear

CCNN

CC

OO

OO

SS

OO

OO

CCNN

CC

OO

OO

SS

OO

OO

OO CC

OO

HH

CCNN

CC

OO

OO

SS

OO

OO

OO CC

OO

HH

++ HHOO CC

OO

HHCCll

PPyyrriiddiinnee

....

HH

CCll

--HHCCll

[[2277]]



۷۷

strong absorption band at 1699 cm-1 n(C=O) aldehyde. Other absorption bands appeared at 1593 cm-1, 1370 cm-1, 1186

cm-1 and 1360 cm-1 n(C=C) aromatic, asym. n(SO2) and sym. n(SO2) and

n(C-N) imide respectively.

1H-NMR spectrum of compound [27] showed signals at δ= (7.37-

8.13) ppm for aromatic protons and signal at δ= 9.99 ppm for aldehyde

proton .

13C-NMR spectrum of compound [27] showed signals at δ= (123.2-

153.5) ppm due to aromatic ring carbons, signal at δ= 167 ppm due to

n(C=O) imide and signal at δ= 193 ppm for n(C=O) aldehyde.

Chemical test compound [27] gave positive result in test for carbonyl

compounds(164) and this is a good additional proof for preparation of

compound [27].

33]-[28 benzylidene sulfonate] phenyl phthalimidyl)-(N-[4'-4 -2-3-3

The titled Schiffs bases [28-33] were prepared via condensation

reaction of compound [27] with different primary aromatic amines.

Mechanism(167) of this reaction involved nucleophilic attack of

primary amine on carbonyl group of compound [27] producing [I] which

subsequently eliminated water molecule to afford the desirable compounds

as shown in Scheme (3-9).

CC

OOHH


۷۸

CN

CO

O

S

O

O

O C

O

H

[27]

CN

CO

O

S

O

O

O C

OH

CN

CO

O

S

O

O

O C

OH

1-

RNH2

..

CN

CO

O

S

O

O

O C

OH

CN

CO

O

S

O

O

O C

OH

NR

H

H

CN

CO

O

S

O

O

O C

H

N

HOH

R

[I]

CN

C

O

O

S

O

O

O C

H

N

OH2

R

H

-H2O

H2OC

NCO

O

S

O

O

O CH

N R

[28-33]

2-

R =

CH3 ,

, ,

H3C O2N

Cl ,

Cl

Cl NO2

,

Scheme(3-9)

+ +



CH3COOH

CH3COOH

CH3COO

CH3COO

CH3COO+

+

H

H

H

H


۷۹



absorption band at 1699 cm-1 n(C=O) aldehyde and appearance of clear

strong absorption band at (1620-1631) cm-1 due to n(C=N) imine.

Other absorption bands appeared at (1740-1741) cm-1, (1720-1722)

cm-1, (1585-1596) cm-1, (1365-1375) cm-1, (1168-1199) cm-1 and (1300-

1355) cm-1 which were attributed to asym. n(C=O) imide, sym. n(C=O)

imide, n(C=C) aromatic, asym. n(SO2), sym. (SO2) and n(C-N) imide

respectively.

All details of FT-IR spectral data of compounds [28-33] are listed

in Table (3-8).

1H-NMR spectrum of compound [31] showed multiplet signals at δ=

(7.29-8.13) ppm for aromatic protons and clear signal at δ= 8.58 ppm for

imine proton (-N=CH-).

13C-NMR spectrum of compound [31] showed signals at δ= (122-

151.7) ppm due to aromatic ring carbons, signal at δ= 162.4 ppm for

n(C=N) and signal at δ= 166.83 ppm for (C=O) imide.

1H-NMR spectrum of compound [32] showed clear singlet signal at

δ= 2.08 ppm due to (CH3) group protons, multiplet signals at δ= (7.27-

8.12) ppm for aromatic protons and singlet signal at δ= 8.61 ppm for imine

proton (-N=CH-), while 13C-NMR spectrum of the same compound

showed signal at δ= 31.1 ppm (CH3) group, signals at δ= (121.4-151.5)

ppm for aromatic carbons , signal at δ= 159 ppm (C=N) and signal at δ=

166 ppm (C=O) imide.


۸۰



Melting Points

°C

Yield %


28 C

NCO

O

SO2 OHC=N

Off white 180-182 70 Dioxane

29 C

NCO

O

SO2 OHC=N

CH3

Yellow 270-272 88 Ethanol

30 C

NCO

O

SO2 OHC=N

NO2

Deep yellow 177-178 76 Acetone

31 C

NCO

O

SO2 OHC=N Cl

Cl

White 184-186 61 Dioxane

32 C

NCO

O

SO2 OHC=N CH3


33 C

NCO

O

SO2 OHC=N Cl

O2N

Yellow 190-191 84 Acetone


۸۱




n(C-H) aromatic

n(C=O) imide

n(C=N) imine

n(C=C) aromatic

n(SO2) asym.

n(SO2) sym.

n(C-N) imide others

28 C

NCO

O

SO2 OHC=N

3080 1720 1620 1585 1375 1190 1345 -

29 C

NCO

O

SO2 OHC=N

CH3

3040 1740 1720

1623 1590 1375 1180 1300 -

30 CN

CO

O

SO2 OHC=N

NO2

3040 1741 1720 1630 1593 1371 1199 1310

n(NO2) 1523 1352

31 CN

CO

O

SO2 OHC=N Cl

Cl

3060 1741 1720 1629 1596 1370 1186 1350 n(C-Cl)

1093

32 C

NCO

O

SO2 OHC=N CH3

3080 1740 1722 1630 1593 1373 1186 1346 -

33 C

NCO

O

SO2 OHC=N Cl

O2N

3101 1720 1631 1593 1365 1168 1338

n(NO2) 1504 1404

n(C-Cl) 1068

82

% T



CCNN

CC

OO

OO

SSOO22 OO CC

OOHH

83

% T



CCNN

CC

OO

OO

SSOO22 OO

HHCC==NN

84

% T



CCNN

CC

OO

OO

SSOO22 OOHHCC==NN CCll

CCll

85


CCNN

CC

OO

OO

SSOO22 OO CC

OOHH

86


CCNN

CC

OO

OO

SSOO22 OO CC

OOHH

87


CCNN

CC

OO

OO


CCll

88


CCNN

CC

OO

OO


CCll

89


CCNN

CC

OO

OO

SSOO22 OO

HHCC==NN CCHH33

90


CCNN

CC

OO

OO

SSOO22 OO

HHCC==NN CCHH33


۹۱

3-٤-Part Four

3-4-1- N-(4-phenyl phenacyl) phthalimide [34] The titled compound was prepared via reaction of phthalimide

potassium salt with 4-phenyl phenacyl bromide according to Gabrial

synthesis.

Unsubstituted phthalimide(170) was converted to its potassium salt

since the later is the stronger nucleophile which attack the electron-

deficient carbon atom bonded to halogen in para phenyl phenacyl bromide

as shown in Scheme (3-10).

Compound [34] was purified by recrystallization from ethanol and was

obtained as reddish brown crystals in 65% yield with melting point (106-

108)oC. FT-IR spectrum of compound [34] showed appearance of clear

absorption band at 1689 cm-1 due to n(C=O) ketone.

CCNN

CC

OO

OO

HHKKOOHH ((aallccoohhoolliicc))

CCNN KK

CC

OO

OO

CCHH22 CC

OO

BBrrCC

NN KKCC

OO

OO

++

CCNN

CC

OO

OO

CCHH22 CC

OO

[[3344]]


KKBBrr++


۹۲

Other absorption bands appeared at 1716 cm-1, 1600 cm-1 and

1392 cm-1 due to n(C=O)imide, n(C=C) aromatic and n(C-N) imide

respectively.


due to (-CH2-) protons and signals at δ= (7.44-8.19) ppm due to aromatic

ring protons.


δ= 34.41 ppm due to (-CH2-) carbon and signals at δ= (123.8-139.1) ppm,

δ= 145.66 ppm and δ= 191.78 ppm due to aromatic ring carbons, (C=O)

imide and (C=O) ketone respectively.

Compound [34] gave positive result in treatment with 2,4-dinitro

phenyl hydrazine(164) and this was a good proof for the formation of this

compound.

3-4-2-N-phthalimidyl-4-phenyl benzylidene methane[35-40] The titled compounds [35-40] were prepared via reaction between

N-(4-phenyl phenacyl) phthalimide and different primary aromatic amines.

During this reaction the electron-deficient carbon of carbonyl group in

compound [34] was attacked by the strong nucleophile (primary amine)

producing [I] followed by elimination of water molecule(167) producing the

desirable imides [35-40] as shown in Scheme (3-11).


۹۳

CCNN

CC

OO

OO

CCHH22 CC

OO

[[3344]]

11--CC

NNCC

OO

OO

CCHH22 CC

OOHH

CCNN

CC

OO

OO

CCHH22 CC

OOHH

RRNNHH22

....22--

CCNN

CC

OO

OO

CCHH22 CC

OOHH

CCNN

CC

OO

OO

CCHH22 CC

OOHH

NNRR

HH

HH

CCNN

CCOO

OO

CCHH22 CC

OOHH

NNHH

RR

CCNN

CCOO

OO

CCHH22 CC

OOHH22

NN

HH

RR--HH22OO

CCNN

CCOO

OO

CCHH22 CC NN RR

[[3355--4400]]


RR ==

CCHH33 ,,

,, ,,

HHOO

CCll

NNOO22

,,

OOHHBBrr

CCHH33CCOOOOHHCCHH33CCOOOO++

++

++

++

CCHH33CCOOOOHH

CCHH33CCOOOOHH++ ++ HH22OO

CCHH33CCOOOOHH // HH PPrroottoonnaattiioonn

CCHH33CCOOOO

CCHH33CCOOOOHH // HHPPrroottoonnaattiioonn


۹٤



absorption band at 1689 cm-1 due to n(C=O) ketone and appearance of

absorption band at (1620-1681) cm-1 due to n(C=N) imine.

Also all spectra showed clear absorption bands at (1697-1725) cm-1,

(1523-1604) cm-1 and (1311-1396) cm-1 due to n(C=O) imide, n(C=C)

aromatic and n(C-N) imide respectively.

All details of FT-IR, spectral data of compounds [35-40] are listed in

Table (3-10).

1H-NMR spectrum of compound [35] showed signal at δ=5.19

ppm due to (-CH2-) protons and signals at δ=(7.25-8.1)ppm due to

aromatic ring protons.


δ= 44.9 ppm due to (-CH2-) carbon and signals at δ= (112.8-135.2) ppm

due to aromatic ring carbons and signal at δ= 168ppm due to (C=O)

ketone and (C=N) imine.


۹٥



Melting Points

°C

Yield %


35 CN

CO

O

CH2 C=

N

NO2

Pale green 162-163 92 Acetone

36 CN

CO

O

CH2 C=

N

Br

Brown 136-138 77 Ethanol

37 CN

CO

O

CH2 C=

N

Cl

Yellow 116-117 81 Dioxane

38 CN

CO

O

CH2 C=

N

OH

Deep brown 129-130 90 Ethanol

39 CN

CO

O

CH2 C=

N

CH3

Red 112-114 64 Acetone

40 CN

CO

O

CH2 C=

NOH

Deep green 165-167 85 Ethanol


۹٦




n(C-H) aromatic

n(C=O) imide

n(C=N) imine

n(C=C) aromatic

n(C-N) imide others

35 CN

CO

O

CH2 C=

N

NO2

3062 1697 1624 1597 1350 n(NO2) 1450 1327

36 CN

CO

O

CH2 C=

N

Br

3035 1718 1674 1600 1352 n(C-Br) 688

37 CN

CO

O

CH2 C=N

Cl

3059 1725 1701 1631 1600 1311 n(C-Cl)

1083

38 CN

CO

O

CH2 C=

N

OH

3055 1716 1681 1647 1361 n(O-H)

Phenolic 3425

39

3028 1716 1620 1558 1319 -

40 CN

CO

O

CH2 C=

NOH

3000 1720 1703 1681 1590 1396

n(O-H) Phenolic

3456

CCNN

CC

OO

OO

CCHH22 CC==

NN

CCHH33

97

% T



CCNN

CC

OO

OO

CCHH22 CC

==OO

98

% T



CCNN

CC

OO

OO

CCHH22 CC==

NN

NNOO22

99

% T



CCNN

CC

OO

OO

CCHH22 CC==

NN

OOHH

100


CCNN

CC

OO

OO

CCHH22 CC

==OO

101


CCNN

CC

OO

OO

CCHH22 CC

==OO

102


CCNN

CC

OO

OO

CCHH22 CC==

NN

NNOO22

103


CCNN

CC

OO

OO

CCHH22 CC==

NN

NNOO22


104

Biological Activity

The synthesized imides in this work were expected to possess

biological activity since they have two active moieties in their molecules

(phthalimide and Schiffs base), thus a prileminary evaluation of anti-

bacterial activity for some of the new imides were tested against two types

of bacteria Staphylococcus aureus (Gram-positive) and Escherichia coli

(Gram-negative). The results showed that most of the tested imides possess good anti-

bacterial activity as shown in Table (3-11).

Table(3-11):Anti-bacterial activity for some of the Synthesized Schiffs bases

Comp. No. Gram-positive bacteria Gram-negative bacteria

Staphylococcus aureus Escherichia coli

5 + + + + +

6 + + + + -

7 + + + + + + + +

10 + + + + +

11 - + +

12 + + + + + +

14 + + + + +

16 + + + + +

17 + + + + +

18 + + + + + + + Key to symbols = Inactive = (-) inhibition Zone< 6 mm Slightly active = (+) = inhibition Zone 6-9 mm

Moderately active = (++) inhibition Zone 9-12 mm Highly active = (+++) inhibition Zone 13-17 mm

Very high activity = (++++) inhibition Zone > 17 mm


105

Suggestions for future work

The following suggestions are found suitable for future work:

1. Synthesis of other new imides linked to Schiffs bases by following

other strategies.

2. Evaluation of antibacterial activity of all the Synthesized imides in

this work against other types of bacteria and comparision the results

with those of known biologically active control compounds.

3. Evaluation of antifungal activity of all Synthesized compounds in

this work against different types of fungi.

4. Synthesis of new carbonyl compounds (or heterocyclic aldehydes

and ketones) and new primary amines (or heterocyclic amines) then

introducing them in synthesis of new imides linked to Schiffs base.

References

۱۰٦

References 1- H. Schiff, Ann. Chem., 131(1), 118 (1864).

2- S.A. Abbas, M. Munir, A. Fatima, S. Naheed and Z. Ilyas, E. Journal

of life sciences., 1(2), 37 (2010).

3- I. Kilic, F. Ersahin, E. Agar and S. Isik, Japan. Soc. Anal. Chem., 25,

25 (2009).

4- S.T. Ha, L.K. Ong , Y. Sivasothy, G.Y. Yeap, P.L. Boey and H.C.

Lin, Am. J. Appl. Sci., 7(2), 214 (2010).

5- Y. Zheng, K. Ma, H. Li, J. Li, J. He and X. Sun, Catal. Lett., 128, 465

(2009).

6- R.B. Moffett In: N. Rabjohn editor, Organic synthesis, Vol.4. New

York, USA: John Wiley & Sons, Inc, 605-608 (1963).

7- B.E. Love and J. Ren, J. Org. Chem., 58(20), 5556 (1993).

8- G.C. Look, M.M. Murphy, D.A. Campbell and M.A. Gallop,

Tetrahedron Lett., 36(17), 2937 (1995).

9- A.K. Chakrabrti, S. Bhagat and S. Rudrawar, Tetrahedron Lett.,

45(41), 7641 (2004).

10- J.S.M. Samec and J.E. Backvall, Chem. Eur. J., 8(13), 2955 (2002).

11- N. Baricordi, S. Benetti, G. Biondini, C. Risi and G.P. Pollini,

Tetrahedron Lett., 45(7), 1373 (2004).

12- P. Panneerselvam, R.R. Nair, G. Vijayalakshmi, E.H. Subramanian

and S.K. Sridhar, Eur. J. Med. Chem., 40(2), 225 (2005).

13- R. Dalpozzo, A.de Nino, M. Nardi, B. Russo and A. Procopio,

Synthesis., 7, 1127 (2006).

14- H. Naeimi, F. Salimi and K. Rabiei, J. Mol. Catal. A Chem., 260 (1-

2), 100 (2006).

15- A. Kulkarni, S.A. Patil and P.S. Badami, Eur. J. Med. Chem., 44(7),

2904 (2009).

References

۱۰۷

16- K. Tanaka and R. Shiraishi, Green Chem., 2(6), 272 (2000).

17- C.K.Z. Andrade, S.C.S Takada, L.M. Alves, J.P. Rodrigues and

P.A.Z. Suarez, Syn. Lett., 12, 2135 (2004).

18- M. Gopalakrishnan, P. Sureshkumar, V. Kanagarajan, J. Thanusu

and R. Govindaraju, J. Chem. Res., 5, 299 (2005).

19- K.P. Guzen, A.S. Guarezemini, A.T.G. Orfao, R. Cella, C.M.P.

Pereira and H.A. Stefani, Tetrahedron Lett., 48(10), 1845 (2007).

20- M. Gopalakrishnan, P. Sureshkumar, V. Kanagarajan and J. Thanusu ,

Res. Chem. Intermed., 33(6), 541 (2007).

21- G. Roman and M. Andrei, Bull. Chem. Tech. Macedonia., 20(2),

131 (2001).

22- H.J. Yang, W.H. Sun, Z.L. Li and Z. Ma, Chine. Chem. Lett., 13(1),

3 (2002).

23- A.A. Jarrahpour, M. Motamedifar, K. Pakshir, N. Hadi and M. Zarei,

Molecules., 9, 815 (2004).

24- S. Baluja, A. Solanki and N. Kachhadia, J. Iran. Chem. Soc., 3(4),

312 (2006).

25- V.S.V. Satyanarayana, P. Sreevani, A. Sivakumar and V.

Vijayakumar, A. Rkivoc., XVII, 221 (2008).

26- A. Naqvi, M.Shahnawaaz, A.V. Rao, D. Seth and N. Ksharma, E. J.

Chem., 6(51), 575 (2009).

27- A. Naqvi, M. Shahnawaaz, A.V. Rao, G. Saxena, A. Chaudhari and

D. Seth, Orient. J. Chem., 23(2), 683 (2007).

28- S. Kumar, M.S. Niranjan, K.C. Chaluvaraju, C.M. Jamakhandi and

D. Kadadevar, J. Curr. Pharm. Res., 1, 39 (2010).

29- G. Kumar, D. Kumar, C.P. Singh, A. Kumar and V.B. Rana, J. Serb.

Chem. Soc., 75(5), 629 (2010).

30- Z. Yang and P. Sun, Molbank., 514 (2006).

References

۱۰۸

31- S. Patai, The chemistry of the carbon-nitrogen double bond, John

Wiley & Sons Ltd., London (1970).

32- M. Imran, J. Iqbal, S. Iqbal and N. Ijaz, Turk. J. Biol., 31, 67 (2007).

33- S.N. Pandeya, D. Sriram, G. Nath and E.D. Clercq., Eur. J. Med.

Chem., 35(2), 249 (2000).

34- N. Raman, J.D. Raja and A. Sakthivel, J. Chem. Sci., 119 (4), 303

(2007).

35- O. Pouralimardan, A.C. Chamayou, C. Janiak and H.H. Monfared ,

Inorg. Chim. Acta., 360(5), 1599 (2007).

36- C. Spinu, M. Pleniceanu and C. Tigae, Turk. J. Chem., 32, 487

(2008).

37- Z. Cimerman, S. Miljanic and N. Galic, J. Croat. Chemi. Acta.,

73(1), 81 (2000).

38- Y.J. Hamada, Trans. Electron. Devices., 44, 1208 (1997).

39- A.M. Awadallah and N.M. El-Halabi, J. Islamic, University of

Gaza., 13(2) (2005).

40- R. Vidyavati, N. Patil, T. Reddy and S.D. Angadi, E.J. Chem., 5(3),

529 (2008).

41- L. Wang, Y. Feng, J. Xue and Y. Li, J. Serb. Chem. Soc., 73, 1

(2008).

42- I. Sakiyan, E. Logoglu, S. Arslan, N. Sari and N. Sakiyan,

Biometals., 17, 115 (2004).

43- Z.H. Chohan, M. Arif, Z. Shafiq, M. Yagub and C.T. Supuran, J.

Enzy. Inhib. Med. Chem., 21, 95 (2006).

44- Y.P. Wang, Y.N. Xiao, C.X. Zhang and R.M. Wang, J. Macromol.

Sci., Part A 38, 1099 (2001).

45- A. Hussen, A.A.A.J. Coord. Chem., 59, 57 (2006).

46- M.S. Karthikeyan, D.J. Prasad, B. Poojary and K.S. Bhat, Bioorg.

Med. Chem., 14,7482 (2006).

References

۱۰۹

47- K. Singh, M.S. Barwa and P. Tyagi, Eur. J. Med. Chem., 41, 1

(2006).

48- P. Pannerselvam, R.R. Nair, G. Vijayalakshmi, E.H. Subramanian

and S.K. Sridhar, Eur. J. Med. Chem., 40, 225 (2005).

49- S.K. Sridhar, M. Saravan and A. Ramesh, Eur. J. Med. Chem., 36,

615 (2001).

50- K.N. Venngopal and B.S. Jayashree, Indian J. Pharm. Sci., 70, 88

(2008).

51- M.A. Baseer, V.D. Jadhav, R.M. Phule, Y.V. Archana and Y.B.

Vibhute, Orient J. Chem., 16, 553 (2000).

52- A.H. El-Masry, H.H. Fahmy and S.H.A. Abdelwahed, Molecules., 5

1429 (2000).

53- A.S. Kabeer, M.A. Baseer and N.A. Mote, Asian J. Chem.,13, 496

(2001).

54- P.P. Dholakiya and M.N. Patel, Synth. React. Inorg. Met. Org.

Chem., 32, 753 (2002).

55- S.P. Ranga, S. Sharma, V. Chowdhary, M. Parihar and R.K. Mehta,

J. Curr. Bio. Sci., 5, 98 (1988).

56- Z.H. Chohan and H. Zahid, Met. Based Drugs., 6, 75 (1999).

57- S.R. Bhusare, V.G. Pawar, S.B. Shinde, R.P. Pawar and Y.B.

Vibhute, Int. J. Chem. Sci., 1, 31 (2003).

58- K. Singh, M.S. Barwa and P. Tyagi, Eur. J. Med. Chem., 41, 147

(2006).

59- P.G. More, R.B. Bhalvankar and S.C. Pattar, J. Ind. Chem. Soc., 78,

474 (2001).

60- F. Ding, Y. Jia, and J. Wang, Yingyong Huaxue., 21, 835 (2004).

61- V.V. Mulwad and J.M. Shriodkar, Indian J. Hetero. Chem., 11, 199

(2002).

References

۱۱۰

62- S.N. Pandeya, D. Sriram, G. Nath and E. Declercq , IL Farmaco 54,

624 (1999).

63- W.M. Singh and B.C. Dash, Pesticides., 22, 33 (1988).

64- S.N. Pandeya, D. Sriram, G. Nath and E. Declercq, Eur. J.

Pharmacol., 9, 25 (1999).

65- S.N. Pandeya, V.S. Lakshini and A. Pandey, Indian J. Pharm. Sci.,

65, 213 (2003).

66- B. Dash, P.K. Mahapatra, D. Panda and J. M. Patnaik, J. Indian

Chem. Soc., 61, 1061 (1984).

67- R. Ramesh and M. Sivagamsundari, Synth. React. Inorg. Met. Org .

Chem., 33, 899 (2003).

68- R.N. Sharma, A. Kumar, A. Kumari, H.R. Singh and R. Kumar,

Asian J. Chem., 15, 57 (2003).

69- Y. Li , Z.S. Yang, H. Zhang, B.J. Cao and F.D. Wang, Bioorg and

Med. Chem., 11, 4363 (2003).

70- B. De, E.M. Marbaniang, R. Kalita, M. Debnath, M.C. Das, U.

Kalita, S. Lalfukmawia and J.K. Gupta, J. Inst. Chemists., 77, 20

(2005).

71- R. Villar, I. Encio, M. Migliaccio, M. G.Gil and V.M. Merino,

Bioorg and Med. Chem., 12, 963 (2004).

72- S.B. Desai, P.B. Desai and K.R. Desai, Hetrocycle. Commun., 7, 83

(2001).

73- P. Pathak, V.S. Jolly and K.P. Sharma, Orient. J. Chem., 16, 161

(2000).

74- P. Pathak, V.S. Jolly and K.P. Sharma, Orient. J. Chem., 16, 493

(2000).

75- M.M. Ali, M. Jesmin, M.K. Sarker, M.S. Salahuddin , M.R. Habib

and J.A. Khanam, Int. J. Biol. Chem. Sci., 2, 292 (2008).

References

۱۱۱

76- M.A. Bhat, M. Imran, S.A. Khan and N. Siddiqui, J. Pharm. Sci., 67,

151 (2005).

77- S.J. Wadher, M.P. Puranik, N.A. Karande and P.G. Yeole, Inter. J.

Pharm. Tech. Res., 1, 22 (2009).

78- R. Mladenova, M. Ignatova, N. Manolova, T. Petrova and I.

Rashkov, Eur. Polym. J., 38, 989 (2002).

79- O.M. Walsh, M.J. Meegan, R.M. Prendergast and T.A. Nakib, Eur. J.

Med. Chem., 31, 989 (1996).

80- S. Samadhiya and A. Halve, Orient. J. Chem., 17, 119 (2001).

81- E.A. Elzahany, K.H. Hegab, K.H. Safaa, K.S. Youssef and N.S.

Youssef, Austral. J. Basic and apply. Sci., 2(2), 210 (2008).

82- K. Arora and K.P. Sharma, Synth. React. Inorg. Met. Org. Chem.,

32, 913 (2003).

83- P.A. Vigato and S. Tamburini, Coord. Chem. Rev., 248, 1717

(2004).

84- P. Przybylski, A. Huczynski, K. Pyta, B. Brzezinski and F. Bartl,

Curr . Org . Chem., 13(2), 124 (2009).

85- M. Jesmin, M.M. Ali, J.A. Khanam, Thai. J. Pharm. Sci., 34, 20

(2010).

86- M.K. Haergreaves, J.G. Pritchard and H.R. Dave, Chem. Res., 70,

439 (1970).

87- S.M.Sami, R.T.Dorr, D.S. Alberts, A.M. Solyom and W.A. Remers,

J. Med. Chem., 43, 3067 (2000).

88- V.C. Filho, F. decampos, R. Correa, J. R. Nunes and R.A. Yunes,

Quim. Nova., 26, 230 (2003).

89- A.M. Al-Azzawi, Iraqi J. Chem., 26(4), 813 (2000).

90- A.S. Hamad, Ph.D. Thesis, Chem. Dept. College. Sci. Univ. of

Baghdad (1992).

References

۱۱۲

91- T.M. Pyriadi, A.M. Al-Azzawi and N.Y. Nazhat, J. IBN Al-Haytham

pure and appl. Sci., 2, 1 (1990).

92- T.M. Pyriadi and A.M. Al-Azzawi, Iraqi J. Chem., 15(1), 19

(1990).

93- T.M. Pyriadi and K.S. Hadi, Arab Gulf. J. Scient. Res. Math. Phys.

Sci., A(3), 341 (1987).

94- M.S. Ali, MSc. Thesis, Chem. Dept. College . Sci. Univ. of Baghdad

(2006).

95- A.M. Al-Azzawi and M.S. Ali, Tikrit. J. Pure. Sci., 14(3), 192

(2009).

96- N.E. Searl, U.S. Patent 2,444,536 (1948), C.A., 42, 7340 (1948).

97- M. Cava, A. Deana, K. Mauth and M. Mitchell, Org. Syn., 41, 93

(1961).

98- T.M. Pyriadi and M. Fraih, J. Macromol. Sci. Chem., A(18), 159

(1982).

99- M.M. Farhan, MSc. Thesis, Chem. Dept. College . Sci. Univ. of

Baghdad (1986).

100-M.T. Dajani, MSc. Thesis, Chem. Dept. College . Sci. Univ. of

Baghdad (1996).

101-T.M. Pyriadi and A. Shehab, J. Poly. Sci., 34(23), 5283 (1996).

102-I.A. Jassim, Ph.D. Thesis, Chem. Dept. College . Sci. Univ. of

Baghdad (1997).

103-N.A. Al-Asli, Ph.D. Thesis, Chem. Dept. College . Sci. Univ. of

Baghdad (2000).

104-T.M. Pyriadi and A.S. Berizinji, Designed monomers and polymers., 6,

115 (2003).

References

۱۱۳

105-T.M. Pyriadi and H.J. Harwood, J. Org. Chem., 36, 821 (1972).

106-W.R. Roderick, J. Org. Chem., 29, 745 (1964).

107-W. Warren and R. Briggs, Ber., 26, 64B (1931), C.A.25, 2418 (1931).

108-W.R. Roderick, J. Am. Chem. Soc., 79, 1710 (1957).

109-J. Cotter, C. Sauers and J. Whelane, J. Org. Chem., 26, 14 (1961).

110-L. Kulev, R. Gireva and G. Stepova, Obshch. Khim., 32, 2812 (1931).

111-A.E. Kretov and N.E. KulChitskaya , J. Gen. Chem. U.S.S.R., 26, 221

(1956).

112-M.Z. Barakat, S.K. Shehat and M.M. Elsadr, J. Chem. Soc., 23, 4133

(1957).

113-T.M. Pyriadi and A.M. Al-Azzwai, J. Ploy. Sci., Part A , 37, 427

(1999).

114-M.A. Yasin, MSc. Thesis. Chem. Dept. College of Sci. Univ. of

Baghdad (2007).

115-A.M. Al-Azzawi, Ph.D. Thesis. Chem. Dept. College of Sci. Univ. of

Baghdad (1997).

116-A.M. Al-Azzwai and K.K. Al-Obaidi, Nation. J. Chem., 12, 576

(2003).

117-A.M. Al-Azzawi and M.S. Ali, J. Um-Salama for Sci., 4(1), 110

(2007).

118-A.M. Al-Azzwai and M.S. Ali, Nation. J. Chem., 25, 158 (2007).

119-A.M. Al-Azzwai and M.S. Ali, J. Um-Salama for Sci., 3(4), 677

(2006).

References

۱۱٤

120-A.M. Al-Azzwai and M.S. Ali, J. Al-Nahrain Univer.sci., 10(1), 38

(2007).

121-T.M. Pyriadi and N.S. Al-Asli, J. Poly. Sci. Part A. Poly. Chem., 27,

2491 (1989).

122-E.J. Prill, U.S. Patent 2, 524, 136 (1950).

123-M.M. Langade, Der. Pharma. Chemica., 3(2), 283 (2011).

124-K. Kankanala, V.R. Reddy, K. Mukkanti and S. Pal, J. Braz. Chem.

Soc., 21(6), 1060 (2010).

125-D. Rennison, S. Bova, M. Cavalli, F. Ricchelli, A. Zulian, B. Hopkins

and M.A. Brimble, Bioorg-Med. Chem., 15, 2963 (2007).

126-A. Shoji, M. Kuwahara, H. Ozaki and H. Sawki, J. Am. Chem. Soc.,

129, 1456 (2007).

127-K. Nakae, Y. Nishimura, S. Ohba and Y.Akamatsu, J. Antibiot., 59,

685 (2006).

128-W.W.K.R. Mederski, M. Baumgarth, M. Germann, D. Kux and T.

Weitzel, Tetrahedron., 44, 2133 (2003).

129-Y. Hijji and E. Benjamin, Heterocyles., 68, 2259 (2006).

130-E. Benjamin and Y. Hijji, Molecules., 13, 157 (2008).

131-K. Mogilaiah and B. Sakram, Indian J. Chem., 46B, 207 (2007).

132-M. Wiecek and K.K. Kononowicz, Acta. Poloniae. Pharmaceutica-

Drug Research., 66(3), 249 (2009).

133-R. Varala, V. Kotra, M.M. Alam, N.R. Kumar, S. Ganapaty and S.R.

Adapa, Indian J. Chem., 47B , 1243 (2008).

References

۱۱٥

134-Y. Shibata, K. Sasaki, Y. Hashimoto and S. Iwaski, Chem. Pharm.

Bull., 44, 156 (1996).

135-A.D. Andricopulo, C. Filho and R. Correa, Pharmazie., 53, 49 (1998).

136-D.S. Stiz, M.M. Souza and V. Golim, Pharmazie., 55, 12 (2000).

137-A.D. Andricopulo, R.A. Yunes, C. Filho, J.R. Nunes, J.W. Frazer and

E.H. Cordes, Pharmazie., 54 , 698 (1999).

138-E.O. Lima , A.D. Andricopulo, J.R. Nunes , R.A. Yunes ,R. Correa

and C.Filho, Bol. Soc. Chil. Quim., 44, 185 (1999).

139-C. Filho , R. Correa, Z. Var, J.B. Calixto, J.R. Nunes , T.R. Pinheiro,

A.D. Andricopulo and R.A. Yunes , IL Farmaco., 53, 55 (1998).

140-S.M.Sondhi, R.Rani, P.Roy, S.K.Agarwal and A.K.Saxena , Bioorg.

Med. Chem.Lett.,

141-D.P. Jindal, V. Bedi, B. Jit, N. Karkra, S. Guleria, R. Bansal, A.

Palusezak and R.W. Hartmann, IL Farmaco., 60, 283 (2005).

142-A.L. Machado, L.M. Lima, A. Jo, J.X. Jr, C.A. Fraga, V.L.G. Koatz

and F.J. Barreiro, Bioorg. Med . Chem. Lett., 15, 1169 (2005).

143-S.S. Bhawani, M. Deepika, K.B. Lalith and G.L. Talesara, Indian J.

Chem., 43B, 1306 (2004).

144-B.M. Khadikar and S.D. Samant, Indian J. Chem., 32B , 1137 (1993).

145-V.K. Pandey, T. Sarah, T. Zehra, R. Raghubir, M. Dixit, M. Joshi and

S.K. Bajpai, Indian J. Chem., 43B, 180 (2004).

146-N.B. Birchfield and J.E. Casida, Pestic. Biochem. Physiol., 57, 36

(1997).

References

۱۱٦

147-P. Boger and K. Wakabayashi, Z. Natur Forsch., 50C , 159 (1995).

148-J. Vamecq, P. Bac, Ch. Herrenknecht, P. Maurois, P. Delcourt and J.P.

Stables, J. Med. Chem., 43, 1311 (2000).

149-V. Bailleux, L. Vallee, J.P. Nuyts and J. Vamecq, Chem. Pharm.

Bull., 42, 1817 (1994).

150-H. Sano, T. Noguchi, A. Tanatani, H. Miyachi and Y. Hashimoto,

Chem. Pharm. Bull., 52, 1021 (2004).

151-J.M. Jr. Chapman, P.J. Voorstad, G.H. Cocolas and H. Hall, J. Med.

Chem., 26, 237 (1983).

152-Y. Hashimoto, Bioorg. Med .Chem., 10, 461 (2002).

153-S.K. Sahu, S.K. Mishra, S. Mandal , P. Choudhury, S. Sutradhar and

P.K. Misro, J. Indian. Chem. Soc., 83, 832 (2006).

154-S.P. Mahapatra, P. Ghode, D.K. Jain, S.C. Chaturvedi, B.C. Maiti and

T.K. Maity, J. Pharm. Sci. and Res., 2(9), 567 (2010).

155-W. Pluempanupat, S. Adisakwattana, S.Y. Anun and W. Chavasiri,

Arch. Pharm. Res., 30(12), 1501 (2007).

156-N. Haider, R. Jbara, J. Kaferbock and U. Traar, ARKivoc., (VI), 38

(2009).

157-S.A. Mehdi, MSc. Thesis. Chem. Dept. College . Sci. Univ. of

Baghdad (2008).

158-A.M. Al-Azzwai and A.S. Hassan, Diyala J. Pure. Sci., 6(1), 89

(2010).

159-H.K. Al-Amerri, MSc. Thesis. Chem. Dept. College . Sci. Univ. of

Baghdad (2010).

References

۱۱۷

160-A.M.Al-Azzawi and M.S.Ali , J. of Al-Nahrain University Sci.,

11(3),15(2008).

161-T.M.Pyriadi, A.M.Al-Azzawi and K.K.Al-Obaidi, j. of Al-Nahrain University Sci., 12(2), 1(2009).

162-A.M.Al-Azzawi and S.A.Mehdi, Baghdad Sci.J.,7(1),641(2010)

163- A.M.Al-Azzawi and A.S.Hamd,Al-Anbar J.Vet.Sci.,4(2) , 152 (2011).

164- A. I. Vogel “ A Text book of practical organic chemistry ” Third Edition Longman group limited , London (1974).

165- R.M. Silverstein and G.C. Bassler “spectrometric identification of organic compounds”, 4th Edition (1981), Jhon Wiley & Sons Ltd, New York.

166-G.J. Crewed, O.R. Quist and M.M. Cambell., “spectral analysis of organic Compounds”, 2nd Edition (1988).

167-J. McMurry ,”Organic Chemistry”, 7th Edition (2008).

168-R.T. Conley, “Infrared spectroscopy”, 2nd Edition, Boston (1972).

169-R.L. Shriner , R.C. Fusion and D.Y. Curtin , “ The Systematic identification of Organic Compounds ” , 5th Edition (1964) , United states of American.

170- R.T.Morrison and R.N.Boyd , “Organic Chemistry”, 6th Edition (2002).

الخالصة

ق ائ��طر مرتبط��ة بقواع��د ش��يف باس��تخدام ةفث��ال ايماي��د جدي��دت ش��تقاتض��من البح��ث تحض��ير م

: هذا البحث الى أربعة أجزاء رئيسية تحضير مختلفة، لذلك تم تقسيم

ف عن طريق مرتبطة بقواعد شيفثال ايمايد جديده اتشتقالجزء االول تضمن تحضير م .۱

حيث تم تحضير هذه المركبات عن طريق ,)۱مخطط ( [5-18] مجموعة فنيل سلفون أميد

-اتباع الخطوات التالية:

.لينيمن خالل تفاعل انهيدريد الفثاليك مع االن [1]فنيل فثال أميك -Nتحضير حامض - أ

الخطوة (أ) باستخدام انهيدريد في فنيل فثال أميك المحضر-N ء من حامضسحب الما - ب

[2].المائية كعامل ساحب للماء لتكوين الفثال ايمايد المقابل لالخليك وخالت الصوديوم ا

سلفنة مع حامض كلورو (ب) بتفاعلادخال الفثال أيمايد المحضر في الخطوة - ج

. [3]فثال ايمايد للفونيك للحصول على كلوريد سلفونيالكلوروس

مع الهيدرازين هايدريت للحصول على فثال ايمايد فنيل سلفونيل [3]عل المركب اتف - د

[4]. هيدرازين

فثال ايمايد فنيل سلفونيل وذلك عن طريق تفاعل [5-18]تحضير عدد من قواعد شيف -ه

.الروماتيةديهايدات والكيتونات االلمع مختلف ا [4] هيدرازين

د شيف عن أما الجزء الثاني من البحث فيتضمن تحضير فثال ايمايدات جديدة مرتبطة بقواع .۲

-يلي:احيث تم تحضير هذه المركبات باتباع م [20-26] طريق مكونة الفنيل سلفونات

عن طريق تفاعل فثال ايمايد [19]اسيتوفينون فنيل سلفوناتتحضير مركب فثال ايمايد - أ

.هيدروكسي اسيتوفينون 4-الجزء االول مع المحضر في [3]سلفونيل كلورايد فنيل

مع عدة أمينات اروماتية أولية معوضة هالمحضر في الخطوة (أ) بتفاعل [19]المركب - ب

.)۲مخطط ( [20-26]سنحصل على قواعد شيف

الجزء الثالث من البحث يتضمن تحضير فثال ايمايدات جديدة مرتبطة بقواعد شيف عن طريق .۳

-وذلك عن طريق أتباع الخطوات التالية: [28-33] اتمكونة الفنيل سلفون

فنيل عن طريق تفاعل الفثال ايمايد [27]بنزالديهايد تاسلفونفنيل تحضير فثال ايمايد - أ

.هيدروكسي بنزالديهايد 4-المحضر في الجزء االول مع [3]سلفونيل كلورايد

اولية معوضة الخطوة (أ) مع عدة امينات اروماتية المحضر في [27]تفاعل المركب - ب

.)۳مخطط ([28-33] سنحصل على قواعد شيف

البحث فيتضمن تحضير فثال ايمايدات جديدة مرتبطة بقواعد شيف عن أما الجزء االخير من .٤

-تم تحضير هذه المركبات عن طريق الخطوات التالية: [35-40]لين يطريق مجموعة المث

فنيل فيناسيل -4فنيل فيناسيل برومايد لتكوين 4-تفاعل ملح البوتاسيوم للفثال ايمايد مع - أ

. [34]فثال ايمايد

ماتية ومع عدة امينات ار (أ) في الخطوهالمحضر [34]فنيل فيناسيل فثال ايمايد -4تفاعل - ب

.)4مخطط ( [35-40]اولية معوضة لتكوين قواعد شيف الجديدة

مطيافية االشعة عن طريق وشخصت طيفيا درجات االنصهار للمركبات المحضرة تعين

و 1H-NMRمطيافية الرنين النووي المغناطيسي بنوعية استخدمت وكما FT-IRتحت الحمراء 13C-NMR في تشخيص بعض المركبات المحضرة.

المحضرة ضد ية البايولوجية لعدد من االيمايدات الجديدهكذلك تضمن البحث دراسة الفعال

المحضرة فعالية جيدة ضد انواع وقد اظهرت النتائج بان لاليمايدات الجديدهانواع من البكتريا

البكتريا قيد الدراسة.

العراق جمهورية وزارة التعليم العالي والبحث العلمي

كلية العلوم -جامعة بغداد Áقسم الكيميا

ℌⅬ℞ℂ₧ Ⅵ ℘Ⅼ℆№₧ ₆ ⅕₍€ℱ Ⅱ℈Ⅻ℈₯ ₥₌℈Ⅻ₍⅜Ⅻ

ℰⅬℕ ℈℩₌Ⅶℶ₡ Ⅲ⅘ℚ₨⅛

جزء من متطلبات نيل درجة الماجستير وهي جامعة بغداد -رسالة مقدمة إلى كلية العلوم العضويةكيمياء / الكيمياء الفي علوم

هاتقدم

مروة شوقي عبد الرزاق الجبوري ٢٠٠٨بكالوريوس علوم الكيمياء

بإشراف

الدكتورة أحالم معروف العزاوي

1433å ٢٠١٢ã

Synthesis and Characterization of New Phthalimides linked ... and... · Synthesis and...

Documents

Transcript of Synthesis and Characterization of New Phthalimides linked ... and... · Synthesis and...