Modification Structure of Chalcone Compounds and Synthesis ... Structure of Chalcone... · Modification Structure of Chalcone Compounds and Synthesis of Their Nickel(II) and Copper(II)

Modification Structure of Chalcone Compounds and Synthesis of Their Nickel(II)

and Copper(II) Complexes

Rose Chua Siaw Chin (22196)

A project report submitted in partial fulfillment of the

Final Year Project II (STF 3015)

Supervisor: Dr. Tay Meng Guan

Co-Supervisor: Associate Professor Dr. Zainab Ngaini

Resource Chemistry

Department of Chemistry

Faculty of Resource Science and Technology

University Malaysia Sarawak

2012

I

Declaration

I hereby declare that the work described in this thesis was carried by me under the

supervision of Dr. Tay Meng Guan at the Department of Chemistry, Faculty of Resource

Science and Technology, Universiti Malaysia Sarawak and no portion of this dissertation

has been submitted in support of an application for another degree of qualification of this

or any other university or institution of higher learning.

Rose Chua Siaw Chin

Program of Resource Chemistry

Faculty of Resource Science and Technology

Universiti Malaysia Sarawak

II

Acknowledgements

First of all, I would like to express my thanks to my supervisor, Dr Tay Meng Guan for

providing the necessary advice, guidance, encouragement, support and facilities throughout

the project. I also would like to thank the postgraduate students, Mr. Tiong Mee Hing and

Ms. Emelia, for giving me guidance and support. In addition, I want to thank all technical

staffs and lab assistances for their great help and collaboration. Finally, I am very thankful

to my family for their love, encouragement and support.

III

Table of Contents

Declaration I

Acknowledgements II

Table of Content III

List of Abbreviations V

List of Figures VII

List of Schemes X

List of Tables XI

Abstract 1

1.0 Introduction 2

1.1 Chalcone 2

1.2 Chalcone Metal Complexes 5

2.0 Objectives 10

3.0 Literature Review 11

3.1 Chalcone Synthesis Methods 11

3.1.1 Suzuki reaction 11

3.1.2 Ultrasound irradiation 12

3.1.3 Microwave irradiation 13

3.1.4 Claisen-Schmidt condensation 14

3.2 Mechanism of Chalcones Synthesis 16

3.2.1 Base catalysed reaction 16

3.2.2 Acid catalysed reaction 18

3.3 Applications of Chalcones and Their Complexes 20

3.3.1 Pharmacological applications 20

3.3.2 Electronic applications 24

4.0 Methodology 27

4.1 Reagents and Materials 27

4.2 Characterisation 27

4.3 Preparation of 4’-(N-butyl)aminoacetophenone (1) 27

4.4 Synthesis of Bis-Chalcones

IV

4.4.1 Synthesis of 1,4-bis(2-benzoylvinyl)benzene (2) 28

4.4.2 Synthesis of 1,4-bis{2-(4-nitrobenzoyl)vinyl}benzene (3) 29

4.4.2 Synthesis of 1,4-bis{2-(2-hydroxybenzoyl)vinyl}benzene (4) 30

4.4.4 Synthesis of 1,4-bis{2-[4-(N-butyl)aminobenzoyl]vinyl}benzene (5) 31

4.5 Synthesis of Bis-Chalcone Complexes

4.5.1 Synthesis of the complex of Ni(NO3)2∙6H2O with compound 2 32

4.5.2 Synthesis of the complex of CuCl2∙2H2O with compound 2 32



4.5.5 Synthesis of the complex of Ni(NO3)2∙6H2O with compound 4 (1:1 ratio) 33

4.5.6 Synthesis of the complex of Ni(NO3)2∙6H2O with compound 4 (2:1 ratio) 33




5.0 Results and Discussion 35

5.1 Alkylation Studies on 4-(N-butyl)aminoacetophenone (1) 35

5.2 Synthesis of Bis-Chalcone Compounds 39

5.3 Spectral Studies on the Substituents Effects 41

5.3.1 IR spectra 41

5.3.2 1H NMR spectra 53

5.3.3 UV spectra 63

5.4 Spectroscopic Studies on Bis-Cchalcone Nickel and Copper Metal Complex 67

6.0 Conclusion 73

7.0 Suggestions for Future Work 74

8.0 References 75

9.0 Appendices 80

V

List of Abbreviations

AlCl3 Aluminium chloride

Ba(OH)2 Barium hydroxide

BF3-Et2O Borontrifluride-etherate

Cs2CO3 Cesium carbonate

˚C Degree Celsius

CDCl3 Deuterated chloroform

d Doublet

DCM Dichloromethane

DMF Dimethylformamide

DMSO Dimethylsufoxide

EtOH Ethanol

FTIR Fourier transform infrared

GC-MS Gas chromatography mass spectroscopy

g Gram

h Hour

HCl Hydrochloric

J Coupling constant

MgSO4 Magnesium sulfate

MIC Minimum inhibitory concentration

mL Milliliter

mmol Millimole

min Minute

NMR Nuclear magnetic resonance

VI

% Percentage

KBr Potassium bromide

K2CO3 Potassium carbonate

KF-Al2O3 Potassium fluoride-aluminium oxide

KOH Potassium hydroxide

KI Potassium iodide

NaOH Sodium hydroxide

Pd(PPh3)4 Tetrakistriphenylphosphine

TMS Tetramethylsilane

s Singlet

SOCl2 Thionyl chloride

t Triplet

TiCl4 Titanium(IV) chloride

UV-Vis Ultraviolet-visible

VII

List of Figures

Figure Title Page

1 Examples of the family of flavonoid 2

2 Basic structure of chalcone 3

3 Structure of Licochalcone A 4

4 Structure of o-hydroxychalcones 6

5 Square planar geometry of chalcone metal complexes 7

6 Octahedral geometry of chalcone metal complexes 8

7 The proposed chalcone structure with different substituents 9

8 Structure of bischalcone derivatives with potent antimicrobial

activity 21

9 Anti-HIV chalcone 23

10 Oxygenated chalcone having antimalarial activity 23

11 Structure of 1-(2-pyridyl)-5-(4-dimethylaminophenyl)-penta-2,4-

diene-1-one 25

12 Structure of 4-dimethylamino-2,5-dihydroxychalcone 25

13 The novel UV-sensitive bis-chalcone derivatives 26

14 IR spectrum of compound 1 37

VIII

15 1H NMR spectrum of compound 1 38



18 The effect of electron withdrawing nitro group on C=O bond 45


20 The electron donating effect of hydroxyl group on C=O bond 48

21 Formation of intramolecular hydrogen bonding between OH and

carbonyl group 48


23 The electron donating effect of monosubstituted amino group on

C=O bond 50


25 Delocalisation of electrons within the structure of the compound 53




29 The UV-Vis spectrum of compound 2 65


IX



33 The IR spectrum of compound 4 nickel(II) complex (1:1) 69

34 The IR spectrum of compound 4 nickel(II) complex (1:2) 71

35 The UV-Vis spectrum of compound 4 nickel(II) complex (1:1) 72

36 The UV-Vis spectrum of compound 4 nickel(II) complex (1:2) 72

37 The proposed chalcone related compounds for future works 74

X

List of Schemes

Scheme Title Page

1 Synthesis of chalcones via Suzuki reaction 11

2 Synthesis of chalcones under ultrasound irradiation 12

3 Synthesis of chalcones under microwave irradiation 13

4 Claisen-Schmidt condensation reaction 14

5 Mechanisms for the base catalysed reaction 17

6 Mechanisms for the acid catalysed reaction 19

7 The mechanism for alkylation of 4-aminoacetophenone 36

8 Synthesis of compound 2, 3, 4 and 5 39

9 The formation of enolate by reacting substituted

acetophenones with hydroxide ion 40

XI

List of Tables

Table Title Page

1 The physical data of the compound 2 – 5 40

2 The IR data of the compound 2 – 5 (cm-1

) 41

3 The 1H NMR data of 2 – 5 (ppm) 54

4 The UV-Vis data of the compound 2 – 5 63

1

Modification Structure of Chalcone Compounds and Synthesis of Their Nickel(II)

and Copper(II) Complexes

Rose Chua Siaw Chin

Resource Chemistry Programme

Faculty of Science and Technology

Universiti Malaysia Sarawak

Abstract

Four bis-chalcone compounds with different para- or ortho-substituted were synthesised

by Claisen-Schmidt condensation of terephthaladehyde and para- or ortho-substituted R-

acetophenone under base condition. These bis-chalcone were used as the ligands for

synthesising their nickel(II) and copper(II) complexes. All the synthesised bis-chalcones

and their complexes were characterised by IR, 1H NMR, and UV-Vis spectroscopy. The

spectra data showed that the introducing of different para- or ortho-substituents on the

aromatic rings have a great influenced on the carbonyl group, vinylic protons, and charge

transfer within the whole molecule of bis-chalcones. The comparison of the IR spectra of

the bis-chalcones and their metal complexes indicated that only the bis-chalcone with the

hydroxyl substituent was successfully coordinated to nickel(II) ion in 1:1 molar ratio to

form the complex through the oxygen atoms of the carbonyl and phenolic group.

Keywords: Chalcones, Claisen-Schmidt condensation, substituents’ effects, nickel, copper

Abstrak

Empat bis-kalkon sebatian dengan pelbagai para atau orto pengganti telah dihasilkan

melalui tindak balas kondensasi Claisen-Schmidt antara terefalaldehid dan para- atau

orto-pengganti R-asetofenon dalam keadaan alkali. Bis-kalkon ini digunakan sebagai ligan

untuk mensintesis kompleks nikel(II) dan kuprum(II). Semua sebatian bis-kalkon dan

kompleknya dicirikan dengan menggunakan inframerah (IM), ultralembayung (UL), dan

resonans magnet nucleus (RMN 1H) spektroskopi. Spektra data ini menunjukkan bahawa

dengan memperkenalkan gantian para atau ortho yang berbeza pada gelang aromatik

mempunyai pengaruh yang besar ke atas kumpulan karbonil, proton vinilik, dan

pemindahan caj dalam seluruh molekul kalkon. Perbandingan antara spektra IM kalkon

dan kompleksnya menunjukkan bahawa hanya kalkon dengan gantian hidroksil telah

berjaya terkordinat dengan ion nikel(II) dalam nisbah 1:1 untuk membentuk kompleks

melalui kumpulan atom oksigen karbonil dan fenolik.

Kata kunci: Kalkon, kondensasi Claisen-Schmidt, kesan penggantian, nikel, kuprum

2

1.0 Introduction

1.1 Chalcone

Chalcone, which was named by Kostanecki and Tambar in 1899, is considered as essential

groups of natural products in the flavonoid family (Figure 1) (Parmar & Ghosh, 1980).

Chalcone is also known as benzalacetophenone or 1,3-diphenyl-2-propen-1-one and the

compounds are usually used as the precursors in the synthesis of all flavonoids such as

anthocyanins, flavones and flavanones (Wong, 1968).

O

Flavonoid

O

O

Flavone

O

O

OH

Flavonol

O

Anthocyanidin

O

O

Flavanone

O

Chalcone

Figure 1: Examples of the family of flavonoid

In general, chalcones contain α,β-unsaturated ketone with two planar aromatic rings on

both sides (Figure 2). The β carbon and carbonyl carbon of chalcones are the most electron

deficient (Go et al., 2005), and it causes the both carbon to be readily attacked by

nucleophiles. The introduction of electron withdrawing groups on the ring A and B

respectively enhance the electron deficiency of the β carbon and carbonyl carbon. However,

the presence of electron donating groups on either ring A or B has the opposite effect.

3

O

A BR1 R2

2

3

4

5

6

2'

3'

4'

5'

6'

α

β

Figure 2: Basic structure of chalcone

Chalcones can exist in two forms, either E or Z configuration due to the presence of the

unsaturated linkage in the structure. The E configuration of chalcones is

thermodynamically more stable than the Z isomer. Iwata and co-workers (1997) reported

that the E form of chalcone transformed into the Z form when it exposed to sunlight in

methanol solution. However, the presence of the hydroxyl group at the 2’-position on the

ring B can inhibit the photo-isomerisation of E into Z isomer (Shibata, 1994). Besides that,

Ducki et al. (1998) have found that the carbonyl and Cα-Cβ double bonds were positioned

cis with respect to each other in the X-ray chalcones crystal structures.

Chalcones also possess conjugated double bond with a completely delocalised π electrons

system on the structure which enables them to undergo electron transfer reactions. For

example, delocalisation of the electrons along the α,β-unsaturated carbonyl linkage cause

the carbonyl carbon–α-carbon bond to show partial double bond character and the C=O to

show single bond character. The presence of the chromophore, -CO-CH=CH-, in chalcones

make them to be coloured compounds. Typically, chalcones are yellow colour in nature.

Chalcones has been report to exhibits various pharmacological activities such as

antimicrobial, antitumor, anti-HIV, antimalaria, anti-inflammatory, and anticarcinogenic

activities (Prasad et al., 2008). The α,β-unsaturated ketone linker in chalcone molecules

plays an important role in their biological activities. Most of these biological effects are

related to its ability to create the electrophilic site that is the binding site of the biological

4

targets (Selvi et al., 2012). The nonlinear optical properties of chalcones such as excellent

blue light transmittance and good crystallisation ability have also been reported (Patil et al.,

2007). They show good optical limiting with nanosecond laser pulse at 532 nm wavelength.

All these properties of chalcone are largely depended on the type and positions of

substituents in either of the two aromatic rings.

Chalcones can be found in many plants such as Angelica, Glycyrrhiza, Humulus and

Scutellaria (Ducki, 2007). Licochalcone A (Figure 3) is an example of chalcone that

isolated from Glycyrrhiza (Shibata et al., 1991). However, it is very difficult to isolate

chalcones from plants because of the presence of enzyme chalcone synthetase will convert

them into flavonones (Shah et al., 2011). Therefore, the synthetic chalcones have drawn

much attention in many organic chemists. Chalcones with different heterocyclic rings or

substituents such as methyl (-CH3), methoxy (-OCH3), nitro (-NO2), hydroxyl (-OH), and

halogen on either side of the aromatic rings are readily synthesised in the laboratory. These

substituted chalcones can be coordinated to metal ions to form chalcone metal complexes.

HO

O OCH3

OH

H3C CH3

H2C

Figure 3: Structure of Licochalcone A

There are several methods available for the synthesis of chalcones. The most widely used

methods are Claisen-Schmidt condensation, Suzuki reaction, ultrasound and microwave

irradiation (Eddarir et al., 2003; Dhar & Lal, 1958; Li et al., 2002; Srivastava, 2008).

5

Choosing a suitable synthetic method is significant because some methods may lead to the

formation of side products and give low yields. In order to improve the yield of the

products, most of the researchers have sought alternative catalysts to synthesise chalcones

such as potassium carbonate, alumina, and KF/natural phosphate for base catalysed

reactions and SOCl2/EtOH, silica-sulphuric acid, and TiCl4 for acid catalysed reactions

(Zangade et al., 2011).

1.2 Chalcone Metal Complexes

Chalcone metal complexes have been known over the past fifty years. Since twentieth

century, the chalcones have been used to form complexes with Y(III), La(III), Pr(III) and

Nd(III) for the first time (Singh & Rathi, 1980). Later, various substituted chalcone ligand

was introduced and used to form complexes with different type of metal ions. However,

there was still having no comprehensive or systematic study on the metal complexes of

chalcones.

Chalcones have been used as ligands in the formation of metal complexes. They can act as

monodentate, bidentate or polydentate species towards the metal complexes depend on the

number of donor atoms present the compound. If there is one or more donor atoms present

near to the carbonyl group, the chalcones can form chelate metal complexes. The most

widely studied chalcone ligands is o-hydroxychalcones (Figure 4) such as 3-(phenyl)-1-

(2’-hydroxynaphthyl)-2-propen-1-one, 3-(3,4-dimethoxypheny)-1-(2’-hydroxyphenyl)-2-

propen-1-one, 3-(4-chlorophenyl)-1-(2’-hydroxynaphthyl)-2-propen-1-one and so on.

These ligands have the capability to form chelates with metal ions through the oxygen

atoms of carbonyl and phenolic group (Viswanathamurthi & Muthukumar, 2010).

6

O OH

Figure 4: Structure of o-hydroxychalcones

Chalcone derivatives can form complexes with different metal ions due to their good

synthetic flexibility, selectivity and sensitivity towards the central metal atom (Vyas et al.,

2010). They are able to form complexes with Mn(II), Co(II), Ni(II), Cu(II), Zn(II), Cd(II),

Ru(III) and Rh(III). The metal complexes of chalcones can be tetrahedral, square planar or

octahedral geometry depend on the coordination number in the complex, the nature of the

metal atom, and the magnitude of the ligand field (Reddy et al., 2006).

Palaniandavar and Natarajan (1980) studied the Co(II), Ni(II), and Cu(II) complexes of 2’-

hydroxy-5’-X-chalcone where X = H, CH3, Cl. They reported that metal(II) complexes of

2’-hydroxychalcone have low-spin square planar configuration (Figure 5) (Palaniandavar

& Natarajan, 1980). The extensive conjugation of carbonyl group with the phenyl ring led

to greater electrons delocalisation. This delocalisation lowered the energy level of the anti

π orbital. Consequently, the M → L back bonding occurred and led to an increase in the

ligand field strength. Therefore, the ligand field produced is strong enough to stabilise the

square planar coordination and the spin-pairing occur.

Rao and his coworkers (1988) had studied the coordinating behavior of 3-(2-pyridyl)-1-(2-

hydroxy phenyl)-2-propen-1-one (PHPO), 3-(1-naphthyl)-1-(2-hydroxy phenyl)-2-propen-

1-one (NHPO) and 3-(3,4-dimethoxy phenyl)-1-(2-hydroxy phenyl)-2-propen-1-one

(DMPHPO) with Co(II), Ni(II), Cu(II), Zn(II) and Cd(II). The ligand PHPO was found to

act as uninegative tridentate towards Co(II) and Ni(II) and bidentate towards Cu(II), Zn(II)

7

and Cd(II). While, the NHPO and DMPHPO ligands act as uninegative bidentate towards

all metal ions. Based on their electronic spectral data, the PHPO complex of Co(II) and

Ni(II) are octahedral and NHPO and DMPHPO complex of Cu(II) and Ni(II) are square

planar. The complex of Zn(II) and Cd(II) showed tetrahedral geometry.

M

O

O

X

X

O

O

M = Co(II), Ni(II), Cu(II) and X = H, CH3, Cl

Figure 5: Square planar geometry of chalcone metal complexes

Habib and his co-workers (2011) studied a series of substituted 2’-hydroxychalcones

Co(II), Ni(II) and Cu(II) complexes. The stoichiometry of the complexes was 1:2 metals to

ligand ratio and the substituted 2’-hydroxychalcone ligands acted as mononegative

bidentate towards the metal complexes. Based on their findings, Co(II) and Ni(II)

complexes were found to have octahedral geometry due to presence of two coordinated

water molecules in the complexes (Figure 6). In contrast, the geometry of Cu(II)

complexes was square planar. Tharmaraj and coworkers (2011) had also studied a series of

metal(II) complexes of 2-hydroxyphenyl-3-(1H-indol-3-yl)-prop-2-en-1-one ligand. Co(II),

Ni(II), Zn(II), Cd(II) and Mn(II) complexes are found to have octahedral geometry and

oxovanadium is square pyramidal geometry.

8

M

O O

O O

R1

R2

HO

Br

Br

R2

R1

OH

Br

Br

OH2H2O

M = Ni(II), Co(II), R1 = H or CH3, R2 = H or I

Figure 6: Octahedral geometry of chalcone metal complexes

In this project, the modification of the chalcone template involved increasing its

conjugation chain length. The chalcones synthesised have two α,β-unsaturated ketone

groups with two phenyl rings at the both end sides and one phenyl ring in the center

(Figure 7). Besides, different types of substituents such as nitro, hydroxy and N-

butylamino groups were introduced on the both end of the aromatic rings. The nitro group

is a representative hydrophobic and electron withdrawing group and hydroxyl and N-

butylamino as hydrophilic and electron donating group. The synthesised molecules with

electron withdrawing groups attached at the both end create an acceptor-acceptor-acceptor-

acceptor (A-A-A-A) type of structure and with electron donating groups attached at the

both end create a donor-acceptor-acceptor-donor (D-A-A-D) type of structure.

9

O

O

R R

R = H, 4-NO2, 2-OH, 4-(C4H9)NH

α

β

β

α

Figure 7: The proposed chalcone structure with different substituents

10

2.0 Objectives

The objectives of the study are:

i. To synthesise and characterise a series of bis-chalcone derivatives and their Ni(II)

and Cu(II) complexes using FTIR, NMR, and UV-Vis spectroscopy.

ii. To study the substituents effects on carbonyl and vinyl group of bis-chalcone

derivatives.

iii. To study the coordination mode of the synthesised bis-chalcone and its derivatives

with Ni(II) and Cu(II) metals.

11

3.0 Literature Review

3.1 Chalcone Synthesis Methods

There are several methods available for the synthesis of chalcone and its derivatives. The

most widely used method is Claisen-Schmidt condensation; however, other alternative

synthesis approaches such as Suzuki reaction, ultrasound irradiation and microwave

irradiation have also been reported (Eddarir et al., 2003; Dhar & Lal, 1958; Li et al., 2002;

Srivastava, 2008).

3.1.1 Suzuki reaction

Synthesis of chalcones 8 via Suzuki reaction involves the coupling of benzoyl chloride 7

and phenylvinylboronic acid 6 in the presence of cesium carbonate solution as base and

anhydrous toluene as solvent (Scheme 1) (Eddarir et al., 2003). This reaction was

catalysed by palladium tetrakistriphenylphosphine [Pd(PPh3)4] to give chalcones in almost

quantitative yield. However, [Pd(PPh3)4] is very air and light sensitive and due to its

limited reactivity, it has to be used in amounts of up to 10 mol%. Furthermore, the used of

[Pd(PPh3)4] as a catalyst in Suzuki coupling may be toxic and is difficult to separate from

the reaction mixture (Ren & Meng, 2008).

OMe

B

OHHO

+

MeO

MeO

Cl

O O

MeO

MeO

OMe

86 7

Cs2CO3, toluene

[Pd(PPh3)4]

Scheme 1: Synthesis of chalcones via Suzuki reaction

12

3.1.2 Ultrasound irradiation

Ultrasound assisted synthesis is a sonochemical process where the reaction mixture

irradiates with the power ultrasound (Sharma et al., 2008). This process involves the

generation of cavitation’s bubbles in the liquid medium and collision of the bubbles to

cause the sonochemical reactions to occur. This method takes place at room temperature

and catalyses by pulverised KOH or KF supported on alumina (Li et al., 2002). The

ultrasound-assisted method accelerates chemical reactivity of the system which shorter the

reaction times. Li and his co-workers (2002) reported that synthesis of chalcones by using

ultrasound irradiation method gave 83-98% yields under mild conditions.

The benzaldehyde 9, acetophenone 10, and pulverised KOH are subjected to ultrasound

irradiation for 25 min to produce 1,3-diphenylpropenone 11 (Scheme 2). This reaction

gave products in 80% yield (Li et al., 2005).

H

O

+

O O

9 10 11

KOH

U.S.

Scheme 2: Synthesis of chalcones under ultrasound irradiation

The major advantages of this method are good yields, less reaction times, and no side

products (Calvino et al., 2006). Sonicated reactions, on the contrary, are very solvent

sensitive. This is because viscosity and surface tension of the solvent will inhibit cavitation

to occur.

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Modification Structure of Chalcone Compounds and Synthesis ... Structure of Chalcone... · Modification Structure of Chalcone Compounds and Synthesis of Their Nickel(II) and Copper(II)