View
39
Download
0
Category
Tags:
Preview:
DESCRIPTION
contoh
Citation preview
SOLVENT-FREE SYNTHESIS OF CHALCONE BY ALDOL CONDENSATION CATALYZED BY SOLID SODIUM
HYDROXYDE (NaOH)
MUHAMAD FARIDZ BIN OSMAN
BACHELOR OF SCIENCE (Hons.)CHEMISTRY
FACULTY OF APPLIED SCIENCESUNIVERSITI TEKNOLOGI MARA
APRIL 2009
SOLVENT-FREE SYNTHESIS OF CHALCONE BY ALDOL CONDENSATION CATALYZED BY SOLID SODIUM HYDROXYDE
(NaOH)
MUHAMAD FARIDZ BIN OSMAN
Final Year Project Report Submitted inPartial Fulfilment of the Requirements for the
Degree of Bachelor of Science (Hons.) Chemistryin the Faculty of Applied Sciences
Universiti Teknologi MARA
APRIL 2009
COPYRIGHT UiTM
ii
COPYRIGHT UiTM
iii
ACKNOWLEDGEMENTS
Upon completion of this project, I would like to express my gratitude to many parties. My heartfelt thanks go to my supervisor, Assoc. Prof. Yazan Zakaria because she gave me a lot of help, advice and support during the completion of this project. I also want to thank my partner, Norizan binti Tajudin who always help me and right here beside me whenever I need helps. Other than that, thank you to all my lecturers and friends who had involved directly and indirectly in accomplishing this project.
Muhamad Faridz bin Osman
COPYRIGHT UiTM
iv
TABLE OF CONTENTS
Page
ACKNOWLEDGEMENT iiiTABLE OF CONTENTS ivLIST OF TABLES viLIST OF FIGURES viiiLIST OF ABBREVIATIONS xABSTRACT xiABSTRAK xii
CHAPTER 1 INTRODUCTION1.1 Background of study 1
1.1.1 Mechanism of aldol condensation 41.2 Problem statement 61.3 Significance of study 71.4 Objectives of study 7
CHAPTER 2 LITERATURE REVIEW2.1 Previous studies on the synthesis of chalcone 8
2.1.1 LiOHH2O as a novel dual activation catalyst for highly 8efficient and easy synthesis of 1,3-diaryl-2-propenones by Claisen-Schmidt condenation under mild conditions
2.1.2 Synthesis of chalcones using boron trifluoride-etherate 9(BF3-Et2O)
2.1.3 SOCl2/EtOH: Catalytic system for synthesis of chalcones 122.1.4 Studies on synthesis, crystal growth and non-linear optical 13
(NLO) property of new chalcones2.1.5 Synthesis chalcone, flavanones and flavones as antitumoral 14
agents: Biological evaluation and structure-activity relationship2.1.6 RuCl3 catalyses aldol condensations of aldehydes and ketones 152.1.7 Dramatic activity enhancement of natural phosphate catalyst 18
by lithium nitrate. An efficient synthesis of chalcones
COPYRIGHT UiTM
vCHAPTER 3 METHODOLOGY3.1 Materials 213.2 Methods
3.2.1 Procedure to synthesize chalcone using solid sodium hydroxide 22(NaOH)
3.2.2 Procedure to synthesize chalcone using aqueous sodium hydroxide 22(NaOH)
CHAPTER 4 RESULTS AND DISCUSSION4.1 Aldol syntheses of chalcones catalyzed by strong base NaOH 244.2 IR spectral analysis of the chalcones 274.3 1H NMR spectral analysis of the chalcones
4.3.1 Synthesis of 3-nitro-4-methoxychalcone using solid NaOH 334.3.2 Synthesis of 3-nitro-4-methoxychalcone using aqueous NaOH 384.3.3 Synthesis of 4,4-dimethoxychalcone using solid NaOH 404.3.4 Synthesis of 4,4-dimethoxychalcone using aqueous NaOH 454.3.5 Synthesis of 4-chloro-4-methoxychalcone using solid NaOH 474.4.6 Synthesis of 4-chloro-4-methoxychalcone using aqueous NaOH 50
4.4 13C NMR spectral analysis of the chalcones 52
CHAPTER 5 CONCLUSION AND RECOMMENDATIONS 55
CITED REFERENCES 56APPENDICES 57
COPYRIGHT UiTM
vi
LIST OF TABLES
Table Caption Page
2.1 LiOHH2O-catalyzed Claisen-Schmidt reaction of Ar1COCH3 9
with Ar2CHO
2.2 Synthetic chalcones prepared using BF3Et2O 11
2.3 Synthesis of chalcones promoted by SOCl2/EtOH 13
2.4 Reaction of various aromatic aldehydes with acyclic ketones in the 17presence of 0.02 molar equivalents of Ru(III) in sealed tube at 120oC
2.5 Reaction of aldehydes with ketones in the presence of 0.02 molar 18equivalents of Ru(III) in sealed tube at 120oC
2.6 Synthesis of several chalcones by LiNO3/NP catalyzed ClaisenSchmidt 20condensation
3.1 Physical properties of starting materials 21
4.1 Summary of results showing the time of completion of reaction, 25the % yield and the melting point of the three chalcones synthesized using solid NaOH and aqueous NaOH
4.2 Frequencies of infrared spectrum of 4-chloro-4-methoxychalcone 28
4.3 Frequencies of infrared spectrum of 4,4-dimethoxychalcone 30
4.4. Frequencies of infrared spectrum of 3-nitro-4-methoxychalcone 32
4.5 Interpretation of 1H NMR spectrum of 363-nitro-4-methoxychalcone synthesized by solid NaOH
4.6 Interpretation of 1H NMR spectrum of 393-nitro-4-methoxychalcone synthesized by aqueous NaOH
4.7 Interpretation of 1H NMR spectrum of 424,4-dimethoxychalcone synthesized by solid NaOH
COPYRIGHT UiTM
vii
4.8 Interpretation of 1H NMR spectrum of 454,4-dimethoxychalcone synthesized by aqueous NaOH
4.9 Interpretation of 1H NMR spectrum of 484-chloro-4-methoxychalcone synthesized by solid NaOH
4.10 Interpretation of 1H NMR spectrum of 504-chloro-4-methoxychalcone synthesized by aqueous NaOH
4.11 Interpretation of 13C NMR spectrum of 3-nitro-4-methoxychalcone 53
COPYRIGHT UiTM
viii
LIST OF FIGURES
Figure Caption Page
1.1 The reaction scheme of aldol condensation 3
1.2 Mechanism of reaction using NaOH catalyst 5
2.1 A schematic representation of the synthesis and the chemical structures 12of chalcones
4.1 Scheme of the aldol condensation reaction 24
4.2 IR spectrum of 4-chloro-4-methoxychalcone catalyzed by 27solid NaOH
4.3 IR spectrum of 4-chloro-4-methoxychalcone catalyzed by 27aqueous NaOH
4.4 IR spectrum of 4,4-dimethoxychalcone catalyzed by solid NaOH 29
4.5 IR spectrum of 4,4-dimethoxychalcone catalyzed by aqueous NaOH 29
4.6 IR spectrum of 3-nitro-4-methoxychalcone catalyzed by solid NaOH 31
4.7 IR spectrum of 3-nitro-4-methoxychalcone catalyzed by aqueous NaOH 31
4.8 The structure of 3-nitro-4-methoxychalcone 33
4.9 The 300-MHz integrated 1H NMR spectrum of 343-nitro-4-methoxychalcone (solid NaOH)
4.10 The expanded and interpreted 1H NMR spectrum of 353-nitro-4-methoxychalcone (solid NaOH)
4.11 The 300-MHz integrated 1H NMR spectrum of 393-nitro-4-methoxychalcone (aq. NaOH)
4.12 The expanded and interpreted 1H NMR spectrum of 403-nitro-4-methoxychalcone (aq. NaOH)
4.13 The structure of 4,4-dimethoxychalcone 41
COPYRIGHT UiTM
ix
4.14 The 300-MHz integrated 1H NMR spectrum of 4,4-dimethoxychalcone 42(solid NaOH)
4.15 The expanded and interpreted 1H NMR spectrum of 434,4-dimethoxychalcone (solid NaOH)
4.16 The 300-MHz integrated 1H NMR spectrum of 4,4-dimethoxychalcone 46 (aq. NaOH)
4.17 The expanded and interpreted 1H NMR spectrum of 464,4-dimethoxychalcone (aq. NaOH)
4.18 The structure of 4-chloro-4-methoxychalcone 47
4.19 The 300-MHz integrated 1H NMR spectrum of 484-chloro-4-methoxychalcone (solid NaOH)
4.20 The expanded and interpreted 1H NMR spectrum of 494-chloro-4-methoxychalcone (solid NaOH)
4.21 The 300-MHz integrated 1H NMR spectrum of 514-chloro-4-methoxychalcone (aq. NaOH)
4.22 The expanded and interpreted 1H NMR spectrum of 514-chloro-4-methoxychalcone (aq. NaOH)
4.23 Structure of 3-nitro-4-methoxychalcone 52
4.24 The 13C NMR spectrum of 3-nitro-4-methoxychalcone run on a 54varian 300 MHz instrument
COPYRIGHT UiTM
xLIST OF ABBREVIATIONS
GCMS : Gas Chromatography-Mass Spectrometry
IR : Infrared
NLO : Non-linear optical
NMR : Nuclear Magnetic Resonance
TLC : Thin layer chromatography
COPYRIGHT UiTM
xi
ABSTRACT
SOLVENT-FREE SYNTHESIS OF CHALCONE BY ALDOL CONDENSATION CATALYZED BY SOLID SODIUM HYDROXIDE (NaOH)
Chalcones represent a group of compounds with interesting biological activities that are formed from an aldol condensation between a benzaldehyde and an acetophenone in the presence of NaOH as a catalyst. Although traditionally synthesized using aqueous sodium hydroxide in organic solvents, in this study three different chalcones were synthesized using a solventless procedure. The solvent-free synthesis of three chalcones was carried out by grinding the benzaldehyde (3-nitro, 4-methoxy, 4-chloro) and 4-methoxyacetophenone in the presence of solid sodium hydroxide with a mortar and pestle. Chalcones were obtained in high yields (76-86%), high purity, and shorter reaction time (within five minutes). The results seemed to indicate the success of the solvent-free aldol synthesis which is simple, highly efficient and eco-friendly. For comparison, the three chalcones were also synthesized by the traditional aldol condensation catalyzed by aqueous sodium hydroxide in ethanol afforded lower yield(62-72%) and required longer reaction time (62-75 min).
COPYRIGHT UiTM
xii
ABSTRAK
SINTESIS CHALKON BEBAS PELARUT DARIPADA KONDENSASI ALDOL DIMANGKINKAN OLEH PEPEJAL NATRIUM HIDROKSIDA (NaOH)
Chalkon mewakili satu kumpulan sebatian dengan aktiviti biologi yang menarik, hasil daripada kondensasi aldol di antara benzaldehid dan asetofenon dengan kehadiran natrium hidroksida (NaOH) sebagai pemangkin. Walaupun disintesis secara tradisional dengan menggunakan larutan NaOH, dalam kajian ini, tiga jenis chalkon berlainan telah disintesis melalui prosedur tanpa pelarut. Sintesis tanpa pelarut ketiga-tiga chalkondijalankan dengan menumbuk benzaldehyde (3-nitro, 4-metoksi, 4-kloro) dan 4-metoksiasetofenon bersama pepejal NaOH dengan menggunakan lesung. Semua chalkonterbentuk dengan peratusan hasil yang tinggi (76-86%), ketulenan yang tinggi dan masa tindak balas yang singkat (dalam masa lima minit). Keputusan membuktikan bahawa sintesis aldol tanpa pelarut adalah mudah, efisyen dan mesra alam. Sebagai perbandingan, tiga jenis chalkon lain telah disintesis menggunakan kaedah tradisional kondensasi aldol yang dimangkinkan oleh larutan NaOH dalam etanol. Peratusan hasil adalah rendah (62-72%) dan memerlukan masa tindak balas yang lama (62-75 min).
COPYRIGHT UiTM
1CHAPTER 1
INTRODUCTION
1.1 Background of study
Chalcone is an aromatic ketone that forms the central core for a variety of
important biological compounds. Other names for chalcone are
benzalacetophenone and phenyl styryl ketone. Chalcones show antibacterial,
antifungal, antitumor and anti-inflammatory properties. They are also
intermediates in the biosynthesis of flavonoids, which are substances widespread
in plants and with an array of biological activities. Chalcones are also
intermediates in the Auwers synthesis of flavones. Chalcone can be prepared by
an aldol condensation between a benzaldehyde and an acetophenone in the
presence of a catalyst. Aldol condensation ia also known as Claisen-Schmidt
rection.
The aldol condensation relies on the reactivity of a carbonyl group to build a
new carbon-carbon bond. The aldol reaction is one of the most powerful
methods available for forming a carbon-carbon bond. In this reaction, the
conjugate base of an aldehyde or ketone adds to the carbonyl group of another
aldehyde or ketone to give a -hydroxyaldehyde or -hydroxyketone product.
This is the intermediate product of the crossed-aldol reaction.
COPYRIGHT UiTM
2A crossed-aldol condensation leads to a number of different products unless one
of the carbonyl compounds involved cannot form an enolate ion which means
the compound has no -hydrogens. A good choice for such a compound is an
aromatic aldehyde. This is because only one enolate ion will form, which is from
other carbonyl compound. Once formed, the nucleophilic enolate ion attacks
carbonyl carbon to form a -hydroxycarbonyl product. The -hydroxycarbonyl
product then eliminates a molecule of water to form a conjugated system
composed of a double bond and the carbonyl group. The conjugation is extended
through two benzene rings as well, producing a very stable product,
benzalacetophenone.
There are several methods available for the synthesis of chalcones. The most
widely used is the base-catalyzed such as sodium hydroxide (NaOH), potassium
hydroxide (KOH), barium hydroxide Ba(OH)2 and lithium hydroxide
(LiOHH2O). The acid-catalyzed that had been used to synthesize chalcones
includes aluminum trichloride (AlCl3), dry HCl, boron trifluoride-etherate (BF3-
Et2O), titanium tetrachloride (TiCl4) and ruthenium trichloride (RuCl3) (Bhagat
et al., 2006)
In this project, the catalysts that were used are solid sodium hydroxide (NaOH)
and aqueous NaOH. The first solid NaOH method was introduced by Palleros in
2004.
COPYRIGHT UiTM
3Figure 1.1 shows the reaction of aldol condensation.
O
MeO
H
O
O
MeO
XX
+
Substituted benzaldehyde4-methoxyacetophenoneTrans-chalcone
NaOH
X = -NO2, OCH3, Cl
Figure 1.1 The reaction scheme of aldol condensation.
COPYRIGHT UiTM
41.1.1 Mechanism of aldol condensation
Figure 1.2 shows the mechanism for the base-catalyzed aldol condensation
between 4-methoxyacetophenone and 4-chlorobenzaldehyde which involves the
following steps.
Step 1: Formation of enolate ion
First is an acid-base reaction. Hydroxide functions as a base and removes an
acidic -hydrogen giving a reactive enolate.
Step 2: Alkoxide formation (nucleophilic addition)
The nucleophilic enolate attacks the carbonyl carbon of 4-chlorobenzaldehyde in
a nucleophilic addition process giving an intermediate alkoxide.
Step 3: Protonation of alkoxide
The alkoxide deprotonates a water molecule producing a hydroxide ion and a -
hydroxyketone, the aldol product.
Step 4: Dehydration
The hydroxide acts as a base and removes an acidic -hydrogen giving the
reactive enolates. The electrons associated with a negative charge of the enolate
are used to form a carbon-carbon double bond (C=C) and displace a leaving
group, regenerating the hydroxide giving the final product, the conjugated
ketone.
COPYRIGHT UiTM
5H3CO C
O
CH2
H
OH H3CO C
O
CH2
Cl C
O
H + C OCH3H3C
O
Formation of enolate ion
Alkoxide formation (nucleophilic addition)
4-methoxyacetophenone
4-chlorobenzaldehyde
Cl CH
O
CH
C
O
OCH3
Cl CH
O
CH
C
O
OCH3
HO H
Protonation of alkoxide
Cl CH
OH
CH
C
O
OCH3
H
Cl CH
OH
CH
C
O
OCH3
H
OH
Dehydration
H
H
CH
CH
C
O
OCH3Cl
Step 1:
Step 2:
Step 4:
Step 3:
Figure 1.2 Mechanism of reaction using NaOH catalyst.
COPYRIGHT UiTM
61.2 Problem statement
Green chemistry is a term coined in the late 1980s to indicate the design and
use of chemical processes that reduce or eliminate the use and generation of
chemicals hazardous to the environment. More simply stated, it means that one
does a reaction on a small scale and uses safer chemicals, thus producing less
hazardous waste. The aldol synthesis of chalcones is considered a green
experiment because it is carried out without solvent. Instead, the benzaldehyde,
acetophenone, and sodium hydroxide are mixed in a mortar and pestle for a few
minutes to produce the chalcone. The product is washed with a little of water,
and if necessary a small amount of it is recrystallized from ethanol. There has
been tremendous interest in the application of solvent free aldol and crossed-
aldol reactions which are employed for synthesis of carbonyl compounds due to
the operational simplicity, simple work-up, high yields and eco-friendly nature.
The condensation of ketones with aldehydes is of special interest and the
crossed-aldol condensation is an effective pathway for those compounds
preparations. However the traditional base-catalyzed reactions suffer from the
reverse reaction and self condensation of starting molecules (Palleros, 2004)
COPYRIGHT UiTM
71.3 Significance of study
Chalcones are the main precursor for the biosynthesis of flavonoids, which are
frequent components of the human diet. Licochalcone A isolated from the roots
of Glycyrrhiza inflata (licorice) has in vitro and in vivo antimalarial and
antileishmanial activity. 3-Methoxy-4-hydroxyloncocarpin isolated from the
roots of Lonchocarpus utilis inhibits NADH:ubiquinone oxidoreductase activity
and synthetic chalcones such as 2,4-dimethoxy-4-allyloxychalcone and 2,4-
dimethoxy-4-butoxychalcone had been reported as antileishmanial agents.
Recent studies on biological evaluation of chalcones revealed some to be anti-
cancer, anti-inflammatory, antimitotic, anti-tubercular, cardiovascular, cell
differentiation inducing, nitric oxide regulation modulatory and anti-
hyperglycemic agents (Narender et al., 2007)
1.4 Objectives of study
1. To synthesize chalcones using two different catalysts; solid NaOH and
aqueous NaOH in ethanol;
2. To explore the feasibility and effectiveness of using solid NaOH as catalyst
in chalcone synthesis, in place of aqueous NaOH;
3. To characterize chalcones using NMR and IR spectrometry.
COPYRIGHT UiTM
8CHAPTER 2
LITERATURE REVIEW
2.1 Previous studies on the synthesis of chalcone
2.1.1 LiOHH2O as a novel dual activation catalyst for highly efficient and easy synthesis of 1,3-diaryl-2-propenones by Claisen-Schmidt condenation under mild conditions
According to Bhagat et al. (2006), commercially available LiOHH2O was found
to be a highly efficient dual catalyst for Claisen-Schmidt condensation of
various aryl methyl ketones with aryl/heteroaryl aldehydes by providing an easy
synthesis of 1,3-diaryl-2-propenones under mild conditions. The reactions were
carried out at room temperature and in short times affording high yields.
Excellent chemoselectivity was observed with carbonyl substrate bearing
halogen atom and nitro group without any competitive aromatic nucleophilic
substitution. The resultant chalcones did not undergo Michael addition with the
ketone enolate. The rate of ClaisenSchmidt condensation was found to be
dependent on the steric and electronic factors of the carbonyl substrates. In this
study, they carried out the ClaisenSchmidt condensation of 4-
methoxyacetophenone with 4-methoxybenzaldehyde in the presence of
LiOHH2O (10 mol%) and they observed that a quantitative formation (GCMS)
of 4,4-dimethoxychalcone took place after 45 min in ethanol. The Claisen
Schmidt condensation of various aryl methyl ketones with different aromatic and
heteroaromatic aldehydes was carried out in the presence of LiOHH2O. The
results are shown in Table 2.1. Excellent results were obtained in each case. The
COPYRIGHT UiTM
9reactions were carried out in short times (2 min4 h) and were monitored by
GCMS, IR and TLC. No competitive side reactions such as product
decomposition, aromatic nucleophilic substitution and Michael addition were
observed (GCMS). In general, the reactions were clean and the isolated products
were obtained in pure form (IR, NMR and GCMS) without further purification.
Table 2.1 LiOHH2O-catalyzed Claisen-Schmidt reaction of Ar1COCH3 with Ar
2CHO.
Entry Ar1 Ar2 Time (min) Yield (%)
1 C6H5 C6H5 5 85
2 C6H5 4-OMe-C6H4 15 88
3 C6H5 4-Cl-C6H4 15 90
4 C6H5 4-NO2-C6H4 2 80
5 4-OMe-C6H4 C6H5 15 80
6 4-OMe-C6H4 4-Cl-C6H4 30 90
7 4-OMe-C6H4 4-OMe-C6H4 45 96
8 4-OMe-C6H4 4-NO2-C6H4 2 95
9 4-NO2-C6H4 C6H5 1 82
10 4-NO2-C6H4 4-OMe-C6H4 1 95
11 4-Cl-C6H4 4-OMe-C6H4 15 73
2.1.2 Synthesis of chalcones using boron trifluoride-etherate (BF3-Et2O)
According to T. Narender and K. Papi Reddy (2007), synthesis of chalcones
catalyzes by boron trifluoride-etherate is a simple and highly efficient method.
They synthesized several chalcones by reacting various substituted
acetophenones and substituted benzaldehydes using 0.5 equiv of BF3-Et2O. Most
of the products were formed within 15-150 min and the trans double bond was
COPYRIGHT UiTM
10
obtained exclusively. The reaction mixture was washed with water to remove
BF3 complexes, concentrated and recrystallized to give pure chalcones in high
yields without column chromatography in most cases. In aqueous KOH or
NaOH assisted reactions, reaction times were much longer (2-4 days), with high
probability of side reactions such as the Cannizzaro reaction. By using BF3-
Et2O, they obtained chalcones exclusively, within 15-150 min and no side
reactions were observed. They concluded that their method has many advantages
over existing methods such as high yields, simple work-up, short reaction times,
no side reactions, no column-chromatography in most cases, a convenient source
of BF3.
COPYRIGHT UiTM
11
Table 2.2 Synthetic chalcones prepared using BF3Et2O.
EntryKetone Aldehyde Chalcone (product)
Time (min)
Yield (%)
Mp (C)
1 30 87 148150
2 15 90 5657
3 150 80 196198
4 150 93 187189
5 60 92 192194
6 150 90 194196
7 150 75 134136
COPYRIGHT UiTM
Recommended