A Thesis Submitted By Talal Ahmed Awad Mohammed B.Sc.(Hons

A Thesis Submitted By
Talal Ahmed Awad Mohammed
B.Sc.(Hons)
For The M.Sc. Degree in Chemistry
Department of Chemistry
Faculty of Science
University of Khartoum
June 2005
DEDICATION
™ To the Memory of My Mother
™ To My Brothers, Friends, and all whom I love
Acknowladgement
I wish to express my deepest gratitude to my supervisor
Dr. Christina Y. Ishak for her indispensable help, encouragement and
direction throughout the course of this work.
My sincere thanks to Dr. Mohammed Osman El-Faki for his guidance,
continuous encouragement, and for his advices.
My thanks and appreciations are extended to Dr. Huda Henry Ryad, and
Dr. Alex Yong for their help in running the 1H NMR, and Mass Sepc ,
under the name of Professor Thomas T. Tidwell (Department of
Chemistry, University of Toronto).
My thanks are extended to Dishman Pharmaceuticals and Chemicals Co.
Ltd. (India) for their help in supplying with free samples of phase
transfer catalyst (PTC).
Thanks are also due to Mr. Ali M. Shareif and Mr Omer El-tyeb for
their help. My thanks are also extended to Mr. Saad for his generous
help in running the UV and IR spectra for our Samples.
Abstract
A number of cyclohexenone derivatives have been prepared through
addition of chalcones to ethyl acetoacetate.
Chalcones were initially reacted with ethyl β-methoxycrotonate ester
under phase transfer catalysis (PTC) conditions. Tetrabutyl ammonium
iodide was used as phase transfer catalyst, 50% sodium hydroxide as an
aqueous phase, and toluene was served as an organic phase.
Reactions of the same chalcones with ethyl acetoacetate under PTC
conditions were carried out, in this case tetrabutyl ammoniumhydrogen
sulphate was used as PTC catalyst, 10 % sodium hydroxide as an
aqueous phase, and toluene as an organic phase.
Reaction products were intensively investigated using various
spectroscopic techniques; all results were in agreement with the
proposed structure and confirmed the cyclohexenone compounds.
‫ﻣﻠﺨﺺ اﻟﺒﺤﺚ‬
‫ﰎ ﲢﻀﲑ ﻋﺪﺩ ﻣﻦ ﻣﺮﻛﺒﺎﺕ ﺍﳍﻴﻜﺴﻴﻨﻮﻥ ﺍﳊﻠﻘﻴﺔ ﻋﻦ ﻃﺮﻳﻖ ﺇﺿﺎﻓﺔ ﻣﺮﻛﺒﺎﺕ ﺍﳉﺎﻟﻜﻮﻥ‬
‫ﺍﱄ ﺍﺳﺘﺮ ﺍﺳﻴﺘﻮﺍﺳﻴﺘﺎﺕ ﺍﻹﻳﺜﻴﻞ‪.‬‬
‫ﻓﻮﻋﻠﺖ ﺍﳉﺎﻟﻜﻮﻧﺎﺕ ﺃﻭ ﹰﻻ ﻣﻊ ﺍﺳﺘﺮ ﺑﻴﺘﺎ ﻣﻴﺜﻮﻛﺴﻲ ﻛﺮﻭﺗﻮﻧﺎﺕ ﺍﻹﻳﺜﻴﻞ ﲢﺖ ﻇﺮﻭﻑ ﲢﻔﻴﺰ ﺗﺒﺎﺩﻝ‬
‫ﺍﻟﻄﻮﺭ‪ .‬ﺍﺳﺘﺨﺪﻡ ﺭﺑﺎﻋﻲ ﺑﻴﻮﺗﻴﻞ ﻳﻮﺩﻳﺪ ﺍﻷﻣﻮﻧﻴﻢ ﻛﺤﺎﻓﺰ ﻟﺘﺒﺎﺩﻝ ﺍﻟﻄﻮﺭ‪ ،‬ﻛﻤﺎ ﺍﺳﺘﺨﺪﻡ‬
‫ﻫﻴﺪﺭﻭﻛﺴﻴﺪ ﺍﻟﺼﻮﺩﻳﻮﻡ ‪ % ٥٠‬ﻛﻄﻮﺭ ﻣﺎﺋﻲ‪ ،‬ﻭﺍﺳﺘﺨﺪﻡ ﺍﻟﺘﻮﻟﻮﻳﻦ ﻛﻄﻮﺭ ﻋﻀﻮﻱ‪.‬‬
‫ﻓﻮﻋﻠﺖ ﻧﻔﺲ ﺍﳉﺎﻟﻜﻮﻧﺎﺕ ﻣﻊ ﺍﺳﺘﺮ ﺍﺳﻴﺘﻮﺍﺳﻴﺘﺎﺕ ﺍﻹﻳﺜﻴﻞ ﲢﺖ ﻇﺮﻭﻑ ﲢﻔﻴﺰ ﺗﺒﺎﺩﻝ ﺍﻟﻄﻮﺭ ﻭ ﰲ‬
‫ﻫﺬﻩ ﺍﳊﺎﻟﺔ ﺍﺳﺘﺨﺪﻡ ﺭﺑﺎﻋﻲ ﺑﻴﻮﺗﻴﻞ ﻛﱪﻳﺘﺎﺕ ﺍﻷﻣﻮﻧﻴﻢ ﺍﳍﻴﺪﺭﻭﺟﻴﻨﻴﺔ ﻛﺤﺎﻓﺰ ﻟﺘﺒﺎﺩﻝ ﺍﻟﻄﻮﺭ‪ ،‬ﻛﻤﺎ‬
‫ﺍﺳﺘﺨﺪﻡ ﻫﻴﺪﺭﻭﻛﺴﻴﺪ ﺍﻟﺼﻮﺩﻳﻮﻡ ‪ % ١٠‬ﻛﻄﻮﺭ ﻣﺎﺋﻲ‪ ،‬ﻭﺍﺳﺘﺨﺪﻡ ﺍﻟﺘﻮﻟﻮﻳﻦ ﻛﻄﻮﺭ ﻋﻀﻮﻱ‪.‬‬
‫ﰎ ﲢﻠﻴﻞ ﻧﻮﺍﺗﺞ ﺍﻟﺘﻔﺎﻋﻞ ﺑﺎﺳﺘﺨﺪﺍﻡ ﺗﻘﻨﻴﺎﺕ ﺍﻟﺘﺤﻠﻴﻞ ﺍﻟﻄﻴﻔﻲ ﺍﳌﺨﺘﻠﻔﺔ‪ .‬ﻛﻞ ﺍﻟﻨﻮﺍﺗﺞ ﺗﻮﺍﻓﻘﺖ ﻣﻊ‬
‫ﺍﻟﺒﻨﻴﺔ ﺍﻟﺘﺮﻛﻴﺒﻴﺔ ﺍﳌﻘﺘﺮﺣﺔ ﻭﺃﻛﺪﺕ ﺃ‪‬ﺎ ﳌﺮﻛﻴﺎﺕ ﺍﳍﻴﻜﺴﻴﻨﻮﻥ ﺍﳊﻠﻘﻴﺔ‪.‬‬
Contents
Dedication…………………………………………………………………………….
(I)
Acknowledgement……………………………………………………………………
(II)
Abstract
(English)…………………………………………………………………...(III)
Abstract(Arabic)…………………………………………………………………...
(IV)
List of contents………………………………………………………………………
(V)
List
of
Tables………………………………………………………………………...(VI)
List of figures………………………………………………………………………
(VII)
Chapter (1)
1.
Introduction…………………………………………………………... 1
1.1.
Introduction
to
Phase
catalysis……………………………………… 2
1.1.1. Historical
Background………………………………………………………… 3
Transfer
1.1.2.
Principles
of
PTC……………………………………………………………. 4
1.1.3.
Ion
Pairs………………………………………………………………………. 8
1.1.4.
Extraction
of
ion
pair
from
aqueous
solution………………………………… 9
1.1.5
Factors affecting PTCreactions………………………………………………
10
1.1.5.1. Solvent……………………………………………………………………….
10
1.1.5.2. Salting out-effect……………………………………………………………
12
1.1.5.3. The onium cation……………………………………………………………
13
1.1.5.4. The Anion…………………………………………………………………...
14
1.1.6.
Phase Transfer Catalysts……………………………………………………
14
1.1.6.1. Quaternary Ammonium Salts……………………………………………….
15
1.1.6.2. Quaternary Phosphonium and Arsonium compounds………………………
16
1.1.6.3. Crown ethers and Cryptates…………………………………………………
16
1.1.6.4.
Chiral Catalysts…………………………………………………………….
17
1.1.6.5.
Amine
Catalysis…………………………………………………………….. 19
1.1.7.
Catalyst Stability…………………………………………………………...
19
1.1.8.
The Mechanism of PTC reactions………………………………………….
22
1.1.8.1.
The Starks Extraction Mechanism………………………………………….
22
1.1.8.2.
The Makosza Interfacial Mechanism………………………………………
24
1.1.8.3.
Liotta Modification of the Makosza interfacial mechanism………………
27
1.1.9.
Advantages of PTC over conventional techniques………………………...
28
1.2.
The chemistry of chalcones………………………………………………..
30
1.2.1.
30
α,β-unsaturated carbonyl compounds……………………………………..
1.2.2.
Occurrence of chalcones…………………………………………………...
31
1.2.3.
Synthesis of chalcones…………………………………………………….
33
1.2.4.
Reactions of chalcones……………………………………………………
37
1.2.4.1.
Reaction with Ethyl methylmalonate……………………………………..
38
1.2.4.2.
Reaction with Ethylcyanoacetate…………………………………………
39
1.2.4.3.
Reaction with Ethyl acetoacetate…………………………………………
40
1.2.4.4.
Reaction
with
Ethyl
β-methoxy
crotonate………………………………… 41
1.2.4.5.
Synthesis of Flavanones………………………………………………….
42
1.2.4.6.
Synthesis of substituted Pyridones………………………………………..
43
1.2.4.7.
Synthesis of substituted 2-pyrazolines……………………………………
44
1.2.4.8.
45
Epoxidation of chalcones …………………………………………………
1.2.4.9.
Synthesis of 1,3-Diarylpropanes…………………………………………
46
1.2.4.10.
Photodimerization of chalcones…………………………………………..
47
1.2.4.11.
Reaction with organometalic compounds………………………………..
48
1.2.4.12.
Synthesis
of
fused
Pyrazoles
and
Isoxazoles
……………………………...49
1.2.4.13. Reactions of chalcones under PTC conditions……………………………
50
1.2.5.
Biological importance of chalcones………………………………………
54
1.3.
Aim of our work…………………………………………………………..
55
Chapter (2)
2.
Experimental and results……………………………………………..
57
2.1
Preparation of chalcones………………………………………………………
58
2.1.1. 1,3-Diphenyl-2-propen-1-one (Benzalacetophenone) (Ia)…………………...
58
2.1.2. 3-(4-methylphenyl)-1-phenylprop-2-en-1-one (Ib)…………………………...
59
2.1.3. 3-(4-methoxyphenyl)-1-phenylprop-2-en-1-one (Ic)…………………………
59
2.1.4. 3-(3-methylphenyl)-1-phenylprop-2-en-1-one (Id)…………………………...
60
2.1.5. 1-(4-bromophenyl)-3-phenylprop-2-en-1-one (Ie)……………………………
60
2.1.6. 1-(4-methylphenyl)-3-phenyl-2-propen-1-one (If)……………………………
61
2.1.7. 1-(4-nitrophenyl)-3-phenyl-2-propen-1-one (Ig)……………………………...
61
2.1.8. 3-(4-methylphenyl)-1-(4-nitrophenyl)prop-2-en-1-one (Ih)………………….
62
2.1.9. 3-(4-methoxyphenyl)-1-(4-nitrophenyl)prop-2-en-1-one (Ii)………………...
62
2.1.10. 3-(4-chlorophenyl)-1-(4-nitrophenyl)prop-2-en-1-one (Ij)…………………...
63
2.2.
Ethyl β-methoxycrotonate…………………………………………………….
67
2.3.
General procedure for the synthesis of 6-aroyl-3-methoxy-5-phenylcyclohex-2-en-1-one through the 50 % NaOH- catalized cyclocondensation of chalcones (Ia, Ib, Ic, and Id) with ethyl β-methoxycrotonate
in presence of tetrabutyl ammoniumiodide…………………………………..
67
2.4.
General procedure for the synthesis of 6-aroyl-3-methoxy-5-phenylcyclohex-2-en-1-one through the 10 % NaOH- catalized cyclocondensation of chalcones (Ia and If) with ethyl β-methoxycrotonate in presence
of ammoniumhydrogen-sulphate…………………………………………….
69
2.5.
General procedure for the synthesis of Ethyl 2-oxo-4,6-diarylcyclohex-3-ene-1-carboxylate through the 10 % NaOH- catalized cyclocondensation of chalcones (Ia-If) with ethyl acetoacetate in presence
of tetrabutyl ammoniumhydrogen sulphate…………………………………..
70
2.4.1. Ethyl 2-oxo-4,6-diphenylcyclohex-3-ene-1-carboxylate (IIa)………………...
70
2.4.2. Ethyl
6-(4-methylphenyl)-2-oxo-4-phenylcyclohex-3-ene-1-carboxylate
(IIb)
..71
2.4.3. Ethyl 6-(4-methoxyphenyl)-2-oxo-4-phenylcyclohe ene-1-carboxylate (IIc) .. 72
2.4.4. Ethyl
6-(3-methylphenyl)-2-oxo-4-phenylcyclohex-3-ene-1-carboxylate
(IId)……72
2.4.5. Ethyl 4-(4-bromophenyl)-2-oxo-6-phenylcyclohex-3-ene-1-carboxylate(IIe)…...
73
2.4.6. Ethyl 4-(4-methylphenyl)-2-oxo-6-phenylcyclohex-3-ene-1-carboxylate (IIf)….
73
Chapter (3)
3.
Discussion 81
3.1.
Preparation of chalcones from the reaction of acetophenones and benzaldehydes.. 82
3.2.
Reaction of ethyl acetoacetate with trimethyl orthoformate………………………...
87
3.2.1. Mechanism of the reaction of ethyl acetoacetate with trimethyl orthoformate……... 87
3.3.
Reaction of chalcones with ethyl β-methoxy crotonate in presence of 50% sodium
hydroxide and tetrabutyl ammoniumiodide (PTC)……………………………….… 88
3.4.
Reaction of chalcones with ethyl acetoacetate in presence of 10% sodium hydroxide
and tetrabutyl ammoniumhydrogensulphate as PTC…………………………….…
91
3.4.1. General Mechanism of the reaction of chalcones with ethyl acetoacetate under
PTC conditions……………………………………………………………………. 104
3.4.2. Comparison between the mechanism of the addition of Ethyl β-methoxy
crotonate and Ethyl acetoacetate to chalcones………………………………………
105
3.4.3. The mechanism of the reaction of chalcones with ethyl acetoacetate under phase
transfer catalysis conditions, applying the Liotta interfacial model…………….…
107
4.
References…………………………………………………………… 111
List of Tables
1- Table (1) Physical properties of chalcones (Ia-Ij)…………………………………
64
2- Table (2) Properties of compounds (IIa-IId)………………………………………
68
3- Table (3) Properties of Cyclohexenones (IIa-IIf)…………………………………
75
4- Table (4) 1H NMR Data of Compound (IIb)………………………………………
93
5- Table (5) Comparison between the mechanism of the addition of Ethyl - βmethoxycrotonate and ethyl acetoacetate to chalcones………………...
106
List of Figures
Figure (1), The 1HNMR spectrum for chalcone (Ia)…………………………………
65
Figure (2), The Mass spectrum for chalcone (Ia)…………………………………….
65
Figure (3), The 1HNMR spectrum for chalcone (Id)……………………………...…
66
Figure (4), The 1HNMR spectrum for chalcone (Id)…………………………………
66
Figure (5), The IR spectrum of compound (IIa)……………………………………...
76
Figure (6), The IR spectrum of compound (IIb)……………………………………...
76
Figure (7), The IR spectrum of compound (IIc)…………………………………...…
77
Figure (8), The IR spectrum of compound (IId)……………………………………..
77
Figure (9), The IR spectrum of compound (IIe)……………………………………...
78
Figure (10), The IR spectrum of compound (IIf)…………………………………….
78
Figure (11),The 1H NMR spectrum of compound (IIb)……………………………...
79
Figure (12), The MS spectrum of compound (IIb)…………………………………...
79
Figure (13), Fragmentation Pattern of compound (Ia)……………………………….
85
Figure (14), Fragmentation Pattern of compound (Id)……………………………….
86
Figure (15), The fragmentation patterns of compound (IIb)…………………………
95
Figure (16), The electronic 1H NMR of compound (IIa)…………………………….
97
Figure (17), The electronic 1H NMR of compound (IIb)…………………………….
98
Figure (18), The electronic 1H NMR of compound (IIc)…………………………….
99
Figure (19), The electronic 1H NMR of compound (IId)…………………………...
100
Figure (20), The electronic 1H NMR of compound (IIe)…………………………...
101
Figure (21), The electronic 1H NMR of compound (IIf)……………………………
102
Chapter (1)
INTRODUCTION
1.
1.1.
Introduction
Phase Transfer Catalysis:
Phase transfer catalysis (PTC) technique has appeared as a new
method developed for overcoming problems of mutual solubility as well
as offering the potential for activation of anions1. It is concerned with
conversions between chemical species situated in different phases.
Common cases are reactions between salts dissolved in water or present
in the solid state, and substance dissolved in organic media. Without a
catalyst such reactions are usually slow and ineffective or do not occur
at all. In other words PTC is the extraction of cations even of neutral
molecules from one phase to another with the help of the catalyst 2.
Most problems are that the nucleophile is salt-like and water soluble and
the electrophile is organic-like and water insoluble. Before the
development of PTC technique these problems were solved by addition
of co-solvents or dipolar aprotic solvent to the reaction mixture, but both
have disadvantages, such as high boiling points, difficulty of removal
from reaction mixture, long purification time and they are more
expensive 1.
1.1.1. Historical Background :
Phase transfer catalysis is a relatively new field of chemistry that
originated in the work of three independent groups. M. Makosza, C. M.
Starks, and A. Brandstörm who laid the foundations in the mid to late
1960s2. PTC as known today originated in the work of Makosza and coworkers, which started in 1965 2. They began a systematic exploration
of alkylations and subsequently of other reactions in two – phase
systems containing mainly concentrated aqueous alkali metal hydroxide.
The descriptive terms used by them were “catalytic two phase
reactions”, “catalytic alkylation of anions”, “catalytic generation of
carbenes”, etc. Makosza prefered those terms even now, for mechanistic
reasons in many cases. That work became more widely known in 1969 3
for his dichlorocarbene generation discovery. Reactions involving phase
transfer phenomena were performed even earlier, and a considerable
number of such reactions were buried in the older literature, and
especially in patents. The oldest one presently known being from 1913.
Some of the original authors entered the field more or less incidentally
and did not apparently reflect on the mechanisms involved in such
catalytic reactions 2.
Brandstörm started from a more physicochemical and analytical point of
view. His first paper appeared in 1969 4 , followed by an early review in
1970. Brandstörm used the term “extractive alkylation” for alkylations
in a two phase mixture in the presence of molar amount of catalyst. The
term “phase transfer catalysis” was coined by Starks and first used in
patents in 19682. The recognition of the new technique, and the term
phase transfer catalysis probably originated from Starks 1971 paper 5.
For the first time the scope of the method was clearly outlined, and
extended beyond the original applications i.e. alkylation and carbene
generation. Furthermore, a unifying mechanistic concept for all of those
reactions was proposed. Thus provided an enormous impact to the
development of the field. Since then a flood of papers had appeared
expanding PTC to new type of reactions 2.
1.1.2.
Principles of PTC :
PTC methodology is applicable to a great variety of reactions in
which inorganic and organic anions and also carbenes react with organic
substrates. It consists in the use of heterogeneous two phase systems,
one phase being a reservoir of reacting anions or base for generation of
organic anions, whereas organic reactants and catalyst (source of
lipophilic cations) are located in the second phase (organic phase) 6.
The reacting anions are continuously introduced into the organic phase
in the form of lipophilic ion pair with lipophilic cations supplied by the
catalyst.
Reactions to which PTC is applicable can be divided into two major
categories:
1-Reactions of anions that are available as salts, for example sodium
cyanide, sodium azide, sodium acetate, etc.
2- Reactions of anions that should be generated in situ, such as
alkoxides, phenolates, N-anions of amides or heterocycles, etc, and
particularly carbanions. In the former case the salts are used as aqueous
solutions or in the form of powdered solid, whereas the organic phase
contains organic reactants. Since the phases are mutually immiscible,
the reaction doesn’t proceed unless the catalyst – most often tetraalkyl
ammonium cations (Q+X-) serves this purpose - is present. The catalyst
transfers continuously reacting anions into the organic phase in the form
of a lipophilic ion-pair produced according to the ion exchange
equilibrium, scheme (1-1), (Ia), where they react further, for example,
with alkyl halides affording nucleophlic substitution, scheme (1-1), (Ib).
IaIb-
Na+ Y-aq +
Q+ Y-org
+
Q+ X-org
R-X
Na+ X- aq
R-Y
+ Q+ Y-org
+
Q+ X-org
Scheme (1-1)
A variety of other reactions with participation of inorganic anions such
as addition, reduction, oxidation, etc. is efficiently executed using these
methodologies 6.
Phase transfer catalyzed reactions of organic anions are
mechanistically more complicated. In this case the inorganic phase
contains base such as concentrated aqueous or solid sodium hydroxide
or potassium hydroxide or solid potassium carbonate, whereas the
organic phase contains the anion precursor, an electrophilic reactant and
eventually a solvent.
Alkylation of phenyl acetonitrile via its carbanion with alkyl halide
exemplifies application of this methodology and helps to describe how
the system operates. No reaction occurs when a mixture of phenyl
acetonitrile and alkyl halide and 50% aqueous sodium hydroxide is
vigorously stirred. Upon introduction of tetraalkyl ammonium halide in
a catalytic amount, usually 1% molar, an exothermic reaction produces
phenylalkylacetonitrile scheme (1-2).
PhCH2CN org
+
+
+ Na OH aq
PhCHCNNa int
+
H2O
+
PhCHCNQ+org
+
Na X aq
+
PhCHCNNa int + Q X org
PhCHCNQ+org +
R
Ph
X
R
CHCN org
+
+
+ Q X org
Scheme (1-2)
In a similar way numerous other (CH) acids, alcohols and NH acids are
efficiently alkylated as exemplified with N-alkylation of indol,
scheme (1-3).
+
+
N
H
R
X
QX
NaOH aq
N
R
Scheme (3)
On other basis of numerous reports6 it is evident that phase
transfer catalysis is the most efficient way for generation and reaction of
these and similar intermediates. This methodology is efficiently
applicable to a plethora of other base–induced reactions of organic
anions particularly Michael reaction, generation and reactions of
sulfonium ylides etc 6.
1.1.3.
Ion Pairs:
PTC reactions are usually carried out in aprotic solvents of low
polarity. Their dielectric constants ranges from 8.9 (methylene chloride)
to 4.7 (chloroform), and 4.2 (diethyl ether) to 2.3 (benzene) and 1.9
(hexane). Although the solubility of typical inorganic salts in these
solvents is negligible, organic quaternary ammonium, phosphonium and
other onium salts, as well as organically masked alkali metal salts are
often quite soluble, especially in methylene chloride, and chloroform. In
these solvents the concentration of free ions is negligible, ion pair being
the dominant species. Since interaction between the ion pairs and
solvent molecules are weak, reaction with electrophiles in organic
medium is fast2, and some weak nucleophiles
(eg acetate) appear
strong. From both physical and kinetic evidence it is thought that two
types of ion pair exist, for which various names have been given2:
1- Loose, extracted or solvent separated ion pair.
2- Tight, internal, intimate or contact ion pair.
A solvated ion can approach its counter ion without difficulty up to the
point where the two solvation shells touch, thus forming a loose ion
pair. If the two ions come even closer together and squeeze out of the
solvent molecules, separating them, a contact ion pair is formed 2.
1.1.4.
Extraction of ion pair from aqueous solution
The most simple two phase (water/organic) substitution reaction
between the anion of a salt and an organic substance involves a number
of equilibria:
a- Overall reaction:
Na +(aq) Y -(aq) + RX (org)
[Q+X-]
Na +(aq) X -(aq) + RY (org)
The overall equation can be broken down into two contributions:
b- Chemical reaction in the organic phase
RX (org) +
Na +(aq) Y -(aq)
RY (org)
+ [Q+X-] (org)
c- Extraction equilibria:
[Q+X-] (org) + Na +(aq) + Y -(aq)
[Q+Y-] (org) + Na +(aq) + X -(aq)
Information concerning the factors determining equation (c) may be
obtained by considering the following simple extractions:
d-
Q+ (aq) + X -(aq)
[Q+X-] (org)
e-
Q+ (aq) + Y -(aq)
[Q+Y-] (org)
The latter equation is essential in order to understand all PTC.
Fortunately, experimental methods for investigation of these extractions
have been developed, and many numerical values for the development
of analytical processes have been determined 2.
1.1.5
Factors affecting PTC reactions
1.1.5.1.
Solvent:
Brandstörm2 has determined a large number of apparent
extraction constants between water and various solvents for the standard
quaternary ammonium salt, tetrabutylammonium salts.
A solvent for PTC work should be immiscible with water because
otherwise highly hydrated (Shielded) ion pairs of low reactivity are
present. In order to avoid hydrogen bonding to the ion pair anion, the
solvent should be also aprotic. Inspection of the data collected by
Brandstörm from the extraction constants shows that, solvents such as:
C2H5COCH3 , CH3NO2 , n-C3H7NO2 , ClCH2COOC2H5 , NCCH2COOCH3 , n-C4H9OH , CH3CHOH-C2H5 , ClCH2CN , Cl3C-CN ,
CH2=CHCN , are generally unsuitable for PTC work 2, some of them
are partially miscible with water, other are too reactive and would
interfere in many processes.
Solvents such as:
CH2Cl2 , CHCl3 , CDCl3 , CCl4 , CH3CHCl2 , ClCH2CH2Cl, ClCH2CHCl2,
Cl2CH-CHCl2, Cl2CH-CCl3, n-C3H7Cl show large variation
of extraction capability with seemingly small structural changes.
Specific interaction between solvents and solute must play a role even in
these supposedly non solvating solvents. What is more important from a
practical point of view is that the low boiling, chlorinated hydrocarbons
(chloroform, methylene chloride and to a lesser extent 1,3dichloroethane) appear to be the best solvents, because they exhibit a
high extraction capability, also they are cheep and easily removed. Such
solvents give rise to side chain reactions but most PTC reactions are also
fast that this is not a big danger2.
1.1.5.2.
Salting out-effect:
Extraction constants are not only influenced by the solvent
system, but also by foreign salts. Most extraction constants found in the
literature, were determined at constant ionic strength. There is however,
a very salting-out effect.
Brandstörm2 examined the conditional extraction constants of N+Bu4Cl
and N+Bu4Br between water and methylene chloride in presence of
potassium carbonate. Linear parallel dependences on molarity of
potassium carbonate were found. There is no competitive extraction of
carbonate or hydrogen carbonate observed. So a genuine salting-out
must occur. Two moles of potassium carbonate per liter increased the
extraction constant about a thousandfold. Thus salting-out effect is of
great importance for PTC especially with concentrated
50 % aqueous
sodium hydroxide. In this medium almost all quaternary ammonium
salts are sparingly soluble and easily extracted. In addition it acts as
desiccant for organic phase.
Solvents miscible with water (acetonitrile or THF) can be used if foreign
salts make two-phase system possible. Thus the action of the salt is
twofold : it separate the organic solvent and salt-out the ion pair 2.
1.1.5.3.
The onium cation:
There is a relation between cation size and extraction constant.
This is the important aspect for PTC work. It is obvious that any
increasing in the number of C atoms surrounding the central N atom of
the ammonium cation will increase their lipophilicity thus raising the
extraction constant EQX. For PTC purposes quaternary ammonium ions
are of special interest because they are less likely to interfere in
reactions.
The result of the work done by Gustavii
Czapkiewiz
2
2
and then by Tutaj and
is that the logarithm of extraction constants of
homologous series of quaternary ammonium salts rise by a more or less
constant factor of about 0.5 per added C atom, irrespective of the nature
nonpolar aprotic solvent and anion.
Similar general trends are observed with alkyltriphenyl phosphonium
and arsonium ions. Arsonium ions seems to be slightly more lipophilic.
An allyl residue makes a phosphonium ion more hydrophilic relative to
the n-propyl analogue. The following order of lipophilicity has also been
obtained 2 ;
+
+
+
+
+
+
Nhex4 >NPent4 > AsPh4 >N(iso-C5H11)4 >PbBu4 >NBu4
1.1.5.4.
The Anion:
Cliford and Irving
2
arrived at the following order of
extractabilities, going from the
lipophilic ion CLO4-
to the most
hydrophilic ion PO43– for chloroform/water system.
ClO4 - >>CLO3->NO3 ->Cl->HSO٤->OH- >SO4 2->CO3 >PO4 3Other results are 2 :
For water/CH2Cl2 or ClCH2–CH2Cl :
ClO4 - >SCN - >I - >CLO3- >NO3 - >Br ->BrO3 - >Cl For water /xylene:
ClO4 - >SCN - >I - >NO3 - >Br ->Cl –
For water/toluene or water/ CH2Cl2 :
ClO4 - >I - >CLO3- >NO3 - >C6H5CO2 - >Br ->Cl - >HSO٤- >HCO3 >CH3CO2 - >F - >OH–
Finally Makosza and co-worker 2 included cyanide:
I - >Br - >CN - >Cl - >OH – >F - >SO4 2-
1.1.6.
Phase Transfer Catalysts :
A phase transfer catalyst must be lipophilic and either charge
diffused or with buried charged cation capable of paring with an anion 1.
Numerous
quaternary
ammonium,
phosphonium,
arsonium,
antimonium, bismuthonium, and tertiary sulfonium salts have been
claimed as catalysts. In practice, however, only a limited number of
ammonium and phosphonium salts are widely used
1.1.6.1.
Quaternary Ammonium Salts :
these are charged lipophilic cations. Not all ammonium cations
serves
effectively as phase transfer catalyst, tetramethylammonium
cation is not lipophilic enough to afford a significant reaction in
nucleophilic two–phase system 2.
In general the more the number of carbon atom present, the more
effective is the catalyst7,8. The most commonly used ammonium
catalysts are: Tetrabutylammonium bisulphate (bromide or iodide),
Trioctylmethylammonium chloride (Aliquat 336 and Adogen 464), and
Benzyltriethylammonium chloride (BTEAC) or (TEBAC), the latter
catalyst was first popularized by Makosza in his extensive alkylation
and carbene studies 3. It has been widely adopted because the pure
compound is readily available and because there is considerable
precedent for its use.
1.1.6.2.
Quaternary Phosphonium and Arsonium compounds :
In addition to quaternary ammonium salts both quaternary
phosphonium and arsonium compounds have been used as phase
transfer catalysts. The use of quaternary phosphonium compounds is
more widespread than the use of arsonium compounds because of their
availability. Although quaternary phosphonium compounds tend to be
somewhat more expensive than the corresponding ammonium
compounds, they have the advantage of being more stable than the
latter 1.
1.1.6.3.
Crown ethers and Cryptates:
Other catalysts are the crown ethers and cryptates 9. Crowns are
defined as macroheterocycles usually containing the basic unit
(-Y-CH2-CH2)n where Y is O,S, or N10. Crown ethers and cryptates 1, 2,
3, 4, and 5, can complex with an alkali metal cation and solvate it to
provide a lipophilic exterior which can be solvated by the organic
medium. A crown complex between a potassium halide and 18–crown–
6 is illustrated below, scheme (1-4):
O
O
O
O
O
O
K+
+ K+ X O
O
O
X
-
O
O
O
(1) 18-crown-6
O
O
O
O
O
O
O
O
O
O
O
O
(2) Dibenzo-18-crown-6
(3) dicyclohexano-18-crown-6
O
O
O
N
O
O
O
O
O
O
N
O
N
N
O
(4) [2.2.2]-Cryptate
(5) Open-chained polyethers
Scheme (1-4)
1.1.6.4.
Chiral Catalysts :
Catalysts derived from Cinchona alkaloids 11 (6) and (7) and from
ephedrines 11 (8) and (9) in which chiral centers are located both on the
quaternary nitrogen and on carbon framework, have been used to
achieve phase transfer catalysis reactions. These catalyst work in the
same manner as their nonchiral counterparts in that they associate with
the anion and carry it across the aqueous/organic interface where the
anion react with the substrate. This association between the anion and
the chiral catalyst allow for reaction on only one face of the anion and
therefore a non-racimic product may be formed 12.
(6)
(7)
N-Benzylcinchoninium chloride
(8)
(+)-Ephedirine Derived Catalysts
N-Benzylcinchonidinium chloride
(9)
(-)-Ephedirine Derived Catalysts
1.1.6.5.
Amine Catalysis :
It has been known for many years that amines will catalyze
nucleophilic substitution reactions. The alkylation of Phenylacetonitrile
with benzyl chloride was shown13 to be catalyzed by triethylamine. Also
It has been found that
13
the function of triethylamine in the reaction
between benzylchloride and potassium acetate, scheme (1-5), is to form
benzyltriethylammonium chloride in situ and this substance acts as
phase transfer catalyst 1٣.
Ph CH2 –N(C2H5)3 (which is Q+Cl – )
Ph –CH2 –Cl + N(C2H5)3
Ph –CH2 –Cl + KOAc
Q+Cl –
Ph –CH2 –OAc + KCl
Scheme (1-5)
1.1.7.
Catalyst Stability:
A factor which contributes to effective selection of a catalyst and
may affect many other conditions for phase transfer catalysis is the
catalyst stability. There are two major mechanisms by which quaternary
onium salts decompose : nucleophilic displacement and Hoffmann
elimination.
Nucleophilic displacement reactions are of great concern when the
negative counter ion is a good nucleophile such as thiophenoxide and
when -NR3 is a good leaving group. In this case the attacking anion
perform an SN2 displacement reaction on the quaternary ammonium
cation producing a trialkylamine while alkylating the nucleophile,
scheme (1-6).
R3NCH3
X–
+
NR3
+ H3C X
scheme (1-6)
The Hoffmann elimination mechanism is rather important when
performing base-catalyzed PTC reactions at high temperature in a strong
base (50 % NaOH). Here, a base removes a β-proton by a concerted E2
Mechanism, producing a trialkylamine, an alkene and water, scheme
(1-7).
+
R-CH2-CH2-NR′3 + OH
-
R-CH=CH2 + NR′3 + H2O
scheme (1-7)
Quaternary ammonium and phosphonium salts are stable up to
temperature of 100º - 170º C under liquid – liquid PTC conditions in
neutral or acidic media. Phosphonium salts are reasonably stable
catalysts up to temperature of 150º - 170º C while ammonium salts loose
their reactivity rather rapidly at temperature greater than
110º - 120º.
Other high efficient catalysts (cryptates and crown ethers) are
chemically stable in presence of concentrated alkaline aqueous
solutions. However their relatively high costs and/or toxicity limit their
usage. On the other hand quaternary onium salts are inexpensive and
widely available. Therefore, they are quite often the PTC of choice even
in strongly alkaline aqueous solutions regardless of their low stability 13.
1.1.8.
The Mechanism of PTC reactions:
The mechanisms used to describe PTC processes can be grouped
into two categories, PTC and PTC/OH. Reaction conducted under
neutral or acid conditions (numerous displacement reactions, oxidations,
and reductions) fall into the normal PTC category. Reactions conducted
in the presence of strong bases (alkylations, eliminations, additions
hydrolysis reactions) fall into the PTC/OH category.
1.1.8.1.
The Starks Extraction Mechanism:
Normal PTC reactions generally follow the Starks extraction
mechanism. The mechanistic model explains that :
1- The reaction takes place in the organic phase.
2- The desired anion is transferred to the organic phase.
3-The catalyst is important for both reaction steps and the transfer step.
Starks
(Y
–
5,14
reported that an ion pair, formed by the extraction of anion
) into the organic phase by the onium salt cation (Q +), scheme
(1-8), undergoes a fast displacement with (RX) The new salt [Q+X-] then
return to the aqueous phase, where (Q+ ) picks a new Y- ion for the next
cycle.
Organic phase
RX + [Q Y- ]
RY + [Q X ]
................................................................................... Interface
Na
Y
Q
X
Aqueous phase
Scheme (1-8)
This mechanistic view has stood for normal PTC reactions, however, it
does not satisfactorily explain observed effect for many PTC/OH
reaction. For example, stirring rate has a minimal influence on the
reaction rate for systems operating according to the extraction
mechanism. However it has been observed that the reaction rate
increases as the stirring rate increases for several PTC/OH reactions.
Developing the best mechanistic model for PTC/OH reactions (reactions
involving generation of carbanions) remains a subject of controversy.
Two models for PTC/OH reactions are presented by M. Makosza and C.
L. Liotta 15.
Makosza has concluded that the Starks’ extraction mechanism
does not operate for the generation of carbanions (PTC/OH) based upon
theoretical and observed effects. In theory, the extraction mechanism
would require the transfer of hydroxide anions into the organic phase as
an ion pair with the quat. The quat hydroxide would then act as a base in
the organic phase, however, because the affinity of hydroxide anion to
the organic phase is much smaller compared to chloride anions, the
hydroxides anions do not enter the organic phase. The conversion of the
quat chloride to the corresponding quat hydroxide proceeds only to a
very small extent. Thus the conversion cannot be a step in the catalytic
process. In addition to this equilibrium effect, observed effects such as
stirring rate affecting the reaction rate, no hydrolysis of active
intermediates (indicates no OH – or water present in the organic phase),
and highly lipophilic quats practically insoluble in water, performing as
mechanistic picture15.
1.1.8.2.
The Makosza Interfacial Mechanism:
The crucial point of the Makosza interfacial mechanism is that
deprotonation of CH acid by hydroxide anion occur at the interfacial
region. The carbanions formed cannot enter the aqueous phase because
of the strong salting-out effect nor can they enter the organic phase,
because the accompanying sodium cation cannot move with carbanions
to the organic phase. In the interfacial region the carbanions are in low
concentration and have low chemical activity. The quat salt forms
lipophilic ion pair with carbanions helping them enter the organic phase
where further reactions proceed. This mechanistic concept is illustrated
in scheme (1-9)
Scheme (1-9)
The first step in Makosza interfacial mechanism involves the reaction of
OH
–
with the organic acid at the interfacial region to produce the
corresponding solvated carbanion. The second step involves the transfer
of the carbanion from the interfacial region into the bulk organic phase
as an ion pair with the phase transfer cation. The final step is the
alkylation reaction within the organic phase to produce product. It is
important to recognize that the deprotonation of the organic acids takes
place at the aqueous-organic interfacial region. The role of the phase
transfer cation is to complex the already formed carbanion in order to
carry it into the organic electrophile. The Makosza interfacial
mechanism assumes the phase transfer cation plays no important role in
deprotonation of organic acid. This assumption is not always consistent
with
experimental
observations.
It
has
been
experimentally
demonstrated that the quaternary salt reduce the interfacial tension
between the organic and the aqueous phases. As a consequence, the
quaternary salts must be located at the interfacial region of the system. If
deprotonation of organic acid by hydroxide ion takes place at the
interfacial region, it is reasonable to conclude that the counter cation
will be the quaternary cation since the interfacial region is highly
populated with the quaternary salt. This model is consistent with isotope
exchange reaction rates15.
1.1.8.3.
The Liotta Modification of the Makosza interfacial
mechanism:
A mechanism which addresses the above issue is shown in
scheme (1-10);
Scheme (1-10)
In the Liotta modification of the Makosza interfacial mechanism
deprotonation takes place at the interfacial region and is assisted by the
quaternary cation.
The two interfacial mechanisms proposed differ as to the role of catalyst
and consequently as to which catalyst would perform best for PTC with
carbanions (PTC/OH). The Makosza interfacial mechanism suggested
that the optimal (PTC) catalyst can vary as long as the resulting
Quat/carbanion ion pair formed is sufficiently soluble in the bulk
organic phase. In contrast, the Liotta modified mechanism suggested
that the optimal PTC catalyst must be balanced between interfacial
activity (accessible positive charge) in order to attract OH–, and
lipophilicity in order to facilitate the distribution of the carbanion from
the interfacial region into the bulk organic phase. The latter mechanism
explains the observed success of accessible quats as catalyst for wide
variety of PTC/OH reactions. The Makosza and Liotta mechanisms are
alike in that each being interfacial, each sees an increase in reaction rate
as stirring rate increases. In contrast, the Starks’ extraction mechanism
soon reaches a point beyond which stirring rate has no effect 15.
1.1.9.
Advantages of PTC over conventional techniques :
There are hundred industrial applications of PTC for a variety of
processes of organic synthesis. Always these technologies require less
investments, consume less energy, and generate much less industrial
wastes as compared to the traditional ones. It is obvious that all
measures which save energy and investments offer directly or indirectly
substantial benefits to the environment6. Major advantages of PTC in
industrial applications are listed below:
- Elimination of organic solvents.
- Elimination of dangerous, inconvenient, and expensive reactants
(NaOH, KOH, K2CO3, etc. instead of NaH, NaNH2, t-BuOK, R2Nli,
etc.).
- High reactivity and selectivity of the active species.
- High yield and purity of the products.
- simplicity of the procedure.
- Low investment cost.
- Low energy consumption.
1.2.
The chemistry of chalcones :
1.2.1. α,β-unsaturated carbonyl compounds
These are compounds that consist of carbon-carbon double bond
and carbon-oxygen double bond which are separated by just carboncarbon single bond (1), that is, the double bonds are conjugated, because
of this conjugation, such compounds possess not only the properties of
individual functional groups, but certain other properties beside
16
. In
our present work it is more conveniently to study chalcones extensively
as class of these compounds.
C
C
β
C
α
O
(1)
Chalcones (2) (Benzalacetophenone or 1,3-diphenyl propene-1one) are a diverse group of naturally occurring plant metabolites that can
be regarded as open-chain flavonoids, in which two aromatic rings are
bridged by an α,β-unsaturated carbonyl moiety
17
.They represent an
important class of compounds employed as such for their interesting
medical importance, or due to their chemical flexibility as synthons for
the production of five and six-membered ring systems18.
O
CH
CH
C
(2)
1.2.5. Occurrence of chalcones :
Chalcones occur in Legume sp. Mainly as yellow pigments in
flowers (eg. Grose, Ulex europeaus) or as trace constituents in heart
wood (eg. Acacia sp.). six chalcones have been identified in this family.
They all lack a hydroxyl at the 6`position (corresponding to the
5-hydroxy in the flavone nucleus) and in fact occur with the related
flavones, flavanols and leucoanthocyanidins in Acacia and Robinia
species . A typical legume chalcone is isoliquiritigenin (3) which was
first isolated from Liquorice root (Glycyrrhiza) by Claisen and
Claparade (1881) and has since been found in other genera19.
OH
HO
OH
O
(3)
Other chalcones were extracted from the seeds of Psoralea Corylifolia,
these
are
;
neobavachalcone
(4)
(5`-formyl-2`,4`-dihydroxy-
4`-methoxychalcone),
isoneobavachalcone
dihydroxychalcone),and
bavachromanol
(5)
(6)
(5`-formyl-4`,4`-
(4,4`,5``,trihydroxy-
6``,6``,dimethyl dihydroxy pyrano(2``,3``:2`,3`) chalcone)19.
OH
OH
CH3O
OHC
O
(4)
OH
OH
H O
O CH3
4
5
HO
OH
6
O
O
O
O
(5)
(6)
Flowers of Limonium var. were found to contain chalcones such as
3,4,2`,4`,6`, pentahydroxy chalcone (7) 19.
OH
OH
OH
HO
OH
O
(7)
Antirrhinium sp. (A. majus) contains chalcones as chalcononaringenin4`-glucoside and 3,4,2`,4`,6`, pentahydroxy chalcone-4`-glucoside 19
Imperato19 have reported for chalcones extracted from the flowers of
Acacia cyanophylla and Acacia dealbata eg, isosalipurposide (8)
(2,4,4,6-tetrahydroxy-3-methoxy chalcone-2-O-D glucoside).
HOCH2
HO
O
OCH3
O
C CH
OH
CH
OH
O
OH
(8)
1.2.3. Synthesis of chalcones:
Chalcones have been known as natural products since 1880s19.
But synthetic compounds appeared in the early 1900s 20.
Franz Kunckell and Hammerschmidt20 had reported the synthesis of
some substituted chalcones eg. Acetamino-2-hydroxy-2-nitrochalcone,
AcNH(HO)C6H3COCH=C6H4NO2,
O-O2NC6H4CHO.
from
AcNH(HO)C6H5
and
21
J.Tmbor
has also reported for the preparation of 2,4,3-
trihydroxychalcone from m-HOC6H4-CHO and (HO)2C6H3AC, and in
the same way he obtained 2,4,3-trimethoxychalcone.
Chalcones are prepared by the nucleophilic addition-elimination
reactions between acetophenones and benzaldehydes, or so-called aldol
condensation22. The condensation of acetophenone with benzaldehyde to
give Benzalacetophenone (chalcone) has been studied under conditions
of both base-catalysis which was reported by E. Coombs and D. P.
Evans2٣ scheme (1-11), and acid catalysis, which was studied kinetically
and mechanistically by S. Donald and A. William2٤ scheme (1-12).
EtO
O
O
_
EtO H
+ Ph
+
_
Ph
+ Ph
O H
Ph
Ph
_
O H
H
O
O
Ph
O
Ph
_
O
O
Ph
+
_
EtO H
H
OH
Ph
Ph
_
O
H
Ph
OH
Ph
+
EtO H
_
O
Ph
H
O
OH
Ph
Ph
_
Ph
+ OH
_
+ EtO
Scheme (1-11)
Condensation in basic conditions ( EtOH with NaOEt)
O
+O
+
H
H
+
Ph
+ H 3O
H
+
Ph
H
Ph
H
+O
H
Ph
+
O
+
O H
Ph
O + H 3O
O
Ph
O
+ H2O
Ph
+ H 3O
Ph
H
+
H
+
O
OH
H
Ph
O H
Ph
H
Ph
+
OH 2
Ph
O
OH2
Ph
+ H2O
Ph
Ph + H2 O
Scheme (1-12)
Condensation in acid conditions ( HOAC, H2O, H2SO4)
Scheme (10) and (11) shows that, while the enolate ion can attack the
free aldehyde Carbonyl group, the less nucleophilic enole requires acid
catalysis. In the base catalyzed reaction it has been shown that the βhydroxy ketone is converted into benzaldehyde and acetophenone more
rapidly than it is dehydrated to chalcone, so, dehydration is the rate
determining step2٢.
One of the most commonly used procedure for preparing
chalcones in presence of alkaline agents25, is the condensation of
benzaldehyde and acetophenone in presence of aqueous sodium
hydroxide and ethanol at low temperatures (15-30º C), with vigorous
stirring. By achieving these conditions a good yield of chalcone can be
afforded, scheme (1-13).
O
O
O
H3 C
H
NaOH / EtOH
(15-30 oC)
+
Scheme (1-13)
An example for synthesis of chalcones under acid catalysed conditions
is the condensation of acetophenone with benzaldehyde in presence of
borontrifluoride 26 scheme (1-14)
O
O
H3 C
H
O
BF3
+
Scheme (1-14)
Also it was possible to synthesize nitrochalcones from the reaction of
resorcinol (a phenol) with 4-nitrocinnamic acid, in presence of BF3
etherate 27, scheme (1-15),
NO2
NO2
HO
HO
+
BF3 etherate
HO
OH
O
OH
O
Scheme (1-15)
Another, but amazing technique is the clay-catalysed solventless
synthesis of chalcones28. R. Ballini and co-workers used three different
types of acidic clay (montmorillonites, hectorite, and kaolin) in the
model reaction between benzaldehyde and acetophenone scheme (1-16),
carried out under solventless condition at 130º C for 4 hours, leading to
a very good yield of chalcones with excellent selectivity. This technique
represents a step towards solvent free processing.
O
O
H3 C
H
+
O
Clay (1g)
4h (130o C )
Scheme (1-16)
1.2.4. Reactions of chalcones
The α,β-unsaturated skeleton of chalcones are considered as one
of the most common Michael acceptors, the presence of the double bond
adjacent to the carbonyl group allow them to add active C-H acids29.
The following scheme shows the general mechanism of the Michael
addition:
CH 2 RR +
C
C
C
Base
H Base
O + CH RR
CH RR
+
C
C
C
O
CH RR
C
C
C
O
+ H Base
C
C
C
O
H
CH RR
CH RR
Scheme (1-17)
The function of the base is to abstract a proton from the C-H
system and thus generates a carbanion which can then act as a
nucleophilic reagent, that can attack the conjugated system.
1.2.4.1.
Reaction of chalcones with Ethyl methylmalonate :
Reactions of chalcones via Michael addition had been studied30.
Benzalacetophenone was taken as Michael acceptor whereas ethyl
methylmalonate was served as C-H acid, scheme (1-18):
C H CH CHC OC H
5
6 5
6
C H CHCH(COOC2 H5 )COC2H5
NaOEt
+
6 5
CH3CHCOOC2H5
CH3CH (COOC2 H5 )2
C H CH C(CH3 ) COOC2H5 +
6 5
C H COCH COOC2H5
6 5
2
Scheme (1-18)
The product has clearly undergone reversal Michael condensation
(cleavage). The cleavage products were designated as rearrangementretrogression products.
1.2.4.2.
Reaction of chalcones with Ethylcyanoacetate:
Another type of similar reactions is the trimolecular Michael
reaction. It has been reported
30
that chalcones may cyclize, when two
moles of a chalcone is reacted with one mole of ethylcyanoacetate in
presence of sodium ethoxide and absolute ethanol it gives the
corresponding substituted cyclohexanol (9) , scheme (1-19)
O
O
Ar CH CH C Ar
+
C O CH CH 3
2
2
(1 mole)
N C CH
(2 moles)
R.T
O
Ar C
(9)
HO
Ar
N C
NaOEt / EtOH
Ar
Ar
C O CH CH
2 3
O
Scheme (1-19)
1.2.4.3.
Reaction of chalcones with Ethyl acetoacetate :
Michael addition reaction of chalcones and azachalcones with
ethyl acetoacetate have been successfully performed in presence of
catalytic amount of potassium carbonate (10 mol %) and under high-
speed vibration milling conditions (HSVM) 32. The reaction took place
at ambient temperature without any solvent, and the reaction is
completed in a very short time (20-40 minutes). The desired Michael
adducts were exclusively obtained (98-86% yield), consisting of two
diastreoisomers anti (10) and syn (11), scheme (1-20).
O
O
Ar
CH3COCH2COOEt
X
Ar
O
H3C
X
CO2Et
K2CO3 (HSVM)
(anti)
X = CH, N
O
Ar
(10)
O
H3C
X
CO2Et
(syn)
(11)
Scheme (1-20)
This new protocol provided a very stereoselective technique with high
yield, besides, it is fast, clean, and of low cost.
1.2.4.4.
Reaction of chalcones with Ethyl β-methoxy crotonate:
Shandala and co-workers 33 described the cyclization of chalcones
upon reacting with ethyl β-methoxycrotonate ester in presence of
sodium hydride as base and dry THF. It has been shown that this
reaction proceed by a conjugated addition of the ester anion to the
chalcone followed by an Intramolecular Claisen condensation to give
the corresponding substituted 2-cyclohexen-1-ones (12), scheme (1-21).
CH 3 O
H3CO
CH 3 O
CH2 O
NaH
OEt
OEt
H3CO
THF
H
OEt
H3CO
H
O
Ar
O
Ar
O
Ar
Ar
O
Ar
Ar
Ar
O
H 3C O
Ar
O
H3C O
O
OEt
H3CO
OEt
(12)
Scheme (1-21)
When the obtained 2-cyclohexen-1-ones (12) reacts with hydrazine
hydrate a substituted dihydroindazole,(13) produced. Scheme (1-22)
Ar
Scheme (1-22)
O
(13)
Ar
H 3C O
O
HN=NH
+
(13)
This reaction reflects the importance of chalcones as precursors for the
synthesis of heterocyclic compounds.
1.2.4.5.
Synthesis of Flavanones:
One of the most important reactions of chalcones is the
intramolecular cyclization of 2’-hydroxychalcones (14) into the
corresponding flavanones, this reaction can proceed under various
conditions
using
acids,
bases,
thermolysis
photolysis34,35. K. Tanaka and T. Sugino
36
electrolysis
and,
had reported the conversion
of 2’-hydroxychalcones (14) in the presence of sodium hydroxide or
pyridine into flavanones (15), in a water suspension medium, scheme
(1-23). Furthermore cyclization of 2’-hydroxychalcones (14) to 2,3dihydroflovanols (16) using NaOH and H2O2 in a water suspension was
also reported, scheme (1-24)
O
O
NaOH
OH
Ph
rt, 1h, H2O
(14)
O
Ph
(15)
Scheme (1-23)
O
O
OH
NaOH
OH
Ph
H2O2 , H2O
O
Ph
(16)
(14)
Scheme (1-24)
1.2.4.6.
Synthesis of substituted Pyridones:
A. R. Katritzky37 has described the reaction of resin-bounded
chalcones (17) with 2(benzotrizol-1-yl) acetamide (18), this was the first
protocol for solid phase synthesis of 4,6-disubstituted pyrid-2-ones (19),
scheme (1-25)
O
O
O
Br
NH2
(18)
R2
O
NH
NaOH, THF/EtOH (5:1)
70 0C , 24 h
O
R1
R2
R1
(17)
OH
NH
O
R2
R1
Scheme (1-25)
1.2.4.7.
(19)
Synthesis of substituted 2-pyrazolines:
Chalcones (22) prepared from the condensation of 1-acetyl
naphthalene (20) with 1-naphthaldehyde (21), were shown to react with
hydrazine hydrochloride, phenyl hydrazine, and semicarbazide in
presence of dry acetic acid to give the corresponding 2-pyrazolines (23).
It has been reported that these heterocycles possess antimicrobial
potential 38, scheme (1-26).
COCH3
CHO
R1
NaOH
+
O
R2
R3
R2
(20)
CH
C CH
EtOH
R3
R1
(22)
(21)
ACOH
R4NHNH2
(reflux)
R4
N
N
H
R2
R3
R1
H
H
(23)
Scheme (1-26)
1.2.4.8.
Epoxidation of chalcones:
One of the first reported examples of peptide catalysed reactions
of chalcones is the Juliá-Colonna asymmetric epoxidation of
chalcones39, catalysed by polyamino acids in a triphasic system,
discovered and developed by Juliá and Colonna. Advances in this field
have been made through the introduction of a biphasic protocols,
leading to an expantion in the range of enones which can be epoxidized
with good stereoselectivity. These methodologies has been successfully
applied to reach various synthetic targets. For such synthetic work
polyleucine is used as catalyst and the reaction proceeds as follows,
scheme (1-27) .
O
O
aq NaOH, aq H 2O2
Ph
O
Ph
Ph
O O
Ph
Catalyst
+
Ph
Ph
Scheme (1-27)
1.2.4.9.
Synthesis of 1,3-Diarylpropanes:
1,3-Diarylpropanes have been synthesized to confirm structures
of some natural products, Paulo et al
40
reported for the preparation of
1,3-Diarylpropanes by catalytic hydrogenation of chalcones scheme
(1-28)
OR1
O
OR1
O CH2Ph
R2O
+ H2
Pd / ACOH
50 psi 4-5 hr
1- R1 = Me, R2 = CH2Ph
2- R1 = Ch2Ph , R2 =Me
3- R1 = R2 = Me
Scheme (1-28)
1.2.4.10.
Photodimerization of chalcones:
R2O
O CH2Ph
The photodimerization of various chalcones and their derivatives
in solution, solid and molten states have been studied41 .Under
photochemical UV-Vis irradiation conditions chalcones undergo
dimerization to produce cyclobutane rings (24). This type of reaction is
classified as intermolecular 4n(2+2) photocycloaddition reaction,
scheme (1-29);
O
H
CH3
R
O
O
NaOH / 95% EtOH
+
R
R = o-, m-, p-OCH3
hv, CHCl3
O
O
R
R
1- R = o-OCH3
2- R = p-OCH3
3- R = m-OCH3
(24)
Scheme (1-29)
1.2.4.11.
reaction with organometalic compounds:
It has been shown that phenyl magnesium bromide (Grignard
reagent)
can
add
1,4
to
Benzalacetophenone,
to
give
β,β-
diphenylpropiophenone (25) 42, scheme (1-30).
Ph
CH
CH
CH C
O
+
PhMgBr
[HOH]
CH2 C
O
(25)
Scheme (1-30)
But with phenyllithium, it has been reported to add 1,2 to
benzalacetophenone to give diphenylsterylcarbinol (19), scheme (1-31).
Ph
CH
CH
CH C
O
+ PhLi
[HOH]
CH C
OH
(26)
Scheme (1-31)
Gilman and Kirby
42
had arrived to the fact that moderately reactive
phenyl-metallic compounds (those of beryllium, magnesium, zinc,
aluminum and manganese) have been shown to give 1,4-addition with
benzalacetophenone. The highly reactive phenyl-metallic compounds of
calcium and potassium, show 1,2 addition. Compounds of intermediate
reactivity (those of lithium and sodium) show both 1,2-addithion and
1,4-addition.
1.2.4.12.
Synthesis of fused Pyrazoles and Isoxazoles:
Venkatapuram et al
43
reported the preparation of new class of
fused pyrazoles and isoxazoles, using chalcones as starting materials
6-carbethoxy-3,5-diarylcyclohexnones
(27)
were
prepared
by
Knoevenagel condensation of ethyl acetoacetate and 1,3-diaryl-2propen-1-ones (chalcones) in the presence of sodium ethoxide, this
compound
is
underwent
decarboxylation
to
give
3,5-diaryl-2-
cyclohexenones (28), the Claisen condensation of (28) with ethyl
formate in the presence sodium ethoxide gave 6-hydroxy methylene-3,5diaryl-2-cyclohexenones (29).the cycloaddition of (29) with hydrazine
hydrate in AcOH afforded 4,5-dihydrobezo[3,4d]pyrazoles (30), and
cycloaddition with hydroxylamine hydrochloride gave isoxazoles (31),
scheme (1-32) ;
O
O
O
CO2Et
O
Ar
Ar
CO2Et
+
Ar
Ar
O
OH
HCO2Et
Ar
Ar
Dry Benzene
10 % NaOMe
Dil HCl
Ar
Ar
(29)
(28)
N
N
O
Ar
Ar
N
O
N
Ar
Ar
Ar
N
Ar
Ar
N
Ar
(31)
(30)
Scheme (1-32)
Ar
Ar
(28)
(27)
O
+
1.2.4.13.
Reactions of chalcones under PTC conditions :
Reactions of chalcones under phase transfer catalysis conditions
were rarely investigated and less information were found in recent
reports, however, catalytic enantioselective Michael addition reactions,
were investigated and well studied. Reactions of such type were carried
out in presence of catalysts, for instance, cinchona alkaloid derived
quaternary ammonium salts, crown ethers, and organometallic
compounds can serve as efficient catalysts.
Shandala and his co-workers 44 reported the reaction of chalcones
with phenylacetonitrile in presence of TEBA catalyst and potassium
carbonate, to give two stereoisomers threo (32) and erthro (33), scheme
(1-33);
Ar
O
Ar +
Ar
H
TEBA
CH2COAr
H
PhCH2CN
CN
K2CO3
(32)
Ph
+
Ar
Ar OCH2C
H
NC
H
(33)
Ph
Scheme (1-33)
this reaction is one of the rare examples of chalcones reactions under
PTC conditions.
Kim et al
45
reported the addition of chalcones to malonate,
scheme (1-34) and nitromethane to produce compound (34) and (35)
respectively, using chiral quaternary ammonium salts (36), scheme (135)
CO2R
RO2C
O
Ar
Ar
+
CH2 (CO2R)2
O
Catalyst (36)
K2CO3 / Toluene
Ar
Ar
(34)
Scheme (1-34)
O2N
O
Ar
Ar
+
O
Catalyst (36)
CH3NO2
Ar
Ar
t-BuOK / Toluene
(35)
-
+
N
H
Br
O
OMe
N
Catalyst (36)
Scheme (1-35)
Recently Kim was reported the addition of diethylfluoromalonte to
chalcones46
using chiral ammonium salts derived from cinchona
alkaloids, in presence of different bases such as K2CO3 , Cs2Co3 ,
RbCO3, scheme (1-36)
COOEt
EtOOC
O
Catalyst
Ph
Ph
F
O
O
O
+
OEt
EtO
Base/Toluene
Ph
Ph
F
Scheme (1-36)
Loupy et. al 47 reported the addition of diethylacetyl amine to chalcones
using N-methyl-N-benzyl ephedrinium bromide as catalyst to produce
compound (37) as shown in scheme (1-37).
O
H 3C
NHCOCH3
O
Ar
Ar
+
H
CO2Et
CO2Et
Catalyst
Ar
CO2Et
CO2Et
O
KOH
Scheme (1-37)
1.2.5.
N
Biological importance of Chalcones
Ar
(37)
Chalcones belong to the largest class of plant secondary
metabolites the flavonoids, which, in many cases, serve in plant defense
mechanism to counteract reactive oxygen species (ROS) in order to
survive and prevent molecular damage by parasites, they are known to
have antioxidant character at various extents. The antioxidant activity of
natural compounds like chalconoides is related to a number of different
mechanisms such as free radical scavenging, hydrogen donation, single
oxygen quenching metal ion chelation, and acting as substrate for
radicals such as superoxides and hydroxides 41.
Chalcones are also intermediate compounds in the biosynthetic
pathway of very large and widespread group of plants constituents the
flavonoides. Among the naturally occurring chalcones and their
synthetic
analogues
several
compounds
displayed
antibacterial,
antiviral, antifungal, antiprotozoal as well as antineoplastic (cytotoxic)
activity. Recently chalcones has been investigated for in vitro antitumer
activities48.
1.2.5.
Aim of our work:
It has been reported that cyclohexenone derivatives were obtained
under specific reaction conditions; when 1,3-diaryl-2-propene-1ones
undergoes Michael addition followed by intramolecular cyclization with
active methylene compounds under catalytic conditions 30, 33, 43, 51.
We thought it might be of interest to use Phase Transfer Catalysis
(PTC) techniques in the condensation reactions of different compounds
of α β-unsaturated Michael acceptors with active methylene compounds,
such as ethyl β-methoxycrotonate and ethyl acetoacetate, employing
different reactions conditions, and to verify the synthetic pathways
proposed.
One of the objectives of the work is : in any stage of synthesis suitable
mechanistic pathways should be justified.
Chapter (2)
EXPERIMENTAL
and
RESULTS
2.
Experimental and Results
Chemicals and instrumental:
All chemicals used in this work were of General Purpose Reagent
grade (GPR). The phase transfer catalyst was supplied by Dishman
Pharmaceutical and chemicals Co. Ltd. (India).
Melting points were taken in 9100 Electrothermal melting point
apparatus. IR spectra were recorded on Fourier Transform IR
spectrophotometer (FTIR) and Perkin Elmer 1330 IR spectrophotometer
in KBr disc. UV spectroscopic analysis was performed on Jenway 6505
UV/Vis spectrophotometer.
Mass spectroscopy and 1H NMR analysis were done at the University of
Toronto (Canada).The Mass spectra were run by Dr. Alex Young using
electron impact (EI) as ionization method on Perkin Elmer
spectrophotometer. The 1H NMR was run by Dr. Huda Henry Ryad, and
spectra were obtained in CDCl3 and tetramethylsilane as internal
standard using 400 MHz Varian Unity spectrophotometer.
2.1
Preparation of chalcones
2.1.1. 1,3-Diphenyl-2-propen-1-one (Benzalacetophenone) 49 (Ia):
A solution of sodium hydroxide (22g) in 200 ml of water and
rectified spirit (100g, 122.5ml) was placed in 500 two-necked roundbottom flask provided with mechanical stirrer. The flask was Immersed
in a bath of crushed ice. Freshly distilled acetophenone (52g) was added,
while stirring, pure benzaldehyde (46g, 44ml)
was added. The
temperature of the mixture was kept at about 25º C. The mixture was
stirred vigorously for 3 hours. The reaction mixture was left in an ice
chest for overnight. The product was filtered with suction in Büchner
funnle and washed with cold water until the washings were neutral to
litmus,
and then washed with ice-cold rectified spirit. The crude
chalcone after drying in air, wt, 73 g The yield of pure
Benzalacetophenone was 78 % , m.p 57º C , (lit 56 – 57º C ), VC=O 1658
cm-1, VC=C 1600 cm-1, λmax (EtOH) 310 nm, Rf 0.3 (Pet. ether,
dichloromethane 1:2 )
The same procedure was adopted in the preparation of the nine
chalcones there in.
2.1.2.
3-(4-methylphenyl)-1-phenylprop-2-en-1-one (Ib):
O
CH3
Acetophenone
0.1 mol (12g)
p-Tolualdehyde
0.1 mol (12g)
Sodium hydroxide
4g
Distilled water
40 ml
Ethanol
100 ml
The chalcone was formed after 30 minutes of stirring as a pale
yellow needles, m.p 95-96 ºC, yield 70 %, recrystallized from ethanol.
2.1.3.
3-(4-methoxyphenyl)-1-phenylprop-2-en-1- one (Ic):
O
OCH3
Acetophenone
0.1 mol (12g)
p-Anisaldehyde
0.1 mol (13.6 g)
Sodium hydroxide
4g
Distilled water
40 ml
Ethanol
100 ml
The chalcone was formed after stirring for one hour as a hard pale
yellow needles, m.p 75-77 ºC, yield 75 %, recrystallized from ethanol.
2.1.4.
3-(3-methylphenyl)-1-phenylprop-2-en-1-one (Id):
O
CH3
Acetophenone
0.1 mol (12g)
m-Tolualdehyde
0.1 mol (13.6g)
Sodium hydroxide
4g
Distilled water
40 ml
Ethanol
100 ml
The chalcone was formed after stirring for one hour as a pale
yellow prisms m.p 65-66 ºC, yield 87%, recrystallized from ethanol.
2.1.5.
1-(4-bromophenyl)-3-phenylprop-2-en-1-one (Ie):
O
Br
p-Bromoacetophenone
0.1 mol (19.9g)
Benzaldehyde
0.1 mol (10.6g)
Sodium hydroxide
4g
Distilled water
40 ml
Ethanol
100 ml
The chalcone was formed after stirring for one hour as yellow
needles, m.p102-104 ºC, yield 80%, recrystallized from ethanol
2.1.6.
1-(4-methylphenyl)-3-phenyl-2-propen-1-one (If):
O
H3C
p-methylacetophenone
0.1 mol (13.4g)
Benzaldehyde
0.1 mol (10.6g)
Sodium hydroxide
4g
Distilled water
40 ml
Ethanol
100 ml
The chalcone was formed after stirring for one hour as yellow
needles, m.p 52-54 ºC, yield 85%, recrystallized from ethanol.
2.1.7.
1-(4-nitrophenyl)-3-phenyl-2-propen-1-one (Ig):
O
O 2N
p-nitroacetophenone
0.1 mol (16.5 g)
Benzaldehyde
0.1 mol (10.6g)
Sodium hydroxide
4g
Distilled water
40 ml
Ethanol
100 ml
The chalcone was formed immediately after the addition of the
benzaldehyde,
as
yellow
prisms
m.p140-142
ºC,
yield
71%,
recrystallized from ethylacetate.
2.1.8.
3-(4-methylphenyl)-1-(4-nitrophenyl)prop-2-en-1-one (Ih):
O
O 2N
CH3
p-Nitroacetophenone
0.1 mol (16.5 g)
p-Tolualdehyde
0.1 mol (12g)
Sodium hydroxide
4g
Distilled water
40 ml
Ethanol
100 ml
The chalcone was formed after stirring for 10 minutes, as yellow
prisms, m.p165-166º C, yield 75%, recrystallized from ethylacetate.
2.1.9.
3-(4-methoxyphenyl)-1-(4-nitrophenyl)prop-2-en-1-one (Ii):
O
O 2N
OCH3
p-Nitroacetophenone
0.1 mol (16.5 g)
p-Anisaldehyde
0.1 mol (13.6g)
Sodium hydroxide
4g
Distilled water
40 ml
Ethanol
100 ml
The chalcone was formed after stirring for 10-15 minutes, as
yellow prisms m.p175º C, yield 97%, recrystallized from ethylacetate.
2.1.10. 3-(4-chlorophenyl)-1-(4-nitrophenyl)prop-2-en-1-one (Ij):
O
O 2N
Cl
p-Nitroacetophenone
0.1 mol (16.5 g)
o-Chlorobenzaldehyde
0.1 mol (14.2 g)
Sodium hydroxide
4g
Distilled water
40 ml
Ethanol
100 ml
The chalcone was formed immediately after the addition of the
o-chlorobenzaldehyde, as yellow needles , m.p. 164 -165 º C, yield 71%,
recrystallized from ethylacetate.
Table (1) shows general properties and physical constants of these
chalcones.
Figures 1,2,3 and 4 present the NMR and Mass spectra for compounds
(Ia) and (Id) respectively.
No.
Structure
Formula
M.wt
Yield
%
M.p
ºC
UV
λmax
nm
IR ( v cm -1 )
C=O C=C
Rf
Pet.ether
:DCM
1:2
I-a
O
I-b
C15H12O
208
75
56-57
310
1658
1600
0.3
C16H14O
222
57
95-96
320
1650
1590
0.29
C16 H14 O2
238
75
75-77
340
1671
1600
0.22
C16 H14 O
222
87
65-66
315
1645
1580
0.43
C15 H11 Br O
287
80
102-104
315
1655
1588
0.45
C16 H14 O
222
85
52-54
310
1657
1611
0.61
C15 H11 N O3
287
71
140-142
325
1660
1585
0.53
C16 H13 N O3
253
75
165-166
340
1645
1560
0.31
C16 H13 N O4
267
90
175
360
1645
1560
0.41
O
CH3
I-c
O
OCH3
I-d
O
CH3
I-e
O
Br
I-f
O
H3C
I-g
O
O 2N
I-h
O
O 2N
I-i
CH3
O
O2N
OCH 3
I-j
C15 H10 Cl N O3
O
O 2N
283
70
164-165
315
Cl
Table (1)
Physical properties of chalcones (Ia-Ij)
O
Figure (1), The NMR spectrum for chalcone (Ia)
1650
1580
0.58
O
Base Peak
With relative
abundance 100%
Molecular
ion (M +)
Figure (2), The Mass spectrum for chalcone (Ia)
O
CH3
Figure (3), The NMR spectrum for chalcone (Id)
O
CH3
Base Peak
With relative
abundance 100%
Molecular
ion (M +)
Figure (4), The NMR spectrum for chalcone (Id)
2.2.
Ethyl β-methoxycrotonate
50
:
Ethyl acetoacetate (130 g, 1 mol) was mixed with redistilled
trimethylorthofrmate (106 g, 1 mol) and dry methanol 100 ml, and
concentrated hydrochloric acid (0.5 ml) were added. The mixture was
distilled immediately to give ethyl β-methoxycrotonate (95 %) bp.
188 ºC
(lit 188-194 ºC), C=o Ester 1700 cm-1, C=C 1610 cm-1.
CH3
O
H3CO
OEt
H
Ethyl β-methoxycrotonate
2.3.
General procedure for the synthesis of 6-aroyl-3-methoxy-5phenylcyclohex-2-en-1-one through the 50 % NaOH- catalized
cyclocondensation of chalcones (Ia, Ib, Ic, and Id) with ethyl
β-methoxycrotonate in presence of tetrabutyl
ammoniumiodide.
A mixture of Chalcone (Ia, Ib, Ic, and Id) separately (0.01 mole),
Ethyl β-methoxycrotonate (0.01 mole), tetrabutyl ammoniumiodide
catalyst (0.5 gm) and 40 ml of toluene, were stirred mechanically.
Aqueous sodium hydroxide solution (50 %, 2 ml) was added drop wise
while stirring at room temperature. The reaction was followed by TLC.
Stirring was continued for 4 hours. A yellowish-brown precipitate was
formed. The precipitate was filtered off, washed with water, and
recrystallized from ethanol. Table (2) shows properties of the obtained
Michael adducts :
No.
IIa
Yield
M.p
%
40 140-142
UV
IR
λmax C=O C=O C=C
nm Ester
215 1700 1659 1602
IIb
60
148-150
285
1738
1657
1600
IIc
25
149-152
225
1740
1700
1607
IId
35
139-141
220
1740
1700
1605
Table (2)
Physical Properties of compounds (IIa-IId)
2.4.
General procedure for the synthesis of 6-aroyl-3-methoxy-5-
phenylcyclohex-2-en-1-one through the 10 % NaOH- catalized
cyclocondensation of chalcones (Ia and If) with ethyl βmethoxycrotonate in presence of ammoniumhydrogen-sulphate:
To a mixture of chalcones (Ia, If),separately, (2.08 g, 0.01mol),
ethyl β-methoxycrotonate (1.3 ml, 0.01mol), tetrabutyl ammoniumhydrogensulphate (PTC) (0.001 mol), 10 % sodium hydroxide (2 ml),
toluene (20 ml) was added, The mixture was stirred for 3 hours at room
temperature, after evaporation of solvent under vacuum, the residue was
washed with distilled water, and recrystallised from ethanol, a yellow
needles were obtained. m.p.(Ia; 75 ºC, If; 85 ºC),
Melting points show that the produced compounds were the starting
chalcones.
2.5.
General procedure for the synthesis of Ethyl 2-oxo-4,6diarylcy clohex-3-ene-1-carboxylate through the 10 % NaOHcatalized cyclocondensation of chalcones (Ia-If) with ethyl
acetoacetate in presence of tetrabutyl ammoniumhydrogen
sulphate
2.5.1 Ethyl 2-oxo-4,6-diphenylcyclohex-3-ene-1-carboxylate (IIa)
To a mixture of chalcone (Ia) (2.08 g, 0.01mol), ethyl
acetoacetate (1.3 ml, 0.01mol), tetrabutyl ammoniumhydrogensulphate
(PTC) (0.001 mol), 10 % sodium hydroxide (2 ml), in toluene (20 ml)
was added, The mixture was stirred for one hour at room temperature,
after evaporation of solvent under vacuum, the residue was washed with
distilled water, and recrystallised from ethanol, white needles were
obtained, yield 87.8 %, m.p.144-145 ºC, IR (KBr disc): 1700 cm-1
(VC=O ketone), 1743 cm-1 (VC=O ester), 1602 cm-1, (VC=C conjugated),
λ max (MeOH) 260 nm.
Other compounds were prepared using the same method.
2.5.2 Ethyl 6-(4-methylphenyl)-2-oxo-4-phenylcyclohex-3-ene-1carboxylate (IIb):
Chalcone (Ib)
0.01 mol (2.22g)
Ethyl acetoacetate
0.01 mol (1.3 ml)
PTC
0.001 mol (0.17g)
NaOH
2 ml
Toluene
20 ml
Stirring time
1 hour
White needles, yield 70.5 %, m.p148-150 ºC, IR (KBr disc): 1657 cm-1
(VC=O ketone), 1738 cm-1 (VC=O ester), 1600 cm-1, (VC=C conjugated),
λ
max
(MeOH) 290 nm.1H NMR (400 MHz,CDCl3): δ 1.07 (3H,t , J 7.1
Hz, CH2 –CH3), δ 2.335 (3H, s, Ar-CH3), δ 2.916 (1H, m CH-Ar ),
δ 3.11 (1H, dd, J trans 2.9 Hz, J cis 16.7, CHCOOC2H5), δ 3.752 -3.801
(2H, m CH2CHAr), δ 4.062 (2H, q CH2CH3), δ 6.56 (1H, s =CHCO),
δ 7.136-7.555 (9H, m H-Ar). Mass spec : M/e 234.
2.5.3.
Ethyl 6-(4-methoxyphenyl)-2-oxo-4- phenylcyclohex-3ene-1-carboxylate (IIc):
Chalcone (Ic)
0.01 mol (2.38 g)
Ethyl acetoacetate
0.01 mol (1.3 ml)
PTC
0.001 mol (0.17g)
NaOH
2 ml
Toluene
20 ml
Stirring time
1 hour
White needles, yield 75 %, m.p139-141 ºC, IR (KBr disc): 1707 cm-1
(VC=O ketone), 1743 cm-1 (VC=O ester), 1607 cm-1, (VC=C conjugated),
λ max (MeOH) 275 nm.
2.5.4.
Ethyl 6-(3-methylphenyl)-2-oxo-4-phenylcyclohex-3-ene1-carboxylate (IId):
Chalcone (Id)
0.01 mol (2.22 g)
Ethyl acetoacetate
0.01 mol (1.3 ml)
PTC
0.001 mol (0.17g)
NaOH
2 ml
Toluene
20 ml
Stirring time
1 hour
White needles, yield 87.8 %, m.p142-143 ºC, IR (KBr disc): 1707 cm-1
(VC=O ketone), 1743 cm-1 (VC=O ester), 1605 cm-1 (V C=C conjugated), λ
max (MeOH)
265 nm
2.5.5.
Ethyl 4-(4-bromophenyl)-2-oxo-6-phenylcyclohex-3-ene1-carboxylate (IIe):
Chalcone (Ie)
0.01 mol (2.87g)
Ethyl acetoacetate
0.01 mol (1.3 ml)
PTC
0.001 mol (0.17g)
NaOH
2 ml
Toluene
20 ml
Stirring time
1 hour
White needles, yield 75.0 %, m.p 99-100 ºC, IR (KBr disc): 1657 cm-1
(VC=O ketone), 1736 cm-1 (VC=O ester), 1607 cm-1, (V
C=C
conjugated),
λ max (MeOH) 295 nm.
2.5.6.
Ethyl 4-(4-methylphenyl)-2-oxo-6-phenylcyclohex-3ene-1-carboxylate (IIf):
Chalcone (If)
0.01 mol (2.22 g)
Ethyl acetoacetate
0.01 mol (1.3 ml)
PTC
0.001 mol (0.17g)
NaOH
2 ml
Toluene
20 ml
Stirring time
50 minutes
White needles, yield 88.5 %, m.p 100-102 ºC, IR (KBr disc): 1657 cm-1
(VC=O ketone), 1735 cm-1 (V
C=O
ester), 1602 cm-1, (V C=C conjugated),
λ max (MeOH) 300 nm.
The p-nitro substituted chalcones (Ig, Ih, Ii, Ij) were reacted
similarly with ethyl acetoacetate . A Black material was obtained.
Extraction and purification afforded the starting chalcones.
Table (3) shows the physical properties of the compounds (IIa - IIf) .
Figures (5-10) show the IR spectra of compound (IIb), figures (11 and
12) show the 1H NMR and Mass spectra of compound (IIb).
No.
Structure
IIa
O
Formula
O
M.wt
M.p
ºC
144-145
UV
λmax
nm
260
C=O
Ester
1743
IR
C=O C=C
OH
1700
1602
3392
C21H20O3
320.382
Yield
%
87.8
C22H22O3
334.408
70.5
148-150
290
1738
1657
1600
-
C22H22O4
350.408
75.0
139-141
275
1743
1707
1607
3393
C22H22O3
334.408
79.0
142-143
265
1743
1707
1605
3390
399.278
75.0
99-100
295
1736
1657
1607
-
334.408
88.5
100-102
300
1735
1657
1602
-
OC2H5
IIb
O
O
OC2H5
CH3
IIc
O
O
OC2H5
OCH3
IId
O
O
OC2H5
CH3
IIe
O
C21H19BrO3
O
OC 2H5
Br
IIf
O
C22H22O3
O
OC 2H5
H3C
Table (3)
Physical Properties of Cyclohexenones (IIa-IIf)
Figure (5), The IR spectrum of compound (IIa)
Figure (6), The IR spectrum of compound (IIb)
Figure (7), The IR spectrum of compound (IIc)
Figure (8), The IR spectrum of compound (IId)
Figure (9), The IR spectrum of compound (IIe)
Figure (10), The IR spectrum of compound (IIf)
O
O
O
CH3
CH3
Figure (11),The 1H NMR spectrum of compound (IIb)
Base Peak
With relative
abundance 100%
Molecular
ion (M +)
Figure (12), The MS spectrum of compound (IIb)
Chapter (3)
DISCUSSION
3.
DISCUSSION
Chalcones are valuable intermediates in organic synthesis, because of
their ability to act as activated unsaturated systems in conjugated
addition reactions of carbanions in the presence of basic catalysts. They
react with carbonyl compounds to give synthetic cyclic products of
some naturally occurring ring compounds and could also be of
biological activity.
Hence the chalcones were reacted separately;
(1) With ethyl β-methoxycrotonate in the presence of 50 % sodium
hydroxide and a phase transfer catalyst (PTC) in toluene at room
temperature. The reaction afforded cyclohexenones in rather very
low yields.
(2) With ethyl acetoacetate at room temperature in the presence of
10 % sodium hydroxide and PTC for (30 min- 1 hour). This was
a satisfactory route to obtain six cyclohexenones of the type
ethyl-2-oxo-4,6-diaryl-cyclohex-3-ene-1-carboxylate.
O
O
O
Ar
Ar
CH3
3.1.
Preparation of chalcones from the reaction of acetophenones
and benzaldehydes:
Chalcones were obtained in a good yield (70-89%) as yellow
crystalline solids, soluble in methanol, ethyl acetate, and slightly soluble
in ethanol. Unsubstituted and methyl-substituted chalcones showed
relatively low melting points (52-96º C) whereas the nitrosubstitued
chalcones exhibited a relatively high melting points (165 -176 º C).
Scheme (3-1) illustrate the reaction of benzaldehydes and acetophenones
in presence of sodium hydroxide to give the corresponding chalcones.
O
O
O
CH3
H
+
Y
NaOH
X
EtOH
Y
Ia : X= H , Y= H
Ib : X= p-CH3 , Y = H
Ic: X= p-OCH3 , Y = H
Id : X= m-CH3 , Y = H
Ie : X= H , Y = p-Br
If: X= H , Y = p-CH3
Ig: X= H , Y = p-NO2
Ih: X= CH3 , Y = p-NO2
Ii: X= OCH3 , Y = p-NO2
Ij: X= Cl , Y = p-NO2
Scheme (3-1)
X
(I)
Structural analysis of chalcones was based on IR, NMR, and MS,
spectral data.The IR spectra, table (1),(page 64 ), revealed sharp strong
absorption bands at about (1600 – 1671 cm
-1
), attributed to the
conjugated carbonyl group. Furthermore, another sharp strong
absorption bands at about (1566-1611 cm
-1
) were assigned to the C=C
bond conjugated to the carbonyl group.
1
H-NMR spectra for compound Ia showed peak at δ 7.259 ppm with
the intensity corresponding to one hydrogen (Ha), which appeared at
lower field due to the deshielding effect of the л electrons of the double
bond. Peaks at δ (7.4-8.04) ppm with the intensity corresponding to 11
protons were attributed to the ten aromatic protons and (Hb). Owing to
the strong anisotropic effect of the carbonyl group, (Hb) is deshielded
and it appeared at lower field relative to (Ha), and its signal interfere
with (Ar-H) signals, fig (1) 1HNMR (Ia).
O
B
Ha
Hb
A
Ia
Compound Id shows a peak at δ 2.4ppm corresponding to three protons,
appearing as singlet. This peak is characteristic for the meta-methyl
substituent of ring (A), other peacks at δ 7.2-8.037 ppm with intensity
corresponding to 11 protons were attributed to Ha, Hb , and Ar-H (9H).
For the same reasons mentioned before the signals of these two protons
interfere with those of the benzene ring.
O
Ha
CH3
B
H
b
A
Id
Results obtained from the mass spectra gave the exact masses,
m/e 208 and m/e 222 for compounds Ia and Id respectively, fig (2) and
fig (4). The following figures shows the fragmentation patterns of
compounds (Ia) and (Id) respectively, which were done using the
ACD/Chemsketch (v. 8) software.
1
2 O
3
(Ia)
M+= 208.25518
1-
C6H5
77.0391 Da
2-
C8H7
103.0548 Da
C7H5O
105.034 Da
3-
C9H7O
131.0497 Da
C6H5
77.0391 Da
C9H7O
131.0497 Da
Figure (13)
Fragmentation Pattern of compound (Ia)
4
2 O
1
3
CH3
(Id)
M+ = 222.28176
1-
CH3
15.0235 Da
C15H11O
207.081 Da
2-
C8H7
103.0548 Da
C8H7O
119.0497 Da
3-
C9H7O
131.0497 Da
C7H7
91.0548 Da
4-
C6H5
77.0391 Da
C10H9O
145.0653 Da
Figure (14)
Fragmentation Pattern of compound (Id)
3.2.
Reaction of ethyl acetoacetate with trimethyl orthoformate to
give ethyl β-methoxycrotonate:
ethyl β-methoxycrotonate was conveniently prepared in 95 %
yield from ethyl acetoacetate and trimethyl orthoformate in presence of
hydrochloric acid, scheme (3-2).
O
H3C
O
OCH3
OEt
+ (CH3O)3CH3
HCl
H3C
O
OEt
Scheme (3-2)
3.2.1. Mechanism :
The carbonyl of the ethyl acetoacetate is attacked by the methoxy
group provided by the trimethyl orthoformate to give the intermediate
(I). Eventually, in presence of hydrochloric acid a water molecule is
released to give ethyl β-methoxycrotonate (II), scheme (3-3) .
O
H3C
O
O-
O
CH3OH
+ (CH3O)3CH3
OEt
OEt
H3C
CH3O -
O-
O
H
H3C
OH
+
OEt
H3C
OCH3
H
O
OEt
OCH3
(I)
OCH3 O
-H2O
OEt
H3C
(II)
Scheme (3-3)
3.3.
Reaction of chalcones with ethyl β-methoxycrotonate in
presence of 50% sodium
hydroxide
and
tetrabutyl
ammonium iodide (PTC):
The use of high concentrations of strong bases (50 % NaOH or
solid K2CO3) in the reaction of chalcones with ethyl β-methoxycrotonate
in the presence of PTC is probably a very drastic condition The products
from those reactions were in very poor yields. But compound (IIb),
Table (2), was in a comparatively good percentage yield.
IR spectra for compound (IIb), table (2) , shows bands at about
1738 cm-1 and 1657 cm-1 attributed to the ester carbonyl and the
conjugated carbonyl respectively.
1
HNMR spectrum for compound (IIb), fig (5) , shows a triplet peak at δ
1.07 ppm (with intensities corresponding to 3 hydrogens ), and a quartet
peak at δ 4.06 ppm (with intensities corresponding to 2 hyrogens), these
peaks are characteristic for an ester ethyl group (CH3CH2-). Furthermore
mass spectrum for the same compound gave a molecular peak m/e 234,
and shows that the first fragment that leave the molecule is the ester
group fig (6).
From these data it was concluded that the products obtained were
not the required compounds that forms from the reaction of ethyl βmethoxycrotonate and chalcones, in other words they are not the
reported 6-aroyl-5-aryl-3-methoxy-2-cyclohexen-1-one
33
, shown in
scheme (3-4).
Ar
OCH3
H3C
O
O
O
CH3
+
Ar
NaH
Ar
Ar
Scheme (3-4)
THF
H3CO
O
According to spectroscopic study concentrated on the ester group, we
found that the obtained compound was the product of the reaction of
ethyl acetoacetate with chalcone (Ib) scheme (3-5), since IR and NMR
results gave a strong evidence for the presence of the ester group which
is not found in the proposed compound.
O
O
O
O
O
+
CH3
(Ib)
CH3
O
H3 C
OEt
50 %NaOH
PTC
Ethyl actoacetate
CH3
(IIb)
Scheme (3-5)
Ethyl β-methoxycrotonate in presence of highly concentrated sodium
hydroxide (50 %), may suffer hydrolysis, which results in formation of
ethyl acetoacetate, which may react with chalcones and give the unexpected products (IIb) in a poor percentage yield.
3.4.
Reaction
of
presence
of
chalcones
10%
with
sodium
ethyl
hydroxide
acetoacetate
and
in
tetrabutyl-
ammonium hydrogensulphate as PTC:
The unexpected results that obtained from the reaction of ethyl βmethoxycrotonate and chalcones, led us to use ethyl acetoacetate as
alternative to ethyl β-methoxycrotonate, and to study its reaction with
chalcones (Ia-Ij) in presence of PTC and 10 % sodium hydroxide.
Chalcones (Ia, Ib, Ic, Id, Ie and If) gave products with ethyl
acetoacetate in a high percentage yield (70 – 88.5 %), scheme (3-6).
O
O
O
O
O
O
10% NaOH, PTC
+
H3C
OC 2H 5
X
Y
CH3
Toluene , r.t.
X
Y
(II)
(I)
IIa : X= H , Y= H
IIb : X= p-CH3 , Y = H
IIc: X= p-OCH3 , Y = H
IId : X= m-CH3 , Y = H
IIe : X= H , Y = p-Br
IIf: X= H , Y = p-CH3
Scheme (3-6)
Structural analysis of compounds II (a, b, c, d, e and f) scheme
(3-6), comprised IR spectra table (3), (page 75), figures (6,7,8,9,10, and
11) which revealed sharp strong absorption bands at about 1743-1736
nm
-1
correlated with the ester function, and other sharp strong bands at
about 1707-1657 cm-1 that could be assigned for the conjugated
carbonyl group. Further absorption band at 1600-1607 cm
-1
was
attributed to the (C=C) bond conjugated with the ketone carbonyl group.
Compounds IIa, IIc, and IId have shown sharp strong bands at 33903393 cm-1 and these could be attributed to the keto-enol forms of the
cyclohexenones, scheme (3-7).
O
OH
O
O
X
CH3
Y
O
O
X
Keto form
Y
Enol form
(IIa) X= H, Y= H
(IIc) X= H, Y= p-OCH3
(IId) X= H, Y= m-CH3
Scheme (3-7)
CH3
The 1HNMR of compound IIb, figure (6), (page 76), table (4) shows the
following values of chemical shifts ; δ 1.07 ppm, 3 protons as triplet,
attributed to CH2 –CH3, δ 2.335 ppm, 3 protons as singlet attributed to
Ar-CH3, δ 2.916 ppm, 1 proton, as multiplet attributed to CH-Ar , δ 3.11
ppm, 1 proton, as double of doublet, attributed to CHCOOC2H5 , δ
3.752 -3.801 ppm, 2 protons , as multiplet attributed to CH2CHAr, δ
4.062 ppm 2 protons, as quartet attributed to CH2CH3, δ 6.56 ppm 1
proton, as singlet, attributed to =CHCO, and δ 7.136-7.555 ppm 9
protons, as multiplet, attributed to H-Ar.
O
O
O
CH3
CH3
(IIb)
δ ppm
1.07
2.33
2.91
3.11
3.75-3.80
4.06
6.56
7.13-7.55
3H, t
3H, s
1H, m
1H, dd
2H, m
2H, q
1H, s
9H, m
CH2-CH3
Ar-CH3
CH-Ar
CHCOOC2H5
CH2CHAr
CH2CH3
=CHCO
H-Ar
Integration
Protons
Table (4)
1
H NMR Data of Compound (IIb)
Mass spectrum of compound IIb figure (12), (page 79), shows a
molecular peak m/z 334 corresponding to the molecular mass of the
compound, also it shows that the main fragment that depart the molecule
is the ester group, giving a base peak m/z 261with relative abundance of
100 %, the following figure shows the fragmentation patterns of
compound (IIb) :
O
1 O
5
O
CH3
4
3
2
CH3
(IIb)
M+ = 334.40828
1-
C19H17O
261.1279 Da
C3H5O2
73.029 Da
2-
C15H15O3
243.1021 Da
C7H7
91.0548 Da
3-
C16H17O3
257.1178 Da
C6H5
77.0391 Da
4-
C10H8O
144.0575 Da
C12H14O2
190.0994 Da
5-
C2H5
29.0391 Da
C20H17O3
305.1178 Da
Figure (15)
The fragmentation patterns of compound (IIb)
Structures of compounds (IIa-IIf), when fed to the 1H NMR
predictor software (ACD/HNMR predictor v.8.03), their spectra showed
high similarity to those of the actual ones, these spectra allowed us to
confirm the structures of our products. The following figures show the
electronic HNMR spectra of compounds (IIa-IIf) which were displayed
using ACD/HNMR Viewer (v. 8.03);
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0.60
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1.04
O
O
0.50
[4.04]
[6.59]
[7.41]
[7.11]
0.40
O
[3.50]
[7.25]
[1.04]
[7.20]
[2.74; 2.82]
[7.41]
[7.36]
7.21
7.20
CH3
[4.28]
[7.20]
[7.25]
[7.11]
[7.20]
(IIa)
97
4.03
4.05
0.30
1.02
1.05
7.11
7.40
0.20
7.42
7.13
6.59
7.09
4.26
4.29
4.07
4.02
0.10
3.48
3.52
3.50
3.46
3.54
0.00
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
2.75
2.77
2.81
2.83
2.85
3.0
2.73
2.5
Figure (16), The electronic 1H NMR of compound (IIa)
2.0
1.5
1.0
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O
O
1.20
[4.04]
7.08
[6.59]
1.10
O
[4.28]
CH3
[1.04]
[3.45]
[2.74; 2.82]
[7.41]
[7.11]
1.00
[7.41]
[7.36]
[7.08]
[7.07]
[7.11]
0.90
[7.07]
[7.08]
CH3
[2.18]
2.18
0.80
(IIb)
0.70
98
0.60
1.04
0.50
0.40
4.03
4.05
1.02
1.05
0.30
7.40
7.42
7.11
0.20
6.59
4.07
4.02
3.43
3.47
7.37
0.10
0.00
4.26
4.30
3.49
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.45
3.45
3.41
2.75
2.77
2.79
2.81
2.85
3.0
2.73
2.71
2.5
Figure (17), The electronic 1H NMR of compound (IIb)
2.0
1.5
1.0
0.5
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O
O
1.10
3.69
[4.04]
[6.59]
O
[4.26]
CH3
[1.04]
1.00
[3.43]
[2.72; 2.80]
[7.41]
[7.11]
[7.41]
[7.36]
0.90
[7.28]
[6.83]
[7.28]
[7.11]
[6.83]
O
CH3
[3.69]
0.80
(IIc)
0.70
1.04
0.60
99
0.50
0.40
7.26
7.29
7.40
7.42
0.30
6.84
6.81
7.11
1.02
1.05
4.03
4.05
0.20
7.09
6.59
4.24
4.28
4.07
4.02
3.45
0.10
0.00
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
2.73
2.75
3.41
2.77
3.43
2.79
2.83
3.0
2.71
2.69
2.5
2.0
Figure (18), The electronic 1H NMR of compound (IIc)
1.5
1.0
0.5
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O
O
[4.04]
0.90
[6.59]
[4.28]
O
CH3
[6.98]
CH3
[1.04]
[3.53]
[2.74; 2.82]
[7.41]
[7.11]
0.80
[7.41]
[7.36]
[7.07]
[7.11]
2.11
[2.11]
[6.95]
[7.13]
0.70
(IId)
0.60
100
1.04
0.50
0.40
7.11
7.13
0.30
4.03
4.05
1.05
1.02
7.40
6.98
0.20
7.42
6.96 6.59
6.94
7.37
0.10
0.00
4.26
4.29
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.07
4.02 3.55
3.53
3.57
4.0
3.53
3.51
3.5
2.75
2.77
2.79
2.81
2.83
2.85
3.0
2.73
2.5
2.0
Figure (19), The electronic 1H NMR of compound (IId)
1.5
1.0
0.5
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O
O
[4.04]
[6.68]
O
[4.28]
CH3
[1.04]
[3.50]
[2.77; 2.84]
[7.36]
[7.28]
0.60
[7.36]
Br
[7.25]
[7.20]
[7.25]
[7.28]
[7.20]
1.04
[7.20]
0.50
(IIe)
0.40
7.21
7.29
7.20
101
4.03
4.05
0.30
1.05
1.02
7.35
7.24
0.20
7.37
6.68
4.26
4.29
4.07
4.02
0.10
3.48
3.52
3.50
3.50
3.46
3.54
2.79
2.83
2.85
2.87
0.00
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.81
2.77
2.75
2.73
2.5
2.0
Figure (20), The electronic 1H NMR of compound (IIe)
1.5
1.0
0.5
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O
O
[4.04]
1.00
[6.58]
O
[4.28]
CH3
[1.04]
[3.50]
[2.74; 2.82]
[7.26]
[6.85]
0.90
2.29
[7.20]
[7.25]
[7.26]
H3C
[7.25]
[7.20]
[7.20]
[6.85]
[2.29]
0.80
(IIf)
0.70
0.60
1.04
102
0.50
0.40
7.21
7.25
7.20
4.03
4.05
0.30
1.05
1.02
6.86
7.27
6.84
0.20
6.58
4.26
4.29
4.07
4.02
0.10
3.48
3.52
3.54
3.50
3.50
3.46
7.29
0.00
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
2.75
2.77
2.79
2.81
2.83
2.85
3.0
2.73
2.5
2.0
Figure (21), The electronic 1H NMR of compound (IIf)
1.5
1.0
0.5
G. Roman51 had reported the addition of 3-aryl-1-(2-thienyl)prop-2ene-1-ones (chalcones) (I) to ethyl acetoacetate (II) to produce
cyclohexenone derivatives (III), scheme (3-8), 10 % sodium hydroxide was
used as catalyst, and the reaction was carried out under reflux for two
hours, the product yield was 43-79 %.
O
O
O
Ar
+ H3C
S
COOC2H5
COOC 2H5
Base
Ar
S
(I)
(II)
(III)
Scheme (3-8)
In our present work the same procedure was adopted . Alternatively, the
reaction was carried out under phase transfer cataylsis conditions ; thus in
addition to 10 % NaOH a PTC was used, these conditions collectively led
to reduction in reaction time (30 min-1 h), increase in product yield % (70
– 88.5 %) , furthermore reactions were performed at room temperature.
These results show the advantages of the
PTC technique over other
conventional methods, and reflects its importance as a convenient
synthetic technique for preparation of organic compounds.
I
3.4.1. General Mechanism of the Reaction of chalcones with ethyl
acetoacetate to produce cyclohexenone derivatives :
The reaction of chalcones with ethyl acetoacetate in presence of
catalytic amount of sodium hydroxide occurred via Michael addition
followed by an intramolecular cyclocondensation.The role of the base is to
deprotonate the ethyl acetoacetate (I) and forms the carbanion (II), which
undergoes Michael addition with chalcones (III) which has the ability to
act as activated unsaturated system in conjugated addition reactions of
carbanions in presence of basic catalysts. The addition takes place at the βcarbon of the chalcone, resulting in Michael addition product
(intermediate) (IV). In presence of the basic medium, further deprotonation
of the ethyl acetoacetate occurred (V), then the Michael addition
intermediate turns to the corresponding cyclohexenone (VI) through the
methyl group originating from ethyl acetoacetate, and the ketone function
from the initial chalcone, scheme (3-9).
II
O
O
O
O
OH H3C
CH 2
OEt
H3C
CH
(I)
OEt
( II )
O
O
H3C
O
CH
O
OEt
+
O
H3C
Ar
Ar
CH
O
OEt
O
H3C
O
OEt
O
Ar
Ar
Ar
Ar
( III )
O
O
H3C
O
( IV)
O
OEt
OH -
H 2C
O
O
O
OEt
OEt
-
O
Ar
Ar
Ar
Ar
Ar
Ar
( VI)
(V)
Scheme (3-9)
Comparison between the mechanism of the addition of Ethyl
β-
methoxycrotonate and ethyl acetoacetate to chalcones.
In α , β-unsaturated carbonyl bear
β Cα
C
C
β α
C
C
O
O δ-
O
O
O
C
C
C
C
C
C
C
Scheme (3-10)
III
C
C
δ+ C δ+
The carbonyl carbon and the β-carbon atoms bear a partial positive charge.
Hence nucleophilic reagents are expected to attack either the carbonyl
carbon or the β-carbon in a conjugate fashion. The following table shows
the addition of chalcone (α , β-unsaturated ketone) to ethyl βmethoxycrotonate and ethyl acetoacetate.
Table (5)
Comparison between the mechanism of the addition of Ethyl βmethoxycrotonate and ethyl acetoacetate to chalcones
Addition to Ethyl β-methoxycrotonate
Addition to Ethyl acetoacetate
IV
O
H
C
O
OH
OEt
H 3C
OEt
H 3C
OEt
H3CO
H
O
O
O
+
Ar
Ar
O
H3C
H
O
OH
Ar
Ar
H2 C
H3C
O
CH3
O
H3CO
O
O
OEt
H3CO
O
O
OEt
Ar
O
Ar
OH
Ar
O
H 3C
O
Ar
OEt
Ar
O
Ar
(Michael addition intermediate)
Ar
Ar
O
H3C
H3CO
OEt
O
The Michael addition intermediate would be
(Michael addition intermediate)
turned
Through
the
methylene
cyclocondensation
group
intermediate
the
Michael
of
the
into
the
cyclohexenone
intramolecular cyclocondensation of the methyl
addition
group of the acetoacetic ester and the ketone
can be easily converted to
function of the chalcone.
cyclohexenone.
3.4.2.
through
The mechanism of the reaction of chalcones and ethyl
acetoacetate under phase transfer catalysis conditions,
applying the Liotta interfacial model 15 :
V
Chalcone,ethyl acetoacetate, and tetrabutyl ammoniumhydrogensulphate (PTC), were added to the toluene (organic phase), the mixture was
initially stirred, then 10 % sodium hydroxide solution (the aqueous phase)
was added.
The aqueous phase may constitute But4NOH, NaHSO4, and NaHSO4
species according to the following equilibrium, scheme (3-11):
NaOH +
+
+
But4N HSO4
NaHSO4
But4N OH +
Scheme (3-11)
Tetrabutyl ammonium hydroxide (But4NOH) then deprotonates the ethyl
acetoacetate, hence an ion pair of the carbanion and the ammonium cation
is formed, scheme (3-12);
O
+
But4N OH +
H3C
O
O
OEt
H3C
O
-
OEt
+
H2O
+
N But4
(Ion pair)
Scheme (3-12)
The above equilibrium occurred according to the interfacial mechanism, at
the interfacial region, located between the lower aqueous layer and the
VI
upper organic layer. The formed ion pair is soluble in the bulk organic
phase, so it is transferred to the solvent layer to react with the chalcone
giving the required product, in addition to the ammonium cation (But4N+),
scheme (3-13).
O
O
O
Ar
Ar +
H3C
O
O
OEt
-
H3C
O
OEt
+
+
N But4
Ar
But4N
Ar
Scheme (3-13)
The ammonium cation transfers back to the interfacial region to perform a
new cycle of the reaction by carrying a new carbanion ions to the organic
layer, and so on. Scheme (3-14) shows the entire PTC process;
VII
+
Organic layer
O
O
O
Ar
Ar
+
O
O
H3C
H3C
O
OEt
-
OEt
N But4
Ar
+
+
+
But4N
Ar
----------------------------------------------------------------------------------------------------------------------------------------------------------------Interfacial region
O
+
But4N OH + H3C
O
O
OEt
-
HSO4
O
H3C
OEt
+ H2O
+
N But4
+
But4N OH
+
NaHSO4
NaOH
+
+
But4N HSO4
----------------------------------------------------------------------------------------------------------------------------------------------------------------Aqueous layer
NaHSO4
NaOH
Scheme (3-14)
The PTC mechanism of the reaction of chalcone with ethyl
acetoacetate
VIII
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