A Thesis Submitted By Talal Ahmed Awad Mohammed B.Sc.(Hons
Transcription
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 ﺃﺎ 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); 08/Jun/2005 13:21:27 ACD/HNMR VIEWER (v.8.03) 0.60 File Name G:\New Folder (2)\nmr spectra\acd.HSP (modified on 19 FEB 2005) 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 08/Jun/2005 13:43:45 ACD/HNMR VIEWER (v.8.03) File Name G:\New Folder (2)\nmr spectra\b.HSP (modified on 19 FEB 2005) 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 08/Jun/2005 13:54:48 ACD/HNMR VIEWER (v.8.03) File Name 1.20 G:\New Folder (2)\nmr spectra\c.HSP (modified on 19 FEB 2005) 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 08/Jun/2005 14:11:38 ACD/HNMR VIEWER (v.8.03) File Name G:\New Folder (2)\nmr spectra\d.HSP (modified on 19 FEB 2005) 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 08/Jun/2005 14:15:02 ACD/HNMR VIEWER (v.8.03) File Name G:\New Folder (2)\nmr spectra\e.HSP (modified on 19 FEB 2005) 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 08/Jun/2005 14:18:39 ACD/HNMR VIEWER (v.8.03) File Name G:\New Folder (2)\nmr spectra\f.HSP (modified on 19 FEB 2005) 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 REFERENCES IX References 1- G. W. Gokel and W. P. Weber, J. Chem. Edu. 55, 353, (1978). 2- E.V. Dehmlow and S. S. Dehmlow, “Phase Transfer Catalysis”, Monographs in modern chemistry vol. 11, 2nd revised edition Weinhein, Deerfield.Florida ; Verlag Chemie, pages (1-41), (1983). 3- M. Makosza and W. Wawrzyniewiewicz, Tet. Lett.,4659, (1969). 4- A. Brandstörm and K. Gustavii, Acta. Chem. Scand., 23, 1215, (1969). 5- C. M. Starks and D. R. Napier, J. Am. Chem. Soc., 93, 195, (1971). 6- M. Makosza, Pure App. Chem. 72, 1399-1403, (2000). Copyright © IUPA 2000. 7- A. W. Herriot and D. Picker Tet. Lett, 4517, (1972). 8- A.W. Herriott and D. Picker J. Am. Chem. Soc., 97, 2345, (1975). X 9- B. Dietrich and J. M. Lehn. Tet. Lett., 1225, (1973). 10- C. J. Pederson and H.K. Frensdroff, Angew. Chem, 84, 16, (1972). 11- B. Lygo, J. Grosby, I. R. Loudon, and P. G. Wainright, Tet. Lett., 38, 2343, (1997). 12- F. Paul, Technical Reports (Albany Molecular Research Inc.), 4, (1999). Copyright © Albany Molecular Research Inc. 1999. 13- Charles Liotta and Kris Griffith, Phases (The Sachem phase transfer catalysis review) , issue 6 , 1, (1999).Copyright © 1999 Sachem Inc. 14- C. M. Starks and R. M. Owens, J. Am. Chem. Soc., 95, 3613, (1973). 15- M. Makosza, C.L. Liotta, and S. I. McCoy Phases (The Sachem phase transfer catalysis review) , issue 2 , 13, (1997). Copyright © 1997 Sachem Inc. 16- R. T. Morrison and R. N. Boyed, Organic Chemistry, sixth edition, USA, page 971, (1992). XI 17- Dinkova-Kostove et al. , Medical Sciences, 98, No. 6, 340, 2001. 18- D.G. Powers. et al , Tetrahedron, 54, 4085, 1998. 19- A. M. Rizk, The Phytochemistry of the Flora of Qatar, Scientific and applied research centre, University of Qatar, Printed in UK by Kingprint of Richmond. Pages 44, 227, 276, 313, 363, (1986). 20- F. Kunckell and Hammerschmidt, Chem. Abst., C26, page 100, (1914). 21- J. Tambor, Chem. Abst., 11, page 1969 2 , (1917) 22- R. W. Alder, R. Baker, and J. M. Brown, Mechanism in Organic Chemistry ,Unwin Brothers Ltd. England. 322, (1971). 23- E. Coombs and D. P. Evans, J. Chem. Soc., 1295, (1940). 24- S. Donald and A. William, J. Am. Chem. Soc., 77, 1397, (1955). 25- A. I. Vogel “A Text Book of Practical Organic Chemistry” Longmans, London, 3rd edition page 718, (1962). 26- D. S. Breslow and C. R. Houser J. Am. Chem. Soc., 62,2385, (1940). 27- J. B. Daskiewicz and D. Barron, Natural Product Research, 17, 347-350, (2003). XII 28- R. Ballini et al, Green Chemistry, 3, 178, (2001). Copyright © The Royal Society of chemistry 2001. 29- R. T. Morrison and R. N. Boyed, Organic Chemistry, sixth edition, USA, 979, (1992). 30- R. Conner and D. B. Andrews, J. Am. Chem. Soc., 56, 2713, (1934). 31- M. M. Al-Arab and B. S. Ghanem, Tetrahedron, 45, 6545-6552, (1989) 32- Ze Zhange et al, Chemistry Litt, 33, 168, (2004). Copyright ©2004 The Chemical Society of Japan. 33- M.Y. Shandala, M. T. Ayoub and A. A. Kareem, J. Heterocyclic Chem., 21, 1757, (1984). 34- W. P. Gullen et al, J. Chem. Soc., J. Chem. Soc. 2848, (1971). 35- T. R. Gormley and W. I. O’sulliran, Tetrahedron, 29, 369-373, (1973). 36- K. Tanaka and T. Sugino, Green Chemistry, 3, 133-134, (2001). Copyright © The Royal Society of chemistry 2001. 37- A. R. Katritzky et. al , web site : http://www:pubs.acs.org XIII 38- D. Azarifar and M. Shaebanzadeh, Molecules, 7, 885-895, (2002). Web site: http://www.mdpi.org 39- P. A. Bentley et al, Chem Commun., 1616-1617, (2001). Copyright ©The Royal Society of chemistry 2001. web site: www.rsc.org/chemcomm 40- Paulo A. de Almeida et. Al. J. Brazilian Chem. Soc., 10, No. 5, (114), 1999. 41- N.Yayli et al, Turk. J. Chem., 28, 515-521, (2004). 42- H. Gilman and R.H. Kirby, J. Am. Chem. Soc., 63, 2046, (1941). 43- V. Pedmavathi et al, Molecules, 5 , 1281-1286, (2000). 44- Mohammed Osman El-faki, MSc. Thesis, University of Mosul, College of Science, page 17, 1997. 45- D. Y. Kim, S. C. Huh and S. M. Kim, Tetrahedron Asymmetry, 42, 6299, (2001). 46- D. Y. Kim et al , Bulletin of the Korean Chem. Soc., 24, 1425, (2003). 47- A. Loupy and A. Zaparucha. Tet. Lett., 34, 473, (1993). XIV 48- Katalin Monostroy et al. Toxicology, 184, Issue 2-3, 203-210, 2003, (Copyright©2002 Elsevier science Ireland Ltd) 49- A. I. Vogel “A Text Book of Practical Organic Chemistry” Longmans, London, 3rd edition page 718, (1962). 50- E. Smissmann and A. Voldeng, J. Org. Chem. 29, 3161, (1964). 51- G. Roman, Acta Chim. Slov., 51, 537-544, (2004). XV