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Ionic liquid have recently emerged as a major solvent of interest for wide range of organic synthesis because of its properties, such as lack of vapour pressure, liquid at room temperature, high thermal stability and its ability to recycle. Due to these properties they are also known as solvents for green synthesis and have rise as an alternative to the traditional damaging solvents (Earle and Seddon, 2000). These solvents are highly suitable for reactions, such as the Knoevenagel condensation reaction and produce high yield of product without any further purification (Liu et al., 2008). However, there are some limitations concerned with these ionic liquids; for example, they might undergo degradation in the presence of water, oxidising agents and ultrasonic reactions (Chowdhury, Mohan and Scott, 2007). To avoid the decomposition, task specific ionic liquids containing imidazolium salts were developed. These ionic liquids are highly water stable and can be applied successfully to the Knoevenagel condensation reaction which yields water as a by-product (Lee, 2006).
This document proposes a Knoevenagel condensation reaction using either [bmim]BF4 (1-butyl-3-methylimidazolium tetrafluoroborate) or [bmim]PF6 (1-butyl-3-methylimidazolium hexafluorophosphorate) as an ionic liquid in the presence of a catalyst, tetrabutylammonium hydroxide (TBAH). This research proposal will scrutinize the optimum amount of catalyst required for the proposed reaction, the reaction rates of two different ionic liquids at the room temperature and their tendency to get recycled and reused. Further studies include various methods of extraction, purification and analysis of the product obtained. The results obtained will illustrate the percentage yield, purity and the melting point of the products. This proposal includes plan and methods for achieving the objectives and a schedule for completing the project.
During the last decade, tremendous research came into action for the development
of a successful alternative to the most damaging volatile organic compounds (VOCs)
used in the synthetic organic chemistry. The quest for replacing the traditional high temperature molten solvents led to the discovery of new environmental friendly ionic liquids. Ionic liquids (IL) are generally solvents which are liquid at room temperature with no measureable vapour pressure and hence are also known as 'room temperature ionic liquids' (RTIL). The RTILs have been linked to green chemistry due to its attractive solvent properties and enhanced reactivity, thermal stability, reusability, low viscosity, ease of preparation, handling and product recovery (Chowdhury, Mohan and Scott, 2007; Harjani, Nara and Salunkhe, 2002; Welton, 2004).
Ionic liquids are salts composed of a cation and an anion where either or both the ions could be large. Most of the ionic liquids consist of a large cation with a low degree of symmetry in order to reduce the lattice energy of the crystalline salt, thereby reducing its melting point (Welton, 2004; Harjani, Nara and Salunkhe, 2002; Earle and Seddon 2000, Wilkes, 2002). Further studies have focused on altering the properties of the ionic liquids by changing their N-alkyl substituent, anion or by incorporating functional groups, creating 'task specific' ionic liquids (TSIL). For example, mixtures of 1, 3-dialkylimidazolium chloride (cation) and aluminium chloride (anion) act as a solvent and a catalyst in a Friedel-Crafts reaction (Lee, 2006).
Basic ionic liquids have interestingly developed an increased application in several base catalysed reactions, such as the Knoevenagel condensation reaction (KCR). KCR was used as an easy alternative to the traditional Wittig and Grignard reactions, which were expensive methods, gave toxic phosphine yield and produced equal amounts of E and Z isomers (Taha, Sasson and Chidambaram, 2008). On the other hand, Knoevenagel condensation is a simple method for the formation of a carbon-carbon single bond between active methylene and carbonyl compounds in the presence of a catalyst and a solvent (IL). This reaction is known for its high industrial importance in the preparation of substituted olefins, stilbenes and coumarins used widely as an antivirus, anti-inflammatory, antifouling agents, cosmetics, herbicides and insecticides (Harjani, Nara and Salunkhe, 2002; Forbes, Law and Morrison, 2006; Xuewei et al., 2008; Taha, Sasson and Chidambaram, 2008; Khan et al., 2004; Hangarge, Jarikote and Shingare, 2002; Liu, 2008; Taha, Sasson and Chidambaram, 2008).
KCR system discussed above suffers from a readily formed by-product, water and the work up steps for the product separation leading to ionic liquid destruction (Welton, 2004). Therefore, a wide variety of water stable imidazolium cation-based ionic liquids were developed using 1,3-dialkylimidazolium salts consisting of anions, such as PF6-, CH3COO-, BF4- etc. Imidazolium ionic liquids act as TSILs and can possess special properties when functionalised at either cation or anion, or both the sites. Recent advances in imidazolium TSILs have shown that it can be used as a catalyst to facilitate separation of the product, and can be recycled several times. They behave like a solid support bound covalently to the various kinds of aromatic aldehydes in the KCR, resulting in bound product which can be easily purified by simple washing. The catalyst used in the KCR is immobilised by the IL. Hence, they stay together and can be easily recovered by phase separation. In spite of the IL induced catalyst immobilisation, the catalyst has a tendency to undergo leaching by the co-solvents used for the extraction of the product. Therefore, to avoid losing the catalyst a safe and economical method was introduced; by the incorporation of the imidazolium salt motif which enhanced the catalyst reusability (Lee, 2006).
Table 1a: Structure and abbreviations for the anions and cations in a di or tri-alkylimidazolium salts (Chowdhury, Mohan and Scott, 2007).
Recent investigation of several catalytic approaches for the synthesis of stilbene (substituted olefin) derived from the KCR, led to the development of phase transfer catalysts (PTC) such as TBAB (tetrabutylammonium bromide). A series of PTC tested were found suitable for the complete conversion of the Knoevenagel condensation reaction, yielding more than 90% of the product after four hours. Whereas, tests performed without PTC produced only 22% of the stilbene form their weak acidic substrate. Further studies observed that the PTCs were more active in the extraction mechanism and hence, are a promising solution to the problem of product separation (Taha, Sasson and Chidambaram, 2008).
Further advancements in the study of ionic liquids for Knoevenagel condensation reactions gave rise to L-proline as a potential promoter. L-proline and ionic liquid system has emerged as an environmental friendly process for organic synthesis. It was observed that the reactions with salicylaldehyde and ethyl acetoacetate in ionic liquid did not react for 24 hours. But, on the subsequent addition of L-proline the reaction yield increased to 95% (Liu et al., 2008).
Statement of Problem
There are some limitations and weaknesses of the proposed research regarding the Knoevenagel condensation reaction using ionic liquids. These are due to several factors: acyclic ketones, IL degradation, excess of one of the starting materials, e-donating groups, and additional reactions such as Michael addition which are discussed below.
Experiments using substituted benzaldehydes, malonate and ionic liquid gave significant quantitative yield of Knoevenagel product. However, several tests detected the presence of other products apart from the product of concern. It was found that the Knoevenagel product is an excellent Michael acceptor which has a tendency to undergo Michael's addition, forming a Michael product. Hence, two products of different ratios were observed. The maximum yield of Knoevenagel product was obtained when the aldehyde, malonate and the ionic liquid's molar ratio were 1:1:0.5 respectively. Furthermore, it was illustrated by a series of reactions that the Lewis acidity of IL had a major impact on the ratio of the two products i.e., Knoevenagel: Michael (K: M) ratio. The increase in the Lewis acidity of IL resulted in a fall of K/M ratio, thereby increasing the conversion (Harjani, Nara and Salunkhe, 2002).
Ionic liquid's high thermal stability and its use in reactions with elevated temperatures, is often overestimated. Most of the ionic liquids bearing cations, such as di or tri-alkyl imidazolium, pyridinium etc. might undergo degradation by the neucleophilic attack of their anions forming a neutral product. These reactions occur at an elevated temperature and their degradation temperature depends on the neucleophilicity of the anion. Ionic liquids bearing a halide anion have a tendency to undergo decomposition, except phosphonium based ionic liquids. Ultrasound mediated reaction with ionic liquids, such as [bmim][BF4], [bmim][PF6] and [bmim][Cl] are prone to decomposition. The report taken through 1HNMR analysis during the sonication of all imidazolium ionic liquids produced new peaks of decomposed ILs. Moreover, the so-called water-stable ionic liquids possessing PF6- anion may also undergo hydrolysis in the presence of aqueous nitric acid. Other degradation reactions might occur when subjected to an oxidising agent, UV radiaton and photocatalysis (Chowdhury, Mohan and Scott, 2007).
Figure 1b: Neucleophilic attack:of the ionic liquid anion with; 1) di or tri-alkyl imidazolium ; 2) tetra-alkylammonium; 3) tetra-alkylphosphonium; and 4) pyridinium cations. (Chowdhury et al., 2007)
It is evident from several studies that the Knoevenagel condensation reaction between acyclic ketones and an active methylene group fails due to the steric hindrance. Whereas, cyclic ketones and aldehydes are very reactive compared to the hindered acyclic ketone and produce high percentage yield. In order to synthesize quantitative yield from acyclic ketones, high pressure effect was used. It was observed that under high pressure of 300MPa, acyclic ketones produced high amounts of sterically complex olefins through Knoevenagel condensations. The amount of pressure required for the successful conversion is directly proportional to the bulkiness of the acyclic ketones. Even though most of the conversions took place under high pressure conditions, ketones such as pinacolone do not react. Furthermore, the high pressure condition may raise the freezing point of the medium. Therefore, it is necessary to limit the pressure and use temperature to sustain the liquid state of the media. Another approach for the condensation reaction with ketones involved its activation using titanium tetrachloride and by the formation of ketimines from ammonia. But, the yield produced was still low due to the strong steric complexity (Song, Wang and Lam, 2003; Jenner, 2001; Harjani, Nara and Salunkhe, 2002).
Not every aldehyde shows a high rate of reactivity towards Knoevenagel condensation reactions. Aldehyde, such as 4-methoxybenzaldehyde have an electron-donating group at the para position which causes reduced reactivity. The substrates bearing a strong electron-withdrawing group reacts in a few hours and attains high productivity. But, if the reactants are in excess, it may react with the product formed and thus decrease its yield and purity (Song, Wang and Lam, 2003; Harjani, Nara and Salunkhe, 2002).
Therefore, these problems suggest that special care must be exercised when using an ionic liquid as a solvent for a particular reaction such as reaction involving ultrasound, elevated temperatures, high pressures, oxidising agents, UV radiation and photocatalysis. A suitable ionic liquid must be selected and attention must be paid when using the reactants as it may undergo or suffer from additional reactions, such as Cannizzaro reaction and Michael addition (Taha, Sasson and Chidambaram, 2008; Harjani, Nara and Salunkhe, 2002; Chowdhury, Mohan and Scott, 2007).
I propose to review the available literature on how ionic liquids can be used as a solvent in a base catalysed Knoevenagel condensation reaction. In my research project, I will try to achieve the following three criteria:
To determine the optimum amount of catalyst required for the proposed reaction.
To compare the rate of reaction using two different ionic liquids at room temperature.
To check how many times the catalyst system can be recycled and reused without any reduction in the product yield.
The purpose of this study is to devise a high-performance Knoevenagel condensation reaction system in an imidazolium salt ionic liquid using either [bmim]BF4 (1-butyl-3-methylimidazolium tetrafluoroborate) or [bmim]PF6 (1-butyl-3-methylimidazolium hexafluorophosphorate), with tetrabutylammonium hydroxide (TBAH) as a catalyst, that could be directly recycled several times.
One of the most significant factors is to optimise the amount of catalyst and the ionic liquid required to produce the maximum yield and how the reaction rate will be affected. This can be investigated by adding catalyst equivalent to 5% (mol/mol) of one of the starting material and then increasing it further to 20 and 40 % (mol/mol), till it gives maximum product yield. In my research, I will also investigate the time required for the completion of each reaction. On the basis of the percentage yield and the time, I will explain my first criteria and assess how well they meet the criteria.
The second goal of my research is to compare the reaction rates for a particular reaction using two different ionic liquids, [bmim]BF4 and [bmim]PF6 under similar conditions. One of the past methods observed the condensation reactions of aldehydes and ketones dissolved in [bmim]BF4 and [bmim]PF6 with malononitrile. The reaction mixture was stirred at room temperature (rt) with or without a catalyst. It was determined that the reaction occurred at a relatively slow rate in [bmim]BF4 as compared to [bmim]PF6 (Khan et al., 2004). Therefore, my aim is to further discuss the influence of these ionic liquids on the reaction rate and determine the most convenient ionic liquid system for the Knoevenagel condensations.
The third criterion is to recycle the catalyst and the ionic liquid system and to check its reusability. Ionic liquid can be recycled several times to produce high yield of the product which makes it an easy and convenient methodology for the reduction in experimental cost (Earle and Seddon, 2000). For example, in a Knoevenagel condensation of aldehydes with reactive methylene compounds using [bmim]Im (1-butyl-3-methylimidazolium imidazolide), the ionic liquid was successfully reused 12 times producing 90% of the yield (Xuewei et al., 2008). I will try to account for the possible number of recycles of the ionic liquid and the catalyst system, involved in Knoevenagel condensation of various compounds.
In order to reuse the ionic liquid and the catalyst, it must be extracted back as a mixture in appropriate amounts. Therefore, complete conversion of the starting material must take place and should be monitored by TLC (thin layer chromatograhy). After the successful conversion, the product and the ionic liquid can be isolated by using a simple phase separation method or by filtration (Hangarge, Jarikote and Shingare, 2002; Yue et al., 2008). To meet these objectives, I will rely on various purification and chromatographic separation techniques, such as IR (infrared spectroscopy), column chromatography, HPLC (high pressure liquid chromatography), NMR (nuclear magnetic resonance) spectroscopy, MS (mass spectrometry) and TLC. In this research, TLC will be used to determine the completion of the reaction and the purity of the product. The components of the complete reaction mixture can also be separated by passing it through a column packed with an adsorbent and monitoring it by TLC after certain time interval. However, in the case of ionic liquid and L-proline, high purity product was obtained by simple filtration and therefore, no further purification method such as column chromatography was required. (Liu et al., 2008)
In my research project, I will demonstrate the results quantitatively and explain how well the method works. Based on the background provided, ionic liquids with imidazolium salts are highly stable with strong basicity and possess good solvent properties for most of the compounds. In addition, these task specific ionic liquids offer a good yield of Knoevenagel condensation product at room temperature (rt) and can be easily recycled and reused without affecting the productivity (Yue et al., 2008). In some situations disagreements and unsuccessful experiments might exist. In such cases, I will present the limitations and drawbacks which may be justified with time as well as by the early developmental stage of my research.
Intended design and method of investigation
This section presents my plan for obtaining the objectives as discussed in the previous section. The study will conduct laboratory experiments and quantitative analysis to test the hypothesis. I will be working under the guidance and supervision of Dr. Qinguo Zheng to successfully complete the proposed research project.
The instruments used for the Knoevenagel reactions are mainly simple glassware and other equipments for analysis which are listed as follows:
Glassware such as conical flask, beaker, round bottom flask, condenser, graduated measuring cylinder, separating funnels, glass bottles, glass stoppers, evaporating dish, capillary tubes, glass rod, distillate etc. which are ideal for mixing liquids, thermally stable, resistant to chemical attack and produce accurate measurements (Helmenstine).
Magnetic stirrer and hot plate, vacuum inlet, thermometer, weighing boats.
Chromatographic equipments, such as TLC plates, glass column (for column chromatography) and HPLC for separating mixtures, identifying and purifying a compound.
Analytical instruments such as IR, NMR, and mass spectroscopy which are used for the determination of the components of a particular compound.
I plan to begin by developing a method gathered by various sources for the synthesis of ionic liquid and utilising it in a proposed Knoevenagel condensation reaction. I will discuss the best and appropriate extraction methods for product isolation and to recycle ionic liquid. The proposal will consider purification and analytical techniques for collecting data, such as rate of reaction, number of times the ionic liquid was reused and the percentage yield in order to satisfy the objectives.
Synthesis of 1-butyl-3-methylimidazolium tetrafluoroburate [bmim]BF4: a basic imidazolium ionic liquid.
One mole of freshly distilled 1-methylimidazolide will be mixed with excess of 1-bromobutane followed by stirring, heating and refluxing it for 24 hours in ethylacetate.
Two layers will be formed on the completion of the reaction. The top layer containing the unreacted compounds will be discarded and the bottom layer will be washed with ethyl acetate and diethyl ether. Further evaporation of the layer will obtain pure [bmim]Br (butylimidazolium bromide) (Hangarge, Jarikote and Shingare, 2002; Malham, Letellier and Turmine, 2008).
To the solution of [bmim]Br, a solution of NaBF4 (sodium tetrafuoroburate) in acetone will be added slowly and stirred at room temperature for four days.
The mixture would be then filtered besides the removal of acetone by rotary evaporation. The left over liquid will be dissolved in dichloromethane (CH2Cl2) and washed with water until it precipitates AgBr (silver bromide) on the addition of concentrated AgNO3 (silver nitrate).
The CH2Cl2 will then undergo rotary evaporation and the traces of other solvents will be removed by freeze drying at the beginning to obtain colourless [bmim]BF4. This can be further confirmed by NMR spectroscopy (Malham, Letellier and Turmine, 2008).
Synthesis of the substituted olefins
The following reaction mechanism is for the synthesis of the substituted olefins under Knoevenagel condensation reaction.
Scheme 1. Knoevenagel condensation reaction catalysed by TBAH in either [bmim]BF4 or [bmim]PF6. (Khan et al., 2004).
Equal molar ratio of the two starting materials will be charged in a 50 mL conical flask.
A few mL of ionic liquid will be added to dissolve the reactants. Catalyst equivalent to 5 % (mol/mol) will be added to start with the first reaction. Same reaction will be repeated using an increased amount of the catalyst to 10, 20, 40% (mol/mol) and so on. Their resulting percentage yield will be studied to detect the optimum amount of the catalyst.
The reaction mixture will be stirred continuously using the magnetic stirrer at room temperature till the reaction has completed. The completion of the reaction would be detected by either TLC or any solidification that occurs. The time taken by the reaction to complete will be observed.
The product then formed will be isolated by simple filtration using the Butchner apparatus (Lui et al., 2008, Yue et al., 2008).
In a 100 mL two necked round bottom flask, the first neck would be either connected to a trap or a silica gel tube to prevent any water from interfering. The second tube will be used for charging the starting materials.
Equal molar ratio of the reactants will be charged with ionic liquid and catalytic amount of TBAH. The reaction mixture will then be stirred and refluxed in ethanol at room temperature (Song et al., 2003; Taha, Sesson and Chidambaram, 2008).
In some cases, little temperature might be applied to the solvent mixture, if required and a condenser may be attached to the reflux system.
The reaction would complete after the crystals appear in the solvent.
The product will be extracted by simple filtration, followed by washing with ethanol.
The second method of extraction is by separating the organic layer, washing it with water and passing it over sodium sulphate. The organic layer will be concentrated by rotary evaporation. The remaining mixture containing the product and the reactants will be separated by column chromatography (Taha, Sasson and Chidambaram, 2008).
The isolation of the product in such reactions can be performed by three different methods as explained below:
Cold water: The reaction mixture will be poured into the cold water which will cause the solidification of the crude product. The next step will included filtration, followed recrystallisation from a suitable solvent such as ethanol. The filtrate left contains the ionic liquid which will be recovered by its concentration through rotary evaporation and reused for the next reaction (Yue et al., 2008; Hangarge, Jarikote and Shingare, 2002).
Phase Separation: By adding diethylether or toluene to the reaction mixture, two layers will be generated. The supernatant organic layer will contain the product which will be separated from the ionic layer by using a separating funnel. The organic layer will be then dried over sodium sulphate and the product would be obtained by simple rotary evaporation of ether. The ionic layer containing the ionic liquid medium will be reused (Khan et al., 2004; Hangarge, Jarikote and Shingare, 2002).
Distillation: The solvent in the reaction mixture will be distilled under reduced pressure, leaving behind the product (Hangarge, Jarikote and Shingare, 2002).
After the extraction of the crude product, my aim is to consider different methods of collecting data in order to test the propositions. I plan to analyse the isolated product and the recycled ionic liquid, using IR, NMR, HPLC and MS. Mass spectroscopy and HPLC will be used to achieve the percentage conversion of the substrate. If the result produced by the MS is a mixture of the starting material and the product, column chromatography will be used for its purification (Taha, Sasson and Chidambaram, 2008). The IR would compare and determine the difference between the ionic liquid recycled and the fresh ionic liquid synthesized earlier. The difference obtained will explain the reusability of the ionic liquid and would also conclude for the best recycling method (Yue et al., 2008). In addition, NMR is an alternative technique that can be used to test the recycled ionic liquid (Forbes, Law and Morrison, 2006).
After performing the above tests, I will record the data obtained as shown in the figures (Table 2a and 2b) below. I would further try to collect, compare and repeat the experiments over several weeks to produce the best results.
Table 2a: Knoevenagel condensation reaction of different carbonyl compounds with active methylene compounds by substituting the following groups onto the proposed reaction mechanism.
HPLC purity (%)
Melting Point (0C)
Table 2b: Number of possible recycles of ionic liquid ([bmim]BF4 and [bmim]PF6) in Knoevenagel condensation reaction using TBAH and their corresponding product yield.
Product Yield (%)
[bmim]BF4 (cycle 1)
[bmim]PF6 (cycle 1)
[bmim]PF6 (cycle 2)
This research terminates with a formal project report, which will be completed by 31st August 2010. In order to complete this report, I will follow the schedule presented in Figure 3a, where most of my time will be spent in the laboratory to gather the results.
Figure 3a: Gantt chart illustrating the schedule for the completion of my project.