Ionic liquids (ILs) with 1,3-disubstituted imidazolium cations and the dimethyl phosphate (DMP) anion, as well as the chloride anion were prepared and characterized by 1H NMR spectra, chromatographic and titrimetric purity control, and determination of the moisture content and thermal stability. ILs with the DMP anion decompose only at temperatures above 240°C. These ILs were tested as both reaction media (solvents) and catalysts for the Knoevenagel condensation reaction. The impact of the most significant structure elements of ILs was evaluated for the rates and yields of the condensation reaction. IL anions have the greatest effect on the condensation reactions, and even the chloride anion has some catalytic effect on the Knoevenagel condensation. Side chains in the imidazolium cations influence the reaction course very little. The ability of the imidazolium cations to form hydrogen bonding with the transition state of the condensation reaction leads to a remarkable slowdown in the reaction rates.
Condensation reactions have a major role in the transformations of organic substances. These reactions are used for syntheses of both linear and cyclic substances, including heterocyclic compounds. Condensation reactions usually require catalysts―acids or bases, as well as appropriate solvents. Condensation reactions are most commonly performed in the media of organic solvents. However, the use of these solvents involves the risks of intoxication for laboratory workers, combustion or explosion. For eliminating these risks, in the last decades, ionic liquids (ILs), as substances that are environmentally friendly and harmless for workers, have been increasingly used instead of organic solvents. Furthermore, ILs possess an outstanding ability to dissolve most organic and inorganic substances, providing homogeneous media for condensation reactions. ILs also quite often serve as catalysts for these reactions. A particular advantage is the possibility of reusing ILs several times without any purification after every application.
The use of ILs in condensation reactions has been extensively described [
ILs with the 1,3-disubstituted imidazolium cations (1, 2) and dimethyl phosphate and chloride anions were selected for the study because of their increased thermal and chemical stability [
Note: DMP―dimethyl phosphate.
ILs with the DMP anion have already been successfully used in our laboratory simultaneously as reaction media and catalysts in some condensation reactions [
The DMP anion belongs to the soft anions, while the chloride anion―to the hard anions. The contrary character of both anions allows expecting different effects of ILs with these anions on the rates of the investigated condensation reaction.
The Knoevenagel condensation is one of the most significant commonly used reaction for the formation of the C = C bond in organic synthesis. The Knoevenagel condensation reaction between para-methoxybenzaldehyde (4) and ethyl cyanoacetate (5) in the investigated ILs was selected for evaluation of the influence of structural elements of various ILs on the rates of the condensation reaction. ILs served both as reaction media and as catalysts in these reactions. The reaction yields were calculated against the theoretically possible values, according to the reaction equation (see below). The methoxy group in the aromatic aldehyde slightly decreases the condensation reaction rate by comparison with unsubstituted benzaldehyde and thus facilitates determination of the rate of a reaction that is otherwise too fast.
Again, the 1H NMR spectrum (
The influence of two lines of ILs with the same imidazolium cations and chloride or DMP anions on the condensation reaction rates was systematically compared in this paper, the cations having different substituents at the C2 and N3 atoms in the imidazolium ring (1, 2). In this way, the influence of the three most significant structure elements of ILs on transition states of the Knoevenagel condensation reaction and, consequently, the rates of these reactions, were measured:
・ influence of the type of anion;
・ influence of the hydrophobicity (accompanied by the steric effect) of the cation;
・ influence of the ability of the cation to form hydrogen bonds.
The starting reaction conditions were chosen for the condensation of para-methoxybenzaldehyde (4) and ethyl cyanoacetate (5) based on literature data [
determine the necessary duration of the reaction, samples were taken from the reaction mixture in certain time intervals. Every sample was extracted with the mixture of ethyl acetate and saturated NaCl water solution (1:1) several times, the organic layer was separated, and the condensation reaction product―ethyl 2-cyano-3-(4-methoxyphenyl)propenoate (6)―in the joint organic layer was immediately analyzed by gas chromatography (GC). The obtained results are presented in
The performed GC measurements show that the investigated condensation reaction proceeded at 80˚C, reaching the highest yield (94%) as soon as in 15 minutes (
In order to evaluate the influence of the anion of ILs on condensation reaction rates, 16 structurally different ILs with the DMP and chloride anions were compared in the given condensation reaction. The obtained yields of the isolated product 6 are shown in
Yields of the condensation product 6 were always higher in all ILs with the DMP anion than in the corresponding ILs with the chloride anion. The latter does not show any basicity in water solutions. However, the Kamlet-Taft β parameter of the investigated ILs with the chloride anion (1.13) was quite close to the same parameter of IL with the acetate anion (1.18) [
In order to reinforce the hypothesis about the leading effect of the anion, kinetic curves were registered for the condensation reaction in three only slightly different ILs: [BMIm] [DMP] (2d), [BMIm] [Cl] (2c), and [BMMIm] [Cl] (1c) (
Using the same cation in two of the selected ILs allows better evaluation of the effect of different anions (
The third kinetic curve, which has not been considered above, is included in
IL | Yield, %* | IL | Yield, %* |
---|---|---|---|
[MMIm] [DMP] | 85 | [MMIm] [Cl] | 76 |
[BMIm] [DMP] | 89 | [BMIm] [Cl] | 70 |
[BMMIm] [DMP] | 87 | [BMMIm]] [Cl] | 66 |
* Yield of the isolated product (6) after 15 minutes at 80˚C.
IL | Yield, % | IL | Yield, % |
---|---|---|---|
[MMIm] [DMP] | 85 | [MMIm] [Cl] | 76 |
[MMMIm] [DMP] | 85 | [MMMIm] [Cl] | - |
[BMIm] [DMP] | 89 | [BMIm] [Cl] | 70 |
[BMMIm] [DMP] | 87 | [BMMIm] [Cl] | 66 |
[MOIm] [DMP] | 75 | [MOIm] [Cl] | 64 |
[MMOIm] [DMP] | 76 | [MMOIm] [Cl] | 60 |
* Yield of the isolated product (6) after 15 minutes at 80˚C.
The C2-H bond in the imidazolium cations possess a property of a weak C-H acid. Consequently, it is able to form hydrogen bonds between the transition state/states of the condensation reaction and the IL anions, which might be the explanation of the observed facts. The mentioned hydrogen bond might be stronger with the chloride anion (hard base) than with the DMP anion (weak base). As a result, the hard base (chloride anion) decreases the otherwise beneficial effect of the C2-H bond on the transition state/states and lowers the yield of the condensation reaction.
The hydrophilicity of ILs decreases with the increasing length of linear alkyl substituents in their imidazolium cations. Furthermore, a sufficiently long side chain of the cation can coil up into a globe, take a position in the space around the cation, or interfere in some other way with the rate determining the transition state of the condensation reaction and thereby hamper the rate-limiting step of the reaction. Besides, sufficiently long linear alkyl chains in the cation (the octyl and dodecyl groups at the N3 atom in the IL cation) can provide ILs with properties of surfactants with the following formation of micelles. In our experiments, the formation of micelles (and, possibly, their steric effects) were clearly observed only in ILs with the chloride anion and the C2-H bond in their cations (
A small opposite effect was observed when a methyl group was attached to the C2-atom in the IL cation―the yield slightly decreased with the increase in the length of the alkyl chain. This means that the C2-H group in the cation slows down the condensation reaction rate. The micellar effect also did not appear in ILs with a methyl group at the C2-atom, because the chloride ions in these ILs have no sufficiently acidic hydrogen atom to form hydrogen bonds. At the same time, hydrogen bonds appear if ILs have a C2-H bond. Furthermore, as the hydrogen bond is directly responsible for the decrease in the basicity of the chloride anion, the basicity becomes dependent on the substituent (CH3 or H) at the C2-atom in the imidazolium cation. The observed facts allow to put forward a hypothesis that the length of a side chain in imidazolium chlorides slows down the condensation reaction rate only in case if the hard chloride anion is capable to form hydrogen bonds. These facts also confirm the more important earlier observation that the anion type has a considerably higher influence on the transition state of condensation reactions than other structure elements of IL cations. Admittedly, this is only a hypothesis made from observations of just one reaction, therefore requiring further investigation.
Data presented in
The abovementioned micelle formation during the condensation reaction was observed in our experiments when the products were extracted with the mixture of EtOAc and water. Small beads of ILs in water formed in the interlayer between the solvents during the extraction process from ILs with the dodecyl and octyl groups at the N3 atom in IL cations, and it was quite difficult to separate these beads from the EtOAc solution of the product.
In order to ascertain the statement about the effect of the length of the side chain, three kinetic curves were once again registered for the condensation reaction in ILs with the same DMP anion but different substituted imidazolium cations, namely, [BMIm] [DMP] (2d), [MOIm] [DMP] (2f), and [DDMIm] [DMP] (2h) (
IL | Yield, % | IL | Yield, % |
---|---|---|---|
[MMIm] [DMP] | 85 | [MMIm] [Cl] | 76 |
[BMIm] [DMP] | 89 | [BMIm] [Cl] | 70 |
[MOIm] [DMP] | 75 | [MOIm] [Cl] | 64 |
[DDMIm] [DMP] | 87 | [DDMIm] [Cl] | 75 |
[MMMIm] [DMP] | 85 | [MMMIm] [Cl] | - |
[BMMIm] [DMP] | 87 | [BMMIm] [Cl] | 66 |
[MMOIm] [DMP] | 76 | [MMOIm] [Cl] | 60 |
[DDMMIm] [DMP] | 87 | [DDMMIm] [Cl] | 75 |
* Yield of the isolated product (6) after 15 minutes at 80˚C.
IL | Yield, % | IL | Yield, % |
---|---|---|---|
[BMIm] [DMP] | 89 | [BMMIm] [DMP] | 87 |
[HOEtMIm] [DMP] | 72 | [HOEtMIm] [DMP] | 7** |
* Yield of the isolated product (6) after 15 minutes at 80˚C; ** yield determined by GC.
The almost identical kinetic curves also indicate that, in contrast to the influence of the anion (e.g., DMP), the linear alkyl substituents in the cation structures of ILs have only a minor effect on the condensation reaction rates. Yields of the product (6) are high (93% - 97%) in all three reactions, and only an insignificant decrease in the yield can be observed in ILs with the lengthening of the substituent chains in their cations (
If the IL cation contains a hydroxyl group, the latter can form stronger hydrogen bonds with the transition state of the condensation reaction than the C2-H group. The data presented in
The introduction of a hydroxyl group in the imidazolium cation makes the reaction medium partly protic, similar to water or protic solvents. The chloride ion definitely has no measurable basicity in such media and, correspondingly, no capacity to convert ethyl cyanoacetate into the corresponding anion in order to start the catalytic condensation reaction. Further condensation process is not imaginable without this step.
Hence, ILs―imidazolium salts with the DMP anion can be considered as useful media and catalysts at the same time for the Knoevenagel condensation reaction between para-methoxybenzaldehyde and ethyl cyanoacetate and between aromatic aldehydes and activated methylene compounds in general. The influence of the type of anion on rates and yields of the condensation reaction is much more significant than the effects of other structural elements of ILs.
Chemical reagents of high purity were obtained commercially from Alfa Aser or Sigma Aldrich and were used without further purification. 1H NMR spectra were recorded in deuterated solvents with a Bruker Fourier 300 at 300 MHz, using the solvent as the internal standard. Moisture (water content) in ILs before their use was analyzed with a Karl Fisher 836 Titrant Metrohm automatized titrator. Hydranal-Composite 5 (Riede de Haën®) one-component titrant (reagent) was used, the highest systematic error of the analysis being ±0.2%. Melting points were registered with the Stuart SMP3 instrument (accuracy ± 0.1˚C). Purity of ILs was measured by titration: 1) for ILs with the DMP anion―with perchloric acid in glacial acetic acid using Solvotrode (Metrohm AG 9101 Herisau); 2) for ILs with the chloride anion―with silver nitrate in water solution. Gas chromatography (GC) was performed using a YL GC-6100 instrument with an EquityTM-5 (30 m × 0.25 mm × 0.25 mm) flame ionization detector and column, the mobile phase being helium with a constant flow rate of 1.0 mL/min. Gas chromatography-mass spectrometry (GC-MS) was performed using a Shimadzu GCMS-QP2010 instrument with an Agilent DB-5 MS capillary column (25 m, internal diameter 200 µm, layer thickness of the liquid phase―0.2 µm, the mobile phase being helium with a flow rate of 1.1 mL/min at the pressure of 40.7 kPa).
ILs with the DMP anion used for investigation were synthesized in two ways: 1) ILs with the chloride anion were first prepared by the traditional alkylation reaction of 1-substituted imidazoles with the corresponding alkyl chloride, followed by the chloride ion metathesis reaction into DMP with trimethyl phosphate (route A); 2) direct alkylation of 1-substituted imidazole with trimethyl phosphate (route B), as described earlier [
1-Butyl-2,3-dimethylimidazolium chloride (1c). A typical experiment. 1,2-dimethylimidazole (9.61 g; 0.10 mol), 1-chlorobutane (12.03 g; 0.13 mol), magnetic stirrer, and ethyl acetate (6 mL) were placed in a sealed screw-top steel pressure tube. The tube was placed in a glycerol bath and stirred at 80˚C for 72 hours. After cooling to room temperature, the reaction mixture was poured into a round-bottom flask and put in a freezer for 24 hours. The obtained crystalline mass was filtered, washed with ethyl acetate (4 × 25 mL) on the filter, then dried under vacuum at 40˚C and, after that, under high vacuum (0.5 mbar) at 60˚C for 6 hours. IL (1c; 23.34 g; 89%) was obtained as a white crystalline substance with m.p. 93˚C - 94˚C. 1H NMR spectrum (300 MHz, DMSO-d6, δ): 7.63 (2H, s, NCH = CHN); 4.11 (2H, t, NCH2-CH2-CH2-CH3); 3.74 (3H, s, CH3NCCH3); 2.58 (3H, s, CH3NCCH3); 1.68 (2H, m, NCH2-CH2-CH2-CH3); 1.29 (2H, m, NCH2-CH2-CH2-CH3); 0.92 (3H, t, NCH2-CH2-CH2-CH3) ppm.
Other ILs with the chloride ion were obtained in a similar way.
1-Butyl-2,3-dimethylimidazolium dimethyl phosphate (1d) (route A, obtained by the metathesis of the chloride anion). A typical experiment. 1-Butyl-2,3-dimethylimidazolium chloride (18.67 g; 10.0 mmol) and trimethyl phosphate (35.02 g; 25.0 mmol) were placed in a 50 mL round-bottomed flask equipped with a reflux condenser and a CaCl2 drying tube. The obtained mixture was stirred at 110˚C for 24 h. Toluene (5 × 10 mL) was added to the crude product, and the mixture was vigorously stirred and heated to reflux for 10 minutes. The toluene layer was then decanted while hot. The procedure was repeated four more times. Any remaining solvent was removed by vacuum evaporation (10 mbar, 70˚C, 4 h). The pure product was dried under high vacuum (0.5 mbar, 70˚C, 8 h) and was subject to AgNO3 analysis to confirm the absence of a starting material. Dimethyl phosphate (1d; 24.13 g; 92%) was obtained as an oil that solidifies into a white crystalline substance with m.p. 92˚C - 93˚C within 24 h in a refrigerator. 1H NMR spectrum (300 MHz, DMSO-d6, δ): 7.64 (2H, d, NCH = CHN); 4.13 (2H, t, NCH2-CH2-CH2-CH3); 3.74 (3H, s, CH3NCCH3); 3.23 (6H, d, P(OCH3)2); 2.58 (3H, s, CH3NCCH3); 1.67 (2H, m, NCH2-CH2-CH2-CH3); 1.29 (2H, m, NCH2-CH2-CH2-CH3); 0.92 (3H, t, NCH2-CH2-CH2-CH3) ppm.
Other ILs with the dimethyl phosphate anion were obtained in a similar way.
1,2,3-Trimethylimidazolium dimethyl phosphate (1b) (route B, obtained by direct alkylation with trimethyl phosphate). A typical experiment. Trimethyl phosphate (8.41 g; 0.06 mol) was added dropwise to 1,2-dimethylimidazole (4.81 g; 0.05 mol) with vigorous stirring in a round-bottom flask. The mixture was stirred for 1 h at room temperature, and then the temperature was raised to 80˚C. 10 mL of acetonitrile was added after 30 minutes, and the content of the flask was stirred at 80˚C for 48 hours. The hot solution was poured into a conical flask and left at room temperature for 24 hours. The formed precipitate was filtered, washed with ethyl acetate on the filter and then dried in vacuum (0.5 mbar) for 6 hours. IL (1b; 12.66 g; 91%) was a white crystalline substance with m.p. 124˚C - 126˚C. 1H NMR spectrum: (300 MHz, DMSO-d6, δ): 7.59 (2H, s, NCH = CHN); 3.75 (6H, s, CH3N-C(CH3) = NCH3); 3.23 (6H, d, P(OCH3)2); 2.55 (3H, s, NC(CH3)N) ppm.
Other ILs with the dimethyl phosphate anion were obtained in a similar way.
A sample of an ionic liquid with the DMP anion (1, 2, or 3b) (~100 mg) was dissolved in glacial acetic acid (50 mL) and titrated with the solution of perchloric acid in glacial acetic acid (0.05 mol/L) in the equipment for potentiometric titration. The purity (content of the main substance, %) of the sample was calculated from the obtained titration curves.
Ethyl 2-cyano-3-(4-methoxyphenyl)-2-propenoate (6). Ethyl cyanoacetate (0.57 g, 5 mmol) was added to the solution of 4-methoxybenzaldehyde (0.68 g, 5 mmol) in 1-butyl-3-methylimidazolium dimethyl phosphate (1.32 g, 5 mmol), and the reaction mixture was stirred at 80˚C for 15 minutes. Distilled water (3 mL) was added to the obtained yellow reaction mixture and the stirring was continued for another 15 minutes. The mixture was extracted with ethyl acetate (7 × 7 mL), and the joint extract was dried over MgSO4 for 16 h. The filtered solution was evaporated in vacuum, and the obtained yellow substance was crystallized from ethanol. Yellow crystalline ethyl 2-cyano-3-(4-methoxyphenyl)-2-propenoate (1.03 g, 89%) was obtained with m.p. 83˚C - 84˚C (lit. [
Condensation reactions in other ILs were performed in a similar way, and the obtained yields of the product (6) were recorded in Tables 1-4.
ILs with the DMP anion are appropriate reaction media and catalysts at the same time for the Knoevenagel condensation reactions to provide high yields of the condensation product. ILs with the chloride anion also show weaker catalytic properties in these reactions. Anions are the most significant structure elements in the ILs used in the mentioned syntheses. The length of IL cation side chains has a negligible effect on the performance of ILs, whereas the possibility of formation of hydrogen bonds between ILs and transition states of the reaction demonstrates a clearly negative reaction rate-reducing effect.
We gratefully acknowledge the Research Foundation of the University of Latvia for the financial support of this study.
The authors declare no conflicts of interest regarding the publication of this paper.
Zeltkalne, S. and Zicmanis, A. (2018) Different Influence of Structure Elements of Ionic Liquids on the Knoevenagel Condensation Reactions. Green and Sustainable Chemistry, 8, 320-333. https://doi.org/10.4236/gsc.2018.84022