Different Influence of Structure Elements of Ionic Liquids on the Knoevenagel Condensation Reactions

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 H 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.


Introduction
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 [1] [2] [3].Nevertheless, the influence of every structure element of an IL on its catalytic ability is not fully understood, and this does not allow the selection of the very best medium for a specific reaction, nor to choose the optimal structure of IL for a catalytic application.The role of the anion in ILs has been evaluated and described most extensively, and ILs with the acetate or other carboxylate anion have been proposed for the performance of condensation reactions most often [4] [5] [6].Much less is known about the possible utilization of ILs with other anions for the needs of catalysis [7].The role of hydrophilicity (or hydrophobicity) and/or specific solvation ability (hydrogen bond, etc.) has clearly been incompletely appreciated for the acceleration of organic transformations in IL media.On this account, an attempt is made in the present study to evaluate systematically the effect of most significant structure elements of ILs on the rate and yield of a commonly used condensation reaction.

Results and Discussion
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 [1] [2], the imidazolium salts with the chloride anion being used mainly for comparison.The structure of the imidazolium cation is easy to change by introducing different substituents in the aromatic ring to design the structure of IL that imparts the necessary features to the cations of ILs 1 and 2. ILs with aliphatic cation (3) but the same two anions are included in the study just for comparison.ILs with the DMP anion have already been successfully used in our laboratory simultaneously as reaction media and catalysts in some condensation reactions [7] [8], and they are considerably more thermally stable than ILs with the acetate or other carboxylate anions (imidazolium salts with the DMP anion decompose at temperatures ≥ 240˚C [8]).In the present study, ILs with the DMP anion were prepared by direct alkylation of the corresponding 1-substituted imidazole with trimethyl phosphate or by metathesis of the chloride anion in 1,3-disubstituted imidazolium chlorides with the help of trimethyl phosphate, as described elsewhere [7] [8].The obtained ILs were fully characterized by 1 H NMR spectra, chromatography and determination of their moisture content and purity (content of basic substance).The 1 H NMR spectrum of a most frequently used IL with the DMP anion (2d) is presented below (Figure 1), just for illustration.
Resonanse signals of DMP anion protons at 3.26 and 3.23 ppm in comparison with protons at C 4 and C 5 in imidazolium cation at 7.81 -7.74 ppm serve well for confirming its structure.
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.Green and Sustainable Chemistry Again, the 1 H NMR spectrum (Figure 2) is the most convincing proof of the structure of the condensation reaction product (6).
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 C 2 and N 3 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 Choice of Reaction Conditions
The starting reaction conditions were chosen for the condensation of para-methoxybenzaldehyde (4) and ethyl cyanoacetate (5) based on literature data [7] [8] and results of our preliminary experiments, namely, a reaction in 1-butyl-3-methylimidazolium dimethyl phosphate (2d) at 80˚C.In order to Green and Sustainable Chemistry  6)-in the joint organic layer was immediately analyzed by gas chromatography (GC).The obtained results are presented in Figure 3.
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 (Figure 3).The yield did not change afterwards, and, therefore, a 15-minute time span was adopted as sufficient for the reaction to complete in all other ILs at 80˚C, with a molar ratio of 4:5:IL = 1:1:1.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) [9], the last showing an efficient catalytic activity in many Knoevenagel condensation reactions [7].On this account, our experiments suggest that the chloride anion is likely to provide some basicity in IL media, at least in some of them.The isolation of the condensation reaction product 6 was not successful in the IL [MEtOHIm] [Cl] (2i), most likely due to the effect of other structure elements of IL that will be discussed further.Our results convincingly prove the superiority of ILs with the DMP anion in comparison to those with the chloride anion (Figure 4).These results do not come as a surprise, because DMP is a week base even in a water medium.Even if no data about basicity of the DMP anion in ILs has been reported, our results do suggest this.At the same time, differences in the yields of the condensation reaction product 6 strongly confirm minor accelerating or decelerating effects of other structure elements in IL cations.

The Role of the Anion
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 Using the same cation in two of the selected ILs allows better evaluation of the effect of different anions (Figure 5).These kinetic curves confirm once more the fact noticed earlier that ILs with the DMP anion better catalyze the condensation reaction than those with the chloride anion; yields of the product 6, determined by GC, reached 97% in case of the DMP anion against an 84% yield with the chloride anion.The comparison of other ILs demonstrated different divergences, due to various substituents in the imidazolium cations (Table 1).Nevertheless, the trend remained the same: ILs with the DMP anion always provided higher yields of the isolated product than those with the chloride anion.

The Influence of the Substituent at the C2 Atom in the Imidazolium Cation
The third kinetic curve, which has not been considered above, is included in      The C 2 -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 C 2 -H bond on the transition state/states and lowers the yield of the condensation reaction.

The Influence of the Length of the Linear Alkyl Chain at the N3 Atom in the Imidazolium Cation
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 N 3 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 C 2 -H bond in their cations (Table 3).A small opposite effect was observed when a methyl group was attached to the C 2 -atom in the IL cation-the yield slightly decreased with the increase in the length of the alkyl chain.This means that the C 2 -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 C 2 -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 C 2 -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 (CH 3 or H) at the C 2 -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 Figure 4 and Table 3 confirm that the substituent at the C 2 atom in the imidazolium cation affects the condensation reaction rates in a lesser extent in ILs with the DMP anion than in those with the chloride anion.Even more, it is difficult to notice any certain trend in ILs with the DMP anion.Most likely, DMP, being a soft anion, is able to form a weaker hydrogen bond, if any, with the C 2 -H bond than the hard chloride ion.
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 N 3 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) (Figure 6).Table 3.The influence of the length of the linear alkyl chain at the N 3 atom and the substituent at the C 2 atom in the imidazolium cation on the yield of the condensation reaction product.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 (Figure 6).

The Influence of the Possible Formation of a Hydrogen Bond in the Imidazolium Cation
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 C 2 -H group.The data presented in Figure 4 and Table 4 evidence that the presence of OH groups has a clearly negative influence on the condensation reaction rates (and yields).The harmful effect increases in ILs containing the hard chloride ion instead of the soft DMP anion.A drastic decrease in the yield of the product (6) was observed, and sometimes no product could be isolated in the media of ILs with the chloride anion, such as [HOEtMIm] [Cl] (2i), even if a negligible yield (7%) could also be detected by GC in this case.A similar situation can be observed in reactions in the media of choline chloride (3a) and choline dimethyl phosphate (3b).
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 -C 4 H 9 , Y = DMP 2d) R = n-C 4 H 9 , Y = DMP 1e) R = n-C 8 H 17 , Y = Cl 2e) R = n-C 8 H 17 , Y = Cl 1f) R = n-C 8 H 17 , Y = DMP 2f) R = n-C 8 H 17 , Y = DMP Green and Sustainable Chemistry
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 Figure 4.No product 6 was isolated in experiments in the ionic liquid containing 2-hydroxyethyl group in their cation and chloride anion [MEtOHIm] [Cl] (2i), in contrast to IL with the same cation and DMP anion (2j).

Figure 5 .
Figure 5.It is the curve for the reaction in [BMMIm] [Cl] (1c) that would allow to appreciate the minor negative influence of the substituent at the C 2 atom(methyl group) in the imidazolium ring on the reaction course.Yields of the isolated product 6 showed a similar tendency in ILs with both the DMP and the chloride anions: the presence of a methyl group always slightly delayed the reaction and, consequently, decreased the yields (Table2).

Table 1 .
The effect of the type of anion on the yield of the condensation reaction product.

Table 2 .
The effect of the substituent at the C 2 atom in the imidazolium cation on the yield of the condensation reaction product.

Table 4 .
The influence of the possible hydrogen bond formation between the imidazolium cation and the transition state of the condensation reaction*.