1. Introduction
The use of microwave (MW) irradiation as a tool for organic synthesis has been a fast growth area [1-8]. Several examples have shown that the application of MW irradiation reduces the reaction time, increases the product yield and sometimes results in a different product distribution compared to conventional thermal heating method [1-6,9-20]. The rate acceleration observed in organic reactions using MW irradiation is due to material-wave interactions leading to thermal and nonthermal effects. The thermal effects result from a more efficient energy transfer to the reaction mixture, which is known as dielectric heating. This process relies on the ability of a substance (solvent or reactant) to absorb MW and convert them into heat. The reaction mixture is heated from the inside since the MW energy is transferred directly to the molecules (solvent, reactants, and catalysts). This process is known as 'volumetric core heating' and results in a temperature gradient that is reversed compared to the one resulting from conventional thermal heating [1,9-14]. Nonthermal effects result in differences in product distributions, yields, and reaction times. They may result from the orientation effects of polar species in the electromagnetic field that makes a new reaction path with lower activation energy [9-14, 21-23]. It has been suggested [24] that MW activation could originate from hot spots generated by dielectric relaxation on a molecular scale. Currently, thermal and nonthermal effects are being extensively studied mainly to verify the existence or not of nonthermal effects [21-23].
Several studies have reported the application of ionic liquids (ILs) in different areas and, in particular, their use in organic reactions [25-33]. ILs are generally defined as liquid electrolytes composed entirely of ions. Occasionally, a melting point criterion has been proposed to distinguish between molten salts and ILs (mp < 100 °C). However, both molten salts and ILs are better described as liquid compounds that display ionic-covalent crystalline structures [34-35]. Suitably selected, many combinations of cations and anions allow the design of ILs that meets all the requirements for the chemical reaction under study; based on this, they are also known as 'designer solvents' [36]. Properties such as solubility, density, refractive index, and viscosity can be adjusted to suit requirements simply by making changes to the structure of the anion, the cation, or both [37-43].
The junction of the use of MW irradiation with the use of ILs provides a method of high interest in organic synthesis. ILs interact very efficiently with MW irradiation through the ionic conduction mechanism [7-8] and are rapidly heated at rates easily exceeding 10 °C per second [44-50]. Despite few reports on the exact measurement of their dielectric properties and loss tangent values, the experimentally attained heating rates of ILs applying MW irradiation attest to their extremely high MW absorptivity [46,51]. This ability allows that small amounts of ILs can be employed as additives in order to increase the dielectric constant of nonpolar solvents characterizing them as doping agents [52-57]. In particular, ILs can be used as support in the synthesis of organic compounds which are carried out using MW irradiation and less polar solvents. Research groups have used ILs as doping agents for MW heating of otherwise nonpolar solvents such as hexane, toluene, tetrahydrofuran, and dioxane [52-57]. Thus, in view of the good relation between MW and IL, the following topics will be discussed in this chapter: (
2. Behavior of the Solvents Under Microwave Environment
Several organic solvents are used in various types of organic reactions under MW irradiation. The particular ability of the solvents to convert electromagnetic energy into thermal energy is directly related to their dielectric properties. The magnitude of the heating efficiency, in the specific temperature and frequency, is determined by the so-called 'loss tangent' (tan δ), whose formula is represented by Eq. 1 [52].
In Eq. 1, ε’’ is the dielectric loss and ε’ is the dielectric constant. A reaction medium with a high tan δ at the standard operating frequency of a MW synthesis reactor (2.45 GHz) is required for good absorption and, consequently, for efficient heating. Solvents used for MW synthesis can be classified as high with tan δ > 0.5, medium with tan δ 0.1 – 0.5, and low MW absorbing with tan δ < 0.1 (Table 1) [14,58]. In general, the reactions which used solvents with a high tan δ have a good absorption of MW irradiation and, accordingly, an efficient heating [8,59,60]. Solvents such as DMSO and DMF are essential to reactions performed in MW. While these are great solvents for performing the reaction, the subsequent workup procedure is difficult to remove them due to their high boiling point and miscibility with the product [53]. Thus, in certain situations, it is convenient to use solvents which are less polar such as THF, TOL and HEX [14,58,59-60]. However, it is necessary to use a heating agent for the reactions carried out in solvents with low absorption in the MW irradiation. ILs, for instance, can be added to the reaction medium to increase the absorbance level of the MW irradiation [51,59]. Therefore, the use of ILs appears as a support to increase the temperature of the reactions carried out in a MW transparent solvents [53].
Ethylene glycol | 1.350 | 1,2-Dichloroethane | 0.127 |
Ethanol | 0.941 | Water | 0.123 |
Dimethyl sulphoxide | 0.825 | Chloroform | 0.091 |
Methanol | 0.659 | Acetonitrile (ACN) | 0.062 |
1,2-Dichlorobenzene | 0.280 | Tetrahydrofurane (THF) | 0.047 |
Methylpyrrolidone | 0.275 | Dichloromethane | 0.042 |
Acetic acid | 0.174 | Toluene (TOL) | 0.040 |
N,N-Dimethylformamide (DMF) | 0.161 | Hexane (HEX) | 0.020 |
3. Heating Effects of Adding a Small Quantity of Ionic Liquid in Solvents
Systematic studies on temperature profiles and the thermal stability of IL under MW irradiation conditions were studied [52]. In these studies it was found that even the addition of a small amount of an IL resulted in dramatic changes in the heating profiles due to changes in the overall dielectric properties of the reaction medium.
Leadbeater and Torenius [53] studied the heating and contamination effects of several ILs in less polar solvents, such as HEX, TOL, THF and dioxane (DIO) (Figure 2) under MW irradiation. These authors have shown that all solvents used can be heated way above their boiling point in sealed vessels using a small quantity of an IL, thereby allowing them to be used as media for MW assisted chemistry. Table 2 shows the temperatures reached for pure solvents and for doped solvents with ILs using 200 W of power under MW irradiation.
The effects of varying the quantity of IL used to the solvent heating were investigated. The authors found that the best condition used was 2 mL of solvent and 0.2 mmol of IL, resulting in rapid heating. In these studies the contamination, if any, of the parent solvent with the IL or any decomposition products formed as they are heated were also studied [53].
Results showed that both [BMIM][PF6] and [BMIM][BF4] proved to be useful in MW heating of solvents, with [BMIM][PF6] being more effective (Table 3). There was no contamination of the solvent when using [BMIM][PF6] with any of the solvents screened or when [BMIM][BF4] was used with HEX. There was contamination due to the decomposition of [BMIM][BF4] when used with TOL or DIO; the extent was much less in the case of the latter. The [BMIM][BF4] was slightly soluble in THF thus in this case the only source of contamination at the end of the heating experiments was a trace of the parent IL rather than any decomposition. To the experiments, 100 W of the power was used [53].
Leadbeater
HEX | [BMIM][I] | 217 | 10 | 46 | 69 |
[ |
228 | 15 | |||
TOL | [BMIM][I] | 195 | 150 | 109 | 111 |
[ |
234 | 130 | |||
THF | [BMIM][I] | 268 | 70 | 112 | 66 |
[ |
242 | 60 | |||
DIO | [BMIM][I] | 264 | 90 | 101 | 101 |
[ |
246 | 90 |
HEX | [BMIM][PF6] | 279 | 20 | None |
[ |
90 | 300 | None | |
[BMIM][BF4] | 192 | 60 | None | |
TOL | [BMIM][PF6] | 280 | 60 | None |
[ |
79 | 120 | None | |
[BMIM][BF4] | 165 | 90 | Contaminated | |
THF | [BMIM][PF6] | 231 | 60 | None |
[BMIM][BF4] | 95 | 50 | contaminatedb | |
DIO | [BMIM][PF6] | 149 | 100 | None |
[BMIM][BF4] | 184 | 120 | Contaminated |
Hoffmann
A supplementary investigation covered the heating behavior of ILs as doping agent when mixed with solvents less polar in MW irradiation such as TOL and cyclohexane (100 mL of solvent in 1 mL, 3 mL and 5 mL of IL) (Table 4). Therefore, the authors concluded that small amounts of ILs are necessary to significantly reduce the heating time of TOL or cyclohexane under MW conditions. An increase in the MW power generates a reduction in heating time (Table 4). Also in this case, heating time approaches a limiting value even with an increase of the MW power. This was also true for the addition of ILs to both nonpolar solvents (TOL and cyclohexane).
100 : 1 | 100 : 3 | 100 : 5 | ||
[HMIM][Tf2N] | 300 | 318 | 90 | 70 |
[HMIM][Tf2N] | 400 | 167 | 66 | 53 |
[HMIM][Tf2N] | 500 | 112 | 54 | 39 |
[HBIM][PF6] | 300 | 548 | 168 | 143 |
[HBIM][PF6] | 400 | 319 | 126 | 92 |
[HBIM][PF6] | 500 | 229 | 88 | 86 |
Following the direction of these studies, we also performed some experiments using ILs as doping agents with several solvents under MW irradiation. The objective of this study was to check if the data of our MW equipment are in accordance with the data already published. Thus, we performed investigations of power profiles in different solvents with distinguished loss tangent values as DMF, ACN, THF, TOL and HEX in the presence of small quantities of [BMIM][BF4] as doping agent. The solvents doped were submitted under MW irradiation in an attempt to reach a temperature of 150°C (temperature which may be used in organic reactions) [62]. For this, we used various concentrations of IL in different solvents, as shown in Table 5. After reaching the desired temperature, the doped solvents were irradiated for 5 min and we verified that lower concentrations of IL required higher power for all solvents tested (Table 5). During the 5 min of MW irradiation the power remained substantially constant. Solvents with the low loss tangent such as HEX and TOL achieved only 99 and 108 °C, respectively, even though 300 W of power was applied.
1 | DMF | 0.057 | 20.402 |
2 | DMF | 0.107 | 18.679 |
3 | DMF | 0.196 | 16.887 |
4 | DMF | 0.397 | 15.895 |
5 | ACN | 0.048 | 38.967 |
6 | ACN | 0.104 | 31.229 |
7 | ACN | 0.205 | 30.478 |
8 | ACN | 0.407 | 29.402 |
9 | THF | 0.063 | 240.079 |
10 | THF | 0.103 | 185.834 |
11 | THF | 0.218 | 112.582 |
12 | THF | 0.401 | 69.415 |
13 | TOL | 0.045 | -b |
14 | TOL | 0.102 | 119.429 |
15 | TOL | 0.197 | 67.805 |
16 | TOL | 0.403 | 47.317 |
17 | HEX | 0.049 | -c |
18 | HEX | 0.105 | 130.718 |
19 | HEX | 0.210 | 68.858 |
20 | HEX | 0.398 | 60.301 |
Figure 4 illustrates the dependence between the concentrations of [BMIM][BF4] in the solvents and the power irradiated by MW equipment. At low concentrations of [BMIM][BF4] (~ 0.05 mmol.mL-1) a significant increase in the power is required to maintain the temperature of 150 °C. Another point is that, to maintain the temperature of 150 °C, solvents such as DMF and ACN did not require substantial variation of power as that found to HEX, TOL and THF when the concentration of IL ranged from ~ 0.05 mmol.mL-1 to ~ 0.4 mmol.mL-1. These data corroborate previous studies reported [53,61] and highlight the efficiency of [BMIM][BF4] as doping agent of poorly MW absorbing solvents.
4. Ionic Liquids as Doping Agents (ILDA) in Microwave Assisted Reactions
The efficient use of ILs as a doping agent in reaction under MW irradiation was firstly introduced by Ley
Protocols used the reactants thiophosphorylated amine resin and secondary or tertiary amides in a molar ratio of 1:3-20, respectively, to obtain thioamides, and used the reactants thiophosphorylated amine resin and primary amides in a molar ratio of 1:3.5, respectively to furnish nitriles. Reactions were carried out under both MW irradiation at 200 °C for 15 min to obtain the thioamides in 92-98% (Scheme 2) and nitriles in 95 - < 99% yields (Scheme 3). Acetonitrile was also investigated as an alternative MW absorbent and proved to be effective, in spite of being less efficient than the IL.
Eycken
The same authors [56] reported the synthesis of the chloro-pyridine and pyridonefrom the cycloaddition reaction of 2(1
Leadbeater and Torenius [53] described the Diels-Alder reaction from equimolar amounts of 2,3-dimethylbutadieneand methyl acrylate to furnish the [4 + 2] adduct cyclohex-3-ene using a mixture of TOL (2 mL) and [
The same authors studied [53] the reaction of Michael addition from equimolar amounts of imidazole and methyl acrylate to furnish the methyl 3-(imidazol-1-yl) propionate (Scheme 7). The mixture of TOL (2 mL) and [
Garbacia
Leadbeater
[PMIM][I] | 0.5 | PTSA | CH3(CH2)7-I | 81 | 56 |
[PMIM][I] | 1 | PTSA | CH3(CH2)7-I | 53 | 38 |
[PMIM][I] | 0.5 | H2SO4 | CH3(CH2)7-I | 3 | 55 |
[PMIM][I] | 1 | H2SO4 | CH3(CH2)7-I | 38 | 15 |
[ |
0.5 | PTSA | CH3(CH2)7-Br | 68 | 42 |
[ |
3 | PTSA | CH3(CH2)7-Br | 95 | 32 |
[ |
0.5 | H2SO4 | CH3(CH2)7-Br | 73 | 59 |
[ |
1 | H2SO4 | CH3(CH2)7-Br | 42 | 40 |
[BMIM][Cl] | 3 | PTSA | CH3(CH2)7-Cl | 32 | 0 |
[BMIM][Cl] | 3 | H2SO4 | CH3(CH2)7-Cl | 49 | 8 |
[BMIM][Cl] | 10 | PTSA | CH3(CH2)7-Cl | 42 | 35 |
Having found suitable conditions, the reaction was performed to a range of different alcohols. Further optimization of the reaction showed that the best reaction conditions for obtaining the 1-octanol were when IL was used in reaction medium. On the other hand, some dihalogenate 1,8-octanediol have furnished the best results when the co-solvent method was used as showed in Table 7. When using geraniol, not unexpectedly, geranyl iodide could not be isolated, but bromide and chloride could be obtained (Table 7). When using benzyl alcohol, it was possible to obtain the iodide in moderate yield (46%), the bromide in good yield (68%) but only the chloride in low yield (17%). The authors believe that the co-solvent method is better because the organic product is more soluble in the organic solvent than in the IL and that once formed it moves to the organic layer and is protected from decomposition which can occur in the higher-temperature, acid IL environment.
1,8-Octanediolb | [PMIM][I] | I-(CH2)8-I | 3 | 53 |
1,8-Octanediolb | [ |
Br-(CH2)8-Br | 3 | 86 |
1,8-Octanediolb | [BMIM][Cl] | Cl-(CH2)8-Cl | 10 | 50 |
Geraniol | [PMIM][I] | I-CH=C(Me)-(CH2)2-CH=CMe2 | 0.5 | Decc |
Geraniol | [ |
Br-CH=C(Me)-(CH2)2-CH=CMe2 | 3 | 47 |
Geraniol | [BMIM][Cl] | Cl-CH=C(Me)-(CH2)2-CH=CMe2 | 10 | 30 |
Benzyl alcohol | [PMIM][I] | PhCH2-I | 1 | 46 (72)d |
Benzyl alcohol | [ |
PhCH2-Br | 3 | 68 |
Benzyl alcohol | [BMIM][Cl] | PhCH2-Cl | 10 | 17 |
Silva
5. Ionic Liquids as Doping Agents in Microwave Assisted N -Alkylation Reactions
Reactions of
Taking into account the results found by Leadbeater and Torenius [53], Kresmsner
Based on the studies mentioned above, we decided to explore the doping capacity of IL under MW irradiation in the
Thus, we decided to investigate if a change in the alkylant agent reactivity could lead to higher conversions. Since iodine is a better leaving group than bromine, ethyl iodine was chosen to react with 3,5-dimethylpyrazole. Higher conversions were achieved for all tested solvents when compared with the results mentioned previously (Table 9). These results suggest that the nature of the leaving group would have greater influence than the basic catalysis on the product conversion.
Contrary to the results of Leadbeater and Torenius [53], we chose substrates for the reaction that showed moderate to good conversions. Thus, the IL is shown as an alternative to passive heating elements PHE [13].
1 | HEX | - | 0.117 | 59 |
2 | HEX | KOH | 0.123 | 50 |
3 | TOL | - | 0.123 | 17 |
4 | TOL | KOH | 0.127 | 37 |
5 | THF | - | 0.113 | 17 |
6 | THF | KOH | 0.124 | 17 |
7 | DIO | - | 0.108 | 9 |
8 | DIO | KOH | 0.118 | 41 |
1 | HEX | 0.123 | 75 |
2 | TOL | 0.114 | 43 |
3 | THF | 0.120 | 71 |
4 | DIO | 0.118 | 43 |
6. Conclusions
After analysis of the literature and results previously obtained by us about ILs as doping agents under MW irradiation, it is possible to conclude that: (
The examples of ILs as doping agents reviewed in this chapter showed that their applications are little explored and they have the potential to become an area of greater interest in the organic synthesis.
7. List of Abbreviations
ACN | Acetonitrile |
[BMIM][BF4] | 1-Butyl-3-methylimidazolium tetrafluoroborate |
[BMIM][Br] | 1-Butyl-3-methylimidazolium bromide |
[BMIM][I] | 1-Butyl-3-methylimidazolium iodide |
[BMIM][PF6] | 1-Butyl-3-methylimidazolium hexafluorophosphate |
DCE | 1,2-Dichloroethane |
DCM | Dichloromethane |
DIO | Dioxane |
DMF | N,N-Dimethylformamide |
DMAD | Dimethylacetalenedicarboxylate |
[DMMBisIM][I] | (Bis(1-methylimidazol-3-yl))methane iodide |
[DMMBisIM][PF6] | (Bis(1-methylimidazol-3-yl))methane hexafluorophosphate |
[EMIM][Tf2N] | 1-Ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)amide |
Grubbs' catalyst | Grubbs' Catalysts (are a series of transition metal carbene complexes used as catalysts for olefin metathesis) |
[HBIM][BF4] | 1-Buthylimidazolium tetrafluoroborate |
[HBIM][PF6] | 1-Buthylimidazolium hexafluorophosphate |
[HBIM][Tf2N] | 1-Buthylimidazolium bis(trifluoromethylsulfonyl)amide |
HEX | Hexane |
[HEIM][Tf2N] | 1-Ethylimidazolium bis(trifluoromethylsulfonyl)amide |
[HMIM][Tf2N] | 1-Methylimidazolium bis(trifluoromethylsulfonyl)amide |
ILDA | Ionic Liquids as Doping Agents |
[ |
1- |
[ |
1- |
[PMIM][I] | 1-Propyl-3-methylimidazolium iodide |
PTSA |
|
PHEs | Passive Heating Elements |
RCM | Ring-Closing Metathesis |
TOL | Toluene |
THF | Tetrahydrofurane |
Acknowledgments
The authors are grateful to Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq Procs. No. 578426/2008-0; 471519/2009-0), Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS/CNPq-PRONEX Edital No. 008/2009, Proc. No. 10/0037-8) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES/PROEX) for financial support. The fellowships from CNPq (M.A.P.M., J.T.F.), and CAPES (G.S.C., C.P.F., L.B.) are also acknowledged.
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The experiments were performed in a Discover CEM MW using the mode of operation: with simultaneous cooling and temperature sensor fiber optics. The power of the equipment was established at 200 W (or 300 W when necessary). A microwave vessel (10 mL) equipped with a standard cap (vessel commercially furnished by Discover CEM) was filled with solvent (3 mL) and [BMIM][BF4] (quantities indicated in Table 5). After the vessel was sealed, the sample was irradiated for 5 min at 150 °C, which was plotted in Synergies Version 3.5.9 software and a maximum level of internal vessel pressure of 250 psi. The irradiation powers are indicated in Table 5. The solvents doped were subsequently cooled to 50 °C by compressed air. - 63.
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The experiments were performed in a Discover CEM MW using the mode of operation: with temperature sensor fiber optics; without simultaneous cooling. The power of the equipment was established at 200 W. A microwave vessel (10 mL) equipped with a standard cap (vessel commercially furnished by Discover CEM) was filled with 1 mmol of 3,5-dimethylpyrazole and 1.2 mmol of 1-bromobutaneor iodoethane besides the addition of ~ 0.1 mmol.mL of [BMIM][BF4] (quantities indicated on Tables 8 and 9) and 3 mL of solvent (Tables 8 and 9). KOH was also added in equimolar amount to 3,5-dimethylpyrazole (1 mmol) at experiments indicated in Table 8. The vessel was sealed. The sample was irradiated for 30 min at 150 °C under high stirring and a maximum level of internal vessel pressure of 250 psi. The solvent of the resultant mixture was evaporated under reduced pressure. After this step, the conversion was determinate by 1H NMR. The 1H NMR spectra were recorded on a Bruker DPX 400 (1H at 400.13 MHz) and in CDCl3/TMS solutions at 298 K. The spectroscopy data for compounds 1-butyl-3,5-dimethyl-1 H -pyrazole and 1-ethyl-3,5-dimethyl-1H -pyrazole are present in the references: [31] and Potapov A. S., Khlebnikov A. I., Ogorodnikov V. D. (2006). Synthesis of 1-Ethylpyrazole-4-carbaldehydes,1,1’-Methylenebis(3,5-dimethylpyrazole-4-carbaldehyde), and Schiff Bases Derived There from42 4 550 554 respectively