The Beneficial Sinergy of MW Irradiation and Ionic Liquids in Catalysis of Organic Reactions

Abstract

The quest for sustainable processes is becoming more and more important, with catalysis playing a major role in improving atom economy and reducing waste. Organic syntheses with less need of protecting/de-protecting steps are highly desirable. The combination of microwave irradiation, as energy source, with ionic liquids, as both solvents and catalysts, offered interesting solutions in recent years. The literature data of the last 15 years concerning selected reactions are presented, highlighting the importance of microwave (MW) technology coupled with ionic liquids.

1. Introduction

Twenty years have elapsed since the publication of the seminal book by Anastas and Warner [1], where principles of Green Chemistry were formulated and presented in a systematic discussion. Since then, the idea of “eco-friendly” or “sustainable” ways to obtain and to transform chemicals has increasingly spread among the scientific community [2].

Catalysis is an important tool for the development of sustainable processes; among the other ones, alternative energy sources (as provided by microwave heating) and alternative solvents (for example, ionic liquids, ILs) are of major importance. Microwave irradiation rapidly gained importance and was widely applied as a “green” way to provide the necessary energy to reactions. In 2002, a book appeared [3] containing many examples of applications to organic synthesis, followed in 2006 by an increased second edition. In addition, ILs were the object of a book that became a two-volume set after few years [4]. Since then, reviews appeared discussing several aspects of both microwave (MW) and ILs topics, separately (see, for example [5,6,7,8,9,10,11]) and together (for selected examples, see [12,13,14,15,16]).

Nowadays, the use of ILs is quite diffuse, but a brief illustration of their characteristics may be useful for people not yet familiar with them. According to the generally accepted definition [4], Ionic Liquids are salts that are liquid at room temperature (or, at least, below 100 °C). They are non-volatile and non-flammable, which make them interesting substitutes for volatile organic solvents. Their properties depend on the nature of both cation and anion, thus giving access to a large number of compounds, often tailor-made, on the basis of reaction requirements. Moreover, depending on their miscibility or non-miscibility with water or organic solvents, they can be easily recycled, simply by distilling off (or filtering) the reaction product at the end of the reaction, washing with water, drying and reusing them. Generally, catalysts remain in the IL phase, so that addition of reagents allows a second reaction run. Thus, on the basis of their properties, ILs are considered “green solvents”. They are commercially available, with prices that became accessible with time, although purity is still a crucial item. Therefore, it is advisable to prepare them by known, simple, and reproducible procedures, rather than to buy commercial products [4].

One of us became involved in MW-assisted reactions in ILs since 2003, investigating oxidation of electrophilic alkenes by hydrogen peroxide in presence of a base [17]. ILs with1-butyl-3-methylimidazolium cation and different counteranions were used. Generally, epoxides formed quantitatively within few minutes at room temperature. The sustainability of the reaction was granted by the safe and inexpensive oxidant, by the non-volatile solvents, and, moreover, by the extraction of the organic product, performed with supercritical carbon dioxide. Later, screening the oxidation of different substrates with H₂O₂ and V^VO complexes in ILs, we found that MW irradiation had a beneficial effect in oxidation of organic sulfides [18], where a significant improvement in the rate of reaction and an increase in selectivity have been observed, when hydrophobic ILs were used in combination with MW activation. A completely different reaction we investigated was the C–C bond formation in ferrocene Friedel-Craft acylation [19]. Acylation of ferrocene with carboxylic anhydrides, catalyzed by Sc(OTf)₃ in bmimTf₂N occurred with high yields and excellent selectivity (Scheme 1). MW heating decreased reaction times from 50 to 60 min (conventional heating) to 1.5–4.5 min.

After almost a decade, we are interested in examining the state of the art as to the combination of MW as the heating source and ionic liquids as solvents. Considering the literature of the last 15 years only, the number of publication is impressive, amounting to more than five hundred. About 20% of them use the combination ILs/MW to transform biomasses or biomolecules (see, for example, [20,21,22,23,24]), a few papers used MW irradiation to facilitate the IL synthesis (e.g., [25,26]), some recent paper used ILs for the MW-assisted formation of nanoparticles to be used successively (for example, [27,28,29,30,31,32]), and the large majority of reports deal with organic synthesis, with ILs acting as solvents and/or as catalysts. Many organic reactions have been performed combining ILs and MW irradiation: esterification of alcohols [33] and of carboxylic acids [34,35,36], formation of diphenylmethyl ethers from alcohols [37], Michael addition of sulfonamides [38,39], asymmetric organocatalysis [40] or thiol-ene “click” reaction [41], to cite only a few.

In this review, we will focus our attention on oxidation and C–C bond formation reactions, published between 2002 and the beginning of 2017 that benefited from the combined use of microwaves and ionic liquids. Moreover, carbon dioxide functionalization, a hot topic nowadays, will be considered.

Structures and abbreviations of ionic liquids reported in the review are collected in Figure 1.

2. Oxidation Reactions

Different functional groups have been oxidized in ILs with MW assistance. H₂O₂ is one of the “greenest” oxidant, considering that it reduces to water, but also other primary oxidants have been used. Hydrogen peroxide needs an activator, either acid or metal-based. In the latter case, the choice of metal is important to ensure sustainability of the process.

Alcohols—Primary and secondary benzylic alcohols were oxidized to the corresponding carbonyl derivatives using KIO₄ as the primary oxidant, tetraethylammonium bromide (Et₄NBr) as ionic liquid, irradiated with MW without any other solvent [42], as illustrated in Scheme 2.

The selectivity is excellent, because carboxylic acids were never detected and competition experiments showed high substrate selectivity. Even more important, blank experiments demonstrated that oxidation without Et₄NBr does not occur at all, while scarce oxidation products were observed after conventional heating, even with prolonged reaction times. Therefore, the combination IL/MW is necessary to make the reaction efficient (although, strictly speaking, Et₄NBr is nor a real IL, since it should be liquid at ambient temperature or below 100 °C). The same reaction resulted much less efficient with other alkyl alcohols.

Immobilized IL on AuNP was an efficient catalyst in oxidation of benzyl alcohol by H₂O₂ in water [43]. The rationale of the method was to prepare polymeric materials based on poly(ionic liquid)s, to give the so-called “supported ionic liquid-like phases” (SILLPs). They combine the characteristics of ILs with those of polymers, in particular the ability to stabilize metal nanoparticles. Thus, stable AuNPs of different sizes were prepared, taking advantage of the ability of supported ILs to absorb inorganic or organic anions from a solution. AuNPCs–SILLPs were used to efficiently catalyze the oxidation of 1-phenylethanol in water, with H₂O₂ as the primary oxidant and MW irradiation as energy source. While with conventional heating the catalytic efficiency is higher with low-size AuNP [44], here the authors found that higher yields were obtained with the largest AuNPs. A polystyrene-divinylbenzene resin was used for a Merrifield-type linking of imidazolium cation with different anions (Scheme 3). The anion influenced the turnover frequency, with the best TOF (1383 h⁻¹) obtained when BF₄⁻ was the anion.

Interestingly, lignin-derived bio-oils, obtained by pyrolysis or MW heating, containing several benzyl alcohol functionalities, are reported to undergo aerobic oxidation [45] catalyzed by oxidovanadium or copper complexes in ILs. However, the paper is centered mainly on bio-oils and therefore it will not be discussed further.

Aliphatic alcohols are more difficult to oxidize than benzyl ones. An accurate screening on cyclohexanol oxidation showed that it can be selectively oxidized by H₂O₂ with different catalysts in the presence of ILs [46], Scheme 4. The screening examined different catalysts (H₂WO₄ resulted the best one), the influence of the amounts of oxidant, catalyst and ionic liquid, and the nature and role of ILs (considering both the cation and the anion). Imidazolium- ([omim]NTf₂), pyridinium- ([opy]NTf₂), and alkylammonium salts ([oepip]NTf₂, [ompyr]NTf₂, AliquatCl—also known as Aliquat336—and AliquatNTf₂) were used. Structures are reported in Figure 1. The authors concluded that ILs act as phase-transfer catalysts. Finally, MW irradiation was compared to conventional heating and resulted in reduced reaction times (from 90 min to 2.5 min, with Aliquat 336; with sonication, 7.5 min were necessary). Other cycloalkanols resulted less reactive than cyclohexanol. However, with all cycloalkanols, the corresponding cycloalkanones constituted more than 99% of the obtained products.

Alcohols were converted into oximes by reaction with hydroxylamine hydrochloride in ILs with MW irradiation [47]. Among the investigated ILs, 1-methylimidazolium nitrate, [Hmim]NO₃, gave the best results (Scheme 5).

The scope or the reaction is wide and, according to the authors, the protocol presents attractive features such as reduced reaction times, high yields and economic viability of the ionic liquid. Moreover, the IL could be reused at least three times, with limited activity reduction.

Oxidative amidation of alcohols was reported using tert-butylhydroperoxide (THBP) as the oxidant, task-specific ILs, with cations bearing the –SO₃H functionality and polyoxometalate anions, as catalysts, under MW-assisted and solvent-free conditions [48]. A wide range of alcohols and amines were used, the IL catalyst could be recycled six times, maintaining good activity, and when comparison with conventional heating was possible, MW conditions gave better yields in addition to reduced reaction times. One example is shown in Scheme 6.

The same research group applied the procedure to oxidative amidation of aldehydes with N-heteroarylamines [49]. The results are in line with those obtained with alcohols and the best catalyst was again 1-(3-sulfopropyl)pyridiniumphosphotungstate.

Alkenes—The alkene epoxidation was obtained with TBHP, using CpMo(CO)₃CH₃ as the catalyst precursor, at 55 °C [50]. Interestingly, the study compared the reaction output in conventional solvents (1,2-dichloroethane, toluene, hexane) with that in biphasic liquid-liquid, using 1-butyl-3-methylimidazolium tetrafluoroborate, [bmim]BF₄. Moreover, conventional oil-bath heating was compared with MW irradiation. From the comprehensive screening, MW irradiation emerged as the most efficient heating, shortening reaction times without affecting selectivity, which was 100% epoxide from cyclooctene. Efficiency was enhanced by microwave absorbing solvents, such as bmimBF₄. Another Mo catalyst was tested for cyclooctene epoxidation, i.e., pyimMo(CO)₄(where pyim is N-(propyl)-2-pyridylmethanimine) and the immobilized version of it, grafted on mesoporous silica MCM-41 [51]. However, in this example, MW heating was used only to prepare the catalyst, whereas [bmim]BF₄ was used in the subsequent cyclooctene epoxidation.

An interesting oxidation of terminal alkenes to aldehydes by ammonium persulfate was reported [52]; a palladacycle complex was the catalyst and [bmim]BF₄ the solvent (Scheme 7).

The reaction was highly selective in IL solvent, where only traces of ketone were observed, at variance with organic solvents, where phenylpropanone formed in amounts up to 25–40%. In the absence of Pd(II) catalyst no oxidation was observed. MW heating made the reaction to complete in 15 min at 70 °C with 89% yield, while conventional heating required 24 h, with yield decreasing to 73%.

Alkanes—Alkyl substituted aromatics were oxidized by aqueous TBHP in the presence of small amount of bmimBF₄, under microwave irradiation [53]. No other catalyst was necessary. Toluene and substituted methylbenzenes were transformed in the corresponding benzoic acids, while aromatic compounds with other alkyl groups were oxidized to ketones (Scheme 8). Without the IL, the reaction was much less efficient, requiring higher temperatures and prolonged reaction times, to give lower yields. No experiment was performed with conventional heating.

Finally, a recent report illustrated cyclohexane oxidation at 50 °C, under MW irradiation, by H₂O₂ and FeCl₂(tpm) catalyst [54] (tpm = hydrotris-(pyrazol-1-yl)methane). A variety of reaction conditions were investigated, varying the solvent, the reaction time, without or with additives (pyrazinecarboxylic acid, nitric acid, potassium carbonate). At the end of the reaction, before workup, triphenylphosphine was added to reduce the eventually formed cyclohexyl hydroperoxide to cyclohexanol. Although the best overall product yield (28% in 1 h) was obtained in MeCN with pyrazinecarboxylic acid as additive, the authors prefer the reaction in IL, because the relative ratio alcohol:ketone can be tuned changing the anion of IL (Scheme 9). Moreover, higher catalyticactivities under additive-free conditions were achieved and the catalyst could be re-used in several catalytic cycles, especially in bmimBF₄ (13 runs), maintaining its activity and selectivity.

Sulfides—Oxidation of organic sulfides is a very easy reaction that generally does not require harsh conditions. However, this is not the case of thiophene and related sulfur-containing heteroaromatic compounds. Their difficult oxidation requires conditions under which also alkenes are oxidized. This makes the use of oxidative desulfurization of fuels (ODS) not practicable, since, for a valuable fuel, alkenes should remain unaltered. Thus, taking advantage of the chemoselectivity shown by oxido vanadium(V) salen and salophen complexes, able to catalyze sulfides oxidation with H₂O₂, but almost inert towards alkene oxidation, dibenzotiophene was oxidized to the corresponding sulfone, while cyclooctene, chosen as model of alkenes, remained unaffected [55,56] (Scheme 10).

Reduced reaction times to minutes were obtained substituting external heating (oil bath) with MW irradiation [57]. A three-phase system was implemented for VO(V)-catalyzed desulfurization of a model fuel: an organic phase containing benzine, cyclooctene and dibenzothiophene, an aqueous phase containing H₂O₂, and the IL phase with the catalyst. At the end of the reaction, dibenzothiophene sulfone was in IL, while unreacted cyclooctene was in the upper benzine phase.

A similar rationale led to the recently reported extractive catalytic oxidative desulfurization (ECODS) process of diesel fuel model [58] that used H₂O₂ as the primary oxidant, a task-specific IL ([m_CO2Hpy]HSO₄) as the extractant solvent, and VO(acac)₂ as the catalyst. Microwave irradiation was used both for the IL synthesis and for the oxidation reaction (Scheme 11).

3. Carbon-Carbon Bond Formation

3.1. Transition Metal-Catalyzed C–CCoupling Reactions

Reactions catalyzed by transition metals (in primis palladium) that lead to C–C bond formation are of the utmost importance in organic synthesis and it is not surprising that the problem to make them more sustainable received attention, considering in particular the use of microwave activation [59]. Palladium-catalyzed alkoxycarbonylation reaction was recently reviewed considering, among improvements, the use of alternative solvents (ILs, scCO₂) and MW heating [60]. It is worth marking the asymmetric Pd(II)-catalysedoxycarbonylation of racemic pent-4-ene-1,3-diol by kineticresolution in ILs using a chiral ligand for palladium. MW irradiation was used to shorten reaction time [61]. A selection of transition metal-catalyzed coupling reactions are considered in the following.

Suzuki-Miyaura reaction—Palladium-catalyzed C–C coupling reaction between aromatic halides and areneboronic acids has been considered one of the most versatile approaches among the cross-coupling reactions. Several modifications of the original protocol were aimed at improving it not only from the scientific point of view, but also considering sustainability problems, that led to environmentally friendly Suzuki aryl-aryl coupling reaction, as reviewed in 2005 [62]. Good results were obtained in water [63], where aryl bromides reacted with benzeneboronic acid in a few minutes (1–5 min), with a benzimidazole-oxime Pd(II)-complex as catalyst and MW irradiation. The same system was used in the Heck reaction (vide infra) of aryl and heteroaryl bromides, such as 2-acetyl-5-bromobenzofuran [64].

In more recent examples, it was performed using as catalysts Pd complexes of imidazolium-type cations and 2-propanol/water as reaction medium [65]. It was shown that Pd(0) nanoparticles form in solution, but they act mainly as a source of catalytically active soluble palladium species. The reaction gave high yields under moderate heating (40–70 °C) with a variety of aromatic halides (Scheme 12). Conventional and MW heating were compared; the latter resulted in halved reaction times with analogous yields.

The use of nanoparticles has become increasingly diffused in catalysis, because NPs allow very easy recovery of the catalyst, thus rendering transformations eco-friendly.

The combination MW/ILs was used to prepare heterogeneous catalysts, efficient in Suzuki-Miyaura reaction performed under conventional heating [66]. Only in a second paper the reaction was performed in water under MW irradiation [67]. Halloysite, Al₂Si₂O₅(OH)₄·2H₂O, a naturally occurring aluminosilicate nanoclay with a tubular shape, was functionalized on the external surface by MW-assisted grafting of (3-sulfanylpropyl)trimethoxysilane, thus allowing anchoring of vinylimidazoliumionic liquids by a thiol-ene reaction. Two types of Hallosyte nano tubules were prepared and used in coupling reaction, as shown in Scheme 13 and Scheme 14.

The second generation HNT-IL2-Pd catalyst is definitely more troublesome to prepare than the first generation catalyst, but it has the advantage that could be used in five consecutive runs maintaining high efficiency, while HNT-IL1-Pd catalyst lost some efficiency in the second and third run (86% and 85% conversion from 95% in the first run) and became scarce after the fourth run (27% conversion).

An original and very efficient catalyst was recently developed preparing a supported ionic liquid-like phase (SILLP) covalently linking a C₆₀-IL hybrid to silica-based solid supports [68,69] (Scheme 15). This SILLP is able to immobilize and stabilize palladium nanoparticles in a system that was dubbed by the authors as “a sort of matryoshka” system. The silica catalysts are highly recyclable with no leaching above the limit of detection (0.5 ppm).

Heck reaction—Palladium-catalyzed vinylation of aryl halides or triflates has been investigated in a variety of non-conventional systems, from supercritical fluids to ionic liquids, from fluorous media to aqueous solvents, and with a variety of energy sources (microwave, ultrasound, high pressure), as a consequence of its synthetic value [70]. Interestingly, with the aid of microwaves, highly regioselective internal Heck arylation of hydroxyalkyl vinyl ethers by aryl halides could be performed in the “green” solvent water [71].

Considering ILs and MW together, in 2002 it was reported that 4-bromomethoxybenzene reacted quite easily with butyl propenoate when treated with palladium catalysts in IL and with MW heating (Scheme 16), even without addition of phosphine ligands [72], in more eco-friendly conditions than the usual ones.

The same research group succeeded in alkenylating the generally sluggish aryl chlorides, that reacted in the air, in a mixture of 1,4-dioxane-IL, with MW heating [73]. The reaction worked well not only with the most reactive electron-poor aryl chlorides, but also with electron-rich substrates, simply varying reaction times. [bmim]PF₆ was used with 10 mol % tri(t-butyl)phosphonium tetrafluoroborate, (t-Bu)₃PH]BF₄, with the so called “Herrmann’s palladacycle”, trans-di(μ-acetato)bis[o-(di-o-tolylphosphino)benzyl]-dipalladium(II) as catalyst. Reaction times varied from 30 min for the reactive halides to 60 min for the electron rich ones (Scheme 17).

Butyl propenoate was used as vinylating agent of aryl iodides in a Heck reaction in [omim]BF₄ with a simple Pd/C catalyst (3 mol %), that could be recycled up to five times with scarce loss of activity [74]. MW irradiation made reaction times very short (0.5 min), but yields were not always satisfactory; moreover, aryl halides were inert in these conditions.

Instead, Heck alkenylation was successfully achieved on aryl iodides, bromides and chlorides, using an ortho-palladated complex in non-aqueous ionic liquid, such as Bu₄NBr, Bu₄NCl, and [bmim]Br [75]. Other conditions being equal, Bu₄NBr gave the best conversion of halides and therefore was the solvent of choice for the reaction screening. Conventional heating and MW heating were compared, with the latter favoring the reaction in terms of reduced reaction times, thanks to microwave-absorbing nature of Bu₄NBr. Selected results are presented in Scheme 18.

Regioselectivity was discussed in detail in a study that examined the Heck reaction in DMSO/[bmim]BF₄, with MW as heating source [76]. It was observed that regioselectivity was higher in IL solvent and that MW heating reduced the reaction time from hours to minutes. As the catalyst, Pd₂(dba)₃ was used together with a sugar-derived phosphine ligand (methyl 4,6-O-benzylidene-3-deoxy-3-(diphenylphosphino)-α-d-altropyranoside).

MW-assisted Heck reaction was performed using the IL 1-(2-cyanoethyl)-3-(2-hydroxyethyl)-1H-imidazol-3-ium tetrafluoroborate as solvent, ligand and base, i.e., an efficient, air stable and phosphine free catalytic system (PdCl₂ was the precursor of the actual catalyst) [77]. A variety of substrates, with different electronic and steric effects, were treated under these conditions. Significant results are collected in Scheme 19.

A different approach was used by other researchers, that focused on new N-phenylbenimidazolium salts as ILs, while commercial Pd(OAc)₂ was the catalyst [78]. Actually, the salts are not liquid and were used in 2 mol % amounts, in solvents as DMF-H₂O or EtOH-H₂O. The system was used both in Heck and in Suzuki-Miyaura reactions on halopyridines. MW heating was determinant to obtain good results: there are examples of reactions not occurring at all under conventional heating that became practicable with MW irradiation. Reaction conditions are reported in Scheme 20.

An unusual Heck-type alkenylation was obtained directly from aryl alcohols instead of alkenes, in a one-pot reaction that was assisted by ILs and MW [79]. This procedure avoided prone to polymerization alkene reagents, did not require inert atmosphere, and could be applied to a wide range of substrates (Scheme 21).

Sonogashirareaction—The Pd-catalyzed coupling reaction of aryl chlorides and terminal alkynes was accomplished in 10 min using MW heating [80] and worked well also intramolecularly, leading to one-pot synthesis of indoles [81]. However, the procedures were far from being sustainable, since it was necessary to use phosphines, organic solvents, copper compounds, and a base. Instead, the Sonogashira reaction was made more eco-friendly when tetrabutylammonium acetate was introduced as an activator [82] in a copper-free system, with complete substrate disappearance within 15 min (Scheme 22).

Allylic alkylation—Efficient allylic alkylation was performed in tailor-made ILs, with Pd catalysts having phosphine-imidazoline ligands and MW heating [83]. The accurate investigation considered different catalysts, different ILs, MW irradiation, recycling, and enantioselectivity. The best results are shown in Scheme 23. The actual catalyst is formed in situ, by the [Pd(η³-allyl)Cl]₂ precursor and a phosphine-imidazoline ligand in IL (preferably, [bdmim]BF₄). The reaction also occurred at room temperature, but heating increased enantioselectivity.

Cyanation of aryl and vinyl halides—Although with a less wide scope, this reaction is important to prepare aryl and arylvinyl nitriles, useful synthones in organic synthesis. Moreover, cyanide sources are notorious toxic compounds, thus rendering advisable any new eco-friendly procedure.

The non-toxic potassium hexacyanoferrate(II), K₄[Fe(CN)₆], was used as cyanide source in a palladium-catalyzed reaction of several aryl and arylvinyl bromides, in ionic liquid under microwave irradiation [84] (Scheme 24). These conditions had the advantage not only to reduce the reaction time, but also to make product separation and catalyst recycle easier.

Ullmann reaction—A “green” catalyst was prepared treating graphene oxide (GO) with CuSO₄ and then reducing with ascorbic acid. The resulting Cu nanoparticles on reduced graphene oxide (RGO), Cu NPs@RGO, were used to catalyze the Ullmann homocoupling reaction (Scheme 25) [85]. MW irradiation was used with different solvents, ILs included. Optimized conditions were aryl iodides (or areneboronic acids) as the substrates, 10 mol % CuNPs@RGO catalyst, 1-butyl-3-methylpyridinium bis(trifluormethylsulfonyl)imide and H₂O (2:1 ratio) as solvent, and 30 min MW irradiation. Aryl bromides were less reactive, but still interesting yields were obtained (78–91%).

3.2. Friedel-Crafts Aromatic Substitutions

Acylation Reactions—It is well known that Friedel-Crafts acylation is a powerful method to prepare aromatic ketones, but is far from being a “green” procedure, because it requires chlorinated solvents and a more than stoichiometric amount of the “catalyst” AlCl₃. Therefore, attempts have been made to achieve a sustainable electrophilic acylation. Following the finding of metal triflates that, still maintaining strong Lewis acid character, are water resistant [86], some of them were used as catalysts in IL solvents.

The acylation of ferrocene, already discussed in introduction [19], showed that Sc(OTf)₃, Y(OTf)₃, and Yb(OTf)₃, could be used in 10 mol % amount in bmimNTf₂ and was improved by MW heating. Later, Bi(OTf)₃ was used to efficiently acylate methoxybenzene with different carboxylic anhydrides or chlorides in bmimPF₆ [87] (Scheme 26a). MW irradiation efficiently accelerated the acylation with yields generally increased.

The attention was then focused on MW-assisted benzoylation of aromatic compounds that was explored with a variety of substrates, evidencing the product distribution and the high yields [88] (Scheme 26b).

A screening of catalytic efficiency of various metal triflates was performed investigating acetylation of 1,3,5-trimethylbenzene with acetic anhydride [89]. Among the 14metal triflates examined, In(OTf)₃ gave the best results, being superior also to the above discussed Bi(OTf)₃ catalyst. 1-isobutyl-3-methylimidazolium dihydrogen phosphate, [ⁱbmim]H₂PO₄ was the solvent of choice and the reaction was applied to a wide range of aromatic compounds. The combination carboxylic anhydride/[ⁱbmim]H₂PO₄/In(OTf)₃/MW gave good performances and the catalyst could be easily recycled.

Considering the pharmaceutical importance of tetralone derivatives, such as donepezil hydrochloride, a “green” intramolecular Friedel-Craft acylation was carried out with Tb(OTf)₃ catalyst, in ILs (bmim or bupy triflates), under MW irradiation, directly from carboxylic acid [90] (Scheme 27). Tb(OTf)₃ emerged as the catalyst of choice after a screening of 19metal triflates; moreover, it could be recovered and re-used three times, with only slight decrease in product isolated yield.

Another metal triflate, Y(OTf)₃, was the best catalyst for regioselective 3-acylation of indoles [91]. MW irradiation and IL solvent ([bmim]BF₄) contributed to obtain high yields in few minutes (Scheme 28). Moreover, to further improve sustainability of the reaction, it was not necessary to protect the heterocyclic NH, thus eliminating the protection-deprotection steps, in agreement with the eighth principle of Green Chemistry [1].

The recovery of yttrium triflate in [bmim]BF₄ was simple: after product extraction, the ionic liquid containing metal triflate was dried under vacuum and reused. Differently substituted indoles were also acylated in good yields and only few percents of N-acylindoles were occasionally observed.

Aromatic Substitutions by elecrophilic aldehydes. The condensation of indoles with benzenecarbaldehyde was reported to be catalyzed by 1-benzyl-3-methyl imidazolium hydrogen sulphate, [bnmim]HSO₄, and improved by MW irradiation, in terms of higher yields and reduced reaction time [92] (Scheme 29a).

IL acted as an acid catalyst and MW heating shortened reaction times. A variety of aromatic aldehydes were used, with yields in the range 81–95% and reaction times varying from 5 to 19 min and the catalyst could be used in four consecutive runs, with negligible loss of activity.

Also [bmim]Br was found to catalyze reaction of aldehydes with indoles, probably behaving as both acid and base catalyst [93] (Scheme 29b). A wide range of aldehydes was reacted and, once again, the combination IL/MW was decisive in increasing yield and reducing reaction times, with the bonus of easy recovery and recycling.

Later, the synthesis of aryl(bis-3,3′-indolyl)methanes was obtained in good yields with a variety of aldehydes, ammonium-based ionic liquids and microwave heating [94]. Mild reaction conditions were accompanied, according to the authors, by simple product recovery and recycle of ammonium salts. When the indole 3-position was occupied by a methyl group, the reaction worked as well and aryl or alkyl(2,2′-bis-3-methylindolyl)methanes were prepared (Scheme 30).

A related reaction, that probably goes through electrophilic aromatic substitution, formed triphenylmethane and phthalein with catalysis by Brønsted acid ionic liquids and heating by MW [95] (Scheme 31).

MW heating was more efficient than conventional one, reducing reaction time from hours to few minutes. The work up was easy, reaction rates were fast, reaction conditions were mild, yields were good, and ILs could be reused: the combination IL/MW gave facile access to families of compounds important in dyes chemistry and biologically active [95].

Alkylation Reactions—Friedel-Craft alkylation is scarcely used in organic synthesis, because generally it is affected by polysubstituted by-products, since the more alkyl groups are introduced, the more reactive is the aromatic compound. Nevertheless, an interesting report appeared in 2013, where indium(III) triflate catalyzed alkylation of benzenes by alcohols in IL solvents with MW irradiation [96]. Noticeably, only monoalkylated benzenes were obtained (Scheme 32) with benzyl, tertiary, and secondary (but not primary) alcohols as alkylating agents, thus suggesting the possible intermediacy of carbocations. A phosponium-based IL, trihexyl(tetradecyl)phosphonium bis(trifluoromethanesulfonyl)imide, [thtdp]NTf₂, and the imidazolium-based [emim]NTf₂ were examined as solvents, with the latter giving the best results; energy-efficient heating was provided by MWs.

3.3. C–CBond Formation with C-Nucleophilic Reagents

Aldol-type reactions—It is well known that the aldol reaction is one of the most powerful tool for the construction of C–C bonds and it is considered relatively environmentally benign, being also highly atom-economic. However, due to the need of strong bases or acids, the “green” aspect can be improved, as discussed in a 2004 review [97]. Catalysis, biocatalysis, and alternative solvents, among which task-specific ionic liquids (TSILs) [98,99,100], have been the object of following research. Even a MW-assisted aldol reaction was carried on in absence of solvents [101].

The possibility to use together an alternative power source as MW and alternative solvents as ILs was explored in the aldol condensation reactions of aryl aldehydes with acetone [102]. Tetralkylammonium and tetrabutylphosphonium salts were prepared and used, with encouraging results (Scheme 33). The functionalized ILs acted as both solvents and the reaction did not require any strong acid or base to catalyze the aldol condensation. Aldehydes with electron-withdrawing substituents were—as expected—more reactive than the electron-rich ones. The system was effective also in the nitro-aldol condensation (Henry reaction). MW heating was confirmed to provide rate-enhancement with respect to conventional heating.

The condensation of aryl aldehydes with nucleophilic enolates was exploited to prepare bioactive heterocyclic compounds, such as chromanone and thiochromanone derivatives, in a MW-irradiated process, catalyzed by ILs with a basic anion [103] (Scheme 34).

The basic [bmim]OH IL catalyzed the synthesis of 3-styrylchromones from 3-formylchromones and a carbanion precursor, under MW irradiation [104] (Scheme 35). The authors pointed at the advantages of the method (easy work-up, short reaction times, satisfactory yields, reusable catalyst) and at the cytotoxicity of products.

The condensation of aryl aldehydes was achieved also with Brønsted acid ILs, giving xantenedione derivatives [105] (Scheme 36), in a process made fast by MW irradiation. In such reaction, products were simply isolated by filtration and the catalyst reused without treatment, although a dramatic drop in yield was reported from the second run (from 97% to 9%). However, a direct comparison of yields is difficult, because also the reaction time changed (from 10 to 1 min).

The reaction was extended to substituted aldehydes and diketones, with yields in the range 90–97%.

Benzoin condensation—Benzene carbaldehyde underwent benzoin condensation in 1-octyl-3-methyl imidazolium bromide that acted also as catalyst under MW [106] (Scheme 37a) as well as ultrasound [107] irradiation.

Similar results were obtained by another research group that used MW irradiation also in the ILs preparation [108] (Scheme 37b).

A further development was the preparation of diarylglycolic acids in [bmim]BF₄ and KOH, with MW heating [109]. Likely, KOH should deprotonate the imidazolium salt, forming the actual catalyst. This one-pot procedure resulted easy and efficient and was applied to substituted aromatic aldehydes, with results summarized in Scheme 38.

Morita-Baylis-Hillman reaction—DABCO-catalyzed C–C bond formation between an alkene bearing an electron-withdrawing substituent and an electrophilic carbon could be performed in water containing IL, only if MW heating was provided [110]. Under conventional heating, no reaction occurred in 3 h, while with MW irradiation the product formed almost quantitatively (isolated yield, >97%) within 3–7 min, that arrived at 20–40 s, if the reaction is carried on under 40 psi pressure. Nucleophilic α,β-unsaturated esters are less reactive, but the reaction still gives satisfactory yields, even with the sterically crowded t-butyl ester (Scheme 39).

The reaction was tested with good results also varying the aldehyde.

Knoevenagel reaction—In order to solve the scarce sustainability of catalysts used in Knoevenagel reaction, that is the C–C bond formation between aldehydes and active methylene compounds, a range of homogeneous and heterogeneous catalysts have been applied with varying results. Among them, the functionalized ionic liquid [bmim]OH was chosen to catalyze the reaction, because it can provide the necessary basic environment, beside the ionic one [111]. The section was performed in absence of other solvents, under grinding, conventional heating, and microwave irradiation conditions. The first method required longer reaction time than the other two and yields are comparable in all cases. Selected examples are shown in Scheme 40.

An application of MW-assisted Knoevenagel reaction to the synthesis of heterocyclic compounds was also reported [112]. Coumarin derivatives were prepared in high yields, in the determinant presence of imidazolium-based IL that rendered fast an otherwise sluggish reaction (Scheme 41).

Michael reaction—This well-known and versatile conjugated addition could not escape the attention of research aimed at applying modern eco-friendly procedures. Solvent-free metal- catalyzed Michael addition of β-ketoesters to enones was accomplished in tailor made IL, 1-butyl-3-methylimidazolium tetrachloroferrate, with MW irradiation [113]. The IL acted as iron catalyst and the system could be reused, after removal of products by distillation. The synthesis of [bmim]FeCl₄ was straightforward, simply mixing commercial solid [bmim]Cl with FeCl₃∙6H₂O and removing the resulting upper aqueous phase (Scheme 42).

Although not pertinent here (because a bond different from C–C is also formed), aza-Michael reaction has to be mentioned, because the pharmaceutically important family of N-alkyl sulfonamides could be prepared in ILs under MW heating, with green and reusable catalysts MgO [38] and ZnO [39]. Moreover, the addition of imidazole to cyclohex-2-en-1-one, followed by lipase-catalyzed kinetic resolution, led to optically active ILs [114].

Stetter reaction—1,4-Bifunctional compounds, key intermediates in organic synthesis, can be obtained by this reaction, that was investigated in the intramolecular version using IL solvents and microwave irradiation, since ILs only were not much efficient [115]. Among the tested ILs, [bmim]BF₄ allowed best results; 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide was used as the catalyst, with best performances observed when it was 15 mol %. A number of aldehydes were reacted, producing a library of substituted chroman-4-ones (Scheme 43).

Intramolecular Stetter reaction was performed under MW irradiation, either solventless or in ILs, with thiazolium-based ionic liquids that, in turn, were prepared by a one-pot, solvent-free, MW-assisted reaction (Scheme 44) [116].

Blank experiments demonstrated that thyazolium salts are real catalysts, since no reaction occurs without them; the base was necessary as well, while the IL solvent was of help, but the results were satisfactory also under no-solvent conditions.

3.4. Cyclization Reactions to Carbocycles with C–CBond Formation

Cyclotrimerization of alkynes to benzenes was brilliantly achieved using Pd catalyst supported on Au nanoparticles stabilized with thiolates [117]. With a loading of 4 mol % Au-bound Pd(II) catalyst, most of tested alkynes reacted completely in 1 h. The method became appealing when MW heating was used in IL solvent. Under such conditions, 1–5 min were sufficient to obtain quantitative alkyne conversion and good selectivity (Scheme 45).

Diels-Alder reaction—ILs were used as solvents also in this reaction and with time new ILs were synthesized on purpose. For example, a number of ammonium salts were prepared from 2-dimethylaminoethanol and used as the medium of the uncatalyzed and catalyzed Diels-Alder reaction [118]. Cyclopentadiene was chosen as the probe diene and was reacted with a number of dienophiles, with and without Lewis acids (triflates of Y, Sc, Yb, Al, Cu, Zn, Mg, Li).

One of the first studies aimed at investigating ILs combined with microwave heating was applied to Diels-Alder reaction [119]. Actually, the authors were interested in heating non polar solvents above their boiling point in sealed vessels adding a small amount of an ionic liquid, thus rendering the medium more polar and thereby usable for microwave-assisted chemistry. They also checked eventual contamination by IL decomposition after MW irradiation and found almost none, even after prolonged times (30 min at 300 °C). As the probe reaction, they tested the [4+2] cycloaddition between 2,3-dimethylbutadiene and methyl acrylate, that takes 18–24 h in boiling toluene or xylene to occur. Adding a small amount of 1-isopropyl-2-methylimidazolium hexafluorophosphate, [ipmim]PF6, to toluene and irradiating with MW, 80% Diels-Alder adduct formed in 5 min. Noticeably, MW irradiation of toluene without IL required 5 h to give 73% adduct.

Successively, other studies combined MW heating and ILs in Diels-Alder reaction, often in conjunction with Lewis acid catalysts.

A tungsten Lewis acid catalyst was prepared and used in Diels-Alder cycloaddition of a variety of dienes and dienophiles [120]. Water or [bmim]PF₆ were the solvents and MW irradiation accelerated the reaction in both solvents, decreasing them from hours to seconds. However, the selectivity reaction and the catalyst recycling were more favorable in the IL than in H₂O. Selected examples are shown in Scheme 46. The procedure was tested with several combinations of dienes and dienophiles, all with good yields (71–96%) and reaction times from 25 to 60 s.

Unusual dienes derived from oxazolidinone underwent Diels-Alder cycloaddition under different conditions, among which MW heating and IL solvents [121] (Scheme 47). In this case there is not a clear advantage in using the combination MW/IL with respect to the other conditions, shorter reaction time notwithstanding. In fact, yields and selectivity were much better in dichloromethane at −78 °C.

Other procedures used heterogeneous catalysts, such as montmorillonite (a mineral of hydrated aluminum silicate that is neutralized by exchangeable cations and interacts with organic molecules via electrostatic interaction, among alia), embedded in bmim-type ILs (changing the anion did not make any substantial difference) [122]; this protocol gave better yields than the reaction in ILs without montmorillonite and was accelerated by MW irradiation.

A screening of different Lewis acids, different ILs, and different activation modes (high pressure, ultrasound, and MW heating) was performed on Diels-Alder reaction of cyclopentadiene with some dienophiles [123] (Scheme 48).

From the huge amount of collected data, the authors concluded that: (i) the relatively high concentration of Lewis acid catalysts improved selectivity and the yields; (ii) high pressure accelerated the catalysed reaction, with only minor improvements in the selectivity; (iii) microwave irradiation accelerated the reaction considerably; (iv) ultrasound irradiation led to increased yields and selectivities.

A noticeable synergistic effect of the combination of microwave irradiation and protic ILs was evidenced in the Diels-Alder reactions between methylbutadiene and heterocycles as dienophiles [124]. The study was accompanied by DFT calculations, aimed at elucidating the role of IL. It was suggested that the protic IL protonates the pyrrole nitro group, thus favoring an asynchronous transition state.

Further examples of MW-activated Diels-Alder reaction in ILs were provided by the study in imidazolium-base tetrachloroaluminates [125,126]. Lithium bis(trifluorometansulfonyl)amide was used as Lewis acid, but resulted not much determinant in the output of the reaction. Instead, once again, MW irradiation accelerated the reaction, bringing it to completion in few minutes from hours (6–12) of conventional heating.

3.5. Cyclization Reactions to Heterocycles with C–C Bond Formation

The importance of heteroaromatic compounds, especially in pharmaceutical chemistry, is well known. Thus, it is not surprising that the synthesis of key rings has been explored in terms of sustainability, as well illustrated in 2014 reviews discussing alternative reaction methods for the synthesis of quinoline [127] and benzothiazole [128] derivatives, including syntheses promoted by microwave or ultrasound, recyclable and reusable catalysts, non-volatile solvents as ILs, or solvent-free conditions.

Other heteroaromatic compounds were prepared taking advantage of the MW-IL synergistic efficiency. The synthesis of benzofuran derivatives was promoted by [meim]Br and basic alumina [129]. Salicylaldehyde cyclocondensed with α-chloro ketones and esters. MW irradiation was compared to conventional heating and resulted more efficient as to reaction time, but almost the same yields were obtained with the two methods.

Twenty-five aromatic and heteroaromatic haloaldehydes and haloketones were cyclocondensated with ethyl isocyanoacetate to give 2-ethoxycarbonylindoles in a reaction catalyzed by CuI and [bmim]OH, under MW irradiation [130] (Scheme 49).

Tetrahydrocarbazole was prepared in a Fischer-type cyclocondensation catalyzed by pyridinium-based ILs and MW irradiated [131]. Different temperatures and different pyridinium ILs—with and without Lewis acid (ZnCl₂)—were tested; optimized conditions are shown in Scheme 50.

An original approach to substituted pyranes was the functionalization of ionic liquid, in order to obtain a soluble support for one reactant and the successive cyclization, followed by detachment of the formed pyrane [132] (Scheme 51).

3.6. Multi-Component Reactions (MCRs) with C–CBond Formation

Among the examples of carbon-carbon bond forming reactions, the protocols of multi-components reactions were revised, looking for eco-friendly conditions. For example, the Mannich reaction, i.e., the formation of β-amino carbonyl compounds from a non-enolizable aldehyde with an enolizable carbonyl compound and an amine (either primary or secondary), was thoroughly examined, also in view of the opportunity to be involved in tandem or cascade processes, with consequent high atom economy, as discussed in recent reviews [133,134,135].

The features that make MCRs appealing are the possibility of one-pot formation of two bonds and, even more interesting, is the easy access of libraries of compounds, simply changing substituents in any of the component. Ionic liquids and MW technique found application in the MCRs, at first separately [135,136,137], but quite soon the two were used together.

A strategy to use task-specific ionic liquids was developed and applied to the one-pot three-component synthesis of heterocyclic compounds, together with MW irradiation [138]. Imidazolium-based ILs were linked to poly(ethyleneglycol) (PEG), giving matrices to be used for the so called Ionic Liquid Phase Organic Synthesis (IoLiPOS). This method offers the advantage of solid-state synthesis, since side products can be easily removed by simple washing IL-PEG system. Moreover, the combination of IL-PEG/microwave decreases the viscosity of the reaction medium with consequent rate enhancement. Thiazolidinone formation was achieved in 1–2 h in good yields by microwave irradiation with IL-phase bound arylidene imine derivatives (Scheme 52). Primary or secondary amines performed easy cleavage of the ILP-bound thiazolidinones.

By the same procedure, 2-thioxotetrahydropyrimidin-4-(1H)-ones were prepared in good yields in 15 min [139] (Scheme 53). In the latter case, however, MWs were used only in the transesterification reaction to link the IL and the β-ketoester.

The same research group applied the same strategy for the synthesis of dihydropyrimidinones [140] (Scheme 54).

Polyhydroquinolines were prepared by a three-component reaction using ionic liquid-phase bound β-oxo esters that were synthesized by a solventless transesterification without catalyst, under microwave irradiation [141] (Scheme 55). MW heating was not used in the multi-component synthesis.

A complex system of condensed heterocycles was developed by two steps, three-components cascade reactions performed with ionic liquid supported 2-cyanomethylbenzimidazoles, coupled with 2-formylbenzoate and isocyanides under microwave irradiation [142]. All the combinations of N-substitutes benzimidazoles and different isocyanides gave the desired polycyclic isoquinolines, with good overall isolated yields, after detachment from IL (Scheme 56).

A functional ionic liquid, 1-(2-aminoethyl)-3-methylimidazolium hexafluophosphate, catalyzed the synthesis of pyrans with MW heating [143] (Scheme 57). Water was the co-solvent and the aqueous IL was reused, after filtering off the insoluble reaction product, in six more runs, retaining its efficiency.

Imidazolium salts with different alkyl chains were used as catalysts in a MW-irradiated MCR leading to tri-substituted imidazoles [144]. The most efficient catalyst was 1-heptyl-3-methylimidazolium tetrafluoroborate that was also easy to recover and recycle. Different aryl aldehydes reacted within few minutes with excellent yields, as shown in Scheme 58. With conventional heating, in the same IL, the reaction took more than 2 h to complete; however, it is not clear whether IL is really a catalyst, because no blank experiment was reported.

Molten tetrabutylammonium bromide, Bu₄NBr, resulted an efficient and recyclable catalyst for the MCR of β-naphthol and aromatic aldehydes that produced dibenzoxanthenes [145] (Scheme 59). Compared to other catalysts (Brønsted or Lewis acids), Bu₄NBr was one of the most efficient, giving the same yield than those reported for p-toluenesulfonic or sulfamic acids (90–94%). On the other hand, other conditions being the same, reaction times dropped from 60–90 min with conventional heating to 4–6 min with MW irradiation.

Xanthenones were synthesized in a solvent-free one-pot MCR catalyzed by task-specific IL and assisted by MW [146] (Scheme 60). 2-Naphthol, aryl and alkyl aldehydes, and cyclic 1,3-dicarbonyl compounds condensed in the presence of a Brønsted acid IL. Optimization of the reaction conditions showed that 5 mol % functional IL was the best catalyst load and the reaction scope was investigated with different substrates. The reaction worked well with all the types of aldehydes, aromatic, aliphatic and even acid-sensitive ones, but 2-naphthol was the only possible phenolic reagent, while neither 1-naphthol nor phenol reacted at all.

Substituted quinolines could be prepared in IL solvent by a MCR with a Lewis acid catalyst, with MW heating [147]. Different ILs and different metal triflates were used to optimize the reaction conditions that were successively used for the reaction with different substrates. The results are summarized in Scheme 61.

In other cases, the three-component reaction worked better in VOCs than in ILs. For example the best conditions to prepare 3-amino-substituted imidazo[1,2-a]pyridines from 2-aminopyridines, aldehydes and isocyanides were montmorillonite as the catalyst and toluene as the solvent, under MW conditions. On the other hand, in bmim ILs, lower yields and decomposition were observed [148].

Biginelli reaction—As reported in the 2014 chapter on carbonyl compounds as electrophilic reagents in multicomponent reactions [149], the so called Biginelli reaction is one of the most investigated one, with more than 1000 papers and almost 100 reviews at the time [150]. Since 2014, more than 300 other publications appeared, 17 of which are reviews. The interest is mainly due to the importance of multicomponent reactions for drug synthesis.

Classical conditions involve heating in an organic solvent, in the presence of acid catalyst, of an aromatic aldehyde with a 1,3-dicarbonyl compound and urea or thiourea, as in Scheme 62, although the role of the catalyst has been questioned [151].

A sustainable breakthrough was the Biginelli reaction catalyzed by ionic liquids in solvent-free conditions [152], while MWs were introduced later. We want to discuss here examples of the reaction that took advantage of the combined use of MW heating and ILs. The interested reader can find the other details in [150] and references therein.

The ad hoc prepared [bmim]HSO₄ IL in 10 mol % catalyzed a solvent-free Biginelli condensation to dihydropyrimidinones and dihydropyrimidinethiones, with high yields obtained after few minutes, under MW irradiation at 140 °C (Scheme 63) [153]. The procedure resulted in an improvement of reaction output as well as of sustainability.

The heterocyclic products are of potential medical interest, the procedure is sustainable, yields are from moderate to high (75–90% using MW, 67–80% using sonication), and MW irradiation was definitely superior in reducing reaction times (5–10 min, vs. 40–55 min with ultrasounds). However, it must also be considered that the reactions with sonication were performed at 50 °C, a temperature lower than that of MW irradiation. [b_SO3Hpy]HSO₄⁻ resulted the most efficient catalyst and could be recycled at least four times with no significant loss of activity. The reaction performed with conventional heating at 70 °C without solvents also gave high yields in 15 min [154].

Later, the multi-component condensation of β-naphthol with aromatic aldehydes and acetamide or urea was performed in [bmim]Br with MW irradiation [155] (Scheme 64). When a comparison is possible, yields are better than those previously described and reaction times are among the shortest reported. Moreover, the IL could be reused other three times, with negligible difference in results. Thus the procedure can be considered a sustainable alternative for the family of 1-amidoalkyl-2-naphthols, precursors of biologically active 1,3-oxazines.

A model Biginelli reaction (benzenecarbaldehyde, ethyl 3-oxobutanoate and urea) was performed testing different ILs as catalyst [156]. [Hmim]CF₃CO₂ performed better than [Hmim]HSO₄ and much better than non Brønsted acid ILs ([bmim]PF₆ and [bmim]BF₄). Under MW irradiation the reaction was complete in 2 min (99% yield), an improvement with respect to conventional heating that required 2 h at 100 °C. Thirty dihydropyrimidin-2(1H)-ones or thiones were obtained in high yields (Scheme 65).

An example where the synergy between IL catalyst and MW energy source is evident, is the formation of 3,4-dihydropyrimidin-2-(1H)-ones (Scheme 66) [157]. Using the same IL (1-carboxymethyl-3-methylimidazolium tetrafluoroborate), yields are better and reaction times sensibly lower with MW irradiation than with conventional heating. The IL—probably acting as a Brønsted acid catalyst—could be easily recovered and reused for six consecutive runs, showing almost no loss of activity.

A modification of bmim side chain introduced the nitrite group. The prepared [ONObmim]Cl was used to catalyze the formation of dihydropyrimidin-2(H)-ones and thiones, with MW heating at 80 °C. Within 3–4 min, products formed in 87–91% isolated yield. [ONObmim]Cl could be recycled and reused with the same performance for at least five runs [158].

An amino acid ionic liquid, glycine nitrate, was used as catalyst for the multicomponent synthesis of 3,4-dihydropyrimidin-2(1H)-ones and thiones with MW heating [159]. An ample range of substituents on aryl aldehydes confirmed the generality of the reaction. MW irradiation ensured fast reactions (10 min with urea, 20 min with thiourea). Comparing their results to those of previously reported protocols, the authors state that their catalyst is biodegradable and recyclable and could be reused for more than ten cycles without significant loss of activity. Moreover, gram scale synthesis was performed, forming the biologically active Monastrol, a mitotic kinesin Eg5 inhibitor (Scheme 67).

Another IL, [b_SO3Hpy]₃PW₁₂O₄₀³⁻, was used more recently as catalyst, under MW irradiation (120 °C), yielding in 5–10 min several polysubstituted dihydropyrimidinones and thiones [160]. However, the polyanion seems not to be really important, while the acidic functionality of the cation plays a major role in catalyzing the reaction.

The “three-component synthesis” of amino-substituted 1,3-diaza heteroaromatic derivatives was investigated using a variety of ILs, i.e., [bmim] with different counterions (Cl⁻, Br⁻, AcO⁻, BF₄⁻, HSO₄⁻), [b_SO3Hmim] with HSO₄⁻ or TfO⁻ anions, [b_SO3Hpy]HSO₄, and [b_SO3Hm₂cyu](HSO₄)₂ (Figure 1), that acted as catalysts with MW irradiation and as both catalysts and solvents when an ultrasound irradiation was used [161] (Scheme 68).

The versatility of the MW assisted and IL-catalyzed Biginelli reaction prompted the extension of the method to the synthesis of other pharmaceutically relevant heterocyclic compounds. Thus, potentially non-classical malarial antifolates made of pyrazole-linked triazolo-pyrimidine hybrids were prepared by Biginelli-type reaction, using the inexpensive triethylammonium acetate as IL catalyst and MW heating [162]. A library of 30 compounds was prepared, simply changing substituents in the heteroaromatic aldehyde and in the β-dicarbonyl compound (Scheme 69). The IL could be reused at least five times, with some loss in yield only after the third run. MW heating lowered reaction times to 2–3 min from 2.5 to 3.5 h with conventional heating.

Solid-supported IL was prepared from 1-methyl-3-(3-trimethoxysilylpropyl)imidazolium hydrogen sulfate, [p_Simim]HSO₄, and Fe₃O₄ nanoparticles. The magnetic nanoparticles were used in MW-assisted solvent-free Biginelli reaction [163]. According to the authors, this is an eco-friendly method that represents an improvement in terms of reduced reaction times, high turnover frequency, high yields of products, absence of solvent and recyclability.

4. Carbon Dioxide Transformation

The environmental impact of carbon dioxide excessive emission is well known and worldwide research is currently aimed at addressing and possibly solving the problem [164]. Although catalytic technologies were developed by chemical industry to transform carbon dioxide into valuable building blocks, not to speak of polycarbonates or polycarbamates, much more should be done and achieved by targeted research.

Carbon dioxide is thermodynamically stable and kinetically inert, so that activation by catalysts is necessary and the MW/IL combination might play a major role. In the field of carbon dioxide activation, one of the processes most investigated is the formation of organic carbonates, in view of their increasing importance as sustainable and environmentally-friendly alkylating agents [165].

ILs with tetrahaloindate as the anion were used to catalyze the transformation of oxacyclopropanes into cyclic carbonates, but MW irradiation was used only to synthesize them [166] (Scheme 70).

A mechanistic reaction scheme was proposed, where the superior performance of imidazolium tetrachloroindate was attributed to hydrogen bonding formation between Cl of the anion and the H in position 2 of imidazolium cation that increases the Lewis acidity of In(III).

Only years later MW irradiation was used together ILs to form cyclic carbonates from CO₂ and epoxides. The solvent-free coupling reaction of CO₂ with methyloxacyclopropane to produce cyclic carbonate under microwave irradiation was performed in the presence of catalytic amounts of Zn(II) salts and ILs [167], with different combinations of the two. An 11.2–278% TOF increment was observed (depending on the different combination of zinc salt and ionic liquid) with MW heating with respect to oil bath. With the five different ILs tested, the activity order observed is Bu₄NBr > [Hmim]Br > [bmim]Br > [emim]Br > Bu₄I. Under the optimized conditions, other oxacyclopropanes were reacted, with good results (Scheme 71).

A large number of papers dealing with formation of cyclic carbonates is due to the group of Dae-Won Park. They used MW activation without ILs [168,169,170], or ionic liquids without microwave activation [171,172,173,174,175,176], as well as the combination of the two that will be discussed here. ILs with different cations (ammonium, imidazolium) and different anions (chloride, bromide, iodide) were tested as catalysts in MW-assisted reaction of 2-(phenoxymethyl)oxacyclopropane with CO₂ [177]. The study indicated an inverse dependence of reactivity on the ion dimension, with chloride and emim giving the best combination. [bmim]Cl and [bmim]Br were chosen to be grafted on SiO₂, in order to investigate the heterogeneous catalysis. The reaction slowed (from 5 to 30 min with the same IL) but selectivity improved and the catalyst was easily recovered and reused. Finally, different epoxides were reacted, confirming the applicability of the procedure. Significant results are in Scheme 72.

The effects of variations in the morphology of silica support was investigated and published separately [178]. The same research group tested a different solid support, montmorillonite clay [179]. Tetraoctlylammonium chloride was immobilized on K⁺-montmorillonite by ion exchange and was suggested to act both as an activator of the reaction mixture and as a catalyst. The substrate was 2-(allyloxymethyl)oxacyclopropane, that was converted in the corresponding cyclic carbonate without solvent in good yield. The catalyst was reused three times, with yields decreasing slowly from 70.1% in the first run to 66.7% in the fourth one. The same epoxide was subjected to carbon dioxide reaction in a solvent-free treatment with pyridinium-based ILs, under WM heating [180]. Considering conversion, selectivity (vs. polymerization) and TOF, the best catalyst was bupyBr, but what makes the system especially appealing is the reaction time, 20 s, instead of 20–30 min of previous protocols (Scheme 72).

Finally, metal-organic framework (MOF) ligands carboxyl spacers were used to synthesize cyclic carbonates from oxacyclopropane and CO₂ [181]. The carboxyl functional molecular ribbon catalyst (containing bipyridyl, benzenedicarboxylic acid, and Cu or Zn cations) was synthesized with the help of MW irradiation and the formation of the cyclic carbonate benefited of IL co-catalyst, but the MW/IL has not yet tested with this MOF.

Much less investigated was the CO₂ transformation into non-cyclic carbonates. Carbon dioxide was reacted with methanol to yield dimethyl carbonate with K₂CO₃/CH₃I catalyst, with MW heating, in a process that required lower temperature and shorter reaction time when performed in [bmim]Cl [182]. According to the authors, the IL not only accelerates the reaction because it facilitates MW heating, but also, on the basis of density functional theory calculations, it interacts with CO₂, activating it.

5. Outlook

The picture that emerges from survey of the recent literature points at an increasing importance of microwaves as energy source, especially with modern instruments, with infrared temperature control and possibility to regulate pressure, very far from pioneering “domestic” oven of early papers. In addition, the use of ionic liquids evolved over several years, from solvents with peculiar properties to recyclable ones, to catalysts, homogeneous or supported on liquid phase heterogeneous or supported on solid phase. After testing a huge number of cation/anion combinations and after the idea of task-specific ILs, the trend now seems to be to use small amounts of robust ILs, in solvent-free reactions, under MW heating. This makes work-up particularly easy, with less waste and little need for other solvents for product extraction.

The large majority of papers were interested only in the reactions outcome, with wide screening of reaction conditions, experiments performed with systematic change of type and amount of catalyst and eventual additive, temperature, heating modes, accurate choice of IL and even synthesis of task-specific IL, investigation of substituent effects and of reproducibility, recycling of the IL/catalyst system. Unfortunately, scarce, if any, attention was paid to the role played by ILs in combination with MW irradiation. The only paper reporting an investigation aimed at investigating the combination IL/MW was interested in studying their effect on organic solvents, that could be heated in sealed vials, well above their boiling point [119], thus being usable in MW promoted reactions. Therefore, it is difficult to understand the real role of ILs in MW heated reactions. Generally, they may increase the MW heating efficiency rendering the reaction medium more polar. This resulted mainly in increased yields, lower temperatures and reduced reaction times. However, in some reactions they seemed to act as real catalysts.

It always dangerous to foresee the future, but our feeling is that, with melioration of MW instruments technology, the range of reactions performed preferably by MW irradiation with the aid of ILs will increase and, eventually, MW heating will substitute, at least at lab level, oil bath heating, in the same way that this substituted the free flame Bunsen burner.

Finally, it must be stressed that, although beyond the scope of the present review, there are other fields where a development may be found in the near future for the MW/IL combination, such as, for example, the shape memory polymer composites (SMPC), combining the advantages of microwaves and polyIL [183] or microwave therapy [184,185].