The experimental data accumulated so far in a wide scope of organic syntheses in glycerol proves our assumption that glycerol can perform many of the same functions as organic petroleum-based solvents and ionic liquids, as shown in Table 2. Different organic transformations involve both organic and inorganic compounds (March 1992) and are frequently performed in highly polar hazardous organic solvents, e.g., DMF, acetonitrile, and DMSO, or in water–organic biphasic systems. By comparison, our laboratory experience has shown that performing the nucleophilic substitution of benzyl chloride with potassium thiocyanate in glycerol (Table 2, entry 1), e.g., allowed dissolving both substrates in one phase and resulted in high conversion to benzyl thiocyanate.
The reduction of organic compounds is a fundamental transformation in organic synthesis. Metal hydrides are often used as stoichiometric reducing agent due to their relatively low price and to avoid high hydrogen pressure. Sodium borohydride can selectively reduce carbonyl compounds in water, alcohol, or their mixture. The reduction is very exothermic and the reacting mixture is usually cooled to decrease the evaporation of solvent and reactants. Besides dissolving sodium borohydride and benzaldehyde, as representative carbonyl compound, the reaction in glycerol can be performed without cooling due to its high boiling temperature and thermal stability. A stoichiometric amount of sodium borohydride was added to benzaldehyde solution in glycerol and the yield of benzyl alcohol was 100% after 15 min (entry 2). Many other carbonyl compounds such as 1-phenylethanol, 1-octanone, and 2-octanone were also easily reduced in short times under similar conditions.
Catalysis plays an important role in the development of environmental friendly processes (Blaser 1999). It may lead to the replacement of toxic reagents and improvement of activity and selectivity that reduces formation of byproducts and thus leads to simpler, cleaner, and more effective separation processes. Heterogeneous catalysts have the distinct advantage that they can be easily separated and reused, while homogeneous catalysis is usually very active and selective. Heterogenization of TMCs in biphasic systems to combine the advantageous of homogeneous and heterogeneous catalysis is frequently used.
Catalytic reduction with molecular hydrogen is very common. The reduction of styrene, which has low solubility in glycerol, to ethylbenzene was chosen as representative reaction and showed high conversions with both homogeneous (1) and heterogeneous metal catalysts (entry 3). Using glycerol as reaction medium allowed also to recycle the complex. The conversion of the second catalytic cycle after extraction of ethylbenzene with diethyl ether and addition of fresh styrene to the glycerol and the TMC phase was equal to the extraction of the first cycle. Since styrene is poorly miscible in glycerol, addition of low amount of non-ionic surfactant, Pluronic (PE 6400 BASF), to the biphasic system yielded an emulsion system and thereby increased the reaction conversion. Thus glycerol can also offer non-aqueous biphasic and emulsion systems, which find many applications infields other than catalysis and organic synthesis.
Use of a polar solvent is also an advantage in the one phase palladium catalyzed Heck coupling, since it allows dissolving strong inorganic base, which activates the reaction (Alonso 2005). Performing the Heck coupling of iodobenzene and butyl acrylate with both homogeneous palladium complex 2 and supported palladium catalyst and with the addition of sodium carbonate yielded high yield of butyl cinnamate (entry 4). In this reaction, glycerol as BmimPF6 dissolved inorganic, organic, and organometallic compounds and allowed easy separation of the formed product by extraction.
Moreover, glycerol also tolerates the uses of microwave heating. Microwave heating has found many applications in organic synthesis, as it is cleaner and reduces reactions time substantially (Kappe 2004). As previously stated, besides solubility of reactants, a solvent is also utilized to transport heat. In microwave heating, the solvent selection is even more crucial. Microwave heating is based on the ability of a solvent to absorb microwave energy and convert it into heat. It is usually increases when the dielectric constant of the solvent rise and in the presence of hydroxyl groups. Hence, glycerol is a very attractive solvent due to its high polarity and high boiling point. As expected, the microwave-assisted Heck coupling of iodobenzene and butyl acrylate was faster under microwave irradiation than the reaction under conventional heating (entry 4).
Asymmetric catalysis is a powerful tool in the synthesis of fine and special chemicals. Though several chiral TMCs were successfully employed for this purpose, the use of biocatalysts has some advantages, since it proceeds in mild conditions and it does not require tedious complex synthesis. Biocatalysis is usually carried out in water, yet non-aqueous biocatalysis was also reported in organic solvent to overcome the low solubility of organics in water and to avoid side reactions. Lipase-catalyzed kinetic resolution of ester racemate is an example for such successful biocatalytic reaction. It involves the enantioselective transesterification (alcoholysis) of only one of the esters using an excess of alcohol as the resolving agent. The resolution of racemic mixture of 2-methyl heptanoate was hence performed with immobilized Candida antarctica lipase in glycerol (entry 6). It resulted in high alcohol yield and high enantioselectivities of the ester and the corresponding alcohol. In this reaction, glycerol as alcohol, also takes part as resolving agent and abstracts the formed acid.
Enantiopure compounds are also prepared by enantioselective transformation of prochiral compounds. This method increases the theoretical product yield to 100% and avoids complicated separation of the two enantiomers. For example, prochiral carbonyl compounds can be asymmetrically reduced with biocatalysts to the corresponding enantiomer. Several oxidoreductases are capable of efficiently reducing ketones in the combination of a cofactor such as NADPH or NADH, yet using the whole cell like baker's yeast (Saccharomyces cerevisiae) for chiral reduction is simpler, cheaper, and also attractive, since all of the cofactor is supplied by the microorganism. Water is the natural environment for baker's yeasts reductions and glucose or sucrose are usually employed as energy source and as electron donor in the regeneration of the cofactor. However, as previously mentioned, performing the reduction of prochiral ketones with baker's yeasts in water has several drawbacks: low solubility of the organic substrate, undesired side reactions such as hydrolysis, and difficult isolation of the product. Hence, the enantioselective reduction of various prochiral ketones was also studied in different organic solvents such as hexane, toluene, which destroys the cells and has severe environmental impact. Moreover, the low suspension of yeast in organic medium as well as the negligible solubility of glucose in these organic solvents leads to low reaction rates. Performing the reaction in glycerol allows dissolving ethyl acetoacetate and glucose and fine dispersion of the yeast, yielding high product yield and enantioselectivity (entry 5). Besides easy separation, immobilization of the yeast cells keeps some water around them and thus increases their performance.