Chapter 1
Glycerol as Eco-Efficient Solvent for Organic Transformations

Palanisamy Ravichandiran and Yanlong Gu

School of Chemistry and Chemical Engineering, Huazhong University of Science and Technology, Wuhan, China

1.1 Introduction

Organic solvents are used in the chemical and pharmaceutical industries [1]. The global demand for these solvents has reached 20 million metric tons annually [2]. Solvents are unreactive supplementary fluids that can dissolve starting materials and facilitate product separation through recrystallization or chromatographic techniques. In a reaction mixture, the solvent is involved in intermolecular interactions and performs the following: (i) stabilization of solutes, (ii) promoting the preferred equilibrium position, (iii) changing the kinetic profile of the reaction, and (iv) influencing the product selectivity [3]. Selection of appropriate solvents for organic transformations is important to develop green synthesis pathways using renewable feedstock. In the past two decades, green methodologies and solvents have gained increasing attention because of their excellent physical and chemical properties [4-6]. Green solvents should be non-flammable, biodegradable and widely available from renewable sources [7].

Biodiesel production involves simple catalytic transesterification of triglycerides under basic conditions (Figure 1.1) [8]. This process generates glycerol as a by-product (approximately 10% by weight). The amount of glycerol produced globally has reached 1.2 million tons and will continue to increase in the future because of increasing demand for biodiesel [9]. Glycerol has more than 2000 applications, and its derivatives are highly valued starting materials for the preparation of drugs, food, beverages, chemicals and synthetic materials (Figure 1.2) [10].

Figure 1.1 Reaction for biodiesel production.

Figure 1.2 Commercial consumption of glycerol (industrial sectors and volumes).

The biodiesel industries generate large amounts of glycerol as a by-product. As such, the price of glycerol is low, leading to its imbalanced supply. Currently, a significant proportion of this renewable chemical is wasted. This phenomenon has resulted in a negative feedback on the future economic viability of the biodiesel industry and adversely affects the environment because of improper disposal [11]. In this regard, the application of glycerol as a sustainable and green solvent has been investigated in a number of organic transformations (Table 1.1). Glycerol is a colourless, odourless, relatively safe, inexpensive, viscous, hydroscopic polyol, and a widely available green solvent. Glycerol acts as an active hydrogen donor in several organic reactions. Glycerol exhibits a high boiling point, polarity and non-flammability and is a suitable substitute for organic solvents, such as water, dimethylformamide (DMF) and dimethylsulfoxide (DMSO). Thus, glycerol is considered a green solvent and an important subject of research on green chemistry. This review provides new perspectives for minimizing glycerol wastes produced by biomass industries.

Table 1.1 Physical, chemical and toxicity properties of glycerol

Our research group has contributed a comprehensive review on green and unconventional bio-based solvents for organic reactions [12]. However, enthusiasm for using glycerol as a green solvent for organic transformations in particular continues to increase. The present paper thus summarizes recent developments on metal-free and metal-promoted organic reactions in glycerol between 2002 and 2016.

1.2 Metal-Free Organic Transformations in Glycerol

The synthesis of complex organic molecules utilizes harsh reaction conditions, expensive reagents and toxic organic solvents. Most organic transformations use expensive metal catalysts, such as Pd(OAc)2, PdCl2, PtCl2 and AuCl2. The drawbacks of metal-promoted organic reactions are categorized into the following: (i) isolation and reuse of catalysts, (ii) lack of catalytic efficiency in the second usage, and (iii) disposal of metal catalysts. Over the past three decades, both industrial and academic chemists have continuously explored suitable methodologies, such as the use of green solvents. The chemical synthesis of glycerol as a sustainable solvent has gained wide attention because it provides valuable chemical scaffolds. Sugar fermentation produces glycerol either directly or as a by-product of the conversion of lignocelluloses into ethanol. Glycerol promotes this reaction without requiring any metal catalysts because of its excellent physical properties. Moreover, glycerol is widely available from renewable feedstock and is thus an appropriate green solvent for various reactions [13].

Scheme 1.1 Catalyst-free selective synthesis of 2-phenylbenzoxazole.

Scheme 1.2 Green synthesis of benzimidazoles and benzodiazepines in glycerol.

Quinoxaline, benzoxazole and benzimidazole derivatives can be synthesized using different methods; these molecules are commonly prepared through the condensation reaction of aryl 1,2-diamine with 1,2-dicarbonyl compounds [14, 15]. Bachhav et al. [16] developed an efficient, catalyst-free and straightforward method for synthesis of quinoxaline, benzoxazole and benzimidazole ring systems in glycerol; the yield is higher than those of conventional methods. The substrates 2-aminophenol and benzaldehyde are used as counter-reagents for the preparation of 2-arylbenzoxazoles (1). This reaction was tested in different solvent systems, but the desired products were not obtained and only glycerol efficiently promoted the reaction (Scheme 1.1). Radatz et al. [17] reported the same condensation reaction between 1,2-diamine and 1,2-dicarbonyl compound for the synthesis of benzodiazepines and benzimidazoles; the catalyst-free condensation reaction between o-phenylenediamine and benzaldehyde in glycerol produces benzimidazoles (2). The reaction between o-phenylenediamine and ketones produces benzodiazepines (3) when using glycerol as solvent. Furthermore, glycerol can be easily recovered and reused for condensation. However, at the fourth time of using glycerol, it starts to lose its activity (Scheme 1.2).

Nascimento et al. [18] used a similar kind of methodology for one-pot hetero-Diels-Alder reaction between (R)-citronellal and substituted arylamines; glycerol was used as a green, sustainable and recyclable solvent for the catalyst-free reaction and functioned as a model substrate to produce octahydroacridines (4,5) at high percentage yields with an isomeric product ratio of 46 : 54. The reactions proceeded without using acid catalysts (Scheme 1.3). Somwanshi et al. [19] developed a catalyst-free one-pot imino Diels-Alder reaction, with aldehydes, amines and cyclic enol ethers as model substrates to prepare the desired furano- and pyranoquinolines (6). 3,4-Dihydro-2H-pyran was used to prepare pyranoquinolines, and the mixture was obtained as endo-isomers, exo-isomers and errandendo-diastereomers; when furans were used as reagents, a single isomeric product is produced. Glycerol can be used as a sustainable solvent and leads to more efficient reactions than those using other organic solvents (Scheme 1.4).

Scheme 1.3 Catalyst-free synthesis of isomeric mixtures of octahydroacridines.

Scheme 1.4 One-pot synthesis of furanoquinolines by green method.

Cabrera et al. [20] confirmed that glycerol is an efficient solvent for the oxidation of aromatic, aliphatic and functionalized thiols under microwave conditions. The oxidation reactions proceeded quickly, and the preferred disulfides (7) were obtained in good to excellent yields. Thiophenol, a strong nucleophile, was used as model substrate, and sodium carbonate, an inorganic base, was used as catalyst. Glycerol was easily recovered and used for further oxidation of thiols (Scheme 1.5). Zhou et al. [21] reported the condensation reaction between 1,2-diamines and 1,2-dicarbonyl compounds for synthesis of quinoxaline derivatives in glycerol at 90°C for 3 minutes without adding inorganic salts; the desired product (8) exhibited a high degree of purity...