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Recent Achievements in Organic Reactions in Alcohols

Lan Zhao1, Man Zhao1, Meng-Ge Wei2, Hong-Ru Li2, and Liang-Nian He1

1Nankai University, College of Chemistry, State Key Laboratory and Institute of Elemento-Organic Chemistry, 94 Weijin Road, Nankai District, Tianjin, 300071, China

2Nankai University, College of Pharmacy, No 38 Tongyan Road, Jinnan District, Tianjin, 300353, China

1.1 Introduction

Almost all manufacturing and processing industries now rely on the extensive use of solvents, and conventional synthesis depends heavily on environmentally incompatible organic solvents [1]. Most often, the solvents used in organic synthesis are volatile, so they can be removed from the reaction mixture by simple evaporation. The widespread use of these volatile organic solvents raises environmental concerns due to their intrinsic properties. With the growing awareness of the impact of solvents on environmental pollution, energy use, on-air quality, and climate change, sustainable solvents are a topic of increasing interest to the science community and the chemical industry [2].

Alcohols are a more desirable class of green solvents used in a wide range of organic reactions. In the last 15 years, alcohols have started to attract attention as alternatives to traditional organic solvents. These alcohols are able to work as solvents in general and include monohydric alcohols (methanol, ethanol, isopropanol, etc.), dihydric alcohols (ethylene glycol), tertiary alcohols (glycerol), fluorinated alcohols (2,2,2-trifluoroethanol [TFE], hexafluoroisopropanol [HFIP]), perfluoro tert-butyl alcohol [PFTB]), and polymers (polyethylene glycol [PEG], polypropylene glycol [PPG]), as shown in Scheme 1.1. Alcohols are typical proton-polar solvents and are widely used as inexpensive general solvents. The physical and chemical properties of some alcohols are depicted in Table 1.1 [3].

Nowadays, numerous solvent selection guides have emerged from the pharmaceutical industry, such as those from Pfizer [4], GlaxoSmithKline (GSK) [5], and Sanofi [6]. In this regard, Table 1.2 lists several commonly used alcohols evaluated by selected guidelines in Table 1.2 [2]. As a consequence, most of the several short-chain aliphatic alcohols appear to be the preferred solvents from a green chemistry perspective. High-boiling alcohols, glycerol, PEG, and PPG are also considered green solvents for various reactions. Furthermore, fluorinated alcohols are frequently used as solvents in chemical reactions due to their unique properties.

Scheme 1.1 Structure of alcohols.

Table 1.1 Physical and chemical properties of alcohols [3].

Table 1.2 Guidelines for solvents for common alcohols.

a) Selection guide by Pfizer.

b) GSK's solvent selection guide.

c) Sanofi's solvent selection guide.

Monohydric alcohols are organic compounds containing one hydroxyl group, including methanol, ethanol, and isopropanol. They are the most commonly used solvents in the thermochemical processing of lignocellulose due to their easy recovery and low cost. These alcohols have similar solvent properties, such as solvent strength, dielectric constant, critical point, and hydrogen supply capacity. They are usually soluble in polar solvents such as water, ether, and acetone but not in non-polar solvents such as petroleum ether. The hydroxyl groups in monohydric alcohol molecules give them polarity and can form hydrogen bonds with other polar molecules, resulting in high boiling points, melting points, and surface tension. These alcohols can be obtained from various sources such as fossil fuels, biomass, and waste. Methanol can be used in the production of other chemicals such as formaldehyde, methyl methacrylate, and dicarboxylic acid. Ethanol has wide applications in pharmaceuticals, beverages, coatings, cosmetics, and spices. Ethanol can be used to produce chemicals such as ethyl acetate, vinyl acetate, and acetaldehyde. Isopropanol can be used to produce plastics, paints, coatings, and solvents. It can also be used to prepare other chemicals, such as acetone and methyl isopropanol. They have low toxicity and are important clean fuels that can replace traditional fuels [1].

Ethylene glycol, a colorless, odorless, relatively non-volatile, low hygroscopic, and low-viscosity liquid, is the simplest representative of 1,2-diols. Owing to its unique structure, that is, two hydroxyl groups (OH) at adjacent positions along the hydrocarbon chain, allows it to engage in reactions such as esterification, dehydration, oxidation, and halogenation. In terms of solubility, ethylene glycol is completely miscible with numerous polar solvents (such as water, alcohols, glycol ethers, and acetone), but only slightly soluble in nonpolar solvents such as benzene, toluene, dichloroethane, and chloroform. Other than that, it is difficult to crystallize, but becomes highly viscous supercooled mass that solidifies to deliver a glassy substance upon gradual cooling. With regard to toxicity, ethylene glycol is inherently low in toxicity, but can yield toxic metabolites (Oral-rat LD50: 4700 mg/kg; Oral-mouse LD50: 5500 mg/kg) [7].

Glycerol is a ternary...