Green Solvents in Organic Synthesis

Abstract

Solvents are substances that are liquid during application and will dissolve other substances, which can be recovered unchanged on the removal of the solvent. The concept of green solvents indicates the target to decrease the environmental impact resulting from the use of solvents in chemical production. Green solvents are solvents of low toxicity, environment-friendly bio solvents, and less hazardous than traditional organic solvents. The solvents which are not harmful to the environment and human beings are called green solvents. Traditional solvents can be replaced with green solvents as a long-term way to reduce and minimize environmental deterioration. Solvents like ionic liquids and deep eutectic mixtures can be used as green solvents and are used as part of the class of green solvents in organic synthesis. The review focuses on the properties, applications, and limitations of these solvents.

1. Introduction

1.1 Green solvents

What are green solvents…

Green solvents, commonly referred to as environmentally friendly solvents, are products of crop processing.

The United Nations established a new development strategy with an emphasis on sustainability in 2015, based on 17 Sustainable development goals. It acknowledges the necessity of “green chemistry” and “green solvent” Figure 1 for future chemistry that is more environmentally friendly. So-called green, ecological, biodegradable, and sustainable solvents have arisen in this setting [1]. which were created as a less harmful alternative to petrochemical solvents known as biosolvents, which are generated from the processing of agricultural crops.

Figure 1.

Types of green solvents.

1.2 Types of green solvent

1.2.1 Ionic liquid

The term “ionic liquid” is very vast, ionic liquids (ILs) are made solely of ions that belong to a class of non-molecular compounds having melting points lower than 100°C. ILs have several advantages over traditional organic solvents. ILs possess negligible vapor pressure at room temperature as well as high thermal stability and play an important role as ideal solvents in various extraction techniques. The physical and chemical properties of ILs can be varied by simply changing the combination of cations and anions for e.g. viscosity, thermal stability, and solubility in water as well as in other organic solvents.

Over the past two decades, ILs have emerged as a class of promising solvents with unique properties that have several applications in organic synthesis, electrochemistry, catalysis, separation of metals, gas separation, energy storage devices, biomass processing, pharmaceuticals, and tribology. Ionic liquids also recognized by several different names like neoteric solvents, designer solvents, ionic fluids, and molten salts.

In 1914 the first room temperature ionic liquid [EtNH₃][NO₃] (m.p. 12°C) was discovered [1].

The behavior of ionic liquid may be an acidic, basic, or organocatalyst and it is determined by the presence of functional group attached to the cation and/or anion.

1.2.2 Ionic liquid for anhydrous reaction condition

It has been reported that ionic liquids [C₄C₁im][HSO₄] and [C₄C₁im][MeSO₃] can be successfully used for lignocellulosic biomass treatment even in the presence of significant amount of water, in this way use of ILs eliminates the requirement for anhydrous conditions during pretreatment [2].

The saccharification of cellulose and its successive transformation into significant molecules like hydroxymethylfurfural, levulinic acid and furfural, has been well examined and achieved by the use of acidic ionic liquids [3, 4, 5, 6, 7, 8, 9].

1.2.3 Ionic liquid as organocatalyst

Synthesis of sulfur functionalized chiral ionic liquid as an organocatalyst which has been used for the preparation of trans epoxide with high diastereoselectivity and enantioselectivity up to 72% ee, from various aromatic aldehydes with benzyl bromide in aqueous condition.

1.2.4 ILs as support for catalyst/reagents

Importance of ionic liquids as soluble supports for catalyst/reagent immobilization [10] is well studied in various ionic liquid supported synthesis (ILSS) and is applied for a number of organic reactions like Knoevengeal reaction [11], 1,3-cycloadditions [12], oligosaccharide synthesis [13], Suzuki coupling [14], synthesis of thiazolidinones [15], and Grieco’s multicomponent synthesis of tetrahydroquinolines [16]. All of the reported reactions are due to controlled solubility and nonvolatile nature of ILs.

The major drawbacks of common ILs, namely high toxicity, non-biodegradability, complex synthesis requiring purification, and high cost of the starting materials [17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32].

1.3 Deep Eutectice Solvents (DESs)

Deep Eutectic Solvents (DESs), are defined as combinations of non ideal mixture of two biodegradable constituents (HBA and HBD) (Table 1) with strong hydrogen bonding interactions. They are also known in the literature as Deep Eutectic Ionic Liquids (DEILs), Low Melting Mixtures (LMMs), or Natural Deep Eutectic Solvents (NADES), Low Transition Temperature Mixtures (LTTMs) [33].

Table 1.

Types of hydrogen bond acceptor (HBA) and hydrogen bond donor (HBD).

A highly non-ideal mixture of two biodegradable constituents (HBA and HBD) with strong hydrogen bonding interactions is categorized as a Deep Eutectic Solvent (DES).

According to this definition, many DESs have been synthesized and has found much application as a solvent in various organic reactions, extraction of dyes, protein, nucleic acids, metals, azeotropic separation, and more [34, 35, 36, 37, 38].

The concept “Deep Eutectic Solvent” was first coined by Abbott et al. [39] to describe the formation of a liquid eutectic mixture (melting point 12°C) starting from two solid materials with high melting points: (i) choline chloride (ChCl), (2-hydroxyethyl)trimethylammonium chloride, melting point 133°C, and (ii) urea (melting point 302°C) in a ratio 1:2 (1ChCl₂Urea) [40, 41].

A method for determining the polarity and hydrophobicity of DESs was developed by Cichocki et al. [42]. This approach eliminates the necessity for solution preparation, thus in this way does not alter the internal structure of DESs. The presence of an extra component, like as water or another solvent, can cause modifications in the DES molecule’s hydrogen bonding mechanism. The contact angle test, which is one way to determine DESs hydrophobicity without having to prepare their solutions. The method does not require the use of any solvents, only an optical goniometer, and a reference surface.

For classifying DESs properties as hydrophobic and hydrophilic, their contact angle values obtained on glass were taken into consideration with respect to highly hydrophobic rapeseed oil and highly hydrophilic water, respectively as a reference substance. DESs molecules in which contact angle value were found to be in between water and oil contact angle value, were classify as having intermediate properties. The contact angle, therefore, indirectly measures the closeness of DES molecules to the surface of the reference substance. The results of contact angle measurements are summarized in Figure 2.

Figure 2.

Classification of DES properties by contact angle (CA) test.

1.3.1 Types of Deep Eutectic Solvent (DES)

See Table 2.

Type I DES	Quaternary ammonium salt and metal chloride. Imidazolium salts and various metal halides such as ZnCl2, FeCl2, AgCl, CuCl2, CdCl2, LiCl, SnCl2, and SnCl4	[39, 43]
Type II DES	Quaternary ammonium salt and hydrate of metal chloride hydrate	[34]
Type III DES	Quaternary ammonium salt as HBA and HBD. Mainly composed of choline chloride and HBDs (carboxylic acids, alcohols, amides, and carbohydrates, etc.)	[44]
Type IV DES	Metal chloride (particularly transition metal chloride) and HBD	[37, 45]
Type V DES	New class mixture of non-ionic molecular HBA and HBD	[37]

Table 2.

Types of deep eutectic solvent (DES).

DESs were presented using the general formula: R⁺A⁻xB, where R⁺ is ammonium, sulfonium, and phosphonium cation core. A and B are Lewis base with halide anion and Lewis acid, respectively [37].

1.3.2 DES as catalyst

Azizi and Batebi [46] investigated ChCl-SnCl₂ (1:2 molar ratio) as Lewis acid type DES as catalyst for chemoselective ring opening of epoxides with aromatic amines, thiols, alcohols, azide and cyanide.

Synthesis of primary amides from aldehydes and nitriles by Patil et al. [47] was carried out by the used of Lewis -acid type DES ChCl-ZnCl₂. Its performance both as a catalyst and solvent were studied (Figure 3). Various aromatic, aliphatic and conjugated substrates were used and high product yields were obtained (89–94%). Effect of substituents electron donating groups at ortho-para positions on DES catalyzed reactions resulted in excellent yields while ortho- substituted groups’ reactions required greater time due to steric hindrance caused by substituted groups. Another important application of reusability of DES was examined on the synthesis of benzamide from benzaldehyde. The maximum three recycling has been reported for DES performance. The authors work resulted that the use of DES in the reactions given green and atom-efficient synthesis by reducing waste and toxic material.

Figure 3.

Synthesis of amides from aldehydes and nitriles catalyzed by DES ChCl-ZnCl₂ (1:2).

Tran et al. [48] used ChCl-ZnCl₂ as catalyst and green solvent in Friedel-Crafts acylation reactions. They reported high regio- and chemoselectivity in the reactions using acid anhydrides and ChCl-ZnCl₂ (1:3 molar ratio) as catalyst under microwave irradiation (Figure 4).

Figure 4.

Friedel craft acylation reaction by DES ChCl-ZnCl₂ (1:3).

Advantages ChCl-ZnCl₂ as catalyst and green solvent in Friedel-Crafts acylation reaction:

• Ketone products having a majority of p-isomer

• Prevention of both use of moisture sensitive Lewis acids and volatile organic solvents.

• High yields within short reaction times.

• Three new ketone products to be synthesized under the catalyzation of DES. ChCl-ZnCl₂ (1:3)

• DES could be reused up to 5 times conserving its catalytic activity.

Aromatic ketones are valuable and important precursors for the synthesis of agrochemicals, pharmaceuticals, and also for fragrance as well as dyes etc. The synthetic route for these molecules usually involved Friedel-Crafts acylation using Lewis acids as catalyst [49].

Polyethylene terephthalate (PET) is, the most common thermoplastic polymer resin of the polyester family, extensively used in many fields like in fibres for clothing, containers for liquids and foods, textile industry such as disposable soft drink bottles, packaging and also films and tapes. PET consumption in the world has been reported to surpass 13 million tonnes [40]. Therefore, the need for recycling of PET polymer gains much attention and critical importance for the sake of environment [50].

The glycolysis of PET using DESs as catalyst is firs example reported by Wang et al. [51]. PET degradation was carried out by catalytic reaction using urea-metal salt mixtures’ DESs.

H-bonds were between molecules shown in Table 3.

Table 3.

H-bonding between different DES molecules.

In summary, the Wang et al. [51] proposed that DESs mimicked having more catalytic active sites than ionic liquids and metal salts because they could create more H-bonds between various molecules. The reaction’s mechanism is emphasized that the H-bonds allow the hydroxyl group’s O∙H bond in ethylene glycol to lengthen, which increases the oxygen atoms’ electronegativity and thus facilitates the loss of hydrogen atoms from oxygen atom and hence resultant greater nucleophilicity. All this factor made it easier for oxygen to attack PET’s ester group’s carbon. Furthermore, DES and substrate contact was increased by the coordination bonds that existed between PET’s oxygen atom and Zn⁺². The overall effect of all these factors led to an enhanced PET degradation rate by DESs (Figure 5).

Figure 5.

Application of DES [52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74].

1.3.3 Deep Eutectic Solvents: biomedical applications

Neurotransmitters (NTs) are brain’s chemical messengers that are involved in a wide range of neurological processes, including mood, appetite, learning, sleep, and other cognitive processes. Excitatory NTs include epinephrine, norepinephrine, glutamate, serotonin, and acetylcholine; inhibitory NTs include γ-aminobutyric acid, and dopamine (DA) is thought to have both excitatory and inhibitory properties [75]. Severe neuropsychiatric disorders including Parkinson’s, schizophrenia, Alzheimer’s, and epilepsy can be brought on by an imbalance in the concentration of NT [76].

The application of DESs as green solvents in detecting and extracting NTs is described in detail for the first time [77]. Various methods, such as electrochemical [78], positron-emission tomography [79], optical [80], and microdialysis [81], are available for sensing NTs. Various nanocomposites have been utilized for sensing NTs [82]. Because of its vital characteristics, which include cost-effectiveness, biodegradability, and customizable physiochemical qualities that can control and modify the formation of nanocomposites, DESs can be used to synthesize these nanocomposites [83]. To create nanocomposites, DESs can be used as a precursor, reactant, solvent, and shape-controlling agent.

1.4 Conclusion

With the increasing awareness towards environmental issues, researchers are taking great interest and effort to replace toxic and harmful constituents with less harmful constituents. In this direction Ionic liquids (ILs) and Deep eutectic liquids (DES) have found many successful important synthetic applications in many different fields of research. DESs come upon many applications in various areas such as metal processing, trace metal extraction, drug delivery, extraction of polyphenols and flavonoids, organic synthesis, biotransformations and biomedical application as well. DES was taken as a solvent or co-solvent in various reactions, as it has properties of high solubility or miscibility with the substituents. Therefore, DESs as an acid catalyst can readily be adopted as alternative catalysts to conventional ones.

One of the promising features of DES in various organic synthesis as a catalyst is reusability or recycling nature. Flavonoids and phenolic components posses wide range of pharmacological and medicinal values, so the extraction of flavonoids as well as polyphenols have always been a research hotspot and use of DES can replace toxic organic solvents. Due to its biodegradability, as most of the components that make up DESs are natural products, they can be easily converted into different kinds of organisms in nature. DES can act as both as solvent and as well as catalyst, this kind of dual functionality of biodegradable greener solvent will pave a pathway for organic synthesis in future.

Further research in quest of DES for detecting and extracting NTs is needed to explore the full potential of DESs that could have significant implications for the diagnosis and treatment of neurological disorders and to optimize their use for practical applications. This book chapter provides a brief aspect of some of the most recent applications of ILS and DESs in various fields.