Synthesis and Properties of Deep Eutectic Solvents

Synthesis and Properties of Deep Eutectic Solvents: History

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Subjects: Chemistry, Analytical

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The use of deep eutectic solvents (DES) is on the rise worldwide because of the astounding properties they offer, such as simplicity of synthesis and utilization, low-cost, and environmental friendliness, which can, without a doubt, replace conventional solvents used in heaps.

deep eutectic solvents
extraction
organic compounds
green sample preparation
analytical chemistry

1. Introduction

Over the last decades, conventional solvents and extraction techniques—for example, methanol as a solvent or liquid–liquid extraction as a technique—tend to be replaced by new, simpler, inexpensive, and environmentally friendly approaches. The movement of “Green Analytical Chemistry” (GAC) and its 12 principles, presented by P. Anastas in 1998, has especially inspired scientists to switch to greener and alternative solutions for extracting compounds from different matrices [1]. Thus, developing new and sustainable solvents to match the above criteria is of high interest to many researchers globally [2,3,4,5,6,7,8]. A new group of organic salts that possess melting points below 100 °C, called ionic liquids (ILs), have emerged and demonstrate properties that could replace volatile organic solvents. However, ionic liquids pose some problems, such as toxicity, stability, biodegradability, and expense regarding their synthesis.

That is where deep eutectic solvents (DES) emerged in 2001 as the perfect candidate for replacing ILs, demonstrating cheaper and easier synthesis, while their environmentally friendliness is much more evident [9,10,11,12]. Deep eutectic solvents have low melting points due to low lattice energy formed by their large and asymmetrical ions. Habitually, they are formed by the combination of metal salt, called the hydrogen bond donor (HBD), with a quaternary ammonium salt, the hydrogen bond acceptor (HBA). Thus, hydrogen bonds are formed by charge delocalization, and the mixture’s melting point is lower than the separate components of the DES [13,14]. Hydrophilic and hydrophobic DES and natural deep eutectic solvents (NADES) can, without a doubt, be applied to analytical chemistry in different fields to extract molecules from a variety of samples [4,8,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29].

In Figure 1, the main scheme of how DES are used in extraction is presented.

Figure 1. Representative scheme of the typical development of an extraction method by using deep eutectic solvents.

2. Synthesis of Deep Eutectic Solvents

The most common way to synthesize DES is by mixing two or three cheap and safe salts and heating them up in order to obtain a homogenous solution. Molten salts at the ambient temperature can also be prepared through the mixture of metal salts with quaternary ammonium salts [30,31,32]. There are four main types of deep eutectic solvents: type I, where a metal chloride is combined with a quaternary salt, type II, where a hydrated metal chloride is merged with a quaternary salt, type III, where an HBD is put together with an HBA quaternary salt, and type IV, where an organic HBD compound reacts with a metal chloride [2,33]. Table 1 summarizes the four types of the DES, while in Figure 2, the most frequently used HBA and HBD are presented.

Figure 2. Structures of some common HBAs and hydrogen bond donors HBDs used in the synthesis of deep eutectic solvents.

Table 1. The four types of Deep Eutectic Solvents and their formulas.

Type	Formula	Terms
I	Cat⁺X⁻ + zMCl_x	M = Zn, Sn, Ga, In, Al, Fe
II	Cat⁺X⁻ + zMCl_x · yH₂O	M = Cr, Cu, Fe, Ni, Co
III	Cat⁺X⁻ + zRZ	Z = COOH, CONH₂, OH
IV	MCl_x + RZ	M = Al, Zn and Z = CONH₂, OH

Cat⁺ = any phosphonium, ammonium or sulfonium cation, X⁻ = a Lewis base, often a halide anion, MCl_x = metal chloride, RZ = organic compound.

Choline chloride (ChCl) is the most widely used HBA due to its low cost, low toxicity and biodegradability than has the advantage of reacting with safe and inexpensive HBDs, such as carboxylic acids, urea, or glycerol [32,34]. Additionally, type III acidic deep eutectic solvents are synthesized from quaternary organic salts with Brønsted acids (for example, citric acid) and type IV acidic DES from Lewis acids (for instance, zinc chloride or bromide) [35].

3. Properties of Deep Eutectic Solvents

Physicochemical properties of deep eutectic solvents derive from the various interactions between an HBA and HBD, which depend on the molar ratios, the organic compounds themselves, and the nature of the interactions (π-π and/or hydrogen bonding, anion exchange, weak non-covalent interactions) [36]. The properties that need to be considered when using DES and/or NADES are density, acidity, conductivity, viscosity, volatility, the melting and freezing point, and surface tension. Additionally, the toxicity, cost, thermal stability, and biodegradability should not be passed over [2,37]. The value of pH that results from the combination of HBA and HBD can drastically affect the extraction efficiency of the target compounds, so this parameter ought to not be overlooked as well [38]. As described by El Achkar et al. [39] in a thorough review about the properties of DES, viscosity is an important parameter to be studied, among others, since it severely impacts the extraction efficiency of a developed method. Water content is an ambiguous parameter since, for some, it might seem as an impurity, while others rely on it and add water on purpose to expose the reliability of the DES. Molar ratio and temperature of extraction can impact the isolation of organic compounds as well, and they are studied in almost all developed methods of extraction. Consequently, by knowing the parameters that can affect the extraction with the usage of DES, one can exploit their high tunability [40].

4. Extraction of Organic Compounds

In Table 2, the methods developed for the extraction of the organic compounds from pesticides, fungicides, herbicides, flavonoids, phenolic and other bioactive compounds are summarized and presented.

Table 2. Summary and analytical performance of the methods discussed.

Group of Compounds	DES	Molar Ratio	Extraction Technique	Recovery (%)	LOD ¹	Reference
Triazole fungicides	ChCl: 4-chlorophenol	1:2	HS-SDME	94–97	0.82–1.0 mg/L	[41]
Pesticides	Menthol: dichloroacetic acid	1:2	DLLME	56–86	0.32–1.2 ng/g	[42]
Pesticides	ChCl: p-chlorophenol	1:2	LPME	56–93	0.13–0.31 ng/mL	[43]
Neonicotinoid pesticides	Menthol: dodecanoic acid	2:1	LLE	80	N/R ²	[44]
Pesticides	ChCl: decanoic acid	1:2	DLLME	64–89	0.9–3.9 ng/mL	[45]
Acidic pesticides	ChCl: ethylene glycol	1:2	DLLME-SBSE	76–90	7–14 ng/L	[47]
Pesticides	TBAC: dichloroacetic acid	1:1	DLLME	81–94	0.09–0.27 ng/mL	[48]
Fungicides	Menthol: decanoic acid	1:1	UA-DLLME	72–109	0.75–8.45 μg/mL	[49]
Herbicides	ChCl: butyric acid	1:2	LLE-DLLME	70–89	2.6–8.4 ng/kg	[50]
Flavonoids	ChCl: 1,4-butanediol	1:5	UAE	N/R	0.07, 0.09 μg/mL	[56]
Flavonoids	Glycerol: L-proline	2:5	UAE, SPE	81–87	N/R	[57]
Isoflavones	ChCl: citric acid	1:1	UAE	64.7–99.2	0.06–0.14 μg/mL	[58]
Flavonoids	ChCl: 1,2-propanediol	1:4	UAE	86.7–98.9	0.05–0.14 μg/mL	[59]
Flavonoids	ChCl: oxalic acid: ethylene glycol	1:1:3	LLE	N/R	1.11–1.40 mg/g	[60]
Flavonoids	ChCl: acetic acid	1:2	UAE	N/R	1.11–11.57 mg/g	[61]
Flavonoids	Betaine: D-mannitol	N/R	UAE	91.7–95.8	0.14–0.17 μg/mL	[62]
Flavonoids	Different types	Diff. ³	UAE	93.8–107.7	0.14–0.22 μg/mL	[63]
Bioactive compounds	ChCl: malic acid	1:1	UAE	N/R	N/R	[64]
Bioactive compounds	ILs, ChCl based DES	Diff.	Reflux	N/R	N/R	[65]
Anthocyanins	ChCl: glycerol:citric acid	0.5:2:0.5	UAE	N/R	0.02 mg/L	[66]
Anthocyanins	ChCl: malic acid	Diff.	UAE	N/R	0.15–0.28 mg/L	[67]
Anthocyanins	Lactic acid: glucose	1:2	Stirring	N/R	N/R	[68]
Phenolic metabolites	Different types	Diff.	N/R	75–97	N/R	[71]
Phenolics	ChCl: oxalic acid	1:1	MAE, UAE	N/R	0.05–0.37 mg/L	[72]
Phenolics	ChCl: 1,2-propanediol	1:1	Vortex	N/R	N/R	[73]
Phenolics	ChCl: lactic acid	1:2	MAE, HUE, UAE	N/R	N/R	[74]
Phenolics	ChCl + phenolics	N/R	RDSE	66–87	10–60 μg/L	[75]
Polyphenols	ChCl: ethylene glycol	1:4	SLE	N/R	N/R	[77]
Phenolics	Lactic acid: glucose	5:1	UAE	86.0–109.6	0.6–89.1 ng/g	[78]
Polyphenols	Lactic acid: glucose	5:1	SLE	N/R	N/R	[79]
Phenolics	ChCl: malic acid	1.5:1	P-UAE	N/R	N/R	[80]
Phenolics	Glycerol: citric acid: glycine	Diff.	UAE	N/R	N/R	[81]
Flavonoids	ChCl: glycerol	1:1	UAE	95	N/R	[82]
Polyphenols	Lactic acid: glycine:water	3:1:3	UAE	N/R	N/R	[84]
Phenolic acids	ChCl: 1,3-butanediol	1:6	MAE	79.2–86.0	N/R	[85]
Phenolics	ChCl: glycerol	1:2	MAE	77.8–83.8	0.15–0.78 μg/mL	[86]
Phenolics	Tetramethyl ammonuium chloride:urea	1:4	UAE	97.3–100.4	N/R	[87]
Flavanones	Betaine: ethanediol	1:4	Heated LLE	97.0–101.6	N/R	[88]
Bioactive compounds	ChCl: propylene glycol	1:1	UAE	N/R	N/R	[89]
Phenolics	ChCl: acetic acid	1:2	Thermo-shaking	N/R	N/R	[90]
Phenolics	TBAC: hydroquinone	1:2	LLE/DLLME	74–89	0.13–0.42 ng/mL	[91]
Phenols	L-proline: decanoic acid	1:4.2	Stirring	57–62	N/R	[92]

¹ Limit of Detection, ² Not reported, ³ Different molar ratios tested.

In Table 3, all the methods developed for the extraction of the organic compounds from pharmaceutical compounds, preservatives, polycyclic aromatic hydrocarbons, volatile organic compounds, pollutants, polysaccharides, pigments, terpenes and other organic compounds are summarized, and their analytical performances are demonstrated.

Table 3. Summary and analytical performance of the methods discussed.

Group of Compounds	DES	Molar Ratio	Extraction Technique	Recovery (%)	LOD ¹	Reference
Sulfonamide	ChCl: ethylene glycol	1:2	PT-SPE	91.0–96.8	0.01 μg/mL	[93]
Analgetic	Betaine: oxalic acid	1:2	SA-DES-ME	94.2–107.1	14.9 μg/L	[94]
Antibiotics	ChCl: glycerol	1:2	MIPs-SPE	87.0–91.2	N/R ²	[95]
Antivirals	TBAC: p-aminophenol	1:2	LLE	90–96	1.0–1.3 μg/L	[96]
Antimalarial	Menthol: fenchyl alcohol	1:1	Stirring	101	N/R	[97]
NSAID ³	Menthol: acetic acid	Diff. ⁴	LLE	80	N/R	[98]
Antibiotics	TBAC: butanol	1:1	SPE, DLLME	84–99	0.32–0.86 ng/g	[99]
Tocotrienols, tocopherols	ChCl: malonic acid	1:1	LLE	93.0–99.8	N/R	[100]
α-tocopherols	ChCl: sucrose	1:2	LLE	N/R	N/R	[101]
α-, γ-, δ-tocopherols	ChCl: p-cresol	1:2	Vortex	77.6	N/R	[102]
Parabens	Menthol: decanoic acid	2:1	LLME	69.1–78.5	0.6–0.8 mg/mL	[103]
PAHs	Menthol or thymol with fatty acids	Diff.	Stirring	70–91	2–90 ng/kg	[105]
VOCs	ChCl: urea	1:3	MAE, HS-SPME	N/R	N/R	[106]
Polysaccharides	ChCl: 1,4-butanediol	N/R	UAE	N/R	N/R	[107]
Polysaccharides	ChCl: 1,4-butanediol	1:5	MAE	91.2	N/R	[108]
Polysaccharides	ChCl: 1,2-propanediol	1:2	UAE	N/R	N/R	[109]
Polysaccharides	ChCl: glycerol	1:2	Thermal treatment	60.3	N/R	[110]
Natural pigments	Citric acid: glucose	1:1	SPE	88.5–94.4	0.25–0.37 mg/L	[111]
Curcuminoids	ChCl: lactic acid	1:1	UAE	N/R	N/R	[112]
Curcuminoids	ChCl: phenol	1:4	VA-LLME	96–102	2.86 μg/L	[113]
Pigment	Different types	Diff.	UAE	N/R	N/R	[114]
Pigment	ChCl: ethylene glycol	Diff.	N/R	N/R	N/R	[115]
Terpene trilactones	Betaine: ethylene glycol	Diff.	UAE	99.4	N/R	[116]
Benzophenone-type UV filters	Menthol: decanoic acid	1:1	AA-DLLME	88.8–105.9	0.05–0.2 ng/mL	[117]
Organic solvents	Menthol: capric acid	2:1	LLE	N/R	N/R	[118]
Tanshinones	ChCl: -1,3-butanediol	N/R	BMAE	96.1–103.9	5–8 ng/mL	[119]
Catechins	Different types	Diff.	LLE	82.7–97.0	N/R	[120]
Essential oils	ChCl: L-lactic acid	1:3	MAE	N/R	N/R	[121]
Essential oils	ChCl: oxalic acid	1:1	MAE	N/R	N/R	[122]
Steviol glycosides	Tetraethylammonium chloride: ethylene glycol	1:2	UAE	N/R	N/R	[123]

¹ Limit of Detection, ² Not reported, ³ Non-steroidal anti-inflammatory drugs, ⁴ Different molar ratios tested.

This entry is adapted from the peer-reviewed paper 10.3390/molecules27227699

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