The Future of Green Chemistry: Evolution and Recent Trends in Deep Eutectic Solvents Research

Abstract

Deep eutectic solvents are a sustainable and chemically tunable class of solvents formed by strong hydrogen bonding between a hydrogen bond acceptor and a hydrogen bond donor. Their extreme versatility has established deep eutectic solvents in ten key applied areas, including the green extraction of bioactive compounds, CO₂ capture, electrochemistry, and the catalytic media. Research is shifting towards highly innovative frontier trends, such as the role of deep eutectic solvents in dynamic covalent chemistry and as templates for advanced photocatalytic nanomaterials. Other innovative directions include artificial organelles for bioremediation, thermoacoustic deep eutectic solvents for smart drug delivery, and their use as multifunctional interfaces for 2D materials. The future of deep eutectic solvents lies in process engineering and scale-up, supported by computational chemistry, confirming their position as a central pillar of the circular economy. This trajectory marks the transition of deep eutectic solvents from laboratory curiosities to a scalable industrial reality.

1. The Rise of Green Chemistry and the Critical Need for New Solvents

Global chemical production is under increasing pressure to reduce its environmental footprint. The primary goal of green chemistry is to minimize waste generation and the use of hazardous substances. In this context, attention is focused on replacing conventional organic solvents, which often exhibit high volatility, inherent toxicity, and contribute to emission of volatile organic compounds into the atmosphere [1]. The development of green processes and approaches in green chemistry is especially important for reducing the impact of these agents and processes on the environment and ensuring their efficiency and cost-effectiveness. The field of green chemistry is gradually developing with the aim of solving problems such as health risks to humans and environmental hazards. Green chemistry in general seeks to promote sustainability and is currently attracting the attention of the broad scientific community and many international institutions. The principles of green chemistry emphasize reducing solvent consumption, minimizing waste, and using safe green solvents [2,3].

Green chemistry is a key factor in sustainability and is transforming conventional chemical processes by integrating greener methods, advanced techniques, and sustainable materials. Green chemistry integrates renewable resources, green synthesis, and safer solvents to promote sustainability and reduce environmental impact, while adhering to the 12 principles that guide the development of green and efficient chemical processes, minimizing waste, pollution, costs, and risks [4].

2. The Historical Development of Deep Eutectic Solvents

Mixtures or systems with low-temperature phase transitions have been known to the scientific community since the late nineteenth century. In general, a eutectic is a mixture whose eutectic point is lower than the melting point of any of the components that make up the mixture [5]. In other words, the term eutectic introduced by the British physicist and chemist Frederick Guthrie in 1884, refers to a eutectic system formed from two or more substances in such proportions that the melting/freezing point is as low as possible. Therefore, the eutectic temperature is the lowest/melting freezing point of all mixing ratios for the components. Guthrie first described combinations of substances that exhibit the lowest possible melting points in specific compositions. These eutectic systems were initially studied extensively in metallurgy and materials science and laid the foundation for later solvent developments. Regarding the use of the “eutectic solvent,” it dates back to around 1930, and other articles from around the 1950s [5,6].

A major breakthrough occurred in 2003 when Andrew Abbott and his team introduced the term “deep eutectic solvents” (DES). They identified a family of solvents produced by simply mixing choline chloride (a quaternary ammonium salt that functions as the hydrogen bond acceptor; HBA) and urea (a hydrogen bond donor; HBD) in a molar ratio of 1:2. This mixture formed a clear liquid that exhibits a melting point of about 12 °C, remarkably lower than the melting points of choline chloride of 302 °C and urea of 133 °C. This discovery showed that inexpensive, biodegradable, and easily prepared solvents could be created by exploiting intermolecular hydrogen bonding [7]. The first definition of deep eutectic solvents was formulated by a group led by Smith a year later, who sought to explore and explain their differences from ionic liquids (IL) and thus distinguish the two concepts [8].

Following this discovery, DES were initially classified into four primary types on the based of their chemical composition (ionic DES). Type I: quaternary ammonium salt + metal halide (choline chloride + CuCl₂); Type II: quaternary ammonium salt + hydrated metal halide (choline chloride + FeCl₃·6H₂O); Type III: quaternary ammonium salt + various HBD such as amides or carboxylic acids (most studied: choline chloride + urea); Type IV: metal chlorides + HBD (zinc chloride + glycerol). Among these, type III DES have been the most extensively investigated due to their favorable low toxicity and biodegradability [9,10].

DES types I and II contain a metal halide or hydrated metal halide as the HBD, and these two types of DES are similar to IL but are not the same systems, as IL are salts while DES are mixtures. The melting point for these types of DES depends on the symmetry of the cation, while its acidity can be changed by exchanging the metal halide (chloride ion) [11,12]. DES type IV is a combination of transition metal halides and HBD (urea or ethylene glycol). In this case, the melting point depression is caused by the strength of the anionic hydrogen bonding (charge delocalization), and the freezing point depression increases with the strength of the hydrogen bonding [5,6,7,8,9,10,11,12].

Type III DES appears to be the most interesting and exhibits a first-order phase transition through the melting/freezing peak. However, there are also exceptions where a second-order transition occurs, namely, a glass transition (similar to polymers) occurs due to a change in heat capacity. Due to these properties, these mixtures cannot be called DES, but the term low-temperature transition mixtures (LTTM) has been introduced. These systems represent metastable systems where, upon heating, crystallization of the amorphous glass occurs, followed by melting of the crystalline phase. The polarity of HBA and HBD indicates whether DES/LTTM type III are hydrophilic, hydrophobic, or quasihydrophobic [5,13].

In 2011, Yong Hwa Choi, Robert Verpoorte, and colleagues discovered that similar deep eutectic phenomena occur naturally in living organisms. These naturally occurring solvents are termed natural deep eutectic solvents (NADES). NADES are composed of primary metabolites such as sugars, amino acids, and organic acids. NADES have high biodegradability and low toxicity, offering promising applications as green solvents and possible alternatives to water in biological media [11].

As research progressed, a fifth category of DES was identified (since 2019): Type V—non-ionic molecular mixtures formed via strong hydrogen bonding without quaternary ammonium salts or metal halides. Many NADES qualify as Type V DES, including mixtures of sugars and organic acids. Some of these DES are hydrophobic. In addition, specialized variants of DES have emerged (Figure 1):

• Therapeutic DES (TheDES): Incorporation of active pharmaceutical ingredients to improve drug solubility and bioavailability [14,15,16,17,18].
• Hydrophobic DES (HDES): Utilizing hydrophobic components such as long-chain ammonium salts or natural terpenes, these DES dissolve nonpolar substances, useful in extraction and gas capture [19,20,21,22,23,24,25,26].
• Protic DES (PDES): Composed of pairs of acid–base with mobile protons, these are suitable for electrochemical applications [27,28,29,30,31,32].
• DES functionalized: Engineered with specific functional groups for applications in catalysis, sensing, or advanced materials.

Physicochemical and practical significance DES exhibit desirable physicochemical properties such as low volatility, low flammability, tunability by component selection and ratio, and easy preparation through simple mixing with mild heating. Their sustainability, cost-effectiveness, and environmentally friendly nature make them valuable in various applications, including catalysis, pharmaceuticals, biotechnology, material synthesis, and green chemistry [33,34,35,36].

In 2025, Olawuyi et al. characterized menthol- and ibuprofen-based TheDES using multitechnique approaches (thermogravimetry, calorimetry, spectroscopy, and computational techniques). The study focused on elucidating the gas-phase microstructures of TheDES [14]. Díaz et al. determined the solubilities of ibuprofen/thymol and ibuprofen/_L-menthol TheDES in supercritical CO₂ at temperatures of 40, 50, and 60 °C and pressures up to 250 bar. The results showed that the solubilities of the analyzed TheDES were intermediate between those of the pure components. Spectroscopic analysis showed that ibuprofen was present in the form of a dimer or bound to a terpene. When TheDES was dissolved in CO₂, a significant amount of free ibuprofen was also found [15]. In another work, Javed et al. [16] investigated the pharmaceutical applications of TheDES in maximizing drug delivery. TheDES have great potential to enhance drug solubility and permeability (bioavailability). Promising and interesting examples of TheDES are available in the medical, pharmaceutical, and biotechnology fields [14,15,16,17,18]. In a publication by Aroso et al. [17], TheDES was developed as a transporter and carrier of bioactive molecules. The DES consisted of choline chloride or menthol with three active pharmaceutical ingredients (acetylsalicylic acid, benzoic acid, and phenylacetic acid). The results indicated that all synthesized TheDES retained antibacterial activity. DES represent new dissolution enhancers for the development of new and more effective drug delivery systems [15,16,17,18].

HDES are among the DES that meet the requirements of green chemistry and have great potential in areas such as extraction and separation. In addition, they show applications in CO₂ capture and water purification. Illoussamen et al. [19] in their work used HDES for the extraction of phenolic compounds from wastewater, investigating the efficiency of four menthol-based HDES with different HBD (lactic acid, camphor, octanoic acid and borneol). The results showed that the efficiency of the HDES used was correlated with their acidity values. HDES are environmentally friendly solvents that can be used for the regeneration of phenolic compounds in both food and environmental engineering [19,20]. Zhang et al. [21] in their paper focused on redox biocatalysis in lidocaine-based HDES. Because DES are adaptable to a specific application and a versatile combination of their components is possible, HDES have the potential to be compatible with enzymes. In this work, they studied two HDES based on lidocaine with oleic and decanoic acids. The results demonstrated that HDES are useful in the biocatalysis industry as reaction media compatible with enzymes and highly soluble for substrates [21,22]. Other authors have investigated the use of various HDES in the removal of tetracycline from water [23], the extraction of carotenoids from pumpkin by-products [24], the removal of hexavalent chromium from aqueous media, or the intracellular release of Saccharomyces cerevisiae proteins [25,26].

Deng et al. [27] investigated NH₄SCN-based PDES as reversible ammonia (NH₃) absorbents. The authors used glycerol, ethylene glycol, urea, acetamide, and caprolactam as HBD. The authors achieved favorable results, with all synthesized PDES exhibiting exceptional NH₃ absorption capacity and high NH₃/CO₂ selectivity. As mentioned by other authors, high efficiency, reasonable cost, low energy consumption, and easy operation indicate that PDES offer a promising opportunity for sustainable NH₃ capture [27,28,29]. Other authors have investigated various PDES for efficient CO₂ absorption, SO₂ capture, efficient HCl/SO₂ separation, or generally for the electrochemical industry [30,31,32].

Another group of DES are functionalized DES, which are specially adapted in terms of their properties for a given desired application. Such DES include, for example, supramolecular DES, which consist mainly of natural and cheap components (cyclodextrins, acids, polyols), are non-toxic, biodegradable, and reduce the amount of waste. Supramolecular DES are a modern and ecological alternative to DES because of their green properties and improved functionality. They are used mainly due to their special supramolecular nature, which allows them to selectively bind various chemical compounds by the host–guest mechanism: extraction processes, chemical separation and purification, biotechnology or food industry [33,34,35,36].

In recent years, the development and research on DES have brought various terminological names into the lexicon of the scientific community, which can lead to inaccuracies. In particular, for the same types of solvent system, more or less the same names are used, namely IL, DES, NADES, LTTM, or low-melting mixtures (LMM). Most mixtures of these solvents (DES, NADES, IL) show glass transitions instead of melting points, which is why some solvents are named LTTM. As described by Jablonský et al. [37] in their work, it would be appropriate to eliminate the aforementioned terminological inaccuracies, but at the same time preserve the traditional, generally accepted names; therefore, the authors of this article proposed using the term DES-like mixtures for systems where the existence of a eutectic point has not been proven [37].

This term was introduced into this field of research, and some authors used it in their work. Jančíková et al. used DES-like mixtures in their work to study their influence on the properties of unbleached kraft pulp, wheat straw delignification, hemp fiber fractionation, and also summarized the effect of acidity, pH, and water content in DES-like mixtures, their efficiency in obtaining cellulose nanoproducts from biomass or biomass fractionation and the associated mechanism of lignin removal from lignocellulosic materials [38,39,40,41,42,43,44].

Ghigo et al. [45] investigated a copper-free method for the conversion of arendiazonium tetrafluoroborates to aryl halides using DES-like mixtures. DES-like mixtures were synthesized using glycerol as HBD mixed with a halide salt (KBr or KCl). The reaction was carried out at room temperature without metal catalysts and the results showed that DES-like mixtures allow for a controlled reaction in which the diazonium salt is replaced by a halogen atom from the mixtures [45]. Other authors, namely Khovrenko et al. [46] described in their work the use of DES-like mixtures based on urea, thiourea and KOH for the synthesis of phenytoin and thiophenytoin. As a result of this work, it is argued that the DES-like mixtures obtained based on urea, thiourea, and KOH can find applications in base-catalyzed syntheses of heterocyclic compounds [46].

In their paper, Motta et al. [47] proposed eco-friendly electrolytes based on sodium chloride as HBA and glycerol or ethylene glycol as HBD. The authors demonstrated the feasibility of designing electrolytes that balance environmental benefits with desirable and tunable electrochemical properties. This is also evidenced by the favorable ionicity and electrochemical stability of DES and DES-like mixtures compared to their salt-type equivalents in ethylene glycol-based solvents [47]. Martí et al. [48] in turn utilized DES-like mixtures as novel reaction media with compatible catalysts commonly used in Friedel–Crafts reactions. In this work, DES-like mixtures have been shown to be effective alternatives to conventional reaction media and serve as solvents and catalysts [48].

In their paper, Boldrini et al. presented a DES-like mixture based on iodide, which was used as an electrolytic solvent in solar cells. The authors used a DES-like mixture based on ethylene glycol and choline iodide. This method, as well as the structure of the device, is modern and novel and provides a new generation of simpler, cheaper and high-performance solar cells (dye-sensitized) with potential, especially for practical indoor applications [49].

As stated in their work by Nejrotti et al., who assessed the sustainability of choline chloride-based DES, there is a need to define under what conditions a eutectic mixture can be called a DES, i.e., how deep the eutectic should be, especially if one of the components is already liquid at room temperature. It is also necessary to emphasize that not all molar ratios of choline chloride and various HBD in this work can be defined as DES, so it would be more correct to call such systems ‘DES-like’ [50,51].

So, the main argument for adopting a broader nomenclature is that many mixtures with low melting or transition temperatures have not demonstrated the existence of a true eutectic point [52]. Most mixtures, particularly those with high viscosity and components such as sugars or choline chloride, do not crystallize upon cooling. Instead, they transition into an amorphous (glassy) state. Therefore, the measured temperature is the glass transition temperature (T_g) rather than the melting point (T_m). Thus, the term LTTM is more accurate than DES [37,52,53].

The use of the term DES-like mixtures or LTTM is often a terminological precaution taken by researchers to reflect the fact that: The mixture exhibits a low melting/transition temperature (T_m/T_g) as a result of hydrogen bonding. However, the presence of a true eutectic point has not been strictly demonstrated through a complete phase diagram [54]. Therefore, this represents a shift from a strict thermodynamic definition (eutectic) to a phenomenological description (liquid at low temperature). The term DES-like mixtures has begun to appear in certain scientific publications as an umbrella term for various groups of green solvents that share a key property: they are mixtures of two or more components whose combined melting points are significantly lower than those of the individual components, resulting in liquids at or near room temperature. In leading journals, particularly those focused on biomass processing and green chemistry, this categorization is clearly established [38,39,40,41,42,43,44,45,46,47,48,49,50].

For example, in studies investigating the use of these solvents for biomass fractionation, the term DES-like mixtures are used to unify all mixtures that effectively dissolve biomass through hydrogen bonding, regardless of whether they exhibit a sharp eutectic point or a glass transition [37,38,39,40]. Therefore, the use of the terms LTTM or DES-like mixtures has become a terminological bridge between strict thermodynamic research (which requires complete phase diagrams) and applied research. These terms allow authors to avoid misleading the reader by claiming that a mixture is eutectic when a full phase diagram is not available to confirm it. The term DES-like mixtures are mainly used in publications dealing with green chemistry, materials engineering, and biomass processing, where they represent a more ecological and economical alternative to traditional organic solvents [42,43,44,45,46,47,48].

2.1. The Relationship of DES with IL and Their Comparison

In 1914, Walden et al. first introduced and described the concept of IL, which are considered the predecessors of DES. These solvent systems have been an extremely hot topic in the field of chemistry, but knowledge about the nature of IL and their properties has expanded, and some of them pose risks in terms of flammability, volatility, instability, and toxicity [55].

The scientific community has paid considerable attention to IL as potential green solvents in the past two decades. However, over time, the “greenness” of IL has become questionable. The main challenges of IL include poor biodegradability, poor biocompatibility, and non-sustainability [56,57,58,59]. DES are a direct response to these limitations and are perceived as an alternative to IL that benefits from lessons learned from the previous generation. The distinction between these two classes of sustainable media is crucial from the perspective of mass implementation. DES are preferred to conventional IL because they are significantly simpler and cheaper to synthesize, more cost-effective, and typically more environmentally friendly (

Table 1. Comparison of key attributes of DES, IL, and conventional organic solvents [56,57,58,59,60].

Attributes	IL	DES	Conventional Organic Solvents
Synthesis	more complex multi-step	simple and easy	simple and standard
Cost	high	low competitive price	low
Volatility	low	negligible and low	high
Biodegradability	often poor	typically good	variable
Raw materials	non-renewable synthetic	often renewable and available	petroleum base
Toxicity	variable often acute	low	high

) [53].

Although IL and DES have many common properties (physical properties, applications), they are chemically independent of each other and represent different types of substances. In general, DES and IL differ in two basic ways, namely, the nature of the starting materials and the methods of their formation. IL are synthesized from organic heterocyclic cations and inorganic or organic anions, while the synthesis of DES uses two main components, namely HBA and HBD. However, a huge advantage of DES is that they are generally non-toxic, easily available, cheap, and sustainable compounds [8,54].

The low cost of DES is related to the use of renewable and readily available feedstocks. This economic factor is crucial. While IL have often faced financial barriers to widespread industrial use, DES overcome these barriers due to their economic feasibility and ease of preparation. This combination of economic and environmental advantages suggests that DES represent a second, more sophisticated generation of sustainable solvents with a better chance of becoming a widely adopted industrial standard [55].

2.2. Mechanism of Formation and Thermodynamic Stabilization of DES

The deep eutectic phenomenon is a complex thermodynamic process in which a mixture of a HBA and a HBD undergoes a dramatic depression of the freezing point. In contrast to simple eutectic mixtures, where the melting point depression is primarily an entropic phenomenon driven by ideal mixing (according to Van‘t Hoff’s law), DES is dominated by the emergence of specific, controlled, supramolecular interactions [61].

The liquid state of DES is thermodynamically stable when the Gibbs free energy (G) of the liquid phase is lower than that of the solid phase (ΔGmix < 0). The melting point (Tm) is defined by the equilibrium where ΔG = 0. The relationship is given by Equation (1):

$$\ln ({\mathrm{x}}_{\mathrm{i}})={\displaystyle \frac{∆{\mathrm{H}}_{\mathrm{f}\mathrm{u}\mathrm{s},\mathrm{i}}}{\mathrm{R}}}\left({\displaystyle \frac{1}{{\mathrm{T}}_{\mathrm{f}\mathrm{u}\mathrm{s},\mathrm{i}}}}-{\displaystyle \frac{1}{{\mathrm{T}}_{\mathrm{m}}}}\right)-{\displaystyle \frac{∆{\mathrm{G}}_{\mathrm{m}\mathrm{i}\mathrm{x},\mathrm{i}}}{\mathrm{R}{\mathrm{T}}_{\mathrm{m}}}}$$

(1)

where x_i is the molar fraction of component i, ∆H_fus,i is the enthalpy of fusion of pure component i, and T_fus,i is its melting temperature. The core of the DES mechanism is the term ∆G_mix,i which reflects the non-ideal free energy of mixing in the liquid phase. The strong HBA-HBD interaction leads to a highly negative (exothermic) enthalpy of mixing ∆H_mix which effectively reduces the thermodynamic activity of the components in the liquid phase. This reduced activity reduces the tendency of the components to recrystallize, resulting in a significant decrease in the eutectic temperature, T_m. Molecular mechanism [61,62,63]:

(a)

Destruction of the crystal lattice: In DES, the dominant mechanism is the disruption of the strong lattice energy of HBA. A typical HBA (e.g., choline chloride) has a high T_m due to strong interionic coulombic interactions. Therefore, the key role is assigned to the HBA anion.

(b)

Formation of a supramolecular complex: The HBA anion acts as an acceptor for protons originating from the hydroxyl, amide, or carboxyl groups of the HBD. This hydrogen-bond coordination creates a new, large supramolecular ionic cluster. These new complex interactions are energetically favorable but structurally less ordered than the original bonds in the pure crystalline phases.

(c)

Critical stabilization of the anion: The presence of an extensive HBD solvation envelope around the anion (especially chloride) effectively separates and stabilizes the HBA ion pair, dramatically reducing the interaction energy and weakening the original lattice force. As a result, the liquid phase can exist at a significantly lower temperature [63,64,65].

Mechanistic evidence for this phenomenon has been provided by advanced analytical and computational techniques.

(a)

Vibrational spectroscopy (FTIR/Raman): The emergence of strong HBD-anion interactions is confirmed by measurement. Typically, a shift of the O-H and N-H frequencies of HBD to lower wavenumbers is observed, which is direct evidence of the weakening of the original intramolecular HBD bond and its strong participation in intermolecular hydrogen bonding with the HBA anion.

(b)

Diffraction and scattering (WAXS/SAXS): They confirm the loss of long-range order in DES compared to pure solids, which corresponds to a significant increase in configurational entropy (ΔS_mix).

(c)

Molecular dynamics and DFT: Computational simulations accurately model the H-bond distances and charge distribution. They confirm the high coordination preference of the HBA anion over that of the HBD protons, demonstrating the existence of dynamically changing supramolecular clusters instead of free, independent ions. These clusters are the essence of the liquid state and determine the low ionic mobility and high viscosity of DES [64,65,66,67,68].

2.3. Deepening the Supramolecular Levels of Formation of DES

The mechanism of DES formation at the supramolecular level goes beyond the simple arrangement of HBA and HBD; it involves the formation of large, but dynamically unstable, ionic and neutral aggregates that define non-ideal mixing thermodynamics. In contrast to IL where the liquid state is governed by bulky and asymmetric ions, in DES the liquidity is primarily governed by the HBA anion [62,63,64,65]:

• Specific role of the anion: The HBA anion (e.g., Cl-, Br-) usually has a high charge density and acts as a strong H-bond acceptor. This anion becomes the central accepting entity to which a typical number of 1 to 4 HBD molecules (urea, glycerol, etc.) are coordinated via their protic groups (OH, NH), thus forming a stabilized anion complex [66,67].
• Supramolecular network: These anion complexes are then dynamically associated with HBA cations via Coulombic forces. The result is not a homogeneous solution of free ions, but a dynamic supramolecular network. This network is characterized by short-range ordering, which prevents the formation of a rigid, long-range crystal lattice, typical of the original solids [63,64,65,66].
• Nonideal thermodynamics: The HBA-HBD interactions are stronger than HBA-HBA and HBD-HBD interactions in their pure solid phases (often exothermic mixing, ΔHmix < 0). According to the thermodynamic theory of solution, this strong interaction leads to a significant negative deviation from Raoult’s law, thereby reducing the chemical activity of each component (ai < xi) in the liquid mixture. This reduced activity is a thermodynamic force that destabilizes the solid phase and shifts the eutectic point towards lower temperatures [61,62,63,64].

The rational design of DES requires the understanding that the liquid phase is not homogeneous but exhibits microstructural heterogeneity similar to micellar solutions, although without a strictly defined critical threshold:

• Domain formation: Molecular simulations and X-ray scattering experiments (SAXS/WAXS) confirm the presence of two coexisting microdomains:

  ○

  Ionic domains: Ion-rich regions (cations and anion complexes) are primarily responsible for the solvation of polar and charged solutes and ion transport.

  ○

  Polar/hydrogen domains: Excess HBD-rich regions maintain strong H-bonds between themselves. These domains influence the solvation of nonpolar or amphiphilic solutes and are primarily responsible for high viscosity [61,62,63,64,65].

• Viscosity and supramolecular motion: The high viscosity of DES is a direct consequence of the existence of this H-bonded supramolecular network. Ion transport does not occur solely through simple diffusional motion (as assumed by the Stokes-Einstein model), but often through cooperative motion of entire clusters or by hopping transport mechanisms within the network. This dynamic but dense cluster architecture provides the mechanistic basis for the sub-ideal Walden behavior observed in most DES [61,62,63,64,65,66,67,68,69,70].

3. The Most Relevant and Highly Cited Research Areas for Deep Eutectic Solvents

Since their introduction, DES have represented a revolutionary breakthrough in the search for sustainable and green solvents to replace traditional, often toxic, organic solvents. Their unique properties: low toxicity, biocompatibility, non-flammability, and affordability have catapulted DES research into the spotlight [71].

With increasing global pressure for sustainability and the reduction of environmental burden, DES have established themselves as a key pillar of green chemistry. The growing ability to analyze DES has led to a sharp increase in publications in the last decade. The analysis of citation indices and H factors clearly identifies several leading application domains that are the pillars of DES research and generate the largest number of scientific references. These include not only separation and extraction processes, especially from natural sources, but also the use of DES in synthetic chemistry and biotechnology. The properties of DES predispose them to solve complex problems, from biomass processing to hazardous waste recycling [71,72,73].

This proposal outlines the ten most interesting and frequently cited research areas related to DES that offer significant potential for the scientific community. These areas essentially focus on green chemistry, sustainability, and advanced technologies, making DES a more environmentally friendly and efficient alternative to traditional organic solvents. The following sections will examine each of these areas in detail, with an emphasis on the most influential and frequently cited methods and results that define the current state of knowledge in the field of DES. A detailed analysis will show how DES have become the preferred choice in bioextraction, wastewater treatment, and electrochemical applications, confirming their position as one of the most promising innovations in modern chemistry [72,73,74].

3.1. Extraction of Bioactive Compounds: Natural Deep Eutectic Solvents

NADES are a special subcategory of DES that have gained immense popularity because of their green nature. They are made exclusively from natural, biocompatible, and non-toxic components that are commonly found in cells of organisms (primary metabolites). Choline chloride or betaine are used as HBA to create NADES, while sugars, organic acids, polyols, or amino acids are used mainly as HBD. They are extremely popular because of their low toxicity and biodegradability. Their primary use lies in the extraction of valuable compounds. Specific areas of use of NADES [75,76,77,78,79,80]:

• NADES composition optimization: study of the influence of various molar ratios of HBD and HBA on extraction selectivity and yield.
• Green extraction: application of NADES for the extraction of polyphenols, flavonoids, alkaloids, and other phytochemicals from plant materials and agro-food waste.
• Food and pharmaceutical utilization: assess the stability and preservation of extracted bioactive substances within the NADES matrix.
• Recycling and reuse: developing efficient methods to separate NADES from the extract to ensure industrial scalability (Figure 2) [75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90].

Several authors have shown that the use of NADES in the isolation of valuable compounds from plant materials significantly reduces the environmental burden of extraction processes compared to volatile and toxic organic solvents [76,77]. Many studies indicate that NADES often have higher extraction efficiencies for certain groups of bioactive compounds (especially phenolic compounds, flavonoids, anthocyanins, and glycosides) than commonly used solvents [78,79,80,81,82].

The authors often report that the specific combination of components in NADES creates unique interactions (such as strong hydrogen bonds) with polar bioactive molecules, leading to better solubilization of target compounds [76,77,78,79,80,81,82,83,84,85]. Some NADES not only extract bioactive compounds but also stabilize them, protecting them from degradation (oxidation or hydrolysis) during and after extraction. Extracts prepared using NADES show greater stability and preservation of antioxidant activity compared to extracts in conventional solvents [83,84,85,86]. NADES thus serve as both a solvent and a stabilizer. NADES are highly effective in combination with modern extraction techniques, such as ultrasound- and microwave-assisted extraction or high-pressure extraction. Synergistic use of NADES with these methods allows for shorter extraction times, lower energy consumption, and an increased the yield of bioactive compounds, which is important for industrial applications [80,81,82,83,84,85,86,87,88,89,90].

3.2. Application in Electrochemistry and Energy Systems

The topic of DES applications in electrochemistry and energy systems is a vast and rapidly growing field, motivated by the need for safer, greener, and cheaper alternatives to organic solvents and IL. DES can serve as an environmentally friendly and cost-effective electrolyte in various electrochemical devices, such as batteries (especially zinc ions), supercapacitors, and fuel cells. The main research areas of DES applications within this chapter [91,92,93,94,95]:

• Electrolytes for batteries: use of DES in zinc ion batteries as a nontoxic and non-flammable alternative to organic electrolytes.
• Metal electrodeposition: utilizing DES for the electroplating of metals, a process traditionally challenging because of environmentally harmful reagents (chromium, zinc, nickel).
• Nanocatalyst production: preparation and stabilization of nanomaterials (metal nanoparticles and composites) directly in DES to enhance catalytic activity.
• Characterization of ionic conductivity: study of the viscosity, density, and ionic conductivity of DES and their optimization for energy applications [91,92,93,94,95,96,97,98,99,100,101,102].

DES serve as inexpensive, non-flammable, and safe electrolytes that can replace organic electrolytes in batteries and IL in supercapacitors. The authors of many works have found that DES exhibit a wide electrochemical stability window, which allows the operation of power devices at higher voltages, directly leading to higher energy densities in supercapacitors. In addition, DES electrolytes demonstrate excellent long-term cycling stability without causing corrosion of the current collectors. These systems often allow cell construction under ambient conditions, which reduces manufacturing costs and complexity [91,92,93,94].

DES are effective and green solvents for electrochemical plating (electrodeposition) and surface treatment, especially for metals that are difficult or impossible to deposit from aqueous solutions (aluminum, zinc, and various alloys). DES (based on choline chloride) have successfully replaced highly toxic cyanide-containing baths or organic solvents in plating processes (nickel, chromium, or zinc alloys), making the process more sustainable. DES enable the deposition of metal coatings and nanocomposites with new and improved morphological and structural properties, which are crucial for sensing and catalysis [95,96,97].

DES are strong and selective leaching agents for the extraction of critical and valuable metals from waste, especially batteries and electronic components. Studies demonstrate that DES can be used to selectively dissolve metal oxides from lithium-ion battery cathodes (cobalt, nickel, and manganese), thus offering a green and efficient alternative to traditional hydrometallurgical processes (which use strong and hazardous acids). Studies have confirmed that specific DES components, such as polyphenols or organic acids, have excellent complexing properties that facilitate the efficient and selective recovery of metals [95,96,97,98,99,100,101].

3.3. Catalysis and Organic Synthesis: Green Synthesis

DES represent a highly active and promising field of research in the fields of catalysis and organic synthesis (especially green chemistry). DES are increasingly recognized as green reaction media and even as active catalysts for various organic transformations, leading to a reduction in the consumption of hazardous solvents. In general, research on DES in this area focuses on their dual role and environmental benefits [103,104,105,106]:

• Reaction medium replacement: substitution of volatile organic compounds with DES in organic synthesis.
• Heterogeneous and homogeneous catalysis: using DES as precursors for the synthesis of DES-functionalized catalysts or as solvents for enzymatic synthesis.
• Catalyst regeneration: investigate the recycling and reuse of the DES/catalytic system to lower operating costs.
• DES-dependent reactions: discovering novel reactions that are only feasible within the specific environment provided by DES [106,107,108,109,110,111,112].

DES are considered an attractive alternative to conventional organic solvents because they combine low volatility with thermal stability, are easy to formulate from inexpensive components, and can be tailored to specific chemical processes. These distinctive properties contribute significantly to the principles of green chemistry, which is why the use of DES reduces the environmental burden of organic synthesis and is particularly important for sustainable industrial applications [103]. As many authors have shown, DES demonstrate similar or even higher catalytic activity compared to conventional catalysts in some reactions, they allow reactions to proceed under milder conditions (without required an additional acid catalyst), and DES-based catalytic systems are often easily separable and recyclable without significant loss of activity, further reducing costs and waste [104,105,106,107,108].

DES support lipase-catalyzed transesterification, aminolysis, etc., often achieving rates and selectivities comparable to those of conventional organic solvents. DES are used as catalysts in the synthesis of key pharmaceutical molecules, and their unique structural properties (tunable solvation and ionic interactions) enhance the kinetics and selectivity of reactions. Overall, the main conclusions are that DES are highly promising and multifunctional media—they can serve as a solvent, catalyst, and even a reactant in one, thus radically simplifying and greening processes in organic synthesis [102,103,104,105].

3.4. Gas Separation and Purification

DES represent a very promising and more environmentally friendly alternative (amine solutions) in the field of gas separation and, in particular, carbon dioxide (CO₂) capture. They have extremely low vapor pressure, which practically eliminates solvent losses to the atmosphere (a problem with amines). In this chapter, the main focus is on the capture of CO₂ from industrial combustion gases, natural gas, or biogas [113,114,115,116,117,118]:

• CO₂ absorption: designing DES with high capacity and selectivity to capture CO₂ from power plant gases (flue gas) and biogas:
• Interaction mechanisms: physical and chemical studies of gas-DES interactions to understand the absorption mechanism (spectroscopy, simulations).
• DES regeneration: development of energy-efficient methods to release the captured gas and recycle the solvent (via temperature/pressure swing).
• Biogas separation: use of DES to remove impurities, such as siloxanes and hydrogen sulfide, from biogas streams [119,120,121,122,123,124,125].

Because of their negligible volatility (virtually zero vapor pressure) and adjustable solvation capacity, DES show high potential for capturing greenhouse gases. In this context, researchers have focused on the functionalization of DES for chemical absorption (aiming to achieve high absorption capacity and minimize volatility), addressing the problem of high viscosity (by adding water or a cosolvent), optimizing regeneration, and, finally, investigating the absorption mechanism.

Table 2. DES application in gas separation and purification—carbon capture [103,104,105,106,107,108].

Composition of DES and Molar Ratios	Specific Application	Ref.
Choline chloride/Levulinic acid (1:2) Choline chloride/Glycerol (1:2) Choline chloride/Lactic acid (1:2)	Membrane separation of SO2 Creation of blended membranes to remove SO2 from CO2 and N2	[113]
TPAB1, BHDE2, TEAC3 and choline chloride as HBA/Ethylene glycol, lactic acid, glycerol and propylene glycol as the HBD (1:2; 1:3)	DES perfomance in the production of porous fluids CO2 absorption using DES and hypercrosslinked polymers	[114]
TMAC4 as the HBA/Glycerol and ethylene glycol as the HBD (1:3)	Separation of hydrofluorocarbons	[115]
Triethyl benzyl ammonium chloride/Ethylene glycol (1:2)	Olefin extractive separation from fluid catalytic cracking naphtha	[116]
L-carnitine as the HBA/Triethanolamine, ethylene glycol and formic acid as the HBD (1:2)	Mechanism of separation of phenols from coal tar Separation of phenolic compounds from model oils	[117]
Choline chloride/1,2-propanediol/water (1:1:1) Tetrabutylammonium bromide/Decanoic acid (1:2)	Greenhouse gases capture (CO2, N2O)	[118]

TPAB¹—tetrapropylammonium bromide; BHDE²—N-benzyl-2-hydroxy-N,N-dimethylethanaminum chloride; TEAC³—tetraethylammonium chloride; TMAC⁴—tetramethylammonium chloride.

provides an overview of studies addressing these aspects [113,114,115,116,117,118,119,120,121,122,123,124,125].

Gas Capture and Separation Using DES

The capture of carbon dioxide from industrial sources (e.g., flue gas) and its separation from mixtures (e.g., biogas) represents a key environmental and energy challenge. DES, due to their unique properties, offer a significant alternative to highly volatile and corrosive traditional amine solutions such as MEA. The primary advantages of DES in this application are [114,115,116,117,118]:

○

Zero vapor pressure minimizes environmental solvent losses and eliminates the risk of toxic vapor formation.

○

Tunability: by choosing specific HBA and HBD, the CO2 activity quotient in the liquid phase can be modified, thus optimizing capacity and selectivity.

CO₂ absorption in DES occurs predominantly through a physical mechanism (as opposed to chemisorption in amines), and CO₂ solubility is controlled by interactions with the HBD components and the free volume in the DES network. By introducing functional groups such as amines directly into the HBD or HBA component, chemisorption can be introduced to increase capacity. A critical comparison of absorption performance requires the evaluation of two main parameters: absorption capacity (thermal advantage) and regeneration energy (economic advantage) (

Table 3. Comparison of the absorption capacity of CO₂ and the regeneration energy (40 °C; 1 bar) [113,114,115,116,117,118,119,120,121,122,123,124,125].

Solvent	The Type of Mechanism	CO2 Capacity (molCO2/kgsolvent)	ΔHabs (kJ/molCO2)
MEA (30%; aq.)	chemical	4.5–5.0	75–90
IL	physical	1.2–2.5	~20
DES	physical	0.6–1.2	~15–25
Functionalized DES	chemical/hybrid	2.0–4.0	45–65

) [117,118,119,120,121,122].

Although DES (purely physical) do not reach the maximum capacity of MEA, their enthalpy of absorption is significantly lower. This value is directly correlated with the energy required for solvent regeneration (CO₂ release) [114,115,116,117,118,119]. As a result, DES have the potential to reduce the overall energy requirement of the capture process, which is a critical economic advantage. Strategic development is focused on functionalized DES, where an amine group is added to the HBA or HBD structure. These hybrid systems combine the low volatility of DES with the chemical reactivity of amines, achieving significantly higher capacity at moderate regeneration energy. Kinetics is the main weakness of DES. High viscosity prevents rapid diffusion of CO₂ into the liquid phase, which reduces the overall absorption rate and requires longer contact times or more efficient stirred reactors. Due to the absence of volatile components, DES show good chemical stability when processing gases with high impurity content [116,117,118,119,120,121]. The selectivity of DES is generally higher than that of physical IL and can be tuned via the polarity of the HBD. This property is particularly important in biogas purification, where DES can also selectively remove other contaminants such as siloxanes and hydrogen sulfide. The latest frontier research in this area focuses on CO₂-R-DES. These DES change their properties (e.g., phase state or viscosity) in response to CO₂ saturation. A typical example is a DES that becomes less viscous or separates into two liquid phases after CO₂ absorption. The CO₂ rich phase can be easily separated for the regeneration and release of CO₂ with a small change in temperature/pressure, which radically simplifies and reduces the energy consumption of the separation process [122,123,124,125].

3.5. Biocatalysis and Enzyme Applications

DES, particularly NADES, offer a unique environment for the stabilization and enhancement of enzyme activity, which are often inactive or unstable in traditional organic solvents. The authors focused on the following key aspects and applications in their work [126,127,128]:

• Enzyme stability: study of the effect of DES on the tertiary structure and long-term stability of various enzymes (lipases, proteases) under reaction conditions.
• Enhanced activity: optimizing the DES composition and water content to maximize the rate of biocatalytic reactions (esterification and transesterification).
• Biomass and biorefining: utilizing DES for the dissolution and processing of lignocellulosic biomass for the production of biofuels and biochemicals.
• Enzymatic reactions: conducting selective and highly efficient biocatalytic transformations in DES media [126,127,128,129,130].

The authors most often studied the influence of various combinations of DES on the thermostability, operational stability, or enzymatic activity of enzymes compared to those in aqueous media or organic solvents. DES were also studied as reaction media for various enzyme transformations, particularly lipase-catalyzed reactions or oxidoreductases. Studies of DES properties such as viscosity, polarity, and composition demonstrate that these factors strongly influence the solubility of substrates, especially hydrophobic ones. They also affect the stereoselectivity of enzymes (including modulation of enantioselectivity) or mechanisms of interaction between DES components and proteins/enzymes [127,128,129,130]. The results show that DES can stabilize enzymes and extend the half-life. The hydrogen-bond network in DES lowers the chemical potential of these components, thereby preserving enzyme structure. DES are successfully used in various types of enzyme reactions (hydrolytic, synthetic), opening the way to the ecological synthesis of valuable compounds such as biodiesel, bioactive lipids, or pharmaceutical intermediates. Recent reports further highlight that DES can improve enzyme recyclability, allowing multiple reaction cycles without significant loss of activity. In addition, DES-based systems often enable higher substrate loading, which increases productivity in industrial biocatalysis. These advantages make DES promising candidates for scaling up sustainable enzymatic processes [131,132,133,134,135].

3.6. Pharmaceutical Applications and Drug Delivery

DES, especially NADES, can significantly increase the solubility of active pharmaceutical ingredients (API) and can be used as drug carriers (drug delivery systems). Research is focused mainly on the use of DES to improve the properties of drugs. Key areas of research are [136,137,138,139,140]:

• API solubility enhancement: investigation of DES formulations that increase the solubility of poorly soluble drugs (anticancer agents) for improved bioavailability.
• Vehicle/excipient use: formulation of DES as non-toxic, biocompatible components in pharmaceutical preparations (creams, patches, oral forms).
• DES in nanomedicine: the use of DES in the preparation of nanoparticles, liposomes, and other drug carriers for targeted delivery.
• Evaluation of toxicity and biodegradability: conduct detailed in vitro and in vivo studies on the toxicity and metabolism of DES to ensure safety for human use [136,137,138,139,140,141,142,143,144,145].

DES are being investigated as replacements for traditional organic solvents in the extraction, synthesis, and formulation of drugs. Research is focused on the development of systems where the API alone forms the DES or where the API combined with DES creates TheDES. Furthermore, DES are being integrated into various forms and carriers (polymer matrices, nanoparticles, gels) to control release and improve biocompatibility [137,138,139]. In addition, studies are exploring the ability of DES to improve drug penetration through the skin is ongoing. A major challenge in the modern pharmaceutical industry is the low solubility of many new API. DES, especially API-based DES (API-DES), significantly increase the solubility of poorly soluble drugs in water, which results in increased permeability through biological membranes and ultimately in a higher bioavailability of the drug in the body. The drug is not only better dissolved, but DES can also serve as a therapeutic agent itself (providing a synergistic effect) or as an effective vehicle (carrier) to improve stability and targeted delivery [140,141,142]. DES have been used successfully in transdermal delivery (to enhance skin penetration); as a component of drug nanocarriers (for functional surface modification); in polymer matrices (to regulate drug release kinetics); and in experimental applications for oral, topical, and injectable administration [136,137,138,139,140,141,142,143,144,145].

3.7. Responsive DES and Smart Applications

The transition to the field of responsive or switchable DES (R-DES) and their use in smart applications is currently a hot topic in chemistry and materials engineering. R-DES are designed to change their physical or chemical properties (viscosity, polarity, extraction ability, solubility or phase transition) in response to an external stimulus such as temperature, pH, light, the presence of water, CO₂, or an electric field [146,147,148]. After extraction, the conditions can be changed (addition of an antisolvent, change in pH), making the R-DES hydrophobic/hydrophilic or dramatically reducing their solvating power for the extracted substance [147]. R-DES also serve as precursors, additives, or templates for materials that exhibit responsive behavior. In addition, researchers have studied molecular interactions and mechanisms, finding that the primary mechanism of responsiveness lies in the disruption or change of the hydrogen bond network between the DES components under the influence of the stimulus. These studies often use molecular dynamics and quantum chemistry to model the behavior of DES/R-DES. They clarify how changing the stimulus affects:

• the free volume fraction and viscosity;
• the solvation spheres around the solutes;
• The strength and length of hydrogen bonds, which are directly correlated with the solvating power [148,149,150,151,152].

Understanding these interactions allows for the rational design of new R-DES, where the choice of components and their molar ratio is guided by the expected change in behavior upon application of the stimulus. Their main added value lies in the ability to reversibly change properties, greatly simplifying subsequent separation, purification, and recycling. Some areas where R-DES are used [152,153,154,155]:

• Switching mechanisms: studying the molecular interactions and mechanisms that govern the “switching” behavior of DES (CO₂-responsive DES).
• Separation and purification: application of R-DES for the highly efficient separation of biomolecules, trace metals, or pollutants via simple phase transition.
• Smart materials: incorporation of R-DES in membranes, hydrogels, or sensors with adaptive functionality.
• Reusability: quantifying the stability and capacity of R-DES after multiple switching and regeneration cycles [146,147,148,149,150,151,152,153,154,155,156].

3.8. Physicochemical Fundamentals and Molecular Simulations

Physicochemical fundamentals and molecular simulations of DES are the cornerstone of current research because they allow a shift from random experimentation to the rational design of tailor-made solvents. To effectively design new DES, it is essential to understand their fundamental properties at the molecular level. This area is highly regarded because it provides the theoretical basis for applications [157,158,159]:

• Structural characterization and interactions: NMR, Raman, and X-ray diffraction studies used to analyze hydrogen bonding and the supramolecular structure of DES.
• Thermodynamics and phase equilibria: measurement and modeling of phase equilibria, eutectic point topology, and the activity of solutes in DES.
• Theoretical modeling: using quantum chemistry and computational chemistry methods (COSMO-RS and molecular dynamics simulations) applied to predict properties and select optimal DES compositions.
• Transport properties: measurement and modeling of viscosity, density, surface tension, and diffusion in DES systems (Figure 3) [160,161,162,163,164,165,166].

The authors of various works using spectroscopic analyses found that these techniques confirm the transfer of electron density and shifts in chemical spectra, which is direct evidence of the formation of new, strong intermolecular hydrogen bonds. As part of the examination of the supramolecular structure, X-ray diffraction revealed that DES are not just homogeneous mixtures. Many studies indicate the existence of nanostructures (nanodomains) or spatial heterogeneity in DES, which influence dissolving ability [157,158,159,160]. Regarding conformational changes, Raman spectroscopy revealed alterations in the conformation of HBD/HBA molecules during the formation of DES that directly affect their packing density and viscosity. Other works aim to measure and model SLE diagrams to predict the composition and temperature of the eutectic point, to measure and model the activity coefficient at infinite dilution (solubility, selectivity, and extraction efficiency) [162,163,164,165]. Thermodynamic studies have repeatedly confirmed that the presence of water (even in small amounts) disrupts the hydrogen bonding network of the DES, leading to increased activity of the components and changes in solubility and viscosity. COSMO-RS allows researchers to select optimal HBA/HBD (including their molar ratios) for a specific application without the need to synthesize or measure each mixture. Studies consistently show that the addition of water dramatically reduces viscosity and increases diffusion coefficients in DES because water disrupts the extensive hydrogen bonding network. Recent work has applied machine learning methods (Random Forest, XGBoost) to predict transport properties (density, viscosity, conductivity) with high precision, representing the future of rapid DES screening [163,164,165,166,167,168].

3.9. Biomass and Polymer Processing

DES have an excellent ability to disrupt the rigid structure of lignocellulose, especially by dissolving lignin, due to their high hydrogen bonding capacity and often acidic or basic character. In some studies, they have achieved up to 90% lignin solubility with minimal damage to cellulose. This process leads to the production of highly pure cellulose and regenerated lignin (choline chloride/lactic acid). DES allow for the complex valorization of biomass into final chemicals: lignin into aromatic monomers, hemicellulose into furfural, and cellulose into glucose via enzymatic conversion [169,170,171,172,173].

Some works have investigated DES as green dual reagent media that act simultaneously as solvent and catalyst in the chemical depolymerization of complex polymers. DES are particularly promising for the chemical recycling of polyethylene terephthalate (PET) [172,173]. In addition, DES catalyze process such as glycolysis, hydrolysis, or aminolysis of PET. DES are successfully used in various polymerization processes, including radical polymerization, condensation polymerization, and ring-opening polymerization [170,171,172,173,174,175].

In addition, DES are crucial for the dissolution of cellulose and the subsequent synthesis of its derivatives, and they are also used to prepare various functional polymer materials such as gels, membranes, fibers, or DES-polymer electrolytes. Solvation depends on the exact composition of the DES. For example, for the dissolution of polysaccharides (cellulose, chitin), DES with specific compositions are used, while different formulations are applied for the selective dissolution of lignin. This enables the selectivity of the fractionation process. Summary of the main areas of interest [176,177]:

• Lignocellulose dissolution: development of DES for the selective dissolution of lignin and cellulose for subsequent biomass fractionation and bioproduct manufacturing.
• Plastic recycling: DES for the selective dissolution and depolymerization of complex polymers (PET, polyurethane) and the recovery of monomers.
• New material preparation: synthesis of cellulose derivatives and other polymeric materials directly in DES medium.
• Solvation mechanisms: study the mechanism by which DES disrupts the structure of polymers and biomass (Figure 4) [170,171,172,173,174,175,176,177,178,179,180].

3.10. Trace Element Determination and Aalytical Chemistry

Because of their high extraction efficiency and solvent flexibility, DES are frequently used in analytical chemistry for the preconcentration of trace elements or analytes from complex samples prior to final determination. Here are some of the most common applications of DES in this field:

• Microextraction techniques: using hydrophobic DES (HDES) in techniques such as liquid–liquid microextraction for the preconcentration of analytes from aqueous matrices.
• Metal separation: selective extraction and determination of trace toxic metals (mercury, cadmium) and rare earths from environmental and biological samples.
• Nanomaterial modification: use of DES as dispersion media and stabilizers for nanomaterials (graphene, carbon nanotubes) employed in analytical sensors.
• Mobile phase chromatography: application of DES and their mixtures as mobile phase modifiers in high performance liquid chromatography (HPLC) and other chromatographic methods for improved separation [181,182,183,184,185,186,187,188,189,190].

DES contribute to the development of greener analytical chemistry by reducing the volume and toxicity of the solvents used and simplifying separation steps. They demonstrate high extraction efficiency for both inorganic and organic analytes, often with high enrichment factors, and are widely used as extraction agents in various microextraction techniques to preconcentrate trace elements before their determination [182,183,184]. DES have been successfully used for the selective extraction and separation of various metal ions (monovalent and polyvalent) from complex matrices, such as oils, plant materials, or environmental samples. DES are becoming key solvents in the field of solvometallurgy, where it is necessary to accurately and reliably quantify metals dissolved directly in DES [185,186,187].

The authors of several works emphasize that DES can serve as components, precursors, or modifiers for the synthesis and functionalization of various nanomaterials, which are subsequently used in analytical applications (especially as sorbents). DES are also used in chromatography either as additives to the mobile phase or as components in the preparation of stationary phases, with the aim of improving separation characteristics. Their main value lies in their tunable properties and their ability to streamline the green sample-preparation and separation processes [186,187,188,189,190].

4. Innovation and New Trend in DES Research

Research is constantly moving forward, and in recent years, the DES phenomenon has been at the forefront of interest in chemical science, engineering, and materials research. These compounds represent a revolutionary innovation in the field of so-called “green chemistry” and sustainable solvents [191,192,193]. The current trend in DES research is no longer limited to their basic characterization. Key innovative directions are tailored design (creating DES with precisely defined properties for specific applications); combination with new technologies (integration of DES into advanced processes); use of computational methods (application of machine learning and molecular dynamics to predict DES properties and accelerate their development). These high-risk and high-gain topics combine DES with advanced chemistry, engineering, and biosciences, representing frontier research poised for high citation rates [191,192,193,194,195].

4.1. Cascade Synthesis and Dynamic Covalent Chemistry in Reactive DES

This area combines DES as a reaction medium with the principles of dynamic covalent chemistry (DCC) and cascade (multistep) synthesis. Utilizing DES could shift the equilibrium of reversible DCC reactions, leading to more efficient formation of complex molecular architectures [191,192,193,194,195,196]:

• DES as directing scaffolds/templates: exploiting specific DES/NADES interactions for template synthesis or controlling DCC equilibria to increase selectivity and yield.
• Multistep cascade catalysis: development of a unified eutectic system containing multiple active sites (metallic and organocatalytic) to enable sequential reactions without intermediate purification steps (zero-waste).
• Self-healing material formation: synthesis of polymers and supramolecular hydrogels with dynamic bonds (imine, boron-ester linkages) directly in DES, where the DES regulates the speed and reversibility of the self-repair process.
• In situ spectroscopic monitoring: application of advanced methods (in situ NMR and Raman) to study the dynamics of covalent bond formation and cleavage within the nontraditional DES environment.
• Reactive HBD/HBA components: designing DES in which one component (HBD or HBA) is the reactant itself or a catalytically active group, eliminating the need for an external catalyst.
• Composition optimization for green methodological development: design of biocompatible R-DES compositions that allow direct use of the final product without complicated solvent separation steps [191,192,193,194,195,196,197,198,199,200].

4.2. DES Inspired Artificial Organelles for Controlled Bioremediation

This field focuses on the encapsulation and protection of enzymes/microorganisms within a DES/hydrogel matrix that mimics the environment of a natural cell organelle to enhance their stability and efficiency under harsh environmental conditions (remediation of contaminated water and soil).

• Hybrid DES-polymer capsules: fabrication of spherical or lamellar structures where the NADES core protects enzymes or living bacterial cultures [201,202].
• Enzyme activity tuning: optimization of the pH and polarity of the NADES core for maximum and long-term stability of enzymes designed to degrade persistent organic pollutants [202,203,204].
• Selective contaminant transport: design of the DES shell that selectively permeates hydrophobic pollutants to the active enzyme center, thus increasing the efficiency of bioremediation [203,204,205,206].
• Environmental responsiveness: development of capsules with a responsive shell (pH or ion-responsive hydrogels) that release enzymes or bacterial cultures only in specific polluted areas [201,202,203,204,205,206].
• In vivo interaction study: evaluation of the impact of encapsulated DES on soil microbiomes and aquatic ecosystems to ensure the ecological safety of the technology [205,206,207,208].

4.3. Photocatalysis and Up-Conversion Nanomaterials Templated by HDES

This area focuses on creating highly ordered photocatalytic materials using HDES as a dynamic template. HDES can control the growth of nanocrystals and simultaneously act as a medium for efficient electron and energy transfer during photocatalysis:

• Structured nanomaterial synthesis: use of HDES with long alkyl chains (micellar structure) as a soft template for the synthesis of mesoporous semiconducting photocatalysts [209,210,211,212].
• Up-conversion in DES: dispersion of lanthanide nanoparticles (rare earth) in HDES to enhance their photoluminescence properties for applications in solar concentrators or biomedical imaging [210,211,212,213,214,215].
• Enhanced charge transfer: investigating how the viscosity and polarity of HDES affect the separation of photogenerated electron-hole pairs and suppress recombination, thereby increasing the quantum efficiency of catalysis [212,213,214,215].
• Photocatalytic degradation in biphasic systems: applying HDES to extract hydrophobic pollutants from water, followed by photocatalytic degradation in the organic DES phase [210,211,212,213,214,215,216,217].
• DES-modified reactor walls: immobilization of HDES in the inner walls of microfluidic reactors to create a dynamic reactive interface in situ for selective photoredox reactions [214,215,216,217].
• Solar fuels in DES: use of DES as a solvent and cocatalyst for the reduction of CO₂ to methanol or other solar fuels using hybrid DES/photocatalytic systems (Figure 5) [215,216,217,218,219,220].

4.4. DES with Tunable Thermo-Acoustic Response for Smart Therapy

This involves developing DES that change their physical properties (density, viscosity, phase state) in response to sound waves (such as ultrasound) or heat, with potential for non-invasive drug delivery or targeted release of active substance [221,222,223,224,225]:

• Ultrasound-triggered phase transition: designing DES with a eutectic point near body temperature that can undergo a controlled phase transition (liquid–liquid demixing or solid–liquid melting) under the influence of therapeutic ultrasound.
• Thermodynamics of ultrasonication: a precise measurement of viscosity and acoustic impedance changes in DES after ultrasound application to identify optimal trigger DES formulations.
• Targeted drug release: incorporating drugs into such DES for non-invasive, spatially targeted release in deep tissues, triggered by ultrasound-induced cavitation or a change in phase stability.
• DES for hypo/hyperthermia: utilize DES as a thermally conductive medium to enhance the efficiency of localized hyperthermia treatment for tumors.
• Application in in vivo imaging: synthesis of DES enriched with contrast agents that change their acoustic response, making them suitable for monitoring drug release using ultrasound.
• Biocompatibility and bioabsorption study: thorough in vitro and in vivo investigation of the biological fate (metabolism, excretion) of these specialized DES after application, particularly for long-term implants or targeted therapy [221,222,223,224,225,226,227,228,229,230].

4.5. DES as a Multifunctional Interface for 2D Materials

Recent advances highlight the versatility of DES in nanotechnology, where they are increasingly applied to the design and modification of two-dimensional (2D) materials. Their tunable physicochemical properties make them suitable not only as solvents but also as surfactants and functionalizing agents. This area explores the use of DES not only as a solvent but also as a surfactant and functionalizing agent for ultra-light and ultra-strong 2D materials. This is a key topic for advanced electronics and composite materials [230,231,232,233,234,235]:

• Exfoliation and functionalization: Use of DES (especially those with amphiphilic properties) for the efficient, defect-free, and ecological delamination of 2D materials.
• Interlayer structure control: using DES to controllably expand the interlayer distance in MXene, thereby enhancing ion transport for supercapacitors and batteries [231,232,233].
• Nanodispersion stabilization: designing specific DES compositions that act as structural stabilizers for 2D material nanoparticles, preventing their aggregation in composite matrices.
• Electronic inks: employing DES for printable electronics applications, where the DES serves as a non-toxic printing fluid for 2D material nanoflakes and simultaneously as a potential binder after evaporation [232,233,234].
• DES-directed doping: use of DES with active HBD/HBA components (containing N and S) for the chemical doping of 2D materials during synthesis, thus modifying their electronic conductivity.
• Interface modeling: complex molecular simulations to understand the solvation and adsorption of DES molecules on the surface of 2D materials, allowing the prediction of optimal compositions for specific applications [230,231,232,233,234].

5. Summary of DES Research Potential

The versatility of DES lies in their tuneability—the ability to tailor their physicochemical properties simply by choosing the HBD and HBA components, and their molar ratio. This allows researchers to fine-tune the solvent for a specific task, whether for high-selectivity extraction, enhanced electrodeposition, or enzyme stabilization.

The key thread linking all these ten areas is sustainability. DES are emerging as central to the circular economy and green chemistry initiatives because they often replace hazardous, flammable, and volatile organic solvents. Furthermore, the use of NADES, derived from natural components, often edible in origin, significantly reduces both the cost and the environmental impact. The immediate future of DES research is projected to see a major shift from initial proof-of-concept studies to process engineering and scale-up, particularly in the fields of CO₂ capture and biomass processing, where their unique properties offer distinct economic advantages over traditional IL. The combination of computational chemistry (predicting optimal DES properties) and experimental validation will drive the field forward, transforming DES from a laboratory curiosity into an industrial reality.

DES are at the forefront of research and development in sustainable chemistry, catalysis, materials science, energy systems, and biotechnological applications. The focus has shifted from basic DES chemistry to highly interdisciplinary, advanced research areas with strong potential for innovation, scalability, and industrial relevance. The following is an extended and detailed overview that focuses on current and future research directions and breakthrough areas of DES application, including emerging areas and new concepts for future development. Modern DES research is expanding into several highly active and influential areas. These areas offer real solutions to pressing challenges in green chemistry, biotechnology, and materials engineering while enabling new fundamental discoveries.

• Green extraction and separation technologies

DES, in particular, NADES and HDES, are transforming extraction procedures for bioactive compounds, rare elements, and pollutants. Their tunable solvency and environmental safety make them excellent alternatives in natural product extraction, pharmaceutical production, food chemistry, and environmental remediation.

• Energy storage and electrochemistry

DES are being explored as safer, nonflammable, and cost-effective electrolytes for batteries (including zinc–ion, lithium–ion, and flow batteries), fuel cells, and supercapacitors. This supports the growing demand for sustainable energy storage solutions and eco-friendly electroplating and metal recycling processes.

• Green synthesis and catalysis

DES are utilized as reaction media and as catalytic components, enabling organic transformations with less hazardous solvent use. Advances are being made in cascade reactions, multistep synthesis, and chemoenzymatic processes, with emphasis on recyclability and process efficiency.

• Carbon dioxide and gas capture

DES, with nearly zero vapor pressure and easily modifiable binding properties, are increasingly being studied for selective greenhouse gas capture, including carbon dioxide, sulfur dioxide, and ammonia from industrial exhausts and biogas.

• Biocatalysis and biotechnology

Stabilization and enhancement of enzyme activity in DES open new avenues for biofuel production, biorefining, and biopolymer synthesis. Research is focused on optimizing DES compositions to improve enzyme half-life, activity, and substrate selectivity, making biotransformations more efficient and sustainable.

• Pharmaceuticals and drug delivery

DES, particularly NADES, dramatically increase the solubility and stability of API. They are being developed as carrier systems for oral, transdermal, and injectable drugs, as well as matrices for nanoencapsulation and targeted delivery.

• Smart materials and responsive systems

R-DES and DES-based hydrogels, membranes, and composites are engineered to react to external stimuli, such as temperature, pH, light, or the presence of gases, enabling adaptive separation, sensing, and actuation in smart material design.

• Biomass processing and polymer applications

DES facilitate the selective dissolution, depolymerization, and fractionation of lignocellulosic biomass and synthetic polymers. Research now includes advanced recycling, monomer recovery, and direct synthesis of polymer derivatives in DES media.

• Analytical chemistry and sensing

DES play a critical role in trace elemental analysis, nanosensor development, and chromatographic separation. Their unique extraction efficiency and modifiable polarity are utilized for the detection, quantification, and preconcentration of heavy metals, pharmaceuticals, and biomolecules.

• Molecular design, simulation, and physicochemical studies

Fundamental studies using molecular dynamics, quantum chemistry (COSMO-RS), and spectroscopic methods (NMR, IR, Raman) are key to predicting, modeling, and optimizing DES properties and interactions.

Researchers are expanding the field of DES with new frontier concepts and applications. These innovative ideas are shaping the future landscape of solvent design and utilization.

• Cascade synthesis and dynamic covalent chemistry

DES are being investigated as reactive media and templates for multistep cascade reactions, in situ dynamic covalent assembly, and self-healing material synthesis. Optimized DES systems could allow zero-waste synthesis and direct product utilization.

• Artificial organelles and bioremediation capsules

Hybrid DES-polymer capsules mimic cellular organelles, protecting enzymes or microorganisms for targeted, enhanced bioremediation in contaminated environments. Research includes environmental responsiveness, regeneration, and ecological safety assessment.

• Photocatalysis and nanomaterial synthesis

HDES serve as soft templates for photocatalyst and up-conversion nanomaterial synthesis. These systems improve quantum yields, charge separation, and pollutant degradation, with applications in energy harvesting and environmental technology.

• Thermo-ccoustic-responsive DES for therapy

DES with tunable thermal and acoustic response are being developed for drug delivery and smart therapies, enabling ultrasound- or heat-triggered phase changes and controlled active release.

• 2D Material interfaces: graphene and MXene functionalization

DES (including functionalized and amphiphilic types) are unlocking new methods to exfoliate, disperse, and dope advanced 2D materials, revolutionizing electronic inks, sensors, and composite technologies.

• DES-driven circular economy platforms

DES are central to new circular process engineering for sustainable material life cycles, enabling direct biomass valorization, eco-friendly recovery, and scalable recycling in industry.

6. Critical Analysis of DES Limitations and Industrial Challenges

Despite extensive academic interest and promising potential in green chemistry, significant physicochemical and engineering constraints persist and must be critically evaluated and overcome on the path to the comprehensive industrial implementation of DES. The most prominent and frequently cited problem is the inherently high viscosity of most DES at operating temperatures, typically ranging from 10² to 10⁴ mPa·s. This extreme viscosity directly and negatively affects fundamental engineering operations: it increases the energy demands of mixing and pumping systems, where dense liquids require more expensive and robust equipment and can lead to cavitation problems [235,236,237]. Critically, high viscosity severely limits mass and heat transfer as it drastically reduces solute diffusion coefficients, slowing the reaction rates and lowering the efficiency of processes such as chemical reaction, adsorption, or extraction, rendering some DES thermodynamically favorable but kinetically ineffective. A partial solution is sought in temperature optimization (operating at elevated temperatures) or in dilution with a small amount of water or cosolvent (typically 5–15% mol.); however, while dilution reduces viscosity by an order of magnitude, it introduces the risk of altering the fundamental solvating structure and losing selectivity. Therefore, finding an optimal balance is key. An example of a successful low viscosity approach is the use of PDES, which tends to be less viscous due to proton mobility and exhibits better conductivity for electrochemical applications (

Table 4. Data on the viscosity and conductivity values of some DES studied (at 25 °C).

Composition of DES	Dynamic Viscosity (mPa·s−1)	Ref.	Composition of DES	Conductivity (mS·cm−1)	Ref.
Choline chloride/Ethylene glycol	40	[236]	Choline chloride/Ethylene glycol	8.317	[240]
Choline chloride/Sorbitol	19.47	[237]	Choline chloride/Glycerol	1.463	[240]
Choline chloride/Glycerol	350	[238]	N,N-diethyl ethanol ammonium chloride/Glycerol	0.487	[240]
Choline chloride/Urea	750	[239]	Methyl triphenyl phosphonium bromide/Ethylene glycol	1.942	[240]
Choline chloride/Glucose	7992	[239]	Tetra-n-butylammonium bromide/Ethylene glycol	0.635	[241]

) [237,238,239,240,241].

DES are considered a promising and more environmentally friendly alternative to traditional amine solutions or ionic liquids used for CO₂ capture. CO₂ absorption in DES can occur in two main ways: (1) physical absorption—CO₂ is dissolved in the solvent (similar to other liquids); (2) chemical absorption—CO₂ reacts with the HBD (especially when amine groups are present, e.g., monoethanolamine, MEA), thereby increasing the absorption capacity. Factors that affect CO₂ solubility include:

• Composition of the DES: different combinations (e.g., choline chloride with urea, or various amines) lead to very different absorption capacities.
• Water addition: the addition of water often significantly reduces the high viscosity of pure DES, improving the absorption rate and mass transfer. Conversely, in some systems water acts as an antisolvent, decreasing CO₂ solubility (e.g., certain choline chloride-based systems). In other systems, particularly those with reactive amines, water addition can increase or optimize absorption capacity, or only slightly reduce it.
• Temperature and pressure: a higher partial pressure of CO₂ generally increases absorption, and lower temperatures typically lead to higher physical solubility [119,120,121,242].

Another serious operational problem is the strong hygroscopicity of most DES, particularly those based on chloride salts and NADES. This sensitivity to atmospheric moisture leads to uncontrolled water absorption, which changes its composition in situ and subsequently affects key properties unpredictably, such as viscosity, ionic conductivity, and, more importantly, the solubility and selectivity towards target solutes. For industrial applications, this requires expensive storage and handling in controlled or inert atmospheres, increasing both operating cost and system complexity [119,120,121,241].

From an economic perspective, the recyclability and separation of DES from products present a major challenge. Although DES are often promoted as recyclable, their zero or extremely low vapor pressure practically prevents the use of standard distillation for separation, except in very specific cases. Furthermore, strong hydrogen-bonding interactions between the DES and polar products complicate simple phase separation. Methods such as the use of antisolvents (which reintroduce organic solvents into the “green” process) or advanced membrane filtration are technologically demanding and require a high investment [241,242,243]. Therefore, the economics of DES regeneration is a crucial factor; the total costs of cleaning and recycling must be substantially lower than the costs of disposal and purchase of traditional solvents to ensure commercial viability. The most promising solutions lie in the development of R-DES that alert their phase stability in response to an easily removable stimulus, such as CO₂ [242,243].

Finally, corrosion and material compatibility are critical factors for reactor design. DES is not chemically inert. Types I and II containing metal halides (CuCl₂, ZnCl₂) function as strong Lewis acids, and Type III (with organic acids) exhibit Brønsted acidity. These systems are highly corrosive to standard construction steels and require the use of inert materials, such as expensive alloys, glass, or polymeric linings. Together, these challenges underline that the successful transition of DES from the laboratory to industry requires an essential shift from purely chemical research to rigorous chemical engineering [240,241,242,243].

7. Conclusions

DES have transcended their early role as novel green solvents to become central players in the evolution of sustainable chemical, material, and biological technologies. Future and active research is characterized by interdisciplinary innovation, spanning areas such as enzyme stabilization and drug delivery to energy storage, catalysis, smart materials, and bioremediation. The ability to tailor DES properties and create specialized systems, such as NADES, HDES, TheDES, and functionalized DES, will continue to drive new discoveries and commercial breakthroughs. As experimental research converges with computational design and process engineering, the next generation of DES-based solutions is poised to revolutionize multiple fields, advancing both environmental goals and industrial performance.

The concept of eutectic mixtures dates back to 1884, when J. Guthrie first observed that mixtures of select substances could achieve melting points far lower than those of their individual constituents, establishing a foundation for later advances in chemical solvent systems. Over subsequent decades, this phenomenon found utility in metallurgy, materials science, and other technical disciplines, paving the way for the development of deep eutectic solvents. A major turning point came in 2003, when Andrew Abbott and his team coined the term “deep eutectic solvent (DES)” and demonstrated the preparation of a liquid solvent. Abbott’s findings quickly attracted researchers looking for alternatives to volatile, toxic organic solvents and ionic liquids, launching the DES revolution. DES were classified by component types and hydrogen bonding properties into four main groups (2003–2010). In 2011, a pivotal expansion occurred when natural deep eutectic solvents (NADES) were identified by Yong Hwa Choi, Robert Verpoorte, and colleagues. From 2014 to 2019, the DES classification expanded to encompass type V: non-ionic molecular mixtures, formed by hydrogen bonding without quaternary ammonium salts or metal halides. This includes many NADES with hydrophobic properties. Research also gave rise to specialized groups: TheDES; HDES; PDES and functionalized DES.

DES are celebrated for their tunable properties: low volatility, nonflammability, vast solvency range, and customizable physicochemical profiles based on the chosen HBA/HBD pair and mixing ratio. A DES can be prepared easily, typically by simple mixing and mild heating, which further contributes to sustainability and cost effectiveness. Applications now extend across chemistry, green manufacturing, pharmaceuticals, analytical chemistry, catalysis, and advanced materials. Key industrial areas include the following: Bioactive compound extraction (NADES and HDES); sustainable electrolytes for batteries and fuel cells; green catalysis and organic synthesis; carbon capture and gas separations; biocatalysis, enzyme stabilization, and biorefining; drug delivery and nanomedicine; R-DES for smart materials and separations; biomass and polymer processing; analytical preconcentration and chromatography.

DES, including NADES, provide distinct microenvironments that stabilize the enzyme structure and enhance long-term activity, an advance over traditional organic solvents, which may inactivate or destabilize protein catalysts. Carefully optimized DES compositions and water content can considerably accelerate biocatalytic processes such as esterification and transesterification. This opens pathways for green synthesis and scalable process engineering. In biorefining, DES play a transformative role in the dissolution of lignocellulosic biomass, enabling efficient fractionation and conversion to biofuels and value-added chemicals. Selective and high-yield enzymatic transformations in DES have improved yields and selectivity in industrial systems, aligning with the broader push toward sustainable chemistry.

Research now covers critical areas such as cascade synthesis, responsive DES for smart therapy, DES-inspired organelles for environmental remediation, photocatalytic and nanomaterial templating via hydrophobic DES, and multifunctional applications with 2D materials (graphene, MXene). Each topic combines chemistry, biology, materials, and engineering, offering the largest potential for fundamental and applied discovery in sustainability and advanced technologies.

The historical trajectory of DES—from simple eutectic mixtures to designer functionalized systems—demonstrates their rapid rise in importance for sustainable chemistry and technology. Their inherent tunability, low toxicity, and wide application range drive continual innovation, as new variants (NADES, HDES, TheDES, PDES) and interdisciplinary research approaches emerge. Modern DES offer concrete solutions to pressing challenges in green manufacturing, the circular economy, pharmaceutical delivery, and energy systems. In the coming years, the integration of computational design with experimental research will catalyze the transition of DES from laboratory specialties to industrial mainstays, revolutionizing solvent chemistry for a greener future.