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Development of switchable deep eutectic solvents: Applications in extraction of natural products

Yuan Yan ,  Lingqi Shen ,  Yu Wang ,  Bincheng Gong ,  Zuguang Li ,  Hongdeng Qiu

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Citation:  Yuan Yan, Lingqi Shen, Yu Wang, Bincheng Gong, Zuguang Li, Hongdeng Qiu. Development of switchable deep eutectic solvents: Applications in extraction of natural products[J]. Chinese Chemical Letters, 2025, 36(11): 110845. doi: 10.1016/j.cclet.2025.110845 shu

Development of switchable deep eutectic solvents: Applications in extraction of natural products

English

  • 1. Introduction

    Natural products are widely utilized in various fields due to their distinctive bioactivity and structural diversity [1-3]. Plant sources, such as phenolic chemicals [4], flavonoids [5], polysaccharides [6], can play anti-inflammatory and anti-cancer roles, as well as local skin disease treatment, anti-oxidation, and anti-aging [7-9]. However, the variety and complexity of natural products, coupled with their low content, present significant challenges for extraction process. Therefore, the extraction process of natural products is crucial to their development. Conventional extraction techniques (solvent extraction, distillation, pressing sublimation, etc. [10-12]) necessitate large amounts of organic solvents (methanol, ethanol, acetone, hexane, etc.) that are highly volatile, highly toxic, and poorly biodegradable, resulting in potential loss of active compounds. Meanwhile, due to the residual organic solvents, the extract is not suitable for food or pharmaceutical development [13,14]. Recently, ultrasonic extraction, supercritical fluid extraction, microwave-assisted extraction, and other new environmental protection technologies combined with green solvents [15-17] have been implemented in natural product extraction. Deep eutectic solvents (DESs), as innovative eco-friendly solvents, have the characteristics of non-toxicity and biodegradability, and its application in natural product extraction has a prospect that cannot be ignored [18,19].

    DESs were first proposed as new type of green solvents by Abbott et al. [20]. They are typically low eutectic mixture composed with a certain stoichiometric ratio of hydrogen bond acceptors (HBAs, like halide anion) and hydrogen bond donors (HBDs, such as amide, carboxylic acid, and polyol compounds). When it forms a eutectic system, the melting points of DESs are significantly lower than the predicted eutectic temperature due to the formation of hydrogen bonding [21,22]. Currently, stirring heating, grinding, and freeze-drying are the primary synthesis techniques for DESs. The stirring heating method is to mix a certain proportion of HBAs and HBDs and stir under heating conditions until a homogeneous liquid is formed [23]. The method is commonly used to prepare DESs since it is easy to operate with a high yield. Nevertheless, for some DESs contained choline chloride (ChCl) and carboxylic acid, this method may cause an esterification reaction to produce HCl and corresponding esters [24]. Consequently, the grinding method was devised. In this method, HBAs and HBDs are ground together in a mortar at room temperature until a homogeneous liquid is formed [25]. The freeze-drying method is to mix each solid single component through an aqueous solution to prepare DESs [26] by freeze-drying. Compared with traditional solvents and ionic liquids (ILs), DESs have the advantages of low volatility, low-toxicity, biodegradability, and chemical stability [27]. Moreover, research has demonstrated that using DESs in the extraction of natural products might improve the biological activity and stability of active compounds [28,29]. For example, DESs composed of choline chloride as HBA and glucose, fructose, xylose, glycerol, malic acid as HBD were applied to extract the phenolics from grape skin. The study showed that the anticancer activity of the five extracts in the experiment was improved. The DESs utilized in the experiment are also called natural deep eutectic solvents (NADESs), as DESs composed of natural components such as primary metabolites, are considered to be the third liquid phase naturally occurring in living organisms and independent of water and lipids. They have an advantage in extracting natural products due to their greener and more natural compositions, such as terpenoids and long-chain fatty acids [30]. These studies indicate that DESs as green solvents are expected to find wider application in the field of natural product extraction.

    Conventional DESs are difficult to be recovered by simple evaporation due to their low-volatility [31]. The separation is typically conducted using methods such as organic solvent back extraction, microporous resin [32], C18 solid phase extraction [33], dialysis [34], and other techniques. With the development of various green separation technologies, the methods with costly processes and toxic solvents may no longer be suitable for practical application in extraction and separation. And in the last decade or so, designing stimuli-responsive switchable systems has gained a lot of attention in the field of chemistry and materials. They can undergo reversible chemical/physical changes in response to external stimuli such as light, heat, CO2, electricity and pH [35-37]. Extraction of natural products can be accomplished by causing solution systems to transition from single-phase to diphase. Switchable solvents (SSs) as kind of stimuli-responsive switchable systems were first proposed by Jessop in 2005 [38]. It can occur phase transition (hydrophilic/hydrophobic, polarity/nonpolar, liquid/solid) when the system levels (temperature, pH, and CO2/N2) change due to environmental factors. Sed et al. [39] were the first to apply this switchable characteristic to DESs, designing switchable deep eutectic solvents (SDESs), which were also NADESs, to transition between hydrophilic and hydrophobic using CO2 bubbling. Under the action of weak amines, NADESs formed by weak amines and fatty acids will result in the formation of a complex. Subsequently, the introduction of CO2 can disrupt the initial complex structure and enable the reversible switching of this kind of NADESs. This approach does not require any extra solvent, avoids the problem of difficult recovery caused by the low volatility of DESs, and has a long-term application prospect. Since then, the design of SDESs has been the subject of substantial research [40-42]. The switching phase transition ability of SDESs allows for the separation and adaptation of compounds with various polarities to varied extraction conditions, improving selectivity and efficiency in the extraction process. Furthermore, SDESs also contribute to the retention of antioxidant activity and stability of natural products, which are important indicators for assessing the effectiveness of the methodology.

    In the past few years, the research on DESs and SDESs has been growing rapidly as shown in Fig. 1. The figure shows the trends in the number of publications on DESs and SDESs over the last five years. The data results indicate the growth proportion of SDESs in recent years, and the application of SDESs needs to be further expanded in the future.

    Figure 1

    Figure 1.  Research trends on DESs and switchable DESs published over the past five years (Based on Web of Science).
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    This article provides an overview of SDESs' utilization in extracting natural compounds, incorporating prior research. The composition, category, physicochemical properties, and switching mechanism of SDESs were reviewed and investigated. In particular, the application of SDESs in the extraction of natural products under different response conditions (CO2, pH, and temperature), the mechanism of lignin dissolution, some auxiliary extraction methods and optimization conditions were discussed. Compared with traditional solvents, the advantages of SDESs on the retention of active substances in the extraction of natural products were summarized. The review is intended to serve as a point of reference for future research in the relevant field.

    2. SDES

    2.1 Composition and category of SDESs

    SDESs can be classified into three types based on their driving factors: CO2/N2-responsive SDESs, pH-responsive SDESs, and temperature-responsive SDESs (TRDESs). CO2/N2-responsive SDESs are primarily constituted of alcohol amines as HBAs and fatty acids, alcohols, and phenols as HBDs. This type of SDESs design will often utilize nitrogen-containing compounds, which will be beneficial in triggering the response of CO2. For pH-responsive SDESs, HBAs mostly use menthol, thymol, and fatty acids which confers good pH responsiveness to SDESs. The HBAs used in the construction of TRDESs were typically lidocaine, tetracaine, and alkanol amines. Such HBAs usually have temperature-sensitive pKa to allow for easier phase transition reactions. HBDs primarily target fatty acids and phenols. Among them, due to the properties of the constituents, SDESs, which are a combination of alcohol amines and phenolic compounds, are responsive to both CO2 and temperature. These SDESs combined solid-liquid extraction, two-phase aqueous system extraction, three-phase distribution extraction, and other methods for natural product extraction [43-45]. Based on past research, this review briefly summarizes the composition and driving factors of SDESs in recent years as shown in Table 1 [41,46-60]. Most SDES systems are binary components and the raw material synthesis source has limits. The classification and molar ratio of various DESs is regulated to optimize the technology of SDESs in separation and extraction. Meanwhile, the application of SDES in different fields is being investigated.

    Table 1

    Table 1.  Classification of HBAs and HBDs with some representative compounds.
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    HBA HBD Drivers Ref.
    CO2 [46]
    CO2 [47]
    CO2 [48]
    CO2 [49]
    pH [50]
    pH [51]
    pH [52]
    pH [41,53]
    pH [54]
    LCST [55-57]
    LCST [58]
    UCST [59]
    UCST [60]

    2.2 Physical properties of SDESs

    In practical applications, several types of SDESs can be designed and their physical and chemical properties exploited to fulfill specific functions [61]. The physical properties of SDESs, including melting point, viscosity, density, polarity, dipole moment, and dielectric coefficient, are similar to those of DESs. These physical properties will attribute significantly influence to their performance in extraction and separation procedures. Therefore, studying the physical properties of SDESs can facilitate the selection of the most appropriate SDES for enhancement of extraction efficiency with respect to specific targets in extraction processes.

    Most SDESs are liquid at room temperature due to the hydrogen bonding between HBAs and HBDs, which alters the lattice energy between the two components, lowering the melting point of SDESs compared to a single component [62]. Numerous variables will affect melting point, such as molar ratio between components and chain length of the component. Fattahi et al. compared the melting point of SDESs formed by thymol with 1-hexanol, 1-octanol, 1-heptanol, and 1-dodecyl alcohol. Thymol's stronger hydrogen bonding with fatty alcohols caused it to transition from solid compound to liquid at room temperature. And the research discovered that increasing the length of aliphatic alcohol alkyl chains resulted in the formation of SDESs with higher melting point [63].

    The viscosities of DESs reflect hydrogen bonding stability to some degree: A robust network of hydrogen bonding results in a narrower internal molecular movement space, increasing the system viscosity [64,65]. Most DESs have a relatively high viscosity, which decreases as temperature increases. Lu et al. researched the association between the viscosity of three synthesized SDESs and temperature changed from 20 ℃ to 80 ℃ (Fig. 2A) [50]. The study found that the viscosities of the three DESs were notably elevated compared to ordinary solvents, but when the temperature increased, the viscosity decreased exponentially due to the reduction in intramolecular hydrogen bonding. In addition, the viscosity can also be regulated by the alkyl chain length. The longer the carbon chain, the higher the viscosity [54]. Yue et al. [66] tested the viscosities of the prepared DESs (HBDs were decanoic acid, lauric acid, and myristic acid) using deionized water as a reference in the experiment. Validation indicated a correlation between increased viscosity and enhanced fatty acid chain length in synthesized DESs. However, high viscosity affects the mass transfer rate and makes the extraction time longer. The results of the study then hinted at the possibility of solving the problem by adding short-carbon chain fatty acids to long-carbon chain fatty acids. Additionally, the viscosity decline was exponentially enhanced with the increase in temperature. But too low viscosity will also weaken the hydrogen bonding between the target analytes and the SDESs [67]. Niu et al. [52] investigated the viscosity of DESs synthesized from myristic acid and caprylic acid with different molar ratios. Excessive caprylic acid will dilute the viscosity of SDESs, which increases the rate of mass transfer. The molar ratio of 1:7 provides the best extraction efficiency, while increasing the amount of caprylic acid weakens the intermolecular hydrogen bond, leading to a reduction in extraction rate.

    Figure 2

    Figure 2.  Viscosity (A) and density (B) curves with temperature for DES formed by tetrapropylammonium bromide (TPAB) combined with octanoic acid (DES1), TPAB combined with nonanoic acid (DES2), and tetrabutylammonium bromide (TBAB) combined with octanoic acid (DES3). Copied with permission [50]. Copyright 2021, Elsevier.
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    Most DESs have a higher density than water, whereas hydrophobic deep eutectic solvents (HDESs) have lower density [68,69]. Temperature fluctuations also affect DESs density, which decreases as temperature increases [25,70,71]. Muniasamy et al. [72] discovered that the density of the SDESs formed by Triton X 100 and Tween 80 as HBDs combined with ammonium salts such as choline chloride, tetrabutylammonium chloride, and tetrabutylammonium bromide as HBAs rose linearly with decreasing temperature within the range of 293–323 K. In the fibrinolytic protease extraction experiment, temperature had a significant impact on the quaternary ammonium salt. Cooling caused its density to rise in a higher direction. Lu et al. [50] explored the density of the three kinds of pH-responsive SDESs which were all HDESs in their initial state. These SDESs synthesized all have a lower density than water, and previous investigations have found a similar effect [53,63]. As the temperature increased from 20 ℃ to 80 ℃, the density of SDESs decreased linearly (Fig. 2B). Furthermore, the density of SDESs can be adjusted by changing the chain length. Pochivalov et al. found a decrease in SDESs density as the increase of the hydrocarbon chain length of fatty acid [54].

    The polarity of a fluid is a key characteristic of its ability to dissolve solutes, which affects the force of interaction between the compound and the solvent. Typically, DESs display high polarity towards polar molecules and minimal solubility for non-polar substances, attributable to robust hydrogen bonding forces [73]. Polarity of DESs is an important factor influencing extraction efficiency. Liu et al. [74] evaluated whether the polarity of DESs is regulated by the length of the alkyl chain of fatty acids in the experiment determining the decomposition rate of carbon fiber reinforced polymer composites (CFRPs). It was found that with the increase of the carbon chain, the decomposition ratio of CFRPs increases. The reason for this is the decrease in polarity and increase in hydrophobicity of the solvent as the alkyl chain length of the HBD increases. The polarity difference induced by the chain length has a positive contribution to the affinity of epoxy resin and enhances the mass transfer effect in the process. Lee et al. [47] discovered that the DES synthesized by ethanolamine and butanol showed the highest extraction efficiency of isopropanol (IPA) in water among the detected DESs. The similarities in polarity, dipole moment, and dielectric constant between butanol (60.2, 1.66, and 18.2) and IPA (54.6, 1.66, and 18.3) account for this trend. Based on this feature, the hydrogen-bond interaction between butanol and IPA can be employed as a driving force for the separation between isopropyl alcohol and the aqueous phase.

    Research on the thermal stability of DESs can determine its temperature range as a solvent, and reduce its loss in the recovery process [75]. Jing et al. [76] measured the stability of DES (menthol-indole) through thermal gravimetric analyzer (TGA) and obtained the decomposition temperature diagram. It was confirmed that the synthesis of HDESs could significantly reduce the loss of indole. In a similar vein, Li et al. hinted at the low-temperature characteristics of DESs in their study of CO2-responsive SDESs separation of petroleum hydrocarbon pollutants [77]. The study revealed synthesized SDESs thermal decomposition temperature was 35–58 ℃, significantly below its component boiling points.

    2.3 Mechanism of SDESs synthesis and conversion process

    Investigating the switching mechanism of SDESs under different driving factors will assist designers in better building SDESs with specified functionality. Most SDESs realized phase separation behavior by varying hydrophobicity and hydrophilicity. The majority of researchers used 1H NMR, FT-IR, and 13C NMR to characterize the structure of SDESs before and after response.

    As a driving force, CO2 has its unique advantages and the switching process can be completed in environmentally friendly and moderate conditions. CO2, being a reasonably mature switching mechanism, has found widespread usage in a variety of responsive solvents, including switchable hydrophilic solvents, switchable surfactants, switchable ionic liquids, and switchable water additives [78]. Nitrogen-containing compounds like guanidine, tertiary amines, and secondary amines were the crucial components in these switchable solvents, and CO2-responsive SDESs are similar to these nitrogen-containing compounds [78]. In the developed CO2-responsive SDESs, nitrogenous compounds such as imidazole, indole, and alcoholic amines are added to SDESs as HBAs, while phenols and alcohols are added as HBDs. The chemical reaction between nitrogenous bases and CO2 is the primary reason for phase transition of system. For example, SDESs combined with alkanol amines and phenolics were miscible with water before CO2 bubbling. After the introduction of CO2, H2CO3 and other acids with stronger acidity than phenol were formed, breaking the hydrogen bond between alkanol amine and phenol in SDESs. Salting out resulted in enrichment of hydrophobic phenolic compounds in the lower phase. The chemical reaction between alkanol amine and carbonic acid produces carbamate which continues to exist in the aqueous phase. Following the injection of N2, the carbonate structure was destroyed and revert back to the alkanol, which could be regenerated to form SDESs in situ with the underlying phenolic compounds.

    Wang et al. [46] created CO2-responsive SDES with triethanolamine and 4-methoxyphenol and characterized by 13C NMR. After CO2 bubbling, a new signal appeared at δ 160.2 (Fig. 3), indicating the formation of -NHCOO-. The peak disappeared after the triggering of N2, indicating that -NHCOO- was destroyed and the alkanol amine was recovered. Liu et al. [71] applied low-cost nitrogenous base imidazole as HBAs to synthesize CO2-responsive SDESs with several polyols. Through FT-IR characterization, a spectral feature emerged at 1635 cm-1 after CO2 bubbling, which was ascribed to the asymmetric stretching of carbamate, indicating the chemical absorption of CO2 by SDES. The signal disappeared once N2 was triggered, suggesting that SDES had been regenerated. The results of the experiment were similar to the above. Overall, this type of SDESs can accomplish good switching behavior via CO2/N2 bubbling, which provides a sufficient guarantee for extracting target components from diverse substrates with varying properties.

    Figure 3

    Figure 3.  13C NMR spectra of DES formed by triethanolamine and 4-methoxyphenol extract in D2O before and after bubbling CO2. Copied with permission [46]. Copyright 2024, Elsevier.
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    Normally, pH is adjusted in a solution system through introducing suitable proton donors (such as HCl) or deprotonation reagents (such as NaOH) to realize the reversible response. When the pH of system changes, hydrogen bonds break or form, resulting in a change in the polarity of the SDESs. These pH-responsive SDESs often use medium-chain fatty acids, quaternary ammonium salts, menthol, and thymol as HBAs. Fatty acids, alcohols, and phenolic compounds are used as HBDs. The pH-responsiveness of SDESs originates from their ability to disrupt and form ionic or covalent bonds within aqueous systems.

    Niu et al. [52] studied the 1H NMR and FT-IR variations of pH-responsive SDESs before and after response, demonstrating the transformation mechanism of hydrophobic SDESs through caprylic acid and myristic acid synthesis. Hydrogen bonds were formed between myristic acids, which existed as dimers. When polyether amine was added, an electrostatic interaction between the amine and the fatty acid occurred, resulting in the formation of the fatty acid amine complex, which increased the electron density of the system and converted hydrophobic SDESs to hydrophilic. When the fatty acid amine complex was protonated by adding an acidic solution, the SDESs hydrogen bond network could be reformed. This restructuring enables the in-situ formation of hydrophobic SDESs, leading to phase separation. Salamat et al. [79] explored the switching mechanism of formed by different molar ratios of succinic acid and octylamine. The SDESs were prepared by the hydrogen bond interaction between succinic acid and octylamine, which exhibited hydrophilic properties under neutral conditions. Upon alkalizing the solution using NaOH, the above synthesized SDESs proved incapable of mixing with water, yielding heterogeneous solution. The solubility of octylamine diminishes as the size of its hydrophobic alkyl group grows. However, after the combination with succinic acid as the SDES, it could be soluble in water and converted to hydrophobic by adjusting the acidic solution. This can be linked to the regular interaction of HBDs and HBAs. The FT-IR (Fig. 4A) and 1H NMR spectra (Fig. 4B) demonstrated that the composition of SDESs were unchanged, and the reformed SDESs could be fully recycled. Wang et al. [80] provided an explanation of the SDES switching mechanism based on N,N-dimethylethanolamine (DMEA) and heptanoic acid. The hydrogen bonding interaction of DMEA with heptanoic acid was supported by both the shift in the proton signal in 1H NMR spectra and the change in the vibration band in FT-IR spectra. The FT-IR spectra of hydrophobic phase were same with that of heptanoic acid. This suggested that the addition of HCl solution broke the hydrogen bond in SDES, causing the reaction between HCl and DMEA to form the ammonium salt [(CH3)2NH(CH2)2OH]+Cl−, which in turn caused the release of the hydrophobic heptanoic acid and the phase conversion. It can be further confirmed that the extrapolated onset temperature (T) value of the hydrophobic phase recovered was consistent with that of heptanoic acid through differential scanning calorimetry (DSC) characterization.

    Figure 4

    Figure 4.  (A) FT-IR spectra of succinic acid (SA), octylamine (OA), and prepared hydrophilic DES. (B) 1H NMR spectra of SA, OA, and prepared hydrophilic DES before using (pre-DES), and after using (post-DES) in the developed method. Copied with permission [79]. Copyright 2024, Elsevier.
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    TRDESs can be categorized into two types based on its phase transition behavior: SDESs with upper critical dissolution temperature (UCST) and SDESs with lower critical dissolution temperature (LCST). At lower temperature, the two phases of UCST-type SDESs with water are separated, and as temperatures rise, the phases change into a homogenous phase. A homogenous phase is displayed by LCST-type SDESs at a temperature lower than the critical point. Phase separation happens when the temperature rises to the critical point, at which point the two phases become insoluble. The solubility and pKa of HBDs and HBAs are connected to both phase behaviors [56,59].

    In the published studies so far, UCST-type SDESs mainly used alkanol amines as HBAs and phenolic compounds as HBDs, which partially overlaps with CO2-responsive SDESs. In the case of lower than UCST, the SDESs formed by the combination of alkanol amines and phenols are hydrophobic, exhibiting negligible hydrogen bonding with water. But with the increase of temperature, the two phases transmute to a single state. The phase transition mechanism was explained by Cai et al. using variable-temperature FT-IR (Fig. 5A) and variable-temperature 1H NMR (Fig. 5B) [59]. The hydrogen bond absorption peak of ethanolamine-o-cresol (ET-OC) will change blue when adding 50% D2O to SDES, indicating the interaction between SDES and D2O. Furthermore, the intermolecular absorption peak of D2O will shift red with rising temperature, suggesting the weakening of the hydrogen bond interaction of D2O itself. The results showed that as the temperature changed, the hydrogen bond interaction of D2O itself increased and phase separation occurred when the interaction force of the water itself was greater than that of SDESs and water. In variable-temperature 1H NMR, the chemical shift moved towards the higher field as the temperature decreased, further proving that the interaction force between ET-OC and D2O slowly decreased as the temperature decreased, making SDES separated from water solution. Using dynamic light scattering (DLS) measurements, subsequent research by Xiong et al. [81], revealed a sharp rise in aggregate size near the phase transition temperature, implying that the agglomeration of SDESs in water. In additional research by Xiong et al., they examined the role of various components in shaping the USCT of SDESs. They found that escalating pKa values for HBAs and HBDs reduced UCST owing to increased alkaline content and aqueous solubility. In contrast, an elevation in HBDs hydrophobicity sparked an enhancement in UCST.

    Figure 5

    Figure 5.  (A) Variable-temperature FT-IR. (B) Variable-temperature 1H NMR for 50 wt% ET-OC-D2O system. Copied with permission [59]. Copyright 2020, Elsevier.
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    According to the principle of entropy increase, the system always tends to change into a disordered and chaotic state, so there are relatively few studies on LCST-type SDESs, most of which use caine compounds as HBAs and long-chain acids as HBDs. Bica et al. [82] initially introduced the concept of an HDES comprising oleic acid (OA) and lidocaine (LD) in 2011. The temperature response parameters of the HDESs were described by Longeras et al. in 2020 [56]. With increasing temperature, the water-HDES system undergoes phase separation, a consequence of reduced ion abundance. Because of their molecular structure, tertiary amines have a temperature-dependent dissociation constant. LD is a temperature-sensitive tertiary amine that is amphiphilic. The acid-base reaction between LD and OA is not facilitated by rising temperatures since the decrease of LD's pKa value, and the ions that result from this reaction are more soluble in water than molecules. With increasing temperatures, the ionic strength in the system decreases (the ions are transformed into molecular forms), causing a separation between the organic phase and aqueous phase. Julian et al. [83] used mepivacaine against lidocaine comparison to test this theory. Mepivacaine exhibits more severe phase transition temperatures (difficult phase transitions) due to its relatively insensitive pKa value. In the experiment, different HBDs were examined, and it was found that the LCST was also influenced by the hydrophobicity and the pKa value of HBDs. The measurement results of DLS showed that when the temperature rose, the particle size in the SDES-H2O system increased. This suggested that the internal force of SDESs increased, and SDESs aggregated until the phase transition occurred near the LCST.

    Whether UCST-type SDESs or LCST-type SDESs, the internal reason for phase transformation is mainly the intermolecular interaction force. When the interaction force between solvent and solute dominates, the system is homogeneous. The two phases are separated when there is a dominant solvent-solvent or solute-solute interaction.

    3. The application of SDESs in natural product extraction

    Due to its special benefits of responsiveness, effective extraction, gentle conditions, high stability, and ease of recovery, the applications of SDESs as a green solvent in the extraction of natural materials have drawn increasing interest in recent years. SDESs are currently being used to extract and separate a wide range of natural products, including flavonoids, phenols, carbohydrates, lignin, proteins lipids, and so on. We summarize the responsive behavior of SDESs in the extraction of natural products and the recovery performance of SDESs as shown in Table 2 [28,46,49,58-60,72,80,84-94].

    Table 2

    Table 2.  Summary of some mainly applications in natural product extractions.
    DownLoad: CSV
    SDES components (HBA/HBD) and the ratio Research target Responsive behavior DES Recycling Driving factor Ref.
    Dodecanoic acid/Decanoic acid (1:1) Used to separate and purify radish (Raphanus sativus L.) peroxidase (POD). Upon reaching a 1:2 SDES/water volumetric ratio and exceeding a pH value of 7.47 after posting Jeffamine D-230 addition, the system transitions from biphasic to homogenous state. Upon subsequent HCl injection, a reversible switch becomes possible. The utilized SDES from the top phase was collected following each three-phase partitioning (TPP) extraction of the radish POD. To achieve SDES regeneration, add Jeffamine D-230, allow it to stand, then remove the supernatant and add an HCl solution. pH [84]
    Dodecanoic acid/Octanoic acid (1:1) Extract and purify grape seed polysaccharides (GSP) When the SDES to water ratio is 1:5, the solution transitions from two phases to a homogenous phase at a pH higher than 7.0 after adding Jeffamine d-230, and reversible switching occurs after adding HCl solution. The SDES phase at the top of TPP was isolated and collected, and the hydrophilic to the hydrophobic transition of SDES was aided by pH control. After 25 SDES regenerations, the extraction yield drops by just 13.98% (13.69 mg/g). pH [85]
    N,N-dimethylcyclohexylamine/n-Butanol (3:1) Extract β-carotene from millet The hydrophobic SDES was transformed to hydrophilic by adding HCl solution, separated from β-carotene, and reversibly switched by adding NaOH. The NaOH solution was added to the hydrophilic SDES solution. The upper layer of hydrophobic SDES was recovered by centrifugation. After 5 cycles of SDES recovery, the recovery rate of β-carotene in millet remained at 91.01% ± 0.96%. pH [86]
    l-menthol/(1S)-(+) -camphor-10-sulfonic acid (CSA) (5:1) Determination of aflatoxins B1 in cereal samples Adding KOH to convert hydrophobic SDES to hydrophilic allows for the extraction of aflatoxins B1. And by adding HCl, a reversible switch separation from aflatoxin B1 is achieved. By adding HCl, SDES dissolved in aqueous solution was transformed to hydrophobicity, and the regeneration was realized. pH [87]
    Octanoic acid/Linalool (1:1) High hydrostatic pressure (HHP) pretreatment combined with DES extract polyphenols from millet Hydrophilic SDES was converted to hydrophobic by adding HCl solution to the extract, and reversible switching was achieved by adding NaOH. The top hydrophobic SDES obtained from the experiment was transferred to a centrifuge tube, where NaOH was applied to convert the hydrophobic SDES to hydrophilic SDES. After 5 times of use, the yield of millet polyphenol employing the recovered SDES did not drop considerably. pH [88]
    Diethanolamine/Hexanoic acid (1:1) Preconcentration of liposoluble constituents in Salvia Miltiorrhiza using acid-assisted liquid phase microextraction The hydrophilic SDES was added to the sample solution for extraction. After adding HCl, SDES transforms to hydrophobicity to realize phase separation. pH [89]
    Octanoic acid/Decanoic acid (3:1) Extract and recycle β-carotene from pumpkin Ammonium hydroxide was added to SDES extract, hydrophobic SDES was converted to hydrophilic to obtain a single hydrophilic phase, and the precipitated carotenoids were separated by static centrifugation pH [90]
    Tetrabutylammonium chloride/Triton X 100 (1:1) Ultra-pure fibrin digesting enzyme extraction via micellar fermentative methods in Bacillus subtilis Phase separation was achieved by aseptically adding HCl to change the pH of the milky heterogeneous mixture from 7.2 to 6 until two distinct phases were formed. Back extraction of fibrinolytic proteinase-rich SDES was performed, the recovered SDES enriched phase was transferred to a sterile flask, the potassium chloride aqueous solution was added, and the active enzyme was infiltrated into the salinic-rich phase. Excess water from recycled SDES was eliminated, enabling reuse of the solvent within the extraction cycle for fresh batches, resulting in a 95% operational recovery rate. pH [72]
    N,N-dimethylethanolamine (DMEA)/Heptanoic acid (1:1) "Scutellariae Radix": Flavonoid Extraction via Liquid-Liquid Microextraction HCl acted as a phase-switching trigger to break the hydrogen bond of SDES, form ammonium salt with the dissociated DMEA, and release hydrophobic heptanoic acid to complete the phase transformation. pH [80]
    Tetrabutylammonium chloride/Ethylene glycol (1:2) Extraction and in-situ separation of isoflavones from Pueraria lobata By adding NaOH and HCl to adjust the pH, an aqueous two-phase system can be formed between pH 5.0 and pH 6.4. pH [91]
    Triethanolamine (TEA)/4-methoxyphenol (4-MP) (1:1) Strengthening extraction of hesperidin from Fertile orange peel CO2 was injected into the SDES extract to make the solution cloudy. Hydrophobic 4-MP enriched in the lower aqueous layer, whereas TEA carbonate and extract were concentrated in the upper solvent. Post-N2 introduction, TEA was restored, initiating an overall homogenous composition of the system. The 4-MP enriched at the lower layer demonstrated a recovery rate of 60.21%, yet due to pectin's interference, continuous extractions with the filtered SDES extract proved less effective for extracting hesperidin. CO2 [46]
    Choline chloride/Sodium octanoate (1:2) Purification of thrombolytic cysteine protease from Carica papaya peels The homogenate was mixed with SDES under ultrasonic-assisted extraction. CO2 purge yielded phase segregation. CO2 [28]
    Tetramethylguanidine/Menthol (3:1) Sustainable extraction of lipid from Nannochloropsis sp. The sample, SDES, was ultrasonically mixed with ammonium sulfate for extraction. Three transparent phases emerged: an upper phase rich in SDES, a lower phase abundant with salt, and an intermediate solid phase. The top phase SDES phase transition can be switched by CO2/N2. For effective isolation of the SDES-enriched phase from the extracted one and separate the water-insoluble lipids from SDES, CO2 was introduced into the extracted phase. After N2 bubbles, SDES can be extracted and utilized again. The extraction rate of SDES dropped by just 10.6 after five cycles. CO2 [92]
    Monoethanolamine (MEA) /Polyphenol compounds (1:1) Extraction of lingonberry pomace polyphenols by synthetic in-situ DES The residue of Yuexiu fruit was mixed with monoethanolamine, extracted by ultrasonic-assisted extraction, and the phase conversion was carried out through CO2 bubbling. After phase conversion, centrifugation was performed. The alkanol amines, which exist in the water phase as salts, are then separated by precipitation by adding ethanol. After eluting the insoluble ammonium salt and adding N2, the ammonium salt is transformed into a neutral amine at 50 ℃, and MEA is extracted. The recovery rate of SDES has remained >70% ethanol after five test cycles. CO2 [93]
    Choline chloride/Octanoic acid (1:2) Used to extract anthraquinones from fried cassia semen tea infusions Na2CO3 was added to SDES and sample solution, and then H2SO4 was injected to make an effervescent reaction. At the end of the reaction, the ice bath obtained the upper solidified SDES extract. pH /CO2 [49]
    Ethanolamine/m-cresol (1:1) Microwave extraction of flavonoids from waste onion (Allium cepa L.) skins Waste onion skin powder was extracted using microwave-assisted TRDES, and the supernatant was centrifuged for phase separation at room temperature. UCST [60]
    Tetracaine/Lauric acid (1:1) Extraction of Lycium barbarum polysaccharides (LBP) by ultrasound TRDES was ultrasonically mixed with wolfberry powder at LCST temperature, and the supernatant was obtained by centrifugation. The temperature was raised above the LCST of the TRDES to achieve phase separation. The two phases that are generated consist of a hydrophobic TRDES-abundant phase and an aqueous phase enriched with LBP. The recovery rate of TRDES was only reduced by 2.2% after 5 cycles of recycling, indicating that it is reusable. LCST [58]
    Ethanolamine/4-Methoxyphenol (1:1) Ultrasonic extraction and separation of different polar active phytochemicals from Schisandra chinensis (DFCS) TRDES and DFSC were extracted at a temperature higher than UCST, ultrasonic mixing of TRDES and DFSC was reduced to room temperature, and the upper water phase and the lower TRDES phase were obtained by centrifugation. TRDES base phase was treated with anhydrous ethanol for precipitation, then ethyl acetate and H2O were employed post-rotational evaporation to extract lignin from this mixture. After 4 cycles, the extraction rate of polysaccharides and lignin by TRDES remained high. UCST [94]
    Ethanolamine/o-Cresol (1:1) Magnetic stirring to extract polysaccharides from Ganoderma lucidum (G. lucidum) TRDES and G. lucidum powder were mixed by magnetic stirring at a temperature higher than its UCST, filtered, and cooled for phase separation, and ganoderma lucidum polysaccharides (GLPs) in the water phase were recovered At 70°, CO2 is introduced into the recovered ET-OC until the two phases recombine. Separate the ethanolamine salt in the upper phase and pass N2 to recover the ethanolamine. After five ET-OC cycles of TRDES, the extraction rate and recovery rates of GLPs remained stable. UCST/CO2 [59]

    3.1 CO2/N2-responsive SDESs

    As a non-toxic, environmentally friendly, and cost-effective external stimulus method, CO2 is preferred by many researchers as the initiator of process switching. Upon exposure to CO2, the hydrogen bonds in SDESs are easily disrupted, exhibiting dynamic response. After CO2 triggers the phase conversion, a diminished pH level and polarity create an environment conducive to target molecule extraction and separation [46]. In the initial researches, CO2-responsive SDESs were more commonly utilized in the sustainable separation of petroleum and the identification of contaminants in water and relatively less used in the extraction of natural products [77,95]. Subsequently, in 2021, Liu et al. [71] created a series of CO2-responsive SDESs composed of imidazole and several polyols and demonstrated that these SDESs could make CO2-responsive emulsions with olive oil. Cai et al. [92] employed tetramethylguanidine and menthol to create a CO2-responsive SDESs and extracted lipids from microalgae through three-phase partitioning (TPP) extraction (Fig. 6). Since then, CO2-responsive SDESs are increasingly employed for the extraction of natural products, such as lignin [96] and papain [28]. In the latest work, Wang et al. [46] built a number of CO2-responsive SDESs extraction systems with methylphenol and ethanolamine for ultrasonic-assisted solid-liquid extraction of citrus peel flavonoids. Following the extraction with SDESs, the system was exposed to CO2 until turned cloudy, releasing hydrophobic phenols and leaving alkanol amines in the water phase as an ammonium salt. To recover the alkanol amines, N2 is introduced into the system at 65 ℃ because the higher temperature is favorable to amine recovery [93]. The study indicated a positive correlation between hesperetin's separation and extraction efficiency and the polarity of HBDs and HBAs, and SDES prepared from 4-methoxyphenol and triethanolamine had the highest extraction efficiency. In order to ascertain the connection mode and adsorption energy between HBAs and HBDs, density function theory (DFT) calculations were performed. According to the computation results, the primary modes of interaction between hesperidin and SDES are hydrogen bonding and π-π bonding. Apart from the direct prefabrication of DESs as the extraction solvent, one of the employed techniques for the separation and extraction of target chemicals is the in-situ formation of DESs. Zhang et al. [93] used the complexation of N atom in organic amine with an O—H group of secondary metabolites in biomass to form CO2-responsive SDESs in situ, which was used to extract polyphenol compounds from lingonberry pomace. During the extraction process, the lingonberry pomace residue was fully mixed with monoethanolamine for ultrasonic-assisted extraction, and the CO2 bubbling was used for phase conversion after extraction. Prior to exposure in SDESs, CO2 was passed through a water-filled washing tube to avoid water loss in the system during bubbling. Then centrifugation facilitated the transparent phase separation, enabling separation of hydrophobic and water-soluble components. The alkanol amines in the form of salt in the water phase were precipitated and separated by adding ethanol and then reduced to a neutral state after injecting N2 for recycling. Compared with other triggers such as light, oxidants, and acids, CO2 is benign, harmless, and easy to remove, and has greater application potential in natural product extraction.

    Figure 6

    Figure 6.  (A) The lipid extraction through the TPP extraction. (B) Response behavior of SDES during CO2 and N2 bubble application. Copied with permission [92]. Copyright 2021, Elsevier.
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    3.2 pH-responsive SDESs

    SDESs that reversibly separate phases through a simple pH adjustment have exciting potential for natural products advancement. These systems typically overcome the complexities of CO2-responsive counterparts, eliminating the need for expensive bubbling apparatus while conserving resources. Consequently, there's been a surge in studies utilizing pH-responsive SDESs for natural active substance pretreatments recently. Hu et al. developed a new TPP based on SDESs and sugars for the separation and purification of radish (Raphanus sativus L.) peroxidase (POD) [84]. The crude radish POD extract, sugar, and SDESs were ultrasonically mixed and centrifuged to obtain three-phase components, and the aqueous bottom phase and intermediate phase (dissolved in phosphate buffer and filtered) were collected to assess POD activity. Based on SDES (dodecanoic acid: decanoic acid = 1:1) and sucrose concentration of 41% (w/v,%), the POD recovery and purification times of SDES: Radish POD extraction ratio of 2:1 were 101.66% and 11.56 respectively under response surface methodology (RSM) optimization. After 5 rounds of adding Jeffamine D-230 and HCl to modify the pH for SDES switching, the regenerated SDES maintained its high stability. The new TPP can replace the traditional TPP (tert-butanol and ammonium sulfate) perfectly and has a wide application prospect. Zhang et al. [86] extracted β-carotene from millet using SDES made from N-dimethylcyclohexylamine and n-butanol. The process is shown in Fig. 7. HCl was added to the SDES extract to transform SDES from hydrophobic to hydrophilic, allowing for the separation of β-carotene. BHT (2,6-di-tert-butyl-4-methylphenol), a phenolic antioxidant, was shown to be the most effective in preventing β-carotene degradation during extraction. The recovery rate of β-carotene in millet remained at 91.01% ± 0.96% when the hydrophilic SDES was regenerated 5 times with NaOH. This method can also be applied to extract other hydrophobic and active natural compounds. Zhang et al. [88] combined high hydrostatic pressure (HHP) treatment technology with the SDESs extraction method and applied it to the extraction of millet polyphenols. Hydrophilic SDES was synthesized with octanoic acid and linalool (1:1), where β-cyclodextrin serving as an auxiliary extraction reagent. The extraction was achieved through thorough grinding, and then, the SDES was converted to hydrophobic by adding HCl, leaving polyphenols in water. NaOH was added to facilitate the reversible switching of SDES and achieve the recovery. In contrast to the conventional ethanol extraction method, the antioxidant potency in SDES extract significantly improved, and the SDES was highly recyclable. The green recyclable SDES adopted in this study possesses substantial potential for the extraction of hydrophilic bioactive compounds.

    Figure 7

    Figure 7.  Extraction strategy of millet β-carotene with switchable DESs. Copied with permission [86]. Copyright 2023, Elsevier.
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    3.3 Temperature-responsive SDESs

    CO2 and pH-responsive SDESs introduce external factors to the system, and the impact on the product cannot be ignored. It would be desirable if the system could be transformed by temperature regulation. Prior to the proposed TRDESs, the more reversible aqueous two-phase systems with DES/water were presented to achieve phase conversion. For example, Tu et al. [97] recently employed this system to separate glucose from 5-hydroxymethylfurfural (5-HMF). However, the addition of salts such as K2HPO4 to water made the following treatment more challenging. Therefore, TRDESs that can be directly temperature-switched are pursued by researchers. A series of UCST-type SDESs composed of alkanol amines and cresols were first applied for extracting polysaccharides from G. lucidum by Cai et al. [59]. Through magnetic agitation, the SDES aqueous solution was fully in contact with the sample powder at a temperature higher than UCST (uniform system, which is conducive to extraction) to extract GLPs. After filtration, the temperature was reduced to below UCST and the phase separation phenomenon appeared after statically placing. The GLPs contents in the upper and lower phases were determined by the sulfuric acid-phenol method. The results showed that GLPs were retained in the aqueous phase, whereas SDESs can be recovered and used in the next extraction. The recycling experiment results revealed that the composition and proportion of GLPs obtained after the recycling of SDESs were similar to those of the first usage of SDESs, indicating that the recycled SDESs also had good extraction efficiency. SDESs composed of alkanol amines and phenols can also employ CO2 switching mechanism after recycling to recover HBAs and HBDs by pumping CO2 and N2 independently without consuming a lot of energy, resulting in a lower treatment cost and a more ecologically friendly. In addition, UCST-type SDESs made with alkanol amines and phenols are utilized to separate and extract aromatic amino acids, lignin, and flavonoid compounds from waste onion skins, as well as other polar active phytochemicals from Schisandra chinensis (DFCS). In addition to UCST-type SDESs, LCST-type SDESs can also be used in the extraction of natural products. Tang et al. [58] developed a series of LCST-type SDESs with caine compounds as HBAs and long-chain acids as HBDs for the extraction of Lycium barbarum polysaccharides (LBP) (Fig. 8). After mixing Lycium barbarum powder and SDES aqueous solution in test tubes, polysaccharide extraction was carried out at a temperature lower than LCST with ultrasound aid. At this temperature, the hydrophilic property of SDESs was enhanced, which can facilitate the dissolution of hydrophilic GLPs. The total polysaccharide content of the supernatant was measured following centrifugation. With the temperature of the system exceeding the LCST, two-phase stratification appeared, creating a hydrophobic SDESs phase along with an LBP-rich aqueous phase. The SDESs were retrieved and used again. The physicochemical properties of SDESs (polarity, viscosity, etc.) and various interactions with the target substance will affect the extraction efficiency. SDES, which contained tetracaine and lauric acid, had the maximum extraction efficiency due to its neutral polarity and viscosity. Under optimal conditions, the extraction rate of LBP reached 427.2 mg/g after five cycles, which was little different from that of the first extraction (459.9 mg/g), and the recovery rate of SDES was 80.2%. The results of the experiment can sufficiently prove that the SDESs had good recovery and reuse characteristics. Despite less exploration of LCST-type SDESs in natural product extraction, but this experiment signals considerable potential and merits further scrutiny.

    Figure 8

    Figure 8.  Ultrasonic extraction of Lycium barbarum polysaccharide (LBP). Copied with permission [58]. Copyright 2023, Elsevier.
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    3.4 Dissolution mechanism of lignin in SDESs

    In plant fibers, lignin is linked to cellulose and hemicellulose via covalent bonds, hydrogen bonds, and van der Waals forces, making it difficult to dissolve and separate from plant fiber raw materials [98]. DESs can induce electron interaction with cellulose and hemicellulose through anion in HBA, breaking molecular hydrogen bonds in the structure of cellulose and hemicellulose and promoting its dissolution [99]. The DESs formed from quaternary ammonium HBAs and strongly polar HBDs have been found that have a good extraction effect on lignin [100,101]. The anions of quaternary ammonium DESs can induce electron interaction with the electron-deficient hydrogen atoms of the cellulose hydroxyl group, disrupting the original intermolecular hydrogen bonds in the cellulose structure. At the same time, DESs quaternary ammonium cation reacts with cellulose hydroxyl oxygen atom to form a hydrogen bond between solvent and cellulose [99]. As a result, through adjusting the interactions among HBAs, HBDs, and lignin, the solubility of DESs to lignin can be increased, allowing for the full release of active compounds. However, most DESs contain strongly polar components to boost the extraction rate of lignin [102], making it difficult to separate DESs from other solvents during the subsequent recovery process [103]. SDESs can be designed to display polarity in the component separation stage and non-polarity in the recovery process, to effectively improve the recovery rate of solvents without affecting the separation of components. Li et al. [96] designed an SDES applied SIL as the HBA and water as the HBD for the dissolution and regeneration of lignin. The solubility of lignin in the SDES system was regulated by injecting CO2 and the regeneration was achieved through the use of antisolvent acetone. The lignin regenerated by SDES has a good structure, a high molecular mass, and excellent homogeneity without obvious chemical modifications, all of which can promote the downstream process. Furthermore, DES can be used both as a solvent and a catalyst for lignin breakdown [104]. Wang et al. proposed a design method for catalytic degradation of lignin with TRDESs [105]. Optimal catalysts for TRDESs synthesis were selected post-evaluation of frontier orbital energy levels in twenty-two diverse DES catalyst systems. The highest occupied molecular orbital (HOMO)-lowest unoccupied molecular orbital (LUMO) gap of the TRDESs and reaction system showed that TRDESs had a significant catalytic effect on β-O-4 bond breakage, with reasonable temperature response. Additionally, it enhances solubility at elevated temperatures, facilitating a uniform and effective catalytic procedure. Post-temperature reduction, the catalyst is separable and reclaimable. Therefore, as recyclable solvent, SDESs are likely to find a wider range of applications in lignin dissolving.

    3.5 Optimization techniques and methods of SDES

    For a higher extraction rate of natural products, extraction methods (ultrasonic, microwave-assisted extraction) and extraction conditions (water content, solid-liquid ratio, temperature, introduction of phenolic antioxidants, salts, etc.) are frequently optimized.

    To further enhance the efficiency of extraction, Shang et al. [60] combined TRDESs and microwave technology for quantitative analysis of flavonoids from waste onion skins for the first time. The higher yield of 47.83 mg/g flavonoid extraction through microwavable TRDESs method surpasses the conventional 26.78 mg/g via microwaving alone. In addition, ultrasound-induced cavitation disrupts cell membranes, diminishes particle diameter, and enhances mass transport [106]. Yan [94] introduced the ultrasonic-assisted extraction method in the Schisandra chinensis experiment and optimized a series of variables such as the time and power of ultrasonic extraction. Conclusion indicated the optimal yield of lignanoids and polysaccharides is facilitated by 40 min and 150 W ultrasonic applications. Proper water content can modify the viscosity of the DES systems, thus improving the extraction rate of natural products. However, excessive water will destroy the hydrogen bond of the DES systems and affect the extraction effect [107,108]. Wang et al. tested the effect of 15%−55% water content in DESs on extraction rate of hesperidin [46]. Extraction increased and then decreased as water content increased, which could be attributable to the inability of the high-viscosity system to facilitate hesperidin dissolution and mass transfer and the hydrogen bond of DESs was destroyed by an excessive water content. Finally, a water content of 35% was determined for follow-up experiments. For TRDESs, temperature can not only affect the extraction rate but also affects the phase separation behavior of SDESs. Tang et al. [58] analyzed the performance of SDES aqueous solution at 25–55 ℃. At 25–35 ℃, the increase in temperature can decrease the viscosity of SDESs, which can improve the mass transfer and thus increase the extraction rate of target compounds. However, beyond 35 ℃, upon reaching the LCST, the DES aqueous solution displayed enhanced hydrophobicity, resulting in a two-phase separation and a decrease in extraction rate. Therefore, 35 ℃ was chosen for follow-up research. Zhang et al. [86] analyzed phenolic antioxidants impact on the β-carotene yield of millet. 2,6-di-tert-butyl-4-methyl-phenol (BHT) was selected as the best phenolic antioxidant and its concentration was optimized. The finding indicated that BHT can act as an antioxidant even at low concentrations. When the concentration of BHT was too high, it will have a synergistic effect with β-carotene to increase oxidative degradation. Increased levels of salt during extraction may elevate the ionic strength of the aqueous phase, consequently decreasing its extract's solubility within it. Salt precipitation can also be used in the phase separation process of SDES to promote phase separation. Wang et al. [80] examined the influence of salt addition on the target analyte enrichment factor (EF), calculated from the target concentration (Ch) in the hydrophobic phase and its initial concentration (C0) as follows: EF = Ch/C0. They reported that salt induced an increase in the recovery phase volume and wogonoside EF. However, at a salt concentration of 25%, flocculation occurred, impeding further experimentation. Subsequently, they conducted the test using 10% NaCl for enhanced phase separation.

    3.6 Method comparison in activity retention

    In the extraction of natural products, DESs have been found to play additional functions in the extraction process, such as reducing oxidation, antibacterial, and photodegradation, and aid in maintaining the stability of natural products due to their excellent selectivity, solubility, and biological activity [29,30]. As discussed above, Radošević [30] initially demonstrated that NADESs can enhance the biological activity of grape skin extracts containing phenolic compounds. Of the three NADESs tested, extracts made from malic acid and choline chloride demonstrated higher antioxidant activity, which could be attributed to NADESs itself, such as malic acid, an antioxidant [109]. Murador et al. [110] investigated the antioxidant activity and other biological impacts of NADES-derived bioactive compounds and discovered that all of them had a higher advantage in activity retention. However, further development is needed to develop the recovery technology of NADESs. Up to now, several studies have reported the application of SDESs in the extraction of natural products. Compared with traditional solvents, SDESs have higher application possibility for retaining the activity of natural products.

    TPP, a conventional extraction method, integrates inorganic salts (mainly ammonium sulfate) and organic solvents (mainly tert-butanol) to the crude extract. Conventional TPP often uses tert-butanol as the extraction solvent, which is volatile, flammable, and harmful to the environment. The SDESs developed based on the green recyclable DES can be used as an alternative solvent [84,85,92]. Chen et al. [85] compared and measured the activity of extracted grape seed polysaccharides (GSP) using DES-based TPP (GSP-D), t-butanol-based TPP (GSP-T), and hot-water (GSP-H) in the experiment. Results indicated significant antioxidant capacity with 93.32% and 91.32% DPPH scavenging by GSP-D and GSP-T, respectively, with GSP-D exhibiting superior free radical scavenging ability. Stupar et al. [90] tested the stability of carotenoids in the experiment of carotenoids extracted from pumpkin based on pH-responsive NADESs. In a direct comparison between light/darkness and room-temp extracts, responsive NADESs were found to enhance the stability of carotenoid content. Such an outcome may stem from solute's hydrogen bond interactions with solvent particles, or mediate via medium pH [111]. Research by Cai et al. [94] evaluated TRDESs versus traditional solvents like water, ethanol, and methanol. They reported a yield advantage of 1.62-fold for TRDESs in total lignanoids extraction over water, 1.37-fold against methanol and 1.17-fold higher than 70% ethanol. Similarly, the TRDESs yield in total polysaccharide extraction surpassed water by 1.39-fold. TRDESs outperform conventional solvents in terms of activity retention and extraction efficiency of multi-polar phytochemicals. Zhang et al. [88] evaluated the antioxidant activity of millet polyphenols in extracts derived from TRDESs and traditional extracts from ethanol in the experiment. The results showed that the millet polyphenols in the extract had a strong scavenging ability towards DPPH and hydroxyl radicals. TRDESs extraction was more efficient than ethanol extraction, and the isolated millet polyphenols exhibited better antioxidant activity. Tang et al. determined the antioxidant activity of LBP extracted from TRDESs [58]. A significant disparity was observed in the scavenging efficacy between DES-LBP and water-LBP, with DES-LBP exhibiting superior activity due to its elevated glucose content. Hence, as eco-friendly solvent, SDESs are applicable in natural product extraction for replacing traditional solvents. Owing to its substantial bioactive retention capabilities, it can facilitate natural product extraction by minimizing product oxidation and activity reduction.

    4. Conclusions

    As green solvents, DESs have the advantages of low cost, easy preparation, biodegradability, and so on. Since the concept was first provided, its green characteristics have been widely considered by various fields. The introduction of SDESs resolves the shortcoming of the low volatility of traditional DESs. SDESs' switchable nature allow them to be successfully removed from the extract and recycled, eliminating resource waste. Furthermore, the extraction of active compounds preserves most of the activity of natural products. In contrast to traditional organic solvents, SDESs, as responsive green solvents, offer a wide variety of application prospects in the extraction process of natural products.

    This review, building on previous work, covers the properties, switching mechanism, and application in natural product extraction of SDESs, with the goal of providing a broader framework for future relevant research. Currently, pH-responsive SDESs have been used in the majority of natural product extraction applications, but CO2-responsive SDESs are challenging to employ due to the complexity of devices. Additionally, researches have demonstrated that temperature-responsive SDESs have tremendous promise in the extraction of natural products without additional devices or solvents and warrants further investigation. Furthermore, the research of SDESs on lignin breakdown and component separation is still in its early stage, with further investigation and research in this area anticipated in the future. As new type of green solvents, SDESs can be employed as an alternative solvent in aqueous two-phase and three-phase systems. A few existing studies have demonstrated that this application can be used as a long-term approach for extracting bioactive substances. Follow-up systems require further investigation. At present, DESs preparation is now no longer restricted to binary eutectic and is gradually becoming more diverse. Water, carboxylic acid, polyol, and other chemicals can be used to lower the viscosity of DESs, according to studies. The majority of currently synthesized SDESs are binary systems with high viscosity, and the addition of the third component is predicted to improve existing results and the mass transfer effect.

    Nowadays, SDESs extraction of natural products only stays in the laboratory research stage, and there is still a long way to go for its real industrialization. Despite DESs are considered to be more environmentally friendly than conventional organic solvents, its toxicity study still needs to be further deepened. There is little literature about toxicity assessment of SDESs. Current studies focus on biocompatibility and environmental impact. Optimal component selection and strategic utilization are pivotal to mitigate the possible toxicity of DESs. A thorough toxicity assessment of SDESs is needed for responsible reasons. Concurrently, while SDESs can be recycled, its recycling rate is underexplored. Future studies could concentrate on enhancing the recovery of SDESs.

    Declaration of competing interest

    The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

    CRediT authorship contribution statement

    Yuan Yan: Writing – original draft. Lingqi Shen: Writing – original draft. Yu Wang: Writing – review & editing. Bincheng Gong: Writing – review & editing. Zuguang Li: Writing – review & editing. Hongdeng Qiu: Writing – review & editing.

    Acknowledgments

    This work was financially supported by National Natural Science Foundation of China (No. 22174129), the Natural Science Foundation of Zhejiang Province (No. LZY21E030001), the Xin-Miao Talents Program of Zhejiang Province (No. 2024R403B064).


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  • Figure 1  Research trends on DESs and switchable DESs published over the past five years (Based on Web of Science).

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    Figure 2  Viscosity (A) and density (B) curves with temperature for DES formed by tetrapropylammonium bromide (TPAB) combined with octanoic acid (DES1), TPAB combined with nonanoic acid (DES2), and tetrabutylammonium bromide (TBAB) combined with octanoic acid (DES3). Copied with permission [50]. Copyright 2021, Elsevier.

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    Figure 3  13C NMR spectra of DES formed by triethanolamine and 4-methoxyphenol extract in D2O before and after bubbling CO2. Copied with permission [46]. Copyright 2024, Elsevier.

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    Figure 4  (A) FT-IR spectra of succinic acid (SA), octylamine (OA), and prepared hydrophilic DES. (B) 1H NMR spectra of SA, OA, and prepared hydrophilic DES before using (pre-DES), and after using (post-DES) in the developed method. Copied with permission [79]. Copyright 2024, Elsevier.

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    Figure 5  (A) Variable-temperature FT-IR. (B) Variable-temperature 1H NMR for 50 wt% ET-OC-D2O system. Copied with permission [59]. Copyright 2020, Elsevier.

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    Figure 6  (A) The lipid extraction through the TPP extraction. (B) Response behavior of SDES during CO2 and N2 bubble application. Copied with permission [92]. Copyright 2021, Elsevier.

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    Figure 7  Extraction strategy of millet β-carotene with switchable DESs. Copied with permission [86]. Copyright 2023, Elsevier.

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    Figure 8  Ultrasonic extraction of Lycium barbarum polysaccharide (LBP). Copied with permission [58]. Copyright 2023, Elsevier.

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    Table 1.  Classification of HBAs and HBDs with some representative compounds.

    HBA HBD Drivers Ref.
    CO2 [46]
    CO2 [47]
    CO2 [48]
    CO2 [49]
    pH [50]
    pH [51]
    pH [52]
    pH [41,53]
    pH [54]
    LCST [55-57]
    LCST [58]
    UCST [59]
    UCST [60]
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    Table 2.  Summary of some mainly applications in natural product extractions.

    SDES components (HBA/HBD) and the ratio Research target Responsive behavior DES Recycling Driving factor Ref.
    Dodecanoic acid/Decanoic acid (1:1) Used to separate and purify radish (Raphanus sativus L.) peroxidase (POD). Upon reaching a 1:2 SDES/water volumetric ratio and exceeding a pH value of 7.47 after posting Jeffamine D-230 addition, the system transitions from biphasic to homogenous state. Upon subsequent HCl injection, a reversible switch becomes possible. The utilized SDES from the top phase was collected following each three-phase partitioning (TPP) extraction of the radish POD. To achieve SDES regeneration, add Jeffamine D-230, allow it to stand, then remove the supernatant and add an HCl solution. pH [84]
    Dodecanoic acid/Octanoic acid (1:1) Extract and purify grape seed polysaccharides (GSP) When the SDES to water ratio is 1:5, the solution transitions from two phases to a homogenous phase at a pH higher than 7.0 after adding Jeffamine d-230, and reversible switching occurs after adding HCl solution. The SDES phase at the top of TPP was isolated and collected, and the hydrophilic to the hydrophobic transition of SDES was aided by pH control. After 25 SDES regenerations, the extraction yield drops by just 13.98% (13.69 mg/g). pH [85]
    N,N-dimethylcyclohexylamine/n-Butanol (3:1) Extract β-carotene from millet The hydrophobic SDES was transformed to hydrophilic by adding HCl solution, separated from β-carotene, and reversibly switched by adding NaOH. The NaOH solution was added to the hydrophilic SDES solution. The upper layer of hydrophobic SDES was recovered by centrifugation. After 5 cycles of SDES recovery, the recovery rate of β-carotene in millet remained at 91.01% ± 0.96%. pH [86]
    l-menthol/(1S)-(+) -camphor-10-sulfonic acid (CSA) (5:1) Determination of aflatoxins B1 in cereal samples Adding KOH to convert hydrophobic SDES to hydrophilic allows for the extraction of aflatoxins B1. And by adding HCl, a reversible switch separation from aflatoxin B1 is achieved. By adding HCl, SDES dissolved in aqueous solution was transformed to hydrophobicity, and the regeneration was realized. pH [87]
    Octanoic acid/Linalool (1:1) High hydrostatic pressure (HHP) pretreatment combined with DES extract polyphenols from millet Hydrophilic SDES was converted to hydrophobic by adding HCl solution to the extract, and reversible switching was achieved by adding NaOH. The top hydrophobic SDES obtained from the experiment was transferred to a centrifuge tube, where NaOH was applied to convert the hydrophobic SDES to hydrophilic SDES. After 5 times of use, the yield of millet polyphenol employing the recovered SDES did not drop considerably. pH [88]
    Diethanolamine/Hexanoic acid (1:1) Preconcentration of liposoluble constituents in Salvia Miltiorrhiza using acid-assisted liquid phase microextraction The hydrophilic SDES was added to the sample solution for extraction. After adding HCl, SDES transforms to hydrophobicity to realize phase separation. pH [89]
    Octanoic acid/Decanoic acid (3:1) Extract and recycle β-carotene from pumpkin Ammonium hydroxide was added to SDES extract, hydrophobic SDES was converted to hydrophilic to obtain a single hydrophilic phase, and the precipitated carotenoids were separated by static centrifugation pH [90]
    Tetrabutylammonium chloride/Triton X 100 (1:1) Ultra-pure fibrin digesting enzyme extraction via micellar fermentative methods in Bacillus subtilis Phase separation was achieved by aseptically adding HCl to change the pH of the milky heterogeneous mixture from 7.2 to 6 until two distinct phases were formed. Back extraction of fibrinolytic proteinase-rich SDES was performed, the recovered SDES enriched phase was transferred to a sterile flask, the potassium chloride aqueous solution was added, and the active enzyme was infiltrated into the salinic-rich phase. Excess water from recycled SDES was eliminated, enabling reuse of the solvent within the extraction cycle for fresh batches, resulting in a 95% operational recovery rate. pH [72]
    N,N-dimethylethanolamine (DMEA)/Heptanoic acid (1:1) "Scutellariae Radix": Flavonoid Extraction via Liquid-Liquid Microextraction HCl acted as a phase-switching trigger to break the hydrogen bond of SDES, form ammonium salt with the dissociated DMEA, and release hydrophobic heptanoic acid to complete the phase transformation. pH [80]
    Tetrabutylammonium chloride/Ethylene glycol (1:2) Extraction and in-situ separation of isoflavones from Pueraria lobata By adding NaOH and HCl to adjust the pH, an aqueous two-phase system can be formed between pH 5.0 and pH 6.4. pH [91]
    Triethanolamine (TEA)/4-methoxyphenol (4-MP) (1:1) Strengthening extraction of hesperidin from Fertile orange peel CO2 was injected into the SDES extract to make the solution cloudy. Hydrophobic 4-MP enriched in the lower aqueous layer, whereas TEA carbonate and extract were concentrated in the upper solvent. Post-N2 introduction, TEA was restored, initiating an overall homogenous composition of the system. The 4-MP enriched at the lower layer demonstrated a recovery rate of 60.21%, yet due to pectin's interference, continuous extractions with the filtered SDES extract proved less effective for extracting hesperidin. CO2 [46]
    Choline chloride/Sodium octanoate (1:2) Purification of thrombolytic cysteine protease from Carica papaya peels The homogenate was mixed with SDES under ultrasonic-assisted extraction. CO2 purge yielded phase segregation. CO2 [28]
    Tetramethylguanidine/Menthol (3:1) Sustainable extraction of lipid from Nannochloropsis sp. The sample, SDES, was ultrasonically mixed with ammonium sulfate for extraction. Three transparent phases emerged: an upper phase rich in SDES, a lower phase abundant with salt, and an intermediate solid phase. The top phase SDES phase transition can be switched by CO2/N2. For effective isolation of the SDES-enriched phase from the extracted one and separate the water-insoluble lipids from SDES, CO2 was introduced into the extracted phase. After N2 bubbles, SDES can be extracted and utilized again. The extraction rate of SDES dropped by just 10.6 after five cycles. CO2 [92]
    Monoethanolamine (MEA) /Polyphenol compounds (1:1) Extraction of lingonberry pomace polyphenols by synthetic in-situ DES The residue of Yuexiu fruit was mixed with monoethanolamine, extracted by ultrasonic-assisted extraction, and the phase conversion was carried out through CO2 bubbling. After phase conversion, centrifugation was performed. The alkanol amines, which exist in the water phase as salts, are then separated by precipitation by adding ethanol. After eluting the insoluble ammonium salt and adding N2, the ammonium salt is transformed into a neutral amine at 50 ℃, and MEA is extracted. The recovery rate of SDES has remained >70% ethanol after five test cycles. CO2 [93]
    Choline chloride/Octanoic acid (1:2) Used to extract anthraquinones from fried cassia semen tea infusions Na2CO3 was added to SDES and sample solution, and then H2SO4 was injected to make an effervescent reaction. At the end of the reaction, the ice bath obtained the upper solidified SDES extract. pH /CO2 [49]
    Ethanolamine/m-cresol (1:1) Microwave extraction of flavonoids from waste onion (Allium cepa L.) skins Waste onion skin powder was extracted using microwave-assisted TRDES, and the supernatant was centrifuged for phase separation at room temperature. UCST [60]
    Tetracaine/Lauric acid (1:1) Extraction of Lycium barbarum polysaccharides (LBP) by ultrasound TRDES was ultrasonically mixed with wolfberry powder at LCST temperature, and the supernatant was obtained by centrifugation. The temperature was raised above the LCST of the TRDES to achieve phase separation. The two phases that are generated consist of a hydrophobic TRDES-abundant phase and an aqueous phase enriched with LBP. The recovery rate of TRDES was only reduced by 2.2% after 5 cycles of recycling, indicating that it is reusable. LCST [58]
    Ethanolamine/4-Methoxyphenol (1:1) Ultrasonic extraction and separation of different polar active phytochemicals from Schisandra chinensis (DFCS) TRDES and DFSC were extracted at a temperature higher than UCST, ultrasonic mixing of TRDES and DFSC was reduced to room temperature, and the upper water phase and the lower TRDES phase were obtained by centrifugation. TRDES base phase was treated with anhydrous ethanol for precipitation, then ethyl acetate and H2O were employed post-rotational evaporation to extract lignin from this mixture. After 4 cycles, the extraction rate of polysaccharides and lignin by TRDES remained high. UCST [94]
    Ethanolamine/o-Cresol (1:1) Magnetic stirring to extract polysaccharides from Ganoderma lucidum (G. lucidum) TRDES and G. lucidum powder were mixed by magnetic stirring at a temperature higher than its UCST, filtered, and cooled for phase separation, and ganoderma lucidum polysaccharides (GLPs) in the water phase were recovered At 70°, CO2 is introduced into the recovered ET-OC until the two phases recombine. Separate the ethanolamine salt in the upper phase and pass N2 to recover the ethanolamine. After five ET-OC cycles of TRDES, the extraction rate and recovery rates of GLPs remained stable. UCST/CO2 [59]
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  • 发布日期:  2025-11-15
  • 收稿日期:  2024-09-28
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