Deep eutectic systems – bio-based solvents designed with natural molecules

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Introduction

 

Following the 12 principles of green chemistry, listed by Warner and Anastas (1), Ionic liquids (ILs) were one of the first advances in the development of alternative solvents. However, despite the number of scientific publications in the literature over the last two decades, the industrial application of ionic liquids has been hampered by the fact that their biodegradability and biocompatibility are compromised and therefore their sustainability is also called into question. There have been great efforts to design more harmless ionic liquids, but another major disadvantage in using these systems is their production method. The synthesis of these solvents is extremely expensive, given that their production process requires several steps, namely purification steps subsequent to the production process, and often the production yield is also relatively low. Deep eutectic solvents (DESs) are an alternative solvent system that were discovered almost a quarter of a century ago by Andrew Abbott’s group and have been used in many applications over this period. DESs are eutectic mixtures of two or more pure components with a eutectic point temperature significantly lower than that of an ideal liquid mixture. A good example is when choline chloride (ChCl) is mixed with urea in a ratio of 1:2, this is called reline.
There are 5 types of DESs; Type I (organic and metal salts), Type II (Organic and metal salt hydrate), Type III (Organic salt and H-bond donor), Type IV (Metal salt and H-bond donor), and Type V (non-ionic DESs – Hydrogen bond acceptor and Hydrogen bond donor).

 

Properties of NADES

 

Natural deep eutectic solvents (NADES) can overcome most of the limitations of ILs, and are expected to play an important role in different chemical engineering processes in the future. NADES are essentially composed of mixtures of cholines (tetraammonium salts), sugars, organic acids or amino acids, among other molecules (2) and their production only requires the mixing of two or three compounds in such proportions that a profound lowering of the melting point is observed, making it possible to obtain a liquid system at room temperature (3). The individual components are either hydrogen-bonding donors (HBDs) or hydrogen-bonding acceptors (HBA) that establish complex H-bonding networks. Natural examples of such systems are honey, maple syrup or beet syrup. NADES can then be classified into 8 of the 12 principles of green chemistry: i) atom economy – There is no chemical reaction involved in the production of NADES, so we achieve 100% atomic economy, 100% carbon efficiency and 100% production yield; ii) less hazardous chemical synthesis – There is no chemical reaction involved in the solvent production process; iii) design safer chemical products; iv) design less harmful solvents and v) auxiliaries and use renewable sources – NADES are formed from molecules of natural origin and therefore from renewable sources; vi) reduction of derivatives – the incorporation of NADES into final products reduces the need for additional processing and the use of additional reagents, which can generate more waste; vii) biodegradable – NADES, formed from molecules of natural origin, are biodegradable and are cleaved by natural mechanisms into smaller, non-hazardous molecules; viii) Safer chemistry for accident prevention – NADES, unlike volatile organic compounds, are non-flammable and have a low vapor pressure. As mentioned previously, the preparation of NADES is relatively simple and is based on the mixture of two or more compounds in a specific molar ratio generally with heating.
There are already more than 2000 systems reported in the literature, however, the curiosity inherent in any scientist means that this number is continually increasing, even though sometimes the fundamental knowledge of the properties of each of these systems is not reported. This fact will make the scale-up of processes to an industrial scale very difficult. Several articles in the literature are dedicated to the study of theoretical methodologies to estimate the physicochemical properties of eutectic systems, namely density, viscosity, refractive index, surface tension, speed of sound or thermal properties, including melting point, glass transition temperature or heat capacity (Figure 1).

 

All these properties that characterize solvents also serve to categorize them and to help in choosing which solvents are best suited to a given process. The famous maxim known in chemistry as “like dissolves like” is based on Hansen’s solubility principles, which are still poorly described for deep eutectic solvents (4).
In addition to the lack of basic information about the systems, to date there are few studies that have focused on the determination and/or calculation of these parameters.

 

Recently, the introduction of artificial intelligence (AI) and neural networks applied to deep eutectic systems has led to the development of new predictive models. To date, these have been mainly used to develop models that allow the prediction of physicochemical properties (5, 6) and model the responses of the use of NADES in relation to specific challenges such as carbon dioxide capture or the efficient removal of pollutants. However, no one has yet been able to answer one of the questions that scientists have been most eager to answer since the beginning of the study of these systems: “Can I predict the development of a deep eutectic system from compound A and B? And will this system have the properties that I want for my specific application?” But it will certainly not be long before advances in technology, namely the development of AI-based models and the exploration of new molecular dynamics protocols, will allow us to answer these more fundamental questions.

 

Applications of NADES

 

The application of deep eutectic solvents has been explored in parallel with the knowledge generated about their physico-chemical characterization. There are numerous examples of applications for these solvents that are already being applied in the cosmetics industry, a pioneer in the use and launch of NADES-based products (7). The fascination with these systems is precisely their versatility and the possibility of use in the most varied areas of knowledge, from electrochemistry, energy, catalysis, biocatalysis, carbon dioxide capture, cosmetics, pharmaceuticals, biomedicine, among many others.
In this article we will focus in particular on the areas of pharmaceuticals and biomedicine, demonstrating how NADES can bring benefits and solve problems that have so far remained unanswered.

 

One of the main challenges of the pharmaceutical industry is related to the low bioavailability of new drugs, namely insoluble drugs are not absorbed. This low bioavailability, i.e. their low solubility and permeability in aqueous media, leads to an increase in the dosage concentration and consequently an increase in undesirable side effects. Deep eutectic systems have been described in pharmaceutical applications since the beginning of the 20th century, so they are not new. One of the best-known examples of a pharmaceutical product containing a eutectic system is the case of transdermal patches with menthol and flurbiprofen.
In this particular case, menthol plays an important role as a penetrating agent, facilitating the diffusion of the anti-inflammatory flurbiprofen to the site of the lesion, for a more effective result.

 

The novelty in the development of therapeutic deep eutectic systems (THEDES) lies in the fact that it has now been found that active ingredients (APIs) can be amorphized, following a combination with another molecule, in such a way that the systems become liquid at room temperature. This amorphization of APIs results in an increase in solubility that can be up to 65 times and permeability up to 2 times, as is the case for example of dexamethasone (8).

 

Several other examples can be found in the literature and in review articles that gather information on the advances and advantages that deep eutectic solvents present in these cases (9, 10).

 

The principle of using molecules of natural origin can also provide interesting alternatives in pharmacological terms. At a time when antibiotic resistance is one of the main causes of the emergence of multidrug-resistant bacteria, the use of natural compounds with antimicrobial activity, and the possibility of constantly changing these compounds, could prevent bacteria from developing resistance and allow us to continue to have alternatives for combating bacterial diseases. The bibliographic review by Ferreira et al. brings together the work carried out in this area and presents the results of cytotoxicity in various organisms, obtained for several NADES (11).
One of the studies in this area demonstrates that although the antimicrobial activity of NADES is not as efficient as that of synthetic compounds, NADES have the ability to disrupt the biofilm formed and cause the detachment of bacteria, preventing their multiplication and propagation. This ability could be very interesting in applications as wide as the treatment of chronic wounds, the cleaning of hospital or domestic surfaces, the control of the propagation of bacteria in medical devices, or even in applications as distinct from medicine as the prevention of marine biofouling (12).

 

In addition to the example of the antibacterial effect, molecules of natural origin have been described as having many other bioactive effects, namely antioxidant, anti-inflammatory or even anticancer effects. The mixture of these molecules in the form of therapeutic eutectic systems brings advantages due to the possible combination of activities of the two compounds, which could lead to an increase in their selectivity, and therefore efficacy.

 

One example of deep eutectic mixtures for pharmaceutical purposes that is undergoing clinical trials in the United States is based on a mixture of choline and geranic acid. CAGE Bio develops topical products for the treatment of dermatological conditions, while I2O Therapeutics develops products for the oral administration of biological molecules that would otherwise have to be administered intravenously. These examples inspire the scientific community working on the subject, and after the first successful clinical trials they will certainly pave the way for other therapies to be approved.
As mentioned above, these systems can be found in nature and play a crucial role in the survival of various plants and animals (13). For example, it is this liquid medium that allows plants and animals to survive in extreme environments, with extreme temperature variations, since it alters the crystallization properties of water (14). This discovery opened up a new field of research into the development of cryoprotective agents for preserving animal cells. Based on research into the compounds presented throughout the year in animals such as frogs and insects, it was found that the cellular composition varies according to the seasons and examples of these molecules include sugars, polyols or amino acids, all capable of constituting a deep eutectic system. In addition to this example, the presence of NADES has been shown to be crucial in some biochemical pathways, such as enzyme-mediated reactions of poorly water-soluble products such as cellulose, amylose and lignin, and storage of intermediate polarity compounds (15). The presence of NADES, a medium with distinct properties from an aqueous or lipid medium, is essential for the solubilization and transport of molecules in various plants. Based on this knowledge, NADES have been widely used to stabilize small molecules such as vitamins or antioxidants, aromas or for the stabilization of larger compounds such as proteins (16) and virus-like particles (VLPs) with applications in vaccine development (17).

 

What can be considered the greatest disadvantage of NADES in many processes, namely their high viscosity, can in these cases contribute to the successful stabilization of molecules that are generally unstable and have short lifetimes. However, the knowledge generated in experimental tests should now be complemented with computational tools that can help understand the mechanisms of interaction of NADES with biological membranes and/or their interaction with vitamins or proteins to optimize the design of deep eutectic systems with a view to greater efficiency. Despite the apparent simplicity of NADES, their specificities mean that the methods described in the literature cannot always be applied directly and their optimization is necessary. Particularly in molecular dynamics and modeling, it is often necessary to develop protocols that best represent the type of interactions between each of the compounds that constitute the NADES.

 

Roles of NADES in Metal-, Bio- and Organocayalysis

 

In the realm of chemical synthesis, both DESs and NADESs have also had a significant impact. They have been used in several types of reactions, where they function as solvents and (electro)catalysts, but amazingly, they have been used in biomass valorization, biofuel production, polymer degradation, CO2 fixation, etc. It should be stressed that due to the current complexities in the production of active pharmaceutical ingredients (APIs), excessive waste is a problem, principally solvent waste that accounts for about 80% of all Pharma waste (18, 19). Thus, it makes sense to use bio renewable, ecologically friendly solvents like NADES. NADES have been shown to be excellent solvents for all types of reactions, that include, metal-, bio- and organocatalyzed reactions. The latter two categories have received considerable attention over the last 5 years and it has been noted that NADES act both as solvents and a catalysts(20). A nice example of doing biocatalysis in NADES is the enzymatic dehydrogenation of cortisone acetate to prednisone acetate which has anti-inflammatory and anti-allergy properties with immobilized Arthrobacter simplex cells in NADES by Lu’s group (a, Figure 2) (21). Of the three NADES tested, ChCl/Gly, ChCl/EG and ChCl:U, it was the latter that gave the best results, 93% conversion at 6% NADES content. The medium could be recycled up to 5-times. It should be mentioned that NADES can maintain the native structure of enzymes, mitigating deactivation that can occur in organic media and they facilitate easier catalyst recovery.

 

Capriati and coworkers developed a sequential synthetic approach leading to the antihistamine drug Thenfadil (b Figure 2) using a NADES in two crucial steps, involving a reductive amination followed by a Cu-catalyzed Ullmann-type C-N coupling (22). The target compound was obtained in an overall yield of almost 40%, and the reaction could be scaled to a multi-gram level. Other analogues, like Tripelennamine, Methaphenllene and Thonzylamine could be synthesized in a similar manner. In fact, this study was a water-shed in that it clearly shows that NADES can be effectively used at larger scales which is very important from the industrial point of view (vide infra).

 

Capriati and coworkers developed a synthetic pathway to Tacrine-Triazole hybrids using NADES (c, Figure 2) (23).
The cyclodehydration step was very sucessfully run in Lewis-acidic NADES, and the copper-catalyzed Alkyne-Azide Cycloaddition (CuAAC) (click chemistry) also successfully run in NADES.

Interesting functional materials with useful optoelectronic properties, like OLED applications have also been prepared using NADES. For example, Dessi and coworkers have successfully used NADES in key sequential catalytic Miyaura borylation/Suzuki-Miyaura reactions (d, Figure 2) to afford a yellow emitter (known as DQ1) for high-efficiency luminescent solar concentrators (24).
Some reviews have been published on the use of metal catalysts in NADES, like that of Marset and Guillena (25).

 

Asymmetric organocatalyzed reactions can also be performed simply in NADES (26). In fact, in many cases the organocatalyst, like proline or other organocatalysts can be part of the NADES system (27), and we have also shown that it is possible to achieve a good level of enantioselectivity in a Michael reaction run in a NADES system comprised of Betaine/Sorbitol/Water (28).

 

Unlike room temperature ionic liquids (RTILS), NADES have the advantage that their physical and chemical properties can be tuned by judiciously selecting the right combination of HBD and HBA. In the future it should be possible to use particular computational models that will allow the selection of the best NADES for the type of reaction in mind.

 

Comparison of NADES with RTILs

 

Room temperature ionic liquids (RTILs) have been used for various reactions over the last decades, their principal disadvantage is their high toxicity, biodegradability, ecological imprint and expense. Furthermore, RTILs have lower band-width in terms of structural diversity as compared to NADES (with so many permutations possible up to aprox. 106 for binary mixtures). On the positive side RTILs have been used frequently in very useful multi-phase catalytic processes more so than for NADES. In 2022 Pires and coworkers published an excellent review/opinion paper which discussed the advantages and benefits of DESs over RTIL in the context of metal-catalysed reactions (29). They were strongly of the opinion that DESs represent a real alternative to traditional RTILs in these reactions. This is backed up an opinion article by Guzmán who believes that certain DESs can outperform RTILs in terms of selectivity, catalyst recoverability and recyclability (30).
In fact, many cycles can be achieved, which includes up to 9 cycles in some cases (30). Although it appears that currently the breath of coupling reactions that has been performed in RTILs is greater than with NADES, a number of reactions have been successfully conducted, that include: the Ullmann, Heck-Mizoroki, Suzuki-Miyaura, Hiyama, Stille, C-N coupling reactions and many others (29). Catalytic hydrogenations in RTILs are well known, but have been less commonly applied in NADES (29).

 

The uncertainty regarding the microenvironment around the catalytic active center has been a long-standing problem for transition metal catalysis in ionic liquids, but this is also a problem for NADES systems. On the other hand, the high viscosity of many NADES can negatively impact the mass transfer and reaction kinetics, but this can be adjusted by selecting the right combination of HBD and HBA and also by adding water.

 

Conclusions and Future Perspectives

 

The knowledge generated over the last 10 years of intense research into deep eutectic solvents (DESs) or natural deep eutectic solvents (NADES) is still not sufficient for a deep understanding of these systems, and for their translation into industry to be at a mature stage. What we have learned over the last decade has shown us how complex these systems can be, and that their applications will multiply exponentially, diluting the focus of research while opening up countless possibilities for making processes greener and more sustainable, particularly in the cases we have seen in the pharmaceutical and/or biomedical industries. Like in the case with RTILs, the ability of conducting biphasic catalysis with NADES is a very attractive approach to obtaining high-value products, particularly from an industrial angle. NADES have so many advantages over the other solvent types, like conventional solvents and RTILs, particularly their catalytic properties – which are only beginning to be understood – and we expect that they will be applied on a more frequent basis in chemical processes into the future. We are not aware of any industrial production processes that use NADES in their transformations, nor in process development campaigns. Despite reports on a number of fundamental studies at the academic level, the lack of industrial engagement is possibly a result of a lack of knowledge and understanding on the behavior of these solvents at larger scales, although the current indications are that these solvents can be used at larger scales. In fact, the work by Capriati and coworkers above (22) provides significant testimony that this can be achieved at industrial scales. Moreover, with the continued advances in the development of new analytical and computational technologies (that includes Artificial Intelligence/Machine Learning) that can predict the optimal NADES properties for the reactions at hand this objective may not be far away. And as a final remark, we echo the opinion of Guzmán, in that collaborative research efforts between academia and industry will be essential for driving the commercialization of DES-based catalytic systems (30).

 

Acknowledgements

 

This work has received funding from the European Research Council through grants ERC-CoG-725034, ERC-PoC-101067844,ERC-PoC-101138403. This work was financed by national funds from FCT – Fundação para a Ciência e a Tecnologia, I.P., under the scope of the project UID/50006/2023 of the Associate Laboratory for Green Chemistry – LAQV REQUIMTE We also thank the Foundation for Science and Technology (FCT) for funding to the Coimbra Chemistry Centre-Institute for Molecular Sciences (CQC-IMS) via projects; UIDB/00313/2020| UIDP/00313/2020.

 

Figure 1. Envisaged breakthroughs by the application of AI to Deep Eutectic Systems.

 

Figure 2. Some examples of the applications of NADES in catalytic reactions leading to drugs and other high-value-added compounds.

 

References and notes

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