Environ Sci Pollut Res DOI 10.1007/s11356-015-4794-y

REVIEW ARTICLE

Selected issues related to the toxicity of ionic liquids and deep eutectic solvents—a review Błażej Kudłak 1 & Katarzyna Owczarek 1

&

Jacek Namieśnik 1

Received: 22 January 2015 / Accepted: 27 May 2015 # Springer-Verlag Berlin Heidelberg 2015

Abstract Green Chemistry plays a more and more important role in implementing rules of sustainable development to prevent environmental pollution caused by technological processes, while simultaneously increasing the production yield. Ionic liquids (ILs) and deep eutectic solvents (DESs) constitute a very broad group of substances. Apart from many imperfections, ILs and DESs have been the most promising discoveries in the world of Green Chemistry in recent years. The main advantage of ILs is their unique physicochemical properties—they are very desirable from the technological point of view, but apart from these benefits, ILs appear to be highly toxic towards organisms from different trophic levels. DES areas of usage are very spread, because they cover organic synthesis, extraction processes, electrochemistry, enzymatic reactions and many others. Moreover, DESs seem to be a less toxic alternative to ionic liquids. New possibilities of applications and future development trends are sought and presented, including such important solutions of life branches as pharmaceuticals’ production and medicine.

Keywords Green Chemistry . Environmental fate . Ionic liquids . Ecotoxicity . Deep eutectic solvents

Responsible editor: Philippe Garrigues * Katarzyna Owczarek [email protected] 1

Department of Analytical Chemistry, Faculty of Chemistry, Gdańsk University of Technology, Narutowicza Str. 11/12, 80-233 Gdańsk, Poland

Introduction Progress of human development in all branches of life has resulted not only in numerous improvements but also in visible damage and exploitation of natural resources of our planet—mainly because of unsustainability. These resources include not only raw materials such as petroleum, but also clean water, air and animated nature. It is visible in the prominent development of pro-ecological sciences, the use of alternative energy sources and the search for new solutions, including the industrial and laboratory practice. Green Chemistry is a very important tool of sustainable development, and its goal is to prevent or reduce environmental stress caused by technological processes, while simultaneously increasing the production. There are 12 principles of Green Chemistry, namely: prevention, economy, less hazardous chemical syntheses, safer chemicals should be designed, use of safer solvents and other substances, efficient use of energy, use of renewable raw materials, avoidance of derivative processes, use of catalysts and biocatalysts, using the possibility of degradation of used products, monitoring of real-time technological processes, provision of an adequate level of chemical safety. The application of the aforementioned rules provides solutions for the global environmental issues, such as climate change, efficient energy management or the decrease in the sources of natural resources (Gałuszka et al. 2013). One of key issues of Green Chemistry concerns environmentally benign solvents. In many research centres, solutions are developed to eliminate and limit the use of hazardous organic solvents and to replace them with new, milder and more environmentally benign solvents and reaction media. Such activities are aimed at achieving a balance between the development of technology, an increase in the production and a safe and clean environment. Figure 1 presents characteristics

Environ Sci Pollut Res Fig. 1 Characteristics of a solvent complaint with the requirements of Green Chemistry and the life cycle of an ionic liquid (Cvjetko Bubalo et al. 2014)

Biodegradability

Low cost

Non toxic Ideal green solvent

DISPOSAL AND ENVIRONMENTAL FATE ILs RECYCLING

High accessibility

ILs APPLICATION

Recyclable ILs SYNTHESIS

of an ideally ‘green’ solvent and ionic liquids (ILs) life cycle within the frames of green solvents recyclability. Over the last few years, there has been a noticeable progress in the field of green solvent development. New solutions have been found in the field of utilising traditional solvents (such as water as a solvent or water and carbon dioxide) at supercritical state, but the biggest group of them still consists of organic solvents. Table 1 summarises characteristics of green solvents—the biggest group of which constitute esters, (Paryjczak 2008) together with selected milestones in their research (Zabielska–Matejuk 2009; Anugwom et al. 2011; Dominguez de Maria 2012).

discovery. One of the first substances of this type was described in 1941 by a Latvian-German chemist, Paul Walden. It was ethylamine nitrate [EtNH3]+[NO3]−, derived in the reaction of protonation of ethylamine by nitric acid, according to the following chemical reaction:

The history of the discovery and research on ionic liquids

&

Recently, ionic liquids have been more and more widely used as solvents and reaction media, but they are not a new

&

Table 1

C2 H5 NH2 þconc: HNO3 →½C2 H5 NH3 þ ½NO3 

ð1Þ

Few basic milestones in the history of ILs cover: &

1914—synthesis of ethylamine nitrate (Tm =14 °C) in a reaction involving concentrated nitric acid (V) by Paul Walden 1934—creation of melted salt on the basis of pyridine capable of dissolving specific amounts of cellulose 1951—F. Hurley and T. Weir obtained an ionic liquid from N-ethyl pyridine bromide and aluminium chloride

General classification of green solvents and on ionic liquids

Type of green solvents

Description and use

Examples

Ester solvents

Ester solvents of high and low molecular weight are susceptible to degradation, that is, why they are widely used as environmentfriendly solvents

Special solvents

Used as non-reactive solvents in epoxy and polyurethane systems Used in microelectronics, in the production of semiconductors and also as degreasing products The main advantage of liquids in the supercritical state, because of which they are widely used, is a significant increase in the transportation of mass and heat Frequently used in processes accompanying the separation technologies and phase transfer catalysis

Monoesters of fatty acids of glycol and glycerine TOFA—ethylene glycol monoester Various indirect glycerine esters Methyl rapeseed ester (biodiesel) Glycerine carbonates Ethyl-lactate

Solvents in the supercritical state Ionic liquids

ScCO2 ScH2O 1-ethyl-3-methylimizdazoltetrafluoroborate Tributyl-hexylamino-bis (trifluoromethyl-sulfonyl)amide

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& & & & &

1960–1992—creation of the first generation of ionic liquids, which were stable in contact with water and air, by J.S. Wilkes 1970s—R.A. Osteryoung, Ch. L. Hussey and J.S. Wilkes conducted research on the use of aluminium chloride liquids as electrolytes in batteries 1990s—creation of 2nd generation ionic liquids 1999—designing first low temperature ionic liquids for commercial purposes 2000–now—creation of the 3rd generation of ionic liquids

but the main limitation of using ionic liquids on a commercial scale was their high cost. The recent years have brought a new generation of these compounds—more stable and environmentally benign as they are based on biodegradable ions (Dominguez de Maria and Maugeri 2011, Wójciuk 2014). Another approach to the classification of ionic liquids is the one relying on their properties. There are also three generations in that case. Figure 2 shows the properties of each generation of ionic liquids and selected examples of individual generations. The first generation of ionic liquids describes those that are characterised by unique tailorable physical properties. Physical properties that are often tuned are volatility, thermal stability, density and viscosity of a given IL. The second generation consists of ILs of desired chemical properties combined with chosen physical properties. Due to a growing interest in the application of ILs in the material production, second generation ionic liquids can be tailored regarding such properties as reactivity, energy density, oxygen balance and many others. The application of ILs in the

The so-called first generation of ionic liquids appeared in the industry at the beginning of the 1960s. Their biggest disadvantage is that they are sensitive to the presence of water and air. That is why some actions had to be undertaken in order to eliminate their drawbacks and, as a result, in the 1990s, the second generation of ionic liquids was started. These liquids consist of anions of low coordination properties, such as BF4 and PF6. They were the subject of countless studies and numerous applications were documented for them,

1st GENERATION

Generaon 1: Solvents Designing physical properes

Physical properes: Hydrophobicity Viscosity Density Thermal stability Conducvity Melng point

R1 +

N

N

OH

+

N

R4 N R2

S

+

R S

+

N

*

O

N

N

+

N

N

+

H3C

+

N

N

CH3

N

COO-

N

N

O2N

+

O

HN+

Ph

NO 2 N

-

NO2

Cl

N N

CN

O N

CH3

N

NO 2 N

CATIONS

Emolients Anacne Vitamins Anbiocs

N

O

N

CN

OEt

Biological properes:

ANIONS

+

N

Generaon 2: Advanced materials Designing chemical and physical properes

3rd GENERATION

Anbacterial Anfungal Ancholinergic

H3C

Cl

O

+

N

CF 3

O S O

2nd GENERATION

Chemical reacvity High energy density Flammability Solvataon Oxygen balance UV blocker Chiral inducon

-

N S

O

O

Chemical Properes:

+

O

HO S O

O O

O

O F 3C

R3

O O

N

+

O NH

Generaon 3: Pharmaceucals, Drugs Biological, chemical and physical properes

-

O3 S

H3C O

O O

Ph OH

O CH3

H3C

H3C

O +

HN H3C

NH

H3C

CH3

Fig. 2 Classification and properties of each generation of ionic liquids and the chart showing the development of the research on ionic liquids

CH3

Environ Sci Pollut Res

production of energetic materials is a good example here. Combining non-volatility, high thermal stability with low melting points with desirable energetic features can lead to improving safety issues connected with the production of energetic materials (Smiglak et al. 2007). The third generation consists of modern ionic liquids which have specific biological properties combined with selected physicochemical properties. This group includes ionic liquids which are often used for pharmaceutical and medical purposes, e.g. for drug production and delivery. Biological properties that are tailorable are, e.g. antibacterial, antifungal and local anaesthetic activity. These properties can be also influenced by modifying chemical or physical properties of respective combinations of cations and anions (Hough et al. 2007). Switchable ionic liquids (SILs) are a special group of ILs, also called reversible ionic liquids (RILs) that can be found in a neutral or ionic state. The state may be influenced by the use of an external activating factor. Carbon dioxide is such an activating factor often employed to transform a non-ionic liquid into its ionic form. In order for the liquid to become a nonionic substance once again, it is washed with a stream of nitrogen or argon. During the change of the state from ionic to non-ionic one (and vice-versa), the properties (namely the polarity, viscosity and hydrophobicity) of the liquid also change. SILs are used in processes such as CO2 and SO2 capturing, extraction of oil from soybeans, extraction of hemicellulose from pines and oil refining (Hafiidz et al. 2012). SUBSTITUENT

Structure and properties As it has been already mentioned, an ionic liquid is made of ions in which the cation is usually a big, asymmetric organic molecule, and the anion has low coordination properties. Thanks to the big size of the ions, the charged centres of molecules interact with each other but do not bond directly. The asymmetry of molecules and their size disables the possibility of a tight fit. Of great importance is also the length of the alkyl chain, being a part of an ion, while the level of its branching has an influence on the melting temperature. These properties determine its low melting temperature and liquid state at room temperature. A more detailed revision of ionic liquids properties is provided in Tang and Row (2013). The possibility of designing the physicochemical and thermal properties of a liquid by adequate combining cations and anions makes this group of compounds unique and universal as regards their chemical usage. One of additional advantages is the possibility of easy isolation of an ionic liquid from the reaction system, which allows for its repeated use. As presented in Fig. 3, an ionic liquid consists of: 1. An alkyl chain as the functional group within the cation 2. A usually organic cation which constitutes the head group 3. An anion, which is usually inorganic (Wójciuk and Hafiidz et al. 2012; Cvjetko Bubalo et al. 2014) Selected properties of ILs are summarised and commented on in Table 2.

CORE

ANION F

H3C

+

N

-

F

N

F

B F

Anions

Cations

R

4

R

O

3

N +

R

N

R

N

+

N R

2

1

R

R

2

2

R

+

R

3

Amonium

R

2

H3C

+

N

CH3

Choline

-

Cl

Al

-

Cl

H3C

Cl

O

S

F O

-

3-

Sb

O

Tertachloroalumine

R

1

F R

4

+

P

R

O

F

F

Hexafluoranmonic

R

2

S F

O

O

HO

P OH

O

F

F P

-

F

Trifluoromethansulfonium

Dihydrogen phosphate

B

-

F

F

F F

3

Fosfonium

F

F -

F

F

Methansulfonium

O -

F

F

Pirolidynium

CH3

1

N

O

S

O

Methylsulphate

Pirydinium

4

R

1

Imidazolium

R

H3C

+

N

1

O

Cl

Hexafluorphosphate

F

Tertafluorboric

Fig. 3 A schematic structure of an ionic liquid (Cvjetko Bubalo et al. 2014) and captions and anions frequently used to obtain ionic liquids (Hafiidz et al. 2012)

Environ Sci Pollut Res Table 2

Selected properties of ILs

Parameter

Comment

Vapour pressure

Under standard conditions, ionic liquids show insignificantly low vapour pressure. This property distinguishes them from classical organic solvents, which to a large extent belong to the volatile organic compounds (VOC) group and have a high vapour pressure. Thanks to that property, ionic liquids do not evaporate and their boiling temperature is very high. No vapour pressure means that the solvent is not emitted to the atmosphere, which is very beneficial for the natural environment. Thereby, ionic liquids can replace VOC in case of many organic syntheses in a very wide range of temperatures. Even though they have a low vapour pressure, it has been shown that ionic liquids can be subjected to distillation in appropriate pressure and temperature conditions in order to clean them from pollutions and to prepare them for reusing. However, it has to be taken into consideration that the process of distillation of ionic liquids demands much energy (Wójciuk 2014). Ionic liquids show a high capability of creating two and multi-phase systems, which facilitate their subsequent isolation from the reaction system. In addition, what is their great asset is a fact that they dissolve both organic and non-organic compounds. Broad discretion in the selection of the properties of this type of solvents allows for designation of a liquid which dissolves well and mixes with reagents, but at the same time poorly dissolves reaction products, which also facilitates separation of the products from the solvent. The main factor influencing the solubility and miscibility of a given ionic liquid is the type of its anion. This property may be controlled by, for example, changing the anion from [Cl]− to [PF6]−. One of the other factors is the length of the alkyl chain of the cation (Anugwom et al. 2011).

Solubility and miscibility

Acidity/alkalinity

Ionic liquids have acidic and alkaline properties (they can act as the donor or acceptor of protons). In this case, everything also depends on the choice of the cation and anion. The factors influencing the acidity of an ionic liquid is the presence of various groups consisting of nitrogen in its molecules and the length of the hydrocarbon chain (Wójciuk 2014, Hafiidz et al. 2012).

Thermal stability

This property is a very important characteristic of ionic liquids. In comparison to classical organic solvents, ionic liquids are much more stable and less prone to dissolution in high temperatures. Some of widely used ionic liquids are stable in a temperature exceeding 400 °C. Both the cation and the anion have influence on the thermal stability. Researches show that liquids whose structure includes a caprolactam cation are more stable (Hafiidz et al. 2012).

ILs area of usage Because of their universality and the aforementioned possibility of tailoring their physicochemical properties, ionic liquids are used in many chemical and industrial processes. They were successfully used in classical chemical reactions such as the Diels–Alder and Friedel–Crafts ones. It has to be pointed out that their use is not only limited to the role of solvents, but it can also be extended to many branches of the industry, starting from chemistry and biotechnology to the power generation industry and manufacturing (Hafiidz et al. 2012; Gräsvik et al. 2012). Properties of these substances are used in many branches of science and industry, as shown in Fig. 4. What deserves special attention is the wide use of ionic liquids in medicine and pharmacy, where they are used as: – –

Solvents and reaction media in the processes of production and improvement of the quality of the properties of drugs (Duarte dos Santos et al. 2013) Active ingredients of medicines (Active Pharmaceutical Ingredients—APIs)

Studies of Ferraz et al. (2011), Wilkes (2002) and Kumar and Malhotra (2009) even show that ionic liquids may be potential anti-cancer drugs. Six out of 7 of studied liquids contributed to a decrease in a tumour by 60 % in at least one cell line. Research was conducted on the cell of

melanoma, neoplastic cells of bone marrow, lungs, purse seines, ovaries, the prostate and the brain. Examples of those and other compounds which are potentially useful in the treatment of cancer are shown in Fig. 4. The toxicity of some promising biomass-dissolving amidinium-, imidazolium- and phosphonium-based ionic liquids, towards human corneal epithelial cells and Escherichia coli as well as on the size and surface charge of some model liposomes, were studied by Mikkola et al. (2015). Despite the chain length, it was also proven that toxicity depends on hydrophobicity and surface charges and size distributions of model liposomes, which may disrupt the lipid bilayer. The impact of five different (water soluble) imidazolium-based ILs on the properties of the bacterial plasma membrane was investigated by Lim et al. (2014). The study shows how cations are inserted into the bacterial membranes and how such insertions change their properties. Moreover, the different roles of cations and anions were determined. Apart from the aforementioned applications, the literature mentions the following areas of ILs’ applications: &

Biodiesel production—an increasing tendency to use ionic liquids can be observed in the production of biodiesel obtained from vegetable and animal fats. They replace conventional organic and non-organic solvents which pose a threat to the environment. In the production of

Environ Sci Pollut Res

POTENTIAL ANTI-CANCER DRUGS

C6H13

(C 2F 5)3 PF3-

H13 C6 P

+

P

+

PF3-

BF4-

C6H13 +

C6H13

H13 C6 P C6H13

H13 C6

H13 C6 CN N

C6H13

NH-(CF3 SO2 )2

-

NC

Material production - small spheric particles of Ag, Ni, Fe and C

+

N

+

H13 C6 P C6H13

-

+

H13 C6

N(CF3SO2)2

Elektrochemistry -electrolytes in the capacitors -lithium batteries -semiconductors and metals electrodeposition

N

SELECTED IONIC LIQUIDS USED IN MEDICINE

Medicine and pharmacology

Fields of ILs applications

H3C n

+

CH3

N

O

CH3

S

-

N

[BA][Sac]

O

Other - liquid crystals production - liquid membranes production

-

N n

+

CH3

H3C

N

O

CH3

[BA][Ace] H3C H21 C10

+

N

O

S

O

Cl H29 C14 N

O

CH3

N

C10 H21

S

-

+

CH3

Biotechnology - protein purification and extraction - biocatalysis

Nanotechnology -electrolytes for nanoparticles production (Al, Fe, Pd) and Al-Mn alloys

N

-

H3C

O

O

3-methyl-1-tetradecyl-1H-imidazol-3-ium chloride

O

Anti-biofilm agent

[DDA][Ace]

Fig. 4 Usage of ionic liquids in various branches of science (Duarte dos Santos et al. 2013; Pham et al. 2010; Simka et al. 2009), chemical structures of chosen ionic liquids used in medicine (Ferraz et al. 2011)

biodiesel, an ionic liquid may serve both as a catalyst and as a solvent (see Fig. 5.) Cellulose processing—attempts to dissolve cellulose with the use of ionic liquids gain more and more interest. Even though the elaboration of this method is still at its initial stage, there it is possible that it will be widely used in the cellulose processing industry

ILs APPLICATION IN BIODIESEL SYNTHESIS

&

Chemistry -medium in GC and HPLC - solvents for metal extraction - UV-MALDI technique matrix - catalysis -polimerization

O

O

H3C

Power engineering - refrigerant in nuclear reactors - fuel cell - thermofluids

and chemical structures of potential anti-cancer drugs (Ferraz et al. 2011; Kumar and Malhotra 2009)

& & & &

Hydrogenation and hydroformylation (reactions catalysed by ILs) Processes of heavy metals removal Fuel production for rocket engines Capture of greenhouse gases (Gräsvik et al. 2012)

Characteristics of ionic liquids Catalyst

Solvent for enzymecatalyzed transestrificaon

Assistant catalyst

Lipid extracon

Fig. 5 Use of ionic liquids in the biodiesel synthesis (Hafiidz et al. 2012)

Ionic liquids constitute a very wide group of chemical substances. The majority of them consist of a big organic cation and an anion of an inorganic character, rarely organic. As they have unique physicochemical properties (very desirable from the technological point of view), they are used in many industrial and laboratory processes, replacing classical solvents, reaction media and catalysts in many cases. Their universality and the possibility of tailoring resulted in an interest in ionic liquids and studies conducted by many research centres all over the world. According to the most general definition, an IL is a chemical compound made of anions and cations of a melting temperature lower than 100 °C. They are often called ‘molten

Environ Sci Pollut Res

salts’; however, this notion is inaccurate. While salts melt at a temperature above 200 °C, ionic liquids, as it has been mentioned before, are characterised by a melting temperature below 100 °C. In addition, melted salts are also characterised by higher viscosity and corrosiveness than ILs. Even though they are in a liquid state, ionic liquids have physicochemical properties which resemble the properties of solids, rather than those of liquids (Rodrigues et al. 2007).

Ionic liquids—a threat to the health and the environment—the unknown side of ionic liquids The aforementioned properties of ionic liquids which distinguish them from the majority of conventional solvents may also have a toxic influence on the environment. The low vapour pressure may not be confused with a lack of toxicity. Good water miscibility and solubility in aqueous solutions are properties which increase a potential threat to the aquatic environment and organisms living in it. In addition, the aforementioned stability of ionic liquids makes them poorly biodegradable and persistent in the environment for a long time (Arednarczyk et al. 2011). There are many studies referring to the biological effects of ILs and their toxicity to living organisms at various levels of the organisation and place of the food chains, including:

Cytotoxicity Many studies on the influence of ionic liquids on organisms were conducted in regard to the cytotoxicity. Various cell lines used in the tests are shown in Table 3. Of special importance are the tests using human cell lines as tool in analysing the mechanisms of the toxic activity of ILs at a cellular level and in the assessment of the potential effect on a human body as a result of an exposure to ionic liquids. In the majority of tests of this type, epithelial cells are used as they are the first to be directly exposed to toxins. To get to know the toxicity of various types of human cells, various cell lines were used: LoVo and DLD-1 (colorectal adenomas), HepG2 (liver cancer), AGS (stomach adenoma), A549 (lungs cancer), HaCaT (immortal human keratinocyte). The liquid studied was [DDA][Sac] (didecyldimethylammonium saccharine) which has shown an increased toxicity to the lungs and skin cells (A549 and HaCaT lines) (Jodynis-Liebert et al. 2010). The toxicity tests by Gulhane et al. (2014) proved that the [Bmim]Cl inhibit the growth of soil microorganisms including bacteria and Actinomycetes, causes the pH change in the soil micro-ecological system. It suggests that [Bmim]Cl can impact the ecosystems by inhibiting the growth of soil microorganisms and altering the physicochemical properties of soil.

Toxicity to invertebrates Biological effects at the enzymatic level Enzymes have many important functions in living organisms; mainly, they play the role of catalysts of metabolic reactions. Any interference in their activity results in a cascade of negative changes as they are necessary to achieve the adequate speed and efficiency of almost every chemical reaction. Widely used ILs are capable of inhibiting various types of enzymes, including acetylcholinesterase, AMP deaminase, alcohol dehydrogenase or anti-oxidant enzymes in the liver of a mouse. Acetylcholinesterase is a key enzyme in the correct functioning of the nervous system. It catalyses the reactions of hydrolysis of acetylcholinesterase, especially acetylcholine (a neurotransmitter). The results of the blockage of the activity of the acetylcholine esters are a distortion of numerous neurological processes, which lead to cardiac diseases and myasthenia in humans. It has been shown that the organic cation of an ionic liquid is mainly responsible for the inhibition. Liquids on the basis of pyridinium and imidazole cations have the biggest influence on the inhibition of the activity of enzymes. The type of the anion does not have any significant influence, which can be explained by the non-significant interaction between the anion and the active centre of acetylcholinesterase (Pham et al. 2010; Stasiewicz et al. 2008).

Invertebrates are a very important element of both soil and aquatic environments. They are often the core of food chains and that is why each interference in their population may have a negative effect on the functioning of the whole ecosystem. Their inbreeding in a laboratory is usually simple and cheap, and when combined with the high vulnerability of these animals to toxic substances, they become perfect models for ecotoxicity studies. A lot research has been conducted on the harmful effects of ionic liquids to animals found in aquatic environments. An organism which is frequently studied in the scope of ecotoxicology is Daphnia magna. The most frequently studied ILs are those on the basis of imidazole and pyridine cations and quaternary ammonium anions. Experiments with the use of D. magna confirm the direct correlation between the length of the alkyl chain and the toxicity of a compound. Once again, the type of the anion has a much lower impact on the toxicity of a given liquid than the cation. In addition, the number of aromatic nitrogen atoms has a great impact on the harmful effects of the ionic liquid to living organisms (Wang et al. 2015). It also depends greatly on the energy of the lowest unoccupied molecular orbital (LUMO). Another freshwater living animal—Physa acuta, a snail, has been proven to be sensitive to ILs concentration ranges between 3.5 and 1800 μM.

Environ Sci Pollut Res Table 3

Cell lines used in the researches on the cytotoxicity of ILs

Cell line

Type of cells

Description

IPC-81

Neoplastic cells of the bone marrow of a rat (leukaemia)

It is a cell line frequently used for tests. The indicator of the cell viability is the reaction of reduction of the WST-1 reagent. Generally, on the basis of these tests, it is possible to state that ionic liquids which consists of polar functional groups (such as a hydroxyl or nitrile group) in the alkyl side chains are less toxic to the cell than the liquid that consists of simple and non-complicated side chains. It is suspected that the aforementioned functional groups impede the transfer of ions of a liquid into the membrane of cells and reduce their lipophilicity (Pham et al. 2010).

CCO

Channel catfish ovary

This line has been used in in vitro studies on the toxicity of ionic liquids created on the basis of an imidazole cation, which differ in anions and alkyl side chains. As the concentration of each of the liquid tested increased, its cells showed a decrease in viability. A correlation has been observed between the length of the side chains and the number of necrotic cells. A microscopic analysis has shown changes in the morphology of cells (Radošević et al. 2013).

CaCo-2

Human colorectal adenocarcinoma cells

The tests conducted with the use of this line have shown that ionic liquids with longer alkyl side chains are more lipophilic than those with shorter chains. That means that they can bond with cell membranes. It explains the toxicity of this type of ILs (higher permeability through membrane to the interior of the cell is destructive for the cell). In addition, it is suspected that the toxicity of imidazole liquids is a result of the fact that they are similar to various kinds of antibiotics, detergents and pesticides (Pham et al. 2010; Cheng et al. 2009; Cho et al. 2007).

P. acuta, D. magna and other invertebrates are very important elements of freshwater food chains. For this reason, there is a threat that if ionic liquids accidentally reach the aquatic reservoir, they can harm those organisms and the homeostasis in such an ecosystem will be significantly damaged (Pham et al. 2010). Soil ecosystems are of no less importance; however, the amount of data in the literature concerning the toxicity of chosen ILs to invertebrates living in soil is significantly lower. An important representative of such environments is the earthworm (Eisenia fetida). The earthworm is known to be sensitive to compounds such as heavy metals and pesticides. Taking into consideration the easiness of its inbreeding and low cost, it is a model organism in studies on toxic effects of various substances on the soil invertebrates. The toxicity tests of imidazole ionic liquid have shown that they caused: &

& &

A significant decrease in the growth from 7 to 14 days from the moment of commencing the exposure. The growth decrement ranged between 8.5 and 42.5 % and depended on the concentration of the ionic liquid. A significant decrease in the juveniles in comparison to the control group (55 % decrease in reproduction). Inhibition of the activity of enzymes (ATPase). No inhibition of the enzyme activity in the initial stage of the experiment was observed; however, during the tests concerning subchronic activity of ATPase, it was reduced even in the presence of small amounts of the ionic liquid (1–5 mg/kg of the soil) (Luo et al. 2010).

Toxicity to vertebrates It is essential to reassess the toxicity of a chemical substance to vertebrate animals. It allows us to get to know the effects and damages that the substance may cause to the environment and to assess the danger resulting from a contact between the given compound and human beings. ILs, depending on their structure, may have a different effect on vertebrate organisms. Using the example of the zebrafish (Danio rerio), it has been proven that ionic imidazole, pyridine and pyrrolidine liquids are not highly toxic to these fish species. However, the LC50 values for ammonium salts were much lower (higher toxicity) than for organic solvents and tertiary amines (Pham et al. 2010). They also show a potential immunotoxic activity, which has been proven by the results of studies on the activity of lysozyme in the plasma, kidneys and spleen of a carp (Cyprinus carpio). For each studied concentration of the chosen liquid ([C8MIM]Br— 300 mg/L), a competitive inhibition of the immune system of the fish has been observed when it was exposed to the liquid for a period of more than 7 days (Li et al. 2012). When it comes to the ILs’ toxicity to amphibians, it greatly depends on the developmental stage of a given species (the studies were conducted on a frog of the Rana nigromaculata species). Amphibians are frequently object of studies on the toxicity to an aquatic environment because their larvae (tadpoles) live only in water. In case of ionic liquids, embryos are the most vulnerable to their toxic activity as their mortality increases with an increase in the concentration of the ionic liquid in the water (Pham et al. 2010). What is more, the harmful activity of ILs (in this case— IM14 Cl) to foetuses and embryos has been shown. In this case, a significant decrease in the weight of foetuses has been

Environ Sci Pollut Res

shown. It suggests potential teratogenic activity of ILs. Generally, invertebrates are much more vulnerable to the negative influence of ionic liquids than vertebrates (Pham et al. 2010). Ionic liquids, with all their functionality and universality, are undeniably harmful to living organisms. Reaching the soil and aquatic environments in large quantities (as a result of an accidental spillage or as a stream of industrial sewage) may result in a significant deterioration of those ecosystems. That is why a new direction in the production of compounds of this type is to create ILs from less harmful synthons or substrates, which occur in nature, such as amino acids. Such ionic liquids show very low toxicity to human cells and aquatic organisms (Gouveia et al. 2014). On the other hand, biotests are an undeniably useful tool to assess the total toxicity of compounds such as ILs. In Fig. 6, there are presented stages that should be taken into account when designing a battery of biotests in order to assess the toxicity. Removal of ionic liquids residues Even though ILs are nowadays designed in such a way that they can be repeatedly reused, there are limits to their applicability. The life span of a liquid consists of a specific number of cycles—afterwards, it becomes a waste. This chemically and thermally stable output becomes a problem in regard to the disposal of wasted ionic liquids. Studies have shown that the release of large quantities of ILs (without their previous degradation to make them less toxic) will result in changes in

the ecosystems they would be released into. The life cycle of an ionic liquid has been previously shown in Fig. 1. Chemical degradation, especially with the use of thermal decomposition or oxidation, is one of the ways of detoxification of ionic liquids. In the literature, there are described few basic methods which give good results. Those methods are summarised in Table 4. The methods of chemical wastes disposal considered to be much more environment-friendly are those based on the biological decomposition of substances by microorganisms. Unfortunately, almost none of the ILs widely used in the industry is susceptible to biodegradation. Sometimes, alkyl chains are decomposed by bacteria, but the head group consisting remains untouched. In that case, intermediates are characterised by various ecotoxicity levels may be created. Because of the aforementioned difficulties, attempts have been made to design easily biodegradable ILs. Usually, they had to have in their structure molecules of oxygen in the form of hydroxyl, carboxyl or aldehyde groups. In most cases, the properties favourable for the biodegradation are not accompanied by the properties that are expected from good industrial reaction media or solvents point of view (Cvjetko Bubalo et al. 2014; Pham et al. 2010). Environmental fate Low vapour pressure values are the reason why ILs pose almost no threat to air, but aquatic and soil ecosystems are the

Fig. 6 Schematic presentation of a battery of tests to assess the ecotoxicity of ionic liquids (Pham et al. 2010)

Cytotoxicity

Toxicity towars microorganisms

Phytotoxicity

Enzyme inhibion

Toxicological threat of Ionic Liquids

Toxicity towards vertebrates

Toxicity

towards invertebrates

Environ Sci Pollut Res Table 4

Methods of disposal of ionic liquids residues

Method

Description

References

UV radiation

UV radiation was used together with oxidation in the presence of a catalyst, for example, hydrogen peroxide or titanium dioxide. The method gave good results. Oxidation supported Oxidation of ionic liquids was made in the presence of iron at the zero oxidation level, by ultrasounds embedded in active carbon. The level of decomposition of the ionic liquid achieved over 95 %. Degradation to 1-butyl-3-methyloimidazol chloride. The reaction scheme is presented in Fig. 8a. Systems of oxidation The vulnerability of an ionic liquid to decomposition in the presence of the OH· radicals based on the Fenton reaction is determined by its chemical structure, especially the length of the alkyl chain and decreases as its length increases. Phosphonium ionic liquids show higher vulnerability to decomposition than imidazole and pyridinium liquids. Wet mineralisation Mineralisation leads to the removal of the non-organic anion and is followed by photocatalytic decomposition of the organic cation. Electrochemical It is a method allowing the achievement of very satisfying results. As a result of the decomposition with electrolysis, a complete decomposition occurs almost immediately and its products the use of BBD are harmless and easily biodegradable. An expensive diamond electrode with a relatively short life span with the admixture of boron (BBD) was successfully replaced by a lead anode (PbO2), what made this method more cost-efficient.

potential recipients of those substances, which can be released in the form of post-industrial water (sewage) or as a result of an accidental spillage. For this reason, it is important to learn the ways of their spreading, potential bioaccumulation and environmental fate in the most endangered environmental compartments. In the case of soils and sediments, the mobility and retention of ionic liquids is connected not only with the chemical structure and properties of the compound but also to the matrix characteristics. Sorption on the soil molecules and sediments in the case of imidazole ILs is determined by electrostatic interactions. Another factor influencing this phenomena is the hydrophobicity of the molecules of the liquid, which in turn is determined by the length of the alkyl chain. Liquids with a long alkyl chain (more hydrophobic) will bind more strongly with the matrix and the mobility of those with short chains (hydrophilic) will be high, which can result in a migration of such liquids to groundwater and its contamination. When it comes to the type of the matrix, it turns out that the retention on loose sea sediments and in various types of clay soils is significantly higher than that of peat soil.

Deep eutectic solvents Apart from many assets of ionic liquids, they are expensive and their preparation is often very difficult. What is more, many of them show a high toxicity level. That is why, it was necessary to find alternative solvents, which would combine the universality of ionic liquids with the principles of Green Chemistry and lower costs. The number of solvents which comply with these strict requirements seems to be limited, but deep eutectic solvents (one of variations of ionic liquids), are a relatively new

Siedlecka et al. 2013 Zhou et al. 2013

Pham et al. 2010

Cvjetko Bubalo et al. 2014 Cvjetko Bubalo et al. 2014; Siedlecka et al. 2013

discovery. In recent years, it has been disputable if deep eutectic solvents belong to ILs because, apart from ions, they include neutral molecules. A deep eutectic solvent (DES) consists of a few (usually two or three) ingredients. Those ingredients create an eutectic mixture of a melting temperature lower than the melting temperature of each of them, which is a result of the creation of intermolecular hydrogen bonds. An example of a simple eutectic mixture is the combination of two solids: urea (Tm = 133 °C) and choline chloride (Tm =302 °C) in the molar ratio of 2:1. As a result, a liquid mixture is obtained of a melting temperature of 15 °C (Gałuszka et al. 2013). Choline chloride is a quaternary ammonium salt—safe, cheap and of low toxicity. It is a widely used component of deep eutectic solvents; it is usually combined with compounds capable of creating hydrogen bonds (e.g. amides, acids and alcohols). Types of deep eutectic solvents Table 5 contains selected information on the possible combinations of compounds creating deep eutectic solvents (Gałuszka et al. 2013; Luo et al. 2010). Typical compounds being the donors of hydrogen bonds are carboxyl acids, amides, alcohols and hydrocarbons. From the technological point of view, the mixtures of choline chloride and compounds being the donors of hydrogen bonds are very important as they have similar physicochemical properties to toxic, but more widely used, ionic liquids (Abbott et al. 2006). Basic physicochemical properties of deep eutectic solvents Deep eutectic solvents show similar physicochemical properties to ionic liquids, but they are much cheaper and safer to the

Environ Sci Pollut Res Table 5

Types of deep eutectic solvents

Type

Description

Example

Type 1 Type 2 Type 3

Combination of metal and organic salts—MClx·R1R2R3R4+X− A hydrate of metal salt and organic salt MClx·yH2O·R1R2R3R4+X− A compound being the donor of a hydrogen compound and organic salt R5Z·R1R2R3R4+X−, where Z=–OH, –COOH, –CONH2 Combination of metal chloride with a compound being the donor of a hydrogen bond

ZnCl2 +choline chloride CoCl2·6H2O+choline chloride Choline chloride+urea

Type 4

MClx +urea/ethylene glycol/ acetamide

The information was adapted from E. Smith et al. 2014 and B. Tang et al. 2013 and Abbott et al. 2007

environment. Their toxicity is usually very low as they are made of compounds naturally occurring in the environment. Their basic physicochemical properties are shown in Table 6 (Pena-Pereira and Namieśnik 2014).

Natural deep eutectic solvents Recently, natural compounds such as amino acids, organic acids, sugars, choline and urea have been attracting a lot of interest. They constitute a very versatile group of substances for the production of new ionic and eutectic liquids. They are very promising as, apart from their great chemical diversity, they are easily biodegradable and their low toxicity allows for their application in the pharmaceutic industry. Theories on the occurrence of ionic and eutectic solvents in tissues of living organisms are very interesting. They would explain the occurrence of such a great number of chemical reactions in cells, which seems to be unbelievable taking into account the presence of only two types of solvents—water and generally understood lipids. ILs and DES could gather, dissolve and transport water-insoluble metabolites. The number of combinations of substances which can create eutectic mixtures is very high. Various types of sugars and organic acids may create liquids, for example, maleic acid with citric acid or glucose with sorbitol and maleic acid. Many of those combinations may be also observed in plants. The analyses of the nectar composition have shown that it consists of sugars which are solid in the room temperature when separated, but when combined, they occur in a liquid form. It is so in the case of honey. Natural deep eutectic solvents (NADES) probably occur also in organisms living in difficult conditions, especially those which must survive long droughts and frosts. As an example, one can mention the desert plant of the Selaginella species, microorganisms such as lichens and plants resistant to low temperatures for which sugars, alcohols and prolines constitute a safety barrier (Dai et al. 2013). In Table 6, their basic properties are given. NADES have very promising properties in regard to their future application in such branches as the food industry or pharmaceuticals’ manufacturing. A point in case is the use

of solvents for the stabilisation of, for example, herbal dyes, such as carthamin, which can be found in the flowers of safflower. The extract from the flowers of this plant is widely used as a natural dye, a food and cosmetics additive and in natural medicine to cure coronary diseases. Carthamin is a phenolic dye, very unstable and sensitive to the influence of external factors. Studies conducted on the stability of this compound in NADES (GCH—glucose combined with choline chloride, PMG—proline combined with maleic acid and others) have shown their significant increase in various conditions, such as an increase in the temperature and light, in comparison to the stability of conventional solvents (e.g. water, ethanol). The capability of stabilising dyes probably results from the creation of hydrogen bonds between the molecules of the solvent and the dissolved substance (Abbott et al. 2006).

Revision of chosen deep eutectic mixtures and their usage As DESs are the cheaper substitutes of ILs having similar properties, they are used in applications similar to ILs. They are used more frequently in the processing of metals, in electrochemistry, in the glycerol extraction from biodiesel and as catalysts and reaction media. Below selected applications of deep eutectic solvents are enumerated: Biodiesel production 1. A deep eutectic solvent created on the basis of N,Ndiethyl ethanol ammonium chloride (DEAC) combined with PTSA in the molar ratio 1:3. 2. The mixture created was successfully used as a catalyst in transesterification of free fatty acids in the production of biodiesel (Hayyan et al. 2013a). 3. The mixture of choline chloride with glycerol prepared at the molar ratio of 1:2 was used as a solvent in enzymatically catalysed reaction of biodiesel production from the soybeans. The main advantages of this method are the high level (88 %) of triglycerides

All studied NADES have shown a density greater than that of water.

In the majority of cases, the density is higher than that of water. Deep eutectic solvents usually have greater density than the density of the substance being the donor of the hydrogen bond. Eutectic mixtures have a higher density which may be a result of an occurrence of a strong hydrogen bond between molecules. van der Waal’s interactions and electrostatic interaction have a great impact on the density. Density

conversion, non-toxicity and a low cost of the solvent used as well as its biocompatibility with the lipase enzyme (Zhao et al. 2013). Electrochemistry

Eutectic mixtures on the basis of organic acids are the most polar; second to them are only the mixtures on the basis of amino acids. The mixtures on the basis of sugars and polyalcohol are the least polar (Dai et al. 2013).

The conductivity is strictly related to the viscosity of the given system, and it increases with the increase of the salt content in the system. The majority of eutectic mixtures may be compared to ionic liquids in this regard.

Physicochemical properties to a large extent depend on the structure of a given liquid. Among 100 NADES tested, the majority have shown sustainability in high temperatures (over 200 °C), and only those which had sugar in their structure, decomposed in a temperature of about 135 °C. Those liquids have maintained their properties also in low temperatures, what proves the hypothesis that they are one of the mechanisms which protect an organism from cold.

Conductivity

Thermal stability

4. The mixture of choline chloride and malonic acid at the molar ratio of 1:1 used for residue removal after etching of copper plates (Taubert et al. 2013). 5. Choline chloride with ethylene glycol used as an electrolyte in the process of electrodeposition of nickel and cobalt alloys (You et al. 2012). Absorption and solubility of carbon dioxide

Polarity

Viscosity

It depends mainly on the percentage of water and the temperature. It has been shown on the example of a mixture composed of glucose, choline chloride and water that it decreases as they increase.

Natural deep eutectic solvents Deep eutectic solvents Physicochemical properties

Table 6

Selected properties of deep eutectic solvents and natural ones

Environ Sci Pollut Res

6. A deep eutectic solvent containing choline chloride and ethylene glycol has been studied in regard to the absorption of carbon dioxide (Leron and Li 2013). Similar studies on the CO2 absorption by deep eutectic solvents have been conducted with the use of various mixtures. Three basic salts were used, that is, choline chloride, DEAC and methyltriphenylphosphonium bromide. As the compounds being the donors of hydrogen bonds (HBDs)—glycerol, ethylene glycol, triethylene glycol, 2,2,2-trifluoroacetamide and 1,4butanediol were chosen. On the basis of the results of the studies, it can be concluded that the solubility of carbon dioxide depends on various factors, such as the type of salts and HBDs used, the molar ratio of both DES ingredients, the temperature and pressure (Ali et al. 2014; Caparanga et al. 2013). 7. As a result of combining tetrabutylphosphonium bromide and propylene glycol with sulfolane, two deep eutectic solvents were obtained, which are potential extracting agents that could be used to separate the mixture of toluene and heptane. The studies have proved the usability of those solvents to the industrial extraction of aromatic hydrocarbons from, for example, petroleum (Kareem et al. 2012). Medical and pharmaceutic usage 8. The solubility of chosen soluble chemical compounds in DES on the basis of choline chloride with malonic acid (case 1) or urea (case 2) has been tested. The compounds studied were benzoic acid, danazol, griseofulvin, itraconazole and the AMG517 medicine, which is in the phase of clinical trials. In each case, the solubility of DES was higher by several or several dozen times—in comparison to water. Taking into consideration the capability of dissolving sparingly soluble compounds and low toxicity, they have a great potential to be used in medicine and the pharmaceutical industry (Morrison et al. 2009). 9. A very interesting and promising medical usage of DES is a transdermal drug delivery system. This

Environ Sci Pollut Res

way of taking medicines is becoming popular; however, the skin barrier, which the drug must penetrate, poses an obstacle. It has been shown that medicines in solid form, transformed into highly concentrated mixtures that have a liquid form at room temperature, show a significantly higher capability of penetration through skin because of their high thermodynamic activity. Examples of these types of drugs are eutectic mixtures of ibuprofen, which is a popular analgesic, terpenes and the mixture of propanol and fatty acids (Karande and Mitragotri 2009). Chemical synthesis 10. Eutectic mixtures based on the aforementioned choline chloride with urea have many applications. Among them, there are processes of production of ionic thermal materials, chemical permeation of CO2 and transesterification of lipases catalysed by an enzyme. They have also been successfully used in the process of the synthesis of fluorescent dyes made on the cyanocoumarin basis, where they played the role of a catalyst and a solvent. The dyes obtained showed very good photoluminescent properties (Phadtare et al. 2013). 11. Deep eutectic solvents prove to be effective as reaction media in chemical syntheses. Another example is a newly developed method of oxazole compounds synthesis. The eutectic mixture was prepared from choline chloride and urea. The reaction was supported by ultrasounds which resulted in an efficiency higher when compared to the thermal method. Additional assets are significant energy savings (over 85 %) and the fact that the eutectic mixture used showed a great resistance to ultrasounds, which allowed for their repeated use. The reaction scheme and the proposed mechanism of DES are shown in Fig. 7a, b. (Singh et al. 2013). Activation of enzymes and biocatalysis 12. The capability to activate and stabilise lipase by eutectic solvents (based on choline chloride and acetate) has been studied. The results obtained have shown that, in comparison to the reference values, the activity of this enzyme has increased by 2.4–18.4 times in the DEP studied. It gives promising perspectives for application of those solvents, especially in enzyme catalysed processes (e.g. in the production of biodiesel) (Huang et al. 2014). 13. Durand et al. (2012) proved that strict conditions are necessary to promote biocatalysis in DESs media and that not all eutectic mixtures can be used as efficient media for lipase-catalysed reactions (a preliminary grinding was crucial in order to get an

14.

15.

16.

17.

efficient reaction kinetics and some DESs can react and compete with the substrates in the reactions of alcoholysis leading to DES destruction). Also, in case of dicarboxylic acids based DESs, the viscosity increases significantly with side reactions taking place, which makes stirring and recycling difficult. The choline chloride:ethanediol (ET), choline chloride:glycerol (GLY) and choline chloride:urea (REL) DESs were utilised by Lindberg et al. (2010) in the reaction mixtures with epoxide and the potato epoxide hydrolase StEH1 to study elevations of KM (up to 20-fold) and turnover numbers. The regioselectivity in hydrolysis of the (1R,2R)-2trans-methylstyrene oxide was also altered. The DES solutions dissolved 1.5-fold higher epoxide concentrations as compared to phosphate buffer. To assess the activity of DES proteases, a mixture of choline chloride and glycerol in the molar ratio 1:2 was used. The enzyme was immobilised on chitosan. Thanks to the use of deep eutectic solvents, a high activity of proteases was achieved as well as its high selectivity (98 %) in the transesterification of 1-propanole with an Nacetyl-L-phenylalanine ethyl ester. Those results are very optimistic and encouraging to look for new applications of DEP in the processes of biotransformation (Zhao et al. 2011). The activity, stability and chemical structure of horseradish peroxidase (HRP) were studied in DEP created on the basis of choline chloride and choline acetate. Those salts were combined by four different HBD compounds (urea, glycerol, acetamide and ethylene glycol) in various molar ratios. It turned out that the concentration of salt had the biggest influence on the enzymatic activity. The activity increased with the increase of the salt content in DEP, and what is more, each mixture had an excellent capability of peroxidase stabilisation. The results of these studies are extremely important in regard to the industrial waste water purification from phenol compounds as the peroxidase enzyme is widely used in the process of their removal. The eutectic mixtures on the basis of chloride and choline acetate may be extremely useful in increasing the efficiency of the purification (Wu et al. 2014). Highly efficient lipase‐catalysed alcoholysis reactions for a wide range of lipophilic derivative compounds of phenolic acids were studied by Durand et al. 2014. The authors recommend ratios as iCALB‐catalysed reactions of methyl ferulate and methyl p‐coumarate in the ternary mixture ChCl:water:urea were, respectively, 1:2:2 and

Environ Sci Pollut Res Fig. 7 a The scheme of a synthesis reaction between an oxazole compound and phenacyl bromide (1) and amino derivative (2) in the presence of DEP and ultrasounds. A similar reaction with the use of the thermal method has been conducted for comparison. b The proposed mechanism of the reaction explaining the role of DEP

A

R

B

O

NUS METHOD

Br

+ R

O NH2

R1

N R1

Deep eutectic solvent, 65 C deg

O

US METHOD Deep eutectic solvent Ultrasound, RT

Where R=-H, -Br, -NO2 R1=-NHPh, -CH2CN, -PhNO2

R

H

C H3C

CH3 + CH 3 N

N H

O

O

N H

Br

H

Cl

H

O

OH H

N

N

H

H

H

(-HBr)

R1

N

R

O O

R H O

CH2

N R1

+

O

(-H2O) H

N

O N

R1

R1

R O

OH

H

N R1

1:1.5:2, and the catalysis should be realised in a molar ratio 1:6 between substrate and alcohol. In this way, numerous lipophilic derivatives of ferulic and coumaric acid could be synthesised. 18. Gorke et al. (2008) used the lipase-catalysed transesterification of ethyl valerate with 1-butanol and showed conversions comparable to that in toluene for five of the 8 DESs tested. 19. Singh and Lobo (2011) used DES for studies on selective N-alkylation of aromatic amines offering new solutions in recycling processes of amines. Other applications 20. A mixture of p-toluenesulfonic acid (PTSA) with quaternary ammonium salts, which create a strong Brönsted acid. Examples of ammonium salts are

R

O

shown in Fig. 8a. Deep eutectic solvents created by mixing PTSA with the aforementioned quaternary ammonium salts in an appropriate molar ratio were used as a reaction medium for the esterification of carboxyl acids with alcohols (De Santi et al. 2012). 21. A mixture of choline chloride and oxalic acid in the molar ratio 1:2 (ChCl:Ox) was used as a solvent to determine the content of copper, iron and zinc in tissues of fish. A newly developed method has proved to be highly efficient, and its main advantages are the simplicity of the analytical procedure, low cost of reagents and possibility of quick preparation of samples prior to analysis (Habibi et al. 2013). 22. Deep eutectic solvents are also used in many biotransformation processes, including the reaction

Environ Sci Pollut Res Fig. 8 Quaternary ammonium salts used for DES preparation (De Santi et al. 2012) and the structure of ions constituting deep eutectic solvents studied (Hayyan et al. 2013a, b, c)

A

B Br

O O O

O

O

+

P

Gl

O MTPB

catalysed with lipase enzymes (transesterification, aminolysis, polymerisation with the opening of lactones’ rings, epoxidation). In the majority of cases, those reactions occurred with higher efficiency than while using traditional organic solvents (Dominguez de Maria and Maugeri 2011). 23. The deep eutectic solvents on the basis of choline chloride were used in research on the catalyst properties of complex compounds of ruthenium in the isomerization of secondary alcohols to their carboxyl derivatives (Vidal et al. 2014).

Toxicity of deep eutectic solvents As it has been mentioned before, because of the natural origin of the majority of components and low harmfulness, deep eutectic solvents are usually non-toxic. However, taking into account their potential application in the pharmaceutical industry and in the food production, Radošević et al. 2015; Hayyan et al. 2015 and Wen et al. 2015 conducted studies to assess the risk connected with the use of this kind of solvents as they are not well understood yet. What deserves special attention is the synergy effect between DES ingredients, which results in a greater toxicity of the mixture than the toxicity of each of its ingredients separately (Hayyan et al. 2013b; Paiva et al. 2014).

EG

O

O

O

TEG

The toxicity of DEP based on choline chloride and four compounds being the donors of hydrogen bonds to bacteria has not been proven. No inhibitory effect on the development of Escherichia coli, Bacillus subtilis, Staphylococcus aureus and Pseudomonas aeruginosa has been observed. On the other hand, the ionic liquids tested have shown some cytotoxicity to the Artemia salina aquatic organisms. Each time, it was higher for the mixture than for each of its ingredients by themselves (Hayyan et al. 2013b). In another scientific work, the toxicity and cytotoxicity of phosphonium (on the basis of MTPB) deep eutectic solvents to the bacteria and larvae of Artemia salina were studied. Once again, the aquatic organism proved to be vulnerable to the activity of DES and the toxicity of the mixture was much higher than those of its ingredients considered separately, which indicates the occurrence of a synergy/additivity effect. Nevertheless, the mortality of larvae could be an effect of other factors, such as low oxygen availability or high viscosity of liquids tested, making the organisms immobilised. In addition, in contrast to choline chloride-based DES, those on the basis of MTPB have shown an inhibitory effect on the development of the bacteria tested. It makes those mixtures potential candidates for the production of antibacterial products (Hayyan et al. 2013c). Structures of the ionic liquids prepared on the basis of MTPB described in this study are shown in Fig. 8b.

Environ Sci Pollut Res

Another example of studies on the toxicity of eutectic solvents are tests conducted on an aquatic invertebrate—Hydra sinensis. Those organisms are highly vulnerable to chemical pollution. After exposure, they are subject to major morphological changes. The DES tested was a combination of choline chloride with urea. Polyps were exposed to the mixture and to each of its ingredients separately. The combination of ingredients into a deep eutectic solvent proved to be less toxic than the activity of each ingredient separately or choline chloride and urea mixed physically (Huang et al. 2014).

Summary Solvents are undoubtedly substances indispensable in industry or an experimental branch of natural science. The technology of their production has evolved over the years, and its latest achievements are ionic liquids of 3rd generation and deep eutectic solvents. Each of these groups has great advantages over classical organic solvents, which usually are far from compliance with the requirements of Green Chemistry. Main disadvantages of ILs are the difficulties in their preparation, high costs and significant toxicity, while the use of DES has been limited mainly to organic reactions and extractions, electrochemistry and enzymatic reactions, which constitute only a small percentage of the universality of ILs. What is more, studies are constantly conducted in order to learn as much as possible about the properties of both types of solvents and their fate. This can be proved by the enormous amount of publications of research centres from all over the world. New possibilities of applications are sought, including solutions for branches important for the quality of life such as drug production and medicine. In the majority of cases, the lack of sufficient knowledge on possible side effects and mechanisms which have an effect on their occurrence pose an obstacle. Stating that those kinds of substances are the ideal solvents would be too much; however, their rational use may bring many benefits. Apart from many imperfections, ILs and DES are the most promising discoveries of recent years in the area of Green Chemistry. Future trends in development and studies on ILs and DES must be focused on: – – – –

Synthesising less harmful substances based on non-toxic substrates Determining basic toxicological parameters for standardised biotests of different trophic levels Assessing interactions with co-present pollutants (e.g. based on work of Biczak et al. 2014 or Ge et al. 2014) Determining toxicity for standard cell lines to systemize knowledge, modes of action and applicability in medicine and pharmacy



Degradation techniques to selectively remove/decompose these substances with enzymatic/oxidation methods in diluted sewage waters

Acknowledgments The work has been co-financed by the Polish Ministry of Science and Higher Education grant no. IP2011 028071.

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Selected issues related to the toxicity of ionic liquids and deep eutectic solvents--a review.

Green Chemistry plays a more and more important role in implementing rules of sustainable development to prevent environmental pollution caused by tec...
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