NON-IONIC DEEP EUTECTIC MIXTURES FOR USE AS SOLVENTS AND DISPERSANTS

Abstract

Use of a non-ionic deep eutectic mixture consisting of A and B, A being R1R2NCONR3R4 and B being selected from the group consisting of R5R6NCOCH3 and R7R8NCONR9R10, and wherein each of R1-R10 is independently H, CH3 or alkyl, as a solvent or dispersant in chemical synthesis, material synthesis or fabrication, chemical or enzymatic catalysis, food, cosmetic or pharmaceutical formulation, separation or partitioning, heat transfer, and as detergents or cleaners, as well as such mixtures, is disclosed.

Claims

1. A method comprising using a non-ionic deep eutectic mixture consisting of A and B, A being R.sup.1R.sup.2NCONR.sup.3R.sup.4 and B being selected from the group consisting of R.sup.5R.sup.6NCOCH.sub.3 and R.sup.7R.sup.8NCONR.sup.9R.sup.10, and wherein each of R.sup.1-R.sup.10 is independently H, CH3 or alkyl, as a solvent or dispersant in chemical synthesis, material synthesis or fabrication, chemical or enzymatic catalysis, food, cosmetic or pharmaceutical formulation, separation or partitioning, heat transfer, and as detergents or cleaners.

2. The method according to claim 1, wherein B is R.sup.5R.sup.6NCOCH.sub.3, wherein R.sup.1 and R.sup.5 are CH.sub.3 or alkyl, R.sup.2, R.sup.4, and R.sup.6 are H, and R.sup.3 is H or CH.sub.3 or alkyl.

3. The method according to claim 1, wherein B is R.sup.7R.sup.8NCONR.sup.9R.sup.10, wherein R.sup.1 and R.sup.2 is H or CH.sub.3 or alkyl, R.sub.3 and R.sub.4 is H, R.sup.7 is CH.sub.3 or alkyl, R.sup.10 is H, and R.sup.8 and R.sup.9 is H or CH.sub.3 or alkyl.

4. The method according to claim 1, wherein the mixture contains 30-80% by weight of A and 70-20% by weight of B.

5. The method according to claim 1, wherein the melting point of the mixture is 8-99 C., such as 8-71 C., such as 12-46 C.

6. The method according to claim 1, wherein R.sup.1 is CH.sub.3, R.sup.2 and R.sup.4 is H and R.sup.3 is H or CH.sub.3.

7. The method according to claim 6, wherein B is R.sup.5R.sup.6NCOCH.sub.3, R.sup.6 is H, and R.sup.5 is CH.sub.3 or H, preferably CH.sub.3.

8. The method according to claim 7, wherein the mixture contains 70-80% by weight of A and 30-20% by weight of B.

9. The method according to claim 6, wherein B is R.sup.7R.sup.8NCONR.sup.9R.sup.10, R.sup.7 and R.sup.9 is CH.sub.3, and wherein preferably R.sup.8 and R.sup.10 is H.

10. The method according to claim 1, wherein the mixture consists of urea and acetamide.

11. A non-ionic deep eutectic mixture consisting of A and B, A being R.sup.1R.sup.2NCONR.sup.3R.sup.4 and B being selected from the group consisting of R.sup.5R.sup.6NCOCH.sub.3 and R.sup.7R.sup.8NCONR.sup.9R.sup.10, and wherein each of R.sup.1-R.sup.10 is independently H, CH3 or alkyl, with the provisio that the non-ionic deep eutectic mixture does not comprise a mixture of urea and acetamide.

12. The non-ionic deep eutectic mixture according to claim 11, wherein B is R.sup.5R.sup.6NCOCH.sub.3, wherein R.sup.1 and R.sup.5 are CH.sub.3 or alkyl, R.sup.2, R.sup.4, and R.sup.6 are H, and R.sup.3 is H or CH.sub.3 or alkyl.

13. The non-ionic deep eutectic mixture according to claim 11, wherein B is R.sup.7R.sup.8NCONR.sup.9R.sup.10, wherein R.sup.1 and R.sup.2 is H or CH.sub.3 or alkyl, R.sub.3 and R.sub.4 is H, R.sup.7 is CH.sub.3 or alkyl, R.sup.10 is H, and R.sup.8 and R.sup.9 is H or CH.sub.3 or alkyl.

14. The non-ionic deep eutectic mixture according to claim 11, wherein the mixture contains 30-80% by weight of A and 70-20% by weight of B, and/or wherein the melting point of the mixture is 8-99 C., such as 8-71 C., such as 12-46 C.

15. The non-ionic deep eutectic mixture according to claim 11, wherein R.sup.1 is CH.sub.3, R.sup.2 and R.sup.4 is H and R.sup.3 is H or CH.sub.3.

16. The non-ionic deep eutectic mixture according to claim 15, wherein B is R.sup.5R.sup.6NCOCH.sub.3, R.sup.6 is H, and R.sup.5 is CH.sub.3 or H, preferably CH.sub.3.

17. The non-ionic deep eutectic mixture according to claim 16, wherein the mixture contains 70-80% by weight of A and 30-20% by weight of B.

18. The non-ionic deep eutectic mixture according to claim 15, wherein B is R.sup.7R.sup.8NCONR.sup.9R.sup.10, R.sup.7 and R.sup.9 is CH.sub.3, and wherein preferably R.sup.8 and R.sup.10 is H.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0011] A more complete understanding of the abovementioned and other features and advantages of the present invention will be apparent from the following detailed description of preferred embodiments in conjunction with the appended drawings, wherein:

[0012] FIG. 1 shows surface topography mapped using scanning electron microscopy (SEM) for the MIP film coated on Au/quartz electrosynthesized in binary eutectic solvent, and

[0013] FIG. 2 shows variation in the resonant frequency of the Au-coated quartz resonator coated with biotin imprinted polymer film prepared in binary eutectic solvent upon injection of the biotin methyl ester under flow injection analysis conditions.

DETAILED DESCRIPTION

[0014] As the mechanism underlying the urea-acetamide deep eutectic solvent had not previously been elucidated, the present inventors used a combination of molecular modeling studies of the behavior of urea-acetamide mixtures 35:65 at over 343 K over 30 ns and statistical analysesradial distribution studies and assessments of life times of hydrogen bonds present over the time frame. The results of these studies are presented in table 1 below:

TABLE-US-00001 TABLE 1 Sum of all averaged hydrogen bond occupancies for non-ionic eutectic mixture components AAM.sup. URA.sup. AAM 40,309 65,832 URA 50,939 # Values presented were calculated through summation of all hydrogen bond occupancies presented in the simulated system. AAM = acetamide, URA = urea

[0015] Statistical analysis of the molecular dynamics simulation data revealed that at the relative stoichiometry, 1:2 urea:acetamide, corresponding to that at the eutectic point, the interactions between urea and acetamide were more frequent than those between molecules of the same type. This unique insight allowed the identification of a mechanism to increase the favorability of these complexes relative to interactions between complexes, in particular selectively limiting the number hydrogen bonding sites in the participating species. This led to the design of other systems where acetamide, or acetamide derivatives, combined with urea, or urea derivatives, and urea (or derivatives) combined with urea derivatives could be predicted to have non-ionic deep eutectic behavior, see Table 2 for examples.

TABLE-US-00002 TABLE 2 Non-ionic deep eutectic mixtures comprised of components A and B where the general structures of A is R.sup.1R.sup.2NCONR.sup.3R.sup.4 and that of B is either R.sup.5R.sup.6NCOCH.sub.3 or R.sup.7R.sup.8NCONR.sup.9R.sup.10 mp Example R.sup.1 R.sup.2 R.sup.3 R.sup.4 R.sup.5 R.sup.6 R.sup.7 R.sup.8 R.sup.9 R.sup.10 C. A:B 3 i H H H H H H 56 2 35:65 ii H H H H CH.sub.3 H H H 61 2 30:70 iii H H H H CH.sub.3 H CH.sub.3 H 69 3 30:70 iv H H H H CH.sub.3 CH.sub.3 H H 97 2 70:30 v CH.sub.3 H H H H H 42 3 50:50 vi CH.sub.3 H H H CH.sub.3 H 14 2 80:20 vii CH.sub.3 H H H CH.sub.3 CH.sub.3 H H 76 4 80:20 viii CH.sub.3 H H H CH.sub.3 H CH.sub.3 H 49 3 50:50 ix CH.sub.3 CH.sub.3 H H H H 68 3 80:20 x CH.sub.3 CH.sub.3 H H CH.sub.3 H CH.sub.3 H 84 4 80:20 xi CH.sub.3 H CH.sub.3 H H H 43 3 50:50 xii CH.sub.3 H CH.sub.3 H CH.sub.3 H 12 4 70:30

[0016] Studies of the phase behaviour of this range of systems confirmed the discovery.

[0017] Accordingly a group of non-ionic deep eutectic mixtures comprising a mixture of A and B, where A is R.sup.1R.sup.2NCONR.sup.3R.sup.4 and that of B is either R.sup.5R.sup.6NCOCH.sub.3 or R.sup.7R.sup.8NCONR.sup.9R.sup.10, and where each of R.sup.1-R.sup.10 is H, CH3 or alkyl, has been found. As will be seen in the examples section further below these mixtures can be used instead of other known solvents in various applications with advantageous effects.

[0018] Thus, the first aspect of the present invention concerns use of a non-ionic deep eutectic mixture consisting of A and B, A being R.sup.1R.sup.2NCONR.sup.3R.sup.4 and B being selected from the group consisting of R.sup.5R.sup.6NCOCH.sub.3 and R.sup.7R.sup.8NCONR.sup.9R.sup.10, and wherein each of R.sup.1-R.sup.10 is independently H, CH3 or alkyl, as a solvent or dispersant in chemical synthesis, material synthesis or fabrication, chemical or enzymatic catalysis, food, cosmetic or pharmaceutical formulation, separation or partitioning, heat transfer, and as detergents or cleaners.

[0019] Correspondingly, the second aspect of the present invention concerns a non-ionic deep eutectic mixture consisting of A and B, A being R.sup.1R.sup.2NCONR.sup.3R.sup.4 and B being selected from the group consisting of R.sup.5R.sup.6NCOCH.sub.3 and R.sup.7R.sup.8NCONR.sup.9R.sup.10, and wherein each of R.sup.1-R.sup.10 is independently H, CH3 or alkyl, with the provisio that the non-ionic deep eutectic mixture does not comprise a mixture of urea and acetamide.

[0020] In certain embodiments of the use according to the first aspect of the present invention the non-ionic deep eutectic mixture is used as a solvent or dispersant in chemical synthesis, material synthesis or fabrication, or chemical or enzymatic catalysis.

[0021] For these applications the mixture may be N-methyl acetamide:N-methyl urea, 80:20, urea:acetamide, 1:2, or N-methyl urea:N,N-dimethyl urea, 1:1, the ratios being molar ratios or by weight, the ratios preferably being molar ratios.

[0022] A mixture comprising N-Methyl urea (NU) and N-Methyl Acetamide (NUA) may for example be used for both solution and solid phase peptide synthesis instead of the conventional solvents N,N-dimethylformamide or dichloromethane.

[0023] In certain embodiments of the use according to the first aspect of the present invention the non-ionic deep eutectic mixture is used as a solvent or dispersant in food, cosmetic or pharmaceutical formulation.

[0024] In certain embodiments of the use according to the first aspect of the present invention the non-ionic deep eutectic mixture is used as a solvent or dispersant in separation or partitioning.

[0025] For these applications the mixture may be urea:acetamide 1:2 or N-methylurea:N-methylacetamide, 20:80, the ratios being molar ratios or by weight, the ratios preferably being molar ratios.

[0026] In certain embodiments of the use according to the first aspect of the present invention the non-ionic deep eutectic mixture is used as a solvent or dispersant in heat transfer i.e. as a heat transfer medium.

[0027] For these applications the mixture may be urea:acetamide, 1:2, the ratio being molar ratio or by weight, the ratio preferably being molar ratio.

[0028] In certain embodiments of the use according to the first aspect of the present invention the non-ionic deep eutectic mixture is used as a solvent or dispersant in detergents or cleaners.

[0029] In preferred embodiments of the non-ionic deep eutectic mixture according to the second aspect of the present invention the mixture does not comprise a 1:2 (molar ratio) mixture of urea and acetamide, preferably the mixture does not comprise a mixture of urea and acetamide, more preferably the mixture does not contain urea or acetamide, even more preferably the mixture does not comprise urea and acetamide.

[0030] Here a 1:2 mixture of urea and acetamide is to be understood to also encompass a mixture of 33 mole percent urea67 mole percent acetamide.

[0031] In the context of the present invention the ratios and percentages given are molar ratios and mole percent if not otherwise specified. However, as the molecular masses of the components of the mixtures are similar, the ratios and percentages may alternatively be by weight.

[0032] Thus the mixture preferably does not comprise a 1:2 (by weight) mixture of urea and acetamide.

[0033] In the context of the present invention alkyl as a group or part of a group means a straight chain or, where available, a branched chain alkyl moiety. For example, it may represent a C1-4 alkyl.

[0034] In preferred embodiments of the use and non-ionic deep eutectic mixture according to the first and second aspects of the present invention B is R.sup.5R.sup.6NCOCH.sub.3, wherein R and R.sup.5 are CH.sub.3 or alkyl, R.sup.2, R.sup.4, and R.sup.6 are H, and R.sup.3 is H or CH.sub.3 or alkyl.

[0035] This provides generally lower melting points allowing the mixtures to be used in reactions or applications requiring lower temperatures.

[0036] In alternative embodiments of the use and non-ionic deep eutectic mixture according to the first and second aspects of the present invention B is R.sup.5R.sup.6NCOCH.sub.3, wherein R and R.sup.5 are CH.sub.3 or alkyl, R.sup.2, R.sup.4, and R.sup.6 are H, and R.sup.3 is H or CH.sub.3 or alkyl.

[0037] This provides mixtures with generally higher melting points, which may be useful for applications or reactions requiring higher temperatures.

[0038] In preferred embodiments of the use and non-ionic deep eutectic mixture according to the first and second aspects of the present invention the mixture contains 30-80% by weight of A and 70-20% by weight of B. The sum of the percentages of A and B should be 100%. In other words the percentages by weight are percentages of the total weight of A and B in the mixture.

[0039] More preferably the mixture may in some embodiments comprise 70-80% by weight of A (and thus 30-20% by weight of B). In other embodiments the mixture comprises 30-70% by weight of A (and thus 70 to 30% by weight of B).

[0040] As A and B have similar molar masses the ratio between them may alternatively be expressed by mole percent.

[0041] Thus the mixture may contain 30-80 mole percent of A and 70-20 mole percent of B. As above the sum of the percentages of A and B should be 100%. In other words the mole percentages are percentages of the total amount of moles of A and B in the mixture.

[0042] More preferably the mixture may in some embodiments comprise 70-80 mole percent of A (and thus 30-20 mole percent of B). In other embodiments the mixture comprises 30-70 mole percent of A (and thus 70-30 mole percent of B).

[0043] Preferably the mixture consists of A and B.

[0044] In certain embodiments of the use and non-ionic deep eutectic mixture according to the first and second aspects of the present invention the melting point of the mixture is 8-99 C., such as 8-71 C., such as 12-46 C.

[0045] In preferred embodiments of the use and non-ionic deep eutectic mixture according to the first and second aspects of the present invention R is CH.sub.3, R.sup.2 and R.sup.4 is H and R.sup.3 is H or CH.sub.3. This provides mixtures with lower melting points. In these embodiments B is preferably R.sup.5R.sup.6NCOCH.sub.3, R.sup.6 is H, and R.sup.5 is CH.sub.3 or H, preferably CH.sub.3. This also provides mixtures with lower melting points, especially if R.sup.5 is CH.sub.3. In these embodiments the mixture preferably contains 70-80% by weight of A and 30-20% by weight of B. Alternatively in these embodiments B is R.sup.7R.sup.8NCONR.sup.9R.sup.10, R.sup.7 and R.sup.9 is CH.sub.3, and preferably R.sup.8 and R.sup.10 is H.

[0046] In certain embodiments of the use according to the first aspect of the present invention the non-ionic deep eutectic mixture comprises, contains, or consists of, urea and acetamide. Preferably the mixture comprises or contains 20-40 mole percent (or % by weight) of urea and 80-60 mole percent (or % by weight) of acetamide. More preferably the mixture comprises or contains a 1:2 (molar ratio, corresponding to 33 mole percent urea and 67 mole percent acetamide) mixture of urea and acetamide.

[0047] Following is a series of studies demonstrating the utility of these non-ionic deep eutectic mixtures as solvents or dispersants in various applications.

Examples

A. As Alternative to Conventional Solvents in Polymer Synthesis

[0048] Example 1: Cross-linked polymer monoliths are synthesized in the non-ionic eutectic mixture (N-methyl acetamide:N-methyl urea, 80:20 ratio by weight) described using functional monomers such as methacrylic acid (MAA) or hydroxyethylmethacrylate (HEMA) together with a cross-linking monomers, e.g. ethylene glycol dimethylacrylate (EGDMA), divinylbenzene and 1,4-bis(acryloyl)piperazine (BAP). Polymers were synthesized under thermally initiated conditions with 2,2-azobis(2-methylpropionitrile) (AIBN) as initiator. These polymers with same Functional Monomers (EMs) and Crosslinking monomers (CLs) were also prepared in conventional solvents, in this case water, acetonitrile and toluene, to serve as control. Effects of composition of the non-ionic deep eutectic mixture in the polymerization medium on the polymer textures and structures of the synthesized polymer materials was analyzed with Brunaeur-Emmett-Teller (BET) adsorption isotherm, scanning electron microscopy (SEM), infrared spectroscopy (FTIR), surface charge and particle size and swelling rate measurements. Polymerisation was successful in both the conventional solvent and the non-ionic deep eutectic mixture, giving the same yield of polymer monolith. The materials thus prepared varied in terms of surface area, pore volume and pore diameter; 127-534 m.sup.2/g, 0.2-1.5 cm.sup.3/g and 5.2-12.6 nm, respectively. The recovery of the non-ionic deep eutectic mixture after polymerization by first extensive washing, then evaporation of the water highlighted the utility of the non-ionic deep eutectic mixture for replacing ionic liquids as well as volatile and toxic organic solvents in polymer synthesis.

B. In Biotin-Selective (Molecularly Imprinted) Polymer Thin Film Preparation.

[0049] Example 2: An acetamide-urea-based non-ionic deep eutectic mixture was used in the electrochemical synthesis of thin polymer recognition films. In a typical example, cyclic voltammetric conditions were employed for the synthesis of polymer film by electrochemical co-polymerization of 16 mM of p-aminobenzoic acid (4-ABA) and 100 mM of pyrrole in the presence and absence of 4 mM biotin, in the non-ionic deep eutectic mixture of acetamide:urea in the proportions 67:33 ratio by weight on an Au/quartz electrode. Potential scan rate was 0.05 V/s and 34.6% of NH.sub.4NO.sub.3 was used as supporting electrolyte. Molecular imprinting of biotin (biotin being the template) using 4-ABA-pyrrole produced copolymer films displaying porous morphology, see FIG. 1 which shows surface topography of the film mapped using scanning electron microscopy (SEM) for the MIP film coated on Au/quartz electrosynthesized in binary eutectic solvent. The films synthesized with the mixture had enhanced recognition for biotin relative to those electrosynthesized using water or methanol as solvent (REF), see Table 3 below.

TABLE-US-00003 TABLE 3 Sensitivity and stability constants, K.sub.s of the biotin-MIP and biotin REF film interactions Correlation coefficient Recognition Sensitivity of K.sub.s (st.d.) film Hz/mM sensitivity M.sup.1 MIP film 6.47 0.56 0.990 107 prepared in aqueous medium Ref film 3.01 0.32 0.996 75 prepared in aqueous medium MIP film 16.57 0.27 0.997 1430 prepared in Binary eutectic solvent Ref film 6.68 0.56 0.993 84 prepared in Binary eutectic solvent

[0050] See also FIG. 2 which shows variation in the resonant frequency of the Au-coated quartz resonator coated with biotin imprinted polymer film prepared in binary eutectic solvent upon injection of the biotin methyl ester under flow injection analysis conditions.

C. As an Alternative to Conventional Solvents in Organic Synthesis and Chemical Catalysis

[0051] Example 3: Cu-catalyzed synthesis of triazoles via the click reaction. Eutectic mixtures of N,N-dimethylurea and N-methylurea can be employed as a medium for the Huigesan click reaction. By one-pot three-component click reaction a series of triazoles was obtained by reaction between corresponding in situ generated organic azide, and terminal alkynes.

[0052] In a typical procedure, the reaction of benzyl bromide (1), with phenyl acetylene (4) the formation of 5 was observed in the presence of catalyst, see reaction scheme below:

##STR00001##

[0053] After a screening of reaction conditions in different eutectic mixtures, optimum conditions for the 1,2,3-triazole formation were identified as 1:1 w/w (i.e. ratio by weight) mixture of N-methylurea (NMU) and N,N-dimethyl urea (NNDMU) at 60 C. in a glass vial in presence of 5 mole % of Cu-cellulose catalyst. The reaction also proceeds in other eutectic mixtures, see table 4 below:

TABLE-US-00004 TABLE 4 Yields for click reaction performed using various non-ionic eutectic mixture solvents Ratio T Yield Conversion Entry Liquid mixture (W:W) ( C.) (%) (%) 1 Urea + 65:35 80 80 90 Acetamide 2 Urea + NMU 70:30 63 90 90 3 NMU + NN DMU 80:20 79 95 99 4 NMU + NN DMU 50:50 50 99 100 5 NMA + NN DMU 70:30 20 96 95 NMU = N-Methyl Urea, NN DMU = N,N Dimethyl Urea, NMA = N-Methyl Acetamide

[0054] In another example a mixture comprising N-Methyl urea (NMU) and N-Methyl Acetamide (NMA) is used for both solution and solid phase peptide synthesis instead of the conventional solvents N,N-dimethylformamide or dichloromethane.

D. As an Alternative to Conventional Solvents in Extraction

Example 4: Limonene from Lemon Peel

[0055] Finely chopped lemon peel (25 g) was added to an eutectic mixture of acetamide:urea, 67:33 (ratio by weight)(100 mL) and heated at 85 C. for 2 h. The residual lemon peel was removed by filtration. To the filtrate 300 ml (3 times the volume of eutectic mixture) of Milli-Q grade water was added and mixed vigorously to dissolve the components of the eutectic mixture. Ethyl acetate (320 mL) was added and the organic layer was collected separately. The organic phase was dried, filtered and evaporated to afford the limonene (200 mg) corresponding to 0.8% yield by mass. The identity of the product was confirmed by GC-MS.

Example 5: Betulin from Birch Bark

[0056] Dry white birch bark (2.5 g) was cut and macerated and placed in a 100 ml round-bottomed flask. To that 25 ml of an eutectic mixture comprising N-methylurea:N-methylacetamide, 20:80 (ratio by weight), was added and heated at 85 C. for 2 hours. The remaining solid material was removed by filtration and the filtrate was treated with 75 ml (3 times the volume of eutectic mixture used) of Milli-Q grade water and mixed vigorously to dissolve the component of the eutectic mixture. The above solution is extracted with ethylacetate (320 mL) in a separating funnel and the organic layer was collected. Ethyl acetate in the organic extract was dried then removed under reduced pressure and the sample dried under vacuum before characterization by MALDI-MS and .sup.1H-NMR. Betulin was obtained in 400 mg (16% yield by mass).

E. As an Alternative to Heat Transfer Agents

[0057] Example 6: A sample of an urea:acetamide, 33:67 (ratio by weight), non-ionic eutectic mixture was heated to 150 C. and the sample maintained at this temperature for 5 min before cooling until solidification. This cycle was repeated 10 times with no apparent change in the melting point of the non-ionic eutectic mixture.