Ionic Liquids as Fragrance Precursors: Smart Delivery Systems for

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Ionic Liquids as Fragrance Precursors: Smart Delivery Systems for Volatile Compounds Paula Berton, Julia L. Shamshina, Katharina Bica, and Robin D. Rogers Ind. Eng. Chem. Res., Just Accepted Manuscript • DOI: 10.1021/acs.iecr.8b02903 • Publication Date (Web): 22 Aug 2018 Downloaded from http://pubs.acs.org on August 26, 2018

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Industrial & Engineering Chemistry Research

Ionic Liquids as Fragrance Precursors: Smart Delivery Systems for Volatile Compounds Paula Berton,1 Julia L. Shamshina,2 Katharina Bica,3 and Robin D. Rogers4*

1

Chemical and Petroleum Engineering Department, University of Calgary, Calgary, AB T2N 1N4, Canada

2

Mari Signum Mid-Atlantic, LLC, 3204 Tower Oaks Boulevard, Rockville, MD 20852, USA

3

Institute of Applied Synthetic Chemistry, Vienna University of Technology, Getreidemarkt 9/163, 1060 Vienna, Austria

4

525 Solutions, Inc., P.O. Box 2206, Tuscaloosa, AL 35403, USA

Keywords: Ionic Liquids; pH Release; Pro-Fragrance; Thermal Release

Abstract The low volatility of many ionic liquids (ILs) can be used to design a specific delivery system with a triggered release mechanism for volatile fragrances. We present two different strategies for IL-supported pro-fragrance compounds based on common fragrance alcohols. When the fragrance was attached to the cation, its release was triggered by heat; while the fragrance attached to the anion was released under basic conditions. The selection of the counterion allowed not only to control the physical properties of the resulting compound, but also to add a second functionality. Our design strategy shows that the choice of the IL components can 1

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result in safe, biocompatible ionic pro-fragrances, suitable for applications such as topical nutraceutical or cosmetic formulations. Introduction Fragrance and flavor formulations suffer from limited lifetimes since their volatile constituents tend to fade by evaporation, oxidation, chemical degradation, interaction with other ingredients, or be lost during storage.1,2 The fragrance and flavor industry has addressed the issue of performance loss by developing specific fragrance delivery systems, usually based on microencapsulation3,4 through either chemical (coacervation, co-crystallization or molecular inclusion) or mechanical (spray-drying, chill drying).5 Another way of tackling this matter is through the use of less volatile and odorless precursor molecules (pro-fragrances) that release the fragrance under defined chemical conditions, which may include variations of temperature, enzymatic or pH-dependent hydrolysis, oxidation or (ultraviolet) light.6,7 Due to their tunable properties, ionic liquids (ILs, defined as salts with melting points below 100 °C8) have attracted a great deal of interest as alternative solvents9 and for material applications, among other uses.10 Yet, their role in fragrance and flavor technologies has not been extensively explored: there are less than 80 hits on SciFinder for the search terms ‘fragrance’ and ‘ionic liquids’), including scientific journals and patents.11 This is surprising, given that the negligible vapor pressure of many ILs at ambient conditions should render them ideally suited for use in volatile fragrance and flavor formulations.12,13 Suggested uses mainly deal with solvent applications for the synthesis of fragrance and flavor materials in ILs14-16 or for the extraction of natural compounds.17-23 Only a few examples can be found in literature where ILs were used either to delay24-27 or accelerate28 the rate of evaporation of the perfume (volatile) component, when used in 2


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formulations as fragrance dissolution media. The selection of the IL was however crucial to control the release of volatile components,29-31 especially considering that depending on composition, the primary components of the ILs could be detected in the headspace of ILfragrance mixtures.24 Another example included the incorporation of fragrances as a cation of the IL formulation prior to fragrance ionization.32 Depending on the resulting ionized fragrance, it was prepared by metathesis reaction of various ammonium halides into respective sulfonates, acesulfame or docusate anions, to change hydrophilicity of the target IL.32 An interesting approach to control the release of fragrances from ILs is the use of ILs in pro-fragrance applications, very similar to that utilized in the pro-drug concept, where pro-drugs are defined as drug derivatives that undergo in vivo chemical change and liberate the active parent drug.33 Linking the IL to the fragrance would ensure not only very low volatility of the pro-fragrance and thus prevent fading, but also could be used to modify the physical properties of the final pro-fragrance by choice of appropriate IL’s components (Figure 1). To our knowledge, the pro-fragrance strategy, bonding covalently the fragrance to the ILs, has been reported with the fragrances released using a trigger mechanism initiated by water34,35 or enzymatic hydrolysis.36

Neutral Fragrance

Linker

(±) IL

Figure 1. Ionic Liquids as support for volatile fragrances. Although the possibility of including fragrances to ILs and their release triggered by 3



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external stimuli has been demonstrated, the great versatility of the IL approach to design final products for specific applications is still to be explored. In this paper, following the hypothesis that ILs could serve to effectively anchor pro-fragrances in their non-volatile structure, we investigated thermal and pH-labile release for IL-based pro-fragrances as linked support materials for the immobilization and storage of volatile fragrance alcohols. Here, we propose using a smart design of the linking unit to allow fragrance released to be triggered using temperature, expanding the applicability of the IL-based pro-fragrance strategy. In addition, we evaluated the use of generally regarded as safe (GRAS) components for the formation of IL, which would ensure easier adoption in consumer products.

Results and Discussion The design of an IL-supported fragrance requires the presence of a covalent yet easily breakable bond for release, such as an ester functionality, which is widely used in profragrance and flavor designs6 due to its susceptibility to cleavage under a variety of conditions.37 We therefore decided to test the IL pro-fragrance concept on the basis of fragrance

alcohol

derivatives

of

N-methylimidazole,

namely

3-methyl-1-

(alkyloxycarbonylmethyl)imidazolium cations that could be obtained in a straightforward 3step synthesis. Furthermore, the C-O ester bond in the alkyl chain of ILs was found to be susceptible to enzymatic cleavage, desirable for fragrance release, and a contributing factor to the biodegradability of the IL.38-40 Geraniol, a primary monoterpenoid fragrance alcohol with a rose-like odor, was chosen as a model fragrance and underwent esterification with chloroacetylchloride using pyridine as a 4


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base, under anhydrous conditions, to provide the corresponding ester (Ger-ester, Scheme 1). The Ger-ester was subsequently alkylated with N-methylimidazole (NMI), to form the imidazolium chloride (geraniol-NMI chloride, [Ger-NMI]Cl). This alkylation reaction was completed in a solvent-free fashion, at a rather low temperature of 40 °C. Such relatively mild reaction conditions are explained by the presence of a carbonyl group in the α-position of carbon atom being alkylated (the so-called neighboring group participation effect41), important for alcohols that will not survive typically harsh alkylation of aliphatic chlorides. We have previously shown that a variety of ILs could be prepared using an anionic surfactant, sodium docusate, by metathesis of corresponding ammonium halides.42 Thus, a final metathesis with the sodium docusate, a common counterion for hydrophobic ILs, resulted in the formation of the IL geraniol-NMI docusate, [Ger-NMI][Doc], as an easily separable second layer that appeared on the surface of the reaction mixture after completion of the reaction.

Scheme 1. Preparation of IL-supported fragrances where the fragrance is immobilized into the IL cation (exemplified with geraniol).

5



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The synthetic protocol was followed with a variety of commercially available fragrance alcohols of saturated, unsaturated, and cyclic origin including mono- (geraniol, citronellol) and sesquiterpenes (farnesol), and the saturated cyclic alcohol (menthol) to form citronellolNMI chloride ([Cit-NMI]Cl), farnesol-NMI docusate ([Farn-NMI][Doc]), and menthol-NMI docusate ([Ment-NMI][Doc]) (Fig. 2). While the compounds [Ger-NMI][Doc], [FarnNMI][Doc], and [Ment-NMI][Doc] were evaluated as docusate ILs due to their high hydrophobicity, we were also interested whether the chloride ILs could be used as a profragrance ‘as is’ without conversion to docusate, and thus, tested [Cit-NMI]Cl as obtained. All syntheses resulted in the desired compounds isolated as yellow oils in quantitative yields. The formation of the final compounds, as well as, 1:1 stoichiometry between the ions were confirmed using nuclear magnetic resonance spectroscopy (1H and

13

C NMR, see

Experimental section). Regardless of the fragrance alcohol used, when docusate was used as counterion, room temperature, hydrophobic ILs were obtained. All isolated compounds were obtained with purities >90% (established through 1H NMR integration), and the water contents were found to be below 1% (evaluated by the integration of the water peak in DMSO-d6 located at 3.33 ppm) in 1H NMR spectra. The resulting docusate-based compounds didn’t show melting or crystallization transitions within the studied range (-70 to 110 °C, using differential scanning calorimetry, DSC, Fig. S1), while a melting point for [Cit-NMI]Cl was observed at 50 °C.

6


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Figure 2. Structures of the synthesized IL-supported pro-fragrances with the fragrance in the cation. When assessing the thermal properties of the fragrance-NMI docusate ILs via thermal gravimetric analysis (TGA), we observed a distinctive two-step decomposition step for [GerNMI][Doc] and [Farn-NMI][Doc] when heated in the presence of moisture as typically observed for thermolabile pro-fragrances. This decomposition is specific to allylic esters and was observed here for the ILs based on the allylic alcohols. On the other hand, only a single step decomposition was observed for the saturated fragrance [Ment-NMI][Doc] (Fig. 3) and for [Cit-NMI]Cl (Fig. S2), indicating that, irrespective of the counterion, an allyl ester bond is required for the thermal hydrolysis of the fragrance. In those cases where two decomposition steps were observed, the weight loss for the first decomposition step observed in the TGA corresponded to the mass percentage of the fragrance that is selectively cleaved from the ester bond. The actual temperature of fragrance release is further dependent on the type of fragrance, with [Farn-NMI][Doc] more thermally stable (179 °C, 28% mass loss) than [GerNMI][Doc] (166 °C, 23% mass loss).

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Figure 3. Two-step decomposition of [Ger-NMI][Doc] (―) and [Farn-NMI][Doc] (―) vs. single-step decomposition of [Ment-NMI][Doc] (―).

While these IL pro-fragrances demonstrate the concept and potential of using an IL as support for immobilization and targeted release of volatile fragrances, toxicity concerns might be a major drawback for their application in consumer products. To overcome this drawback, we developed a second approach to synthesize biocompatible pro-fragrances, replacing the imidazolium-based ILs with ions entirely composed of pharmaceutically acceptable components, generally recognized as safe (GRAS).43 In this second approach, the fragrance was immobilized into the anion of the IL in a simple and scalable 2-step synthesis. The first step involved the esterification of succinic anhydride with a fragrance alcohol by homogeneous catalytic reactions. Here again the monoterpenoid fragrance geraniol, was chosen as a model fragrance. First, the hemisuccinate of geraniol was prepared through a 4-(dimethylamino)pyridine (4-DMAP)‐catalyzed 8


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carboxylation reaction by mixing geraniol, succinic anhydride, and a catalytic amount of the 4-DMAP catalyst in anhydrous dichloromethane, followed by stirring for 24 h at room temperature (Scheme 2). The isolated hemisuccinate (Ger-hemisuccinate, see Experimental section) was reacted with the permanent cationic choline hydroxide ([Cho][OH]), to give the IL pro-fragrance [Cho][Ger-Succ] (Scheme 2). Except for the fragrance itself, the starting materials are considered GRAS compounds, since both the vitamin choline and the succinic acid are commonly found in nutraceuticals or pharmaceuticals.43 The formation and stoichiometry between the ions were confirmed using 1H and

13

C

NMR. The isolated compound was obtained with purity >95% (established through 1H NMR integration) and in quantitative yield. No melting or crystallization points were observed for [Cho][Ger-Succ] within the studied range (-70 to 110 °C, using DSC, Fig. S3).

Scheme 2. Preparation of IL-supported fragrances where the fragrance is immobilized into the IL anion (exemplified with geraniol).

The synthesized [Cho][Ger-Succ] did not exhibit thermolabile ester cleavage but showed a single decomposition step at 156 °C (Fig. S4). As thermal cleavage did not result in the 9



desired outcome, we studied the release of the fragrance under hydrolytic conditions. As proof of concept for pH-triggered release, [Cho][Ger-Succ] was dissolved in buffered solutions at acidic and basic pH (pH 3 and 9, respectively) and stirred under thermostatted conditions at 25 °C. These pH values were selected based on a previous study, used to evaluate the release of fragrances from nanoencapsulated fragrances triggered by pH.44 At different intervals, an aliquot was taken from the mixture, diluted with d6-DMSO and measured immediately via 1H NMR spectroscopy. Integration of the well separated α-CH2-protons of geraniol in free form or as hemisuccinate pro-fragrance at 4.2 or 4.8 ppm, respectively, allowed for a simple quantification and the determination of release kinetics. As can be seen in Fig. 4, [Cho][GerSucc] was observed to be more stable under acidic conditions (pH 3), while considerably faster hydrolysis was observed under basic conditions (pH 9) with complete cleavage in 250 min. This behavior has been previously reported for ester pro-drugs, where base-catalyzed hydrolysis was observed for cannabinoid ester pro-drugs, while stability increased at acidic pH.45,46 100

Decomposition (%)

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80

60

40

20

0 0

100

200

300

400

Time (min) 10


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Figure 4. Decomposition of [Cho][Ger-Succ] under basic (pH 9, ▼) or acidic (pH 3, ●) conditions.

The synthetic strategy of making a hemisuccinate-fragrance used for the synthesis of [Cho][Ger-Succ], also allows one to include a second active cation to form a dual functional IL. To test this hypothesis, Ger-hemisuccinate (Scheme 2) was reacted with the permanent cationic tetrabutylphosphonim and benzethonium hydroxides ([P4444][OH] and [Benz][OH], respectively), resulting in [P4444][Ger-Succ] and [Benz][Ger-Succ] (Scheme 2). The composition and purity of the resulting ILs was confirmed using NMR, while no melting or crystallization points were observed within the studied range (-70 to 110 °C, using differential scanning calorimetry, Fig. S3). Like [Cho][Ger-Succ], a single decomposition step was observed at 143 and 188 °C for [Benz][Ger-Succ] and [P4444][Ger-Succ], respectively (Fig. S4). This pro-fragrance approach demonstrates that one can choose a complimentary cation that allows one to modify the physical properties of the pro-fragrance liquid without modification of the active ingredient. Here, replacing the choline cation with a phosphonium cation leads to an increase in the hydrophobicity of the resulting IL. Surfactant qualities can easily be incorporated by exchanging the choline cation with a long-chain quaternary (alkoxy)ammonium cation commonly found as cationic surfactants in laundry detergents.47,48 Although these examples are thermally stable, the release of the fragrances can still be induced in basic pH, due to the labile ester bond present in the anion containing the profragrance.

11



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Conclusions Overall, we have developed two different high-yielding synthetic strategies to transfer neutral fragrance molecules into an IL cation or anion that can be generally applied to any alcohol. The IL pro-fragrance approach can prevent premature evaporation and fading of the fragrance alcohols, and a careful design of IL-supported fragrances can lead to selective cleavage under controlled conditions. If attached to the cation of the IL, the fragrance can be released with heat; while attaching the fragrance to the anion makes the compounds we prepared thermally stable, but release can still be induced under basic conditions. The selection of the counterion allows one to not only control the physical properties, e.g., hydrophobicity, but also to add a second functionality such as antimicrobial activity or fabric softener qualities. Further, in light of possible applications in consumer products, the ILs can be designed to be biocompatible and entirely composed of pharmaceutically acceptable, nontoxic components. Our approach allows the flexibility to design IL pro-fragrances depending on the desired application. Applications where pro-fragrances with high temperature stability are required, such as dryer sheets, pro-fragrance containing detergent powder, or tanning blankets (for application in direct sunlight) can benefit from this approach, while products like laundry or dish detergents might prefer fragrance released at high pH values. Following this logic, based on the conditions in which the IL pro-fragrance will be used, the IL approach allows the selection of the IL’s components to prevent the generation of toxic byproducts or metabolites during their degradation pathway. We believe that the fragrance and flavor industries will benefit from such new broad possibilities in the design of their fragrances based on each specific application. 12


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Experimental

Materials All chemicals and solvents (dichloromethane, anhydrous diethyl ether) unless otherwise stated were purchased from Aldrich Chemical Company (Dorset, UK) and used without further purification. Sodium docusate was obtained from Cytec (Niagara Falls, ON, Canada). N-Methylimidazole was purified through addition of potassium hydroxide pellets to N-methylimidazole followed by distillation prior to use. Choline hydroxide and tetrabutylphosphonium hydroxide were purchased as ~40% aqueous solutions and were titrated with 0.1 M HCl prior to use, to determine the exact concentration. Benzethonium hydroxide was purchased as a 1 M solution in MeOH and similarly titrated before use.

Methods Nuclear magnetic resonance (NMR) spectra were recorded in DMSO-d6 at 25 °C on a Bruker (Coventry, UK) 300 DRX spectrometer. The solvent peak was used as reference. Thermogravimetric analysis (TGA) was performed on a Mettler Toledo Stare TGA/DSC unit (Leicester, UK) under nitrogen flow. Samples between 5 and 10 mg were placed in open alumina pans and were heated from 25 to 600 °C with a heating rate of 5 °C/min. Decomposition temperatures (T5%dec) were reported from onset to 5 wt% mass loss. All samples were corrected by subtraction of a blank crucible. Differential scanning calorimetry (DSC) was performed on a Mettler Toledo Stare DSC unit (Leicester, UK) under nitrogen flow. Samples between 5 and 10 mg were heated from 25 °C to 110 °C at a heating rate of 5 °C/min followed by a 5 min isotherm. A 13



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cooling rate of 5 °C/min to -70 °C was followed by a 5 min isotherm at -70 °C, and the cycle was repeated twice. The second and third cycle proved to be identical and only the third heating run was used for interpretation of the results.

Synthesis of ((E)-3,7-dimethylocta-2,6-dienyl 2-chloroacetate) (Ger-ester) To a round-bottom flask, equipped with a thermometer, an addition funnel and a Tefloncoated magnetic stir bar, anhydrous dichloromethane (200 mL) was placed under a positive pressure of nitrogen. Geraniol (7.711 g, 50 mmol) and pyridine (3.955 g, 50 mmol) were successively added to this flask using magnetic stirring. The resultant solution was then chilled to 0 °C, using an ice/water bath. After chilling, chloroacetylchloride (5.647 g, 50 mmol) was placed into an addition funnel, and then added slowly to the flask at a rate slow enough so that the temperature of the solution did not exceed 2 °C. After that, the reaction was allowed to warm to room temperature, and the resulting solution was stirred for 24 h, under nitrogen. After 24 h, DI water (100 mL) was added to the reaction mixture, and the organic layer (bottom) was separated. The upper aqueous layer was extracted with dichloromethane (3 x 100 mL), and the combined organic layers were successively washed with 2 N HCl, saturated sodium bicarbonate (NaHCO3) solution, and brine. After washing, the combined organic layers were dried over anhydrous MgSO4, and the solvent was evaporated using a rotary evaporator. Remaining volatiles were removed under high vacuum (0.01 mbar), to yield the product Ger-ester as a yellow liquid in 97% yield. Ger-ester was pure according to 1H NMR and directly subjected to the next step without further purification.

14


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1

H NMR (300 MHz, DMSO-d6) δ (ppm) = 5.31 (t, J = 7.4 Hz, 1H), 5.06 (m, 1H), 4.64 (d,

J = 7.4 Hz, 2H), 4.38 (s, 2H), 2.03 (m, 4H), 1.68 (s, 3H), 1.64 (s, 3H), 1.56 (s, 3H). 13C NMR (75 MHz, DMSO-d6) δ (ppm) = 167.3, 142.4, 131.1, 123.7, 117.8, 62.2, 41.1, 38.9, 25.7, 25.4, 17.5, 16.2.

Synthesis

of

(E)-1-(2-(3,7-dimethylocta-2,6-dienyloxy)-2-oxoethyl)-3-methyl-1H-

imidazol-3-ium chloride ([Ger-NMI]Cl) In a round-bottom flask, equipped with a Teflon-coated magnetic stir bar, Ger-ester (2.307 g, 10 mmol) and N-methylimidazole (0.821 g, 10 mmol) were mixed with no solvent, under nitrogen flow and stirred in a sealed vessel at 40 °C (oil bath) for 24 h. After 24 h, a lightbrown solid was formed which was suspended in anhydrous diethyl ether. The solid precipitate was filtered using a fritted filter, and additionally washed with fresh diethyl ether (2 x 5 mL). After washings, the precipitate was dried under reduced pressure (0.01 mbar) to give [Ger-NMI]Cl in 97% yield as a colorless hygroscopic solid. 1

H NMR (300 MHz, DMSO-d6) δ 9.33 (s, 1H), 7.80 (s, 2H), 5.66 – 5.20 (m, 3H), 5.06 (s,

1H), 4.68 (d, J = 7.0 Hz, 2H), 3.93 (s, 3H), 3.42 (s, 3H), 2.03 (s, 3H), 1.65 (d, J = 12.0 Hz, 6H), 1.56 (s, 3H). 13C NMR (75 MHz, DMSO-d6) δ 167.28, 142.99, 138.14, 131.51, 124.03, 123.99, 123.70, 117.93, 62.75, 49.80, 36.29, 26.13, 25.83, 17.92, 16.57 (Fig. S5).

Synthesis

of

(E)-1-(2-(3,7-dimethylocta-2,6-dienyloxy)-2-oxoethyl)-3-methyl-1H-

imidazol-3-ium docusate ([Ger-NMI][Doc]) To a round-bottom flask, equipped with a Teflon-coated magnetic stir bar, 20 mL of acetone/H2O 1:1 was placed under a positive pressure of nitrogen. The [Ger-NMI]Cl (312.8 15



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mg, 1 mmol) and sodium docusate (444.6 mg, 1 mmol) were dissolved in this solvent mixture and stirred overnight at room temperature, resulting in a suspension. The suspension was diluted with 50 mL of H2O, and then the product was extracted with dichloromethane (3 x 50 mL). The organic layer was washed successively with water until no more chloride ions could be detected in the washings (checked by addition of AgNO3 solution), dried over anhydrous MgSO4, and the solvent was evaporated using a rotary evaporator. Remaining volatiles were removed under high vacuum (0.01 mbar), to give the [Ger-NMI][Doc] in quantitative yield as a yellow oil. 1

H NMR (300 MHz, DMSO-d6) δ(ppm) = 9.07 (s, 1H), 7.71 (s, 2H), 5.33 (t, J = 7.3 Hz,

1H), 5.24 (s, 2H), 5.07 (m, 1H), 4.69 (d, J = 7.3 Hz, 2H), 3.91 (s, 3H), 3.90 (m, 4H), 3.62 (dd, J1 = 11.39 Hz, J2 = 3.88 Hz, 1H), 2.86 (m, 2H), 2.04 (m, 4H),1.68 (s, 3H), 1.65 (s, 3H), 1.57 (s, 3H), 1.49 (m, 2H), 1.24 (m, 16 H), 0.84 (m, 12H). 13C NMR (75 MHz, DMSO-d6) δ(ppm) = 171.1, 168.1, 166.9, 142.7, 137.7, 131.2, 123.7, 123.6, 123.4, 117.6, 66.2, 66.1, 62.4, 61.4, 49.5, 38.1, 35.6, 34.1, 29.8, 29.6, 28.3, 25.8, 25.5, 23.2, 23.0, 22.4, 17.6, 16.2, 13.9, 10.8 (Fig. S6). Tg -32 °C (Fig. S1), T5%dec 174 °C.

Synthesis of 1-(2-((3,7-dimethyloct-6-en-1-yl)oxy)-2-oxoethyl)-3-methyl-1H-imidazol-3ium chloride ([Cit-NMI]Cl), 3-methyl-1-((2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1yl)-1H-imidazol-3-ium

docusate

([Farn-NMI][Doc]),

and

methylcyclohexyl)oxy)-2-oxoethyl)-3-methyl-1H-imidazol-3-ium

1-(2-((2-isopropyl-5docusate

([Ment-

NMI][Doc]) Following the procedure above described, citronellol-NMI chloride ([Cit-NMI]Cl), farnesolNMI docusate ([Farn-NMI][Doc]), and menthol-NMI docusate ([Ment-NMI][Doc]) were 16


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synthesized. The purity and composition of the resulting pro-fragrance ILs were confirmed using 1H and 13C NMR. [Cit-NMI]Cl: 1H NMR (300 MHz, DMSO-d6) δ 9.30 (s, 1H), 7.80 (d, J = 1.5 Hz, 2H), 5.34 (s, 2H), 5.09 (ddd, J = 7.1, 5.8, 1.3 Hz, 1H), 4.18 (dd, J = 12.2, 5.8 Hz, 2H), 3.94 (s, 3H), 3.39 (s, 1H), 2.13 – 1.79 (m, 2H), 1.70 – 1.56 (m, 6H), 1.46 (ddd, J = 21.6, 15.3, 7.1 Hz, 2H), 1.24 (dddd, J = 21.7, 15.2, 7.6, 4.8 Hz, 2H), 0.89 (d, J = 6.4 Hz, 3H). 13C NMR (75 MHz, DMSOd6) δ 171.41, 168.72, 138.07, 124.79, 124.07, 123.74, 66.45, 64.49, 61.79, 49.83, 38.49, 36.79, 36.30, 35.10, 34.47, 30.10, 29.19, 28.69, 25.85, 25.21, 23.53, 23.35, 22.94, 22.77, 19.45, 17.87, 14.27, 11.14 (Fig. S7). Melting point: 50 °C. T5%dec 162 °C.

[Farn-NMI][Doc]: 1H NMR (300 MHz, DMSO-d6) δ 9.08 (s, 1H), 7.73 (dd, J = 3.1, 1.5 Hz, 2H), 5.33 (t, J = 6.9 Hz, 1H), 5.24 (s, 2H), 5.07 (d, J = 7.3 Hz, 2H), 4.68 (t, J = 7.2 Hz, 2H), 3.88 (dd, J = 8.7, 7.2 Hz, 6H), 3.63 (dd, J = 11.4, 3.8 Hz, 1H), 3.36 (d, J = 7.0 Hz, 9H), 2.85 (ddd, J = 21.0, 17.2, 7.6 Hz, 2H), 2.22 – 1.83 (m, 7H), 1.79 – 1.41 (m, 12H), 1.29 (dd, J = 20.7, 13.5 Hz, 12H), 0.84 (dt, J = 10.7, 6.9 Hz, 10H).

13

C NMR (75 MHz, DMSO-d6) δ

171.40, 168.72, 167.21, 143.07, 138.08, 135.17, 131.29, 131.03, 124.69, 124.41, 124.05, 123.81, 123.75, 117.91, 66.44, 62.76, 61.80, 49.80, 38.50, 36.29, 34.46, 31.83, 30.10, 29.98, 29.92, 28.70, 26.52, 26.36, 26.06, 25.82, 23.53, 23.35, 22.77, 22.74, 17.88, 17.81, 16.55, 16.13, 14.26, 14.23, 11.12, 11.08 (Fig. S8). Tg -35 °C (Fig. S1), T5%dec 162 °C.

[Ment-NMI][Doc]: 1H NMR (300 MHz, DMSO-d6) δ 9.10 (s, 1H), 7.74 (d, J = 1.6 Hz, 2H), 5.27 (dd, J = 36.7, 17.6 Hz, 2H), 4.69 (td, J = 10.9, 4.4 Hz, 1H), 4.05 – 3.76 (m, 6H), 3.62 (dd, J = 11.4, 3.8 Hz, 1H), 2.84 (ddd, J = 21.1, 17.2, 7.6 Hz, 2H), 2.07 – 1.76 (m, 2H), 1.65 17



Page 18 of 27

(d, J = 10.7 Hz, 2H), 1.60 – 1.42 (m, 3H), 1.43 – 1.15 (m, 15H), 1.05 (dt, J = 23.2, 10.1 Hz, 2H), 0.97 – 0.80 (m, 16H), 0.72 (d, J = 6.9 Hz, 3H). 13C NMR (75 MHz, DMSO-d6) δ 171.41, 168.73, 166.84, 138.10, 124.09, 123.75, 76.06, 66.44, 61.79, 49.75, 46.65, 38.49, 36.30, 34.48, 33.84, 31.10, 30.11, 29.98, 28.70, 25.91, 23.53, 23.35, 23.18, 22.77, 22.75, 22.17, 20.92, 16.61, 14.27, 11.14 (Fig. S9). Tg -16 °C (Fig. S1), T5%dec 245 °C.

Synthesis

of

(E)-4-(3,7-dimethylocta-2,6-dienyloxy)-4-oxobutanoic

acid

(Ger-

hemisuccinate) To a round-bottom flask, equipped with a Teflon-coated magnetic stir bar, 50 mL of dichloromethane was placed under a positive pressure of nitrogen. Geraniol (1.542 g, 10 mmol), succinic anhydride (1.201 g, 12 mmol), and 4-DMAP catalyst (10 mg, catalytic amount) were suspended in anhydrous dichloromethane. After proper mixing, pyridine (0.791 g, 10 mmol) was added and the reaction mixture was stirred for 24 h at room temperature. After 24 h, the reaction mixture was transferred into a separatory funnel and successively washed with 2 N HCl (50 mL) and H2O (50 mL), dried over anhydrous Na2SO4, and the solvent was evaporated using a rotary evaporator. Remaining volatiles were removed under reduced pressure (0.01 mbar) to yield product (Ger-hemisuccinate) as a yellow liquid in 99% yield. 1

H NMR (300 MHz, DMSO-d6) δ 12.22 (s, 1H), 5.29 (dd, J = 7.0, 6.0 Hz, 1H), 5.17 – 4.94

(m, 1H), 4.55 (d, J = 7.0 Hz, 2H), 2.49-2.48 (4H, m), 2.20 – 1.85 (m, 4H), 1.66 (d, J = 3.1 Hz, 6H), 1.58 (s, 3H). 13C NMR (75 MHz, DMSO-d6) δ 173.72, 172.39, 141.60, 131.43, 124.09, 118.88, 61.07, 29.04, 26.16, 25.83, 17.91, 16.50 (Fig. S10).

18


Page 19 of 27 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Synthesis of 2-hydroxy-N,N,N-trimethylethanammonium (E)-4-(3,7-dimethylocta-2,6dienyloxy)-4-oxobutanoate ([Cho][Ger-Succ]) In a round bottom flask equipped with Teflon-coated magnetic stir bar and an addition funnel, Ger-hemisuccinate (1.0173 g, 4 mmol) was dissolved in 10 mL of methanol and chilled to 0 °C using an ice-water bath. Choline hydroxide 40% in methanol solution (1.13 mL, 4 mmol) was added dropwise using an addition funnel and the reaction mixture was stirred for 5 min at 0 °C. After the reaction, the solvent was evaporated, and the remaining volatiles were removed under reduced pressure (0.01 mbar) to yield [Cho][Ger-Succ] as a yellow liquid in quantitative yield. 1

H NMR (300 MHz, DMSO-d6) δ 5.28 (dt, J = 6.9, 3.5 Hz, 1H), 5.18 – 4.97 (m, 1H), 4.49

(d, J = 6.9 Hz, 2H), 3.96 – 3.71 (m, 2H), 3.62 – 3.48 (m, 1H), 3.48 – 3.38 (m, 2H), 3.14 (s, 9H), 2.52 (dt, J = 3.5, 1.8 Hz, 1H), 2.36 (td, J = 7.1, 3.1 Hz, 2H), 2.16 – 1.88 (m, 6H), 1.66 (s, 6H), 1.58 (s, 3H). 13C NMR (75 MHz, DMSO-d6) δ 174.07, 173.92, 140.98, 131.40, 124.13, 119.34, 67.67, 60.50, 55.30, 53.50, 53.45, 53.40, 40.73, 40.45, 40.17, 39.90, 39.62, 39.34, 39.06, 33.30, 31.57, 26.18, 25.84, 17.92, 16.50 (Fig. S11). Tg -62 °C (Fig. S3), T5%dec 156 °C (Fig. S4).

Synthesis oxobutanoate

of

(E)-4-(3,7-dimethylocta-2,6-dienyloxy)-4-

tetrabutylphosphonium ([P4444][Ger-Succ])

and

benzethonium

(E)-4-(3,7-dimethylocta-2,6-

dienyloxy)-4-oxobutanoate ([Benz][Ger-Succ]) Following the procedure described for [Cho][Ger-Succ], tetrabutylphosphonium geraniolsuccinate ([P4444][Ger-Succ]) and benzethonium geraniol-succinate ([Benz][Ger-Succ]) were

19



Page 20 of 27

synthesized. The purity and composition of the resulting pro-fragrance IL was confirmed using 1H and 13C NMR:

[P4444][Ger-Succ]: 1H NMR (300 MHz, DMSO-d6) δ 5.28 (dd, J = 6.9, 5.8 Hz, 1H), 5.18 – 4.97 (m, 1H), 4.48 (d, J = 6.9 Hz, 2H), 2.40 – 2.11 (m, 10H), 2.11 – 1.90 (m, 6H), 1.66 (s, 6H), 1.58 (s, 3H), 1.54 – 1.28 (m, 16H), 0.93 (t, J = 7.0 Hz, 12H).

13

C NMR (75 MHz,

DMSO-d6) δ 174.19, 172.73, 140.81, 131.38, 124.14, 119.45, 60.38, 34.00, 32.03, 26.18, 25.85, 23.84, 23.64, 23.05, 22.99, 18.00, 17.92, 17.37, 16.50, 13.63 (Fig. S12). Tg -67 °C (Fig. S3), T5%dec 189 °C (Fig. S4).

[Benz][Ger-Succ]: 1H NMR (300 MHz, DMSO-d6) δ 7.64 – 7.26 (m, 5H), 7.17 (d, J = 8.8 Hz, 2H), 6.75 (d, J = 8.8 Hz, 2H), 5.18 (dd, J = 7.4, 6.2 Hz, 1H), 5.07 – 4.88 (m, 1H), 4.60 (s, 2H), 4.38 (d, J = 6.9 Hz, 1H), 4.03 (dd, J = 5.4, 3.4 Hz, 2H), 3.92 (s, 2H), 3.82 (t, J = 11.9 Hz, 1H), 3.78 – 3.65 (m, 2H), 3.56 – 3.48 (m, 2H), 3.47 – 3.36 (m, 1H), 2.96 (s, 6H), 2.47 – 2.35 (m, 1H), 2.24 (td, J = 7.3, 2.1 Hz, 2H), 2.04 – 1.78 (m, 7H), 1.57 (d, J = 10.8 Hz, 6H), 1.48 (s, 4H), 1.20 (s, 6H), 0.58 (s, 9H).

13

C NMR (75 MHz, DMSO-d6) δ 174.69, 174.17, 173.17,

156.35, 141.89, 140.81, 135.38, 133.59, 131.37, 131.13, 130.53, 129.16, 128.66, 127.28, 126.04, 124.40, 124.12, 119.42, 113.94, 69.20, 67.64, 66.95, 64.35, 63.45, 62.82, 60.40, 57.87, 56.68, 51.10, 50.01, 37.92, 33.94, 33.89, 32.36, 31.90, 31.75, 31.05, 26.37, 26.18, 25.85, 17.91, 16.49, 16.36 (Fig. S13). Tg -31 °C (Fig. S3), T5%dec 143 °C (Fig. S4). Acknowledgments This research was initiated in 2008 at the Queen’s University Ionic Liquid Laboratory at Queen’s University Belfast and continued in the Department of Chemistry of McGill 20


Page 21 of 27 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


University. This research was undertaken, in part, thanks to funding from the Canada Excellence Research Chairs Program. Associated Content Supporting Information. The following file is available free of charge (PDF). DSC of [GerNMI][Doc], [Farn-NMI][Doc], [Ment-NMI][Doc], [Cho][Ger-Succ], [Benz][Ger-Succ], and [P4444][Ger-Succ];

TGA

of

[Cit-NMI]Cl,

[Cho][Ger-Succ],

[Benz][Ger-Succ],

and

[P4444][Ger-Succ]; 1H and 13C NMR spectra of synthesized compounds. Author Information Corresponding Author: [email protected] References

1 Quellet, C.; Schudel, M.; Ringgenberg, R. Flavors & Fragrance Delivery Systems. Chimia 2001, 55, 421. 2 Gygax, H.; Koch, H. The Measurements of Odours. Chimia 2001, 55, 401. 3 Rogers, K. Controlled Release Technology and Delivery Systems. Cosmet. Toiletries 1999, 114, 53. 4 Gautschi, M.; Bajgrowicz, J. A.; Kraft, P. Fragrance Chemistry - Milestones and Perspectives. Chimia 2001, 55, 379. 5 Madene, A.; Jacquot, M.; Scher, J.; Desobry, S. Flavour Encapsulation and Controlled Release – A Review. Int. J. Food Sci. Technol. 2006, 41, 1. 6 Herrmann, A. Controlled Release of Volatiles under Mild Reaction Conditions: From Nature to Everyday Products. Angew. Chem. Int. Ed. 2007, 46, 5836. 21



Page 22 of 27

7 Kuhnt, T.; Herrmann, A.; Benczédi, D.; Weder, C.; Foster, E. J. Controlled Fragrance Release from Galactose-Based Pro-Fragrances. RSC Adv. 2014, 4, 50882. 8 Holbrey, J. D.; Rogers, R. D. Melting points and phase diagrams. In: Wasserscheid, P.; Welton, T. (Eds.) Ionic Liquids in Synthesis, 1st ed., pp. 41-55, 2002, Weinheim: WileyVCH Verlag GmbH & Co. KGaA. 9 Rogers, R. D.; Seddon, K. R. (Eds.) Ionic Liquids: Industrial Applications for Green Chemistry. ACS Symposium Series 818, American Chemical Society: Washington DC, 2002. 10 Smiglak, M.; Metlen, A.; Rogers, R. D. The Second Evolution of Ionic Liquids: From Solvents and Separations to Advanced Materials—Energetic Examples from the Ionic Liquid Cookbook. Acc. Chem. Res. 2007, 40, 1182. 11 SciFinder search. Search term ‘ionic liquids,’ refining on ‘fragrance,’ accessed June 09, 2018. 12 Rebelo, L. P. N.; Lopes, J. N. C.; Esperanca, J. M. S. S.; Filipe, E. On the Critical Temperature, Normal Boiling Point, and Vapor Pressure of Ionic Liquids. J. Phys. Chem. B 2005, 109, 6040. 13 Earle, M. J.; Esperança, J. M. S. S.; Gilea, M. A.; Canongia Lopes, J. N.; Rebelo, L. P. N.; Magee, J. W.; Seddon, K. R.; Widegren, J. A. The Distillation and Volatility of Ionic Liquids. Nature 2006, 439, 831. 14 Lozano, P.; Bernal, J. M.; Lajarin, A.; Romera, D.; Garcia-Verdugo, E.; Sanchez-Gomez, G.; Pucheault, M.; Vaultier, M.; Burguete, M. I.; Luis, S. V. A Green Approach for Producing Solvent-free Anisyl Acetate by Enzyme-catalyzed Direct Esterification in

22


Page 23 of 27 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Sponge-like Ionic Liquids Under Conventional and Microwave Heating. Curr. Green Chem. 2014, 1, 145. 15 Forsyth, S. A.; Gunaratne, H. Q. N.; Hardacre, C.; McKeown, A.; Rooney, D. W.; Seddon, K. R. Utilisation of Ionic liquid Solvents for the Synthesis of Lily-of-the-Valley Fragrance {beta-Lilial (R); 3-(4-t-butylphenyl)-2-methylpropanal}. J. Mol. Catal. A 2005, 231, 61. 16 de los Ríos, A. P.; Hernández-Fernández, F. J.; Tomás-Alonso, F.; Gómez, D.; Víllora, G. Synthesis of Flavour Esters Using Free Candida Antarctica Lipase B in Ionic Liquids. Flavor Fragr. J. 2008, 23, 319. 17 Bica, K.; Gaertner, P.; Rogers, R. D. Ionic Liquids and Fragrances – Direct Isolation of Orange Essential Oil. Green Chem. 2011, 13, 1997. 18 Domańska, U.; Okuniewska, P.; Markowska, A. Phase Equilibrium in Binary Systems of Ionic Liquids, or Deep Eutectic Solvents with 2-Phenylethanol (PEA), or Water. Fluid Phase Equilib. 2016, 424, 68. 19 Xia, S. Method for extracting flavor from Passiflora edulis fruit, Faming Zhuanli Shenqing, CN 104450185A, 2015. 20 Jiao, J.; Gai, Q.-Y.; Zu, Y.-G.; Luo, M.; Zhao, C.-J.; Li, C.-Y. Microwave-Assisted Ionic Liquids Treatment Followed by Hydro-Distillation for the Efficient Isolation of Essential Oil from Fructus forsythiae Seed. Sep. Purif. Technol. 2013, 107, 228. 21 Zhai, Y.; Sun, S.; Wang, Z.; Cheng, J.; Sun, Y.; Wang, L.; Zhang, Y.; Zhang, H.; Yu, A. Microwave Extraction of Essential Oils from Dried Fruits of Illicium verum Hook. f. and Cuminum cyminum L. Using Ionic Liquid as the Microwave Absorption Medium. J. Sep. Sci. 2009, 32, 3544.

23



Page 24 of 27

22 Hu, F.; Li, M.; Li, P. A method for extracting ginger essential oil, Faming Zhuanli Shenqing Gongkai Shuomingshu CN 104232311A, CN 104232311B, 2014. 23 Arce, A.; Pobudkowska, A.; Rodriguez, O.; Soto, A. Citrus Essential Oil Terpenless by Extraction Using 1-Ethyl-3-methylimidazolium Ethylsulfate Ionic Liquid: Effect of the Temperature. Chem. Eng. J. 2007, 133, 213. 24 Berton, P.; Bica, K.; Rogers, R. D. Ionic Liquids for Consumer Products: Dissolution, Characterization, and Controlled Release of Fragrance Compositions. Fluid Phase Equilib. 2017, 450, 51. 25 Petrat, F.-M.; Schmidt, F.; Stutzel, B.; Kohler, G. Fragrance composition comprising at least one ionic liquid, method for production and use thereof, US Pat., 20060166856 A1, 2003. 26 Li, M.; Li, Z. Long-acting fragrance fixing agent, Faming Zhuanli Shenqing Gongkai Shuomingshu CN 103656721A, 2014. 27 He, J. Faint scent type car glass cleaning agent, Faming Zhuanli Shenqing Gongkai Shuomingshu CN 103614252A, CN 103614252B, 2014. 28 Holland, L. A. M.; Todini, O.; Eike, D. M.; Velazquez Mendoza, J. M.; Tozer, S. A.; Mcnamee, P. M.; Stonehouse, J. R.; Staite, W. E.; Fovargue, H. C. R.; Gregory, J. A.; Seddon, K. R.; Gunaratne, H. Q. N.; Puga, A. V.; Estager, J.; Wu, F.-L.; Devine, S. D.; Blesic, M.; Ferrero Vallana, F. M. Fragrance compositions comprising ionic liquids, PCT Int. Appl. WO 2017075299 A1 20170504, 2017. 29 Ferrero Vallana, F. M.; Girling, R. P.; Nimal Gunaratne, H. Q.; Holland, L. A. M.; Mcnamee, P. M.; Seddon, K. R.; Stonehouse, J. R.; Todini, O. Ionic Liquids as Modulators of Fragrance Release in Consumer Goods. New J. Chem. 2016, 40, 9958. 24


Page 25 of 27 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


30 Ferrero Vallana, F. M.; Holland, L. A. M.; Seddon, K. R.; Todini, O. Delayed Release of a Fragrance from Novel Ionic Liquids. New J. Chem. 2017, 41, 1037. 31 Cetti, J.; Eike, D.; Ferrero Vallana, F. M.; Gunaratne, H. Q. N.; Holland, L. A. M.; Puga, A. V.; Seddon, K. R.; Todini, O. Modeling the Vapor–Liquid Equilibria of Ionic Liquids Containing Perfume Raw Materials. J. Chem. Eng. Data 2017, 62, 2787. 32 Bianchetti, G. O.; Tozer, S. A.; McNamee, P. A.; Holland, L. A. M.; Seddon, K. R.; Gunaratne, H. Q. N., Devine, S. D.; Estager, J.; Wu, F.-L.; Puga, A. V. Ionic liquid systems, US 2016/017722 A1 20161229, 2016. 33 Schwab, M. (Ed.) Encyclopedia of Cancer, 2011 ed., 2011, Springer, Berlin, Heidelberg. 34 Gunaratne, H. Q. N.; Nockemann, P.; Seddon, K. R. Pro-Fragrant Ionic Liquids with Stable Hemiacetal Motifs: Water-Triggered Release of Fragrances. Chem. Commun. 2015, 51, 4455. 35 Devlin, C. Ionic liquids come up smelling of roses. Chemistry World, April 16, 2015. https://www.chemistryworld.com/news/ionic-liquids-come-up-smelling-ofroses/8455.article, accessed June 9, 2018. 36 Blesic, M.; Gunaratne, H. Q. N.; Nockemann, P.; McCarron, P.; Seddon, K. R. Controlled Fragrance Delivery in Functionalised Ionic Liquid-Enzyme Systems. RSC Adv. 2013, 3, 329. 37 Bamford, C. H.; Howlett Tipper, C. F.; Compton, R. G. Ester formation and hydrolysis and related reactions, In: Comprehensive Chemical Kinetics, Vol. 10, Elsevier, 1972. 38 Gathergood, N.; Garcia, M. T.; Scammells, P. J. Biodegradable Ionic Liquids: Part I. Concept, Preliminary Targets and Evaluation. Green Chem. 2004, 6, 166.

25



Page 26 of 27

39 Garcia, M. T.; Gathergood, N.; Scammells, P. J. Biodegradable Ionic Liquids: Part II. Effect of the Anion and Toxicology. Green Chem. 2005, 7, 9. 40 Gathergood, N.; Scammells, P. J.; Garcia, M. T. Biodegradable Ionic Liquids: Part III. The First Readily Biodegradable Ionic Liquids. Green Chem. 2006, 8, 156. 41 Neighbouring group Participation, IUPAC Gold Book. https://goldbook.iupac.org/html/N/N04100.html, accessed May 22, 2018. 42 Hough, W. L.; Smiglak, M.; Rodríguez, H.; Swatloski, R. P.; Spear, S. K.; Daly, D. T.; Pernak, J.; Grisel, J. E.; Carliss, R. D.; Soutullo, M. D.; Davis, J. H.; Rogers, R. D. The Third Evolution of Ionic Liquids: Active Pharmaceutical Ingredients. New J. Chem. 2007, 31, 1429. 43 U.S. Food & Drug Administration. Select Committee on GRAS Substances. https://www.accessdata.fda.gov/scripts/fdcc/?set=SCOGS, accessed May 29, 2018. 44 Hofmeister, I.; Landfester, K.; Taden, A. pH-Sensitive Nanocapsules with Barrier Properties: Fragrance Encapsulation and Controlled Release. Macromolecules, 2014, 47, 5768. 45 Munjal, M.; ElSohly, M.A.; Repka, M. A. Chemical Stabilization of a ∆9Tetrahydrocannabinol Prodrug in Polymeric Matrix Systems Produced by a Hot-melt Method: Role of Microenvironment pH. AAPS PharmSciTech 2006, 7, E1-E12. 46 Pop, E. Nonpsychotropic Synthetic Cannabinoids. Curr Pharm Des. 2000, 6, 1347-1360. 47 Boethling, R. S.; Lynch, D. G. In: de Oude, N. T. (Ed.) The Handbook of Environmental Chemistry. Springer-Verlag: Berlin, 1992; Vol. 3, p 144. 48 Boethling, R. S. In: Cross, J., Singer, E. J. (Eds.) Cationic Surfactants. Marcel Dekker, Inc.: New York, 1994; Vol. 53, p 95. 26


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