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Aggregation and Morphological Aptitude of Drug-Based Ionic Liquids in Aqueous Solution Onkar Singh,† Pankaj Singla,† Vinod Kumar Aswal,‡ and Rakesh Kumar Mahajan*,† †

Department of Chemistry, UGC-Centre for Advanced Studies-I, Guru Nanak Dev University, Amritsar 143005, India Solid State Physics Division, Bhabha Atomic Research Centre, Mumbai 400085, India

‡

S Supporting Information *

ABSTRACT: Here, we present how replacing the usual inorganic counter ion with a pharmaceutically active aromatic one can greatly affect the interfacial as well as bulk properties of ionic liquids (ILs). We have synthesized a series of novel drug-based ILs, namely, 1-alkyl-3methylimidazolium diclofenate ([Cnmim][DF]; n = 6, 8, 10, 12, and 14) abbreviated as DF-ILs, wherein DF− is a well-recognized analgesic and nonsteroidal anti-inflammatory drug. We show strong synergistic interactions between Cnmim+ and aromatic DF− attributed to reduced electrostatic repulsions and increased hydrophobicity from their incorporation, reflecting a 300-fold smaller critical aggregation concentration than that of their Cl− analogue [Cnmim][Cl]. Interfacial properties for such strongly associating systems are discussed and clearly established to have remarkably improved properties than those of their Cl− analogues. The decreasing polarity of the cybotactic region of pyrene with increase in the chain length “n” indicates an increased extent of packing of cationic head groups in the Stern layer. DF− ion seems to play a vital role in the formation of the resulting aggregates, as probed by small angle neutron scattering and transmission electron microscopy. The thermodynamical insights of the aggregation process have been studied using isothermal titration calorimetry and temperature-dependent conductivity experiments. Unilamellar vesicles are formed at extremely low concentration, and also it is the first report that puts into picture the formation of vesicles for [C6mim][DF] with such a short chain. interfacial and micellar behavior.4,11,18,22−26 However, the ILs having imidazolium cation, [Cnmim]+ are being more broadly explored for their behavior.4−8,11,13,18 In this regard, aggregation behavior of the series of ILs [Cnmim][Cl] and [Cnmim][Br] with n = 4−12 have been well reported in aqueous medium using various techniques.7,27,28 The aggregation of [C4mim][BF4] is well reported, although it is having too short an alkyl chain to exhibit micellization, which is a good achievement in this field.22,29 Rao et al. characterized the surfactant properties of a new class of ILs having hydrophobic amino acid counter ion and dodecylsulphate as anion, which is called amino acid ILs (AAILs), using conductivity, surface tension (ST), fluorescence, transmission electron microscope (TEM), and dynamic light scattering (DLS).5 The properties of AAILs are reported to be superior to those of conventional surfactants with similar alkyl chains, and their aggregation behavior was suggested to be altered depending upon the type of amino acids governed by entropic parameters. On similar lines, recently Singh et al. have synthesized, characterized, and investigated the self-assembly behavior of new ester-functionalized surface active ILs based on nicotine [CnENic][Br] (n = 8,

1. INTRODUCTION The interest in ionic liquids (ILs) from past decades is motivated by their environment friendly alternative to traditional organic solvents due to their extraordinary physiochemical properties, such as high conductivity, low vapor pressure, thermal stability, wide potential window, liquid−liquid extraction.1−3 From the first reported IL, there is growing interest in improving the properties of ILs by fine-tuning of the head group, variation of the counter ion, as well as fictionalization of the hydrophobic part preparing ILs with enhanced properties over those of conventional ionic surfactants.4−9 A large amount of work is reported in the area of ILs, documenting their remarkable improved properties and still sparking a considerable interest.10−15 Since then, ILs emerge into three generations classified according to their specific properties and characteristics.16,17 ILs in first generation are well documented with their unique physical properties, such as decreased vapor pressure and high thermal stability.18 Progressing to the next stage that is called the second generation of ILs will be by retaining the core desired features, with modified properties produced by both physical and chemical alterations.19−21 In this regard, various surface-active ILs having different cations, such as morpholinium, pyridinium, imidazolium, pyrolidinium, nicotine, and amino acids, have been extensively studied to explore their © 2017 American Chemical Society

Received: May 9, 2017 Accepted: June 23, 2017 Published: July 7, 2017 3296

DOI: 10.1021/acsomega.7b00578 ACS Omega 2017, 2, 3296−3307

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10, and 12), with bromide counter-ions.15 These ILs are found to have lower critical micellar concentration (cmc) than that of homologous ILs or conventional cationic surfactants and also reported to be noncytotoxic toward C6 glioma cell line for their possible deployment in diverse biomedical applications. Heading toward the next generation, third generation ILs have been explored for their biological activity and broadening their applicability as potentially valid active pharmaceutical ingredients (APIs).16,30−33 Solid forms of APIs are often known to suffer from poor solubility, and also polymorphic conversion influences their therapeutic effects.11 APIs with IL properties (API-ILs) are largely discussed in the above stated context and have been proven to have the highlighted advantages.30,34−36 Thus, it is important to design novel API-ILs having pharmaceutical importance and also to study their physiochemical properties in detail. As far as we know, there are only few reports on the development of novel API-ILs, with their detailed micellar and interfacial behavior. In this regard, Viau et al. synthesized and investigated the micellization behavior of [Cnmim]+ (n = 4, 6, and 8) and ibuprofenate anion in their aqueous solutions, using ST, conductivity, NMR self-diffusion, and DLS techniques.34 In their later study, they also studied the aggregate structures using DLS, cryogenic-TEM, 1H NMR measurements, and atom-scale molecular dynamics simulations.35 Recently, the IL transdermal system has been developed for the treatment of pain and inflammation, for which nonclinical and clinical results showed the safety and tolerability of the product, proving to be a great success in this field.37 Although API-ILs have potential of a very promising pharmaceutical strategy, various aspects, such as toxicity and biodegradability of ILs, are yet to be considered.38 The environmental fate of ILs is now opening doors to expand the number of studies on toxicity and biodegradability of ILs. In some cases, imidazolium-based ILs (used in the present study) were also reported to be toxic; however, at the same time, these ILs were also verified to have remarkable inhibitory results, such as low concentrations of C16mimCl that strongly inhibited growth of multidrug-resistant Candida tropicalis. Gathergood et al.39 proposed that toxicity is significantly reduced with the insertion of an oxygen atom in the side chains of the imidazolium cation and enhances primary biodegradability.40 Despite the fact that cytotoxicity increases with the elongation of the alkyl chain some exceptions were also reported.41,42 Moreover, the physical and chemical (lipophilic and/or unstable nature) characteristics of anions that constitute ILAPI also influence the cytotoxicity.43 Costa and his co-workers evaluated bioassays on the basis of inhibition of human carboxylesterase 2 and Vibrio fischeri to judge the ecotoxicity of some selected IL-APIs.44 Interesting results were drawn; accordingly, 1-ethyl-3-methylimidazolium salicylate may be considered practically harmless, although it is slightly toxic than its starting material; benzalkonium salicylate and cetylpyridinium salicylate were slightly toxic.44 Thus, by exchanging the inorganic anion with one having pharmaceutically active species may result in decrease of cytotoxicity of employed ILs. Both cation and anion structures play an important role in determining the toxicity, and future studies (including our own research group) now involve the cytotoxicity study of IL-API, which is to be used in higher stages of drug development. In the case of micelles, vesicles, bilayers, and so forth, transformation among these various self-assembled structures

upon exchanging the inorganic counter ion by pharmaceutically important ions have also been a wide area of research.4,6,30,34−36 Vesicles gained much importance due to their widespread applications in drug−gene delivery, bioseparation, sensitivity for cosmetic industry and nanostructured systems, and sensing.45 However, because of their ease of preparation, long-term stability, low cost, and ease of storage, catanionic vesicles are well deployed in the pharmaceutical industry.46 However, to date, toxicity as well as low entrapment efficiency of catanionic vesicles greatly limit their further possibility in the field of the drug-delivery system.45 Therefore, it is of great interest to minimize toxicity, enhance the entrapment efficiency, and lessen the tedious chemical synthesis so as to discover an excellent drug-delivery application.45 Here, we have synthesized the highly viscous prodrug liquid by simple mixing of an equimolar amount of diclofenac sodium salt (DFNa) and 1methyl-3-alkylimidazolium chloride in butanol by removing NaCl with filtration. By this method, we have synthesized a series of novel DF-ILs (Scheme 1), namely, 1-alkyl-3Scheme 1. Structure of DF-ILs, [Cnmim][DF]

methylimidazolium diclofenate ([Cnmim][DF]; n = 6, 8, 10, 12, and 14), wherein DF− is a well-recognized analgesic and nonsteroidal anti-inflammatory drug (NSAID). Thus, the property of ILs can be fine-tuned for their use as API simply by replacing inorganic anions (Cl−, Br−, BF4−, etc.) with anions having pharmaceutical importance. The motive of the present work is to investigate the effect of DF− on the micellization and aggregation behavior of imidazolium-based cations. Another fundamental interest of this study lies in the fact that substitution of DF− may affect micellization and structure of resulting aggregates. It is also interesting to compare the properties of synthesized ILs with those of other reported homologous amphiphilic ILs [Cnmim][Cl]. However, their pharmaceutical potential is yet to be discovered and will constitute a part of our future studies. The interfacial behavior of [Cnmim][DF]; n = 6, 8, 10, 12, and 14, has been largely discussed in terms of various parameters, such as ST at critical aggregation concentration (cac), that is, γcac, adsorption efficiency (pC20), the ST reduction effectiveness (Πcmc), saturation adsorption (Γmax), and minimum surface area per molecule (Amin). The improved properties of these DF-ILs by comparing with [Cnmim][Cl] have also been highlighted. The degree of counterion binding (β) and various thermodynamic parameters, such as standard free energy of aggregation (ΔG°agg), standard enthalpy of aggregation (ΔH°agg), and standard entropy of aggregation (TΔG°agg) have been evaluated and discussed using conductivity and isothermal titration calorimetry (ITC) measurements. Information about micropolarity using pyrene as probe is provided by steady state fluorescence. Morphology of the formed unilamellar vesicles (ULVs) have been well charac3297


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terized and discussed using small angle neutron scattering (SANS) and TEM after a preliminary visual inspection and turbidity measurements.

Table 1. cac Determined Using ST, Conductivity (Cond.), Steady-State Fluorescence (Flu.), Turbidity (Turb.), and Comparison of Their cac with Chloride Analogues ILs [Cnmim][Cl]a

[Cnmim][DF]

2. RESULTS AND DISCUSSION 2.1. Micellization: cac. The micellization of synthesized DF-ILs was studied by ST (γ), conductivity, and fluorescence measurements. The change in γ as a function of DF-IL concentration (C) viz. [Cnmim][DF] (n = 6, 8, 10, 12, and 14) at 298.15 K is shown in Figure 1. It is observed from Figure 1 a

n

ST

6 8 10 12 14

2.948 1.432 0.652 0.223 0.050

cond.

flu.

turb.

ST

cond.

3.118 0.848 0.255 0.063

3.791 2.69 0.901 0.451 0.078

3.672 2.603 0.870 0.205 0.069

900 220 55.0 13.17 3.40

234 60.0 13.47 3.15

8.

in the chain length.5 It is well reported in the literature that electrostatic and hydrophobic interactions play a vital role in the formation of micelles and vesicles.6,48 The huge decrease in cac values of DF-ILs may be due to the following two reasons. First, the electrostatic repulsions between positively charged imidazolium headgroups of Cnmim+ are well screened by negatively charged aromatic diclofenate (DF−) due to their poor hydration as compared to that of the heavily hydrated small Cl−. These decreased electrostatic repulsions enhance adsorption of Cnmim+ at the air/liquid interface before aggregation as well as facilitate an early formation of aggregates.6 Second, the increased hydrophobicity from the incorporation of the DF− aromatic group can also be responsible for decreased cac values. DF− has a weak tendency to be moved away from the palisade layer of aggregates because of the hydrophobic effect, which plays a crucial role in promoting vesicle formation (discussed later on). The explanation of reduced cac may also be explained on the basis of π−π interaction owing to the aromatic counter ion DF−. It is also well established in our previous study that there are strong π−π stacking interactions between the oppositely charged moieties, contributing a synergic effect to aggregation.49 Plots of specific conductance (κ) as a function of DF-IL concentration (C) at 298.15 K measured by conductivity are shown in Figure 2, and in these plots, the intersection point is regarded as cac. Thus, evaluated cac values are found to be in fair agreement with the values observed from ST (Table 1). The free counter-ions are responsible for the conductivity of aqueous solution before the formation of aggregates. But when aggregates are formed after cac, the free counter ions bind at the stern layer of the aggregates, decreasing the conductivity of the solution. Because the sensitivity of conductivity depends upon the degree of counter-ion binding phenomenon, it is unable to depict the cac of [C6mim][DF]. There may be three possible reasons for these observations (i) there is no aggregation for [C6mim][DF], (ii) even before micellization, DF− remains partially associated with C6mim+ due to their ion−pair complex formation tendency; (iii) extensive hydration of C6mim+ due to its smaller size, which weakens the hydrophobicity of C6mim+. The absence of aggregation is ruled out because aggregation is confirmed by SANS and TEM measurements. Moreover, all of the studied DF-ILs are speculated to form ion−pair complexes similar to those of C6mim+; however, they show a sharp break point. 2.2. Counter-Ion Binding and Effect of Temperature. The degree of counter-ion binding (β) can be estimated from electrical conductivity measurements using the equation β = 1 − α. Here, the degree of counter-ion dissociation (α) can be obtained by Frahm’s method, that is, from the ratio between

Figure 1. Plots of ST (γ) as a function of concentration (C) of DF-ILs ([Cnmim][DF]) in aqueous solution at 298.15 K. Inset shows the variation of ln cac versus number of carbon atom (n) of the alkyl chain of DF-ILs ([Cnmim][DF]).

that with gradual addition of DF-ILs γ decreases initially up to a certain concentration and then remains constant. The initial decrease in γ clearly indicates that DF-IL molecules are adsorbed at the air/solution interface. A constant value of γ, regarded as the breakpoint in γ versus C plots, is referred as cac, confirming the formation of micelles. The absence of any minimum at the breakpoint just denied the presence of any surface active impurity in the synthesized DF-ILs.47 Further purity of these DF-ILs was confirmed by high-resolution mass spectrometry (HRMS) and 1H NMR. Similarly, cac values are also obtained from conductivity and fluorescence measurements from their obvious changes and are provided in Table 1 together with corresponding cac values of [Cnmim][Cl] (Cl analogue) reported elsewhere.8 If we compare their cac values from Table 1, it is observed that cac values of DF-ILs are much smaller than those of their corresponding Cl− analogues. Moreover, the cac values of DF-ILs are even much lower than those of the ILs associating an aromatic ibuprofenate anion and [Cnmim+; n = 4, 6, 8] cation.34 Thus, we may propose that our newly synthesized DFILs are best in terms of their reduced cac. Further, on considering the effect of alkyl chain length (n) on cac values, a linear relationship between ln cac and “n” was observed, as shown in inset of Figure 1. The cac value decreased by a factor of 60 on going from n = 6 to 14, indicating a considerable enhancement in the spontaneity of aggregation with an increase 3298


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Figure 2. Plots of specific conductivity (κ) as a function of concentration (C) of DF-ILs ([Cnmim][DF]) for (a) n = 6 and 8 and (b) n = 12 in aqueous solution at 298.15 K. Inset shows similar plots for n = 10 and 14 analogue.

the slopes of conductivity curves above and below the cac. The values of β for DF-ILs at different temperatures are summarized in Table S1 in Supporting Information. The β values of DF-ILs are found to be larger than those of their corresponding Cl− analogues. Because the degree of hydration of smaller sized Cl− is more as compared to that of larger aromatic DF−, this in turn weakens Cl− binding to aggregates. Also, it is worth mentioning here that β decreases with increasing n in DF-ILs, which is in accordance to general observations.50 Further, to know the temperature dependence of cac, it is determined at three different temperatures in the range 298.15−318.15 K, as shown in Figure S1. It can be concluded from the summarized values in Table S1 that cac values decrease with increasing temperature. Two opposite processes may alter the cac values, the predominant factor will finally decide the observed trend. First, with increasing temperature, the hydration degree of DF− may decrease, facilitating aggregate formation, and this should decrease cac values. Second, intensification of molecular thermal motion with increasing temperature may destroy the ordered water structures surrounding the hydrophobic group which disfavors aggregation and hence increases cac values. The increase in cac values being dependent on temperature (Table S1) indicate the predominant role of the first process in aggregation. Moreover, β values are found to decrease with increasing temperature, reflecting that the stronger thermal motion of DF− plays a predominant role in weaker hydration. 2.3. Interfacial Parameters. The capability of an amphiphile to decrease the ST can be measured by two interfacial parameters: (i) the efficiency of adsorption at air/ solution interface (pC20) and (ii) the effectiveness of ST reduction (Πcac). pC20 is calculated by taking the negative logarithm of C20, where C20 stands for the concentration of amphiphile required to reduce the ST of pure solvent by 20 mN m−1.51,52

pC20 = −log C20

Table 2. Various Interfacial Parameters Obtained from ST Measurements at 298.15 K for DF-ILs [Cnmim][DF] n

γcac (mN m−1)

Πcac (mN m−1)

pC20

Γmax × 106

Amin (Å2)

6 8 10 12 14

41.5 34.6 32.4 32.4 32.3

30.4 34.6 39.5 39.5 39.6

2.99 3.52 3.99 4.49 5.01

1.75 1.90 1.94 2.02 2.42

94.8 87.3 85.4 81.9 68.6

values are suggestive of amphiphiles with higher adsorption efficiency.4 Furthermore, on comparing pC20 values with those of other ILs, it is quite clear that pC20 values are higher for newly synthesized DF-ILs.4−18,22−29,34−36 The higher pC20 of DF-ILs reveals their enhanced efficiency to adsorb at the air/ solution interface on increasing the hydrophobicity either by increasing the alkyl chain length or by introducing aromatic counter ion (DF−). The Πcac, which is known as surface pressure at cac, defined as πcac = γ0 − γcac (2) where γ0 is the ST of double distilled water and γcac is the ST at cac. The higher Πcac of DF-ILs than those of their Cl− analogues reflected the changed monolayer composition as well as compactness in case of the former, confirming that the monolayer at the air/solution interface not only contains imidazolium cations (Cnmim+) but also Cnmim+DF− ion pairs. Furthermore, as can be seen from Table 2, γcac of DF-ILs decreased from n = 6 to 14, indicating the greater efficiency of C14mimDF in reducing ST at the air/solution interface. Moreover, their γcac values are quite lower than those of their Cl− and Br− analogues.7,27,28 Moreover, low γcac values for DFILs represent an interface that is densely packed. This was demonstrated by estimating the maximum surface excess concentration (Γmax) and the minimum surface area of molecule (Amin) at the air/solution interface. Γmax and Amin are calculated by applying the Gibbs adsorption isotherm.53

(1)

As can be seen from Table 2, pC20 values increases by increasing the alkyl chain length (n), and these higher pC20 3299


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Γmax =

− 1 ⎛ dγ ⎞ ⎜ ⎟ mRT ⎝ d ln c ⎠

(3)

A min =

1020 NA Γmax

(4)

ratios remain constant initially and then decrease rapidly until cac is reached. After cac, the I1/I3 ratios again remain almost constant with further increase in the concentration of DF-ILs. The solubilization of pyrene in hydrophobic regions of aggregates, as a consequence of aggregation, leads to decrease in I1/I3. The concentration corresponding to the middle point of the transition is considered as cac and is provided in Table 1. The obtained values of cac are in good agreement with those obtained from other methods within limits of the technique used. The I1/I3 values upon aggregation for different DF-ILs follows the order: [C14mim][DF] (1.86) > [C12mim][DF] (1.75) = [C10mim][DF] (1.75) > [C8mim][DF] (1.49) ≈ [C6mim][DF] (1.46), which indicates the decreasing polarity of the cybotactic region of pyrene. The cybotactic region is assumed to be the region around the solute molecule where the ordering of solvent molecules is modified by the presence of solute and the I1/I3 ratio of pyrene is very much sensitive to the polarity of cybotactic region.54 The variation can be analyzed in terms of the increased extent of packing of cationic head groups in the Stern layer of aggregates while going from [C6mim][DF] to [C14mim][DF]. The observations are in line with variation in the degree of counter-ion binding (β) for the studied DF-ILs, indicating the increased compactness of vesicular structures. With increase in the alkyl chain length, the aggregates become more and more compact due to greater hydrophobic interaction between DF− and the alkyl chain. The I1/I3 ratio for [C14mimDF] is 1.77, which is found to be close to that of water (1.86), suggesting that the pyrene molecules are partly exposed to the bulk; this is only possible if the probe molecules are solubilized in nonspherical aggregates like a flat bilayer or highly compact vesicular structures.55 A similar explanation of high I1/I3 values for sodium 2-dodecylnicotinate was reported by Roy et al.55 Dey et al. also reported similar kind of results for sodium-N-(11-acrylamidoundecanoyl)-glycinate and L-alaninate.56 2.5. Thermodynamics Properties of Micellization. The standard Gibbs free energy of aggregation ΔG°agg for DF-ILs at different temperatures was calculated using the following equation51

where dγ/d ln c is the maximum slope obtained in the plots of γ versus log[C]. NA, R, C, and T are Avogadro’s number, gas constant, concentration of surfactant, and temperature (K), respectively. The value of “m” represents the number of solute species whose concentration varies with the IL’s concentration at the interfacial layer and is taken as 2. The summarized Γmax values in Table 2 clearly depict that on increasing n in the [Cnmim][DF] series Γmax values increase and consequently Amin values decrease. This indicates that the interactions between oppositely charged Cnmim+ and DF− were electrostatic, accompanying hydrophobic interactions, and indicative of Cnmim+DF− ion pairing under cooperative interactions. Thus, the synergic effect between the positively charged imidazolium ring and negatively charged DF− moieties is resultant from both π−π stacking and electrostatic attraction, in addition to hydrophobic interactions.49 It is previously reported that DF− intercalated in the hydrophobic microdomain near the imidazolium ring.49 Because of this penetration of DF−, the electrostatic repulsion between imidazolium rings significantly screened, resulting in decrease of Amin, that is, increase in the packing of molecules, which in turn leads to the formation of vesicles (discussed later on). 2.4. Micropolarity: I1/I3 Ratio of Pyrene. To investigate the microenvironment of the self-assembly, fluorescence studies were performed using pyrene as an extrinsic fluorescence probe because pyrene molecules bind preferentially to the hydrophobic region of the self-assemblies. Relative intensities of the vibronic bands (I1/I3) of pyrene fluorescence in the aqueous solutions of various DF-ILs as a function of concentration are plotted in Figure 3. For all of the DF-ILs, the respective I1/I3

ΔG°agg =(1 + β)RT ln Xcac

(5)

where β, R, T, and Xcac are degree of counter ion binding, gas constant, temperature, and cac of DF-ILs expressed in terms of mole fraction, respectively. ΔG°agg is negative at all temperatures, indicating spontaneity of the processes, and becomes larger with increase in the alkyl chain length (Table S1). The hydrophobic forces of attractions between the alkyl chain lengths increase upon increasing their lengths, which in turn favors the formation of aggregates. Moreover, the obtained values ΔG°agg for DF-ILs are higher than those of their chloride analogue, indicating that the process of aggregation is more feasible in the case of the former.27,57−60 This again justifies the important role of weakly hydrated aromatic DF− in acceleration of the aggregation process by increasing the hydrophobicity and at the same time decreasing the electrostatic repulsion between headgroups as compared to that in heavily hydrated Cl−. The enthalpy of aggregation ΔH°agg was calculated by applying the Gibbs−Helmholtz equation. ΔH °agg = −(1 + β)RT 2(∂ ln Xcvc /∂T )P

Figure 3. Plots of pyrene polarity ratio (I1/I3) as a function of concentration (C) of DF-ILs ([Cnmim][DF], n = 6, 8) in aqueous solution at 298.15 K. Inset shows similar plots for n = 10, 12, and 14 analogue.

(6)

The obtained ΔH°agg values are found to be negative for all of the studied DF-ILs and become more negative with increasing 3300


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of counterion binding (β), aggregation number (Nagg), and the dilution of micelles.63 However, the enthalpy changes after cmc are mainly contributed by dilution of added micelle or electrostatic repulsion between the forming micelles. The shapes of enthalpy curves reveal very interesting results: (i) the first plateau in the enthalpy curve of [Cnmim][DF] (n = 6, 8, and 10) is sloped, which is more pronouncedly sloped for n = 6, (ii) whereas the enthalpograms for n = 12 and 14 are relatively flat; (iii) the second plateau is almost similar and flat in all studied ILs. In the case of shorter chain ILs, cmc is quite high as a result of higher concentrations used in the injected solution and so the behavior of the solution in the sample cell cannot be assumed to be ideal. Moreover, the enthalpy curves for n = 6 and 8 could be classified as type B; that is, change is less sharp, in which the micelle−micelle interactions commence to impact the enthalpy changes.64 The enthalpy curves for n = 10, 12, and 14 could be classified as type A, wherein heat changes sharply between the two plateaus.64 The graphical extrapolation method is adopted, as mentioned elsewhere, to obtain ΔH°agg and cac values.17 Thus, the obtained cac values are used in eq 5 to evaluate ΔG°agg, and these values are used in the Gibbs−Helmholtz equation to calculate ΔS°agg. The evaluated ΔG°agg values are in accordance with those observed from conductivity measurements; however, ΔH°agg obtained from conductivity and ITC techniques differed in magnitude. The difference arises due to contribution of a different physiochemical process other than that of the aggregation in the ITC experiment involving enthalpy change.65 Although ΔH°agg values differ in magnitude, their variation trend is similar. The variation of β with increase in n [Cnmim][DF] follows the reverse order to that of enthalpy change. This indicates that the enthalpy changes are not controlled only by the screening of electrostatic repulsions between ionic head groups which are known to give rise to exothermic changes. Thus, possible π−π interactions between DF− ion and the Cnmim+ head group and also hydrophobic interactions due to hydrophobic nature of DF governs the total enthalpy change. As observed from Table 3, aggregation of

temperature, which is in accordance with results of conventional ILs/surfactants (Tables S1).61,62 The negative ΔH°agg indicates that the process of micellization is exothermic in the investigated temperature range.6 The entropy of aggregation (ΔS°agg) was calculated using the following equation ΔS°agg = (ΔH °agg − ΔG°agg )/T

(7)

The entropy of aggregation is found to be positive for all studied temperatures, and its magnitude decreases with increase in temperature (Table S1). The aggregation process is mainly driven by entropy initiated by the highly ordered caged water structure molecules around the IL monomers. The contribution of entropy toward aggregation decreases upon increasing the temperature because water molecules become less ordered around the hydrophobic domain of DF-ILs at higher temperatures. ITC is very useful to understand the reorganization of IL monomers into aggregates, which relies only on determining the heat evolved during the molecular interaction. ITC, in addition to conductivity, was also employed to determine cac, ΔG°agg, ΔH°agg, ΔS°agg (Table 3), and the calorimetric titration Table 3. ITC Derived cac, Enthalpy of Aggregation (ΔH°agg), Standard Gibbs Free Energy of Aggregation (ΔG°agg), and Entropy of Aggregation (TΔS°agg) of DF-ILs in an Aqueous Medium at 298.15 K [Cnmim][DF] n

cac (mM)

ΔH°agg (kJ mol−1)

ΔG°agg (kJ mol−1)

TΔS°agg (kJ mol−1)

6 8 10 12 14

2.654 1.695 0.784 0.168 0.082

−19.6 −0.4 −1.25 −2.08 −6.61

−44.07 −46.76 −51.30 −48.63

43.67 45.51 49.22 42.02

curves of DF-ILs as a function of concentration (C) at 298.15 K are presented in Figure 4. The enthalpy changes in the aqueous IL solution are dependent upon various factors, such as degree

Figure 4. Plots of enthalpy changes as a function of concentration (C) of DF-ILs ([Cnmim][DF], n = 14, 12) in aqueous solution at 298.15 K. 3301


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Figure 5. Phase behavior and pictorial representation of structural transitions of [Cnmim][Cl] to [Cnmim][DF], where n = 6, 8, 10, 12, and 14.

Figure 6. (a) Representative SANS data patterns and (b) variation of ULV’s thickness (t) versus number of carbon atoms (n) of alkyl chain for DFILs ([Cnmim][DF], n = 6, 8, 10, 12, and 14).

different from that of chloride analogues. First, we looked upon the phase behavior of the above synthesized DF-ILs by visual inspection, and the results are further evidenced by turbidity measurements. Considering this, a series DF-ILs and their chloride analogues at a concentration 10 times that of cac were prepared and the typical image sequence for this is shown in Figure 5. It clearly depicts that the solution of CnmimCl is transparent over a range of alkyl chain lengths from n = 6 to 14, whereas the synthesized DF-ILs turn out to be turbid, with a bluish color arising, which seems to be quite interesting. This infers that these cloudy solutions may contain larger aggregates, above tens of nanometers. The vesicles appear to be stable for weeks (no aggregation within the vesicular solution detectable, as evidenced from visible inspection). Figure S2 represents the turbidity versus C curve for the synthesized DF-ILs in aqueous solution. The characteristic feature of these curves is an abrupt

studied DF-ILs is an entropy-driven phenomenon because of its greater contribution to the variation in ΔG°agg.

3. MORPHOLOGY: SIZE AND SHAPE OF AGGREGATES 3.1. Phase Behavior by Visual Inspection and Turbidity Measurements. In conventional ILs (first generation), the counter ion bound at the stern layer cationic micelles and reduced the electrostatic repulsions among the surfactant headgroup thus facilitating the aggregation. Exchanging the heavily hydrated small inorganic ions (Cl− and Na+) with the poorly hydrated aromatic diclofenate (DF−) may endow an additional π−π stacking interaction between the imidazolium headgroup and diclofenate rings. Owing to the synergistic interactions already discussed, we may expect that the morphology of resulting aggregates of the DF-ILs should be 3302


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Figure 7. TEM images of ULVs formed by [Cnmim][DF], n = 6, 8, 10, 12, and 14. Inset to each image shows the enlarged TEM image of the area enclosed by dashed lines.

increase in turbidity as C is increased progressively. This behavior signalizes aggregation after attaining a particular concentration corresponding to cac, and these obtained values of cac are in good agreement with those obtained from other techniques (Table 1). Thus, following these initial qualitative evaluations, the fine details of these aggregates were probed by SANS and TEM measurements 3.2. SANS Measurements. The SANS scattering curves for the synthesized DF-ILs at a concentration 10 times that of cac and their associated fits are shown in Figure 6a. The absence of any correlation peak and scattering on a log− log scale at a low Q range suggested the formation of ULVs for all of the synthesized DF-ILs in these concentration regions (Figure 6a). A slope of −2 on a log−log scale corresponds with the formation of ULVs. Further, the absence of the multilamellar structure is confirmed from the fact that scattering data do not show any Bragg peak coming from the repetition of lamella.49 The thickness of the vesicles is decided by cutoff in the higher-Q region, and thus evaluated thicknesses of vesicles are plotted and listed in Figure 6b. The thickness (t) of the vesicles increases from 1.5 to 3.8 nm, as the alkyl chain length increases from n = 6 to 14. On comparing the Cl− analogues of DF-ILs, it is found that they form only prolate micelles and not vesicles even at their much higher concentration than that used in the present study.29,66 The role of specificity of the counterion interactions with the headgroup of ionic surfactants to generate vesicles can be better explained in light of Collin’s law.67−69 Cosmotropic ions undergo strong hydration owing to

high surface charge density, whereas the opposite is true for chaotropic ions (weak hydration). Imidazolium rings of ILs have large surface areas and thus are regarded as chaotropic. Cl− is assumed to be cosmotropic due to concentration of negative charge on a small atom, whereas DF− is considered to be chaotropic because the charge is localized on a larger aromatic moiety. Thus, DF− ions may interact with the imidazolium headgroup more sturdily than Cl− and as a result dehydration of the head group and the counterion occurs following Collin’s law. Moreover, DF− has more hydrophobicity, favoring the strong binding of DF− to the alkyl chain of Cnmim+ and deep penetration into the interior of the palisade layer of the ULVs releasing water molecules. Furthermore, dehydration of the head group and counter ion during binding decreases the area of headgroup (a) and increases packing parameter (P), facilitating the vesicle formation.70 Thus, following this the synthesized DF-ILs result in spontaneous formation of vesicles, whereas their Cl− analogues are no longer in appropriate conditions even at higher concentrations to form vesicles.67,68 To facilitate interpretation of the data, the measured bilayer thickness of the vesicles for each DF-IL given along with the extended chain length calculated using Tanford’s formula are plotted in Figure 6b.71 It is clearly depicted from Figure 6b that the measured bilayer thickness of DF-IL is approximately equal to the double of the fully extended chain length of Cnmim+. Thus, it may be concluded that the alkyl chains at either end do not form looped conformations in bilayers of vesicles. In salt 3303


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free vesicles (no Na+ and Cl+), DF− is a full-time counter-ion worker deeply penetrated in the bilayer. The rigidity of DF− appears to prevent looped conformations and thus promotes a bilayer spanning conformation having thickness approximately equal to double that of the extended chain length. It is important to mention here that in our previous study the reported bilayer thickness of the mixed system of C12mimBr + DFNa and C14mimBr + DFNa was 1.46 and 1.73 nm, respectively, even lower than that of the extended chain length of Cnmim+.49 Flexible ILs, especially long saturated alkyl chains, can form looped conformation in aggregates.72 So, in a mixed system, due to the presence of counter-ion Cl− and Na+, the DF− moieties are partially inserted into the vesicle bilayer and the coiling of the flexible Cnmim+ chain leads to the formation of looped conformation having smaller thickness. However, in the present study, exchanging the counter-ion Cl− by DF− (removing Na+ and Cl−) leads to the transformation from prolate micelles to vesicles, with thickness comparable to the double of that of the extended chain length of Cnmim+. So, only exchanging the Cl− with DF− leads to the spontaneous formation of vesicles at extremely low concentration and these formed vesicles are also known as salt-free vesicles. It is also significant to compare ULV bilayer thickness of the studied ILs with the thickness of other IL mixed systems reported earlier. In this regard, our own research group monitored the ULV thickness of ILs using SANS measurements in a mixed system of CnmimCl (where n = 8, 10, and 12) and sodium dodecylbenzenesulphonate (SDBS).73 ULVs are formed in the range of 0.2−0.8 mole fraction of sodium dodecyl sulfate (XSDBS) at a total concentration of 100 mM. In each of these studied mixed systems, the bilayer thickness measured by SANS was found to be quite lower than the double of that of extended chain lengths of 8, 10, and 12 carbon-atom chains. These results further support the above mentioned coiling and looping phenomenon; that is, the absence of rigidity in one component easily leads to looping of chains and results into smaller “t” values. Interestingly, Thakkar et al. have examined the aggregation behavior of salt-free catanionic vesicles of 1-alkyl-3-methyl-imidazoliumoctylsuphate (CnmimC8SO4, where n = 8 and 12), using SANS and the bilayer thickness close to their corresponding extended chain lengths.74 Further, these results support our hypothesis of full time chain/organic-moiety counter-ion workers; that is, on removing the inorganic counter-ions, the shell thickness increases, which is also observed in our present study. As explored by SANS measurements, [C6mim][DF] surprisingly forms vesicles even though possessing a very small alkyl chain of six carbon atoms. It is important to mention here that no studies have yet reported anything that puts into picture the formation of vesicles of such short alkyl chains. 3.3. TEM Measurements. The TEM technique was used to visualize the actual morphology of the aggregates. Figure 7 is a series of TEM images of aggregates of synthesized DF-ILs at a concentration two times that of cac.Moreover, the highresolution TEM images are provided in Figure S3. The aggregates were confirmed to be vesicles by observing a void likely enveloped with a bilayer in the case of all of the studied ILs. Torn bilayers can be observed in Figure 7, leaving a hole on the vesicles. This was presumably caused by the evaporation of encapsulated water upon drying the samples. Vesicles are first assembled in an ordered arrangement and then fused together to provide different shapes (dried form), depending upon the alkyl chain length. Moreover, it is interesting to note that the

formed vesicles of [C6mim][DF] having sizes of 20−30 nm are arranged in an elliptical-shaped structure, like that of the leaf of a mango tree, along with some rod-shaped structure, whereas the vesicles of [C8mim][DF] having sizes of 25−35 nm are engrafted in the shape of a leaf of grass, although the vesicles of [C10mim][DF] and [C12mim][DF] are simply embedded in the rod-shaped structure, having sizes of 40−50 and 12−21 nm, respectively. Interestingly, the vesicles of [C14mim][DF] having sizes of 20−51 nm are self-assembled in the form of beautiful bouquet.

4. CONCLUSIONS NSAID-based DF-ILs, [Cnmim][DF] (n = 6, 8, 10, 12, and 14) have been synthesized and investigated for their interfacial and bulk behavior in aqueous solution. DF-ILs are found to have 70−305-fold smaller cacs than those of their Cl− analogues. The synthesized ILs have better interfacial, thermodynamics, and bulk properties in terms of pC20, Πcac, Γmax, Amin, β, ΔG°agg, etc. than those of their Cl− analogues. All of these improved properties and lower cac values are mainly because of three reasons: (i) The electrostatic repulsions between Cnmim+ are effectively screened by aromatic DF−, which is due to weak hydration of DF− as compared to that of the smaller Cl−. (ii) The aromatic DF− offer π−π stacking between oppositely charged Cnmim+ and DF−, contributing a synergic effect to the aggregation. (iii) The total hydrophobicity of molecules are increased due to the insertion of aromatic DF−. ULVs are formed at an extremely low concentration by only exchanging counter-ion Cl− with DF−, as evaluated by SANS and TEM measurements. The chaotropic ion−chaotropic ion interactions due to surface charges and hydrophobic interactions are attributed to the binding of the DF− ion to the Cnmim+ head group, as per Collins’ law. Moreover, the alkyl chains at either end in the bilayer of vesicles do not form looped conformation in bilayer thickness. The rigidity of DF− appears to prevent the looped conformations and thus promotes a bilayer spanning conformation having thickness approximately equal to double that of the extended chain length. Interestingly, these formed vesicles are grouped into various shapes (dried forms) depending upon the alkyl chain length analyzed by TEM images. Moreover, this is the first report that puts into picture the formation of vesicles for such a short six carbon alkyl chain. 5. EXPERIMENTAL SECTION 5.1. Materials. DFNa, 1-hexyl-3-methylimidazolium chloride, 1-chlorooctane, 1-chlorodecane, 1-chlorododecane, 1chlorotetradecane, 1-methylimidazole, and pyrene were purchased from Sigma-Aldrich, having purity ≥98% and used without further purification. Methanol, butanol, acetone, and diethyl ether (analytical reagents grade) were purchased from SD Fine-Chem Ltd., Mumbai, India. The procedure of synthesis of [Cnmim][DF] (n = 6, 8, 10, 12, and 14) along with their characterization data (1H NMR and HRMS) are provided in Section S1. Scheme 1 shows the molecular structure of synthesized DF-ILs. 5.2. Methods. 5.2.1. ST Measurements. ST measurements were carried out using a Krüss EasyDyne Tensiometer-K20 from KRÜ SS GmbH, Hamburg, Germany, using a platinum ring within the accuracy of ±0.1 mN m−1, at 298.15 K. The ST of doubly distilled water 72 ± 0.1 mN m−1 was used for calibration purposes. 3304


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ORCID

5.2.2. Conductivity Measurements. Specific conductivity measurements were carried out using a digital conductivity meter from Systronics-306, India, having the cell constant of 1.01 cm−1. Specification of conductivity measurements are: type of current is alternating current, frequency: 100 Hz or 1 kHz automatically selected according to the conductivity range, and cell constant. After every addition, the solution was equilibrated for 120 s to reach thermal equilibrium. 5.2.3. Fluorescence Measurements. Steady-state fluorescence measurements were performed using F-4600 fluorescence spectrophotometer from Hitachi, Ltd., Japan, using pyrene as an external fluorescent probe (2 μM), at an excitation wavelength of 334 nm at 298.15 K. The emission spectra of pyrene were recorded between 350 and 450 nm using excitation and emission slit widths of 2.5 nm, each. 5.2.4. ITC Measurements. ITC measurements were performed with a MicroCal iTC200 microcalorimeter at 298.15 K. The sample cell was filled with 200 μL of double distilled water. Forty microliters of DF-ILs stock solutions prepared in double distilled water were taken in an instrumentcontrolled Hamiltonian syringe, and 2 μL aliquots were added to the sample cell with continuous stirring (300 rpm). 5.2.5. Turbidity Measurements. Turbidity measurements were performed using a Digital Nephelo-Turbidity meter from Systronics-132, India, at 298.15 K after equilibration for 5 min. The temperature for the above-mentioned techniques was kept constant using an Orbit water thermostat, with an accuracy of ±0.1 K. For these measurements, the titration method was used, wherein stock solution of the respective DF-IL was added to the fixed volume of water in a sample holder followed by stirring for complete solubilization. Measurements for ST, conductivity, fluorescence, and turbidity were performed in duplicates, with an uncertainty of less than 0.4, 0.5, 0.4, and 0.3%, respectively. 5.2.6. SANS Measurements and Theoretical Details. SANS measurements were carried out, as reported earlier, using the SANS diffractometer operating at Dhruva reactor, Bhabha Atomic Research Centre, Mumbai, India.49 Theoretical details regarding SANS measurements are provided in Section S2. 5.2.7. TEM Measurements. TEM measurements were performed on a JEM-2100 electron microscope from JEOL at a working voltage of 200 kV, without staining the sample. A drop of DF-ILs solution was placed on a carbon-coated copper grid (300 mesh); thereafter the residual solution was blotted off and dried in air at room temperature for 24 h before measurements.

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Vinod Kumar Aswal: 0000-0002-2020-9026 Rakesh Kumar Mahajan: 0000-0002-3358-8934 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Financial support from UGC, New Delhi [Project F. No. 42278/2013 (SR)] and DST, New Delhi (Project No. SR/S1/ PC-02/2011) is strongly acknowledged. The authors gratefully acknowledge UGC-DAE (Bhabha Atomic Research Center, BARC), Trombay, India, and a research project (ref no. CRSM-194) for carrying out SANS measurements. One of the authors O.S. is thankful to the UPE scheme, Guru Nanak Dev University, Amritsar, for the award of research fellowship.

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(1) Wasserscheid, P.; Welton, T. Ionic Liquids in Synthesis, 2nd ed.; Wiley: New York, 2007; pp 1−776. (2) Kadokawa, J. Ionic Liquids−new Aspects for the Future; InTech: Croatia, 2013. (3) Mehnert, C. P.; Cook, R. A.; Dispenziere, N. C.; Afeworki, M. Supported Ionic Liquid Catalysis-A New Concept for Homogeneous Hydroformylation Catalysis. J. Am. Chem. Soc. 2002, 124, 12932− 12933. (4) Rao, K. S.; Singh, T.; Trivedi, T. J.; Kumar, A. Aggregation Behavior of Amino Acid Ionic Liquid Surfactants in Aqueous Media. J. Phys. Chem. B 2011, 115, 13847−13853. (5) Rao, K. S.; Trivedi, T. J.; Kumar, A. Aqueous-Biamphiphilic Ionic Liquid Systems: Self-Assembly and Synthesis of Gold Nanocrystals/ Microplates. J. Phys. Chem. B 2012, 116, 14363−14374. (6) Bi, Y.; Zhao, L.; Hu, Q.; Gao, Y.; Yu, L. Aggregation Behavior of Imidazolium-Based Surface-Active Ionic Liquids with Photoresponsive Cinnamate Counterions in the Aqueous Solution. Langmuir 2015, 31, 12597−12608. (7) Blesic, M.; Marques, H.; Plechkova, N. V.; Seddon, K. R.; Rebelo, L. P. N.; Lopes, A. Self-Aggregation of Ionic Liquids: Micelle Formation in Aqueous Solution. Green Chem. 2007, 9, 481−490. (8) Łuczak, J.; Hupka, J.; Thö ming, J.; Jungnickel, C. SelfOrganization of Imidazolium Ionic Liquids in Aqueous Solution. Colloids Surf., A 2008, 329, 125−133. (9) Blesic, M.; Lopes, A.; Melo, E.; Petrovski, Z.; Plechkova, N. V.; Lopes, J. N. C.; Seddon, K. R.; Rebelo, L. P. N. On the SelfAggregation and Fluorescence Quenching Aptitude of Surfactant Ionic Liquids. J. Phys. Chem. B 2008, 112, 8645−8650. (10) Jiao, J.; Han, B.; Lin, M.; Cheng, N.; Yu, L.; Liu, M. Salt-Free Catanionic Surface Active Ionic Liquids 1-alkyl-3-methylimidazolium alkylsulfate: Aggregation Behavior in Aqueous Solution. J. Colloid Interface Sci. 2013, 412, 24−30. (11) Kamboj, R.; Bharmoria, P.; Chauhan, V.; Singh, S.; Kumar, A.; Mithu, V. S.; Kang, T. S. Micellization Behavior of Morpholinium Based Amide Functionalized Ionic Liquids in Aqueous Media. Langmuir 2014, 30, 9920−9930. (12) Fang, D. W.; Guan, W.; Tong, J.; Wang, Z. W.; Yang, J. Z. Study on Physicochemical Properties of Ionic Liquids Based on Alanine [Cnmim][Ala] (n = 2, 3, 4, 5, 6). J. Phys. Chem. B 2008, 112, 7499− 7505. (13) Singh, G.; Singh, G.; Kang, T. S. Micellization Behavior of Surface Active Ionic Liquids Having Aromatic Counterions in Aqueous Media. J. Phys. Chem. B 2016, 120, 1092−1105. (14) Bhadani, A.; Misono, T.; Singh, S.; Sakai, K.; Sakai, H.; Abe, M. Structural Diversity, Physicochemical Properties and Application of Imidazolium Surfactants: Recent Advances. Adv. Colloid Interface Sci. 2016, 231, 36−58. (15) Singh, G.; Kamboj, R.; Mittu, V. S.; Chauhan, V.; Kaur, T.; Kaur, G.; Singh, S.; Kang, T. S. Nicotine-Based Surface Active Ionic Liquids:

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsomega.7b00578. Synthesis and characterization of [Cnmim][DF], DF-ILs; theoretical details of SANS measurements; κ−C curves for [Cnmim][DF] at different temperatures and corresponding data; turbidity−C curves for [Cnmim][DF]; high-resolution TEM images (PDF)

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REFERENCES

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*E-mail: [email protected]. Phone: +91 01832257675. Fax: +91 183 2258820. 3305


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Synthesis, Self-Assembly and Cytotoxicity Studies. J. Colloid Interface Sci. 2017, 496, 278−289. (16) 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., Jr.; Rogers, R.D. The Third Evolution of Ionic Liquids: Active Pharmaceutical Ingredients. New J. Chem. 2007, 31, 1429−1436. (17) Ferraz, R.; Branco, L. C.; Prudencio, C.; Noronha, J. P.; Peteovski, Z. Ionic Liquids as Active Pharmaceutical Ingredients. ChemMedChem 2011, 6, 975−985. (18) Deetlefs, M.; Seddon, K. R.; Shara, M. Predicting Physical Properties of Ionic Liquids. Phys. Chem. Chem. Phys. 2006, 8, 642− 649. (19) Earle, M. J.; Mccormac, P. B.; Seddon, K. R. The First High Yield Green Route to a Pharmaceutical in a Room Temperature Ionic Liquid. Green Chem. 2000, 2, 261−262. (20) Holbrey, J. D.; Seddon, K. R. Ionic Liquids. Clean Technol. Environ. Policy 1999, 1, 223−236. (21) Rogers, R. D.; Seddon, K. R. Ionic Liquids IIIB: Fundamentals, Progress, Challenges, and OpportunitiesTransformations and Processes; ACS Symposium Series 902; American Chemical Society: Washington, DC, 2005. (22) Singh, T.; Kumar, A. Aggregation Behavior of Ionic Liquids in Aqueous Solutions: Effect of Alkyl Chain Length, Cations, and Anions. J. Phys. Chem. B 2007, 111, 7843−7851. (23) Sharma, R.; Mahajan, S.; Mahajan, R. K. Physicochemical Studies of Morpholinium Based Ionic Liquid Crystals and their Interaction with Cyclodextrins. Fluid Phase Equilib. 2014, 361, 104− 115. (24) Garcia, M. T.; Ribosa, I.; Perez, L.; Manresa, A.; Comelles, F. Aggregation Behavior and Antimicrobial Activity of Ester-Functionalized Imidazolium- and Pyridinium-Based Ionic Liquids in Aqueous Solution. Langmuir 2013, 29, 2536−2545. (25) Khupse, N. D.; Kumar, A. Contrasting Thermosolvatochromic Trends in Pyridinium-, Pyrrolidinium-, and Phosphonium-Based Ionic Liquids. J. Phys. Chem. B 2010, 114, 376−381. (26) Anouti, M.; Jones, J.; Boisset, A.; Jacquemin, J.; Cailloncaravanier, M.; Lemordant, D. Aggregation Behavior in Water of New Imidazolium and Pyrrolidinium Alkycarboxylates Protic Ionic Liquids. J. Colloid Interface Sci. 2009, 340, 104−111. (27) Jungnickel, C.; Łuczak, J.; Ranke, J.; Fernanadez, J. F.; Muller, A.; Thoming, J. Micelle Formation of Imidazolium Ionic Liquids in Aqueous Solution. Colloids Surf., A 2008, 316, 278−284. (28) Goodchild, I.; Collier, L.; Millar, S. L.; Prokeš, I.; Lord, J. C. D.; Butts, C. P.; Bowers, J.; Webster, J. R. P.; Heenan, R. K. Structural Studies of the Phase, Aggregation and Surface Behavior of 1-Alkyl-3Methylimidazolium Halide+Water Mixtures. J. Colloid Interface Sci. 2007, 307, 455−468. (29) Bowers, J.; Butts, C. P.; Martin, P. J.; Vergara-gutierrez, M. C.; Heenan, R. K. Aggregation Behavior of Aqueous Solutions of Ionic Liquids. Langmuir 2004, 20, 2191−2198. (30) Pinto, P. C. A. G.; Ribeiro, D. M. G. P.; Azevedo, A. M. O.; Justina, V. D.; Cunha, E.; Bica, K.; Vasiliou, M.; Reis, S.; Saraiva, M. L. M. F. S. Active Pharmaceutical Ingredients Based on Salicylate Ionic Liquids: Insights into the Evaluation of Pharmaceutical Profiles. New J. Chem. 2013, 37, 4095−4102. (31) Hough, W. L.; Rogers, R. D. Ionic Liquids Then and Now: From Solvents to Materials to Active Pharmaceutical Ingredients. Bull. Chem. Soc. 2007, 80, 2262−2269. (32) Hough-troutman, W. L.; Smiglak, M.; Griffin, S.; Reichert, W. M.; Mirska, I.; Jodynis-liebert, J.; Adamska, T.; Nawrot, J.; Stasiewicz, M.; Rogers, R. D.; Pernak, J. Ionic Liquids with Dual Biological Function: Sweet and Anti-Microbial, Hydrophobic Quaternary Ammonium-Based Salts. New J. Chem. 2009, 33, 26−33. (33) Variankaval, N.; Cote, A. S.; Doherty, M. F. From Form to Function: Crystallization of Active Pharmaceutical Ingredients. AIChE J. 2008, 54, 1682−1688. (34) Tourné-Péteilh, C.; Devoisselle, J. M.; Vioux, A.; Judeinstein, P.; In, M.; Viau, L. Surfactant Properties of Ionic Liquids Containing

Short Alkyl Chain Imidazolium Cations and Ibuprofenate Anions. Phys. Chem. Chem. Phys. 2011, 13, 15523−15529. (35) Tourné-Péteilh, C.; Coasne, B.; In, M.; Brevet, D.; Devoisselle, J. M.; Vioux, A.; Viau, L. Surfactant Behavior of Ionic Liquids Involving a Drug: From Molecular Interactions to Self-Assembly. Langmuir 2014, 30, 1229−1238. (36) Viau, L.; Tourné-Péteilh, C.; Devoisselle, J. M.; Vioux, A. Ionogels as Drug Delivery System: One-Step Sol-Gel Synthesis Using Imidazolium Ibuprofenate Ionic Liquid. Chem. Commun. 2010, 46, 228−230. (37) ClinicalTrials.gov, 2016.https://clinicaltrials.gov/show/ NCT01161615. (38) Petkovic, M.; Seddon, K. R.; Rebelo, L. P. N.; Silva Pereira, C. Ionic Liquids: A Pathway to Environmental Acceptability. Chem. Soc. Rev. 2011, 40, 1383−1403. (39) Gathergood, N.; Scammells, P. J.; Garcia, M. T. Biodegradable Ionic Liquids: Part III. The First Readily Biodegradable Ionic Liquids. Green Chem. 2006, 8, 156. (40) Morrissey, S.; Pegot, B.; Coleman, D.; Garcia, M. T.; Ferguson, D.; Quilty, B.; Gathergood, N. Biodegradable, Non-Bactericidal Oxygen-Functionalised Imidazolium Esters: A Step towards “greener” Ionic Liquids. Green Chem. 2009, 11, 475. (41) Stepnowski, P.; Skladanowski, A. C.; Ludwiczak, A.; Laczyńska, E. Evaluating the Cytotoxicity of Ionic Liquids Using Human Cell Line HeLa. Hum. Exp. Toxicol. 2004, 23, 513−517. (42) Deetlefs, M.; Seddon, K. R. Enzymatic microreactors utilizing non-aqueous media. Chim. Oggi-Chem. Today 2006, 24, 16−23. (43) Tundo, P.; Perosa, A.; Zecchini, F. Methods and Reagents for Green Chemistry: An Introduction, 3rd ed.; Wiley: New York, 2007; pp 105−130. (44) Costa, S. P.; Justina, V. D.; Bica, K.; Vasiloiu, M.; Pinto, P. C.; Saraiva, M. L. Automated Evaluation of Pharmaceutically Active Ionic Liquids’ (Eco)toxicity through the Inhibition of Human Carboxylesterase and Vibrio fischeri. J. Hazard. Mater. 2014, 265, 133−141. (45) Jiang, Y.; Luan, Y.; Qin, F.; Zhao, L.; Li, Z. Catanionic Vesicles from an Amphiphilic Prodrug Molecule: A New Concept for Drug Delivery Systems. RSC Adv. 2012, 2, 6905−6912. (46) Wang, X.; Danoff, E. J.; Sinkov, N. A.; Lee, J.-H.; Raghavan, S. R.; English, D. S. Highly Efficient Capture and Long-term Encapsulation of Dye by Catanionic Surfactant Vesicles. Langmuir 2006, 22, 6461−6464. (47) Ghosh, A.; Dey, J. Physicochemical Characterization and Tubelike Structure Formation of a Novel Amino Acid-Based Zwitterionic Amphiphile N-(2-Hydroxydodecyl)-L-valine in Water. J. Phys. Chem. B 2008, 112, 6629−6635. (48) Dong, B.; Zhao, X.; Zheng, L.; Zhang, J.; Li, N.; Inoue, T. Aggregation Behavior of Long-chain Imidazolium Ionic liquids in Aqueous Solution: Micellization and Characterization of Micelle Microenvironment. Colloids Surf., A 2008, 317, 666−672. (49) Singh, O.; Kaur, R.; Aswal, V. K.; Mahajan, R. K. Composition and Concentration Gradient Induced Structural Transition from Micelles to Vesicles in the Mixed System of Ionic Liquid−Diclofenac Sodium. Langmuir 2016, 32, 6638−6642. (50) Wang, J.; Wang, H.; Zhang, S.; Zhang, H.; Zhao, Y. Conductivities, Volumes, Fluorescence, and Aggregation Behavior of Ionic Liquids [C4mim][BF4] and [Cnmim][Br] (n = 4, 6, 8, 10, 12) in Aqueous Solutions. J. Phys. Chem. B 2007, 111, 6181−6188. (51) Rosen, M. J. Surfactants and Interfacial Phenomena, 2nd ed.; Wiley: New York, 1989. (52) Dong, B.; Li, N.; Zheng, L.; Yu, L.; Inoue, T. Surface Adsorption and Micelle Formation of Surface Active Ionic Liquids in Aqueous Solution. Langmuir 2007, 23, 4178−4182. (53) Jaycock, M. J.; Parfitt, G. D. Chemistry of Interfaces; John Wiley & Sons: New York, 1981. (54) Kalyanasundaram, K.; Thomas, J. K. Environmental Effects on Vibronic Band Intensities in Pyrene Monomer Fluorescence and Their Application in Studies of Micellar Systems. J. Am. Chem. Soc. 1977, 99, 2039−2044. 3306


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Interaction with Triton X-100 Micelles. RSC Adv. 2016, 6, 80585− 80594.

(55) Roy, A.; Maiti, M.; Roy, S. Spontaneous Formation of Vesicles by Sodium 2-dodecylnicotinate in Water. Langmuir 2012, 28, 12696− 12703. (56) Roy, S.; Dey, J. Spontaneously Formed Vesicles of Sodium N(11-Acrylamidoundecanoyl)-Glycinate and L-Alaninate in Water. Langmuir 2005, 21, 10362−10369. (57) Ao, M.; Kim, D. Aggregation Behavior of Aqueous Solutions of 1-dodecyl-3-methylimidazolium Salts with Different Halide Anions. J. Chem. Eng. Data 2013, 58, 1529−1534. (58) Ray, D.; Das, S.; De, R.; Das, B. Sodium Carboxymethylcellulose-Induced Aggregation of 1-decyl-3-methylimidazolium Chloride in Aqueous Solutions. Carbohydr. Polym. 2015, 125, 255−264. (59) Cornellas, A.; Perez, L.; Comelles, F.; Ribosa, I.; Manresa, A.; Garcia, M. T. Self-Aggregation and Antimicrobial Activity of Imidazolium and Pyridinium Based Ionic Liquids in Aqueous Solution. J. Colloid Interface Sci. 2011, 355, 164−171. (60) Jungnickel, C.; Łuczak, J.; Ranke, J.; Fernandez, J. F.; Muller, A.; Thoming, J. Micelle Formation of Imidazolium Ionic Liquids in Aqueous Solution. Colloids Surf., A 2008, 316, 278−284. (61) Zhao, M.; Zheng, L. Micelle Formation by N-alkyl-Nmethylpyrrolidinium bromide in Aqueous Solution. Phys. Chem. Chem. Phys. 2011, 13, 1332−1337. (62) Shi, L.; Li, N.; Yan, H.; Gao, Y.; Zheng, L. Aggregation Behavior of Long-Chain N-aryl Imidazolium Bromide in Aqueous Solution. Langmuir 2011, 27, 1618−1625. (63) Bijma, K.; Engberts, J. B. F. N.; Blandamer, M. J.; Cullis, P. M.; Last, P. M.; Irlam, K. D.; Giorgio Soldi, L. Classification of Calorimetric Titration Plots for Alkyltrimethylammonium and Alkylpyridinium Cationic Surfactants in Aqueous Solutions. J. Chem. Soc., Faraday Trans. 1997, 93, 1579−1584. (64) Geng, F.; Liu, J.; Zheng, L.; Yu, L.; Li, Z.; Li, G.; Tung, C. Micelle Formation of Long-Chain Imidazolium Ionic Liquids in Aqueous Solution Measured by Isothermal Titration Microcalorimetry J. Chem. Eng. Data 2010, 55, 147 151 10.1021/je900290w. (65) Chatterjee, A.; Moulik, S. P.; Sanyal, S. K.; Mishra, B. K.; Puri, P. M. Thermodynamics of Micelle Formation of Ionic Surfactants: A Critical Assessment for Sodium Dodecyl Sulfate, Cetyl Pyridinium Chloride and Dioctyl Sulfosuccinate (Na Salt) by Microcalorimetric, Conductometric, and Tensiometric Measurements. J. Phys. Chem. B 2001, 105, 12823−12831. (66) Sastry, N. V.; Vaghela, N. M.; Aswal, V. K. Effect of Alkyl Chain Length and Head Group on Surface Active and Aggregation Behavior of Ionic Liquids in Water. Fluid Phase Equilib. 2012, 327, 22−29. (67) Collins, K. D. Ions from the Hofmeister Series and Osmolytes: Effects on Proteins in Solution and in the Crystallization Process. Methods 2004, 34, 300−311. (68) Collins, K. D.; Neilson, G. W.; Enderby, J. E. Ions in Water: Characterizing the Forces that Control Chemical Processes and Biological Structure. Biophys. Chem. 2007, 128, 95−104. (69) Thapa, U.; Dey, J.; Kumar, S.; Hassan, P. A.; Aswal, V. K.; Ismail, K. Tetraalkylammonium Ion Induced Micelle-to-Vesicle Transition in Aqueous Sodium Dioctylsulfosuccinate Solutions. Soft Matter 2013, 9, 11225−11232. (70) Israelachvili, J. N.; Mitchell, D. J.; Ninham, B. W. Theory of SelfAssembly of Hydrocarbon Amphiphiles into Micelles and Bilayers. J. Chem. Soc., Faraday Trans. 2 1976, 72, 1525−1568. (71) Tanford, C. The Hydrophobic Effect: Formation of Micelles and Biological Membranes, 2nd ed.; John Wiley and Sons: New York, 1980. (72) Hubbard, F. P., Jr.; Abbott, N. L. A Small Angle Neutron Scattering Study of the Thicknesses of Vesicle Bilayers Formed from Mixtures of Alkyl Sulfates and Cationic Bolaform Surfactants. Soft Matter 2008, 4, 2225−2231. (73) Chabba, S.; Kumar, S.; Aswal, V. K.; Kang, T. S.; Mahajan, R. K. Interfacial and Aggregation Behavior of Aqueous Mixtures of Imidazolium Based Surface Active Ionic Liquids and Anionic Surfactant Sodium Dodecylbenzenesulfonate. Colloids Surf., A 2015, 472, 9−20. (74) Thakkar, K.; Bharatiya, B.; Aswal, V. K.; Bahadur, P. Aggregation of 1-Alkyl-3-methylimidazolium octylsulphate Ionic Liquids and their 3307


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