Interaction of Hydrophobic Ionic Liquids with Lipids in Langmuir

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Interaction of Hydrophobic Ionic Liquids with Lipids in Langmuir Monolayers Amélia M. P. S. Gonçalves Da Silva Langmuir, Just Accepted Manuscript • DOI: 10.1021/acs.langmuir.7b04164 • Publication Date (Web): 08 Mar 2018 Downloaded from http://pubs.acs.org on March 11, 2018

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Interaction of Hydrophobic Ionic Liquids with Lipids in Langmuir Monolayers

Amélia M. P. S. Gonçalves da Silva Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, 1049-001 Lisboa, Portugal

E-mail address: [email protected]

ABSTRACT The interaction of two ionic liquids, trihexyl(tetradecyl)phosphonium bis(trifluoromethylsulfonyl)imide and trihexyl(tetradecyl)phosphonium dicyanamide, [P6 6 6 14][Ntf2] and [P6 6 6 14]/ [N(CN)2], with several long chained lipids with a different net charge at the hydrophilic group, a cationic surfactant, dioctadecyldimethylammonium bromide (DODAB), a zwitterionic phospholipid (DPPC), an anionic phospholipid (DPPG) and the neutral stearic acid (SA), was investigated at the water−air interface using the Langmuir trough technique. The experimental surface pressure − area (π−A) isotherms obtained for selected compositions of each binary system reveal distinct interfacial behavior. The degree and the nature of the IL−lipid interaction strongly depend on the charge distribution in the lipid polar group. Miscibility, or immiscibility, at the monolayer was inferred from the comparison of the experimental π−A isotherm with the theoretical curve calculated for the corresponding ideal mixture based on the π−A isotherms of the pure components. Phase separation and partial miscibility occurred in IL/DODAB and IL/DPPC systems respectively. In both the IL/DPPG and the IL/SA systems, a new catanionic complex was found. For the IL/SA system the catanionic complex formation varies with the subphase pH.

Kew words: ionic liquids, lipids, Langmuir monolayers

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INTRODUCTION Ionic liquids (ILs) are currently considered alternatives to traditional solvents for a wide range of industrial applications. 1,2,3 They are called green solvents due to their extremely low vapor pressure, non-flammability and high thermal stability, but their impact on human’s health and environment is not well established. On the other hand, the large range of ILs applications, in particular their use as active pharmaceutical materials4 or as excipients in drugs formulation have to be sustained by a deeper understanding of their potential biological effects and toxicity.5,6 In fact, some ILs have shown to be toxic and this matter has been the motivation of several works. 6,7 All these concerns have been inspired during the last few decades a huge number of studies on the properties of ILs as well as on the interaction of these materials with biological membranes.8,9,10,11 Experimental studies have revealed strong association of ILs with biomembranes, consistent with the observation of phospholipid bilayer disruption, at high concentrations of ILs.12,13 Evans14 reported on the nature of the membrane defects created by two particular IL components in a supported phospholipid bilayer composed of zwitterionic lipids on a silica surface. Furthermore, molecular dynamics (MD) simulations also support the hypothesis of ILs association with phospholipid membranes. Cromie et al.15, using MD simulations, found a strong affinity of two nbutyl-imidazolium ionic liquids [C4mim][Cl] and [C4mim][Ntf2] with a neutral lipid bilayer made of cholesterol molecules, while Bingham et al.16 have shown that the [C4mim]+ cation tend to spontaneously insert into the lipid bilayer of the zwitterionic 1-palmiltoyl-2-oleoylphosphatidylcholine (POPC). The toxicity of ILs depends on both anion and cation and increases significantly with the length of the alkyl side chains, generally present in the cations.6,7,17 As the long chained ILs are structurally similar to traditional surfactants,18 they spontaneously organize at interfaces in single or mixed systems. In fact, the potential amphiphilic behavior of such ionic liquids has recently attracted much attention to the promising studies at interfaces.19,20 In particular, the interaction of ILs with biomembranes components has been the subject of several studies.16,18,21 Since biomembranes consist primarily of lipid bilayers, monolayers of lipids can be considered as a simple model for the study of the interaction of ILs with the protective envelope of cells. The study of systems incorporating ILs in lipid monolayers can contribute to valuable information on the structure and packing of ionic liquids at the interface which is of utmost importance for the 2 ACS Paragon Plus Environment

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rational design of functional materials. A crucial aspect in the design and preparation of those materials is the control of intermolecular interactions and molecular packing in the first few monolayers at the surface.22,23 The Langmuir trough technique can be used to study the interfacial behavior of ILs at the air– water interface.24,25 In a previous work26 we reported the air–water interfacial behavior of two ionic liquids constituted by a common trihexyl(tetradecyl)phosphonium cation, [P6 6 6 14]+ combined with either the bis(trifluoromethylsulfonyl)imide, [Ntf2]–, or dicyanamide, [N(CN)2]–, anions. The obtained surface pressure versus mean molecular area (MMA), π−A, isotherms, and surface potential versus MMA, ΔV−A, isotherms, show distinct interfacial behavior between the two systems. The results were interpreted at a molecular level using molecular dynamics simulations: the different compression regimes along the [P6 6 6 14][Ntf2] isotherm correspond to the self-organization of the ions at the water surface into compact and planar monolayers that coalesce at the liftoff to form an expanded liquid like layer. Upon further compression, the monolayer collapses at a plateau around 12 mN m-1, yielding a progressively thick and less organized layer. These transitions, liftoff and collapse, are much more subdued in the [P6 6 6 14][N(CN)2]

system because of the more hydrophilic nature of the [N(CN)2]- anion. Two main

conclusions were inferred from that study. Firstly, it was confirmed that the extensive alkyl side chains present in the [P6 6 6 14]+ cation confer to the corresponding ionic liquids extremely low values of solubility in water and the possibility of forming Langmuir monolayers at the air−water interface. Secondly, it was found that the monolayer structure, the self-organization and packing of the ions at the water surface, are strongly influenced by the hydrophilic/hydrophobic balance in the [Ntf2]– and [N(CN)2]– counterions. [Ntf2] –, being more hydrophobic than [N(CN)2] –, induces a more stable and more organized monolayer at the air−water interface. In this work, the Langmuir technique is used to investigate the IL−lipid interactions at the air−water interface. The study comprises the interaction of [P6 6 6 14][Ntf2] and [P6 6 6 14][N(CN)2], (Scheme 1) with several long chained lipids with a different net charge at the hydrophilic group: a double-chained cationic surfactant, dioctadecyldimethylammonium bromide (DODAB), a zwitterionic phospholipid (DPPC), an anionic phospholipid (DPPG) and the neutral stearic acid (SA) (Scheme 2). These lipids were used to mimic the biomembrane composition. The choice of DPPC and DPPG is obvious since they are the main components of cellular membranes, DODAB is structurally similar to phospholipids and SA, as a fatty acid, is also an important constituent of cell structures. The behavior of selected binary compositions was examined for each system. 3 ACS Paragon Plus Environment

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Miscibility, or immiscibility, at the monolayer was inferred from the comparison of the experimental π−A isotherm with the theoretical curve calculated for the corresponding ideal mixture based on the π−A isotherms of the pure components. It was confirmed that the long alkyl side chained [P6 6 6 14]+ cation remains at the interface in the presence of charged or uncharged lipid monolayers. However, the degree and the nature of the IL−lipid interaction strongly depend on the charge distribution in the lipid polar group. Phase separation and partial miscibility occurred in IL/DODAB and IL/DPPC systems respectively. In both the IL/DPPG and the IL/SA systems, a new catanionic complex was found. The influence of the subphase pH was also investigated in the last system.

EXPERIMENTAL SECTION Materials. Trihexyl(tetradecyl)phosphonium bis(trifluoromethylsulfonyl)imide [P6 6 6 14][Ntf2] was supplied by IOLITEC with a stated purity greater than 99%. Trihexyl(tetradecyl)phosphonium dicyanamide, [P6 6 6 14][N(CN)2] was prepared at the Centro de Física Molecular (CFM/IST/UL) and at the Institute of Nanosciences and Nanotechnology (IN/IST/UL). The corresponding synthesis, purification and characterization are described elsewhere.27 DPPG (1,2-dipalmitoyl-sn-glycero-3-phospho-(1’-rac-glycerol) (sodium salt) ) and DPPC (1,2dipalmitoyl-rac-glycero-3-phosphotidylcholine) were purchased in powder from Avanti Polar Lipids, Inc. (Alabaster, AL) and used without further purification. Dioctadecyldimethylammonium bromide (DODAB) ≥ 98% purity was obtained from Fluka. Stearic acid (SA), ≥ 99% purity, was purchased from Aldrich. The solvents, chloroform from Fluka (puriss. p.a. grade, ≥ 99.8%) and methanol from Aldrich (Chromasolv, ≥ 99.9%), were used as purchased. The ultra-pure water used in the subphase was distilled and purified with the Millipore Milli-Q system (pH 6, resistivity ≥ 18.2 MΩ cm). Stock solutions of ILs and lipids (0.5−1.0 mM) were prepared in chloroform and chloroform:methanol (9:1, v/v) mixture, respectively. Spreading solutions of mixed compositions were obtained by mixing precise volumes of stock solutions of both components. The solubility of IL1 and IL2 in water, at 25°C, is 1.2 mM and 0.26 mM, respectively. The pH 4 in the water subphase was adjusted with hydrochloric acid and pH 10 with sodium hydroxide.


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Surface Pressure− −Area measurements. Surface pressure − area (π−A) isotherms were carried out on a KSV 5000 Langmuir-Blodgett system (KSV instruments, Helsinki) installed in a laminar flow hood. Procedures for π−A measurements and cleaning were described elsewhere.28 In each measurement, 100 μL of solution were spread on the pure water subphase with a SGE gastight micro syringe. After evaporation of the solvent, the floating layer on the subphase was symmetrically compressed by two barriers at constant speed of 5 mm min-1 (1.24 Å2 molecule-1 min-1). The temperature of the subphase was maintained by a circulating water bath (298±0.2 K). The π−A isotherms did not change either with different amounts of material added at the surface or with the concentration of spreading solution in the interval of concentrations used in the experiments. To assure reproducibility, at least three π-A isotherms were obtained for each composition.

[P6 6 6 14][N(CN)2] (IL1)

[P6 6 6 14][Ntf2] (IL2)

Scheme 1. Molecular structures of [P6 6 6 14][N(CN)2] (IL1) and [P6 6 6 14][Ntf2]] (IL2).


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DODAB

DPPC

DPPG

SA

Scheme 2. Molecular structures of lipids.


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RESULTS AND DISCUSSION This work comprises the study of Langmuir monolayers at the air−water interface involving two ionic liquids, [P6 6 6 14][N(CN)2] and [P6 6 6 14][Ntf2], IL1 and IL2, respectively, in binary mixtures with several long chained lipids: DODAB, DPPC, DPPG, and SA . The experimental π−A isotherms of the mixed monolayers are compared with the theoretical curves calculated for the corresponding ideal mixtures, based on the additivity rule, Atheo = Xlip Alip + XIL AIL

(1)

Atheo/Xlip = Alip + AIL XIL/ Xlip

(2)

Where Atheo is the mean molecular area (MMA) of the ideal mixture, Xlipid and XIL are the mole fractions of the lipid and the IL components, respectively, while Alip and AIL are the areas occupied by the same single components in neat Langmuir monolayers.29

Interaction of DODAB with [P6 6 6 14][N(CN)2]. Figure 1 compares the experimental π−A isotherm of DODAB/IL1 (3:1) mixed monolayer (blue line) with the π−A isotherms of single components, IL1 (black line) and the double-chained cationic surfactant DODAB30 (gray line). The π−A curve of IL1 is reproducible and does not depend on the amount of the spreading material added at the interface. After spreading, the surface pressure slightly increases around 2 mN m−1 at large areas per ion pair or MMA (> 250 Å2 molecule−1). This behavior was ascribed to the hydrophilic nature of the [N(CN)2]− anion. Upon compression, the surface pressure increases continuously up to values higher than 20 mN m−1 for area values of around 50 Å2 molecule−1. The inflection point in the π(A) function at ca. 10 mN m−1 may suggest a second-order phase transition. Such a trend indicates a low cohesion system composed of loosely packed [P6 6 6 14][N(CN)2] ions at low surface pressures and explains the continuous increase in the surface density during compression. Above the inflection point, IL1 forms a more condensed and thicker film that includes ionic species at different distances from the water. This interpretation, presented in the previous work, was supported at a molecular level using molecular dynamics.26 In fact, the probability of finding the [N(CN)2]− anion in the bulk of the water subphase is not negligible, precluding the formation of a compact and planar monolayer and explaining the gradual variation of the surface pressure even at large MMA values.26 7 ACS Paragon Plus Environment

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Pure DODAB (gray line) forms a liquid expanded (LE) monolayer at low surface pressures that gradually evolves to a liquid condensed (LC) state when the surface pressure increases up to the breakdown of the two dimensional organization at air−water interface, the monolayer collapse, at 47 mN m-1. The experimental π−A isotherm of DODAB:IL1 (3:1) mixed monolayer (blue line), is plotted as a function of the area per DODAB molecule (eqn. 2). In such a representation, any deviation to larger areas relatively to the π−A isotherm of pure DODAB can be ascribed to the area occupied by IL1 at the interface plus the possible changes, induced by the presence of IL1, in the area occupied by the DODAB molecules. In fact, the π−A curve of the mixed monolayer shifts significantly to large areas per DODAB molecule at low surface pressures, while at π >18 mN m-1 it follows the curve of the pure DODAB. This behavior indicates that the DODAB and IL1 components coexist in the monolayer at surface pressures lower than 12mN m-1 . The theoretical curve (dashed line) calculated for the (3:1) ideal mixture follows the experimental

π−A isotherm of the mixed monolayer up to the IL1 transition at π ≈12 mN m-1. This feature is compatible with ideal mixing or phase separation. As the repulsive interactions between the positive charges at the head groups of the long chained ions discard the ideal mixing hypothesis, that behavior should indicate the coexistence of two immiscible phases at low surface pressures, the DODAB phase and the IL1 phase. At high surface pressures, above the transition of IL1 and its subsequent squeezing out from the first layer, only the DODAB phase remains in contact with the water surface. In this mixture, the hydrophobic long chains of DODA+ and [P6 6 6 14]+ orient to the air phase, while the positive head groups localize at the water surface. In such organization, the repulsive electrostatic interactions between the positively charged head groups at the surface lead to the immiscibility of DODAB and IL1.


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Figure 1. Comparison of the π−A isotherm of DODAB/[P6 6 6 14][N(CN)2] (3:1) mixed monolayer (blue line) with the calculated curve (dashed line) based on the π−A isotherms of the pure components DODAB (gray line) and [P6 6 6 14][N(CN)2] (black line). The x-axis shows the area per DODAB molecule except for pure [P6 6 6 14][N(CN)2] that represents the area per ion pair.

Interaction of DPPC with [P6 6 6 14][N(CN)2] and [P6 6 6 14][Ntf2]. Figures 2A and 2B show the π−A isotherms of DPPC, with IL1 and IL2, respectively, for selected mixtures, (3:1) and (1:1) molecular proportions at 298 K. The experimental π−A isotherms of the mixed monolayers (thick colored full lines) are plotted as a function of the area per DPPC molecule, and the corresponding theoretical curves (dashed lines) were calculated based on eqn. (2) and on the π−A isotherms of the single components, DPPC (gray line) and ILs (black lines). The well-known behavior of DPPC was reported previously.31,32,33,34 At the room temperature, upon compression from low surface pressures, DPPC forms a LE monolayer that undergoes a phase transition at 10−11 mN m-1 (the LE−LC transition) to a LC state that collapses at high surface pressures (48 mN m-1). The experimental π−A isotherms of DPPC/IL1 mixed monolayers (Figure 2A) shift to larger areas relatively to the isotherm of pure DPPC at low up to intermediate surface pressures while both isotherms superimpose at high surface pressures. The shift at low pressures increases with the IL1 content, i.e., the lift off of the surface pressure from zero (liftoff) of the (1:1) mixture appears at larger areas than the (3:1) mixture and for these mixtures, the overlapping with pure DPPC occurs at π >35 mN m-1 and at π >45 mN m-1, respectively. The π−A isotherms for those compositions 9 ACS Paragon Plus Environment

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present two shoulders, at π ≈11 mN m-1 and π ≈25 mN m-1, which may be ascribed to the progressive exclusion of IL1 from the two coexistent phases at low pressures. (The first shoulder could also be related to the LE-LC phase transition of DPPC). The final collapse surface pressure of mixed monolayers at ≈55 mN m-1 is higher than the collapse surface pressure of pure DPPC (48 mN m-1). The described trend indicates that DPPC and IL1 coexist in the monolayer from low to surface

pressures above the collapse of pure IL1 at π ≈11 mN m-1. Furthermore, the experimental π−A isotherms of mixed monolayers present positive deviations relatively to the corresponding theoretical curves. This observation indicates that IL1 induces an expanding effect in the DPPC monolayer which is compatible with partial miscibility.35 The apparent absence of the LE−LC transition characteristic of pure DPPC in the mixed monolayers reveals some IL1−DPPC interaction. This means that, at least at low surface pressures, the IL1 rich phase coexists with a DPPC rich phase in the monolayer. The first shoulder at ≈11 mN m-1, owing to the collapse of the IL1 phase, is clearly noted in the π−A curve of the (1:1) mixture, but it is quite incipient at the (3:1) mixture due to the small fraction of the minor component IL1 phase. The second shoulder at 25−27 mN m-1 can be ascribed to the progressive squeezing out of IL1 from the DPPC rich phase and or to the LE−LC transition characteristic of pure DPPC affected by the interaction with IL1. At high surface pressures, π >35 mN m-1 for the (3:1) mixture and π >45 mN m-1 for the (1:1) mixture, only the DPPC phase remains at the monolayer that collapses at ≈55 mN m-1. Figure 2B shows the π−A isotherms of DPPC mixed with [P6 6 6 14][Ntf2] (IL2), for the (3:1) and (1:1) molecular proportions at 298 K. IL1 and IL2 differ on the anion. [Ntf2] –, present in IL2, is more hydrophobic than [N(CN)2] – in IL1. 26 Accordingly, the π−A isotherm of pure IL2 (black line) is significantly different from that obtained for IL1. IL2 also forms a reproducible monolayer. The π−A curve of IL2 shows three distinct regions: (i) the pre-liftoff regime, a plateau at very low surface pressures and large values of MMA, (ii) the liquid phase, a low-compressibility region after the lift-off of the surface pressure, (iii) and the collapse, a quasi-plateau starting at 12 mN m−1. The low-pressure plateau is ascribed to the coexistence regime of two phases: liquid-expanded (LE) islands of ionic planar monolayers dispersed in a continuous aqueous subphase (gas phase) at the air−water interface. The low-compressibility regime corresponds to the compression of a continuous liquid like ionic planar monolayer, and the quasi-plateau is due to the LE monolayer collapse, i.e., the formation of a more condensed and


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thicker film that includes ionic species at different distances from the water surface. This interpretation was sustained by molecular dynamics simulations in the previous work.26 The positive deviations of the experimental π−A isotherms of (3:1) and (1:1) DPPC/IL2 mixed monolayers relatively to the pure DPPC increase with the IL2 content at low surface pressures. The experimental π−A curves of mixtures become very close to each other at π ≥ 18 mN m-1, and follow the one of pure DPPC at π ≥38 mN m-1. Both mixtures present two collapses, the first one increases with the DPPC content (18 mN m-1 and 14 mN m-1 for the (3:1) and (1:1) proportions, respectively) while the final collapse approaches the collapse of pure DPPC. The LE−LC transition that occurs in pure DPPC at 8-10 mN m-1 is not visible in the DPPC/IL2 mixed monolayers. On the other hand, the increase of the surface pressure of the first collapse with the DPPC content suggests some kind of interaction between both components, particularly for the (3:1) mixture which presents a positive deviation relatively to the corresponding calculated curve (brown dashed line). The trend described above suggests partial miscibility of IL2 with DPPC at low surface pressures. The first collapse of mixed monolayers, occurring at surface pressures higher than the collapse of single IL2, indicates the beginning of the progressive exclusion of IL2 from the monolayer, while the final collapse, approaching the collapse of pure DPPC, indicates the collapses of the remaining DPPC rich phase.

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Figure 2. Comparison of the π−A isotherms of (A) DPPC/[P6 6 6 14][N(CN)2] and (B) DPPC/ P6 6 6 14][Ntf2] mixed monolayers (full lines) with the calculated curves (dashed lines) based on the π−A isotherms of the pure components DPPC (gray thin lines) and [P6 6 6 14][N(CN)2] or [P6 6 6 14][Ntf2] (black thin lines). The x-axis shows the area per DPPC molecule except for the pure ionic liquids, in these cases represents the area per ion pair or MMA. 11 ACS Paragon Plus Environment

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Interaction of DPPG with [P6 6 6 14][N(CN)2] and [P6 6 6 14][Ntf2]. Figure 3 shows the π−A isotherms of selected mixtures of the anionic phospholipid, DPPG, with IL1 (full lines) and with IL2 (dashed lines) for the (3:1), (1:1) and (1:3) molecular proportions.

The π–A isotherm of pure DPPG (gray line) studied elsewhere,36 is similar to those reported by Vollhardt et al.37 under similar conditions. From the very low surface pressures up to 5 mNm−1 DPPG forms a two-phase regime in the monolayer, with the LE phase gradually undergoing a transition to a liquid condensed (LC) phase. The LC phase corresponds to the steep region in the range 5–40 mN m−1, changing to the solid state (S) at π ≈ 40 mN m−1, where the slope of the π–A isotherm becomes almost vertical up to the collapse of the monolayer at ≈ 58 mN m−1. Monolayers of DPPG and DPPC form in the same range of π–A, however the curves become very distinct at low surface pressures. The LE–LC transition in the DPPC monolayer occurs at a quasi plateau (10−11 mN m-1), while in the case of DPPG that transition is not clearly visible in the π–A curve because it occurs at surface pressures only slightly above the zero pressure. Consequently, the π–A isotherm of pure DPPG becomes very steep from low surfaces pressures up to the collapse surface pressure. The π–A isotherms of DPPG/IL1 mixed monolayers (colored full lines, Fig.3A) vary drastically with composition. For the 3:1 proportion (XIL= 0.25, brown line), the DPPG rich monolayer shows two collapses, the first one at the long plateau at 44 mN m-1 and the final collapse at 56 mN m-1, close to the collapse of pure DPPG. Upon compression of spread mixed monolayer from large areas, a condensed regime forms at MMA [Ntf2]− > [N(CN)2]−. Based on the molecular structures of the three anions we could expect a smaller cross section area for the perpendicular orientation of [DPPG]- at the interface. Therefore, the higher hydrophobic character of DPPG-, with two long alkyl chains, together with the expected smaller cross sectional area, allows [DPPG]− to interact with [P6 6 6 14]+ at shorter distances forming the most stable monolayer with a much higher collapse surface pressure than either IL1 or IL2.


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Figure 3. . (A) π−A isotherms of mixed monolayers for DPPG:[P6 6 6 14] [N(CN)2] (full lines) and DPPG:[P6 6 6 lines). The corresponding proportions (3:1, 1:1, 1:3) are indicated by the included colored legend. (B) Comparison of the π−A isotherm of DPPG:[P6 6 6 14][Ntf2] 1:1 mixed monolayer (red full line) with the calculated curve (red dashed line) based on the π−A isotherms of the pure components DPPG (gray thin line) and IL2 (black thin line). (C) π−A isotherms of three distinct ionic pairs formed by the same [P6 6 6 14]+ cation with three different counter anions: DPPG– (red line), [NTf2]– (blue line) and [N(CN)2]− (black line).

14][Ntf2] (dashed

Interaction of SA with [P6 6 6 14][N(CN)2] and [P6 6 6 14][Ntf2]. Figure 4 shows the surface pressure vs MMA isotherms of selected mixtures of SA with IL1 (colored full lines) and IL2 (dashed lines). The well-known π−A curve of SA at 298 K (Fig.4A, gray line) exhibits two linear regions intersecting at the kink transition, πk=25 mN·m-1.38 The LC state, where the densely packed alkyl chains of SA adopt a tilted orientation to the interface, occurs at π< πk, while the solid state (S), with the alkyl chains perpendicular to the interface, forms at π > πk up to the collapse of the monolayer at πC ≈55 mN·m-1. The π−A isotherms of SA/IL1 mixed monolayers for the 3:1, 1:1 and 1:3 molecular proportions (Fig.4A) vary significantly with composition and show a similar trend to that observed in the DPPG/IL1 system for the same molecular proportions (Fig.3). Each one of these three mixed monolayers of SA/IL1 presents two collapses; the surface pressure of the first one varies strongly with composition, while the final collapse occurs at a plateau in the range of 32−35 mN m-1. The proximity of the three plateaus suggests the formation of a comparable phase, the [P6 6 6 14]+:SAionic complex, with a similar composition and organization in the three mixed monolayers. In fact, at the subphase with a pH 6, SA is partially ionized (pKa of 4.7),39 which means that the anionic stearate (SA-) coexists with the neutral form of SA. Therefore, the formation of the [P6 6 6 14]+:SAionic complex, behaving like the [P6 6 6 14]+:DPPG- ionic complex, is probably responsible for the common features and similarities found in the π−A isotherms of both systems. For the SA rich monolayer (3:1, brown line), two distinct collapses appear at 28 mN m-1 and 34 mN m-1. As the experimental curve does not evidence the presence of the IL1 phase with a low collapse surface pressure, we assume that all the [P6 6 6 14]+ cation from the minor component IL1 combines with SA- to form the SA-:[P6 6 6 14]+ ionic complex phase that coexists with the remaining non-complexed major component, the SA rich phase. Upon compression of the mixed monolayer, the liftoff occurs at ≈80 Å2 molecule-1 and the slope of π−A curve increases continuously up to the first collapse at 28 mN m-1, revealing the formation of a LC monolayer. This collapse surface pressure (close to the kink transition of pure SA, πk=25 mN m-1) is ascribed to the collapse of the 16 ACS Paragon Plus Environment

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SA rich phase in a LC state, while the plateau at 34 mN m-1 is ascribed to the collapse of the remaining ionic complex. This observation indicates that the solid phase of SA (the steep increase of π) does not form in the presence of IL1. For the equimolar composition (1:1), the SA-:[P6 6 6 14]+ ionic complex coexists with the remaining species, the neutral SA and the non-complexed fraction of IL1. Above the liftoff, the slope of the

π−A curve increases continuously with the surface pressures up to π ≈23 mN m-1. Upon compression, the slope decreases in the range 23 − 33 mN m-1 due to the gradual collapse of the non-complexed components, while the remaining ionic complex collapses at nearly constant surface pressure, the plateau at 33 mN m-1. For the IL1 rich monolayer (1:3), the ionic complex coexists with the non-complexed IL1 and with a small fraction of neutral SA. The π–A curve of the SA/IL1(1:3) mixed monolayer indicates a very expanded state at low surface pressures, dominated by the IL1 major component, with a final collapse at 36 mN m-1 attributed to the presence of the ionic complex. Fig. 4B shows that the π–A isotherms of SA/ IL2mixed monolayers (dashed lines) deviate to smaller areas relatively to the corresponding mixed monolayers with IL1 (full lines). This indicates that [Ntf2]- induces a closer packing of the monolayer components than [N(CN)2]– does, in agreement with the behavior observed in systems with DPPG. Additionally, in systems with SA, the observed deviation at low surface pressures clearly increases with the IL content: not significant at (3:1), significant at (1:1) and very significant at (1:3). This observation should reveal the increasing contribution of the non-complexed IL to the global behavior of the mixed monolayer. For the 3:1 proportion, above the first collapse at 28 mN m-1, the slope of SA/IL2 (dashed brown line) is steeper than the one of SA/IL1 (full brown line), indicating that the dense packing of the SA– :[P6 6 6 14]+ ionic complex is affected by the counter anion [Ntf2]– or [N(CN)2]–. Above the collapse of the SA rich phase at 28 mN m-1, the remaining SA-:[P6

6 6 14]

+

ionic complex interacts with the

underneath layer that comprises the corresponding counter ions. These results indicate that the hydrophobic [Ntf2]– is more efficient than [N(CN)2]– to promote a dense packing of the ionic complex, favoring the attractive interactions in the monolayer. It is relevant to note that this deviation observed for the SA/IL 3:1 mixed monolayers, is opposite to that observed for the DPPG/IL 3:1 mixed monolayers (Fig 3A, arrow 2). In contrast, the anionic monolayer of DPPG, that remains at the interface above the collapse of the 1:1 ionic complex at 43 mN m-1, interacts repulsively with [Ntf2]– or with [N(CN)2]– . The repulsive interactions with [Ntf2]–, being stronger than with [N(CN)2]– disfavor the dense packing characteristic of DPPG monolayer. 17 ACS Paragon Plus Environment

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B

A

40

40

50 Surface Pressure/ mN m-1

(3:1) (1:1) (1:3)

π (mN/m)

50


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

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25

30 0 15

20

20 25 MMA/A2

10

(3:1) (1:1) (1:3)

30

20

10

0

0 0

50

100 MMA / Å2

150

0

200

50 MMA / Å2

100

150

Figure 4. (A) π−A isotherms of SA:[P6 6 6 14] [N(CN)2] mixed monolayers (colored thick lines) and pure components, SA (gray line) and IL1 (black line). The corresponding proportions for mixed monolayers (3:1, 1:1, 1:3) are indicated in the colored legend. The amplification of the π−A isotherm of SA is in the inset. (B) Comparison of π−A isotherms of mixed monolayers for SA:[P6 6 6 14] [N(CN)2] (full lines) with those of SA:[P6 6 6 14][Ntf2] (dashed lines) at the same proportions.

Effect of pH. The pH of the water subphase was varied in order to probe the contribution of the stearate anion to the formation of the SA–:[P6 6 6 14]+ 1:1 ionic complex. Fig. 5 compares the

π−A isotherms of the equimolar SA:IL2 mixed monolayer at pH 4, 6 and 10, with the π−A isotherm of DPPG:IL2 (1:1) mixed monolayer (dashed line) obtained at pH 6. The ionization of SA increases with pH being nearly complete at pH 10. 40 This means that at pH 10, the mixed monolayer should be formed by the SA–:[P6 6 6 14]+ ionic complex, that collapses at the long plateau 39−41 mN m-1. It is interesting to note that the behavior of the SA:IL2 mixed monolayer at pH 10 approaches the behavior of the DPPG:IL2 mixed monolayer, supporting the formation of similar structures. However, the negative deviation of the SA:IL2 mixed monolayer (with two long alkyl chains per ion pair) from that of DPPG:IL2 (with three long alkyl chains per ion pair) being much lower than 20 Å2 (the minimal area expected per long alkyl chain), indicates a more open structure for the SA:IL2 ionic complex. At pH 6, the ionization of SA is not complete and thus a significant fraction of the non-complexed species, IL and the neutral SA, coexist with the 1:1 ionic complex. The presence of these components explains the shoulder or gradual collapse starting at lower surface pressures (∼25 mN m-1). At pH 4, the ionization degree of SA is even lower than at pH 6, decreasing then the contribution of the SA- anion to the ionic complex formation. The surface pressure of the final 18 ACS Paragon Plus Environment

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collapse, at the plateau, increases with pH in agreement with the increasing contribution of the ionic complex to the stability of mixed monolayer. The deviation of the π−A isotherms to larger MMA with the increasing pH also indicates the increasing contribution of the ionic complex. In fact, the required electro neutrality in the two dimensional ionic structure formed by [P6 6 6 14]+ and SA– at the interface imposes that the coordination number of the cation is equal to the coordination number of the anion. Additionally, the [P6 6 6 14]+ cation is much more bulky than the SA– anion, and such dissimilarity on the size of these ions induces an open structure for the SA–:[P6 6 6 14]

+

ionic complex. These observations confirm that at pH 6 the SA-:[P6 6 6 14]+ 1:1 ionic complex

presents a significant contribution to the behavior of the mixed monolayer SA/IL as suggested above. 60 Surface Pressure /mN m-1

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

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50

pH 10 pH 6 pH 4

40 30 20 10 0 0

30

60

90

120

150

MMA /Å²

Figure 5. π−A isotherm of SA/[P6 6 6 14][Ntf2] (1:1) mixed monolayer at the subphase pH 4 (brown line), pH 6 (red line) and pH 10 (purple line). The π−A isotherm of DPPG/[P6 6 6 14][Ntf2] (1:1) mixed monolayer (black dashed line) was included for comparison.

Summary and conclusions The main objective of this study was to investigate the interaction of the long-chained ionic liquids (IL1 and IL2) with charged and uncharged amphiphilic components that form monolayers, such as the double-chained cationic surfactant, (DODAB), the zwitterionic phospholipid (DPPC), the anionic phospholipid (DPPG) and stearic acid (SA). IL1 and IL2 organize at the interface either when pure or in the presence of those lipids. The behavior of pure IL1 is very distinct from the one of IL2, but some discrepancies tend to become attenuated in their mixtures with lipids. The organization and packing of the long chained species ([P6 6 6 14]+ and amphiphiles) at the interface are commanded by the lateral interactions between hydrophobic chains together with the polar and 19 ACS Paragon Plus Environment

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ionic interactions involving the charged polar groups and water. The variable degree of IL−lipid interaction and packing depend on the signal and charge distribution at the polar group of the lipid component. Mixed monolayers of DODAB/IL1 system present two collapses, the first one occurs at the collapse surface pressure of IL1 and the second one occurs at the collapse surface pressure of DODAB. This behavior suggests phase separation induced by the repulsive ionic interactions between the charged head groups of the two long chained cations, the phosphonium group, [P6 6 6 14]+, and the dioctadecyldimethylammonium, DODA+, that coexist at the interface. Mixed monolayers of DPPC with either IL1, or IL2, reveal partial miscibility at low surface pressures. The π−A isotherms exhibit a shoulder (collapse) at surface pressures higher than the collapse of pure IL and lower than the collapse of DPPC. The partial miscibility can be due to the attractive interaction between the cationic phosphonium group and the anionic phosphate group in the polar group of DPPC. Mixed monolayers of DPPG with either IL1, or IL2, reveal a different behavior from that observed in the previous systems. At the equimolar compositions, the π−A isotherms show a single collapse at nearly constant surface pressure (∼44 mN m-1). This behavior was ascribed to the complete combination of P6 6 6 14]+ with DPPG- to form the 1:1 catanionic complex. At the other compositions (3:1 and 1:3) investigated the 1:1 complex also forms at an extent determined by the minor component molar fraction (0.25). Consequently, for those asymmetric compositions two phases coexist in the mixed monolayers, the catanionic complex and the non-complexed fraction of the major component. For the DPPG rich monolayer (3:1), the non-complexed DPPG phase, that remains at the monolayer after the collapse of the catanionic complex at π = 44 mN m-1, is significantly disturbed in the system with IL2 while remains nearly unaffected in the system with IL1. This effect was ascribed to the different hydrophobicity of ILs counterions: [Ntf2]–, being more hydrophobic than [N(CN)2]–, is more retained at the interface disturbing more efficiently the negatively charged monolayer of DPPG. The behavior of mixed monolayers of both ILs with SA shows some similarities to that observed in the systems with DPPG. This can be explained by the presence of the stearate anion (SA–) resulting from stearic acid ionization. The SA– interacts with [P6 6 6 14]+ forming the 1:1 catanionic complex that behaves like DPPG-:[P6

6 6 14]

+

and coexists in the monolayer with the additional non-

complexed components (SA and/or IL). The contribution of the SA–:[P6 complex to the global behavior of the SA:[P6

6 6 14][Ntf2]

6 6 14]

+

1:1 catanionic

mixed monolayers increases with pH,


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which was confirmed by measuring the π−A isotherm of the equimolar composition at several values of pH in the water subphase. As the ionization of SA is nearly complete at pH 10, the major component of the mixed monolayer is SA-:[P6 6 6 14]+ that presents a long plateau at 39−41 mN m-1 close to that observed for DPPG-:[P6 6 6 14]+ at 42 mN m-1. This behavior confirms the relevance of catanionic structures that form at the air water interface. In conclusion, this study revealed that the long-chained cation trihexyl(tetradecyl)phosphonium can be incorporated in lipid monolayers and that the more hydrophobic counterion, [Ntf2]–, induces more compact structures than [N(CN)2]–. However, it was found that the influence of these counterions at the IL1,2:DPPG equimolar composition is only residual, which confirms the combination of P6 6 6 14]+ with DPPG- to form the 1:1 catanionic complex. We believe that the experimental studies of IL−lipid systems in Langmuir monolayers at the air−water interface present a valuable contribution to the characterization of water-immiscible ionic liquids in complex systems with potential in a large variety of fields and industrial applications.

ACKNOWLEDGMENTS Financial support was provided by Fundação para a Ciência e Tecnologia (FCT). The author is grateful for discussions with Professor A.C. Fernandes. Professor J. A. Fareleira is acknowledged for the generous contribution of a purified sample of [P6

6 6 14][N(CN)2].

The ionic liquid was

synthesized and characterized by Carolina S. Marques and Professor Carlos A. M. Afonso under FCT-funded project PTDC/QUI/66826/ 2006.


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50 Surface Pressure, mN/m

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P+

40 30 20 10 0 0

100 Mma / Å2

200

O_

π−A isotherms of three distinct ionic pairs formed by the same [P6

6 6 14]

+

cation with three

different counter anions: DPPG- (red line), [NTf2]- (blue line) and [N(CN)2]− (black line). The collapse surface pressure and the monolayer stability vary with the hydrophobic character of the anion: [DPPG]− > [Ntf2]− > [N(CN)2]−.


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thermodynamic study and BAM observation at the air–water interface and AFM and FTIR analysis of LB monolayers. Chemistry and Physics of Lipids 2007, 149, 1–13. (39) Guidechem, Chemical Trading Guide http://www.guidechem.com/. (40) Mercado, F. V.; Maggio, B.; Wilke, N. Phase diagram of mixed monolayers of stearic acid and dimyristoylphosphatidylcholine. Effect of the acid ionization. Chemistry and Physics of Lipids 2011, 164, 386– 392.


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Interaction of Hydrophobic Ionic Liquids with Lipids in Langmuir

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