Mixing of Partially Fluorinated Carboxylic Acids and Their

Graduate Center for Toxicology and College of Pharmacy, University of Kentucky, ... ogy, University of Kentucky Medical Center, 306 HSRB, Lexington,...
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Langmuir 2000, 16, 10161-10166

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Mixing of Partially Fluorinated Carboxylic Acids and Their Hydrocarbon Analogues with Dipalmitoylphosphatidylcholine at the Air-Water Interface Hans-Joachim Lehmler,* Michael Jay,† and Paul M. Bummer† Graduate Center for Toxicology and College of Pharmacy, University of Kentucky, Lexington, Kentucky 40536 Received December 7, 1999. In Final Form: September 12, 2000 The interaction of partially fluorinated carboxylic acids with a biologically relevant surfactant, dipalmitoylphosphatidylcholine (DPPC), was investigated at the air-water interface. The compression isotherms of mixtures of three partially fluorinated carboxylic acids (1-3) and their hydrocarbon analogues (4-6) with DPPC were recorded at various compositions on hydrochloric acid (pH ) 1.9, 32 ( 2 °C) as a subphase. The mixing behavior was assessed by analyzing the concentration dependence of the average molecular area at constant film pressure (area/mole fraction or A-X diagram). All six carboxylic acids (1-6) show a negative deviation from ideal behavior at surface pressures between 3 and 25 mN/m, which is indicative of an attractive interaction with DPPC in the mixed monolayer at the air-water interface. With the exception of nonafluorpentadecanoic acid (1), all carboxylic acids investigated show a concentration dependence of the breakpoint of the phase transition from the liquid-expanded to the liquid-condensed state, which supports the interpretation of the A-X diagrams.

Introduction The surface energy of a fluorocarbon surface is known to be lower than that of a hydrocarbon surface. Similarly, the surface activity of a fluorinated surfactant is higher than the hydrocarbon analogue. The unique properties of perfluorinated materials are used for various technical applications such as fire extinguishing media, electroplating bath, water proofing sprays, and lubricants.1 Partially fluorinated materials2-4 and surfactants2,5-8 are of great interest for biomedical applications as a result of improved stability and biocompatibility. Partially fluorinated, odd numbered carboxylic acids, such as acids 1-3 (see Figure 1), have been incorporated into a large variety of amphiphiles of potential interest for biomedical applications.9-15 * Corresponding author’s address: Graduate Center for Toxicology, University of Kentucky Medical Center, 306 HSRB, Lexington, KY 40536-0305. Phone: (859) 268-5276. Fax: (859) 323-1059. E-mail: [email protected]. † College of Pharmacy. (1) Kissa, E. Fluorinated Surfactants; Dekker: New York, 1994; Vol. 50. (2) Lehmler, H.-J.; Bummer, P. M.; Jay, M. CHEMTECH 1999, 29, 7-12. (3) Riess, J. G.; Krafft, M. P. Biomaterials 1998, 19, 1529-1539. (4) Renard, G. Bull. Acad. Natl. Med. 1996, 180, 659-665. (5) Krafft, M. P. Cosmet. Sci. Technol. Ser. 1998, 19, 195-219. (6) Krafft, M. P.; Riess, J. G. Biochimie 1998, 80, 489-514. (7) Riess, J. G. J. Liposome Res. 1995, 5, 413-430. (8) Riess, J. G. J. Drug Targ. 1994, 2, 455-468. (9) Rolland, J.-P.; Santaella, C.; Vierling, P. Chem. Phys. Lipids 1996, 79, 71-77. (10) McIntosh, T. J.; Simon, S. A.; Vierling, P.; Santaella, C.; Ravily, V. Biophys. J. 1996, 71, 1853-1868. (11) Clary, L.; Santaella, C.; Vierling, P. Tetrahedron 1995, 51, 13073-13088. (12) Santaella, C.; Vierling, P.; Riess, J. G.; Gulik-Krzywicki, T.; Gulik, A.; Monasse, B. Biochim. Biophys. Acta 1994, 1190, 25-39. (13) Santaella, C.; Frezard, F.; Vierling, P.; Riess, J. G. FEBS Lett. 1993, 336, 481-484. (14) Nivet, J. B.; Le Blanc, M.; Riess, J. G. Eur. J. Med. Chem. 1991, 26, 953-960. (15) Santaella, C.; Vierling, P.; Riess, J. G. New J. Chem. 1991, 15, 685-692.

Figure 1. Structures of partially fluorinated carboxylic acids 1-3.

The interaction of fluorocarbons and hydrocarbons in liquids and gases is highly nonideal.16,17 The nonideality also manifests itself in a wide variety of systems involving interfaces, such as micelles and liposomes. It is well-known that mixtures of fluorocarbon and hydrocarbon amphiphiles will phase separate into two types of micelles, one rich in the fluorocarbon surfactant and one rich in the hydrocarbon surfactant.16,18-21 The extent to which fluorocarbon and hydrocarbon amphiphiles are miscible depends on their chemical structure. Headgroup interac(16) Mukerjee, P. Colloids Surf. A 1994, 84, 1-10. (17) Patrick, C. R. Chem. Br. 1971, 7, 154-156. (18) Funasaki, N.; Hada, S. J. Phys. Chem. 1983, 87, 342-347. (19) Funasaki, N.; Hada, S. J. Phys. Chem. 1980, 84, 736-744. (20) Shinoda, K.; Nomura, T. J. Phys. Chem. 1980, 84, 365-369. (21) Mukerjee, P.; Yang, A. Y. S. J. Phys. Chem. 1976, 80, 13881390.

10.1021/la991598v CCC: $19.00 © 2000 American Chemical Society Published on Web 11/23/2000

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tions, such as that of opposite charges, most frequently result in complete mixtures. An increase in the number of carbon atoms of either fluorocarbon or hydrocarbon amphiphile decreases their mutual solubility. Little is known about the factors influencing the behavior of perfluorinated or partially fluorinated surfactants and their mixtures with (hydrocarbon) amphiphiles in insoluble monolayers. The mixing behavior of binary mixtures of fluorocarbon and synthetic hydrocarbon amphiphiles has been studied at the air-water interface22-25 and, more recently, in Langmuir-Blodgett films.26,27 Mixed insoluble monolayers of fluorocarbon amphiphiles and structurally related hydrocarbon amphiphiles have been investigated.23,25 Because of the highly nonideal behavior of fluorocarbons and hydrocarbons, these systems are considered to behave nonideally, and thus, both components are immiscible in the monolayer. On the other hand, the introduction of a hydrocarbon moiety into a fluorocarbon amphiphile resulted in a deviation from ideality, indicating miscibility in the monolayer.22,24 Atomic force studies with monolayer Langmuir-Blodgett films supported the interpretation that the systems investigated by conventional monolayer methods were most likely phase-separated.26,27 Langmuir-Blodgett films of eicosanoic acid (C19H39COOH)/ perfluorooctadecanoic acid (C17F35COOH), perfluorotetradecanoic acid (C13F27COOH)/eicosanoic acid, and perfluorotetradecanoic acid/perfluorooctadecanoic acid,26 as well as immobilized organosilane monolayers prepared from octadecyltrichlorosilane and [2-(perfluorooctyl)ethyl]trichlorosilane,28 exhibited phase separation. The growing interest in these partially fluorinated materials for biomedical and a variety of technical applications triggers the question: Does the nonideality of mixing between fluorocarbon and hydrocarbon chains influence the interaction of partially fluorinated amphiphiles with hydrocarbon amphiphiles in a monolayer? The goal of the present study is to examine the interaction of three partially fluorinated carboxylic acids (1-3) with a biologically relevant surfactant, dipalmitoylphosphatidylcholine (DPPC), at the air-water interface and to compare the behavior of the partially fluorinated acids (1-3) to that of their hydrocarbon analogues (4-6). A better understanding of these interactions might allow the rational design of novel, fluorinated amphiphiles for a broad range of biomedical applications.3,5,29 Materials and Methods The structures of the partially fluorinated carboxylic acids 1-3 used in this study are shown in Figure 1. The partially fluorinated acids 1-3 were synthesized as described earlier and their spectroscopic data (1H, 13C and 19F NMR and FT-IR) are in agreement with the proposed structures.30-32 Their purity as determined by gas chromatography was >99% (based on relative peak area). DPPC was obtained from Avanti Polar Lipids in >99% (22) Liang, K.-N.; Hui, Y.-Z. Chin. J. Chem. 1992, 10, 481-486. (23) Zhang, L.-H.; Zhu, B.-Y.; Zhao, G.-X. J. Colloid Interface Sci. 1991, 144, 483-490. (24) Zhang, L.-H.; Zhao, G.-X.; Zhu, B.-Y. J. Colloid Interface Sci. 1991, 144, 491-496. (25) Elbert, R.; Folda, T.; Ringsdorf, H. J. Am. Chem. Soc. 1984, 106, 7687-7692. (26) Imae, T.; Takeshita, T.; Kato, M. Langmuir 2000, 16, 612-621. (27) Meyer, E.; Overney, R.; Lu¨thi, R.; Brodbeck, D.; Howald, L.; Frommer, J.; Gu¨ntherodt, H.-J.; Wolter, O.; Fujihira, M.; Takano, H.; Gotoh, Y. Thin Solid Films 1992, 220, 132-137. (28) Ge, S.; Takahara, A.; Kajiyama, T. J. Vac. Sci. Technol. A 1994, 12, 2530-2536. (29) Riess, J. G.; Krafft, M. P. MRS Bull. 1999, 42-48. (30) Brace, N. O. J. Chem. Soc. 1962, 4491-4498. (31) Brace, N. O. J. Org. Chem. 1972, 37, 2429-2433. (32) Brace, N. O. J. Fluorine Chem. 1982, 20, 313-327.

Lehmler et al. purity. Penta- (4), hepta- (5) and nonadecanoic acid (6) were obtained from Sigma in >99% purity and used without further purification. 2-Propanol, toluene, and n-hexanes were HPLC grade and were purchased from Fisher Scientific. Concentrated hydrochloric acid was also obtained from Fisher Scientific. Deionized water was distilled first from basic potassium permanganate followed by distillation from sulfuric acid. The interaction of surfactants with DPPC was studied using the method described by Wiedmann and Jordan.33 All monolayer experiments were carried out in a rectangular Teflon trough (306 × 150 mm) held at 32 ( 2 °C (KSV-3000, Finland). The surface pressure was measured by the Wilhelmy plate method. Paper plates (15 × 58 mm) were used because of wetting difficulties with a platinum plate. Approximately 50% of the paper plate was submerged in the aqueous subphase. Every surface area-surface pressure isotherm was determined on a freshly poured subphase (hydrochloric acid, pH ) 1.9). The subphase was allowed to equilibrate for 10 min at 32 ( 2 °C. Surface active impurities were removed from the air-water interface with a slight vacuum after compression of the barrier. Acid, phospholipid, and acid-phospholipid solutions with a concentration of 1-2 mg/mL were freshly prepared every day in n-hexanes:2propanol ) 9:1.34 A known quantity (30-80 µL) of solutions was spread on the surface, and exactly 10 min at 32 ( 2 °C was allowed to elapse for solvent evaporation before the start of the compression. A constant compression speed of 15 cm2/min (10 mm/min) was used. All experiments were repeated at least four times. Within the experimental error, the compression isotherms were independent of the volume of solution applied to the airwater interface.

Results and Discussion This study investigates the mixing behavior of three important partially fluorinated carboxylic acids 1-3 and their hydrocarbon analogues 4-6 with an important biological amphiphile, DPPC. Several phenomenological criteria of miscibility have been summarized by Do¨rfler:35 (1) concentration dependence of the breakpoint of the phase transition from the liquid-expanded to the liquidcondensed state, (2) concentration dependence of the average molecular area at constant film pressure (area/ mole fraction or A-X diagram),36 (3) concentration dependence at the collapse pressure, and (4) long-time analysis of mixing and demixing processes. As explained below, this study investigated the miscibility of six carboxylic acid-DPPC systems using (1) the concentration dependence of the breakpoint of the phase transition and (2) the concentration dependence of the average molecular area at constant film pressure as criteria for miscibility in a binary monolayer. (1) Concentration Dependence of the Breakpoint of the Phase Transition from the Liquid-Expanded to the Liquid-Condensed State. The surface-phase rule can be applied if the π-A isotherm shows a liquidexpanded to liquid-condensed phase transition,35,37 and analysis of the concentration dependence of the breakpoint allows statements to be made concerning the miscibility of the two components in both film states. In general, a concentration dependent phase transition points to the complete miscibility of the components, whereas concentration independence is a sign of immiscibility of the components.35 (2) Concentration Dependence of the Average Molecular Area at Constant Film Pressure (Area/ Mole Fraction or A-X Diagram). Binary monolayer (33) Wiedmann, T. S.; Jordan, K. R. Langmuir 1991, 7, 318-322. (34) Bernett, M. K.; Zisman, W. A. J. Phys. Chem. 1963, 67, 15341540. (35) Do¨rfler, H.-D. Adv. Colloid Interface Sci. 1990, 31, 1-110. (36) Gaines, G. L. Insoluble monolayers at liquid-gas interfaces; Interscience Publishers: New York, 1966. (37) Motomura, K. J. Colloid Interface Sci. 1974, 48, 307-318.

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Figure 2. Compression isotherms of mixtures of partially fluoroinated carboxylic acids (1-3) and DPPC for different mole fractions of DPPC (32 ( 2 °C, hydrochloric acid, pH ) 1.9-2.1): (a) nonafluoropentadecanoic acid (1) and DPPC, (b) tridecafluoroheptadecanoic acid (2) and DPPC, and (c) heptadecafluorononadecanoic acid (3) and DPPC.

mixtures can be treated as the two-dimensional analogue of mixing two components in the bulk phase.38,39 The two components of the mixture can either be completely miscible or show complete phase separation and form an isolated monolayer of one compound in a monolayer of the second compound. In ideal behavior, the average area per molecule of any mixture is the sum of the areas occupied by each species at the surface

A(π) ) XAcidAAcid + XDPPCADPPC

(1)

(X is the mole fraction of each component present at the air-water interface and A is the average area per molecule of the pure component). This “additivity rule” gives the expected area per molecule, A(π), for ideal mixing or complete phase separation. Miscibility can be observed as a result of interaction between the two components. An attractive interaction will lead to a negative deviation, and a repulsive interaction will lead to a positive deviation from ideal behavior. The attractive or repulsive forces can result from interactions between different headgroups and/or hydrophobic tails. For example, mixing of fatty acids with significantly different chain lengths showed a positive deviation from ideality,40 and an atomic force microscopy study of mixtures of palmitic acid (C15H31COOH) and lignoceric acid (C23H47COOH) showed that both acids are immiscible and form distinct domains of the respective fatty acid.41 In addition, studies with mixtures of a fluorocarbon and a hydrocarbon surfactant suggest that the introduction of a perfluoroalkyl group would promote the tendency to phase separate.21,25,26 To investigate their mixing behavior, the compression isotherms of mixtures of the partially fluorinated carboxylic acids (1-3) and their hydrocarbon analogues (46) with DPPC were recorded at various compositions at 32 ( 2 °C (Figure 2). This temperature was chosen because it is well below the chain melting temperature of DPPC (∼41 °C).38 The breakpoint of the phase transition from the liquid-expanded to the liquid-condensed state, the limiting area, and the collapse pressure for all π-A isotherms were determined and are summarized in Table 1. The A-XDPPC diagrams of all carboxylic acid-DPPC mixtures are shown at 3 and 25 mN/m in Figure 3. (38) Jones, M. N.; Chapman, D. Micelles, Monolayers, and Biomembranes; Wiley-Liss, Inc.: New York, 1994. (39) Birdi, K. S. Lipid and Biopolymer Monolayers at Liquid Interfaces; Plenum Press: New York, 1989. (40) Rakshit, A. K. J. Colloid Interface Sci. 1981, 80, 474-481. (41) Ekelund, K.; Sparr, E.; Engblom, J.; Wennerstro¨m, H.; Engstro¨m, S. Langmuir 1999, 15, 6946-6949.

Table 1. Phase Transition, Limiting Area, and Collapse Pressure of Compression Isotherms of Carboxylic Acid-DPPC Mixtures (32 ( 2 °C, Hydrochloric Acid, pH ) 1.9-2.1)

XDPPC DPPC acid 1 0.12 0.27 0.45 0.70 acid 2 0.20 0.40 0.60 0.80 acid 3 0.20 0.40 0.60 0.80 acid 4 0.20 0.40 0.60 0.80 acid 5 0.20 0.40 0.60 0.80 acid 6 0.20 0.40 0.60 0.80 a

phase transition area 2 (Å /molecule)

surface pressure (mN/m)

58.3 ( 1.4 none none none none 48.3 ( 0.7 46.4 ( 0.8 none none 46.3 ( 1.3 50.1 ( 1.2 none none none 52.3 ( 0.6 54.3 ( 0.7 26.6 ( 0.5 36.4 ( 0.3 45.2 ( 0.8 50.5 ( 1.2 59.3 ( 2.1 none none none none 64.2 ( 0.7 none none none none

20.3 ( 0.1

19.5 ( 0.6 7.0 ( 0.4 15.8 ( 0.8 17.5 ( 0.5

7.7 ( 0.3 12.9 ( 0.7 13.5 ( 1.0 6.3 ( 0.1 3.7 ( 0.3 4.9 ( 0.3 7.5 ( 0.9

4.4 ( 0.6

limiting area (Å2/molecule)

collapse pressure (mN/m)

50.0 ( 3.0 48.4 ( 0.7 45.3 ( 0.1 46.9 ( 1.8 53.5 ( 0.4 44.8 ( 0.8 38.1 ( 1.0 41.9 ( 0.6 42.5 ( 0.9 nd 43.7 ( 0.8 35.3 ( 0.3 38.9 ( 0.2 40.5 ( 0.2 40.9 ( 0.2 43.2 ( 0.3 20.1 ( 0.7 23.9 ( 0.3 27.2 ( 1.1 31.2 ( 0.7 42.1 ( 0.8 20.8 ( 0.9 23.4 ( 0.7 27.6 ( 0.2 33.7 ( 2.7 41.1 ( 0.7 19.6 ( 0.3 23.5 ( 0.3 27.6 ( 0.2 33.1 ( 0.4 39.2 ( 0.8

nda 35.7 ( 0.5 39.5 ( 0.2 44.9 ( 0.4 nd 53.5b 36.7 ( 0.5 40.6 ( 0.3 48.5 ( 0.4 55.7 ( 1.0 nd 42.8 ( 0.4 45.5 ( 0.5 53.8 ( 1.3 56.9 ( 1.3 58.1 ( 0.5 35.6 ( 0.3 nd 53.7 ( 1.9 56.5 ( 0.7 70.0 ( 1.1 41.3 ( 0.5 55.0 ( 0.7 52.7 ( 1.0 57.6 ( 2.5 69.7 ( 1.8 46.5 ( 2.0 57.5 ( 2.0 52.6 ( 1.2 69.3 ( 0.9 68.9 ( 1.6

nd ) not determined. b n ) 2.

Pentadecanoic Acid (4) and DPPC. The A-XDPPC diagram of pentadecanoic acid (4) and DPPC at 3 mN/m shows a negative deviation from the additive behavior of the average molecular areas (Figure 3a). Within this low pressure range only the liquid-expanded film state is present. Between 5 and 20 mN/m, the A-XDPPC curves show a fairly complex behavior (for example at 7 mN/m) with a negative deviation from an additive behavior.35 In this midpressure region both the liquid-expanded and the liquid-condensed film states exist (a more detailed discussion for this behavior is given by Matuo and co-workers for the hexadecanoic acid ethyl ester-DPPC system42). Above 20 mN/m, the monolayer exists only in the liquid-

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Figure 3. A-XDPPC diagrams of carboxylic acid-DPPC mixtures (32 ( 2 °C, hydrochloric acid, pH ) 1.9-2.1): (a) Pentadecanoic acid (4) and DPPC, (b) heptadecanoic acid (5) and DPPC, (c) nonadecanoic acid (6) and DPPC, (d) nonafluoropentadecanoic acid (1) and DPPC, (e) tridecafluoroheptadecanoic acid (2) and DPPC, and (f) heptadecafluorononadecanoic acid (3) and DPPC.

condensed state, and only a slight negative deviation from an additive behavior is observed. The negative deviation from the additivity rule over the entire pressure range not only indicates an attractive interaction between pentadecanoic acid and DPPC but also misciblity in the expanded one-phase state as well as the condensed onephase state. As shown in Table 1, the surface pressure of the transition point in the pentadecanoic acid-DPPC system decreases with addition of acid 4, exhibits a minimum at XDPPC ) 0.4, and again increases upon further addition of acid 4. The tetradecanoic acid-DPPC as well as several other DPPC-containing systems behave in a similar way.42-44 For example, the tetradecanoic acid-DPPC system exhibits a minimum of the breakpoint at XDPPC ) 0.5 (25 °C).42-44 Such behavior, which appears to be characteristic for DPPC-containing mixtures,43 is interpreted as miscibility in the expanded one-phase state as well as the condensed one-phase state, which is in agreement with our analysis of the A-XDPPC diagram. In this type of system, the mutual interactions between the two components in the mixed monolayer are stronger than the interactions between the pure components themselves.42 However, Matuo and co-workers also report that the pentadecanoic acid-DPPC system behaves differently at 25 °C.44 It is believed that these differences are due to the different temperatures employed in both studies (25 °C vs 32 °C). This interpretation is supported by the fact that the phase transition of pentadecanoic acid is highly (42) Matuo, H.; Motomura, K.; Matuura, R. Chem. Phys. Lipids 1982, 30, 353-365. (43) Matuo, H.; Motomura, K.; Matuura, R. Chem. Phys. Lipids 1981, 28, 281-289. (44) Matuo, H.; Motomura, K.; Matuura, R. Chem. Phys. Lipids 1981, 28, 385-397.

temperature dependent.45 A temperature increase of 7 °C from 25 to 32 °C is reported to increase the surface pressure at which the phase transition occurs by ∆π ∼ 8 mN/m (9 vs 17 mN/m), which appears to be in agreement with the data of Matuo and co-workers for 25 °C and our data for 32 °C, as shown in Table 1. Heptadecanoic Acid (5) or Nonadecanoic Acid (6) and DPPC. As shown in Table 1, a concentration dependent liquid-expanded to liquid-condensed phase transition is observed for the heptadecanoic acid-DPPC system at higher concentrations of DPPC (XDPPC > 0.6). The monolayers of the mixtures are highly condensed for XDPPC < 0.6, and all π-A isotherms for XDPPC e 0.6 show a phase transition from the condensed to the solid state.46 The A-XDPPC diagram of heptadecanoic acid (5) and DPPC shows a negative deviation from additivity over the entire surface pressure range studied (Figure 3b). The concentration dependent phase transition as well as the concentration dependence of the average molecular area at constant film pressure point to partial miscibility between both compounds in the monolayer. The nonadecanoic acid (6)-DPPC system also shows a negative deviation from additivity over the entire surface pressure range studied (Figure 3c), but the concentration dependence of the phase transition is not as evident (Table 1). This indicates that nonadecanoic acid (6) and DPPC are still partially miscible, but to a lesser extent compared to the heptadecanoic acid or pentadecanoic acid-DPPC systems. Our observation that the miscibility of hydrocarbon acids with DPPC decreases with increasing chain length of the carboxylic acids 5 and 6 is in agreement with the trends observed by Matuo and co-workers for binary mixtures of DPPC and distearoylphosphatidylcholine (45) Harkins, W. D.; Boyd, E. J. Phys. Chem. 1941, 45, 20-43. (46) Bibo, A. M.; Peterson, I. R. Adv. Mater. 1990, 2, 309-311.

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(DSPC) with tetradecanoic acid, pentadecanoic acid (4), and octadecanoic acid.42,44 Nonafluoropentadecanoic Acid (1) and DPPC. Figure 2a shows the surface pressure-surface area or π-A isotherms of mixtures of nonafluoropentadecanoic acid (1) and DPPC. The π-A isotherm of DPPC shows the well-studied transition of the liquid-expanded to the liquidcondensed state.47 The limiting molecular area of DPPC on hydrochloric acid (50 ( 3 Å2 at 32 °C) is similar to the limiting molecular area reported for DPPC monolayers on water (57 ( 3 Å2 at 25 °C9 and 52 at 20 °C48 on water, 51 Å2 at 22 °C on 0.1 M sodium chloride49). The addition of the fluorinated acid 1 to DPPC (XDPPC ) 0.69) does not alter the shape of the compression isotherm significantly (Figure 2). The isotherm still shows the transition of the liquid-expanded to the liquidcondensed state at a surface pressure of ∼20 mN/m (Table 1). Further addition of acid 1 (XDPPC ) 0.45) results in disappearance of the phase transition, and the isotherm shows the characteristics for one single phase at all measured pressures. The concentration independence of the phase transition seems to indicate immiscibility of both compounds at the air-water interface. However, the A-XDPPC diagram of nonafluoropentadecanoic acid (1) and DPPC shows a pronounced negative deviation from additive behavior between 3 and 25 mN/n (Figure 3d). The negative deviations are less pronounced at higher surface pressures. This observation points to the partial misciblity of both components in the composed film. Matuo and co-workers report that DPPC tends to show miscibility with carboxylic acids and carboxylic acid esters,43 which suggests that the partially fluorinated acid 1 may be miscible with DPPC. Tridecafluoroheptadecanoic Acid (2) and DPPC. Figure 2b shows the π-A isotherms of mixtures of tridecafluoroheptadecanoic acid (2) and DPPC at 32 ( 2 °C. The concentration dependence of the phase transition in the tridecafluoroheptadecanoic acid-DPPC system is complex. The transition of the liquid-expanded to the liquid-condensed state occurs at a continuously lower surface pressure with increasing concentration of acid 2 as shown in Table 1, and disappears at XDPPC < 0.6. The π-A isotherms between XDPPC ) 0.2 and 0.4 exhibit an isotherm characteristic for one single condensed phase. An apparent phase transition from the liquid-expanded to the liquid-condensed state is observed at 7.0 mN/m for pure acid 2. The concentration dependence of the phase transition resembles the one observed for the pentadecanoic acid-DPPC system, but the change of the concentration dependence at higher mole fractions of DPPC is not as significant. The A-XDPPC diagram of tridecafluoroheptadecanoic acid (2) and DPPC shows a negative deviation from additivity over the entire surface pressure range studied (Figure 3e). The deviation shows a maximum around XDPPC ≈ 0.7 at surface pressures between 10 and 25 mN/m due to the phase transition. Thus, monolayers show attractive interactions both in the expanded state as well as the condensed state. Heptadecafluorononadecanoic Acid (3) and DPPC. Figure 2c shows the surface pressure-surface area isotherms of mixtures of heptadecafluorononadecanoic (47) Lance, M. R.; Washington, C.; David, S. S. Pharm. Res. 1996, 13, 1008-1014. (48) Albrecht, O.; Gruler, H.; Sackmann, E. J. Phys. 1978, 39, 301313. (49) Phillips, M. C.; Chapman, D. Biophys. Biochim. Acta 1968, 163, 301-313.

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acid (3) and DPPC at 32 ( 2 °C. The liquid-expanded to liquid-condensed phase transition of DPPC is concentration dependent and disappears at higher concentrations of the fluorinated acid (XDPPC < 0.6). At surface pressures between 3 and 25 mN/m, the A-XDPPC curve shows a slight negative deviation from ideality (Figure 3f). These results show that both components are partially miscible with DPPC, but to a lesser extent compared to the two partially fluorinated acids 2 and 3. Although the mixing behavior of carboxylic acid-DPPC mixtures appears to be fairly complex, two general observations can be made for both hydrocarbon and fluorocarbon systems. First, at 32 °C all A-XDPPC diagrams show a negative deviation from ideality at surface pressures below or above the phase transition from the liquidexpanded to the liquid-condensed state, for example at 3 mN and 25 mN/m. Such a negative deviation was also observed by Matuo and co-workers for various hydrocarbon acid-DPPC or -DSPC mixtures at 25 °C.42-44 With the exception of the nonafluoropentadecanoic acid-DPPC system, all systems showed a concentration dependent onset of the phase transition. Together, these findings indicate interactions, if not (partial) miscibility, between both components. In addition, a trend to decreased miscibility (ideal behavior) with increasing chain length is apparent in both the hydrocarbon and the fluorocarbon series. Thus, the terminal perfluoroalkyl groups do alter the interactions between the carboxylic acid and DPPC, but the interactions still show the above-mentioned characteristics of carboxylic acid-DPPC mixtures. The attractive interactions observed for both hydrocarbon and fluorocarbon-DPPC mixtures are most likely the result of headgroup interactions, because only the hydrophobic tails are different in these systems. At this time we can only speculate about the nature of these interactions, but the formation of hydrogen bonds between the carboxylic acid group and the phosphate diester function in the monolayer seems to be a plausible explanation. Several factors might contribute to an altered behavior of partially fluorinated amphiphiles and their mixtures with DPPC at the air-water interface. Similar to the bulk phase,17 the mixing of perfluorocarbon and hydrocarbon surfactants in micelles,16,18-21 and monolayers23,24 often shows nonideal behavior because of the low affinity of the fluorocarbon tail for the hydrocarbon tail. Very little work with mixtures of fluorocarbon and hydrocarbon surfactants has been done at insoluble monolayers at the airwater interface. Monolayer mixtures of perfluorocarbon surfactants with similar structure and molecular weight show an apparent ideal behavior thought to be the result of a complete phase separation.23 Insoluble monolayers of mixtures of structurally different fluorocarbon-hydrocarbon amphiphiles show phase separation at higher pressures and a positive deviation from the apparent ideal behavior at lower surface pressures.24 Furthermore, negative deviations from ideality have been observed in a mixture of a fluorinated and a partially fluorinated surfactant.24 The nonfluorocarbon moiety (a benzene ring) seems to reduce the mutual phobic interaction between the two different surfactants and to prevent a phase separation. Mixtures of highly fluorinated double-chain amphiphiles with palmitic acid were found to show immiscibility or partial miscibility in the monolayer, depending on the length of the hydrocarbon segment of the partially fluorinated amphiphile.22 According to Liang and Hui,22 a decreasing degree of fluorination in a partially fluorinated amphiphile results in better miscibility with a hydrocarbon surfactant. This conclusion was supported by a DSC (differential scanning calorimetry) study, which

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demonstrated that the miscibility between DPPC and partially fluorinated phosphatidylcholines was improved by introducing more methylene groups.50 The findings of these conventional monolayer studies were confirmed with atomic force microscopy studies of mixed LangmuirBlodgett films of eicosanoic acid with perfluorooctadecanoic or perfluorotetradecanoic acid,26 as well as immobilized organosilane monolayers prepared from octadecyltrichlorosilane and [2-(perfluorooctyl)ethyl]trichlorosilane.28 The reduced miscibility between the partially fluorinated carboxylic acids 1-3 and DPPC observed with increasing chain length and, hence, increasing degree of fluorination is in agreement with the above-mentioned results. These observations can be explained with (1) the increasing chain length of the carboxylic acids 1-3 or (2) the increasing phobicity of the hydrocarbon tails of DPPC with the terminal fluorocarbon tail of the acids. At this point it is not possible to quantify the contribution of each factor, but the phobicity between hydrocarbon and perfluorocarbon chains does not appear to play a major role. Two other factors may influence the packing of the molecules, and thus their interactions, in the mixed monolayer. Partially fluorinated carboxylic acids such as 1-3 have more expanded compression isotherms compared to hydrocarbon and perfluorocarbon carboxylic acids as a result of the strong dipole moments associated with the unsymmetrical CH2-CF2 linkage as well as the larger cross sectional area of the perfluoroalkyl group.34,51,52 As (50) Rolland, J.-P.; Santaella, C.; Monasse, B.; Vierling, P. Chem. Phys. Lipids 1997, 85, 135-143. (51) Kato, T.; Kameyama, M.; Ehara, M.; Imura, K.-i. Langmuir 1998, 14, 1786-1798.

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discussed by Bernett and Zisman,34 both factors reduce the interactions between the hydrophobic tails of the acid with itself and, in mixed monolayers, with other amphiphiles such as DPPC. In conclusion, simple partially fluorinated carboxylic acids appear to show an attractive interaction with DPPC in a mixed monolayer at the air-water interface and, thus, behave similar to their hydrocarbon analogues.42-44 Consequently, partly fluorinated acids might combine properties of their hydrocarbon analogues as well as of perfluorocarbon surfactants, such as enhanced thermal stability and biocompatibility. Technical and biomedical applications of partially fluorinated carboxylic acids and related fluorinated surfactants are currently under investigation in our and other laboratories.2,53 Acknowledgment. The authors would like to thank Prof. George Zografi (UWsMadison) and Dr. Yen-Lane Chen (3M) for fruitful discussion during the preparation of the manuscript. The authors would also like to thank the unknown referees of the manuscript for their helpful suggestions. Supporting Information Available: The compression isotherms of all six carboxylic acid-DPPC mixtures are shown. This material is available free of charge via the Internet at http://pubs.acs.org. LA991598V (52) Gaines, G. L. Langmuir 1991, 7, 3054-3056. (53) Bertoluzza, A.; Bonora, S.; Fini, G.; Morelli, M. A. J. Raman Spectrosc. 1981, 11, 225-230.