Synthesis and Solution Properties of Nonionic Hybrid Surfactants with a Benzene Ring

1 1 1,2 1＊,2 Haruhiko MIYAZAWA , Yutaka WAKATSUKI , Yukishige KONDO and Norio YOSHINO 1 Department of Industrial Chemistry, Faculty of Engineering, Tokyo University of Science (1-3 Kagurazaka, Shinjuku-ku, Tokyo 162-8601, JAPAN) 2 Institute of Colloid and Interface Science, Tokyo University of Science (1-3 Kagurazaka, Shinjuku-ku, Tokyo 162-8601, JAPAN)

Edited by K. Kubo, Kyusyu Univ., and accepted February 16, 2005 (received for review December 13, 2004)

Abstract: Four nonionic hybrid surfactants with a benzene ring as a spacer,

C6F13C6H4CH[O(C2H4O)mH]C5H11 (F6PH5EOm: m = 4, 8, 10, 14, C6H4 = p-phenylene), were synthesized. The surfactants synthesized were found to be as stable and hardly hydrolyzable as the previously reported ionic hybrid surfactants. F6PH5EO10 and F6PH5EO14 were highly surface-active and water-soluble while their critical micelle concentrations (cmc) determined by surface tension measurements were low compared with those of sulfate-type hybrid surfactants,

C6F13C6H4CH(OSO3Na)C5H11 (F6PH5OS, C6H4 = p-phenylene), and phosphate-type hybrid

surfactants, C6F13C6H4CH[OPO2(OC6H5)Na]C5H11 (F6PH5PPhNa, C6H4 = p-phenylene, C6H5 = phenyl), both of which also have a benzene ring as a spacer. The cloud point of F6PH5EO14 in

solutions of salts such as NaCl and CaCl2 decreased with increasing salt concentration and the decreasing rate was the largest for NaCl, whereas the surfactant showed solubility high enough for use in physiological saline solution at temperatures around the body temperature. Key words: nonionic hybrid surfactant, synthesis, ethylene oxide, respiratory distress syndrome, water-in-fluorocarbon emulsion, liquid ventilation

1966 that perfluorinated tetrahydrofuran liquid is an 1 Introduction excellent oxygen carrier and they succeeded in allowing Idiopathic respiratory distress syndrome of the new- mice to survive for several hours in the liquid with dis- born is a progressive respiratory failure leading to dysp- solved oxygen (2). Their work led to many studies on nea caused by a deficiency of the pulmonary surfactant liquid ventilation using fluorocarbon compounds (3) produced in alveolar type II cells. Although respirators and the clinical test was performed in 1995 (4). Fluoro- are mainly used to compensate pulmonary respiration, carbon compounds used in liquid ventilation are limited lungs of the new born are premature compared with to 1-perfluorooctyl bromide and 1-perfluorooctylethane those of the adult, and hence, the maintenance of lung for safety. oxygen concentration is hardly achieved by the apparat- Meanwhile, since many fluorocarbon liquids are us. A new method has then been groped to reduce the hydrophobic as well as oleophobic, many pharmacolog- burden on lungs of the newborn and much attention has ically active substances are hardly dispersible in these been paid recently to the liquid ventilation method that liquids and this causes a difficult problem in liquid ven- compensates pulmonary respiration by filling lungs tilation. In order to solve this problem, certain with fluorinated compounds (1). Clark et al. found in approaches have been attempted using prodrugs having

＊ Correspondence to: Norio YOSHINO, Department of Industrial Chemistry, Faculty of Engineering, Tokyo University of Science, 1-3 Kagurazaka, Shinjuku-ku, Tokyo 162-8601, JAPAN E-mail: [email protected]

Journal of Oleo Science ISSN 1345-8957 print / ISSN 1347-3352 online 361 http://jos.jstage.jst.go.jp/en/ H. Miyazawa, Y. Wakatsuki, Y. Kondo et al. a high affinity with fluorocarbons and supramolecular compounds containing many fluorine atoms (5, 6).

Some fluorocarbon surfactants including C6F13C2H4S

[CH2CH(CONHC(CH2OH)3)]5H are known to form prodrugs (7, 8). Yet, the number of pharmacologically active substances is limited that can combine with the surfactants to yield prodrugs and very few compounds form supramolecules, which indicate that both approaches are impractical. In contrast, Sadtler et al. succeeded in preparing long-time stable water-in-fluorocarbon emulsions using Scheme 1 Molecular Formula of Hybrid Surfactants.

C8F17C10H20OPO[N(C2H4)2O]2 with a hydrophilic morpholine group as surfactant in 1-perfluorooctyl bromide with added water-soluble or oil-soluble pharmacologi- ble for Drug Delivery System. This suggests that cally active substances such as antibiotics (9). Never- hybrid surfactants with an ethylene oxide chain are theless, fatty acid salts of morpholine are reported to be human body-friendly and capable of forming water-in- poisonous to the human body and hence the develop- fluorocarbon emulsions 1-perfluorooctyl bromide with ment is eagerly demanded of such human body-friendly dispersed water-soluble and oil-soluble pharmacologi- surfactants that are capable of forming stable water-in- cally active substances. fluorocarbon emulsions containing a variety of pharma- The present authors synthesized four nonionic hybrid cologically active substances. surfactants with an ethylene oxide chain, C6F13C6H4CH

The present authors have so far synthesized ionic [O(C2H4O)mH]C5H11 (F6PH5EOm: m = 4, 8, 10, 14, hybrid surfactants with both fluorocarbon and hydrocar- C6H4 = p-phenylene) and examined the solution proper- bon chains in their molecules, CmF2m+1C6H4COCH ties of the surfactants.

(SO3Na)CnH2n+1 (FmPHnS) (10), CmF2m+1C6H4CH (OSO Na)C H (FmPHnOS) (11), C F C H CH 3 n 2n+1 m 2m+1 6 4 2Results and Discussion [OPO2(OC6H5)Na]CnH2n+1 (FmPHnPPhNa) (12), and

CmF2m+1C2H4CH(OSO3Na)CnH2n+1 (FmEHnOS) (13). 2･1Synthesis of Hybrid Surfactants They have also reported that these hybrid surfactants Scheme 2 shows the synthesis route for the hybrid with an unique structure have characteristic properties surfactants. that cannot be shown neither by surfactants with two F6PH5EOkCl (k = 2, 6) were obtained in 70-85 % hydrophobic chains of the same kind nor by mixtures of yield by introducing an ethylene oxide chain chlorinat- fluorocarbon and hydrocarbon surfactants. Thus, the ed at its terminal into F6PH5A, a hybrid alcohol, using hybrid surfactants are able to coemulsify fluorinated a phase transfer catalyst (PTC). PTC forms an ion pair compounds/water/hydrocarbons (10), form long-lived with a certain compound and the ion pair formed is sol- micelles in terms of nuclear magnetic resonance (14), uble in both aqueous and organic phases, which are raise the viscosity of 10 wt% solution to a surprisingly incompatible with each other, and enhances the reactiv- large extent around 36℃ (15-19), and modify human ity of the compound. Thus, PTC is an excellent catalyst teeth to prevent them from being decayed (12). Scheme and makes ether synthesis easier than the Williamson 1 shows the chemical structures of FmPHnS, FmPHnOS, synthesis (20-23). Although the reaction hardly FmPHnPPhNa, and FmEHnOS. occurred for secondary alcohols in which a bulky func-

Williams et al. found that C4F9C6H4COC5H11, a tional group such as benzene ring and a hydroxyl group hybrid ketone, whose synthesis was reported by the pre- bind to the same carbon atom in the Williamson synthe- sent authors (10), acts as a carrier of pharmacologically sis, the use of a PTC allowed the reaction to proceed active substances in 1-perfluorooctyl bromide (5). On smoothly and the desired ether could be obtained. The the other hand, those surfactants which have ethylene introduction of ethylene oxide chain into F6PH5EOkCl oxide chains like Tweens (ICI America) are generally was performed using the Williamson synthesis, the harmless to the human body and expected to be applica- reaction time of which is shorter.

362 J. Oleo Sci., Vol. 54, No. 6, 361-368 (2005) Synthesis and Solution Properties of Nonionic Hybrid Surfactants

Scheme 2 Synthesis of F6PH5EOm.

2･2Cloud Points, Surface Tensions, and C10H21OSO3Na and n-C10H21OPO3Na2 are 33 and 3.5

Critical Micelle Concentrations (cmc) mM, respectively. The values of gcmc for F6PH5EOm of F6PH5EOm were about 20 mN m-1, showing a high surface tension

Table 1 lists the values of cloud point, Cp, surface lowering ability of the surfactants similar to that for the tension at cmc, gcmc, and cmc for F6PH5EOm, compar- previously reported fluorinated surfactants. Figure 1 ing with those for F6PH5OS (11) and F6PH5PPhNa shows the relationship between surface tension and (12). concentration for aqueous F6PH5EOm solutions. The cloud points for F6PH5EOm were below 25℃ The area occupied by one molecule for F6PH5EOm when m was 4 or 8. The cloud point rose with increas- at the air/solution interface, A, was calculated from the ing length of ethylene oxide chain as those of common surface excess concentration, G (24). nonionic surfactants (24). Although the cmc values for F6PH5EOm increased with increasing m, they were low 1  ∂γ  Γ =−   (1) compared with those for F6PH5OS and F6PH5PPhNa, 2.303RT ∂log C  which shows a tendency similar to that is found when nonionic hydrocarbon surfactants and anionic surfac- where R is the gas constant and T is the absolute tem- tants, both with the same length of hydrophobic group, perature. Equation 2 holds between the area occupied are compared (24). For example, the cmc value of n- by one molecule for F6PH5EOm, A, and the surface

C10H21O(C2H4O)8H is 1.0 mM while those of n- excess concentration, G.

Table 1 Cloud point (Cp), Surface Tension (gcmc), cmc, Surface Excess Concentration (G) and Occupied Area (A) of F6PH5EOm at 25℃.

Cp g Cmc G A Surfactant cmc /℃ /mN m－1 /mM /mmol m－2 /nm2 F6PH5EO4a <0 －－－－ F6PH5EO8a 8 －－－－ F6PH5EO10 28 20 0.63 4.6 0.36 F6PH5EO14 54 22 5.4 3.2 0.52 F6PH5OSc 14b 20 340 1.6 1.04 F6PH5PPhNad 27b 23 210 0.86 1.93 a Cmc, surface tension, and occupied area were not obtained because of low cloud point. b Krafft point c From ref. 11 Fig. 1 Surface Tension Plots of F6PH5EOm against d From ref. 12 Concentration at 25℃.

363 J. Oleo Sci., Vol. 54, No. 6, 361-368 (2005) H. Miyazawa, Y. Wakatsuki, Y. Kondo et al.

A = 1 (2) ΓNA

where NA is Avogadro’s number. Table 1 gives the values of A and G for F6PH5EOm. The value of A increased with increasing m and ranged from 0.36 to 0.52 nm2/molecule, which was small compared with those for F6PH5OS and F6PH5PPhNa. Surfactant molecules with the same sign of charge are hardly packed closely at the air/solution interface due to the electrostatic repulsion between the ionic heads, thereby increasing the value of A. In contrast, the molecules can be closely packed on the surface of electrolyte solu- Fig. 2 Cloud Point Plots of F6PH5EO14 against tion because of suppressed dissociation of the counter Concentration of Inorganic Salts. ions to make the value of A smaller. For instance, the 2 value of A of n-C10H21SO3Na is 0.52 nm /molecule on the surface of aqueous solution, whereas those on the that can bind to ethylene oxide chains through hydro- surfaces of 0.1 and 0.5 M NaCl solutions are 0.43 and gen bonding and the ion raises the cloud point of sur- 0.41 nm2/molecule, respectively (24). Since no electro- factant. In contrast, ion that strengthens hydrogen static repulsion acts between nonionic F6PH5EOm bonding between water molecules by its addition is molecules, the molecules are likely to be packed closely located at a lower position in the series and the ion low- on the solution surface to give a smaller value of A than ers the cloud point. The representative cloud point rais- those for F6PH5OS and F6PH5PPhNa. ing anions are thiocyanate ion, iodide ion, etc while the typical cloud point lowering anions include sulfate, 2･3 Salt Effect on the Cloud Point of phosphate, and chloride ions. The cloud point of

F6PH5EO14 C8H17C6H4O(C2H4O)10H in water is 64℃, whereas that + － + － The use of isotonic physiological saline solution is in aqueous 0.2 M (CH3)4N I and 0.2M NH4 Cl solu- desirable as medium to disperse fluorinated compounds tions rises to 67℃ and falls to 60℃, respectively (24). to be used in liquid ventilation. Since isotonic physio- Cations also affect hydrogen bonding between water logical saline contains electrolytes such as NaCl and molecules but in a way different from that of anions,

CaCl2 to maintain the osmotic pressure at that of body thus giving a different lyotropic series. Ethylene oxide fluid, the cloud points of F6PH5EOm in electrolyte chains of carbon atoms more than 9 form complexes solution should be higher than 36℃, the average human with calcium and magnesium ions and the cloud point body temperature. Figure 2 shows the relationship lowering is suppressed independently of cation species, between the cloud point of F6PH5EO14 in salt solution whereas alkali metal ions except lithium ion form no and salt concentration. complex with ethylene oxide chains and cause dehydra- The cloud point of F6PH5EO14 lowered with tion of the chains to lower the cloud point (25, 26). increasing salt concentration and showed a lowering This fact is in accordance with the results shown in Fig. tendency of NaCl ＞ CaCl2 ≅ MgCl2 with respect to salt 2. In fact, commercially available physiological saline species. The cloud point lowering for nonionic surfac- solution contains NaCl and CaCl2 at about 0.68 and tants in electrolyte solution is known to obey the 0.002 wt%, respectively, and the cloud points of Hofmeister (lyotropic) series (24-27). Nonionic surfac- F6PH5EO14 at these salt concentrations were respec- tants dissolve in water due to the hydration of ethylene tively 49 and 53℃ . Thus, the cloud point of oxide chains through hydrogen bonding. Ion occupying F6PH5EO14 solution is higher than the human body a higher position in the Hofmeister series is the one temperature and hence the surfactant proves itself to be which breaks hydrogen bonding between water usable in liquid ventilation. The surfactants synthesized molecules and increases the number of water molecules in the present work, F6PH5EOm, are expected to be

364 J. Oleo Sci., Vol. 54, No. 6, 361-368 (2005) Synthesis and Solution Properties of Nonionic Hybrid Surfactants usable as surfactant for dispersing electrolyte solution used without further purification. in 1-perfluorooctyl bromide as small droplets to yield a water-in-fluorocarbon emulsion. 4･2Measurements and Measuring Appa- ratuses 4･2･1 Identification of F6PH5EOm 3 Conclusions FT-IR spectra of F6PH5EOm were measured by the Four novel nonionic hybrid surfactants with an ethyl- Attenuated Total Reflection (ATR) method using a ene oxide chain and a benzene ring as a spacer, Nicolet Avatar 360 FT-IR spectrometer. A Bruker

C6F13C6H4CH[O(C2H4O)mH]C5H11 (F6PH5EOm: m = 4, DPX-400 spectrometer was used to measure 400 MHz 1 8, 10, 14, C6H4 = p-phenylene) were synthesized. The H-NMR spectra of the surfactants at 30℃ in CDCl3 cloud point of F6PH5EOm rose with increasing length and CD3OD (internal standard: tetramethylsilane of ethylene oxide chain, m, and those of the surfactants (TMS)). The spectrometer was also used to measure with m larger than 10 were higher than 25℃, while 376 MHz 19F-NMR spectra of the compound at 30℃ in their surface activity was as high as that of ionic CDCl3 or CD3OD (external standard: trifluoroacetic F6PH5OS and F6PH5PPhNa. acid). GC-Mass spectra were measured with a Hewlett While the cmc for F6PH5EOm increased with Packard HP6890 series GC System (Hewlett Packard increasing m, the values were rather small and even the 5973 Mass Selective Detector). A JEOL JMS SX102A value of F6PH5EO14, the largest among those of the was used to measure MS (FAB-MS) of the surfactants surfactants, was only about 1/40 of those of F6PH5OS with added NaI. HPLC analysis of F6PH5EOkCl and and F6PH5PPhNa. The area occupied by one molecule F6PH5EOm was carried out by Develosil ODS-5 col- at the air/water interface increased with increasing m umn (250 × 4.6 mm i.d.) equipped with Hitachi UV and the value ranged from 0.36 to 0.52 nm2/molecule. detector L-7405 (256 nm) at room temperature. Reten-

The cloud point of F6PH5EO14 lowered with tion times (tR) of them were determined using increasing concentration of salt such as NaCl and CaCl2 methanol/water 90/10 as mobile phase at 1.0 mL/min. and the lowering rate was the largest for NaCl. 4･2･2 Measurements of cloud point, surface ten- F6PH5EO14 has a cloud point high enough for it to be sion, and critical micelle concentrations used in physiological saline solution and is then expect- F6PH5EOm samples were used after being freeze- ed as a surfactant in water-in-fluorocarbon emulsions. dried for 2 h to remove hydrated water from the ethylene oxide chains and stored in a dry nitrogen atmos- phere. Surface tension measurements were performed 4 Experimental Section at 25℃ for surfactant solutions at various concentra- 4･1Materials tions by the Wilhelmy method (Krüss Model K12 sur-

IC6H4COC5H11 and C6F13C6H4COC5H11 were synthe- face tensiometer) using a platinum plate. The kink sized according to the method in our previous paper point on surface tension-concentration curve was taken (10). Introduction of hexanoyl chloride into iodoben- as the critical micelle concentration of the surfactant. zene by Friedel-Crafts acylation gave IC6H4COC5H11, Cloud point determinations were made using surfactant which was then allowed to react with perfluorohexyl solutions at concentrations higher than the cmc by heat- iodide to yield C6F13C6H4COC5H11. The hybrid ketone ing them at a rate of 3℃/min in a thermostat and visual- thus obtained was reduced with sodium borohydride to ly observing surfactant deposition. The cloud point was give C6H13C6H4CH(OH)C5H11 (F6PH5A) (11). Sodium defined as the temperature at which surfactant deposits. hydroxide, sodium hydride, diethylene glycol, triethyl- The cloud point of F6PH5EO14 in electrolyte solution ene glycol, tetraethylene glycol, bis-(2-chloroethyl) was determined at surfactant concentration three times ether [(ClC2H4)2O, I] (Kanto Chemicals), and tetra-n- higher than the cmc (16.2 mM). + － butylammonium hydrogensulfate [(C4H9)4N ･HSO4 ] (ICI) were used as supplied. N,N-Dimethylformalde- 4･3 Synthesis hyde (DMF) was purified by distillation after being 4･3･1 Synthesis of Cl(C2H4O)5CH2CH2Cl (II) dried with calcium hydride. Solvents (chloroform, 2- I (168 g, 1.2 mol), diethylene glycol (50.0 g, 472 butanone, hexane, methanol, and ethyl acetate) were mmol), tetra-n-butylammonium hydrogensulfate (1.2 g,

365 J. Oleo Sci., Vol. 54, No. 6, 361-368 (2005) H. Miyazawa, Y. Wakatsuki, Y. Kondo et al.

a b c d e f g h 3.6 mmol), and 50 % sodium hydroxide solution (200 C6F13-) for CH3 CH2 CH2 CH2 CH2 CH [O(CH2 CH2 O) i j 19 ml) were placed in a round bottom flask and the mix- CH2 CH2 Cl]C6H4C6F13; F-NMR (CDCl3) d －81.5 ture was heated for 72 h at 30℃ while stirring. A trans- (3F, br, a), －111.4 (2F, br, f), －122.0 (2F, br, e), － parent colorless liquid (II) was obtained by reduced 122.3 (2F, br, d), －123.4 (2F, br, c), －126.2 (2F, br, b) a b c d e f pressure distillation from the 2-butanone-soluble part of for CF3 CF2 CF2 CF2 CF2 CF2 C6H4CH[O(CH2CH2O) + the reaction product. Yield 63 g (42 %); bp 137℃ / 20 C2H4Cl]C5H11; GC-MS m/z (rel. int.) 602 [M] (0.66), －1 1 + + Pa; IR (cm ) 2840-2960 (nC-H), 1110 (nC-O); H-NMR 531 [M－C5H11] (100), 377 [C6F12C6H5] (18), 127 + (CDCl3) d 3.67 (20H, m, b, c, d, and e), 3.77 (4H, m, a [CF2C6H5] (24); HPLC tR (min) 12.58 (no other peaks). a b c d e f and f) for ClCH2 CH2 O(CH2 CH2 O)4CH2 CH2 Cl; GC- 4･3･3･2 Synthesis of 1-(4-perfluorohexylphenyl) MS m/z (rel. int.) 319 [M]+ (38), 283 [M－Cl]+ (5), 257 hexyl w-chlorohexaethylene glycol ether + + [M－2Cl] (5), 107 [ClC2H4OC2H4] (100). (F6PH5EO6Cl)

4･3･2 Synthesis of HO(C2H4O)8H F6PH5A (10.0 g, 21.6 mmol), II (51.5 g, 1.61 mol), Sodium hydride (6.0 g, 250 mmol) and DMF (100 tetra-n-butylammonium hydrogensulfate (0.6 g, 1.6 ml) were taken into a round bottom flask equipped with mmol), and 50 % sodium hydroxide solution (200 ml) an isobaric dropping funnel, and triethylene glycol were taken into a round bottom flask and the mixture (75.0 g, 500 mmol) was added dropwise into the iced was heated for 72 h at 40℃. A transparent colorless DMF solution while stirring. After the mixture was liquid, (F6PH5EO6Cl), was obtained by column sepa- stirred for 2 h at 80℃, I was added dropwise to it at ration using an eulent (hexane : ethyl acetate = 8 : 1) as room temperature and allowed to react for 7 d at the developing liquid from the 2-butanone soluble part of same temperature. A transparent colorless liquid, the reaction system. Yield 11 g (68 %); IR (cm－1) 1 HO(C2H4O)8H, was obtained by reduced pressure distil- 2851-3049 (nC-H), 1243 (nC-F), 1112 (nC-O); H-NMR lation from the filtrate gained after filtering the reaction (CDCl3) d 0.86 (3H, t, J = 7.1 Hz, a), 1.32 (6H, m, b, c, system to remove NaCl, a by-product. Yield 30 g (41 and d), 1.72 (2H, m, e), 3.48 (2H, br, g), 3.62 (20H, m, －1 %); bp 225℃ / 7 Pa; IR (cm ) 3100-3608 (nO-H), 2880- h, i, j, and l), 3.73 (2H, m, k), 4.30 (1H, t, J = 6.8 Hz, f), 1 3030 (nC-H), 1086 (nC-O); H-NMR (CDCl3) d 1.90 (2H, 7.43 (2H, d, J = 8.1 Hz, m-protons from C6F13-), 7.55 br, a and h), 3.66 (28H, m, c, d, e, and f), 3.73 (4H, m, b (2H, d, J = 8.1 Hz, o-protons from C6F13-) for a b c d e f g h a b c d e f g h i j and g) for H OCH2 CH2 (CH2 CH2 O)6CH2 CH2 OH ; CH3 CH2 CH2 CH2 CH2 CH [OCH2 CH2 O(CH2 CH2 O)4 + k l 19 GC-MS m/z (rel. int.) 370 [M] (38), 89 [C2H4OC2 CH2 CH2 Cl]C6H4C6F13; F-NMR (CDCl3) d －81.5 + + H4OH] (77), 45 [C2H4OH] (100). (3F, br, a), －111.4 (2F, br, f), －122.0 (2F, br, e), 4･3･3 Introduction of terminal-chlorinated ethyl- －122.3 (2F, br, d), －123.4 (2F, br, c), －126.2 (2F, br, a b c d e f ene oxide chain to hybrid alcohol b) for CF3 CF2 CF2 CF2 CF2 CF2 C6H4CH[O(CH2CH2 + 4･3･3･1 Synthesis of 1-(4-perfluorohexylphenyl) O)5C2H4Cl]C5H11; FAB-MS m/z (rel. int.) 801 [M+Na] + + hexyl w-chloroethylene glycol ether (100), 765 [M－Cl+Na] (9), 409 [C6F13C6H5CH] (48), + (F6PH5EO2Cl) 127 [CF2C6H5] (4); HPLC tR (min) 10.51 (no other F6PH5A (75.2 g, 152 mmol), I (173 g, 1.2 mol), peaks). tetra-n-butylammonium hydrogensulfate (3.9 g, 11.5 4･3･4 Synthesis of hybrid surfactant with ethylene mmol), and 50 % sodium hydroxide solution (200 ml) oxide chain were placed in a round bottom flask and the mixture 4･3･4･1 Synthesis of 1-(4-perfluorohexylphenyl) was heated for 72 h at 40℃ while stirring. A transpar- hexyl tetraethylene glycol ether (F6PH5EO4) ent colorless liquid, F6PH5EO2Cl, was obtained by Sodium hydride (0.6 g, 250 mmol) and DMF (50 ml) reduced pressure distillation from the 2-butanone solu- were placed in a round bottom flask equipped with an ble part of the reaction system. Yield 90 g (85 %); bp isobaric dropping funnel and diethylene glycol (5.3 g, －1 138℃ / 20 Pa; IR (cm ) 2826-3017 (nC-H), 1230 (nC-F), 50 mmol) was added dropwise into the iced DMF solu- 1 1121 (nC-O); H-NMR (CDCl3) d 0.86 (3H, t, J = 7.2 Hz, tion. After the mixture was stirred for 2 h at 80℃, a), 1.30 (6H, m, b, c, and d), 1.72 (2H, m, e), 3.48 (2H, F6PH5EO2Cl (15.1 g, 25 mmol) was added dropwise br, g), 3.62 (4H, m, h and j), 3.73 (2H, m, i), 4.33 (1H, to it at room temperature and the system was further t, J = 6.7 Hz, f), 7.44 (2H, d, J = 8.0 Hz, m-protons stirred for 3 d at the same temperature. A transparent from C6F13-), 7.56 (2H, d, J = 8.0 Hz, o-protons from colorless liquid, F6PH5EO4, was obtained by twice of

366 J. Oleo Sci., Vol. 54, No. 6, 361-368 (2005) Synthesis and Solution Properties of Nonionic Hybrid Surfactants column separation using eulents (hexane : ethyl acetate and d), 1.75 (2H, m, e), 2.78 (1H, br, m), 3.46 (2H, br, = 1 : 20 and chloroform : methanol = 20 : 1) as devel- g), 3.64 (36H, m, h, i, j, and k), 3.70 (2H, m, l), 4.30 oping liquids from the filtrate gained by filtering the (1H, t, J = 6.8 Hz, f), 7.42 (2H, d, J = 8.1 Hz, m-protons reaction system to remove the precipitates. Yield 4.9 g from C6F13-), 7.54 (2H, d, J = 8.1 Hz, o-protons from －1 a b c d e f g h (29 %); IR (cm ) 3130-3653 (nO-H), 2773-3003 (nC-H), C6F13-) for CH3 CH2 CH2 CH2 CH2 CH [OCH2 CH2 O 1 i j k l m 19 1233 (nC-F), 1102 (nC-O); H-NMR (CDCl3) d 0.86 (3H, (CH2 CH2 O)8CH2 CH2 OH ]C6H4C6F13; F-NMR t, J = 6.8 Hz, a), 1.34 (6H, m, b, c, and d), 1.74 (2H, m, (CDCl3) d －81.6 (3F, br, a), －111.5 (2F, br, f), e), 3.47 (2H, br, g), 3.65 (12H, m, h, i, j, and k), 3.72 －122.0 (2F, br, e), －122.3 (2F, br, d), －123.4 (2F, br, a b c d e f (2H, m, l), 2.28 (1H, br, m), 4.30 (1H, t, J = 7.1 Hz, f), c), －126.2 (2F, br, b) for CF3 CF2 CF2 CF2 CF2 CF2

7.43 (2H, d, J = 8.2 Hz, m-protons from C6F13-), 7.54 C6H4CH[O(CH2CH2O)10H]C5H11; FAB-MS m/z (rel. + + (2H, d, J = 8.2 Hz, o-protons from C6F13-) for int.) 959 [M+Na] (48), 409 [C6F13C6H5CH] (100), 127 a b c d e f g h i + + CH3 CH2 CH2 CH2 CH2 CH [OCH2 CH2 O(CH2 [CF2C6H5] (11), 89 [C2H4OC2H4OH] (21), 45 j k l m 19 + CH2 O)2CH2 CH2 OH ]C6H4C6F13; F-NMR (CDCl3) d [C2H4OH] (30); HPLC tR (min) 8.15 (no other peaks).

－81.6 (3F, br, a), －111.4 (2F, br, f), －122.0 (2F, br, F6PH5EO14 (F6PH5EO6Cl + HO(CH2CH2O)8H): －1 e), －122.3 (2F, br, d), －123.4 (2F, br, c), －126.2 (2F, colorless liquid, yield 40 %; IR (cm ) 3129-3654 (nO-H), a b c d e f 1 br, b) for CF3 CF2 CF2 CF2 CF2 CF2 C6H4CH[O(CH2 2773-3006 (nC-H), 1233 (nC-F), 1103 (nC-O); H-NMR + CH2O)4H]C5H11; FAB-MS m/z (rel. int.) 695 [M+Na] (CDCl3) d 0.86 (3H, t, J = 6.8 Hz, a), 1.34 (6H, m, b, c, + + (6), 409 [C6F13C6H5CH] (100), 127 [CF2C6H5] (17), and d), 1.74 (2H, m, e), 2.28 (1H, br, m), 3.47 (2H, br, + + 89 [C2H4OC2H4OH] (32), 45 [C2H4OH] (40); HPLC tR g), 3.65(56H, m, h, i, j, and k), 3.72 (2H, m, l), 4.30 (min) 8.28 (no other peaks). (1H, t, J = 7.1 Hz, f), 7.43 (2H, d, J = 8.2 Hz, m-protons

4･3･4･2 Synthesis of nonionic hybrid surfactants from C6F13-), 7.54 (2H, d, J = 8.2 Hz, o-protons from a b c d e f g h (F6PH5EO8, F6PH5EO10, F6PH5EO14) C6F13-) for CH3 CH2 CH2 CH2 CH2 CH [OCH2 CH2 O i j k l m 19 The nonionic hybrid surfactants shown in the above (CH2 CH2 O)12CH2 CH2 OH ]C6H4C6F13; F-NMR brackets were synthesized using different combinations (CDCl3) d －81.7 (3F, br, a), －111.4 (2F, br, f), － of F6PH5EO6Cl and ethylene glycols with different 122.0 (2F, br, e), －122.3 (2F, br, d), －123.4 (2F, br, c), a b c d e f chain lengths. Their purification was performed in a －126.2 (2F, br, b) for CF3 CF2 CF2 CF2 CF2 CF2 C6H4 way similar to that given in 4･3･4･1. CH[O(CH2CH2O)14H]C5H11; FAB-MS m/z (rel. int.) + + F6PH5EO8 (F6PH5EO6Cl + diethylene glycol): col- 1135 [M+Na] (6), 409 [C6F13C6H5CH] (100), 127 －1 + + orless liquid, yield 29 %; IR (cm ) 3184-3675 (nO-H), [CF2C6H5] (17), 89 [C2H4OC2H4OH] (33), 45 1 + 2793-2998 (nC-H), 1253 (nC-F), 1100 (nC-O); H-NMR [C2H4OH] (41); HPLC tR (min) 8.07 (no other peaks).

(CDCl3) d 0.85 (3H, t, J = 6.8 Hz, a), 1.31 (6H, m, b, c, and d), 1.75 (2H, m, e), 2.78 (1H, br, m), 3.46 (2H, br, Reference g), 3.64 (28H, m, h, i, j, and k), 3.70 (2H, m, l), 4.30 (1H, t, J = 6.8 Hz, f), 7.42 (2H, d, J = 8.1 Hz, m-protons 1. T.H. SHAFFER, M.R. WOLFSON and L.C. CLARK Jr., Liquid Ventilation, Pediatric Pulmonology, Vol. 14, 102-109 (1992). from C6F13-), 7.54 (2H, d, J = 8.1 Hz, o-protons from a b c d e f g h 2. L.C. CLARK Jr. and F. GOLLAN, Survival of Mammals C6F13-) for CH3 CH2 CH2 CH2 CH2 CH [OCH2 CH2 O Breathing Organic Liquids Equilibrated with Oxygen at Atmo- (CH iCH jO) CH kCH lOHm]C H C F ; 19F-NMR 2 2 6 2 2 6 4 6 13 spheric Pressure, Science, Vol. 152, 1755-1756 (1966). (CDCl3) d －81.6 (3F, br, a), －111.4 (2F, br, f), － 3. B.P. FUHRMAN, P.R. PACZAN and M. DEFRANCISIS, Per- 122.0 (2F, br, e), －122.3 (2F, br, d), －123.4 (2F, br, c), fluorocarbon-Associated Gas Exchange, Critical Care Med., a b c d e f －126.2 (2F, br, b) for CF3 CF2 CF2 CF2 CF2 CF2 C6H4 Vol. 19, 712-722 (1991).

CH[O(CH2CH2O)8H]C5H11; FAB-MS m/z (rel. int.) 871 4. R.B. HIRSCHL, T. PRANIKOFF, P. GAUGER, R.J. SCHREIN- + + ER, R. DECHERT and R.H. BARTLETT, Liquid Ventilation in [M+Na] (48), 409 [C6F13C6H5CH] (100), 127 + + Adults, Children, and Full-Term Neonates, Lancet, Vol. 346, [CF2C6H5] (11), 89 [C2H4OC2H4OH] (22), 45 [C H OH]+ (31); HPLC t (min) 8.18 (no other peaks). 1201-1202 (1995). 2 4 R 5. T.D. WILLAMS, M. JAY, H-J LEHMLER, M.E. CLARCK, D.J. F6PH5EO10 (F6PH5EO6Cl + tetraethylene glycol): STALKER and P.M. BUMMER, Solubility Enhancement of －1 colorless liquid, yield 31 %; IR (cm ) 3186-3676 (nO-H), Phenol and Phenol Derivatives in Perfluorooctyl Bromide, J. 1 2793-3000 (nC-H), 1254 (nC-F), 1101 (nC-O); H-NMR Pharm. Sci., Vol. 87, 1585-1589 (1998).

(CDCl3) d 0.85 (3H, t, J = 6.8 Hz, a), 1.31 (6H, m, b, c, 6. J.G. RIESS, Highly Fluorinated Systems for Oxygen Transport,

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