Langmuir 2005, 21, 2689-2695
2689
Is the Ether Group Hydrophilic or Hydrophobic? Fredric M. Menger* and Mary E. Chlebowski Department of Chemistry, Emory University, Atlanta, Georgia 30322 Received September 16, 2004 A series of six surfactants, each with two ether oxygens within otherwise all-hydrocarbon chains, were synthesized and examined for their colloidal properties. Since an ether oxygen is sterically and conformationally similar to the methylene group it has replaced, the ether effect on micellization should stem mainly from solvation of the oxygen and, possibly, disrupted hydrophobicity of its adjacent carbons. It was found that critical aggregation values among the surfactants differ only modestly despite the total length of the ether-separated carbon segments ranging from 12 to 18. Shorter ether surfactants with only 12 or 14 total carbons appear to form small, loose aggregates owing, presumably, to a mild hydrophilicity of the ether groups. A surfactant with 18 chain carbons has a greater tendency to associate hydrophobically, but this is counterbalanced by a relatively water-free environment encountered by the ether groups within a more conventional micelle interior. The result is a leveling effect in which the critical aggregation concentration (cac) loses it sensitivity to chain length. Above their cac’s, none of the ether surfactants is a good solubilizer of tetramethysilane or mesitylene. This is not necessarily a predictable finding since it was conceivable that the presence of interior ether groups might actually enhance solubilization (much as ether is a better solvent than hexane). Foamability and solid adsorption studies also indicate that the ethers impair surface activity. In response to the question posed in the paper’s title, two ether groups are not sufficiently hydrophilic to prevent aggregation, but they do manage to alter the micelles’ morphology and properties considerably.
Introduction Ether groups occur in drugs (e.g., colchicine), hormones (e.g., thyroxine), natural products (e.g., reserpine), surfactants (e.g., Brij 35), and lipids (e.g., glycerol ethers). Multiple ether groups, as embodied in oligo(ethylene glycol) chains, have found widespread use for a variety of purposes including bioconjugation,1 casting of films,2 enhancing transfection efficiency,3 improving drug targeting,4 and increasing in vivo half-lives of vesicles.5 Given the ether’s prevalence and importance, it is pertinent to ask a rather fundamental question: “Exactly how hydrophobic or hydrophilic is the ether group?” This question is addressed in the manuscript that follows. Ether hydrophobicity/hydrophilicity can be judged from data already in hand. As a rudimentary criterion, diethyl ether is listed as having a water-solubility of 5.0 wt % compared to 20 wt % for 2-butanol.6 The octanol-water partition coefficient for diethyl ether favors the octanol (log Kow ) +0.89).7 The aliphatic Hansch hydrophobicity parameter (π) equals -0.47 for -OCH3 (compared to -0.71 for -COCH3 and -1.16 for -OH), suggesting that the methoxy group is mildly hydrophilic.8 Water solubility associated with oligo(ethylene glycols) derives, presumably, from an additive effect of many weakly soluble units. * Corresponding author. E-mail:
[email protected]. (1) Wilbur, D. S.; Pathare, P. M.; Hamlin, D. K.; Frownfelter, M. B.; Kegly, B. B.; Leung, W.-Y.; Gee, K. R. Bioconjugate Chem. 2000, 11, 584. (2) Jiang, L.; Hughes, R. C.; Sasaki, D. Y. Chem. Commun. 2004, 1028. (3) Le Bon, B.; Van Craynest, N.; Boussif, O.; Vierling, P. Bioconjugate Chem. 2002, 13, 1292. (4) Warnecke, A.; Kratz, F. Bioconjugate Chem. 2003, 14, 377. (5) Selen, T. M.; Hansen, C.; Martin, F.; Redemann, C.; Yau-young, A. Biochim. Biophys. Acta 1991, 1066, 29. (6) Solubilities of Inorganic and Organic Compounds; Stephen, H., Stephen, T., Eds.; Pergamon: Oxford, 1963. (7) Sangster, J. Octanol-Water Partition Coefficients: Fundamentals and Physical Chemistry; Wiley: Chichester, U.K., 1997. (8) Leo, A.; Hansch, C.; Elkins, D. Chem. Rev. 1971, 71, 525.
We have recently begun assessing the hydrophilicity/ hydrophobicity of non-hydrocarbon functional groups by a “micelle method”.9 The reasoning is quite straightforward: If a functional group residing within a surfactant chain is hydrophilic, then the propensity for the chain to self-assemble into a micelle will be diminished. Ether groups are particularly well-suited for this test because steric, geometric, and conformational perturbations introduced by an ether oxygen within a chain (relative to the methylene that the oxygen replaces) should be minor. Figure 1 lists four cationic and two anionic surfactants (A-F), each bearing two ether oxygens. Conventional ether-free surfactants DTAB and TTAB, studied for comparison purposes, are also shown in the scheme. Table 1 provides, for each of the new surfactants, values of n, m, and p representing the length of the hydrocarbon segments banking the ether oxygens. Figure 2 shows the pathways used to synthesize the ether surfactants. Yields, which were not optimized, are given as a range covering the various analogues. All ether surfactants, and the intermediates leading to them, were characterized for structure and purity by 1H and 13C NMR, FAB/HRMS, and elemental analysis. Each of the modified surfactants A-F possesses two ether oxygens within its chain. Our selecting two oxygens, no more, no less, was an a priori compromise between having a sufficient number of ethers to manifest a perturbation while minimizing the risk of nonmicellization. The choice of n, m, and p values (Table 1) was somewhat arbitrary and was limited only by the task of carrying out multistep syntheses to obtain additional compounds. It was initially unclear how the ethers would affect colloidal behavior relative to surfactants without the ether units. Conceivably, the ether groups (if indeed they are somewhat hydrophilic) could raise the critical micelle concentration (cmc). However, they could also modify (9) Menger, F. M.; Galloway, A. L. J. Am. Chem. Soc., in press.
10.1021/la040113m CCC: $30.25 © 2005 American Chemical Society Published on Web 02/22/2005
2690
Langmuir, Vol. 21, No. 7, 2005
Menger and Chlebowski
Figure 1. Structures of surfactants examined in this work. Table 1. Segment Lengths in the Ether Surfactants
n m p
A
B
C
D
E
F
1 5 5
3 5 5
1 8 5
1 8 8
3 5 5
1 8 8
micelle morphology, foamability, surfactant packing at solid surfaces, adsorption at air/water interfaces, and so forth. Of potential practical importance, ether groups within the micelle interior might enhance the solubilization in water of compounds, such as certain drugs, that are normally not prone to enter hydrocarbon-like regions. The fact that it was difficult to predict the ethersurfactants’ properties made the experiments all the more intriguing. Experimental Section Materials. Solvents used in this synthesis were reagent grade and, if required, dried over 4 Å molecular sieves. Reagents were purchased from Aldrich, Fluka, or Acros and used without additional purification. Methods. 1H and 13C NMR spectra were acquired on either a Varian INOVA 400 mHz (100 mHz for 13C) or a Mercury 300 mHz (75 mHz for 13C) instrument. Mass spectra experiments were completed by the Emory University Mass Spectrometry Center. Tensiometry measurements were conducted on a Fisher Surface Tensiomat following the Du Nouy ring procedure. Dynamic light scattering was measured in toluene on a Coulter N4 Plus machine. Three trials of each sample were run at a 90° angle for 180 s at room temperature. Elemental analyses were performed by Atlantic Microlabs in Norcross, GA. HPLC was conducted on a Shimadzu LC-10AT VP instrument.
Syntheses.10 General Procedure for Monoether Alcohols. NaH (0.15 mol), 60% in oil, was washed with dry hexanes (3 × 30 mL). Under N2, the appropriate diol (0.30 mol) was slowly added. (For 5-butoxypentan-1-ol, dry THF was added prior to diol addition; for 8-ethoxyoctan-1-ol, dry DMF was used to dissolve the diol and the solution was added to the NaH.) After H2 evolution ceased, the iodo-reagent (0.15 mol) was added and the reaction was stirred overnight at room temperature. H2O (150 mL) was added to the reaction flask and the resulting solution was extracted with CHCl3 (7 × 30 mL). The combined CHCl3 layers were washed with brine (2 × 30 mL). (8-Ethoxyoctan-1-ol was further purified by filtering the product through a silica plug with CHCl3.) The organic phase was dried (MgSO4), filtered, and rotary evaporated to a slightly yellow oil. 5-Ethoxypentan-1-ol (n ) 1, m ) 5). Yield 18.5 g (93%). 1H NMR (400 mHz, CDCl3) δ 3.65 (t, 2H), 3.40 (m, 4H), 2.20 (s, 1H), 1.60 (m, 4H), 1.40 (m, 2H), 1.2 (t, 3H). 13C (100 mHz, CDCl3) δ 70.7, 66.2, 62.7, 32.5, 29.5, 22.5, 15.3 ppm. 5-Butoxypentan-1-ol (n ) 3, m ) 5). Yield 5.8 g (76%). 1H NMR (400 mHz, CDCl3) δ 3.61 (t, 2H), 3.40 (m, 4H)1.90 (s, 1H), 1.301.65 (m, 10H), 0.90 (t, 3H). 13C NMR (100 mHz, CDCl3) δ 70.925, 70.895, 62.861, 32.642, 31.967, 29.585, 22.605, 19.510, 14.100 ppm. FAB/LSMS (M+Li)+: Calcd 167.2, found 167.4. Anal. calcd for C9H20O2 (160.1): C 67.45, H 12.58; found: C 67.25, H 12.63. 8-Ethoxyoctan-1-ol (n ) 1, m ) 8). Yield 3.0 g (51% yield). 1H NMR (400 mHz, CDCl3) δ 3.60 (t, 2H), 3.40 (m, 4H), 1.90 (bs, 1H), 1.55 (m, 4H), 1.30 (m, 8H), 1.18 (t, 3H). 13C NMR (100 mHz, CDCl3) δ 70.903, 66.206, 63.005, 32.885, 29.904, 29.593, 29.517, 26.270, 25.837, 15.360 ppm. FAB/HRMS (M+Li)+: Calcd 181.1780, found 181.1782. General Procedure for Tosylate Formation. The appropriate alcohol (22 mmol) was dissolved in 50 mL CH2Cl2. Pyridine (44 mmol) was added and the solution was cooled to 0 °C. pTsCl (33 mmol) was slowly added to the reaction. The solution was allowed to slowly warm to room temperature while stirring overnight. A solution of 5% aqueous pyridine (50 mL) was added to the reaction and stirred at room temperature for 3 h. The aqueous phase was removed and the organic layer was washed with H2O (15 mL), 0.1 M HCl (5 × 25 mL), and brine (3 × 15 mL). The organic phase was dried (MgSO4), filtered, and rotary evaporated to give the tosylate product. Tolune-4-sulfonic acid-5-ethoxy Pentyl Ester (n ) 1, m ) 5). Yield 10.0 g (78%). 1H NMR (400 mHz, CDCl3) δ 7.80 (d, 2H), 7.30 (d, 2H), 4.1 (q, 2H), 4.0 (t, 2H), 3.38 (t, 2H), 2.40 (s, 3H), 1.40-1.70 (m, 6H), 1.20 (t, 3H). 13C (100 mHz, CDCl3) δ 130.0, 128.1, 70.7, 70.3, 66.3, 60.6, 29.3, 28.9, 22.3, 21.8, 15.4, 14.4 ppm. FAB/LSMS (M+Li)+: Calcd 293.3, found 293.4. Toluene-4-sulfonic acid-5-butoxy Pentyl Ester (n ) 3, m ) 5). Yield 4.8 g (69%). 1H NMR (400 mHz, CDCl3) δ 7.8 (d, 2H), 7.35 (d, 2H), 4.05 (t, 2H), 3.4 (m, 4H), 2.5 (s, 3H), 1.3-1.7 (m, 10H), 0.9 (t, 3H). 13C NMR (100 mHz, CDCl3) δ 130.0, 128.1, 70.9, 70.7, 70.6, 32.0, 29.3, 28.9, 22.4, 21.8, 19.5, 14.1 ppm. FAB/HRMS (M+Li)+: Calcd 321.1712, found 321.1701. Toluene-4-sulfonic acid-8-ethoxy-octyl Ester (n ) 2, m ) 8). Yield 5.5 g (76%). 1H NMR (400 mHz, CDCl3) δ 7.8 (d, 2H), 7.35 (d, 2H), 4.0 (t, 2H), 3.45 (t, 2H), 3.4(t, 2H), 2.45 (s, 3H), 1.25-1.7 (m, 12H), 1.2 (t, 3H). 13C (75 mHz, CDCl3) δ 129.989, 128.039, 70.846, 66.230, 29.894, 29.376, 29.011, 28.935, 26.207, 25.415, 25.339, 21.804, 15.406 ppm. General Procedure for Diether Alcohols. NaH (23 mmol), 60% in oil, was washed with dry hexanes (3 × 20 mL). (For 8-(8ethoxy-octyloxy)-octan-1-ol, pure NaH was utilized.) Dry DMF (30 mL) and the appropriate diol (60 mmol) were added and allowed to stir for 1 h. The corresponding tosylate (15 mmol) was slowly added and the reaction was heated to 65 °C. After stirring for 3 days, the reaction was transferred to a separatory funnel with diethyl ether (90 mL) and H2O (50 mL). The organic layer was washed with fresh H2O (6 × 25 mL) and allowed to sit with 100 mL H2O overnight. The organic phase was separated, dried (10) The syntheses drew heavily from the following papers: (a) Katoh, A.; Lu, T.; Devadas, B.; Adams, S. P.; Gordon, J. I.; Gokel, G. W. J. Org. Chem. 1991, 56, 731. (b) Kabalka, G. W.; Varma, M.; Varma, R. S.; Srivastava, P. C.; Knapp, F. F. J. Org. Chem. 1986, 51, 2386. (c) Jaeger, D. A.; Sayed, Y. M. J. Org. Chem. 1993, 58, 2619.
Is the Ether Group Hydrophilic or Hydrophobic?
Langmuir, Vol. 21, No. 7, 2005 2691
Figure 2. Synthesis of ether surfactants. (MgSO4), filtered, and rotary evaporated to the crude product. Purification on silica column (EtOAc/hexane) gave the product as a yellow oil. 5-(5-Ethoxy-pentyloxy)-pentan-1-ol (n ) 1, m ) 5, p ) 5). Yield 2.70 g (83%). 1H NMR (400 mHz, CDCl3) δ 3.63 (t, 2H), 3.40 (m, 8H), 1.80 (s, 1H), 1.40-1.60 (m, 12H), 1.20 (t, 3H). 13C (100 mHz, CDCl3) δ 71.0, 70.9, 70.7, 66.2, 62.8, 32.6, 29.8, 29.7, 29.5, 23.0, 22.6, 15.3 ppm. FAB/LSMS (M+H)+: Calcd 219.3, found 219.5. Anal. calcd for C12H26O3 (218.3): C 65.0, H 12.01; found: C 64.88, H 11.77. 5-(5-Butoxy-pentyloxy)-pentan-1-ol (n ) 4, m ) 5, p ) 5). Yield 2.3 g (72%). 1H NMR (400 mHz, CDCl3) δ 3.6 (t, 2H), 3.4 (m, 8H), 2.2 (bs, 1H), 1.2-1.6 (m, 16H), 0.9 (t, 3H). 13C NMR (100 mHz, CDCl3) δ 70.978, 70.910, 70.812, 62.762, 32.605, 31.944, 29.684, 29.661, 29.547, 22.947, 22.582, 19.479, 14.070 ppm. FAB/HSMS (M+Li)+: Calcd 253.2355, found 253.2358. 5-(8-Ethoxy-octyloxy)-pentan-1-ol (n ) 1, m ) 8, p ) 5). Yield 2.2 g (55%). 1H NMR (300 mHz, CDCl3) δ 3.2-3.7 (m, 10H), 1.1-1.8 (m, 21H). 13C NMR (75 mHz, CDCl3) δ 71.182, 70.938, 66.245, 63.168, 62.970, 32.667, 29.955, 29.879, 29.605, 26.299, 22.642, 15.421 ppm. FAB/LSMS (M+Li)+: Calcd 267.2511, found 267.2511. 8-(8-Ethoxy-octyloxy)-octan-1-ol (n ) 2, m ) 8, p ) 8). Yield 1.65 g (36%). 1H NMR (400 mHz, CDCl3) δ 3.65 (t, 2H), 3.4 (m, 8H), 1.55 (bs, 6H), 1.25 (bs, 18H), 1.2 (t, 3H). 13C NMR (100 mHz, CDCl3) δ 71.123, 70.994, 66.267, 63.240, 32.984, 30.002, 29.949, 29.638, 29.570, 26.338, 25.883, 15.451 ppm. FAB/HSMS (M+Li)+: Calcd 309.2981, found 309.2997. General Procedure for Bromides. The corresponding alcohol (14 mmol) was dissolved in CH3CN (15 mL) and pyridine (22 mmol). The reaction was cooled to 0 °C and dibromotriphenyl phosphorane (18 mmol) was added. The solution was allowed to warm to room temperature slowly and was stirred for 4 days (1-(5-bromo-pentyloxy)-5-ethyoxy-pentane required only 48 h). Reaction was monitored by TLC and the resulting mixture was purified on a silica column (EtOAc/hexane). (1-(5-Bromo-pentyloxy)-5-ethyoxy-pentane could be purified on a simple silica plug with an ether/pentane (1:10) wash.) The solvent was removed under vacuum to give the final product. 1-(5-Bromo-pentyloxy)-5-ethyoxy-pentane (n ) 2, m ) 5, p ) 5). Yield 3.2 g (81%). 1H NMR (300 mHz, CDCl3) δ 3.40 (m, 10H), 1.90 (m, 2H), 1.40-1.70 (m, 10H), 1.20 (t, 3H). 13C (75 mHz, CDCl3) δ 71.0, 70.7, 70.6, 66.2, 33.9, 32.8, 29.8, 29.7, 29.0, 25.1, 23.0, 15.4 ppm. FAB/LSMS (M+H)+: Calcd 281.2., found 281.4. 1-(5-Bromo-pentyloxy)-5-butoxy-pentane(n ) 4, m ) 5, p ) 5). Yield 1.97 g (82%). 1H NMR (300 mHz, CDCl3): δ 3.4 (m, 10H), 1.9 (m, 2H), 1.3-1.6 (m, 14H), 0.9 (t, 3H). 13C (75 mHz, CDCl3) δ 70.999, 70.907, 70.801, 70.633, 33.871, 32.774, 31.997, 29.727, 29.041, 25.095, 22.978, 19.504, 14.095 ppm.
1-(5-Bromo-pentyloxy)-8-ethyoxy-octane (n ) 2, m ) 8, p ) 5). Yield 1.9 g (76%). 1H NMR (300 mHz, CDCl3) δ 3.4 (m, 10H), 1.9 (m, 2H), 1.2-1.6 (m, 19H). 13C (75 mHz, CDCl3) δ 71.151, 70.892, 70.603, 66.185, 33.886, 32.774, 29.940, 29.864, 29.574, 29.422, 29.054, 26.284, 25.095, 15.390 ppm. FAB/HSMS (M+H)+: Calcd 323.1586, found 323.1577. 1-(8-Bromo-octyloxy)-8-ethoxy-octane (n ) 2, m ) 8, p ) 8). Yield 0.15 g (34%). 1H NMR (300 mHz, CDCl3) δ 1.2 (t, 3H), 1.4-1.6 (bm, 22H), 1.9 (q, 2H), 3.4 (m, 10H). 13C (75 mHz, CDCl3) δ 71.163, 71.080, 70.970, 66.251, 34.194, 32.997, 29.998, 29.915, 29.640, 29.475, 28.911, 28.306, 26.338, 26.297, 15.442 ppm. FAB/ HSMS (M+H)+: Calcd 365.2055, found 365.2065. General Procedure for Ammonium Bromides. The appropriate bromide (3.0 mmol) was dissolved in ethyl alcohol (25 mL). Trimethylamine, 30 wt % solution in ethanol (4.5 mmol), was added. The reaction was heated to 45 °C and stirred for 4 days. The ethanol was removed under vacuum and diethyl ether (50 mL) was added to resultant oil. The solution was washed with water (2 × 50 mL) and the aqueous phase was lyophilized to yield the ammonium bromide salt. The organic phase was dried and rotary evaporated to recover any unreacted bromide starting material. ([8-(8-Ethoxy-octyloxy)-octyl]-trimethylammonium bromide was further purified by two recrystallizations in EtOAc.) The lyophilized powder was dried using a vacuum oven. [5-(5-Ethoxy-pentyloxy)-pentyl]-trimethylammonium Bromide A (n ) 2, m ) 5, p ) 5).: Yield 0.89 g (87%). 1H NMR (300 mHz, D2O) δ 3.50 (m, 8H), 3.30 (t, 2H), 3.10 (s, 9H), 1.80 (m, 2H), 1.60 (m, 6H), 1.40 (m, 4H), 1.20 (t, 3H). 13C (75 mHz, D2O) δ 106.7, 70.6, 70.4, 70.1, 66.6, 66.3, 52.9, 28.4, 28.1, 22.3, 22.2, 22.0, 14.2. FAB/LSMS (M-Br)+: Calcd 260.4, found 260.5. Anal. calcd for C15H34NO2Br (339.1): C 52.9, H 10.1, O 9.4, N 4.1; found: C 51.7, H 9.97, O 11.66, N 4.3. (Anal. calcd for 2 C15H34O2NBr:1 H2O (696.3): C 51.7, H 10.13, O 11.48, N 4.01.) [5-(5-Butoxy-pentyloxy)-pentyl]-trimethylammonium Bromide B (n ) 4, m ) 5, p ) 5). Yield 0.4 g (65%). 1H NMR (400 mHz, D2O) δ 3.5 (m, 8H), 3.3 (t, 2H), 3.1 (s, 9H), 1.8 (m, 2H), 1.5-1.7 (m, 8H), 1.3-1.5 (m, 6H), 0.9 (t, 3H). 13C NMR (100 mHz, D2O) δ 70.619, 70.543, 70.141, 66.651, 52.934, 30.932, 28.459, 28.201, 22.390, 22.246, 22.101, 18.847, 13.293 ppm. FAB/HSMS (MBr)+: Calcd 288.2903, found 288.2890. Anal. calcd for C17H38NO2Br (368.3): C 55.55, H 10.43, N 3.81; found C 52.80, H 10.39, N 3.95. (Anal. calcd for 1 C17H38NO2Br:1 H2O (386.4): C 52.96, H 10.46, N 3.64.) [5-(8-Ethoxy-octyloxy)-pentyl]-trimethylammonium Bromide C (n ) 2, m ) 8, p ) 5). Yield 2.2 g (99%). 1H NMR (400 mHz, D2O) δ 3.5 (m, 8H) 3.3 (t, 2H), 3.1 (s, 9H), 1.8 (m, 2H), 1.6 (m, 6H), 1.4 (m, 10H), 1.2 (t, 3H). 13C NMR (100 mHz, D2O) δ 70.899, 70.725, 70.300, 66.643, 66.287, 52.995, 28.983, 28.892, 28.808, 28.338, 25.561, 22.488, 22.344, 14.439. FAB/LSMS (M-Br)+: Calcd
2692
Langmuir, Vol. 21, No. 7, 2005
Menger and Chlebowski Table 2. Data on Six Surfactants
1. # of C (chain) 2. cac (mM) 3. γ at cac (dynes/cm) 4. area/mol, Å2 5. foam height (3xcac) 6. HPLC (retention time, min) 7. TMS solubility (at 40 mM) 8. mesitylene solubility (at 40 mM)
A
B
C
D
DTAB
TTAB
12 9 51.7 74.99 0.34 2.5 0.0 mM 6.4 mM
14 8 59.3 99.9 0.14 3.6 0.0 mM 0.0 mM
15 6 40.7 39.65 0.62 4.0 0.0 mM 0.0 mM
18 5 44.7 46.12 1.9 6.7 0.2 mM 2.05 mM
12 13 41.2 32.01 1.9 6.8 0.51 mM 13.0 mM
14 3 37.0 41.53 3.34 9.5 7.9 mM 35.7 mM
302.3059, found 302.3053. Anal. calcd for C18H40NO2Br (328.4): C 56.66, H 10.57, N 3.67; found: C 55.14, H 10.62, N 3.61. (Anal. calcd for 2 C18H40NO2Br:1 H2O (782.9): C 55.35, H 10.59, N 3.59.) [8-(8-Ethoxy-octyloxy)-octyl]-trimethylammonium Bromide D (n ) 2, m ) 8, p ) 8). Yield 0.57 g (64%). 1H NMR (400 mHz, D2O) δ 3.45 (m, 8H), 3.30 (t, 2H), 3.10 (s, 9H), 1.88 (bm, 2H), 1.55 (bm, 6H), 1.36 (bm, 16H), 1.19 (t, 3H). 13C NMR (100 mHz, D2O) δ 64.440, 64.234, 64.097, 60.231, 59.654, 46.462, 22.790, 22.693, 22.652, 22.597, 22.336, 22.102, 19.337, 19.268, 19.213, 16.049, 8.168 ppm. FAB/ HSMS (M-Br)+: Calcd 344.3529, found 344.3519. Anal. calcd for C21H46NO2Br (424.5): C 59.54, H 10.95, N 3.30; found C 59.12, H 10.78, N 3.30. General Procedure for Sodium Sulfates. The appropriate alcohol (1.77 mmol) and the sulfur trioxide pyridine complex (1.77 mmol) were place in a round-bottom flask and flushed with N2. Dry pyridine (10 mL) was added and the solution was allowed to stir for 48 h. The solution was evaporated and dissolved in MeOH (25 mL). To the solution was added 15 g Biorad AG 50W-X8 resin (Na+ form, 200-400 mesh). This was triturated at room temperature for 15 min and filtered. The solution was concentrated and purified on a silica column (5 CHCl3/1 MeOH). (Sodium [5-(5-butoxy-pentyloxy)-pentyl]-sulfate was purified using a 3 Et2O/1 MeOH solvent.) Sodium [5-(5-Butoxy-pentyloxy)-pentyl]-sulfate E (n ) 4, m ) 5, p ) 5). Yield 0.1 g (7.1%). 1H NMR (400 MHz, D2O) δ 0.90 (t, 3H), 1.30-1.70 (m, 16H), 3.50 (bs, 8H), 4.09 (t, 2H). 13C NMR (150 MHz, D2O) δ 13.295, 18.866, 21.755, 22.099, 28.261, 28.316, 28.468, 30.957, 69.473, 70.463, 70.546, 95.636 ppm. FAB/HSMS (M-Na)-: Calcd 325.1685, found 325.1689. Anal. calcd for C14H29SO6Na (348.5): C 48.3, H 8.30, S 9.20; found C 47.72, H 8.19, S 8.71. (Anal. calcd for 3 C14H29SO6Na:H2O (1062): C 47.5, H 8.40, S 9.00.) Sodium [8-(8-Ethoxy-octyloxy)-octyl]-sulfate F (n ) 2, m ) 8, p ) 8). Yield 0.37 g (51.4%). 1H NMR (400 MHz, D2O) δ 1.19 (t, 3H), 1.23-1.42 (bs, 16H), 1.50-1.75 (bs, 8H), 3.38-3.55 (m, 8H), 4.02 (t, 2H). 13C NMR (100 MHz, D2O) δ 14.773, 25.493, 26.054, 28.983, 29.180, 29.286, 29.362, 29.483, 66.127, 69.200, 70.566, 70.740, 70.922 ppm. FAB/HRMS (M-Na)-: Calcd 381.2311, found 381.2308.
Results and Discussion Let us focus initially upon cationic surfactants A-D (Figure 1). A and B differ from C, D, DTAB, and TTAB in that only A and B are hygroscopic. In fact, A (a waxy solid) will become fluid within minutes when exposed to the open air (a surprising effect since ethers per se are not hygroscopic). Surfactant C is soluble in ether and ethyl acetate, whereas DTAB and TTAB are not. C also dissolves in toluene more readily than do DTAB and TTAB, thereby forming large 780-nm assemblies (presumably reverse micelles) that were not further investigated. The solubility of C in relatively nonpolar solvents may reflect weak packing forces in its solid state more than any specific solute-solvent interaction. Table 2 summarizes much of the physical-chemical data collected on A-D plus the two conventional cationic surfactants. Row 1 gives the total carbon count for the various chain values that represent the “hydrophobic potential” of the surfactants. As a rule of thumb, a twocarbon increase in chain length diminishes the cmc by a factor of 4. If the ether oxygen were innocuous, then A
and DTAB, both with 12 chain carbons, should behave similarly. If, on the other hand, the ether oxygens of A require a measure of hydration deep within the micelles, or must desolvate to reside in this region, then the two surfactants might manifest quite different properties. Ether perturbations of micellization need not be confined to the oxygen sites per se. Structured water surrounding hydrocarbon chains, thought to be the source of hydrophobic association,11 might be disrupted at methylenes directly attached to the ether oxygens. If this is true, then the effect of an ether group is longer-range than implied by the hydration requirements of a single oxygen atom. Intramolecular disruption of hydrophobicity has been reported by the Engberts group.12,13 They studied the effect of short-chain sulfates and ammonium salts on the kinetics of the neutral hydrolysis of 1-benzoyl-1,2,4-triazole. The cosolutes bind to the triazole and inhibit its hydrolysis rate. The key point is that the first two or three methylenes near the ionic groups of the cosolutes do not seem to contribute substantially to the cosolute/triazole binding. It is as if the sulfate and ammonium groups shield the proximal methylenes and impair their availability for hydrophobic association. Of course, because our ether groups are far less polar than ionic groups, ether-shielding should be less extensive. Critical micelle concentrations for the surfactants, listed in row 2 of Table 2, were determined from the point of slope change in plots of surface tension versus concentration. Figure 3 shows such plots for A and D which are seen not to level off at higher surfactant concentrations. This is typical for formation of small micelles of perhaps only 5-10 molecules instead of the more usual 50-100 aggregation number. As micelles become smaller, lack of cooperativity gradually converts self-assembly from a precipitous event to a more stepwise process. Whether or not one calls small aggregates “micelles” is a matter of taste, but we will, to be as noncommittal as possible, refer in row 2 of Table 2 to “critical aggregation concentration” or “cac” instead of “cmc”. Although the change of slope in the surface tension plots reveals the presence of aggregation, we were not able to fix exact values to the aggregation numbers in water. Our 10 mW light-scattering apparatus has a resolution limit of 30 Å, and the ether-surfactant aggregates certainly have diameters less than this. Unfortunately, classical fluorescent methods for measuring aggregation numbers, on the basis of Poisson distributions, are notoriously unreliable for small aggregates. Thus, we must confine our description to a rather vague “small aggregate” terminology with the understanding that this usually signifies aggregation numbers in the 5-10 molecule range. (11) Mailbaum, L.: Dinner, A. R.; Chandler, D. J. Phys. Chem. B 2004, 108, 6778. (12) Noordman, W. H.; Blokzyl, W.; Engberts, J. B. F. N.; Blandamer, M. J. J. Org. Chem. 1993, 58, 7111. (13) Hol, P.; Streefland, L.; Blandamer, M. J.; Engberts, J. B. F. N. J. Chem. Soc., Perkin Trans. 2 1997, 485.
Is the Ether Group Hydrophilic or Hydrophobic?
Figure 3. Surface tension versus concentration for surfactants A and D.
The most striking feature of the cac data for A-D is their constancy with chain length. Now DTAB and TTAB (with 12 and 14 chain carbons, respectively) have cmc values differing by the expected factor of 4. However, A is six carbons shorter than D, yet their cac values lie within a factor of 2. If the rule of thumb mentioned above were applicable, D would have a 64-fold lower cac than A. Thus, an outstanding attribute of the ether group, besides diminishing the size of the aggregates, is that it provides a “leveling effect” on the concentrations at which selfassembly occurs. So do the cac data indicate whether the ether group is hydrophobic or hydrophilic? Comparing A with DTAB (both with 12-carbon chains) shows that A actually has a somewhat lower cac as if the two ether groups in A do not interfere with its aggregation. In contrast, ethersurfactant D, with an 18-carbon chain, has a cac of 5 mM whereas hexadecyltrimethylammonium bromide, with a 16-carbon chain, has a cmc of about 0.8 mM. According to this comparison, therefore, the ether group clearly diminishes the propensity to self-assemble. Thus, an unambiguous assessment of an ether effect is not straightforward, a fact that we attribute to morphology differences. If an aggregate is small, and presumably “loose” and “wet”, as is the case with shorter surfactants such as A, then the presence of ether groups has a minor effect on the cac. If, on the other hand, a somewhat larger aggregate is likely, as with the 18-carbon D, then the ether groups impede the formation of the hydrocarbon-like interior typical of most micelles. This rationale explains the above-mentioned leveling effect for the ether-containing surfactants: Longer carbon segments in C and D promote hydrophobically induced assembly (thus lowering the cac) while, even more importantly, favoring a drier, more compact hydrocarbon environment in which ether disrup-
Langmuir, Vol. 21, No. 7, 2005 2693
tion is accentuated (thus raising the cac). The opposing effects result in a rather constant cac among surfactants A-D. Surface tension provides two other parameters useful for comparing surfactants: γcac (the surface tension at the cac) and Amol (the area per molecule occupied at the air/ water interface). Values of these parameters, given in rows 3 and 4 of Table 2, respectively, reflect the same packing difficulties within the interfacial monolayers that were encountered with the aggregates. Thus, the lowering of the surface tension at the cac for A-D ranges from 41 to 59 dynes/cm as compared to 37 and 41 for TTAB and DTAB, respectively. Lower surface activity for A-D is consistent with reduced interfacial density of the surfactants. Amol (derived in the standard way from pre-cac tensiometric data and the Gibbs adsorption isotherm)14 varies by almost a factor of 2 between pairs A/B and pairs C/D (i.e., 75, 100, 40, and 46 A2/molecule for A, B, C, and D, respectively). A and B appear to lie flat at the air/ water surface where the ethers can contact the water. On the other hand, C and D, having eight-carbon segments, are more prone to stand more or less vertically where the segments can be adjacent to each other and, as a consequence, occupy less space. Foamability experiments were carried out by inverting and uprighting 10 times a 50-mL buret containing 5 mL of a surfactant solution (at concentrations 3 times greater than its cac) and then measuring the volume of the resulting foam.15 Among the four cationic ether surfactants, only D displays an appreciable foamability (1.9 cm as compared to 1.9 and 3.3 cm for DTAB and TTAB, respectively, as listed in row 5 of Table 2). Surfactants A and B in particular are weak stabilizers of soap films, showing once again the deleterious effect of the ether groups. B has 14 chain carbons, the same as TTAB, but B’s two interspersed ether groups reduce its foam height to only 0.14 cm (compared to 3.3 cm for TTAB). High foam production is not always desirable (one does not want foam overflow from a washing machine, for example), and ether insertion is clearly one way of reducing it. HPLC experiments were carried out to assess the binding of the surfactants to an apolar surface in the form of an Alltech Surfactant/R column containing a 7-µm polydivinylbenzene-based column. Samples (1.0 mg/mL CH3CN) were filtered, injected into the chromatograph, and eluted with 60% 10 mM HCl/40% CH3CN for the first 5 min followed by 30% 10 mM HCl/70% CH3CN for the remainder of the run. A nitrogen flow at ambient temperature (1.0 mL/min) was used throughout. Peaks were detected by a Sedex electron spray detector at 40 °C. Table 2, column 6 records the retention times in minutes. Retention times progress smoothly from A to D as the hydrocarbon content of surfactant increases: A: 12 carbons, 2.5 min; B: 14 carbons, 3.6 min; C: 15 carbons, 4 min; and D: 18 carbons, 6.7 min. Even ether-surfactant D, with 18 carbons, has a retention time smaller than that of DTAB with only 12 carbons. The inescapable conclusion is that, relative to the all-hydrocarbon analogues, the ether groups impair adsorption onto the hydrophobic surface of the column and favor solubilization into the aqueous eluent. Solubilization power is one of the most important properties of surfactants, being the basis of a large number of industrial processes. Thus, we examined the new (14) Seredyuk, V.; Alami, E.; Nyden, M.; Holmberg, K.; Peresyphin, A. V.; Menger, F. M. Colloids Surf. 2002, 203, 245. (15) Patist, A.; Axelberd, T.; Shah, D. O. J. Colloid Interface Sci. 1998, 208, 259.
2694
Langmuir, Vol. 21, No. 7, 2005
Figure 4.
Menger and Chlebowski
1
H NMR (400 mHz) of A, C, D, and DTAB in D2O above critical concentrations.
cationic surfactants for their ability to solubilize organics in water. Experiments were carried out by vortexing for 30 min excess amounts (2 µL) of tetramethylsilane (TMS) or 1,3,5-trimethylbenzene (mesitylene) with 40 mM solutions of the various surfactants in D2O. Since 40 mM exceeds the highest cac in Table 2 by severalfold, we are dealing here primarily with micellar systems. 1H NMR analysis, after a suitable period to allow the samples to clarify, provided the concentrations of solubilized material. These are recorded for TMS and mesitylene in rows 7 and 8 of Table 2, respectively. None of the ether surfactants can be categorized as an efficient solubilizer of the nonpolar test compounds, TMS and mesitylene. These results comport with the other data, all of them showing that the ether group, while not directly preventing aggregation, disrupts the formation of classical micelles. Even in D, with hydrocarbon segments that are 2, 8, and 8 carbons long, typical micelle behavior is absent. Stated in another way, a surfactant with 18 chain carbons, but segmented into three units by ether oxygens, cannot match the solubilizing capacity of a surfactant with a mere 12 chain carbons but whose carbons are contiguous. One possible explanation is that the ether group is weakly hydrated and that this alone accounts for the packing difficulties within a micelle core. Another possibility is that the whole is more than the sum of the parts, that is to say, hydrophobic association of chains may not be additive. Thus, a long chain may lead to a far more effective assembly than the combination of two shorter chains whose total number of carbons is identical to that of the long chain. The validity of this conjecture, which undoubtedly depends on the nature of the functionality separating the segments, merits further investigation. It would be interesting in this regard to examine thioether spacers that are decidedly hydrophobic but not known promoters of hydrophobic association. Surfactant D may be our most interesting owing to its total of 18 chain carbons. If one assumes that the two
ether oxygens in D each shield the carbons on either side from participation in hydrophobic association, then the number of carbons engaged in such association is reduced to 14. In actual fact, D behaves like DTAB in certain ways (foamability and HPLC). A more descriptive statement would be that D has its own particular set of properties that is not accurately modeled by any conventional surfactant. NMR line-broadening data above the cac substantiate the notion that the aggregates of the ether surfactants are small but that they increase in size and normality as the carbon content increases. Cursory examination of the NMR spectra in Figure 4 shows that line widths increase in the sequence A ≈ C < D < DTAB. Restricted tumbling within the D micelles does not quite match that of DTAB micelles despite D having six more chain carbons. Finally, two anionic ether surfactants were also synthesized and are listed in Figure 1. Sulfate E, with a total of 14 chain carbons, is the chain-equivalent of B, whereas sulfate F, with a total of 18 chain carbons, is the chainequivalent of D. Owing to limited amounts of purified compound, we restricted ourselves to tensiometric determination of the two anionics’ cac values (Figure 5). As before, the leveling effect creates cac values for E and F values that are far more similar than would be normally expected from the chain-length differences: 8 mM and 5 mM, respectively. Surprisingly and uniquely, however, the surface tension plot for F levels off as is typical for large conventional micelles. Yet, its cac of 5 mM is abnormally high for a surfactant with 18 chain carbons (i.e., sodium dodecyl sulfate has a cmc of 8 mM). It appears as if the ether groups in F diminish the tendency to aggregate, but once a concentration is reached where micellization does occur, the resulting micelles form more precipitously and cooperatively than with A-E. Since F and D differ only in their headgroups, packing at the Stern layer must be critical. Thus, steric and electrostatic factors among the bulky trimethylammonium headgroups, coupled
Is the Ether Group Hydrophilic or Hydrophobic?
Figure 5. Surface tension versus concentration for surfactants E and F.
to ether perturbations within the core, combine to give small, loose cationic aggregates. With a sulfate headgroup, however, Stern layer repulsions are less severe because the anionic charge is distributed among three oxygens of the headgroup. Despite the ether groups, micelles of F form more or less normally once the concentration exceeds an elevated critical value.
Langmuir, Vol. 21, No. 7, 2005 2695
In summary, a series of six surfactants, each with two ether oxygens within otherwise all-hydrocarbon chains, were synthesized and examined for their colloidal properties. Since an ether oxygen is sterically and conformationally similar to the methylene group it has replaced, the ether effect on micellization should stem mainly from solvation of the oxygen and, possibly, disrupted hydrophobicity of its adjacent carbons. It was found that critical aggregation values among the surfactants differ only modestly despite the total length of the ether-separated carbon segments ranging from 12 to 18. Shorter ether surfactants with only 12 or 14 total carbons appear to form small, loose aggregates owing, presumably, to a mild hydrophilicity of the ether groups. A surfactant with 18 chain carbons has a greater tendency to associate hydrophobically, but this is counterbalanced by a relatively water-free environment encountered by the ether groups within a more conventional micelle interior. The result is a leveling effect in which the critical aggregation concentration (cac) loses it sensitivity to chain length. Above their cac’s, none of the ether surfactants is a good solubilizer of tetramethysilane or mesitylene. This is not necessarily a predictable finding since it was conceivable that the presence of interior ether groups might actually enhance solubilization (much as ether is a better solvent than hexane). Foamability and solid adsorption studies also indicate that the ethers impair surface activity. In response to the question posed in the paper’s title, two ether groups are not sufficiently hydrophilic to prevent aggregation, but they do manage to alter the micelles’ morphology and properties considerably. Given the profound effects of ether groups on micellar properties, it is natural to wonder how the presence of phospholipids with etherated chains would affect bilayer properties. Studies of this subject are underway. Acknowledgment. This work was supported by the Petroleum Research Foundation. LA040113M
