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Articles Solubilization of Isomeric Alkanols in Ionic Micelles Yoshiaki Eda,*,† Noboru Takisawa, and Keishiro Shirahama Department of Chemistry, Faculty of Science and Engineering, Saga University, Saga 840, Japan Received September 3, 1996. In Final Form: December 18, 1996X The solubilizations of isomers of alkanols (butanol to octanol) in ionic micelles (sodium dodecyl sulfate and dodecyltrimethylammonium bromide) were measured by using polymer-coated piezoelectric gas sensors to discuss the effect of the molecular shape of alkanols on the solubilization in micelles. Good correlations were obtained both between the micelle/water partition coefficient (K) and the octanol/water partition coefficient of alkanols and between K and the molecular surface area of alkanols. This indicates that the solubilization in micelles depends only on the hydrophobicity of alkanols, because the micelles are too soft to recognize the molecular shape of alkanols.
Introduction When molecular assemblies such as micelles and bilayer membranes incorporate organic compounds, do they recognize the molecular shapes of solubilizates? This question is important in considering the mechanism of chemical reception in living organisms. Biological receptors may be classified into “proteins” and “lipid bilayers”. A receptor protein binds only a specific substrate. In contrast, a lipid bilayer which forms a cell membrane incorporates diverse compounds nonspecifically in its matrix. Most drugs, hormones, pheromones, sweet tastes, and umami tastes are sensed by their specific receptor proteins. On the other hand, inhalation anesthetics,1 odorants,2 and bitter tastes3 must be received by lipid bilayers, judging from a good positive correlation between the bioactivity of these chemicals and the octanol/water partition coefficient (Kow). In other words, a more hydrophobic compound has a greater affinity for apolar lipid bilayers and thus it shows a higher potency. The above hypothesis regarding the lipid bilayers as chemical receptors seems simple and reasonable, but many results that contradict it have been reported.4 For example, Sato et al. discovered the tuning specificity to aliphatic odorants (n-alkanoic acids and 1-alkanols with three to nine carbons) in mouse olfactory receptor neurons (ORNs);5 i.e., the sensitivities of the ORNs either to n-alkanoic acids or to 1-alkanols are the highest for one or two odorants and decreased with increasing difference in the carbon chain length from the “tuned” odorants. In addition, it is known that some chiral odorants show different odors between D- and L-isomers. If the olfactory receptor is really lipid bilayers, these phenomena can be explained only by a new hypothesis that lipid bilayers could discriminate molecular shapes of odorants. It is an essential problem in the theory of the chemical reception whether molecular recognition can be carried † Present address: Department of Chemistry, Oita Industrial Research Institute, 4361-10, Takae-nishi 1, Oita 870-11, Japan. X Abstract published in Advance ACS Abstracts, March 15, 1997.
(1) Butler, T. Pharmacol. Rev. 1950, 2, 121. (2) Nomura, T.; Kurihara, K. Biochemistry 1987, 26, 6135. (3) Kumazawa, T.; Kashiwayanagi, M.; Kurihara, K. Biochim. Biophys. Acta 1986, 888, 62. (4) Franks, N. P.; Lieb, W. R. Nature 1985, 316, 349. (5) Sato, T.; Hirono, J.; Tonoike, M.; Takebayashi, M. J. Neurophysiol. 1994, 72, 2980.
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out on simple solubilization or not. In spite of its importance, little has been reported about it. Okahata prepared a multilamellar bilayer film of a synthetic lipid (dioctadecyldimethylammonium poly(styrenesulfonate)) on a piezoelectric crystal and measured bilayer/water partition coefficients (K) of organic compounds with nine carbons, such as isomers of nonanols, nonyl bromides, and nonyl sulfates.6 As a result, K shows a good correlation with a linear combination (0.623 log Kow + 0.352Sl + 0.802) in terms of log Kow and the molecular slenderness (Sl) of these compounds. A slender molecule shows higher K than a bulky molecule, because the slender one passes between adjacent lipid molecules and penetrates easily into the lipid bilayer. It can be said that this lipid film recognizes the molecular shape. As an opposite example, Walter and Gutknecht7 determined the permeability (P) of organic and inorganic compounds through a plane bilayer membrane of egg phosphatidylcholine and obtained a good correlation between log P and log(Khw, hexadecane/water partition coefficient), which indicates that the lipid bilayer works simply as a thin oil film and does not recognize the molecular shape of the substrates. So it is controversial if there is a tendency for molecular recognition by lipid bilayers or not. The true nature is still unclear. Although micelles are simpler systems than bilayers, no work about the molecular recognition by micelles has been reported. Chart 1 illustrates two types of the transfers of organic compounds from water to apolar fields: the partition type and the inclusion type. The partition type includes the transfers from water to organic solvents. In this type, the equilibrium constant (partition coefficient) is a measure of the hydrophobicity. Alternatively, the inclusion type is seen in the complex formation with cyclodextrins and enzymes. The host molecules can recognize the shape of guest molecules, so the binding constant depends on both molecular shapes and hydrophobicity. The authors have reported the solubilization of 1-alkanols in micelles.8,9 The solubilization in micelles has been treated as a partition between micelles and water, (6) Okahata, Y. Membrane 1991, 16, 26. (7) Walter, A.; Gutnecht, J. Membr. Biol. 1986, 90, 207. (8) Eda, Y.; Takisawa, N.; Shirahama, K. Langmuir 1996, 12, 325. (9) Eda, Y.; Takisawa, N.; Shirahama, K. Prog. Anesth. Mech. 1993, 1, 27.
© 1997 American Chemical Society
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Chart 1. Schematic Representation of Two Types of Transfers of Alkanols from Water to Apolar Fields and Solubilization of Alkanols in Micelles
Figure 1. Experimental setup for the piezoelectric sensor system. Instrumentation. Figure 1 shows the experimental setup for the piezoelectric sensor system. A piezoelectric crystal (6 MHz, AT cut, 8 mm diameter) was obtained from Kinseki and used after removal of its metal casing. The coated piezoelectric crystal was connected to an oscillator circuit fabricated in our laboratory and powered by a 5 V dc power supply. The frequency of the vibrating crystal was measured by a frequency counter (Hioki 3601) connected to a microcomputer (NEC, PC9801). All the measurements were carried out at 25 °C. Amounts of vapors sorbed in the sensor coating could be calculated with the Sauerbrey equation,10 which describes the mass-frequency relationship at an AT cut quartz surface as follows:
Chart 2. Chemical Structures of Isomeric Alkanols
∆F )
since the micelles have no specific binding sites. However, micelles have the following characteristics different from those of ordinary organic solvents: (1) a micelle has a tiny volume; (2) surfactant molecules are highly oriented in micelles; (3) there are water-penetrating parts between adjacent surfactant molecules near micelle/water interfaces. Thus it seems possible that micelles might have weak molecular recognition. In order to clarify this problem, the solubilizations of isomers of alkanols with different molecular shapes in micelles were measured in this work. Experimental Section Materials. The alkanols measured in this work were 2-alkanols (2-CnOH, the number of carbons n ) 4-8), 3-alkanols (3-CnOH, n ) 5-7), 4-heptanol (4-C7OH), 3,3-dimethyl-2-butanol (PinaOH), cyclohexanol (cC6OH), 2-methylcyclohexanol (2MecC6OH), and 4-methylcyclohexanol (4-MecC6OH). Their chemical structures are shown in Chart 2. These alkanols were used as received from Tokyo Kasei. Water was purified by deionization and double distillation, once from alkaline KMnO4 solution. Dodecyltrimethylammonium bromide (DTAB) was obtained from Tokyo Kasei and recrystallized from acetone which contained a slight amount of water. Sodium dodecyl sulfate (SDS) was obtained from Pierce and used as received. Elvaloy HP441 was obtained from Du Pont and used as the sensor coating.
2F02
xAFqµq
∆m ) Cf ∆m
(1)
where ∆F is a measured frequency decrease, ∆m a mass increase on the adsorption of vapor, F0 an intrinsic crystal frequency (6 × 106 Hz), A electrode area (0.20 cm2), Fq the density of quartz (2.65 g cm-3), µq the shear modulus of quartz (2.95 × 1011 dyn cm-2), and Cf the integrated sensitivity (0.42 Hz ng-1). Coating Procedure. As described elsewhere,8,9,11,12 piezoelectric crystals were coated with the polymer by the dip-coating method. A bare crystal of a quartz oscillator was wetted well and cleaned by immersion into tetrahydrofuran (THF). The clean crystal was then dipped into a solution of Elvaloy HP441 in THF and dried in air. The resulting amount of coating could be roughly controlled by changing concentration of the polymer solution and was determined from the frequency decrease (∆FM) of the crystal in reference to eq 1. Calculation of the Molecular Surface Area. The molecular surface areas accessible to water molecules (SA) of alkanols were calculated by means of the molecular modeling software HyperChem Release 4 (Hypercube, Inc., Canada). The calculation was performed on the basis of the method by Bodor et al.13 and the atomic radii of Gavezzoti.14 The radius of the water molecule used is 0.14 nm, which is added to each radius of the constituent atoms of the alkanols to obtain the values of SA.
Results and Discussion Free Energy Change of Transfer of Alkanols from Water to Micelles. As reported,8 the micelle/water partition coefficient (K) of alkanols was determined by the vapor pressure method by using the piezoelectric gas sensor. The free energy change of transfer (∆Gt°) of alkanols from water to micelles was obtained from the (10) Sauerbrey, G. A. Z. Phys. 1959, 155, 206. (11) Eda, Y.; Takisawa, N.; Shirahama, K. Sens. Mater. 1995, 7, 405. (12) Eda, Y.; Takisawa, N.; Shirahama, K. In The Polymeric Materials Encyclopedia: Synthesis, Properties and Application; Salamone, J. C., Ed.; CRC Press: Boca Raton, FL, 1996; Vol. 1, p 223. (13) Bodor, N.; Gabanyi, Z.; Wong, C. J. Am. Chem. Soc. 1989, 105, 3783. (14) Gavezotti, A. J. Am. Chem. Soc. 1989, 105, 5220.
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Figure 2. Free energy change of transfer (∆Gt°) of alkanols from water to SDS micelle as a function of the number of carbons of alkanols.
Figure 3. Correlation between ∆Gt° to micelles and ∆Gow° of alkanols. Table 1. Transfer Free Energies per Methylene Group of Alkanols (∆Gt°(CH2)/kJ mol-1) 1-alkanols 2-alkanols 3-alkanols
SDS
DTAB
octanol15
-2.56 -2.50 -2.45
-2.62 -2.52 -2.40
-3.35 -3.17 -2.94
following equation
∆Gt° ) -RT ln K
(2)
where R and T represent the gas constant (8.3144 J mol-1 K-1) and absolute temperature (298.15 K), respectively. Figure 2 shows the relation between ∆Gt° for SDS micelle and the number of total carbons of alkanols. For each series of alkanols (1-, 2-, and 3-alkanols), ∆Gt°decreased linearly with increasing the number of carbons. These slopes correspond to the transfer free energy per methylene group (∆Gt°(CH2)), which are presented in Table 1. The absolute values of ∆Gt°(CH2) were in the order of 1- > 2- > 3-alkanols. This order is the same as that of the transfer free energies per methylene group of alkanols from water to octanol (∆Gow°(CH2)) which were obtained in the same manner as ∆Gt°(CH2) except
Figure 4. Molecular surface area (SA) of alkanols as a function of the number of carbons of alkanols.
Figure 5. Correlation between ∆Gt° to SDS micelle and the molecular surface area (SA) of alkanols.
for using Kow cited from a reference15 instead of K. The values of ∆Gt°(CH2) for three series of alkanols are all less negative than ∆Gow°(CH2). This shows that palisade layers of micelles, where alkanols are solubilized, are more polar than octanol.8 Among alkanols with the same number of carbons, ∆Gt° is in the order of 1- < 2- < 3- < 4-alkanol < branched alkanol < cyclic alkanols. It shows that a bulkier alkanol was less favorably solubilized in the micelle. This tendency was also observed for DTAB micelle. We cannot conclude from only this result that the micelle can recognize the bulkiness of the alkanols, because this tendency can be explained by the hydrophobicity of alkanols as follows. In principle, a bulky alkyl group is less hydrophobic than a slender alkyl group with the same number of carbons, since the bulky one has a smaller surface area accessible to water. Correlation between the Micelle/Water and the Octanol/Water Partition Coefficients. In order to discuss the effect of the molecular shape, it is necessary to analyze the solubilization in terms of the hydrophobicity. The partition coefficients between 1-octanol and water (Kow) are widely used as a hydrophobicity parameter. The transfer free energy from water to octanol (∆Gow°) can be obtained by use of Kow15 in place of K according to eq 5. (15) Sangster, J. J. Phys. Chem. Ref. Data 1983, 18, 1111.
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Chart 3. A Possible Model of a Flexible Micelle Solubilizing Alkanols
Figure 3 shows the relation between ∆Gt° and ∆Gow°. A good correlation (r ) 0.97-0.98) was obtained. This result shows that the solubilization of alkanols in micelles depends only on the hydrophobicity of alkanols and that there is no effect of the molecular shape of alkanols on the solubilization in micelles. The slope of the straight line is smaller than 1. This is due to the higher polarity of micelle interface than octanol. Correlation between the Micelle/Water Partition Coefficient and the Molecular Surface Area. The hydrophobicity of organic compounds is correlated with the molecular surface area. The unfavorable contact of alkyl groups with water is the origin of the hydrophobic interaction, so their surface areas are an important factor which determines their hydrophobicities. Figure 4 shows the molecular surface area accessible to water molecules (SA) as a function of the number of carbons of alkanols. SA increased linearly with the number of carbons. A bulkier alkanol has smaller SA than a slender alkanol, so it is less hydrophobic. This tendency is the same as the solubilization in the micelles and the partition between octanol and water. Figure 5 shows the relation between ∆Gt° to SDS micelle and SA. This plot has an advantage that SA is determined only by two components, an alkanol and the solvent (water), whereas for the partition coefficient, there are three components, the alkanol and the two solvents. A good correlation (r ) 0.95) was observed between ∆Gt° and SA, which shows more clearly that the solubilization in micelles was dependent only on the hydrophobicity and independent of the molecular shape of alkanols. From these results, it is clear that the micelles cannot recognize the molecular shapes of the alkanols. Since the interior of usual micelles are liquid-like, the micelles are too flexible to recognize the molecular shape of alkanols as illustrated in Chart 3. Correlation between the SDS Micelle/Water and the DTAB Micelle/Water Partition Coefficients.
Figure 6. Correlation between the transfer free energies (∆Gt°) of alkanols from water to SDS and DTAB micelles.
Figure 6 shows the relation between the transfer free energies of alkanols from water to SDS micelle and to DTAB micelle. This plot gives the best correlation (r ) 0.999) among the correlations examined in Figures 3, 5, and 6. Its slope (0.978) was almost equal to 1. This good correlation implies that the different micelles provide a similar environment as the solubilization site of alkanols and supports the high reliability of the measurement. For all the alkanols used in this work, ∆Gt° for SDS micelle was larger than that for DTAB micelle by about 1.3 kJ mol-1. The difference was caused by the hydrogen bonding between the sulfate group of SDS and alkanols on the micellar surface and the closer packing of SDS micelle than DTAB micelle.8 Conclusion Good correlations were obtained between the micelle/ water partition coefficient (K) and the octanol/water partition coefficient (Kow) and between K and the molecular surface area (SA) in the cases of the isomeric alkanols. This result denotes that the solubilization is dependent only on the hydrophobicity of alkanols and that it is independent of the shape of alkanol molecules. The liquidlike micelles are too soft to recognize the molecular shape of solubilizates. In addition, different micelles provide a similar environment as solubilization sites for alkanols. Acknowledgment. The authors thank Dr. K. Yoshizuka (Department of Applied Chemistry, Saga University) for helping with the calculation of the molecular surface areas of alkanols by using the software HyperChem Release 4. LA960856A
