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J. Phys. Chem. B 2001, 105, 760-765
Complex Formation of Benzenesulfonate-r-cyclodextrin Estimated from NMR and Hydrophobic Molecular Surface Areas Noriaki Funasaki,* Hiroshi Yamaguchi, Seiji Ishikawa, and Saburo Neya Kyoto Pharmaceutical UniVersity, Misasagi, Yamashina-ku, Kyoto 607-8414, Japan ReceiVed: July 19, 2000; In Final Form: October 26, 2000
The complex formation of benzenesulfonate (BS) and R-cyclodextrin (R-CD) is investigated by proton NMR and molecular surface area calculations. The 1:1 binding constant K1 is determined from dependence of the chemical shifts of the ortho proton of BS and the R-CD H3 on the concentrations of BS and R-CD. Using this K1 value, the chemical shift variations of all protons of BS and R-CD with complex formation are determined. The chemical shift variations of all R-CD protons are calculated from the Johnson-Bovey theory on the basis of the ring current effect of the incorporated BS molecule. The penetration depth and rotation angle of the phenyl group in the R-CD cavity are determined by best fitting to the observed chemical shift variations: the penetration depth is close to that in the crystal structure of the BS-R-CD complex and the rotation angle is different by 30°. This structure is consistent with the intensities of intermolecular crosspeaks in the ROESY spectrum. Furthermore, the matching hydrophobic surface area decrease ∆Aoo is calculated as a function of the penetration depth and rotation angle of the phenyl group. The structure of the complex exhibiting the maximum ∆Aoo value is regarded as the most stable structure. This is close to the NMR structure. The binding constant estimated from this ∆Aoo value is close to an observed value of K1 ) 9.75 dm3 mol-1. The hydrophobic interaction plays a predominant role in cyclodextrin inclusion. The concept of molecular recognition by hydrophobic molecular surface areas is useful for the prediction of the binding constant and the structure of the complex in a variety of other fields as well.
Introduction Cyclodextrins (CDs) have homogeneous toroidal structures of different molecular sizes: most typical are cyclohexaamylose (R-CD), cycloheptaamylose (β-CD), and cyclooctaamylose (γCD). All glucose units are slightly tilted so that they form a hollow truncated cone. The primary hydroxyl groups are located at the wider rim and the secondary hydroxyl groups are found at the narrower rim. The toroidal structure has a hydrophilic surface, making them water-soluble, whereas the cavity is composed of the glucoside oxygens and methylene hydrogens, giving it a hydrophobic character. As a consequence, the CDs are capable of forming inclusion complexes with compounds having a size compatible with dimensions of their cavity. Geometrical rather than chemical factors are decisive in determining the kind of guest molecules which can penetrate into the CD cavity.1-3 The extent of complex formation also depends on the polarity of the guest molecule. Strongly hydrophilic molecules and strongly hydrated and ionized groups are not, or very weakly, complexable. The included molecules are normally oriented in the host in such a position as to achieve the maximum contact between the hydrophobic part of the guest and the apolar CD cavity.4 The hydrophilic part of the guest molecule remains, as far as possible, at the outer face of the complex.3 The complex formation of CDs and surfactants has been examined by many techniques from a viewpoint of colloid and surface chemistry.4-12 A typical hydrophobic interaction is the micellization of surfactants and is quantitatively analyzed by * Corresponding author. Fax: +81-75-595-4762. E-mail: funasaki@ mb.kyoto-phu.ac.jp.
molecular surface areas of surfactants.13,14 This viewpoint will be applied to the complex formation of CDs with surfactants and other hydrophobic compounds, though very little remains explored.4 Very recently, we have estimated the structures and binding constants of CD complexes from the decrease of hydrophobic molecular surface areas with docking.4 To calculate such molecular areas, one needs to determine the solution structure of their complex in more detail. The crystal structures of many CD complexes are available from the Cambridge Crystallographic Data Center.15-18 On the other hand, the solution structures of such complexes have been estimated by NMR and circular dichroism spectroscopy. These crystal and solution structures are very close to one another for most complexes, but there are exceptions. Even the stoichiometry of complexation is different in the solution and solid states.19-21 Rough solution structures have been inferred from the complexation-induced chemical shifts and intermolecular NOE data with molecular modeling techniques.19-21 The Johnson-Bovey theory has been used for the determination of the fine solution structures of the equimolar complexes of benzene derivatives with CDs.20-23 Because this theory quantitatively estimates the magnitude of the shielding effect of the benzene molecule on the chemical shift of a proton, one can determine the solution structures of the benzene derivatives at the atomic level.24 The crystal structure of the complex of sodium benzenesulfonate (BS) and R-CD is available.25 In the present work we determine the binding constant of this system from the variation of chemical shift of the H3 proton of R-CD with the concentration of BS. The solution structure of this complex is estimated on the basis of the Johnson-Bovey theory and the ROESY
10.1021/jp002579t CCC: $20.00 © 2001 American Chemical Society Published on Web 01/05/2001
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spectrum. Furthermore, we estimate the solution structure of the complex and the binding constant from molecular surface areas. Experimental Section Materials. Commercial samples of R-CD, methanol (Nakalai Tesque, Kyoto), and 99.9% deuterium oxide (Aldrich) were used as received. Sodium benzenesulfonate (BS) (Tokyo Kasei, Tokyo) was recrystallized from a 50%-50% mixture of water and ethanol. NMR Measurements. All NMR experiments were carried out in deuterium oxide at 298.2 K. The NMR spectra were obtained with a JEOL Lambda 500 spectrometer. Chemical shifts were referenced to the internal methanol signal at 3.343 ppm.26 The proton chemical shifts of BS and R-CD were determined as a function of the R-CD concentration (up to 50 mmol dm-3) in the absence and presence of 10 mmol dm-3 BS and as a function of the BS concentration (up to 100 mmol dm-3) in the absence and presence of 5 mmol dm-3 R-CD. Two-dimensional phase-sensitive nuclear Overhauser effect spectroscopy (ROESY) for a solution containing 40 mmol dm-3 BS and 40 mmol dm-3 R-CD was performed at 500 MHz with the JEOL standard pulse sequences; data consisted of 8 transients collected over 2048 complex points. A mixing time of 400 ms, a repetition delay of 1.2 s, and a 90° pulse width of 11.0 µs were used. The ROESY data set was processed by applying an exponential function in both dimensions and zero-filling to 2048 × 2048 real data points prior to the Fourier transformation. Small cross-peaks were neglected, because their magnitude was close to that of noise. Calculations of Molecular Surface Areas. The threedimensional structure of the BS-R-CD complex was expressed in Cartesian coordinate systems, where the origin was located at the center of benzene in the crystal structure of the complex.25 The CD molecule is almost symmetric around the x axis. The side of primary hydroxyl groups has a negative x value, whereas that of secondary hydroxyl groups has a positive x value. The atomic coordinates of the free BS molecule and the BSR-CD complex were taken from the crystal structure of the complex of BS-R-CD,25 and those of the free R-CD molecule were from the crystal structure of its hexahydrate.27 The Bondi atomic radii (r) were used;28 rH ) 0.120 nm, rO ) 0.152 nm, rC ) 0.170 nm, and rS ) 0.180 nm. The water radius of 0.14 nm was usually employed for calculations of water-accessible molecular surface areas. Each area element is generated on a water-accessible surface of a molecule and consists of a rectangle with a width of 0.010 nm. A dot was drawn on the center of the element for showing the molecule.14 All groups constituting a molecule were classified into either hydrophilic groups or hydrophobic groups. The hydrophilic groups include the hydroxyl group, the sulfonate ion, and the ether oxygen atom, whereas the hydrophobic groups include the alkyl group and the phenyl group. Calculations and molecular graphics were carried out simultaneously with a personal computer running on Microsoft Windows 95/NT. The relative position of host and guest can be easily varied on the display.14 All surface areas for a molecule were computed in roughly 25 s. Results Chemical Shifts and Binding Constant. A 500 MHz 1H NMR spectrum of 10 mmol dm-3 BS and 10 mmol dm-3 R-CD in deuterium oxide is shown in Figure 1. The assignments of the protons of BS and R-CD, inferred from the literature,23,28
Figure 1. 500 MHz spectrum of a deuterium oxide solution containing 10.0 mmol dm-3 BS and 10.0 mmol dm-3 R-CD at 298.2 K.
Figure 2. Chemical shift variations of the Ho proton (circles) with increasing R-CD concentration in a 10.0 mmol dm-3 BS solution and those of the H3 proton (triangles) with increasing BS concentration in a 5.0 mmol dm-3 R-CD solution. The solid lines are calculated using a value of K1 ) 9.75 dm3 mol-1 and the best fit values of ∆δGHG(Ho) and ∆δHHG(H3) shown in Table 1.
TABLE 1: Observed and Calculated Chemical Shift Variations of BS and r-CD Protons with Docking for Five Structures calcd observed Ho Hm Hp H1 H2 H3 H4 H5 H6 SS
0.211 0.131 0.073 -0.032 -0.068 -0.204 -0.035 0.014 0.019
X-ray
NMR0
NMR30
Area0
Area30
-0.038 -0.049 -0.313 -0.045 0.044 0.015 0.0132
-0.020 -0.039 -0.210 -0.023 0.082 0.022 0.0058
-0.042 -0.044 -0.238 -0.047 0.003 0.008 0.0022
-0.036 -0.048 -0.310 -0.043 0.051 0.016 0.0130
-0.031 -0.041 -0.244 -0.034 0.060 0.017 0.0045
are included in Figure 1. The signals of two protons H6a and H6b of R-CD are distinguishable from one another, albeit very close, on this spectrum, but we used the average of their chemical shifts for further analysis. We recorded one-dimensional spectra under two sets of experimental conditions: the R-CD concentration was increased up to 100 mmol dm-3 at a fixed concentration of 10 mmol dm-3 BS and the BS concentration was increased up to 50 mmol dm-3 at a fixed concentration of 5 mmol dm-3 R-CD. All BS protons exhibit low-field shifts with the increasing R-CD concentration, namely, positive ∆δ (chemical shift variation) values (Figure 2 and Table 1). The chemical shift of the ortho proton (Ho), which exhibits the largest change among all BS protons, is plotted against the R-CD concentration in Figure 2. Among the protons of R-CD, the signals of the H1, H2, H3, and H4 protons shift to higher field with increasing BS concentration and those of
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Funasaki et al.
the H5 and H6 protons shift to lower field. The chemical shift variation of the H3 proton, exhibiting the largest change among all the R-CD protons, is also plotted against the BS concentration in Figure 2. To analyze these chemical shift data, we assumed the 1:1 complexation of BS (G) and R-CD (H). When its equilibrium binding constant is denoted by K1, one can express the chemical shift δH of an R-CD proton as
δH ) ([H]δHH + [HG]δHHG)/CH ) ([H]δHH + K1[H][G]δHHG)/CH (1) Similarly, the chemical shift δG of a BS proton is expressed as
δG ) ([G]δGG + [HG]δGHG)/CG ) ([G]δGG + K1[G][H]δGHG)/CG (2)
Figure 3. The structures of (a) R-CD‚6H2O and the R-CD/BS inclusion complex: (b) X-ray, (c) NMR0, (d) NMR30, (e) Area0, and (f) Area30.
Here δHH, δHHG, δGG, and δGHG are chemical shifts of the free R-CD proton, the complexed R-CD proton, the free BS proton, and the complexed BS proton, respectively and CH and CG stand for the total concentrations of R-CD and BS. The concentrations of the free R-CD and BS molecules are written as a function of CH and CG:
[H] ) {K1CG - K1CH - 1 + [(K1CG - K1CH - 1)2 + 4K1CG]1/2}/2K1 (3) [G] ) {K1CH - K1CG - 1 + [(K1CH - K1CG - 1)2 +
Figure 4. SS value plotted against the penetration depth of BS in the R-CD cavity at φ ) 0° (curve a) and φ ) 30° (curve b), where x stands for the deviation from the crystal structure.
4K1CH]1/2}/2K1 (4) The chemical shifts, δHH and δGG, of the free R-CD and BS molecules are known from experiments in the absence of BS or R-CD. Thus, one can simultaneously calculate theoretical values of δH and δG at a given set of CH and CG from eq 1 and 2, once K1, δHHG, and δGHG are known. Using the observed chemical shift variations of Ho and H3 protons (Figure 2), we determined the best fit values of K1, δHHG, and δGHG: K1 ) 9.75 dm3 mol-1, ∆δHHG(H3) ) -0.204 ppm, and ∆δGHG(Ho) ) 0.211 ppm (Table 1). Using this K1 value, we determined the best fit chemical shifts of the other protons of BS and R-CD in the complex state from eq 1 or 2. These chemical shift variations are also shown in Table 1. At a first glance, the ∆δGHG values for the BS protons are regular, but the ∆δHHG values for the R-CD protons appear to be irregular in sign and magnitude. Structure of Complex Estimated from Chemical Shifts. The atomic coordinates of the BS-R-CD complex determined by X-ray crystallography are available.25 Figure 3a depicts the cross section of the complex at the plane containing the benzene ring. The chemical shift variations of the R-CD protons will be due to the ring current effect of the entrapped phenyl group.23,24 On the basis of these atomic coordinates of the BS-R-CD complex and the Johnson-Bovey theory for benzene, we calculated the chemical shifts of the R-CD protons induced by this effect. The observed chemical shift is the average over 6 protons of the same kind. The shift induced by the ring current effect of benzene is given as a function of the z and F coordinates in the cylindrical polar coordinate system having the origin at the center of the benzene ring. These coordinates of each proton of R-CD were transformed to z and (x2 + y2)1/2 in the Cartesian polar coordinate system, and the induced shift was calculated. This calculation was carried out for 6 protons of the same kind and then the induced shifts for the 6 protons were averaged for the estimation
of a theoretical shift for the proton of this kind. As Table 1 shows, the induced shifts calculated on the basis of the X-ray structure are in good agreement with the observed ones. This result indicates that the solution structure of the BS-R-CD complex is close to its crystal structure. It is notable that the phenyl group gives rise to rather large shifts of the protons of the outer surface (H1, H2, and H4). To get better agreement between theory and experiment, we moved the BS molecule in the R-CD cavity along with the symmetry axis x of R-CD, keeping the structures of these molecules as rigid bodies. In the distance coordinate of Figure 3, x is assigned a zero value for the crystal structure of the complex and is a negative value at a deeper penetration of BS from this structure. At an x value, we calculated the average shift of each of 6 R-CD protons on the basis of the JohnsonBovey theory and calculated the SS value defined as
SS )
∑6 (δobsd - δcalcd)2
(5)
As Figure 4 shows, SS has the minimum at x ) 0.10 nm. As Figure 3c shows, the BS molecule for this NMR structure (NMR0) penetrates in the cavity more shallowly than that for the crystal structure (Figure 3b). The theoretical shifts of 6 R-CD protons for this NMR structure of the complex are shown in column NMR0 of Table 1. The theoretical value for H3 is remarkably improved. The phenyl group can rotate around the symmetry axis of R-CD, though it is fixed on a diagonal line of hexagon of R-CD (φ ) 0) in the crystal state (Figure 3b). This angle, φ, of rotation being kept constant at 30°, we calculated the SS value as a function of x. As Figure 4 and Table 1 show, the calculated chemical shifts at x ) -0.05 nm and φ ) 30° are in excellent agreement with the observed ones. We did not calculate the SS
Benzenesulfonate-R-cyclodextrin Complexation
J. Phys. Chem. B, Vol. 105, No. 4, 2001 763 TABLE 3: Values of ∆Aoo and K1 Calculated for Five Structures of BS-r-Complex complex
x (nm)
φ (deg)
∆Aoo (nm2)
K1 (dm3 mol-1)
X-ray NMR0 NMR30 Area0 Area30
0.00 0.10 -0.05 0.01 0.02
0 0 30 0 30
1.81 1.65 1.72 1.81 1.82
17.2 9.1 11.8 17.7 18.3
surface area ∆Ao(HG) with the docking of host (H) and guest (G) plays an essential role in determining the stable structure of the complex and the binding constant.4 This decrease consists of the contributions of R-CD (H) and BS (G):
∆Ao(HG) ) Ao(H) + Ao(G) - Ao(HG)
Figure 5. Contour plot of a partial 500 MHz ROESY spectrum of a deuterium oxide solution containing 40.0 mmol dm-3 BS and 40.0 mmol dm-3 R-CD at 298.2 K.
TABLE 2: Intensities of Intermolecular NOE Peaks and Average Intermolecular Proton-Proton Distances (nm) for X-ray and NMR Structures of BS-r-CD Complexa proton Ho
Hm
Hp
b
NOE X-ray NMR0 NMR30 NOE X-ray NMR0 NMR30 NOE X-ray NMR0 NMR30
H1
H2
H3
H4
H5
H6
0.72 0.77 0.70 0.64 0.66 0.64 0.62 0.62 0.63
0.70 0.74 0.69 0.68 0.68 0.69 0.68 0.66 0.70
+ 0.42 0.47 0.41 + 0.41 0.39 0.43 + 0.43 0.39 0.46
0.68 0.74 0.66 0.61 0.63 0.61 0.59 0.59 0.60
0.55 0.63 0.52 + 0.39 0.45 0.38 + 0.33 0.35 0.32
0.77 0.85 0.74 0.61 0.67 0.59 0.54 0.58 0.52
a Distances for Area0 and Area30 are not shown, because they are similar to those for X-ray and NMR structures. b For NOE, “+” ) observed and “-” ) not observed.
value for other angles, because the phenyl group in the R-CD cavity will rotate around the symmetry axis of R-CD. The tilting of the phenyl group for the symmetry axis of R-CD up to 10° did not give significant effects on the calculated shift (data not shown). ROESY Spectrum. To infer the geometry of the inclusion complex from the NOE intensity, we recorded the 500 MHz ROESY spectrum of a 40 mmol dm-3 BS and 40 mmol dm-3 R-CD solution. As Figure 5 shows, several intermolecular NOE peaks were observed, as expected. This result is summarized in Table 2. There is no NOE peak between the protons Ho and H5. Under our conditions, the NOE peak will be observed for a pair of protons below ca. 0.4 nm of interproton distances.19 The average intermolecular distances calculated for the crystal and NMR structures are also shown. For instance, the calculated distance between Ho and H3 was averaged over 12 distances among two Ho protons and 6 H3 protons. For five structures shown in Tables 2 and 3, the NOE peaks were observed below 0.468 nm (H3-Ho for NMR0) and not observed above 0.516 nm (H5-Ho for NMR 30). Thus, the NOE data are consistent with all the proposed structures, though do not provide any criterion for determining the best of these structures. Molecular Surface Area Approach. We have recently proposed that the decrease of hydrophobic (oleophilic) molecular
(6)
) [Ao(H) - Ao(Hc)] + [Ao(G) - Ao(Gc)]
(7)
) ∆Ao(H) + ∆Ao(G)
(8)
Here Ao(Hc) stands for the hydrophobic surface area of R-CD in the complex, ∆Ao(H) denotes the decrease in hydrophobic area of host with the docking, and Ao(Gc) and ∆Ao(G) are the corresponding values for BS. The decreased hydrophobic area, ∆Ao(H), of H consists of two terms ∆Aoo(H) and ∆Aow(H). The first term denotes part of the hydrophobic host surface in complex in contact with hydrophobic group of BS and the latter term stands for that in contact with hydrophilic group of BS. The first matching term promotes docking and the latter mismatching term inhibits it.4 Furthermore, we must consider the corresponding areas for the guest, ∆Ao(G), ∆Aoo(G), and ∆Aow(G). Among these areas, the sum, ∆Aoo, of ∆Aoo(H) and ∆Aoo(G) is the most important parameter and will be termed the matching hydrophobic area decrease. The molecular surface area depends on the molecular conformation. We assumed that the solution structures of R-CD in the free and complexed states are the same with the crystal structures of the hexahydrate and the BS complex, respectively and that the solution structures of benzenesulfonate ion in the free and complexed states are the crystal structure in the BSR-CD complex.25 Hydrophobic and hydrophilic molecular surface areas of R-CD and BS in the free state were calculated for these assumed structures. The crystal structure of R-CD in the hexahydrate (Figure 3a) is much different from that in its BS complex (Figure 3b): the former rim is a deformed hexagon and the latter is a regular hexagon. The solution structures of the BS-R-CD complex deduced from the NMR data and molecular surface areas are also shown in Figure 3c-f. For the five structures of the BS-R-CD complex shown in Figure 3b-f, we calculated hydrophobic and hydrophilic molecular surface areas and the changes in area with docking; namely, ∆Ao(HG), ∆Ao(H), ∆Ao(G), ∆Aw(G), ∆Aw(H), ∆Aw(HG) ∆Aoo(G), ∆Aow(G), ∆Aoo(H), ∆Aow(H), ∆Aoo(H), ∆Aoo(G), and ∆Aoo. These areas were calculated as a function of the penetration depth x of BS into the R-CD cavity at φ ) 0° and 30°. As Figure 6 shows, the ∆Aoo value reaches the maximum at an x value and a φ value, where the complex has the most stable structure.4 The values of x and ∆Aoo at the most stable structures at φ ) 0° and 30° are shown in Table 3, where these structures are named Area0 and Area30. Judging from the ∆Aoo value, Area30 is a more stable structure than Area0, though the difference in their stability is small. The Area30 structure (Figure 3f) is very close to the NMR30 structure (Figure 3d). In these structures, the penetration depth of the phenyl group is
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Funasaki et al.
Figure 6. Decreases ∆Aoo in hydrophobic molecular surface area as a function of the penetration depth x of BS at φ ) 0° (curve a) and φ ) 30° (curve b).
close to that in the crystal structure (Figure 3b), but the rotation angle differs by 30°. According to our molecular surface area approach, the 1:1 binding constant K1 is correlated with ∆Aoo as follows:
Log K1 ) 1.803∆Aoo - 2.023
(9)
This equation was obtained from data for 11 CD inclusion systems that include R-CD, β-CD, γ-CD, monohydroxy, dihydroxy, and trihydroxy alcohols, and aromatic guests.4 Using this equation, we calculated the binding constants from the ∆Aoo values for five structures of the BS-R-CD complex. These theoretical binding constants (Table 3) are close to an observed value of K1 ) 9.75 dm3 mol-1. Discussion Five solution structures of the BS-R-CD complex are proposed on the basis of the data of X-ray diffraction, NMR, and surface areas (Figure 3b-f) and all are close to each other. However, the data of the chemical shifts (Table 1) and molecular areas (Table 3) both suggest that the structure at φ ) 30° is more stable than that at φ ) 0° for the crystal structure. This does not exclude the rotation of the phenyl group around the symmetry axis of R-CD: it will rotate around φ ) 30°. The molecular surface data suggest that the penetration depth of the phenyl group in the R-CD cavity is very close to that in the crystal structure. The ∆Aoo value is insensitive to φ (Figure 6). Chemical-shift variations ∆δ generally include two factors, conformational changes and microenvironmental changes and are not amenable to quantitative analysis.19,21 The structure of the R-CD cavity changes from a deformed cone to a regular circle on complex formation (Figure 3). Because this effect on the ∆δ value of the R-CD protons is not clear, we have considered the ring current effect alone. On the other hand, because BS is a rigid molecule, the ∆δ value must be interpreted in terms of the microenvironmental change alone. The solution structure of the BS-R-CD complex has been established in rather high accuracy. As the NOE data shows, Ho is less crowded by the R-CD protons than Hm and Hp. Nevertheless, the ∆δ value for Ho is larger than that for Hm and Hp (Table 1). This result suggests that the distance and direction of the BS protons to oxygen atoms of R-CD, such as 2- and 3-hydroxyl oxygens, play an important role in determining the ∆δ value. Generally, carbons in the secondary alcoholic side (wider rim) exhibit positive 13C NMR shifts on R-CD inclusion, whereas those in the primary alcoholic side (narrower rim) show negative shifts. This tendency was well reproduced on the basis of quantum mechanical calculations by Inoue.21 This result is consistent with our ∆δ values for the aromatic protons (Table 1). The binding constants predicted from the ∆Aoo values for the BS-R-CD system are close to the observed one, though the
∆Aoo values depend on the structures of the complex. This agreement will be due to some fortune rather than to rigor. First, the binding constant for an inclusion system differs widely depending on the used techniques, data treatments, researchers, and others. For instance, the binding constant for sodium dodecyl sulfate and β-CD spans over three orders in the literature.30 Second, there is no method for determining exact solution structures of complexes or actually there is no single solution structure. Equation 9 is based on these uncertainties. Thus, we cannot judge the validity of structure of the BS-R-CD complex from agreement between the observed and predicted binding constants. Regardless of these limitations, the surface area approach is useful for prediction of molecular structures, binding constants, molecular hydrophobicity, and others.4,14,31-37 Hydrogen bonds and electrostatic interactions play essential roles in the structure and function of proteins and the number of such hydrophilic interactions is often regarded to be proportional to the strength of binding.37-39 However, little is known about a quantitative contribution of hydrophobic interactions to binding constants and molecular structures. The present results provide a quantitative estimation of hydrophobic interactions in such complicated systems and the concept of molecular recognition by hydrophobic areas will be applicable to various compounds. Acknowledgment. This work was supported by grants-inaid for the Scientific Research Program (No. 11672153) and the Frontier Research Program from the Ministry of Education, Science, Culture, and Sports of Japan. References and Notes (1) Bender, M. L.; Komiyama, M. Cyclodextrin Chemistry; SpringerVerlag: Berlin, 1978; Chapters 2 and 3. (2) Szejtli, J. Cyclodextrin Technology; Kluwer Academic Publishers: Dordrecht, The Netherlands, 1988; Chapters 2 and 3. (3) Saenger, W. Angew. Chem., Int. Ed. Engl. 1980, 19, 344. (4) Ishikawa, S.; Hada, S.; Neya, S.; Funasaki, N. J. Phys. Chem. B 1999, 103, 1208. (5) Park, J. W.; Song, H. J. J. Phys. Chem. 1989, 93, 6454. (6) Wan Yunus, W. M. Z.; Taylor, J.; Bloor, D. M.; Hall, D. G.; WynJones, E. J. Phys. Chem. 1992, 96, 8979. (7) Funasaki, N.; Uemura, Y.; Hada, S.; Neya, S. J. Phys. Chem. 1996, 100, 16298. (8) Jobe, D. J.; Verrall, R. E.; Junquera, E.; Aicart, E. J. Phys. Chem. 1994, 98, 10814. (9) Wilson, L. D.; Verrall, R. E. Can. J. Chem. 1998, 76, 25. (10) Ishikawa, S.; Neya, S.; Funasaki, N. J. Phys. Chem. B 1998, 102, 2502. (11) Funasaki, N.; Ohigashi, M.; Hada, S.; Neya, S. Langmuir 2000, 16, 383. (12) Funasaki, N.; Neya, S. Langmuir 2000, 16, 5584. (13) Tanford, C. The Hydrophobic Effect: Formation of Micelles and Biological Membranes; 2nd ed.; John Wiley and Sons: New York, 1980; Chapter 6. (14) Ishikawa, S.; Hada, S.; Funasaki, N. J. Phys. Chem. 1995, 99, 11508 and references therein. (15) Saenger, W. In Inclusion Compounds; Atwood, J. L.; Davies, J. E. D.; MacNicol, D. D., Eds.; Oxford University Press: Oxford, U. K., 1984; Vol. 2; Chapter 8. (16) Saenger, W.; Jacob, J.; Gesseler, K.; Steiner, T.; Hoffmann, D.; Sanbe, H.; Koizumi, K.; Smith, S.; Takaha, T. Chem. ReV. 1999, 99, 1208. (17) Harata, K. In Inclusion Compounds; Atwood, J. L.; Davies, J. E. D.; MacNicol, D. D., Eds.; Oxford University Press: Oxford, U. K., 1991; Vol. 5; Chapter 9. (18) Harata, K. Chem. ReV. 1998, 98, 1787. (19) Schneider, H.-J.; Hacket, F.; Ru¨diger, V.; Ikeda, H. Chem. ReV. 1998, 98, 1755. (20) Schneider, H.-J.; Yatsimirsky, A. K. Principles and Methods in Supramolecular Chemistry; John Wiley and Sons: New York, 2000; Chapter E4. (21) Inoue, Y. Ann. Rep. NMR Spectrosc. 1993, 27, 60. (22) Yamamoto, Y.; Onda, M.; Takahashi, Y.; Inoue, Y.; Chujou, R. Carbohydr. Res. 1988, 182, 41. (23) Hada, S.; Neya, S.; Funasaki, N. J. Phys. Chem. B 1999, 103, 2574.
Benzenesulfonate-R-cyclodextrin Complexation (24) Bovey, F. A. Nuclear Magnetic Resonance Spectroscopy; Academic Press: New York and London, 1969; Chapter 3 and Appendix C. Johnson, C. E., Jr.; Bovey, F. A. J. Chem. Phys. 1958, 29, 1012. (25) Harata, K. Bull. Chem. Soc. Jpn. 1976, 49, 2066. (26) Matsui, Y.; M.; Tokunaga, S. Bull. Chem. Soc. Jpn. 1996, 69, 2477. (27) Manor, P. C.; Saenger, W. J. Am. Chem. Soc. 1974, 96, 3630. (28) Bondi, A. J. Phys. Chem. 1964, 68, 441. (29) Wood, D. J.; Hruska, F. E.; Saenger, W. J. Am. Chem. Soc. 1977, 99, 1735. (30) Funasaki, N.; Yodo, H.; Hada, S.; Neya, S. Bull. Chem. Soc. Jpn. 1992, 65, 1323 and references therein. (31) Hermann, R. B. J. Phys. Chem. 1972, 76, 2754. (32) Honig, B.; Sharp, K.; Yang, A.-S. J. Phys. Chem. 1993, 97, 1101.
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