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Kinetics of Inclusion Reactions of β-Cyclodextrin with Several Dihydroxycholate Ions Studied by NMR Spectroscopy C. T. Yim* Department of Chemistry, Dawson College, 3040 Sherbrooke Street West, Westmount, Quebe´ c, Canada H3Z 1A4
X. X. Zhu De´ partement de Chimie, UniVersite´ de Montre´ al, C.P. 6128, succursale Centre-Ville, Montre´ al, Quebe´ c, Canada H3C 3J7
G. R. Brown† Department of Chemistry, McGill UniVersity, 801 Sherbrooke Street West, Montre´ al, Quebe´ c, Canada H3A 2K6 ReceiVed: August 18, 1998
The 1H NMR spectra of some aqueous dihydroxycholate-β-cyclodextrin systems show separate 18-CH3 signals for complexed and free dihydroxycholate ions. The observed variations in line shapes with concentration and temperature were investigated, and kinetic data were derived for both the formation and decomplexation processes. Analysis of the results indicates that, within the concentration range studied, the dominant exchange mechanism involves a unimolecular decomplexation step (dihydroxycholate, β-cyclodextrin) f dihydroxycholate + β-cyclodextrin. For the chenodeoxycholate system the enthalpies of activation are 43 ( 5 and 45 ( 2 kJ/mol, the entropies of activation are -5 ( 10 and -66 ( 7 J/(K mol) for the formation and decomplexation reactions, respectively, and its decomplexation rate constant is 34 ( 1 s-1 at 300 K. Other dihydroxycholate-cyclodextrin systems show similar activation parameters but slightly lower reaction rates at 300 K. Dehydration plays a major role in the formation process, while the decomplexation rates appear to be controlled by the conformation of the dihydroxycholates.
Introduction Cyclodextrins (CDs) are macrocyclic oligosaccharides capable of forming inclusion complexes with a variety of organic and inorganic molecules in aqueous solutions. The CD molecules take the shape of a truncated cone, with cavities of different sizes depending on the number of glycosidic units. The interior of the cavities is rather hydrophobic, while the exterior remains hydrophilic. The cavities can be used to trap molecules of comparable size, a feature that is of special interest in molecular recognition studies.1,2 The inclusion processes also lead to important modifications of the properties of the guest compounds, and inclusion complexes have found applications in solving numerous practical problems.3-5 The molecular recognition by cyclodextrins has been investigated from theoretical, thermodynamic, and kinetic aspects. Primarily on the basis of thermodynamic and stability data, the driving force for inclusion has been attributed to hydrogen bonding, van der Waals forces, hydrophobic interactions, relaxation of the conformational strain in the CD, and release of hydrogen-bonded water molecules from the cavity.5 Cramer et al.6 reported the first kinetic measurements performed on a series of naphthylazobenzene-R-CD complexes. They found * To whom correspondence should be addressed. E-mail: cyyi@ Musica.McGill.ca. Fax: 514-931-3567. † Present address: University of Northern British Columbia, Chemistry Program, 3333 University Way, Prince George, British Columbia, Canada V2N 4Z9.
that the dissociation rate constants for eight of these complexes varied from 0.01 to 1.3 × 105 s-1, in marked contrast with their binding constants, which ranged only from 270 to 1010 M-1. They attributed the observed kinetic specificity to the involvement of the desolvation of the guest molecules in the ratedetermining step. Their results illustrate the importance of kinetic measurements, which provide valuable dynamic and mechanistic information that is indispensable for understanding the nature of interactions involved in inclusion reactions. Since then, interesting kinetic data have been accumulated for reactions involving CD complexes using a variety of methods such as temperature jump, stopped flow, fluorescence lifetime, and ultrasonic absorption techniques.6-16 For most cyclodextrin inclusion complexes, the exchange between complexed and free species is rapid on the NMR time scale, allowing only average, relatively narrow NMR signals to be observed.17 Although these spectra are valuable for studying structure and properties of inclusion complexes, they contain little information concerning the kinetics of complexation processes. However, in the early 1990s Matsuo et al. reported the observation of distinct 1H NMR signals due to bound and free species in several through-ring R-CD complexes formed by guest molecules possessing a polymethylene chain terminated with charged groups.18,19 Reaction rates and activation parameters were extracted from the observed temperature effect on these signals. On the other hand NMR methods, particularly 23Na NMR, have been used extensively by several
10.1021/jp9833909 CCC: $18.00 © 1999 American Chemical Society Published on Web 01/05/1999
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Figure 2. Normalized total area of C18 methyl signals (0) and area fraction of the complexation induced C18 peak (∆) as a function of molar ratio, β-CD/CDC, for CDC-β-CD at 300 K. The total area was normalized to an initial concentration of CDC ) 3.80 × 10-3 M.
Figure 1. Structure of the dihydroxycholates.
authors to investigate the kinetics of the complexation of alkali metal cations by crown ethers, also a system of considerable interest in molecular recognition studies.20-22 Detailed results on reaction mechanism, activation parameters, and solvent effects were obtained by performing relaxation rate measurements or line shape simulations. These studies illustrate the unique character of the NMR method in its capacity to probe reactions without perturbing the system and provide useful kinetic information about reactions occurring in equilibrium mixtures. It has been demonstrated previously that β- and γ-cyclodextrins form inclusion complexes with bile salts anions.23 The possibility of using cross-linked cyclodextrin resins as bile salt binding agents has also been explored.24 To further probe the “host-guest” interaction in bile salt-CD systems we have examined the kinetics of complexation of β-cyclodextrin with three dihydroxycholate anions: chenodeoxycholate, glycochenodeoxycholate, and ursodeoxycholate. The 1H NMR spectra of these three aqueous dihydroxycholate-β-cyclodextrin systems show separate 18-CH3 signals for complexed and free dihydroxycholate ions. The observed variations in line shape with concentration and temperature were investigated and kinetic data were derived for both the formation and decomplexation processes. Experimental Section The β-cyclodextrin (β-CD), sodium chenodeoxycholate (NaCDC), and sodium glycochenodeoxycholate (NaGCDC) were purchased from Aldrich and used as received. The sodium ursodeoxycholate (NaUDC) was prepared by neutralizing the corresponding acid, also purchased from Aldrich. The chemical structures of these three dihydroxycholates with the corresponding abbreviations are shown in Figure 1. D2O solutions of the dihydroxycholates containing varying amounts of β-CD were prepared. The concentration of chenodeoxycholate was kept between 3.88 and 3.99 mM, glycochenodeoxycholate between 4.03 and 4.30 mM, and ursodeoxycholate between 3.17 and 3.33 mM. These concentrations, which are well below the reported
critical micelle concentrations (cmc) values, were selected to minimize possible interference from micelle formation.25,26 The concentration of β-CD was in the range of 0.5-3.2 mM. The 1H NMR spectra were acquired with a Varian Unity 500 spectrometer operating at 499.84 MHz for protons. The probe temperature was calibrated with standard samples of ethylene glycol and methanol. Results and Discussion In our experiments the attention was focused on the signals from 18-CH3 group. For samples containing dihydroxycholate alone, it is a well-separated sharp singlet at the upfield end of the spectrum.27 The addition of β-CD results in the appearance of a new 18-CH3 peak, located approximately 75 Hz (0.15 ppm) downfield from the original peak. Obviously, this peak can be attributed to the complexed dihydroxycholate ions, which undergo moderately slow exchange with the free ions, as evidenced by the considerable broadening of both signals. The area intensity of the complexed species increased with β-CD concentration at the expense of that of the free dihydroxycholate. Shown in Figure 2 is a representative plot for the CDC-β-CD at 300 K showing the normalized total area of the two signals and the area fraction of the signal due to the complexed ion, as a function of the β-CD/CDC molar ratio. The formation of stable 1:1 complexes is clearly confirmed by the plot. In addition, the constant total area indicates that these two signals are the only ones from the 18-CH3 group. There have been reports of additional signals attributable to reaction intermediates in the proton NMR spectra of several R-CD complexes.15 We did not observe these signals in any of our samples, and any reaction intermediate, if it exists, certainly does not bring about a separate signal. Therefore, the C18 methyl protons will be treated as uncoupled spin systems undergoing two-site exchange. Figure 3 shows the effect of initial concentration of β-CD, [β-CD]0, on the spectra of CDC-β-CD at 300 K. To extract the exchange rates from these spectra, a complete line-shape simulation was performed using the Bloch equation modified for an uncoupled spin system undergoing chemical exchange between two nonequivalent sites,28 site A and site B for the free and complexed dihydroxycholate anion, respectively. The simulation requires the inputs of the chemical shift difference between the two sites (∆ν), the line width in the absence of
Inclusion Reactions of β-Cyclodextrin
J. Phys. Chem. B, Vol. 103, No. 3, 1999 599
Figure 4. Representative plots for determining rate constants k-1 and k2: CDC at 283 K (O); GCDC at 300 K (0); UDC at 315 K (4).
1 1 + ) k-1(1 + R) + k2[DHOC]0 τA τB
Figure 3. Experimental (left) and simulated (right) NMR spectra of CDC-β-CD at 308 K. [β-CD]0 is the initial concentration of β-CD in millimolar. pA and τA are the relative population and lifetime (in milliseconds) of free anions, respectively.
exchange (T2), the lifetime (τA and τB), and the relative population (pA and pB) of each site. The populations and lifetimes are related by
pA + pB ) 1
(1)
pA pB ) τA τB
(2)
For each system the values of ∆ν and T2 were first chosen by careful inspection of the spectra and by trial simulation. They were then kept constant for the simulation of spectra at different temperatures and concentrations. The values of pA and τA were varied until the simulated and experimental spectra could be superimposed. The simulated spectra for the same system, with the values of pA and τA used in the simulation, are also shown in Figure 3. Two possible mechanisms may affect the exchange of bound and free “guest” in inclusion complexes. They are (a) the unimolecular decomplexation k1
z Cpx β-CD + DHOC- y\ k
(3)
where R ) (pB/pA) and [DHOC]0 is the initial concentration of the dihydroxycholate. Equation 3 shows that a plot of ((1/τA) + (1/τB))/[DHOC]0 as a function of (1 + R)/[DHOC]0 should yield a straight line with slope k-1 and intercept k2. Plots of several representative data sets are shown in Figure 4. In all cases, the intercepts have relatively small positive or negative values, which, within experimental error, can be taken as zero. Thus we conclude that, within the concentration range studied, the contribution of the bimolecular mechanism to the overall exchange is negligible. The occurrence of both unimolecular decomplexation and bimolecular interchange processes has been demonstrated for other guest-host systems with the latter becoming, as expected, more dominant at higher concentrations.21,22 Unfortunately, the formation of micelles by dihydroxycholates compelled us to confine this study within a low concentration range. Furthermore, it seems reasonable to expect that the bimolecular interchange process would occur more readily with guest molecules capable of passing through the β-CD cavity. Therefore, in view of the size and the rigidity of the cyclopentaphenanthrene unit, it is doubtful that the bimolecular mechanism would become significant in our systems even at higher concentrations. In this respect, it would be of interest to examine the kinetics of cyclodextrin inclusion complexes having properties more amenable to the bimolecular interchange process. The rate constants at several temperatures are listed in Table 1. Of the three systems studied, the complexation with chenodeoxycholate has the highest rate constants while that for ursodeoxycholate has the lowest, illustrating the importance of the configuration of the 7-hydroxy group. The listed rate constants for the formation reaction, k1’s, show relatively large uncertainties; this reflects the fact that calculation of k1 values involves the equilibrium concentration of β-CD, [β-CD]. In our approach [β-CD] is obtained by
-1
and (b) the bimolecular anion interchange mechanism20-22 k2
Cpx + DHOC-* y\z Cpx + DHOCwhere Cpx and DHOC- represent the inclusion complex and the free dihydroxycholate anion, respectively. It can be shown that τA and τB are related to the rate constants by
[β-CD] ) [β-CD]0 - AFcpx [DHOC]0
(4)
where subscript “0” indicates the initial concentration of the species, and AFcpx is the area fraction of the signal due the complexed species as plotted in Figure 2. The equilibrium concentrations, calculated by eq 4 as the difference between two relatively large numbers, are very sensitive to possible errors in area measurements, leading to large uncertainties in
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TABLE 1: Rate Constants for the Formation (k1) and Decomplexation (k-1) Reactions at Several Temperatures CDC T (K) 283 291 300 308 315
GCDC
k1/104 (M-1 s-1)
k-1 (s-1)
3.5 ( 0.6 6.3 ( 0.7 9.1 ( 1.0 17 ( 2.7
11.9 ( 0.3 22.0 ( 1.1 34.0 ( 1.2 63.6 ( 1.1
UDC
k1/104 (M-1 s-1)
k-1 (s-1)
k1/104 (M-1 s-1)
k-1 (s-1)
4.6 ( 0.7 7.5 ( 1.4 12 ( 1.5 19 ( 3.0
11.1 ( 0.9 18.4 ( 0.6 32.8 ( 0.6 52.1 ( 1.6
4.0 ( 0.7 7.4 ( 1.3 11 ( 2.0 19 ( 3.0
7.9 ( 0.6 15.4 ( 0.6 24.2 ( 1.8 40.5 ( 0.9
Figure 5. Plots of ln(k1/T) vs (1/T) for the formation reactions: CDC (O); GCDC (0); UDC (∆). To avoid overlap, the points for CDC and UDC have been moved by 0.05 × 10-3 deg K-1, to the right and left, respectively.
the derived k1 values. Since [β-CD] is also utilized for evaluating the formation constants (Kf), similar error consideration can be applied to our Kf values. At 300 K they are (2.5 ( 0.4) × 103, (3.7 ( 0.5) × 103, and (4.0 ( 0.7) × 103 mol/L, for the CDC-, GCDC-, and UDC-β-CD complexes, respectively. The large uncertainties in Kf values prevent us from obtaining quantitative information on their temperature dependence. Here we can only report that, at all temperatures studied, UDC forms the most stable inclusion complex and CDC the least stable. The Kf values decrease with temperature, indicating a small negative ∆Hf of about -5 to -10 kJ/mol. On the basis of steric considerations and NMR evidence it has been suggested that the hydrophilic side chain enters and protrudes through the β-CD cavity and that formation of inclusion complexes predominantly involves interactions with the bulky hydrophobic steroid skeleton of the bile salt anions.23 In this regard, it is interesting to note that the presence of the glycine unit at the extreme end of the side chain induces a small but significant decrease in the observed rate constants, supporting the view that the bile salt anions penetrate the β-CD cavity via the hydrophilic end. As reported earlier23 the proton NMR spectra of other systems containing β-CD and cholate or glycocholate anions do not show separate C18, C19, or C21 methyl peaks for the complexed and free anions. However, a more careful examination of the spectra obtained with samples containing sodium cholate revealed a small but significant broadening of the C18 methyl peak. A rough estimate yielded an approximate rate constant (k-1) of 800 s-1 for its decomplexation process at 295 K. Thus, we can conclude that the exchange rates are much faster for bile-salt anions containing the 12R-hydroxyl group. The absence of the 12R-hydroxyl group not only leads to a more stable complex with β-CD, as evidenced by the magnitude of the Kf values, but also significantly slows down the formation and decomplexation processes. Usually, a downfield shift in the proton
Figure 6. Plots of ln(k-1/T) vs (1/T) for the decomplexation reactions: CDC (O); GCDC (0); UDC (4).
TABLE 2: Activation Parameters for Several Dihydroxycholate-β-Cyclodextrin Inclusion Complexes formation
CDC GCDC UDC
decomplexation
∆H‡ (kJ/mol)
∆S‡ [J/(K mol)]
∆G‡ (kJ/mol) at 300 K
43 ( 5 42 ( 6 46 ( 6
-5 ( 10 -10 ( 6 2(7
45 ( 7 45 ( 7 46 ( 7
∆H‡ (kJ/mol)
∆S‡ [J/(K mol)]
44.6 ( 2.0 -66 ( 7 47.1 ( 2.0 -63 ( 7 48.2 ( 2.0 -62 ( 5
∆G‡ (kJ/mol) at 300 K 65 ( 5 66 ( 4 67 ( 4
NMR signals is observed with the formation of CD complexes.15 Interestingly, with the dihydroxycholate samples a much larger shift was observed for C19 methyl (about 0.06 ppm) than for C21 methyl (e0.02 ppm), while the opposite was true for the cholate and glycocholate systems.23 These results suggest that dihydroxycholate anions penetrate the β-CD cavities to a greater extent (see Figure 1). Therefore, we attribute the observed differences in stability and in rates to stronger interactions with the bulky steroid skeleton caused by deeper penetration of the dihydroxycholate anions into the cavities. The rate constants listed in Table 1 were used to construct Eyring plots, shown in Figures 5 and 6. The derived activation parameters (∆G‡, ∆H‡, and ∆S‡) for these three systems, given in Table 2, show quite similar trends, with little difference in both enthalpy and entropy of activation. Furthermore, both the formation and decomplexation reactions have similar activation enthalpies. However, the three decomplexation reactions have relatively large, negative ∆S‡ values, while the ∆S‡ values for formation processes are much smaller and can be of either sign. The contribution of the negative activation entropy leads to a larger, positive ∆G‡ for the decomplexation reactions and thus much smaller rate constants. Several authors have considered various contributions to the free energy change for bimolecular associations in solution, and in some cases their values have been estimated for specific systems for semiquantitative prediction of binding constants.29-32 Following Williams et al.31 and retaining only the important
Inclusion Reactions of β-Cyclodextrin terms relevant to relatively nonpolar guests such as dihydroxycholates and to binding in aqueous medium, the free energy change (∆G) upon bimolecular associations can be expressed as:
∆G ) ∆G(trans+rot) + ∆Gconform + ∆GvdW + ∆Gdehyd (5) The first term, ∆G(trans+rot), relates to the freezing of the translational and rotational freedoms of the guest molecules. The term ∆Gconform accounts for possible conformational changes necessary for the formation of complexes. The third term, ∆GvdW, arises because of the increase in the van der Waals interactions due to the efficient packing achieved in the complexes. The last term, ∆Gdehyd, represents the contribution from the dehydration of the reaction species; this includes the “classical” hydrophobic interaction, a mainly entropic phenomenon involving the dehydration of nonpolar solutes and the rearrangement of H-bond configurations around the solute molecules.33 Only the last two terms, ∆GvdW and ∆Gdehyd, are favorable for association processes. Since similar forces should be involved in the formation of activated complexes, one could rationalize the observed activation parameters in terms of these contributions. The formation of an associative activation complex occurs with at least partial loss of translational, rotational, and conformational freedoms, resulting in an unfavorable, negative entropy contribution. The small activation entropy for the formation reaction in our systems clearly indicates that the entropically favorable dehydration process, involving both hydrophilic and hydrophobic moieties, must be involved in the formation of activated complexes. The rate of complexation is thus predominantly determined by its ∆H‡ value, the energy barrier for the deep penetration of dihydroxycholate anions into the β-CD cavity. The large negative ∆S‡ for the decomplexation processes can be partly ascribed to the conformation of the side chain in the activated complex. It can be argued that in order to retrieve the bile salt anion from the cavity the side chain must adopt a rather straight conformation, thus resulting in a negative entropy. However, this proposition cannot account for the large rate change rendered by the 12R-hydroxyl group, nor for the negligible effect of the glycine unit on the values of activation entropy. Therefore the large negative ∆S‡ might also indicate that, in the activated complex, the steroid skeleton of the dihydroxycholate anions experiences a very restricted environment created by the tight fit of the bulky skeleton into the β-CD cavity. We visualize the inclusion process as consisting of the following steps: (a) Dihydroxycholate ions approach the β-cyclodextrin and adopt an appropriate orientation. (b) Some of the hydrating water molecules are removed from the dihydroxycholate side chain and from the β-CD cavity. The side chain inserts into the cavity via the secondary hydroxy rim, the more open side of the conical cyclodextrin. (c) Dehydration of the steroid skeleton takes place. The skeleton enters the cavity and adopts a more restrictive orientation with respect to the groups lining the interior of the cavity. It is at this stage that the activated state is reached. (d) With deeper penetration of the steroid skeleton a final, stable inclusion complex is formed. The deeper penetration and tight fit ensure stronger van der Waals interactions with the β-cyclodextrin. (e) The dihydroxycholate side chain adopts a more relaxed conformation and rehydration of its protruding moieties may also occur.
J. Phys. Chem. B, Vol. 103, No. 3, 1999 601 Conclusions We first demonstrate that the exchange rates for the inclusion reaction of several bile salt-cyclodextrin complexes can be extracted by line shape simulation of the observed NMR signals. The results reveal that, in the concentration ranges studied, the bimolecular mechanism does not make a measurable contribution to the observed exchange rate. Thus, the decomplexation proceeds via a unimolecular mechanism. The first-order rate constants were derived for decomplexation reaction of the three dihydroxycholate-β-CD complexes; they vary from 7 to 63 s-1 in the temperature range studied. Our kinetic results for the complexation of CDC and GCDC strongly support the suggestion that the dihydroxycholate anions enter the β-CD cavity via the hydrophilic side chain. Similar ∆H‡ and ∆S‡ values were obtained for both the formation and decomplexation of these three inclusion complexes. The small ∆S‡ values for the complexation reaction clearly indicate the involvement of dehydration of the reaction species in the formation of activated complexes. We also noted the relatively larger negative activation entropy for the decomplexation process. It was argued that, for the three dihydroxycholate systems, the high stability of the inclusion complexes and their slow reaction rates can be attributed to the deep penetration of the corresponding anions into the β-CD cavity. This leads to strong hydrophobic and van der Waals interactions, and also brings about a rather restricted environment for the activated complex, as indicated by the large negative activation entropy of the decomplexation reaction. Acknowledgment. Financial support from Fonds FCAR (EÄ quipe) of Quebec and from the Natural Sciences and Engineering Research Council (NSERC) of Canada is gratefully acknowledged. References and Notes (1) Bender, M. L.; Komiyama, M. Cyclodextrin Chemistry; SpringerVerlag: Berlin, 1978. (2) Saenger, M. L. Angew. Chem., Int. Ed. Engl. 1980, 19, 344. (3) Li, S.; Purdy, W. C. Chem. ReV. 1992, 92, 1457. (4) Szejtli, J. Cyclodextrin Technology; Kluwer: Dordrecht, The Netherlands, 1988. (5) Connors, K. A. Chem. ReV. 1997, 97, 1325 and references therein. (6) Cramer, F.; Saenger, W.; Spatz, H.-Ch. J. Am. Chem. Soc. 1967, 89, 14. (7) Rohrbach, R. P.; Rodrigues, L. J.; Erying, E. M.; Wojcik, J. F. J. Phys. Chem. 1977, 81, 944. (8) Berjeron, R. J.; Channing, M. A.. J. Am. Chem. Soc. 1979, 101, 2511. (9) Hersey, A.; Robinson, B. H.; Kelly, H. C. J. Chem. Soc., Faraday Trans. 1 1986, 82, 1271. (10) Schiller, R. L.; Lincoln, S. F.; Coates, J. H. J. Chem. Soc., Faraday Trans. 1 1987, 83, 3237 and references therein. (11) (a) Yoshida, N.; Fujimoto, M. J. Phys. Chem. 1987, 91, 6691. (b) Yoshida, N.; Seiyama, A.; Fujimoto, M. J. Phys. Chem. 1990, 94, 4246 and references therein. (12) Bugnon, P.; Lye, P. G.; Abou-Hamdan, A.; Merbach, A. E. Chem. Commun. 1996, 2787. (13) Yoshida, N.; Hayashi, K. J. J. Chem. Soc., Perkin Trans. 2 1994, 1285. (14) Thomason, H. M.; Wyn-Jones, E. J. Chem. Soc., Faraday Trans. 1990, 86, 1511. (15) Yoshida, N. J. Chem. Soc., Perkin Trans. 2 1995, 2249. (16) (a) Liao, Y.; Frank, J.; Holzwarth, J. F.; Bohne, C. J. Chem. Soc., Chem. Commun. 1995, 199. (b) Liao, Y.; Bohne, C. J. Phys. Chem. 1996, 100, 734. (17) Inoue, Y. Annu. Rep. NMR Spectrosc. 1993, 27, 59. (18) (a) Saito, H.; Yonemura, H.; Nakamura, H.; Matsuo, T. Chem. Lett. 1990, 65, 535. (b) Watanabe, M.; Nakamura, H.; Matsuo, T. Bull. Chem. Soc. Jpn. 1992, 65, 164. (19) Yonemura, H.; Kasahara, M.; Saito, H.; Nakamura, H.; Matsuo, T. J. Phys. Chem. 1992, 96, 5765.
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