Old Drugs, New Tricks: The Effect of Molecule−Ion ... - ACS Publications

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Old Drugs, New Tricks: The Effect of Molecule-Ion Interactions on the Precipitation-Dissolution Equilibrium of Lithium Carbonate in Aqueous Solution and on the Chiral Recognition of Cyclodextrins to D-,L-Tryptophan Le Xin Song* and Lei Bai Department of Chemistry, UniVersity of Science and Technology of China, Hefei, 230026, Anhui, China ReceiVed: March 18, 2009; ReVised Manuscript ReceiVed: June 27, 2009

In the present work, the influence of molecule-ion interactions on the precipitation-dissolution equilibrium of a typical inorganic drug, lithium carbonate (Li2CO3), in water and on the chiral recognition behaviors and binding abilities of R-, β-, γ-, and heptakis(2,6-di-O-methyl)-β-cyclodextrin (CD) to D- and L-tryptophan (Trp) was investigated. Our results revealed that the solubility of Li2CO3 was increased to a large extent and the phase solubility diagram of Li2CO3 belonged to the AN type. This finding provided a new insight into the link between molecule-ion interactions and precipitation-dissolution equilibriums of poorly dissolving inorganic salts. Furthermore, despite having a negative effect on the isomer recognition behaviors, the molecule-ion interaction between CDs and Li2CO3 effectively increased the binding abilities of these CDs to both D- and L-Trp synchronously. The observation gave an important implication that buffer solutions consisting of inorganic salts are used with caution in molecular recognition fields between host and guest or between acceptor and donor. Further analyses confirmed the interaction among Li2CO3, β-CD, and L-Trp using an electrospray ionization mass spectrum. Introduction Possessing a hydrophobic cavity, cyclodextrins (CDs) (Figure 1A) can interact with a variety of guest molecules.1-3 Because of this, they are widely used in various fields, such as pharmaceutical chemistry, organic synthesis, catalysis, molecular recognition, and so on.4-7 On the one hand, studies concerning the effect of CDs on the solubility of poorly dissolving organic drugs in water have attracted much attention in past decades.8-10 The improvement of the solubility of organic drugs in the presence of CDs is ascribed to the intermolecular complexation of CDs to the drug molecules. On the other hand, although the molecule-ion interaction between CDs and some inorganic ions, as well as the improvement of the interaction for the solubility of CDs, has been reported,11,12 the influence of the interaction on the solubility of inorganic salts has not been investigated to date. The current work attempts to quantify the effect of the use of the interaction on the solubilization of inorganic salts in water, aiming at examining whether and how such an interaction alters the equilibrium between precipitation and dissolution of poorly dissolving inorganic salts. Further, various buffer solutions consisting of inorganic salts have been introduced into the systems of host-guest inclusion complexation or molecular recognition.13,14 However, it is not clear what is the interplay between inorganic salts and host-guest intermolecular interactions. The other object of the present work is to evaluate the effect of the presence of inorganic salts on the binding ability and molecular recognition level of CDs to a pair of chiral isomers. Accordingly, lithium carbonate (Li2CO3), an important inorganic drug, is chosen as the representative of inorganic salts for the convenience of phase solubility measurements. The * To whom correspondence should be addressed. E-mail: solexin@ ustc.edu.cn.

Figure 1. Structural features of CDs (A) and Trp (B).

liquid-solid solubility study indicates that Li2CO3 is significantly solubilized by β-CD at room temperature. Interestingly, despite having a negative influence on the isomer recognition behaviors of R-, β-, γ-, and heptakis(2,6-di-O-methyl)-β-CD (DMβ-CD), the molecule-ion interaction between the CDs and Li2CO3 effectively improves the binding abilities of the CDs to both D- and L-tryptophan (Trp, Figure 1B) synchronously. Besides, a 1:1:1 ternary supramolecular complex of Li2CO3, β-CD, and L-Trp was observed in an electrospray ionization mass spectrum (ESI-MS), further demonstrating the interaction among these components. This work adds a very important dimension to the shift of the precipitation-dissolution equilibrium of poorly dissolving inorganic salts from a new perspective. Meanwhile, although Li2CO3 and Trp are only one of numerous inorganic salts and organic compounds, respectively, our approach will give us a new insight into the connection between molecule-ion interactions and molecular recognition. Experimental Section Materials. R-CD was purchased from Nihon Toshin Chemical Company. β-CD was purchased from Shanghai Chemical Reagent Company and recrystallized twice from deionized water. γ-CD and DMβ-CD were kindly donated by Harata. Dand L-Trp are chromatographic grade and used without further purification. Li2CO3 was purchased from Shanghai Guanghua

10.1021/jp902456h CCC: $40.75  2009 American Chemical Society Published on Web 07/31/2009

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TABLE 1: Initial Mass (MI) of Li2CO3 in an Aqueous Solution of β-CD (8.15 × 10-3 mol · dm-3) at Different Temperatures (T) T/K MI/g

293.2 0.480

303.2 0.468

313.2 0.456

323.2 0.432

333.2 0.405

343.2 0.365

TABLE 2: MI of Li2CO3 in Aqueous Solutions of Various Concentrations (C) of β-CD at 298.2 K C/10-3 mol · dm-3 MI/g

0.82 0.350

2.04 0.395

4.08 0.420

8.15 0.450

12.00 0.460

Technology Company and recrystallized from deionized water before use. Sodium carbonate (Na2CO3) was purchased from Shanghai Chemical Factory. Lithium hydroxide monohydrate (LiOH · H2O), lithium sulfate monohydrate (Li2SO4 · H2O), lithium perchlorate trihydrate (LiClO4 · 3H2O), ammonium carbonate [(NH4)2CO3], and potassium carbonate (K2CO3) were purchased from Sinopharm Chemical Reagent Co., Ltd. Lithium chloride monohydrate (LiCl · H2O) and lithium nitrate (LiNO3) were purchased from Shanghai Hengxin Chemical Reagent Co., Ltd. All other chemicals were of general purpose reagent grade unless otherwise stated. Phase Solubility Studies. An aqueous solution of β-CD with a concentration of 8.15 × 10-3 mol · dm-3 was prepared. For each 20 mL of the solution, an excessive quantity of Li2CO3 (see Table 1) was added and stirred vigorously for 3 h at 293.2, 303.2, 313.2, 323.2, 333.2, and 343.2 K using oil bath heating. After standing for a few minutes, the upper solution was removed. Every residue was placed in a desiccator over P2O5 under vacuum at room temperature for 3 h and then transferred to a drying cabinet at 393.2 K for 6 h in vacuum. After the heat/vacuum treatment, samples were analyzed using an elemental analyzer. Further, the solutions of β-CD with concentrations of 8.20 × 10-4, 2.04 × 10-3, 4.08 × 10-3, 8.15 × 10-3, and 1.20 × 10-2 mol · dm-3 were prepared. Each 20 mL of the solution with different concentrations was used to interact with an excessive quantity of Li2CO3 (see Table 2) at 298.2 K for 3 h. Every residue was dried under the same conditions as described above and then analyzed using an elemental analyzer. Binding Behaviors of r-, β-, DM β-, and γ-CD to D-,LTrp in the Absence and Presence of Li2CO3. (1) For the interaction between Li2CO3 and D-,L-Trp in aqueous solution, the initial concentrations of D- and L-Trp were held constant at 2.00 × 10-5 mol · dm-3 and the concentration of Li2CO3 varied from 0.00 to 9.00 × 10-3 mol · dm-3. (2) For the interaction between Li2CO3 and D- and L-Trp in aqueous solution under various concentrations of β-CD, the initial concentrations of Dand L-Trp were held constant at 2.00 × 10-5 mol · dm-3 and the concentration of β-CD varied from 0.00 to 4.00 × 10-3 mol · dm-3 in the absence and presence of Li2CO3 (1.00 × 10-3 mol · dm-3). Instruments and Methods. Elemental analyses were carried out to determine the elemental contents (C, H) in the solid samples from phase solubility measurements by using an elemental analyzer (Vario EL III, Germany). Fluorescence experiments were performed on a SLM-Aminco AB-2 spectrofluorimeter (SLM Instruments) using a quartz cuvette of 5 mm path length with excitation and emission slit widths of 5 nm at 298.2 K. A sample solution containing L-Trp, Li2CO3, and β-CD with the same concentration of 1.00 × 10-5 mol · dm-3 in deionized water was prepared and analyzed by ESI-MS. Before use, the sample was kept for 40 min under ultrasonic vibration at room

Figure 2. Schematic diagram illustrating the solubilization of Li2CO3 by β-CD.

temperature. ESI-MS was recorded on a LTQ linear ion-trap mass spectrometer produced by ThermoFisher Scientific. The sample solution was injected via a syringe pump at a rate of 1-3 µL · min-1. The nebulizer gas was nitrogen, and the ion spray voltage was 5 kV. Results and Discussion Solubility of Li2CO3 in the Presence of a Constant Concentration of β-CD at Different Temperatures. One of the most important applications of CDs is to increase the solubility of drugs in the pharmaceutical field.15-17 The comprehensiveness of the data available enables evaluation of the various analysis methods by comparing the trends in the calculated solubility of drugs in the presence of CDs with the known trend of solubility against temperature in the absence of CDs.18,19 The solubility changes of numberless organic drugs due to addition of CDs have been reported so far.17,20,21 A recent study showed that σ-CD can improve the solubility of C70 in aqueous solution.22 However, most inorganic drugs have a weak or no spectral feature, such as UV-vis, 1H NMR, and fluorescence spectroscopy, in solution, so it is really a challenge to examine the solubility change of an inorganic drug, such as Li2CO3. In the present work, we attempt to use gravimetric determination to obtain the relationship between the solubility of Li2CO3 and the temperature of solution in the presence of the same concentration of β-CD, as well as the relationship between the solubility of Li2CO3 and the concentration of β-CD at the same temperature. Because the molecule-ion interaction between Li2CO3 and β-CD exists in aqueous solution and crystal water molecules may be removed expediently from the obtained damp samples under a severe drying condition, the results of elemental analysis can be applied to determine the content of β-CD in the dried solid samples. As a result, the extra solubility of Li2CO3 in β-CD solutions can be estimated exactly. As described in the Experimental Section, Figure 2 further illustrates some salient features of the present analysis: (1) Upon addition of β-CD, the solid-liquid equilibrium of Li2CO3 in pure water is destroyed immediately. (2) The solubilization of Li2CO3 by β-CD due to the molecule-ion interaction will cause the equilibrium shift in the direction of dissolution. (3) After vacuum-drying, the obtained damp samples are dried in an oven under vacuum at 393.2 K to a constant weight; solid samples are weighed. (4) On the basis of the results of elemental analysis, the mass of β-CD in the solid samples is calculated. (5) The solubility of Li2CO3 (S, g/100 mL of water with β-CD) is determined by the difference between the initial mass of Li2CO3 in the β-CD solution and the residual mass of Li2CO3 in the dried solid samples. The calculation equations are given as follows:

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MI ) MU + (VI × S)

(1)

MD ) MU + MW + Mβ-CD + (VD × S)

(2)

where MI and MU represent the initial mass of Li2CO3 used and the mass of undissolved Li2CO3 in the β-CD solution, respectively. MD is the total mass of the damp residue, which consists of MU, the mass of a little water inside the damp sample (MW), dissolved Li2CO3 in the water (VD × S), and dissolved β-CD in the water. VD and VI represent the volume of the little water inside the damp sample and the initial volume of water, respectively. Mβ-CD is determined based on the content of hydrogen from elemental analysis. VD is calculated by the solubility of pure β-CD, and MW is determined based on the value of VD. The solubility of Li2CO3 at different temperatures (T, K) at a constant concentration of β-CD (8.15 × 10-3 mol · dm-3) is depicted in Figure 3, line A. Additionally, the plot of the solubility of Li2CO3 in 100 mL of water without β-CD at corresponding temperatures is shown in Figure 3, line B.23 Clearly, the solubility of Li2CO3 is increased to a considerable extent by adding β-CD at each temperature, especially at lower and higher temperatures, such as at 293.2 and 343.2 K. The increase of solubility in the middle temperature range from 303.2 to 333.2 K is relatively moderate in comparison with the two ends of the curve. These phenomena reflect that the molecule-ion interaction between β-CD and Li2CO3 is closely related to temperature changes of solutions. Unlike the situation without β-CD, the effect of temperature on the solubility of Li2CO3 with β-CD exhibits a decreasing trend with the increase of temperature. The result provides direct evidence of the fact that the molecule-ion interaction leads to the solubilization of Li2CO3 by β-CD, to a certain extent, in the temperature range from 293.2 to 343.2 K. Undoubtedly, it is necessary to further examine the relationship between the solubility of Li2CO3 and the concentration of β-CD. Solubility of Li2CO3 in the Presence of Various Concentrations of β-CD at 298.2 K. From the limited data available, the complexes formed by CDs with inorganic salts are considerably unstable because the reported formation constants less than 100 mol-1 · dm3 indicate that the molecule-ion interactions are rather weak in aqueous solution.24-26 To understand the actual performance of the interactions, we describe the solubility change of Li2CO3 in aqueous solution with various concentrations of β-CD in Figure 4. Clearly, the pink curve in the inset of the figure shows that the solubility of Li2CO3 increases with increasing concentration of β-CD. According to the description of Uekama and his co-workers,27 the phase solubility diagram of Li2CO3 in the presence of β-CD belongs to the AN type because the dark cyan curve deviates negatively from the orange line. The AN type is considered to be a rather complicated system possibly because those complexes or adducts formed in the system have different stoichiometries and solutes may have an intensive interaction with the solvent.27,28 To all appearances, this is in good accordance with the property of Li2CO3 in an aqueous solution of β-CD. Li2CO3 (1.54 g/100 mL of water) has a slightly lower solubility than that of β-CD (1.85 g/100 mL of water) at room temperature.1b,23 When Li2CO3 is dissolved in the water with β-CD, it may exist in two forms. One is the free Li+ and CO32- surrounded by polar water molecules, and the other is the unfree Li+ and CO32- bound by hydroxyl groups or cavities of β-CD molecules. The latter has been confirmed

Figure 3. Solubility of Li2CO3 in 100 mL of water with β-CD (8.15 × 10-3 mol · dm-3) (A) and without β-CD (B).28

Figure 4. Solubility (S, mol · dm-3) of Li2CO3 in solution with various concentrations of β-CD at 298.2 K.

by the observations from 1HNMR and may be influenced or dominated by the addition of β-CD. At the beginning of the increase of β-CD, the solubility of Li2CO3 almost increases in a good linear manner (correlation coefficient for the left four points, 0.994). However, when the concentration of β-CD is further enhanced, the solubility increase of Li2CO3 becomes less steep after the concentration of β-CD reaches a certain concentration (3.45 × 10-3 mol · dm-3 in Figure 4). This is likely involved in the increase of other interactions, such as the intermolecular interaction between β-CD molecules, which can weaken the binding behavior between β-CD and Li2CO3. It is worth mentioning that pH values in the samples are all about 12.7. Accordingly, the influence of pH on the equilibrium shift of precipitation and dissolution of Li2CO3 in the presence of β-CD is negligible. In short, the solubilization of Li2CO3 by β-CD is closely associated with changes of temperature and concentration of β-CD. This will open up the possibility to enrich and develop the theoretical base and applicatory methods to understand the shift of the precipitation-dissolution equilibrium of poorly dissolving inorganic salts because Li2CO3 is only one of numerous inorganic salts with a relatively low solubility in water. Influence of Li2CO3 on Fluorescence Spectra of D-,L-Trp in Solution. So far, several scholars have elaborately studied ternary inclusion systems, that is, a CD as host; an organic compound as guest; and a third component, such as solvents, small organic molecules, and inorganic salts.13a,29,30 However, most of the studies focused on the effect of the third component on the spectral properties of organic guests in the presence of CDs and, according to this, discussed the interaction between hosts and guests.31,32 Whether and how does the existence of inorganic salts influence the spectral behaviors of the guests without CDs? The current study investigates the fluorescence variations of L-Trp in the presence of Li2CO3 in the first place, and the results are shown in Figure 5.

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Figure 5. Fluorescence spectra of L-Trp (2.00 × 10-5 mol · dm-3) upon addition of Li2CO3 (0.00-9.00 × 10-3 mol · dm-3 from a to i).

Li2CO3 has no fluorescence in the wavelength range from 290 to 500 nm, but D- and L-Trp show medium fluorescence intensity. As can be seen from Figure 5, the presence of Li2CO3 in solution produces a red shift of the λmax of L-Trp from 353.6 to 362.0 nm and a notable increase in signal intensity at the same time in the specific concentration range. When the concentration of Li2CO3 increases to 6.00 × 10-3 mol · dm-3, the fluorescence intensity of L-Trp reaches a peak value of 767 units, with a small fluctuation. Previously, it had been reported that some transition-metal ions, such as Cu2+, Fe3+, and Mo4+, tend to quench the fluorescence intensity of L-Trp, but the increase of pH has a positive contribution to the fluorescence intensity.33 Li2CO3 is a strong base in water; therefore, the enhancement of the fluorescence intensity of L-Trp can be caused by the increase of pH in solution. A similar situation also occurs in the system of D-Trp and Li2CO3. This is because the pH values of the solutions vary from 6.2 to 10.6, corresponding to the concentration of Li2CO3 from 0.00 to 9.00 × 10-3 mol · dm-3. In the case of higher pH solutions, where a plurality of Trp is present in an anion form (see eq 3), they can be more efficiently connected by intramolecular or intermolecular hydrogen bonds, leading to the molecular transformation of Trp.

-COOH + OH- f -COO- + H2O

(3)

The structural transformation may be responsible for the change of fluorescence spectra. For instance, Nishikawa and his co-worker found that the ultrasonic absorption of L-isoleucine after included by β-CD at higher pH values was intensified. They suggested that the proton-transfer reaction was responsible for promoting the intermolecular complexation.34 A complementary experiment is performed to investigate the effect of pH on the fluorescence intensity of Trp. The result indicates that, when Li2CO3 is substituted by LiOH to mediate the pH adjustment process from 6.2 to 10.6, the fluorescence intensity of Trp increases with increasing pH value, but the increase extent is much smaller in the LiOH-Trp system than that in the Li2CO3-Trp system at the same pH. This difference is ascribed to the fact that different ion strengths lead to different molecule-ion interactions between inorganic ions and Trp. Consequently, the molecule-ion interaction has an important influence on the fluorescence intensity of Trp. Optical Isomer Recognition of D-,L-Tryptophan by r-, β-, γ-, and Heptakis(2,6-di-O-methyl)-β-CD in the Absence and Presence of Li2CO3. Molecular recognition has been extensively studied in the recent two decades because of its application in many aspects. Inoue, Liu, and their co-workers have done excellent work in assessing the recognition behaviors of CDs to organic guests, such as chiral amino acids.14a,35,36

Figure 6. Fluorescence spectral changes of (A) D-Trp (2.00 × 10-5 mol · dm-3) and (B) L-Trp (2.00 × 10-5 mol · dm-3) in the presence of Li2CO3 (1.00 × 10-3 mol · dm-3, pH ) 10.4) upon addition of β-CD (0.00-4.00 × 10-3 mol · dm-3 from a to g).

As is evident from the descriptions in previous sections, there is an interaction between Li2CO3 and β-CD, as well as between Li2CO3 and Trp. Furthermore, it is reported that there exists different binding abilities of β-CD to D- and L-Trp, though the inclusion complexes of β-CD with them have a 1:1 chemical stoichiometry in solution.37-39 Herein, we investigate the fluorescence variations of D-,LTrp with β-CD, as well as R-, γ-, and DMβ-CD, in the absence and presence of Li2CO3. Typical spectral changes upon addition of β-CD to a solution of D- or L-Trp (2.00 × 10-5 mol · dm-3) at a constant concentration of Li2CO3 (1.00 × 10-3 mol · dm-3) are plotted in Figure 6. As shown in Figure 6, the fluorescence titrations have brought to light an important phenomenon that the fluorescence intensity of D- or L-Trp gradually decreases with increasing concentration of β-CD with Li2CO3. This must be mediated through the change of the surrounding of the Trp molecules because the penetration of Li2CO3 into the solvation shell leads to a more polar surrounding. The fluorescence intensity decrease of Trp implies that it has experienced an environment transition in the mixed solution of β-CD and Li2CO3. Clearly, the structural suitability between the indole ring of Trp and the hydrophobic intracavity of β-CD plays an important role in this transition process. The result can be due to the intermolecular interaction between β-CD and Trp, by which Trp releases from the aqueous phase with a highly polar environment. To understand the role of Li2CO3 in the molecular recognition, the binding constants (K) of the four CDs to D- or L-Trp are determined based on eq 4:40

(F0 - Fi)-1 ) {(F0 - F∞) · K · [CD]i}-1 + (F0 - F∞)-1 (4) where F0 and Fi are the fluorescence intensities of D- or L-Trp in the absence (blank) and presence of β-CD, respectively; F∞ is the fluorescence intensity of the inclusion complexes of D-

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Figure 7. Binding constants of CDs to D- and L-Trp without and with Li2CO3.

Figure 8. Proposed intramolecular hydrogen bond in the Trp molecule at a higher pH.

or L-Trp with CDs, and [CD]i is the concentration of CDs after each addition. The values of K are shown in Figure 7. As can be seen from Figure 7, the binding abilities of the CDs to D-Trp and L-Trp in the absence of Li2CO3 decrease in the order γ- > β- > R- > DMβ-CD and γ- > DMβ- > R- > β-CD, respectively, but in the presence of Li2CO3, they decrease in the same order γ- > β- > R- > DMβ-CD. All of the four CDs exhibit a bigger binding constant to L-Trp than to D-Trp in both the presence and the absence of Li2CO3. The molecular recognition behaviors (KL/KD) of the CDs decrease in the order DMβ- (17.1) > R- (7.92) > β- (4.47) > γ-CD (2.53) and DMβ(4.17) > R- (2.87) > β- (2.34) > γ-CD (1.97) in the absence and presence of Li2CO3, respectively. First, it is important to note that, in the presence of Li2CO3, the K values increase significantly and the order of them is the same: γ- > β- > R- > DMβ-CD for D- and L-Trp. Apparently, Li2CO3 has a remarkably positive effect on the inclusion interaction between CDs and Trp. When Li2CO3 is introduced in the inclusion systems, the pH values of the solutions increase sharply. The higher polar environment in water makes the indole ring of Trp more preferable to be in the cavities of the CDs. Besides, it was reported that Li+ ions preferred to coordinate to OH groups rather than to ether oxygens,41 especially the primary hydroxyl groups at the narrower rim of the cavities.35 This would result in the decrease of cavity polarity and makes those included indole rings difficult to freely escape the cavities from the top or from the bottom, leading to the increase of the relative fluorescence intensity of Trp in the presence of Li2CO3 with increasing concentration of β-CD. On the other hand, the presence of Li2CO3 weakens the structural selectivity of these CDs toward D- and L-Trp because the values of KL/KD decrease markedly in comparison with those of KL/KD in the absence of Li2CO3. It was found that the structures of guests have a direct impact on the recognition efficiency of the system of guest-CDs.34 Trp at a higher pH is in the form of the anion type, -COO-. This would be in favor of the formation of a more rigid structure through the intramolecular hydrogen bond illustrated in Figure 8. The structural rigidity reduced the conformational difference of the chiral carbon atom between D- and L-Trp. We suggest that this may be the reason why the lower recognition coefficients (KL/KD) were observed in the presence of Li2CO3. It is important to note that the molecular recognition behaviors of the four CDs to D-

Figure 9. Difference of fluorescence intensity (∆F) of D-Trp (2.00 × 10-5 mol · dm-3) and L-Trp (2.00 × 10-5 mol · dm-3) in the presence of a series (1.00 × 10-3 mol · dm-3) of carbonates (A) and lithium salts (B) with β-CD (2.00 × 10-3 mol · dm-3).

and L-Trp are evaluated at the same pH values due to the fact that the value of pH also does not change with the addition of CDs. This is because the concentration of Trp (2.00 × 10-5 mol · dm-3) or Li2CO3 (1.00 × 10-3 mol · dm-3) in the systems is held at the same value. Further, the three native CDs have a weaker isomer selectivity toward D-Trp and L-Trp than that of DMβ-CD. This should be attributed to the fact that fourteen hydroxyls of β-CD are replaced by methoxy groups, implying that the interaction of Li+ · · · O-CH3 has a larger positive effect on the formation and stability of D-Trp-DMβ-CD than on the formation and stability of L-Trp-DMβ-CD. In a word, the results indicate that the three native CDs display a relatively weak recognition level when compared with that of the modified β-CD even if some of them have a bigger binding ability to both D- and L-Trp. For example, γ-CD shows the strongest binding ability to both D-Trp and L-Trp without or with Li2CO3, but the poorest recognition ability among the CDs. Li2CO3 has a remarkably positive effect on the binding behaviors of the CDs to D- or L-Trp, but it weakens the structural selectivity of them to D- and L-Trp. It is worthy of note that the influence of other inorganic salts on the molecular recognition systems of D- and L-Trp, as well as to other aromatic amino acids, deserves to be further investigated. Estimation of the Influence of Li+ and CO32- Ions as Well as pH Effect and Salt Effect on the Recognition Behavior of β-CD to Trp. A series of carbonates, such as (NH4)2CO3, Li2CO3, Na2CO3, and K2CO3, and lithium salts, such as LiCl, LiNO3, LiClO4, and Li2SO4, are employed to investigate which ion groups may play a significant role in the effect of the spectral difference between D- and L-Trp in the presence of β-CD. Figure 9 indicates the changes of the fluorescence intensity (∆F) of D-,L-Trp in the inclusion systems of β-CD between those with and without inorganic salts. Apparently, the presence of (NH4)2CO3 leads to the smallest difference of the fluorescence intensity between D- and L-Trp, but the existence of the other three carbonates, especially K2CO3, shows a much larger value of ∆∆F than those of the noncarbonates used. When cations are limited to Li+ ions, the ∆F values of D-,L-Trp as well as the ∆∆F value between them, in the case of Li2CO3, are

The Effect of Molecule-Ion Interactions

Figure 10. Fluorescence spectral changes of (A) D-Trp (2.00 × 10-5 mol · dm-3) and (B) L-Trp (2.00 × 10-5 mol · dm-3) in the presence of 2.51 × 10-4 mol · dm-3 LiOH (pH ) 10.4) upon addition of β-CD (0.00-5.00 × 10-3 mol · dm-3 from a to g).

obviously bigger than those in the case of the other four lithium salts, such as LiCl, LiNO3, LiClO4, and Li2SO4. Thus, it is concluded that CO32- ions play a more significant role in the recognition behavior of Trp with CDs than that of Li+ ions, though the effect of the latter is also worth noting. Besides, the effect of ion strengths on the binding behavior of β-CD to Trp, in the case of the same pH but different mediums, that is, Li2CO3 and LiOH, is investigated. Typical spectral changes upon addition of β-CD to a solution of D- or L-Trp (2.00 × 10-5 mol · dm-3) at a constant pH of 10.4, corresponding to the concentration (2.51 × 10-4 mol · dm-3) of LiOH, are plotted in Figure 10. Initially, the K values of the binding systems of β-CD to Dand L-Trp in the presence of LiOH at pH 10.4 are determined to be 112.9 and 297.3 mol-1 · dm3, respectively. Obviously, both of them are smaller than those in the presence of Li2CO3 at the same pH. However, the molecular recognition behavior (KL/ KD, 2.63) of β-CD in the presence of LiOH is slightly bigger than that in the presence of Li2CO3 (KL/KD, 2.34). This result indicates that, at the same pH value, the ionic strength has a positive effect on the inclusion behavior but a negative influence on the recognition behavior because the ion strength of the solutions in the case of Li2CO3 is bigger than that in the case of LiOH at the same pH (10.4). Next, according to calculation, LiOH solutions with a concentration of 2.50 × 10-3 mol · dm-3 have the same ionic strength as Li2CO3 solutions with a concentration of 1.00 × 10-3 mol · dm-3. It should be noted that Li2CO3 is apt to hydrolyze in a neutral or alkaline aqueous medium. Therefore, its hydrolysis must be taken into account in the calculation of the total ion strength of solutions. The initial concentration of Li2CO3 is always 1.00 × 10-3 mol · dm-3, and the Ka of H2CO3 is 5.6 × 10-11. Therefore, the concentrations of Li+, HCO3-, CO32-, and OH- in solutions are determined to be 2.00 × 10-3, 4.15 × 10-4, 5.85 × 10-4, and 2.51 × 10-4 mol · dm-3 based on the hydrolysis equilibrium between CO32- and HCO3-. Additionally, the total ion strength is calculated to be 2.51 × 10-3 mol · dm-3 by the concentrations and charges of these ions. The K values for the binding systems of D-Trp-β-CD and

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Figure 11. Fluorescence spectral changes of (A) D-Trp (2.00 × 10-5 mol · dm-3) and (B) L-Trp (2.00 × 10-5 mol · dm-3) in the presence of 2.50 × 10-3 mol · dm-3 LiOH with the same ionic strength as in the case of Li2CO3 (1.00 × 10-3 mol · dm-3) upon addition of β-CD (0.00-5.00 × 10-3 mol · dm-3 from a to g). L-Trp-β-CD in the presence of LiOH with the same ion strength as in the case of Li2CO3 but different pH (11.0) are determined to be 152.7 and 327.8 mol-1 · dm3. Typical spectral changes upon addition of β-CD to a solution of D- or L-Trp (2.00 × 10-5 mol · dm-3) in the presence of LiOH with a concentration of 2.50 × 10-3 mol · dm-3 (pH ) 11.0) are plotted in Figure 11. The values of K show that β-CD has a stronger binding ability in the case of LiOH with a concentration of 2.50 × 10-3 mol · dm-3 (pH ) 11.0) than that in the presence of 1.00 × 10-3 mol · dm-3 Li2CO3 (pH ) 10.4), but the molecular recognition ability of β-CD to L- and D-Trp slightly decreases (KL/KD, 2.15). The result suggests that the increase of pH plays an important role in affecting the binding ability and recognition behavior of the host. In conclusion, the present work demonstrates that both pH effect and salt effect have a considerable impact on the intermolecular interaction between host and guest. As numerous complexation studies are performed in buffer solution, this work demonstrates indirectly that the presence of inorganic salts in the medium should be carefully considered. Formation of the Supramolecular Complex of Li2CO3, β-CD, and L-Trp under ESI-MS Conditions. ESI-MS is a useful method to investigate the formation possibility of CD inclusion compounds during the nebulization process.42,43 Figure 12 shows the ESI mass spectrum of the ternary system of Trp, Li2CO3, and β-CD using deionized water as solvent. Clearly, there is a strong molecule-ion peak at m/z ) 1416.09, corresponding to the formation of the ternary supramolecular adduct (CO32-) · (L-Trp) · (β-CD) · H2O under the conditions of ESI-MS. This result provides direct evidence that there exists a molecular-ion interaction among the three components. The fact that there are no other peaks with an RA of more than 50%, in comparison with that of the supramolecular ion (CO32-) · (LTrp) · (β-CD) · H2O in the range from 840 to 1440 m/z, indicates

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Figure 12. ESI mass spectrum of the ternary system of Trp, Li2CO3, and β-CD using deionized water as solvent (RA, relative abundance).

that the formation of the ternary complex is dominant, rather than other forms, such as β-CD itself, its hydrates, and binary complexes (L-Trp-β-CD and β-CD-CO32-), which is different from the reported results in binary inclusion systems between CDs and amino acids or between CDs and inorganic salts.42b Conclusions In present work, we first illustrated the phase solubility diagrams of an inorganic salt, Li2CO3, in the presence of β-CD. Our results revealed that the solubility of Li2CO3 was increased to a large degree by the molecule-ion interaction and the phase solubility diagram of Li2CO3 belonged to the AN type. Besides, the differences in binding abilities and structural selectivities of R-, β-, γ-, and DMβ-CD to D- and L-Trp in the absence and presence of Li2CO3 were carefully compared based on the values of KL and KD as well as their ratio values. Despite having a negative influence on the isomer recognition behaviors, Li2CO3 effectively increased the binding abilities of the four hosts to both D- and L-Trp synchronously. In these processes of inclusion or recognition between host and guest, CO32- ions seemed to play a more significant role than that of Li+ ions, though the effect of the latter was also worth noting. In addition, both pH effect and salt effect had a considerable impact on the intermolecular interaction between host and guest. Further, the ESI-MS result illustrated the existence of the molecule-ion interaction among Li2CO3, β-CD, and L-Trp. Acknowledgment. We acknowledge the funding support received for this research project from the Innovation Foundation of Graduate Students in University of Science and Technology of China (KD 2008020), Natural Science Foundation of Anhui Province (No. 090416228). References and Notes (1) (a) Szejtl, J. Chem. ReV. 1998, 98, 1743–1753. (b) Connors, K. A. Chem. ReV. 1997, 97, 1325–1357. (c) Song, L. X.; Teng, C. F.; Wang, H. M.; Bai, L. Chin. J. Chem. Phys. 2008, 21, 174–180. (2) (a) Villalonga, R.; Cao, R.; Fragoso, A. Chem. ReV. 2007, 107, 3088–3116. (b) Song, L. X.; Wang, H. M.; Yang, Y.; Xu, P. Bull. Chem. Soc. Jpn. 2007, 80, 2185–2195. (c) Song, L. X.; Xu, P. J. Phys. Chem. A 2008, 112, 11341–11348. (d) Marques, J.; Anjo, L.; Marques, M. P. M.; Santos, T. M.; Almeida Paz, F. A.; Braga, S. S. J. Organomet. Chem. 2008, 693, 3021–3028. (3) (a) Liu, L.; Guo, Q. X. J. Inclusion Phenom. Macrocyclic Chem. 2002, 42, 1–14. (b) Xu, P.; Song, L. X.; Wang, H. M. Thermochim. Acta 2008, 469, 36–42. (c) Breslow, R.; Dong, S. D. Chem. ReV. 1998, 98, 1997– 2011. (d) Song, L. X.; Bai, L.; Xu, X. M.; He, J.; Pan, S. Z. Coord. Chem. ReV. 2009, 253, 1276–1284. (4) (a) Yang, C.; Mori, T.; Origane, Y.; Ko, Y. H.; Selvapalam, N.; Kim, K.; Inoue, Y. J. Am. Chem. Soc. 2008, 130, 8574–8575. (b) Hedges, A. R. Chem. ReV. 1998, 98, 2035–2044. (c) Song, L. X.; Wang, H. M.; Guo, X. Q.; Bai, L. J. Org. Chem. 2008, 73, 8305–8316. (5) (a) Hapiot, F.; Leclercq, L.; Azaroual, N.; Fourmentin, S.; Tilloy, S.; Monflier, E. Curr. Org. Synth. 2008, 5, 162–172. (b) Nishimura, D.;

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