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Experimental and Model Study on Separation of α‑Cyclopentylmandelic Acid Enantiomers by Liquid−Liquid Extraction Kewen Tang, Xiaofeng Feng, Panliang Zhang,* and Weifeng Xu* Department of Chemistry and Chemical Engineering, Hunan Institute of Science and Technology, Yueyang 414006, Hunan China ABSTRACT: Liquid−liquid extraction (LLE) was used for the resolution of α-cyclopentylmandelic acid (α-CPMA) enantiomers, in which environmentally friendly and economical hydroxyethyl-β-cyclodextrin (HE-β-CD) was screened as the optimal selector. The mechanism on equilibrium of the separation system was proposed. Influence of important parameters on the separation performance of αCPMA enantiomers were investigated (e.g., kinds of solvents for the organic phase, types and concentration of selector, pH of extraction phase, temperature). On the basis of the mechanism proposed, a quantitative model was also built to simulate the separation process. Results show that the model predicts the experimental data accurately and it is further used for optimizing the separation process. The optimized process conditions consist of 1,2dichloroethane as organic solvent, pH = 2.5 and the extractant concentration of 0.04 mol·kg−1. Under the optimum conditions, the enantioselectivity toward α-CPMA enantiomers is over 1.70 and performance factor is 0.07.

1. INTRODUCTION The growing demand of the pharmaceutical and chemical industries for enantiomerically pure compounds has spurred the development of new chiral separation techniques. Diverse enantiomers often show different influence on biological activity, pharmacokinetic profiles, and on toxic side effect.1 Since 1992, the U.S. Food and Drug Administration have issued a guideline that the pharmaceutical companies must provide clear pharmacology and toxicity justification for both enantiomers before a new drug is marketed.2 Therefore, separating the racemic mixture to obtain their individual enantiomers is of much importance. During the past two decades, the separation of chiral active substances has been reported in the literature worldwide.3 Numerous novel and outstanding methods, such as chromatographic technologies,4,5 kinetic resolution,6 liquid membrane techniques,7,8 capillary electrophorsis techniques,9,10 and crystallization,11,12 have been developed. These methods promote the development of chiral separation technologies for racemic compounds, but there are some shortcomings unsolved. Chromatoygraphy and capillary electrophoresis techniques have strong separation ability, but the high consumption and low throughput hamper the adhibition of both techniques. The low product yield and need of enzymecatalyzer are the main limitation for the kinetic resolution technology. Liquid membrane techniques are not always applicable on the account of their limited mass transfer flux. Crystallization is a mature technique, but the operation is very complex and the yields are poor. Compared to the above methods, LLE may be the greatest potential technique for largescale application, because of its convenient for continuous operation and easy to implement industrial production. © 2016 American Chemical Society

Recently, great contributions have been made to the development of liquid−liquid extraction.13−17 However, the reports on fundament of engineering design and operation are rare. The extractant is required to recognize the enantiomers in LLE system. Schuur et. al has summarized the kinds of extractants, such as tartrate assisted extractants, crown ethers based reactive extractants, and metal complexes and metalloids extractants.14 Limitations of these chiral selectors are their low versatility or low enantioselectivity and they are mainly used to separate hydrophilic substances but not appropriate for the separation of hydrophobic substances. Therefore, it is very essential to improve chiral extractant to recognize the hydrophobic substances. It is well known that hydrophilic βcyclodextrins can encapsulate variety of substances to form well-defined host−guest complexes and have been considered as a kind of promising hydrophilic chiral extractant for chiral extraction of hydrophobic substances on account of their special physicochemical properties and nontoxic side effects.18,19 Recently, using hydrophilic β-CDs as extractant for the resolution of enantiomers has been reported.15 Mandelic acid derivatives are widely used for synthesis of chiral drugs as important pharmaceutical intermediates. For example, α-cyclohexylmandelic acid is usually used as a significant chiral drug precursor to synthesize oxybutynin. Some reports on the chiral resolution of mandelic acid can be found, while the literatures about enantioseparation of αCPMA (Figure 1) enantiomers are limited, which are regularly about HPLC techniques and high speed counter-current Received: March 1, 2016 Accepted: July 20, 2016 Published: July 29, 2016 3090

DOI: 10.1021/acs.jced.6b00183 J. Chem. Eng. Data 2016, 61, 3090−3097

Journal of Chemical & Engineering Data

Article

were shaken sufficiently under temperature of 278 K for 12 h to reach equilibrium in a freezing thermostat oscillator (Huihong instrument Co. Ltd., Changsha, China). After stratifying, the determination of (R)-α-CPMA and (S)-α-CPMA concentrations in extraction phase were analyzed by HPLC, and those in raffinate were obtained by subtraction method. 2.3. Analytical Method. The determination of α-CPMA enantiomers concentrations in extraction phase were analyzed by HPLC (Waters e2695). The quantitive analysis is performed by UV−vis adsorption detector at the wavelength of 220 nm. An Inertsil ODS-3 C18 column (250 mm × 4.6 mm I.D., 5 μm) is employed and the column temperature is maintained at 298 K. The mobile phase consists of acetonitrile and 0.02 mol·kg−1 HP-β-CD aqueous solution (pH = 2.7), in which the volume ratio is 40:60.20 Other conditions are flow rate of 60 mL·h−1.

Figure 1. Chemical structure of α-CPMA.

chromatography method.20,21 These methods are well suitable for small amount of analysis and preparation, though they are not feasible for the large-scale preparation. Thus, developing a high-efficiency technology for large-scale production is of particular importance and highly desired. In this work, the LLE of α-CPMA enantiomers with hydroxyethyl-β-cylodextrin (HE-β-CD) as chiral extractant was performed in a two-phase extraction system. The effects of process variables on distribution of the enantiomers were studied. An equilibrium model for extraction of α-CPMA enantiomers was also developed to describe the extraction process and optimize the process factors to obtain the optimum extraction efficiency.

3. MECHANISM AND MODEL 3.1. Extraction Mechanism. The extraction mechanism is the basis of understanding the separation process and building the mathematical model. As we all know, reactions may take place either in the aqueous phase, the organic phase, or at the interface for the reactive extraction system.15 In this extraction system, β-CDs is insoluble in organic liquids due to its super hydrophilia; thus, the reactions may only occur either in the aqueous phase or at the interface. Additionally, the solutes of αCPMA enantiomers can partly be dissolved in both the two phases. Thus, a homogeneous reaction mechanism was assumed to research the present extraction system. Figure 2 shows the equilibrium of the reactive extraction system. Equilibrium of the system includes the physical

2. EXPERIMENTAL SECTION 2.1. Materials. The grades and suppliers of reagents are listed in Table 1. 2.2. Extraction Experiments. The extraction phase is obtained by charging β-CD derivatives in NaH2PO4/H3PO4 buffer and the organic phase is acquired by charging racemic αCPMA in organic solvent. Equal volumes of the two phases (3 mL) were placed into the centrifuge tube, respectively, and then Table 1. Specifications for Chemicals Used

chemical name αcyclopentylmandelic n-octanol dichloromethane n-heptanol butyl acetate isobutyl acetate 1,2-dichloroethane Me-β-CD CM-β-CD HP-β-CD HE-β-CD SBE-β-CD HPLC solvents

source

grade

purity by mass fraction

Beijing J&K Co. Ltd.

AR

98%

Hunan Huihong Reagent Co. Ltd. Hunan Huihong Reagent Co. Ltd. Shanghai Aladdin Industrial Inc. Hunan Huihong Reagent Co. Ltd. Hunan Huihong Reagent Co. Ltd. Hunan Huihong Reagent Co. Ltd. Shandong Zhiyuan Biotechnology Co. Ltd. Shandong Zhiyuan Biotechnology Co. Ltd. Shandong Zhiyuan Biotechnology Co., Ltd. Shandong Qianhui Biotechnology Co., Ltd. Shandong Qianhui Biotechnology Co., Ltd. Shanghai Meryer Chemical Technology Co., Ltd.

AR

98%

AR

99%

AR

99%

AR

99%

AR

98%

AR

99%

AR

98%

AR

98%

AR

98%

AR

98%

AR

98%

HPLC

99.9%

Figure 2. Possible mechanism for the chiral extraction of α-CPMA enantiomers by HE-β-CD. R = (R)-α-CPMA, S = (S)-α-CPMA, CD = HE-β-CD.

partition of molecular and ionic α-CPMA between the two phases, the inclusion complexation equilibrium between HE-βCD and α-CPMA enantiomers and the acid−base dissociation equilibrium of α-CPMA. The extraction efficiency can be evaluated by distribution ratio (k) and enantioselectivity (α), which are defined by eqs 1 to 3 kR = kS = α= 3091

C R,W C R,O

(1)

CS,W CS,O kS kR

(2)

assuming k S > kR

(3) DOI: 10.1021/acs.jced.6b00183 J. Chem. Eng. Data 2016, 61, 3090−3097


Article

Table 2. LLE Data for {(R)-α-Cyclopentylmandelic Acid (1) + (S)-α-Cyclopentylmandelic Acid (2) + Hydroxyethyl-βcyclodextrin (3) + Solvent (4)} Systems at pH = 2.5, 0.05 mol·kg−1 Hydroxyethyl-β-cyclodextrin in the Aqueous Phase, T = 278 K, and p = 0.1 MPa Along with Distribution Ratios, k, and Enantioselectivities, αa CS,W organic solvent

mol·kg

n-octanol dichloromethane n-heptanol butyl acetate isobutyl acetate 1,2-dichloroethane a

CS,O

0.094 1.055 0.059 0.075 0.062 1.093

× × × × × ×

−1

CR,W

mol·kg −3

10 10−3 10−3 10−3 10−3 10−3

2.316 0.457 2.379 2.192 2.203 0.494

× × × × × ×

−1

mol·kg −3

10 10−3 10−3 10−3 10−3 10−3

0.051 0.901 0.034 0.042 0.033 0.895

× × × × × ×

CR,O −1

mol·kg−1 −3

10 10−3 10−3 10−3 10−3 10−3

2.359 0.608 2.405 2.224 2.232 0.692

× × × × × ×

10−3 10−3 10−3 10−3 10−3 10−3

kS

kR

α

0.041 2.308 0.025 0.034 0.028 2.212

0.022 1.481 0.014 0.019 0.015 1.293

1.864 1.558 1.786 1.789 1.867 1.711

Standard uncertainties u are u(T) = 0.1 K, u(p) = 2 kPa, and u(pH) = 0.01.

Table 3. LLE Data for {(R)-α-Cyclopentylmandelic Acid (1) + (S)-α-Cyclopentylmandelic Acid (2) + β-Cyclodextrin Derivatives (3) + 1,2-Dichloroethane(4)} Systems at pH = 2.5, 0.05 mol·kg−1 β-Cyclodextrins Derivatives in the Aqueous Phase, T = 278 K, and p = 0.1 MPa Along with Distribution Ratios, k, and Enantioselectivities, αa CS,W β-CD derivatives

mol·kg

HP-β-CD HE-β-CD SBE-β-CD Me-β-CD CM-β-CD a

CS,O

0.707 1.093 0.935 1.036 1.056

× × × × ×

−1

CR,W

mol·kg −3

10 10−3 10−3 10−3 10−3

0.880 0.494 0.652 0.552 0.532

× × × × ×

−1

mol·kg −3

10 10−3 10−3 10−3 10−3

0.663 0.895 0.894 1.032 0.967

× × × × ×

CR,O −1

mol·kg−1 −3

10 10−3 10−3 10−3 10−3

0.924 0.692 0.693 0.556 0.620

× × × × ×

10−3 10−3 10−3 10−3 10−3

kS

kR

α

0.804 2.212 1.433 1.877 1.986

0.717 1.293 1.291 1.856 1.559

1.121 1.711 1.110 1.011 1.274


where CR,O/CS,O and CR,W/CS,W represent the total equilibrium concentrations of (R)-α-CPMA/(S)-α-CPMA in organic phase and aqueous phase, respectively. 3.2. Basic Equations. The thermodynamic equilibrium of this extraction system can be modeled on the basis of the following equations. Equations 4 and 5 are the physical partition coefficients of molecular and ionic α-CPMA respectively, where, [ ] represents the equilibrium concentration of the corresponding species; the subscript of W and O represents the concentrations in aqueous and organic phases, respectively15 [R ]W [S]W P0 = = [R ]O [S]O −

Pi =

eeW =

ϕR = ϕS =

[R−]W [H+] [S −]W [H+] = [R ]W [S]W

Equations 7 and 8 are the inclusion complexation equilibrium constants for (R)- and (S)-α-CPMA, respectively (7)

KS =

[(S)‐CD]W [S]W [CD]W

(8)

(10)

CS,W CS,int

(11) (12)

4. RESULTS AND DISSCUSSION 4.1. Organic Solvent Effect. In this LLE process, organic solvent can affect the stability of inclusion compounds formed by the enantiomers and the chiral extractant. For the purpose of selecting an optimal organic solvent for the extraction separation of α-CPMA enantiomers, preliminary screening experiments were performed in a series of extraction systems, where the HE-β-CD was used as extractant and the temperature was controlled at 278 K. Results show that distribution ratios and enantioselectivity are obviously influenced by the organic solvents as displayed in Table 2. When octanol, heptanol, butyl acetate, and isobutyl acetate are used, high enantioselectivity is acquired while distribution ratios are small. Both enantioselectivity and distribution ratios are comparatively higher with dichloromethane and 1,2-dichloroethane. Herein, 1,2-dichloroethane is selected as a preferred organic solvent for the extraction separation of α-CPMA enantiomers with comprehensive consideration of extraction performance (α, k) and ecofriendly properties.

(6)

[(R )‐CD]W [R ]W [CD]W

C R,int

where CR,int/CS,int is the initial concentration of (R)-/(S)-αCPMA to be added into the system.

(5)

KR =

(9)

C R,W

pfS = ϕSeeW

(4)

Equation 6 shows the acid-dissociation constant of α-CPMA. Ka =

CS,W + C R,W

The extraction fractions of (R)- and (S)-α-CPMA are given by

−

[R ]W [S ] = −W [R−]O [S ]O

CS,W − C R,W

The reactive extraction system is optimized aiming at enhancing the enantiomeric excess (ee), the fractions of solutes (Φ) and performance factor (pf). The definition of ee, Φ, and pf are shown in eqs 9−1215 3092



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Figure 3. Relationship between pH and separation efficiency (k, α). Data points, experimental data: ■ represents kS;● represents kR;▲ represents α. Solid lines: model predictions. Cα‑CPMA = 3.17 × 10−3 mol·kg−1 in 1,2-dichloroethane, CHE‑β‑CD = 0.05 mol·kg−1, T = 278 K, p = 0.1 MPa.

Figure 4. Relationship between extractant concentration and separation efficiency (k, α). Data points, experimental data: ■ represents kS; ● represents kR;▲ represents α. Solid lines: model predictions. Cα‑CPMA = 3.17 × 10−3 mol·kg−1 in 1,2-dichloroethane, pH = 2.5, T = 278 K, p = 0.1 MPa.

4.2. Influence of Extractant Types. The influence of extractant types (HP-β-CD, HE-β-CD, SBE-β-CD, Me-β-CD, and CM-β-CD) on the distribution ratios and enantioselectivity of α-CPMA enantiomers were investigated. Results show that all extractant studied have better discrimination ability for (S)α-CPMA than for (R)-α-CPMA because kS values are always higher than those of kR as displayed in Table 3. It can also be observed in Table 3 that the enantioselectivities are relatively lower though with relatively higher distributions when Me-βCD and CM-β-CD are employed as extractant. As HP-β-CD and SBE-β-CD are adopted as extractant, both the

enantioselectivity and distribution ratios are relatively low. Using HE-β-CD as extractant, both the enantioselectivity and distribution ratios are relatively high. Thus, HE-β-CD was screened as preferred extractant for the separation of α-CPMA enantiomers. 4.3. Influence of pH Value. According to the mechanism hypothesis, two host−guest complexes are formed between molecular α-CPMA and β-CD. However, the states of α-CPMA are obviously influenced by the pH value. Thus, the effect of pH on the distribution behavior should be studied to ensure the separation system kept in a suitable pH range. The relationship

Table 4. LLE Data for {(R)-α-Cyclopentylmandelic Acid (1) + (S)-α-Cyclopentylmandelic Acid (2) + Hydroxyethyl-βcyclodextrin (3) + 1,2-Dichloroethane(4)} Systems at T = 278 K, p = 0.1 MPa, 0.05 mol·kg−1 Hydroxyethyl-β-cyclodextrin in the Aqueous Phase, and Various pH Values Along with Distribution Ratios, k, and Enantioselectivities, αa CS,W pH 2.0 2.5 3.0 3.5 4.0 4.5 a

CS,O

mol·kg 1.074 1.093 1.098 1.036 1.122 1.173

× × × × × ×

−1

CR,W

mol·kg −3

10 10−3 10−3 10−3 10−3 10−3

0.513 0.494 0.489 0.552 0.466 0.414

× × × × × ×

−1

mol·kg −3

10 10−3 10−3 10−3 10−3 10−3

0.872 0.895 0.911 1.032 0.973 1.123

× × × × × ×

CR,O −1

mol·kg−1 −3

10 10−3 10−3 10−3 10−3 10−3

0.716 0.692 0.676 0.556 0.614 0.464

× × × × × ×

10−3 10−3 10−3 10−3 10−3 10−3

kS

kR

α

2.093 2.212 2.244 2.275 2.408 2.833

1.218 1.293 1.347 1.425 1.584 2.417

1.718 1.711 1.666 1.596 1.520 1.172

Standard uncertainties u are u(T) = 0.1 K and u(p) = 2 kPa. 3093



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Table 5. LLE Data for {(R)-α-Cyclopentylmandelic Acid (1) + (S)-α-Cyclopentylmandelic Acid (2) + Hydroxyethyl-βcyclodextrin (3) + 1,2-Dichloroethane(4)} Systems at pH = 2.5, T = 278 K, and p = 0.1 MPa, and Various Hydroxyethyl-βcyclodextrin Concentration Along with Distribution Ratios, k, and Enantioselectivities, αa CHE‑β‑CD mol·kg 0.02 0.04 0.05 0.06 0.08 0.10 a

CS,W

−1

CS,O −1

mol·kg × × × × × ×

0.786 1.045 1.093 1.036 1.122 1.173

CR,W

mol·kg −3

10 10−3 10−3 10−3 10−3 10−3

× × × × × ×

0.801 0.542 0.494 0.552 0.466 0.414

−1

mol·kg −3

10 10−3 10−3 10−3 10−3 10−3

× × × × × ×

0.603 0.846 0.895 1.032 0.973 1.123

CR,O −1

mol·kg−1 −3

10 10−3 10−3 10−3 10−3 10−3

0.984 0.742 0.692 0.556 0.614 0.464

× × × × × ×

10−3 10−3 10−3 10−3 10−3 10−3

kS

kR

α

0.982 1.927 2.212 2.521 3.278 4.075

0.613 1.140 1.293 1.501 1.913 2.427

1.602 1.690 1.711 1.680 1.714 1.679


chiral recognition ability of HE-β-CD toward molecular αCPMA rather than ionic α-CPMA. At pH ≤ 4, α-CPMA mainly exit in the form of molecule, whereas the molecular α-CPMA start to be ionized with the pH rising up and nonselective partition of α-CPMA anion results in a considerable augment of kR and kS and a rapid reduction of α. Thus, the pH value should be in a lower range (pH ≤ 2.5). 4.4. HE-β-CD Concentration Influences. The investigation of extractant concentration for distribution ratios and enantioselectivity is shown in Figure 4 and Table 5, in which the lines are the results of model simulation. The experimental data of kR, kS, and α are basically consistent with the model predictions. The mean relative deviations between model and experiment are 2.66% for kR, 2.75% for kS, and 1.09% for α. Figure 4a illustrates that kR and kS are in direct proportion to the extractant concentration. Figure 4b reveals that α increases rapidly and then slightly with the rising of the extractant concentration. The possible reason for the distribution ratio increased may be that, more and more host−guest compounds between HE-β-CD and α-CPMA are generated in the extractant phase with the rising of HE-β-CD concentration. In addition, the increase of HE-β-CD concentration may strengthen its recognition ability, which makes the enantioselectivity increase. 4.5. Influence of Temperature. As shown in Figure 5 and Table 6, the trends are toward reduction of distribution ratios and enantioselectivity with the temperature. The possible reason for this phenomenon is that the increase of temperature makes the host−guest interaction between HE-β-CD and αCPMA enantiomers gradually weakened and the chiral discrimination power of HE-β-CD is consequently reduced. Furthermore, the results are consistent well with the van’t Hoff model as shown in Figure 5, indicating that the host−guest interactions have not any changes and the structure of

Figure 5. Plots of ln kS (■), ln kR (●), and ln α (▲) versus 1/T. Points: experimental data. Lines: fitted lines, R2 = 0.9874 for ln kS, R2 = 0.9844 for ln kR, and R2 = 0.9898 for ln α. Cα‑CPMA = 3.17 × 10−3 mol· kg−1 in 1,2-dichloroethane, pH = 2.5, p = 0.1 MPa, CHE‑β‑CD = 0.05 mol·kg−1.

between pH and the distribution behavior can also be simulated by the mathematical model. The results of experimental data and model predictions are shown in Figure 3 and Table 4. It is worth to note that the predicted values of kR, kS, and α are consistent well with the experimental data. The mean relative deviations between model and experiment are 3.96% for kR, 2.75% for kS, and 2.43% for α. It can be found from Figure 3a that kR and kS keep almost no change when the pH value increases from 1.5 to 4, and then increase rapidly. As illustrated in Figure 3b, the enantioselectivity is stable at pH value lower than 4, then decreased rapidly with the rising of pH value. It is possibly due to the

Table 6. LLE Data for {(R)-α-Cyclopentylmandelic Acid (1) + (S)-α-Cyclopentylmandelic Acid (2) + Hydroxyethyl-βcyclodextrin (3) + 1,2-Dichloroethane(4)} Systems at pH = 2.5, p = 0.1 MPa, 0.05 mol·kg−1 Hydroxyethyl-β-cyclodextrin in the Aqueous Phase, and Various Temperature Along with Distribution Ratios, k, and Enantioselectivities, αa T K 278 283 288 293 298 303 a

CS,W

CS,O

mol·kg 1.093 0.962 0.890 0.803 0.697 0.651

× × × × × ×

−1

CR,W

mol·kg −3

10 10−3 10−3 10−3 10−3 10−3

0.494 0.625 0.696 0.784 0.890 0.936

× × × × × ×

−1

mol·kg −3

10 10−3 10−3 10−3 10−3 10−3

0.895 0.767 0.700 0.618 0.526 0.495

× × × × × ×

CR,O −1

mol·kg−1 −3

10 10−3 10−3 10−3 10−3 10−3

0.692 0.821 0.887 0.969 1.061 1.092

× × × × × ×

10−3 10−3 10−3 10−3 10−3 10−3

ln kS

ln kR

ln α

0.794 0.432 0.246 0.025 −0.245 −0.362

0.257 −0.068 −0.236 −0.449 −0.701 −0.790

0.537 0.506 0.482 0.474 0.456 0.428

Standard uncertainties u are u(T) = 0.1 K, u(p) = 2 kPa, and u(pH) = 0.01. 3094



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Figure 7. Influence of extractant concentration and pH on the enantiomeric excess (ee) value of α-CPMA. Cα‑CPMA = 3.17 × 10−3 mol·kg−1 in 1,2-dichloroethane, T = 278 K.

Figure 8. Tendency of pfS with the variation of extractant concentration and pH. Cα‑CPMA = 3.17 × 10−3 mol·kg−1 in 1,2dichloroethane, T = 278 K.

Figure 6. Variation of kR (a), kS (b), and α (c) for α-CPMA enantiomers under the combined effect of pH and the extractant concentration. Cα‑CPMA = 3.17 × 10−3 mol·kg−1 in 1,2-dichloroethane, T = 278 K. Figure 9. Relationship between pH and pfS. Diamond points: experimental data. Solid lines: model predictions. Cα‑CPMA = 3.17 × 10−3 mol·kg−1 in 1,2-dichloroethane, CHE‑β‑CD = 0.05 mol·kg−1, T = 278 K.

complexes keeps stable within the scope of the study of the temperature.22 Thus, the extraction separation process for αCPMA enantiomers should be carried out at relatively low temperature. However, with the temperature decreasing, the solubility of the solute is decreased accordingly, and the viscosity of the system is increased. During the actual operation, 278 K was chosen as the best temperature for the system. 4.6. Model Simulation. According to the results of the above studies, the mathematical model built in this work can predict the extract efficiency accurately for the separation of αCPMA enantiomers. Therefore, the model could be employed to research the effects of multifactor process conditions on the

extraction performance to make up for insufficient of single factor experimental design. Figure 6a,b,c show the variation of kR, kS, and α for α-CPMA under the combined effect of pH and the extractant concentration. As shown in Figure 6a−b, the variation of pH and the extractant concentration cause the same trend for kR and kS, they are increased with the rising of these two parameters, respectively. In addition, the low pH value and high 3095



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described above, HE-β-CD shows strong discernment ability for the separation of α-CPMA enantiomers. For a certain concentration of α-CPMA racemate, the concentration of extractant (HE-β-CD) affects the purity and yields of α-CPMA enantiomers. Limited to the mechanism, the pH value has to be in a suitable range because it influences the existing state of αCPMA enantiomers.

5. CONCLUSIONS Enantioseparation of α-CPMA by reactive extraction with hydrophilic β-CD derivatives was investigated. It was found that the extraction conditions (.e.g., organic solvents, extractant, pH value, and temperature) affected the extraction performance obviously. A mathematical model was established based on a homogeneous reaction mechanism and applied to calculate the influence of multifactor conditions on equilibrium of the twophase extraction system. The predicted values and the experimental results are consistent and their mean relative error is always less than 5%. The optimized extraction system was gained by modeling and the optimized conditions were 0.04 mol·kg−1 of HE-β-CD and pH value of 2.5 at 278 K. Under this optimal conditions, α is over 1.70 and the pfS is up to 0.07. The experimental results and model predictions presented here imply that the model is a good way for calculating extraction efficiency in two-phase chiral extraction systems. The adoption of biphasic recognition chiral extraction to improve the extraction efficiency is underway currently.

Figure 10. Relationship between HE-β-CD concentration and pfS. Diamond points: experimental data. Solid lines: model predictions. Cα‑CPMA = 3.17 × 10−3 mol·kg−1 in 1,2-dichloroethane, pH = 2.5, T = 278 K.

extractant concentration can also lead to a high enantioselectivity for α-CPMA (Figure 6c). When the extractant concentration >0.04 mol·kg−1 and pH < 3, the enantioselectivity keeps constant. Figure 7 shows the influence of extractant concentration and pH on the enantiomeric excess (ee) value of α-CPMA. The eew is obviously affected by extractant concentration and pH. The eew is increased with the decrease of pH value, whereas it increases rapidly first and then gradually decreases with the extractant concentration. Thus, the variety of eew in threedimensional space presents a peak with the change of extractant concentration and pH. It is difficult to apply Figures 6c and 7 to define the optimized conditions for extraction separation of α-CPMA enantiomers on account of the opposite trends of ee and α. The performance factor, pfS (eq 12), is employed to represent the extraction performance to optimize this separation system. Figure 8 shows the tendency of pfS with the variation of extractant concentration and pH and demonstrates that a relatively large pfS can be gained at a low pH and an appropriate extractant concentration. When the concentration of α-CPMA is about 3.17 mmol·kg−1 and the equilibrium is 278 K, the best operating conditions of the pH is 2.5 and that of extractant concentration is about 0.04 mol·kg−1 according to Figure 8. In order to further ensure the accuracy of the model prediction about the pfS, the verified experiment was carried out and the results are depicted in Figures 9 and 10. As shown in Figures 9 and 10, the predictions are consistent well with the experimental results and the corresponding mean relative deviations are 4.39% for Figure 9 and 3.13% for Figure 10. With the results in hand, the separation efficiency influenced by some important factors is further investigated. Equilibrium temperature determines the threshold of reaction and affects the discrimination ability. In addition, the distribution ratios and enantioselectivity tend toward reduction with the equilibrium temperature, because the host−guest interaction and the recognition ability of HE-β-CD for α-CPMA gradually weakens with the increase of temperature. The organic solvents affect the distribution obviously, because they can affect the stability and solubility of the diastereomeric compounds. Through the screening experiments, 1,2-dichloroethane was the preferred organic solvent for extraction separation of αCPMA. Chiral selectors of different kinds show large difference in chiral recognition ability owing to their distinctive groups. As

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] (P.L. Zhang). Tel.: +8613786023146. Fax: +86-730-8640921. *E-mail: [email protected] (W.F. Xu). Tel.: +8615173085668. Fax: +86-730-8640921. Funding

This work was supported by the National Science Foundation of China (No. 21376071), Hunan Provincial Natural Science Foundation of China (No. 2015JJ6045). Notes

The authors declare no competing financial interest.

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REFERENCES

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