Article pubs.acs.org/IECR
Continuous Separation of α‑Cyclohexyl-mandelic Acid Enantiomers by Enantioselective Liquid−Liquid Extraction in Centrifugal Contactor Separators: Experiments and Modeling Kewen Tang,*,†,‡ Hui Zhang,‡ and Panliang Zhang† †
Department of Chemistry and Chemical Engineering, Hunan Institute of Science and Technology, Yueyang 414006, Hunan, China College of Chemical Engineering, Xiangtan University, Xiangtan 411105, Hunan, China
‡
ABSTRACT: Multistage enantioselective liquid−liquid extraction (ELLE) in centrifugal contactor separators was developed for separation of enantiomers. Performance of the process was evaluated by product purity (enantiomeric excess, ee) and yield (Y). Enantioselective liquid−liquid extraction of α-cyclohexyl-mandelic acid (α-CHMA) enantiomers with hydrophilic hydroxyphenyl-β-cyclodextrin as extractant (C) was performed in a countercurrent cascade of 10 centrifugal contactor separators (CCSs) at 278 K to investigate the influence of the operation variables including phase ratios and concentrations on extraction efficiency. On the basis of a single stage equilibrium model and the law of conservation of mass, a multistage equilibrium model of enantioselective liquid−liquid extraction was developed to investigate the influence of changes in the process parameters such as phase ratios and concentrations on extraction efficiency. The multistage model predicted the experimental data accurately and was applied to optimize the symmetrical separation of α-CHMA enantiomers. By modeling, the minimum number of stages for eeeq > 97% and eeeq > 99% was predicted as 42 and 48, respectively. Table 1. Advantages and Disadvantages of Different Means for Enantioseparation of α-Cyclohexylmandelic Acid
1. INTRODUCTION Compared with racemic drugs, enantiopure drugs have the advantage of higher pharmacological activity and smaller side effects.1 Thus, the demand for enantiopure drugs is growing dramatically in the past decades,2,3 and the development of new competitive technologies to obtain enantiopure drugs is booming. A well-known technique to obtain enantiopure compounds on industrial scale is resolution of the racemate through crystallization.4 Usage of crystallization is usually limited in separation of acid or basic substrates, which makes the technique not always applicable. Alternatives to this technique, such as simulated moving bed chromatography technique,5−7 liquid membrane technology,8,9 and enantioselective liquid−liquid extraction,10−33 have been developed. Due to the limited transport rates in membrane technology and the high costs of SMB, ELLE seems to be the most promising technology for chiral separation, which has been used in the enantioseparation of amino acid,12,14−17,20−23 amino alcohol,10,24 and aromatic acids.25−33 The most attractive potentiality of ELLE is its versatility and ease for scale up. Although the first report of ELLE was published as early as 1959 and many researchers have attempted the separation of optically active compound by ELLE, the number of publications has only significantly grown in the past decades.10−33 The available works focus mainly on the studies on extraction equilibrium and the synthesis of new chiral selectors. Recently, a few literature studies provide fundamental insights in the reaction engineering mechanism by combining experimental investigation and mathematical modeling to predict and optimize the extraction performance in single stage extraction.11,12,23,24,29 Literature on single stage extraction equilibrium are ample; however, studies concerning multistage enantioselective liquid−liquid extraction are still very few.13,17 © 2013 American Chemical Society
ref ref 26
ref 30 ref 31
refs 32, 33 ref 34
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advantages high enantioselectivity cost-effective easy to scale up high capacity cost-effective cost-effective
high enantioselectivity easy to scale up low cost of stationary phases low solvent consumption high product purity high mass transfer rate high efficiency easy to scale up high product purity
disadvantages low product purity
low efficiency difficult to scale up low enantioselectivity low product purity low mass transfer rate require two selectors low product purity low efficiency significant capital investment high solvent consumption significant capital investment
The centrifugal contactor separators (CCS) is an example of a compact continuous flow device combining the function of fast mixing and fast phase separation in a small volume, and is an ideal instrument to implement process intensification. Besides the excellent mass transfer characteristics, the high centrifugal forces allow for the separation of liquids with density differences of only 10 kg/m3. Due to these advantages, the Received: Revised: Accepted: Published: 3893
November 29, 2012 January 24, 2013 February 17, 2013 February 18, 2013 dx.doi.org/10.1021/ie303291a | Ind. Eng. Chem. Res. 2013, 52, 3893−3902
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Figure 1. Flow scheme of a casade with N CCSs for separation of α-cyclohexyl-mandelic acid enantiomers.
CCSs are suitable for continuous separation of enantiomers by enantioselective liquid−liquid extraction. Recently, centrifugal contactor separator devices have been applied in continuously enantioselective liquid−liquid extraction of amino acid enantiomers, and excellent separation results were achieved.14,16,17 For multistage ELLE in centrifugal contactor separators, there are many process parameters such as the extract phase/ washing phase ratio (W/O), the extract phase/feeding phase ratio (W/F), extractant concentration, enantiomer concentration, and the location of feed, which all influence extraction efficiency. For an economically feasible process, it is necessary to obtain optimum process parameters by optimization. But the studies on modeling and optimization of the multistage ELLE have been rarely reported. A further experimental and modeling study is required to optimize process parameters to realize high yield and good purity at the minimum number of stages. Recently, we reported the equilibrium and the kinetics study for chiral separation of α-cyclohexyl-mandelic acid (α-CHMA) enantiomers in a single stage reactive extraction process and sufficiently efficient selectivity and fast kinetics was obtained which will be helpful in the design of a large-scale extraction processes.26,27,32 In this paper we describe the use of centrifugal contactor separators (CCS) for multistage enantioseparation of α-CHMA enantiomers. A multistage ELLE equilibrium model was established on the basis of governing phase equilibrium equations and equations of mass balance. The experimental data were modeled by this model to explore the influence of various operating conditions on extraction efficiency in a multistage system, and further predict and optimize the separation process. Many researchers have attempted the separation of α-cyclohexyl-mandelic acid by different methods,26,30−34 and obtained different separation efficiency. Also, we discussed the advantages and disadvantages of different technology with our method for enantioseparation of αcyclohexylmandelic acid (Table 1).
Figure 2. Single extraction stage. If j = f, then F ≠ 0, else F = 0, i = R, S.
acetonitrile (65:20:15, v/v) containing 9.5 mmol/L β-CD. Flow rate was set at 1.0 mL/min.35 The pH of the aqueous phase was measured with a pH electrode and a pH meter (Orion, model 720A). 2.3. Multistage Extraction Experiments. Ten CCS devices (maximum throughput, 200 mL/min) were set up in a countercurrent cascade according to Figure 1. The CCSs were equipped with a thermostatic water bath containing circulating cooling water to maintain a constant temperature of 278 K. All the CCS devices were set at a stirring rate of 50 Hz. The extract phase (aqueous phase) was prepared by dissolving HP-β-CD in 0.1 mol/L NaH2PO4/H3PO4 buffer solution maintaining pH = 2.5, and racemic α-CHMA was dissolved in 1,2-dichloroethane to prepare the feeding phase. Extraction experiment was performed by starting the engines of all CCSs and starting the heavy phase (organic phase) pump. The CCSs were filled up in the order from stage 1 to stage 10. When the CCSs were filled with the heavy phase and the heavy phase outflowed from stage 10, the pump of the light phase (aqueous phase) was started. After achieving steady state, the pump of the feed was started. As soon as the feed pump started running, samples were taken every 15 min. The concentrations of AR and AS in extract outlet were analyzed by HPLC.
2. EXPERIMENTAL SECTION 2.1. Materials. Hydroxypropyl-β-cyclodextrin (HP-β-CD) was supplied by Qianhui Fine Chemicals Co., Ltd. (Shangdong, China). α-Cyclohexyl-mandelic acid (α-CHMA, racemate, purity ≥98%) was purchased from Guangde Keyuan Chemical Co., Ltd. (Jiangsu, China). Solvent for chromatography was of HPLC grade. All other reagents used in this work were of analytical grade and bought from different suppliers. 2.2. Analytical Method. The quantification of α-CHMA enantiomers in extract outlet was performed by HPLC with a UV detector (Merck, Hitachi, Japan) operated at a UV wavelength of 220 nm. The column was Lichrospher C18 (250 mm × 4.6 mm i.d., packing material size of 5 μm) (Hanbon Science & Technology Co. Ltd., China). The mobile phase was a mixture of 0.075 mol/L KH2PO4 aqueous solution, alcohol, and
3. MULTISTAGE ELLE EQUILIBRIUM MODEL A flow scheme of a cascade with N CCSs for the separation of racemic α-CHMA (AR,S) into R-α-CHMA (AR) and S-α-CHMA (AS) is shown in Figure 1. AR,S is fed to the cascade at the feed stage, indicated with f. The stages from f to N form the stripping section, where AS is predominantly extracted to the extract phase (aqueous phase). The coextracted AR is washed out of the extract stream from the stage 1 to f-1 (wash section). After multistage extraction, the AS enantiomer is predominantly left in the extract, and the coextracted AR primarily stays in the raffinate. 3894
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Figure 3. Influence of W/O ratio on ee and yield for separation of α-CHMA enantiomers. W/F = 3.0, pH = 2.5, [C] = 0.1 mol/L, [AR,S] = 0.010 mol/L, f = 6, N = 10. (a) Influence on ee. (b) Influence on yield.
Figure 4. Influence of extractant concentration on ee and yield for separation of α-CHMA enantiomers. W/F = 3.0, W/O = 0.6, pH = 2.5, [AR,S] = 0.010 mol/L, f = 6, N = 10. (a) Influence on ee. (b) Influence on yield.
A multistage equilibrium model is established on the basis of chemical and physical equilibrium and mass balance. Figure 2 shows the multistage relations in the cascade follow, in which a single stage from the cascade is displayed. The solvents are assumed to be completely immiscible, and the extractant C is assumed to be completely insoluble in the organic phase. In our previous studies, the single equilibrium stage model was established by a series of equilibrium relations and mass balance equations, and the model predictions were in good agreement with the experiment. The main parameters in this model involve the chemical and physical properties (complexation constants KR and KS, physical partitioning ratio P0, and acid−base dissociation constant Ka1) and the process parameters (concentrations of extractant [C] and racemic mixture [AR,S]). The extent of extraction is characterized by the distribution ratios DR and DS for AR and AS DR =
[AR ]allform aq [AR ]allform org
=
DS =
allform [A S]org
=
[A S]aq + [A S –]aq + [A SC]aq [A S]org
(2)
For each of the stages (j = 1...N), the phase equilibrium relations and mass balance equations are shown as follows: The dissociation constant of AR and AS is defined as K a1 =
[H+]aq, j [AR –]aq, j [AR ]aq, j
=
[H+]aq, j [A S –]aq, j [A S]aq, j
(3)
where [AR]aq and [AS]aq are the concentrations of the free AR and AS in aqueous phase at equilibrium, respectively; [AR−]and [AS−] are the concentration of the ionic AR and AS in aqueous phase at equilibrium, respectively. The complexation equilibrium constants of AR and AS with HP-β-CD in aqueous phase are formulated as follows:
[AR ]aq + [AR –]aq + [AR C]aq [AR ]org
allform [A S]aq
KR =
(1) 3895
[AR C]aq, j [C]aq, j [AR ]aq, j
(4)
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Figure 5. Influence of W/O ratio and extractant excess (W/F ratio change) on ee and yield for separation of α-CHMA enantiomers. pH = 2.5, [C] = 0.100 mol/L, [AR,S] = 0.010 mol/L, feed in middle stage, N = 10. (a) Influence on ee in extract. (b) Influence on ee in raffinate. (c) Influence on yield in extract. (d) Influence on yield in raffinate.
KS =
[A SC]aq, j
W ([A S]aq, j + 1 + [A S –]aq, j + 1 + [A SC]aq, j + 1 ) + O[A S]org, j – 1
[C ]aq, j [A S]aq, j
= W ([A S]aq, j + [A S –]aq, j + [A SC]aq, j ) + O[A S]org, j
(5)
(8)
where [ARC]aq and [ASC]aq represent the concentrations of complex AR-C and AS-C in the aqueous phase at equilibrium, respectively; [C]aq is the concentration of free HP-β-CD in the aqueous phase at equilibrium. The physical partition ratio of molecular AR and AS is P0 =
[AR ]aq, j [AR ]org, j
=
If j = 1, then [AR]org,j‑1 = 0 and [AS]org,j‑1 = 0. For the feed stage, the component balances for AR and AS are, respectively, defined as
[A S]aq, j [A S]org, j
F[AR ]org, F + W ([AR ]aq, f + 1 + [AR –]aq, f + 1 + [AR C]aq, f + 1 ) (6)
+ O[AR ]org, f – 1 = W ([AR ]aq, f + [AR –]aq, f + [AR C]aq, f )
where [AR]org and [AS]org are the concentrations of the free AR and AS in organic phase at equilibrium. For wash section (j = 1...f − 1), the component balances for AR and AS are respectively defined as
+ (O + F )[AR ]org, f
(9)
F[A S]org, F + W ([A S]aq, f + 1 + [A S –]aq, f + 1 + [A SC]aq, f + 1 ) + O[A S]org, f – 1 = W ([A S]aq, f + [A S –]aq, f + [A SC]aq, f ) + (O + F )[A S]org, f
W ([AR ]aq, j + 1 + [AR –]aq, j + 1 + [AR C]aq, j + 1 ) + O[AR ]org, j – 1 = W ([AR ]aq, j + [AR –]aq, j + [AR C]aq, j ) + O[AR ]org, j
(10)
The following equations represent mass balance for AR and AS in stripping section (j = f + 1...N), respectively.
(7) 3896
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Figure 6. Influence of W/O ratio and extractant excess (extractant concentration change) on ee and yield for separation of α-CHMA enantiomers. pH = 2.5, [C] = 0.100 mol/L, [AR,S] = 0.010 mol/L, feed in middle stage, N = 10. (a) Influence on ee in extract. (b) Influence on ee in raffinate. (c) Influence on yield in extract. (d) Influence on yield in raffinate. W ([AR ]aq, j + 1 + [AR –]aq, j + 1 + [AR C]aq, j + 1 ) + (O + F )[AR ]org, j – 1 –
= W ([AR ]aq, j + [AR ]aq, j + [AR C]aq, j ) + (O + F )[AR ]org, j
⎛ K a1 ⎞ ⎟ DR , j = P0⎜⎜1 + KR[C]aq, j + [H+]aq, j ⎟⎠ ⎝
(16)
⎛ K a1 ⎞ ⎟ DS , j = P0⎜⎜1 + KS[C]aq, j + [H+]aq, j ⎟⎠ ⎝
(17)
(11) W ([A S]aq, j + 1 + [A S –]aq, j + 1 + [A SC]aq, j + 1 ) + (O + F )[A S]org, j – 1 –
= W ([A S]aq, j + [A S ]aq, j + [A SC]aq, j ) + (O + F )[A S]org, j
(12)
[AR−]aq,j+1
If j = N, then [AR]aq,j+1 = 0, = 0, [ARC]aq,j+1 = 0, [AS]aq,j+1 = 0, [AS−]aq,j+1 = 0, and [ASC]aq,j+1 = 0. The overall component mass balances for the enantiomers AR, AS, and C are defined as
[C]aq, j =
[C]0 1 + KR[AR ]aq, j + KS[A S]aq, j
(18)
–
F[AR ]org, F = W ([AR ]aq, N + [AR ]aq, N + [AR C]aq, N ) + O[AR ]org,1
From eqs 16 and 17, the distribution ratios DR and DS of each stage are the function of [H+]aq and [C]aq. Equations 7−14 can be simplified by combining eqs 16−18. Enantiomeric excess (ee) was used to measure the optical purity of the raffinate and the extract. The definition of ee depends on which enantiomer dominates, ee > 0 (eqs 19−eq 20). It should be noted that [A]allforms and [A]allforms encompass AR and R S AS in all forms (free, dissociated, and complexed, namely AR, AR−, ARC, etc.) in this equation.
(13) F[A S]org, F = W ([A S]aq, N + [A S –]aq, N + [A SC]aq, N ) + O[A S]org,1
(14)
[C]0 = ([C]aq, j + [A iC]aq, j )
(15)
where [C]0 is the initial concentration of HP-β-CD in aqueous phase. Combining eqs 3−6, eqs 1, 2, and 15 are deduced to 3897
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The output of the model consists of the concentrations of all species and ee and Y for all stages. By modeling, we investigated the influence of the changes in process parameters such as phase ratios, extractant concentration (C), and racemate concentration ([AR,S]) on ee and Y.
4. RESULTS AND DISCUSSION In order to better understand the relationship between process parameters and extraction performance, we investigated the influence of changes in process parameters such as flow ratio (W/O) and extractant concentration on extraction performance by experiment and modeling. 4.1. Influence of W/O Ratio. To evaluate the effect of W/O ratio on extraction performance, experiments with W/O ratio in the range 0.0−1.0 were performed. A comparison of the experimental values with the model predictions of ee and yield is shown in Figure 3. A significant relationship between the W/O ratio and the ee and yield of each exiting stream are observed. A higher wash stream (lower W/O ratio) increases the purity of the extract stream but decreases the purity of the raffinate stream (Figure 3a). It also can be seen from Figure 3b that the yield of AS in extract stream increases with W/O, but the yield of AR in wash stream decreases. The reason is that more ARC and ASC complexes are formed in stripping section, and in wash section more enantiomers are washed back from the extract with the increase of wash stream. It is also observed from Figure 3 that the model predictions of the ee and the yield are in a good agreement with the experimental data, as shown by mean relative errors of 7.41% for eeextract, 7.15% for eeraffinate, 4.20% for Yextract, and 6.87% for Yraffinate, respectively. There is only one crosspoint where the ee in both streams are equal, and the yields are also equal. The crosspoint with eeeq and Yeq is the operating point for symmetric separation. 4.2. Influence of Extractant Concentration. The ee and yield of multistage ELLE of α-CHMA enantiomers were determined with the extractant concentration ranging from 0.0 to 0.1 mol/L at pH = 2.5 and T = 278 K. A comparison of the experimental data with the model predictions of the purity and yield is shown in Figure 4. A good agreement was obtained between model predictions and experimental results, as shown by mean relative errors of 2.48% for eeextract, 3.89% for eeraffinate, 1.95% for Yextract, and 3.52% for Yraffinate, respectively. As shown in Figure 4, the ee in the raffinate and the yield in the extract increase rapidly with the increase of extractant concentration, while the yield in the raffinate deceases. A peculiar effect is observed from Figure 4a that the ee value in the extract first increases with the increase of extractant concentration and then reaches a maximum and finally decreases with a further increase of extractant concentration. eeextract is equal to 0 at extractant concentration of 0 because enantioselectivity is equal to 1. The increase of eeextract is due to the increase of enantioselectivity with the increase of extractant concentration. With the further increase of extractant concentration, the extractant is present in excess with respect to the desired enantiomer and undesired enantiomer will also be extracted in considerable amount, which will lead to a significant drop in the eeextract. 4.3. Multistage Equilibrium Modeling. Experimental results show that CCS equipment is suitable for countercurrently enantioselective liquid−liquid extraction. Comparison of the model predictions with experimental results indicates the established multistage equilibrium model is a good means of predicting the extract performance of separation of α-CHMA
Figure 7. Influence of extractant excess on eeeq and Yeq for separation of α-CHMA enantiomers, extractant excess either by increase W/F, [C] = 0.100 mol/L, or by increase [C], W/F = 3. pH = 2.5, [AR,S] = 0.010 mol/L, feed in middle stage, N = 10. (a) Influence on eeeq. (b) Influence on Yeq.
ee =
[A]allforms − [A]Sallforms R [A]allforms + [A]Sallforms R
(19)
or ee =
[A]Sallforms − [A]allforms R [A]allforms + [A]Sallforms R
(20)
The yield of the enantiomer S in the extract is given by eq 21. Similarly, the yield of the enantiomer R in the raffinate is defined. YS,extract =
total A S extract [mol] total A S feed [mol]
(21)
The established multistage equilibrium model is based on three assumptions: (1) equilibrium at each stage; (2) a constant temperature at all stages; (3) a constant pH at all stages. All equilibrium conditions and mass balances on all stages are solved simultaneously. The multistage equilibrium model was programmed in Matlab using the iteration method to solve the system of nonlinear algebraic equations. The constraint of nonnegative concentration was used, and the initial concentrations of enantiomers and extractant were used as the initial estimates. 3898
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Figure 8. Influence of W/O ratio and enantiomer concentration on ee and yield for separation of α-CHMA enantiomers. pH = 2.5, W/F = 3, extractant excess = 20, feed in middle stage, N = 10. (a) Influence on ee in extract. (b) Influence on ee in raffinate. (c) Influence on yield in extract. (d) Influence on yield in raffinate.
4.3.1.1. Change of W/F Ratio. Figure 5 shows the ee and the yield in both exit streams for separation of α-CHMA enantiomers as a function of W/O ratio and extractant excess by changing W/F ratio. It can be observed from Figure 5 that there is a significant effect of W/O and extractant excess on ee and Y. As shown in Figure 5a,b, the ee in the extract and the ee in the raffinate follow an opposite tendency with the change of W/O and extractant excess. The decrease of W/O and extractant excess can lead to the increase of the ee in the extract and the decrease of the ee in the raffinate. The influence of W/O and extractant excess on Yextract and Yraffinate is also contrary to that on eeextract and eeraffinate. It can be seen from Figure 5c,d that the increase of W/O and extractant excess can result in the increase of the Yextract in the extract and the decrease of the Yraffinate in the raffinate. 4.3.1.2. Change of Extractant Concentration. Figure 6 shows the ee and the yield in both exit streams for separation of α-CHMA enantiomers as a function of W/O ratio and extractant excess by change of extractant concentrations. It can be observed from Figures 5 and 6 that there is a similar tendency between Figure 5b−d and Figure 6 b−d. Therefore, there is a similar effect
enantiomers in a countercurrent cascade of centrifugal contactor separators over a range of experimental conditions. Therefore, we utilized the model to explore the influence of various operating conditions on extraction efficiency in a multistage system to predict and optimize the separation process. 4.3.1. Influence of Extractant Excess and W/O Ratio. In industrial production, it is necessary to work not only at maximum enantiomer concentraction but also at minimal extractant concentraction to obtain a higher purity and higher yield and to reduce the production cost. The concentrations of extractant and enantiomers are characterized by “extractant excess” (eq 22). Values of ee and yield in both the streams were predicted as a function of extractant excess and W/O ratio, respectively (Figures 5 and 6), based on the valid multistage model. extractant excess =
W [C]aq, 0 F[AR, S]f
(22)
In the next section, the influence of extractant excess on the ee and the yield was simulated by change of W/F ratio or by change of extactant concentractions [C]. 3899
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of W/O and extractant excess on eeraffinate and Y by changing either W/F ratio or extractant concentrations. A peculiar effect is observed from Figure 6a that the ee in the extract increases with the increase of extractant excess, and then reaches a maximum, and finally decreases with a further increase of extractant excess. In most cases, even if one of the two enantiomers is much less valuable than the other one, symmetric separation with eeeq and Yeq in both exit streams is needed to obtain a higher yield of the desired enantiomer. As shown in Figure 7, the influence of extractant excess on eeeq and Yeq is explored. The intersecting line of the two surfaces in Figure 5a,b is generated by the twodimensional interpolation method to explore the influence of W/O and W/F on eeeq (Figure 7a). Also, the intersecting line of the two surfaces in Figure 5c,d is generated to describe the influence of W/O and W/F on Yeq (Figure 7 b). Similarly, the two intersecting lines of the four surfaces in Figure 6a,b and Figure 6c,d are obtained to reflect the influence of W/O and extractant concentrations on eeeq and Yeq in Figure 7a,b, respectively. An increase of extractant excess, which is either by increasing W/F
ratio or by increasing [C], will result in a higher eeeq and a higher Yeq in both exit streams and a lower operational W/O ratio (Figure 7). It is also observed from Figure 7 that eeeq and Yeq reach a plateau when extractant excess is above 20. 4.3.2. Influence of Substrate Concentration. In order to better understand the influence of substrate concentration on separation of α-CHMA enantiomers. According to the multistage model, the ee, Y, eeeq, and Yeq are simulated as a function of W/O ratio and substrate concentraction at a fixed extractant excess (Figure 8). Figure 8 shows the ee and the yield in both exit streams for separation of α-CHMA enantiomers as a function of W/O ratio and [AR,S] (substrate concentration) at a fixed extractant excess. It can be observed from Figure 8 that there is a significant effect of W/O and [AR,S] on ee and Y. As shown in Figure 8b,c, the ee in the raffinate and the Y in the extract have a similar tendency with the change of substrate concentractions and W/O ratio: the increase of W/O and [AR,S] can give a rise to the ee in the raffinate and the Y in the extract. It can be seen from Figure 8d that the decrease of W/O and [AR,S] can result in the increase of Y in the raffinate. A peculiar effect is observed from Figure 8a that the ee in the extract increases with the increase of [AR,S], and then reaches a maximum, and finally decreases with a further increase in [AR,S]. Figure 9a illustrates the relation between eeeq and [AR,S], and it clearly indicates that there is no significant effect of [AR,S] on eeeq. Similarly, the relation between Yeq and [AR,S] is simulated (Figure 9b), and there is no significant effect of [AR,S] on Yeq. Therefore, in an industrial production process, to abtain higher purity and higher yield and to reduce production cost, relatively high α-CHMA enantiomer concentractions [AR,S] are proposed. 4.4. Optimum Conditions. Figure 10 shows eeeq and Yeq as a function of the number of stage from 10 stages to 50 stages by feeding in the middle stage. As shown in Figure 10, eeeq and Yeq increase greatly when the number of stages is less than 35, and then the change is slight when the number of stage is above 35. For a symmetrical separation, the minimum number of stages was determined for eeeq > 97% and eeeq > 99%, respectively, by modeling and optimization. The optimized settings for the two cases are listed in Table 2. When the eeeq is higher than 97%, a cascade of 40 stages is sufficient, whereas for eeeq > 99%, a minimum of 48 stages is required. These values are about 1.7 times the predicted values by the Feske equation for full reflux.36
Figure 9. Influence of W/O ratio and enantiomer concentration on eeeq and Yeq for separation of α-CHMA enantiomers. pH = 2.5, W/F = 3, extractant excess = 20, feed in middle stage, N = 10. (a) Influence on eeeq. (b) Influence on Yeq.
Figure 10. Influence of number of stage on eeeq and Yeq for separation of α-CHMA enantiomers. W/F = 3.0, pH = 2.5, [C] = 0.100 mol/L, [AR,S] = 0.010 mol/L, feeding in middle stage. 3900
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P0 = physical distribution ratio for α-CHMA, dimensionless Ka1 = acid dissociation equilibrium constant, mol/L D = distribution ratio, dimensionless K = complexation constants, L/mol A = α-CHMA AR = R-α-CHMA AS = S-α-CHMA AR− = ionic R-α-CHMA AS− = ionic S-α-CHMA N = number of stages ee = enantiomeric excess, dimensionless Y = yield, dimensionless
Table 2. Optimized Settings for Symmetrical Separations with [AR,S] = 0.1 mol/L, pH = 2.5 variable
eeR and eeS > 97% settings
eeR and eeS > 99% settings
N f [C] (mol/L) W/F W/O
42 22 0.1 2.0 0.4
48 25 0.1 2.0 0.6
5. CONCLUSIONS AND OUTLOOK Multistage enantioselective liquid−liquid extraction was carried out for separation of α-CHMA enantiomers with hydroxypropylβ-cyclodextrin as enantioselective extractant. Experimental results show that CCS equipment is suitable for countercurrently enantioselective liquid−liquid extraction of α-CHMA enantiomers and the extraction efficiency is strongly influenced by the process variables such as phase ratios (W/F ratio, W/O ratio), extractant excess, and substrate concentraction. A multistage equilibrium model based on governing phase equilibrium equations and equations of mass balance was established, and the model was verified experimentally with excellent results. The purity and yield can be improved by optimization such as optimization of W/O ratio, extractant excess, and substrate concentration. In the practical application, to obtain a higher yield of the desired enantiomer, the optical purity of both enantiomers should be higher in their appropriate exit streams. By multistage simulation, higher eeeq and Yeq can be obtained at higher extractant excess and lower W/O ratio. The minimum number of stages for full separation was determined at 42 and 48 for eeeq > 97% and eeeq > 99% at both exits, respectively, which are 1.7 times larger than the ones predicted by Fenske equation.36 Considering the economical exploitation of the principle, we will consider the technology of biphasic extraction in our future studies to improve the enantioselectivity by which the number of stages can be reduced and the extraction efficiency can be enhanced. We can also use asymmetrical separation of α-CHMA enantiomers replacing the symmetrical separation described in this paper. The asymmetrical separation allows one to obtain one enantiomer with high purity by fewer number of stages even though the enantioselectivity is moderate.
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Subscripts
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i = index for R,S j = stage index aq = aqueous phase org = organic phase 0 = initial value eq = equal value
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by the Natural Science Foundation of China (No.21176062), Hunan Provincial Natural Science Foundation of China (No. 12JJ2007), the Open Fund Project of Key Laboratory in Hunan University (No. 11K029), Scientific Research Fund of Hunan Provincial Education Department (12B053), and Aid program for Science and Technology Innovative Research Team in Higher Educational Institutions of Hunan Province.
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NOTATION α-CHMA = α-cyclohexyl-mandelic acid enantiomers C = HP-β-CD (hydroxypropyl-β-cyclodextrin) [C] = concentration of HP-β-CD (hydroxypropyl-β-cyclodextrin), mol/L 3901
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