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Simulation and analysis of multi-stage centrifugal fractional extraction process of 4-nitrobenzene glycine enantiomers
Simulation and analysis of multi-stage centrifugal fractional extraction process of 4-nitrobenzenze glycine enantiomers Ping Wen, Tang Jicheng, Zhou, Panliang Zhang PII: DOI: Reference:
S1004-9541(15)00291-8 doi: 10.1016/j.cjche.2015.08.015 CJCHE 370
To appear in: Received date: Revised date: Accepted date:
15 January 2014 20 April 2014 17 June 2014
Please cite this article as: Ping Wen, Tang Jicheng, Zhou, Panliang Zhang, Simulation and analysis of multi-stage centrifugal fractional extraction process of 4-nitrobenzenze glycine enantiomers, (2015), doi: 10.1016/j.cjche.2015.08.015
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多级离心分级萃取分离 4－硝基苯甘氨酸对映体过程模拟和分析
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Graphic Abstract
AD,L F
N
N-1
f+1
D
Slovent O
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Stripping section
Raffinate W+F
Organic feed
f
f-1
Wash feed W
Wash section 2
1 Extract O
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Based on the interfacial ligand exchange model and the law of conservation of mass, the multi-stage enantioselective liquid-liquid extraction model has been established to analyze and discuss on multi-stage
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centrifugal fractional extraction process of 4-nitrobenzenze glycine (PGL) enantiomers. The influence of phase ratio, extractant concentration and PF6- concentration on the concentrations of enantiomers in the extract and raffinate was investigated by experiment and simulation. When the number of stages is 18 stages at extractant
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excess of 1.0 or 14 stages at extractant excess of 2.0, the eeeq (equal enantiomeric excess) can reach to 99%.
ACCEPTED MANUSCRIPT Separation Science and Engineering
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Simulation and analysis of multi-stage centrifugal fractional
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extraction process of 4-nitrobenzenze glycine enantiomers*
Ping Wen(文平)1, Kewen Tang(唐课文)2,, Jicheng Zhou(周继承)1,**, Panliang Zhang(张盼良)2,** 1
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Department of Chemical Engineering, Xiang Tan University, Xiangtan 411105, Hunan, China
2
Department of Chemistry and Chemical Engineering, Hunan Institute of Science and Technology, Yueyang
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414006, Hunan, China
Received 15 January 2014
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Article history:
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Received in revised form 20 April 2014
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Accepted 17 June 2014
*Supported by the Natural Science Foundation of China (No.21176062), Hunan Provincial Natural Science Foundation of China (No. 12JJ2007), Scientific Research Fund of Hunan Provincial Education Department (12B053), Science and Technology Planning Project of Hunan Province (2012GK3107) and Aid program for Science and Technology Innovative Research Team in Higher Educational Institutions of Hunan Province. ** To whom correspondence should be addressed. E-mail: [email protected] (P. L. Zhang), [email protected] (J. C. Zhou)
Abstract Based on the interfacial ligand exchange model and the law of conservation of mass, the multi-stage
enantioselective liquid-liquid extraction model has been established to analyze and discuss on multi-stage
centrifugal fractional extraction process of 4-nitrobenzenze glycine (PGL) enantiomers. The influence of phase ratio, extractant concentration and PF6- concentration on the concentrations of enantiomers in the extract and raffinate was investigated by experiment and simulation. A good agreement between model and experiment was
ACCEPTED MANUSCRIPT obtained. On this basis, the influence of many parameters such as location of stage, concentration levels, extractant
excess and number of stages on the symmetric separation performance was simulated. The optimal location of feed
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stage is the middle of fractional extraction equipment. The feed flow must satisfy a restricted relationship on flow
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ratios and the liquid throughout of centrifugal device. For desired purity specification, the required flow ratios decreases with extractant concentration and increases with PF6- concentration. When the number of stages is 18 stages at extractant excess of 1.0 or 14 stages at extractant excess of 2.0, the eeeq (equal enantiomeric excess)
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can reach to 99%.
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Keywords fractional extraction, multistage model, interfacial ligand exchange, chiral separation
1 INTRODUCTION
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Chirality is important in chemical research and chemical industry[1]. When a molecule is
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chiral, the pharmacological activity and toxicity of the different enantiomers may be largely
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different[2]. For example, (S),(S)-ethambutol is tuberculostatic, while (R),(R)-ethambutol causes blindness[3]. The demand for enantiopure compounds is growing rapidly[4]. The most common
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technique to obtain enantiopure compounds is the racemic resolution through crystallization[5]. However, this technique is not always applicable because of excessive solid handling. With the development of separation technology, other techniques, such as simulated moving bed chromatography technique[6-10], enzymatic resolution or biocatalysis[11-14], liquid membrane technology[15-17], and enantioselective liquid-liquid extraction (ELLE)[18-35], have been developed. However, the high cost of SMB, the limitation of enzyme specifity and activity, and the limited transport rates in membrane technology, have impeded their industrial application, while ELLE has circumvented these imperfections and seems to be the most promising technology to separate the enantiomers, such as amino acid, amino alcohol, and aromatic acids.
ACCEPTED MANUSCRIPT Process intensification is a powerful concept to use smaller equipments that combine multiple operations in single highly integrated devices to replace large, energy intensive equipment or
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processes[36]. The Centrifugal contactor separator (CCS) is a very attractive device to integrate
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dispersion of two immiscible liquids, chemical reaction and subsequent phase separation of liquid-liquid systems, which is beneficial not only to energy and investments saving but also to improvement of the efficiency and the selectivity of the extraction processes. Therefore, the CCS
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is perfectly fit for PI on ELLE and bridges the gap between the typical ELLE laboratory
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experiments in batch to larger scale continuous operation.
In recent years, aromatic acid enantiomers have been successfully separated in CCS
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equipment in the operation conditions optimized by the multi-stage ELLE model on homogeneous
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reaction in our works[37, 38]. 4-Nitrobenzene glycine (PGL) is an important pharmaceutical
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chemicals and can be used as D-serine transporter inhibitor for the treatment of nervous system disorders. Separation of PGL enantiomers is of much importance in its analysis and use. On this
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basis, the multi-stage ELLE model on interfacial reaction was established to investigate the multi-stage centrifugal fractional extraction process of 4-nitrobenzenze glycine enantiomers in this paper.
2 MATERIAL AND METHODS 2.1 Material Tetrakis(acetonitrile)copper(I) hexafluorophosphate ([(CH3CN)4Cu]PF6, purity > 99% (w/w)) was
supplied
by
Hewei
Chemical
Co.,
Ltd.
(Guangzhou,
China).
(S)-(−)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthalene ((S)-BINAP) (purity > 99% (w/w)) was
ACCEPTED MANUSCRIPT obtained from Shengjia Chemical Co., Ltd. (Hebei, China). 4-nitrobenzenze glycine (purity > 98% (w/w)) was purchased from HanHong Biochemical Co., Ltd. (Jiangsu, China). Solvent for
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chromatography was of HPLC (High-performance liquid chromatography ) grade. Purified water
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was obtained by reverse osmosis followed by distillation. All other chemicals were of analytical-reagent grade and supplied by different suppliers.
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2.2 Analytical method
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The quantification of the PGL enantiomers in raffinate was performed by HPLC with a UV detector (Merck, Hitachi, Japan) operated at the UV wavelength 260 nm. The column was
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Lichrospher C18 (250×4.6 mm i.d., 5 μm of the packing materials) (Hanbon Science &
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Technology, China). The mobile phase was a mixture of 30 mmol·L-1 sodium acetate aqueous
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solution and methanol (80:20, V/V) containing 2.0×10-3 mol·L-1 L-phenylalanine and 0.5×10-3 mol·L-1 copper sulfate at pH = 4.8 (pH was measured with a pH electrode and a pH meter (Orion,
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model 720A)). The flow rate was set at 1 mL·min-1, and the column temperature was set at 27 oC.
2.3 Extraction experimental method The aqueous phase was prepared by dissolving NaPF6 in 0.1 mol·L-1 NaH2PO4/H3PO4 buffer solution, and racemic PGL was dissolved in 0.1 mol·L-1 NaH2PO4/H3PO4 buffer solution to prepare the feeding phase. The organic phase was prepared by dissolving BINAP-Cu in 1,2-dichloroethane. Extraction experiment was performed by starting the engines of all CCSs and starting the extract (organic phase) pump. After starting the extract pump, the CCSs were filled up in the order from Stage 10 to Stage 1. After the organic phase outflow from Stage 1, the wash
ACCEPTED MANUSCRIPT streams (aqueous phase) were started. When the aqueous phase ran from Stage 10, the feed pump was started. As soon as the feed pump started running, samples of 0.5 mL were taken every 15 min
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from raffinate. The concentrations of AD and AL (represent the enantiomers of D-PGL and L-PGL
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respectively) in raffinate were analyzed using HPLC.
3 Multi-stage equilibrium ELLE model formulations
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A typical flow scheme of a cascade for the separation of AD,L (represent the 4-nitrobenzenze
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glycine raceme) into the enantiomers AD and AL is depicted in figure 1. The fractional extractor consists of two sections, a stripping section and a wash section. The feed is entered at the feed
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stage and is mixed instantaneously with the aqueous phase that exits the wash section. The stage
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relations in the cascade follow figure 2, in which a single stage from the cascade is displayed. The
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definition of parameters is listed in Table 1. The model parameter values were determined by the thermodynamic studies on the single-stage extraction of 4-nitrobenzene glycine enantiomers in
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our previous work[39].
Raffinate W+F
N Slovent O
AD,L Stripping section N-1
f+1
Organic feed
F
f
f-1
Wash feed W
Wash section 2
1 Extract O
Figure 1 Flow scheme of the multi-stage centrifugal fractional extraction of PGL enantiomers.
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[Ai] j-1 [Ai
-]
j-1
O
Wj-1 [PF 6-]j-1
aqueous phase
[Ai] j
[CuB]j
[Ai-]j
[CuBAi] j
P0
Ai
Ai
organic phase
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Ka Pi
A i-
[A i]j
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H+ Ai -
Fj
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CuPF6{(S)-BINAP} Ki PF6
[PF 6-]j
[Ai] j [Ai-] j
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Table 1 Parameters of the equilibrium model
definitiona
parameter
[ Ai ]aq, j [ H ]aq, j
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[ Ai ]aq, j
[ Ai ]org, j
P0
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[ Ai ]org, j
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Pi
[ Ai ]aq, j
KD
KL
[ Ai ]aq, j
[CuBAD ]org, j [ PF6 ]aq, j [ AD ]aq, j [CuB]org, j [CuBAL ]org, j [ PF6 ]aq, j [ AL ]aq, j [CuB]org, j
Cu{(S)-BINAP}A i
[Ai]j+1
[CuBAi]j+1
[Ai-]j+1
[CuB] j+1
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Wj
Figure 2 Single extraction stage. i = D, L.
Ka
-
O
value
dimensions
1.0×10-5.6
mol·L-1
0.01074
dimensionless
0.08095
dimensionless
4.46
dimensionless
18.90
dimensionless
a
The definitions of the parameters P0, Pi and Ka are valid for both enantiomers.
The component balances for Ai (i = D, L) and PF6- for each of the stages (j = 1 … N) are defined as forms forms forms forms Fj [ Ai ]allj forms Wj 1[ Ai ]all O[ Ai ]all Wj [ Ai ]all O[ Ai ]all aq , j 1 org , j 1 aq , j org , j
W j 1[ PF6 ]aq, j
1
O[CuB]org , j 1 W j [ PF6 ]aq, j O[CuB]org , j
(1) (2)
If j < f, then Fj = 0 and Wj-1 = Wj = W. If j = f, then Fj = F, Wj-1 = W and Wj =.W+F. If j > f, then Fj
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enantiomers Ai are defined as
forms F[ Ai ]all f
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[CuB]0 [CuB]org , j [CuBAD ]org , j [CuBAL ]org , j forms all forms (W F )[ Ai ]all O[ Ai ]org aq , N ,1
(3) (4)
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4 RESULTS AND DISCUSSION
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The model was solved using the software package Matlab.
The fractional extraction of 4-nitrobenzenze glycine enantiomers is an extremely complicated process, which is mainly influenced by various process parameters, such as phase ratio (O/W),
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extractant concentration and PF6- concentration of aqueous phase. In this paragraph, a series of
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experiments and simulations are performed to reveal the objective laws of these process
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parameters on the concentrations of enantiomers in the extract and raffinate.
4.1 Influence of O/W ratio
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The influence of phase ratio on enantiomers concentration in the extract and raffinate was investigated at constant setting for concentration of each component, pH value, O/F ratio and feed flow (F). The results are given in Figure 3. At O/W ratio below 1.0, with the increase of organic phase flow, the L-PGL concentration in the raffinate decreases quickly and increases in the extract. But the D-PGL concentration in the raffinate and in the extract change marginally. After O/W ratio of 1.0, only a few L-PGL exists in aqueous phase, and the L-PGL concentration in the extract decreases with the increase of organic phase flow. The reason for these may be that, L-PGL is preferentially distinguished by the extractant CuPF6{(S)-BINAP}. When O/W ratio is of 1.0 to 2.0, the extractant is present in excess with respect to L-PGL, most of D-PGL are distinguished and
ACCEPTED MANUSCRIPT extracted into the organic phase, and it leads to D-PGL concentration in the raffinate decrease and increase quickly in the extract. After O/W ratio is higher than 2.0, nearly all of D-PGL and L-PGL
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have been extracted into organic phase, D-PGL concentration in the extract is equal to it of L-PGL
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and both of them decrease continuously with O/W. Thus, to get a better separation effect a suitable phase ratio is required. From figure 3 O/W of 1.0 is applicable for separation of PGL enantiomers. all forms
The mean relative error is 1.72% of [A D ]aq , respectively.
all forms
, 2.53% of [A D ]org
and
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all forms
3.08% of [A L ]org
all forms
, 2.24% of [A L ]aq
Figure 3 Influence of O/W ratio on the equilibrium concentrations of PGL enantiomers in the raffinate and extract.
(Lines: model prediction. Symbols: experimental data. Conditions: O/F = 2.0, [AD,L] = 2.0×10-3 mol·L-1, [PF6-] = 2.0×10-3 mol·L-1, [CuB] = 1.0×10-3 mol·L-1, pH = 7.0, f = 6 and N = 10)
4.2 Influence of extractant concentration In the stripping section, the ionic PGL enantiomers in the aqueous phase react with CuPF6{(S)-BINAP} on two-phase boundary and the complexes transfer into the organic stream. To gain insights on the influence of extractant concentration on enantiomers concentration in the extract and raffinate, a series of experiments and simulations were carried out. As shown in figure 4, the simulation results have a good agreement with the experimental data. Both enantiomers are extracted with a preference for L-PGL enantiomer, enantiomers concentration in the raffinate
ACCEPTED MANUSCRIPT decrease with extractant concentration. At extractant concentration higher than 0.001 mol·L-1, D-PGL enantiomers begin to be largely extracted into the organic phase. After CuPF6{(S)-BINAP} concentration higher than 0.0025 mol·L-1, all enantiomers in the aqueous phase are occupied by
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CuPF6{(S)-BINAP} and are extracted into the organic phase. Thus, enantiomers concentration in
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the raffinate drop to be zero and as a result both D-PGL and L-PGL enantiomers concentration in all forms
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the extract change to be constant. The mean relative error is 1.22% of [A D ]aq
, 0.73% of
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all forms all forms all forms [A L ]aq , 1.62% of [A D ]org and 1.14% of [A L ]org , respectively.
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Figure 4 Influence of extractant concentration on the equilibrium concentrations of PGL enantiomers in the raffinate and extract.
(Lines: model prediction. Symbols: experimental data. Conditions: O/F = 2.0, O/W = 1.0, [AD,L] = 2.0×10-3 mol·L-1, [PF6-] = 2.0×10-3 mol·L-1, pH = 7.0, f = 6 and N = 10)
4.3 Influence of PF6- concentration In the wash section, the molecular and ionic PGL enantiomers in the organic stream are redistributed over the aqueous and organic phase, a small percentage of them are washed back to the aqueous stream and then flow into the stripping section. Part of complex enantiomers (CuBAD and CuBAL) from the stripping section are compelled to be decomposed at the interface with a precedence for CuBAD because of the presence of PF6- in the aqueous stream, which will lead to a significant influence on the equilibrium concentrations of PGL enantiomers in the raffinate and extract. It can be seen in figure 5 that the concentrations of PGL enantiomers in the extract
ACCEPTED MANUSCRIPT decrease and the concentrations of PGL enantiomers in the raffinate increase at increasing PF6concentration. Furthermore, in the PF6- concentration region between 0.0 and 0.002 mol·L-1, the influence of increasing PF6- concentration on D-PGL enantiomers concentrations is far more
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significant than on L-PGL enantiomers concentrations. However, after PF6- concentration more
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than 0.002 mol·L-1, most CuBAL complexes begin to be decomposed and it leads to the decrease
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of L-PGL enantiomers concentration in the extract and increase in the raffinate, whereas, D-PGL enantiomers concentration just changes slightly, which will largely cut down the separation performance. Thus, for a better separation performance, a proper PF6- concentration in wash feed all forms
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is needed. The mean relative error is 0.64% of [A D ]aq
all forms
, 1.03% of [A L ]aq
, 2.14% of
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all forms all forms [A D ]org and 2.21% of [A L ]org , respectively.
Figure 5 Influence of PF6- concentration on the equilibrium concentrations of PGL enantiomers in the raffinate and extract. (Lines: model prediction. Symbols: experimental data. Conditions: O/F = 2.0, O/W = 1.0, [AD,L] = 2.0×10-3 mol·L-1, [CuB] = 1.0×10-3 mol·L-1, pH = 7.0, f = 6 and N = 10)
4.4 Concentration profile For the in-depth knowledge on the multi-stage centrifugal fractional extraction process of PGL enantiomers, concentration profile of each component at steady state is given in figure 6 through simulation. Note that the flow direction for the aqueous stream is from 1 stage to 10 stage, and for the organic stream counter-currently from 10 stage to 1 stage. Figure 6 shows that the
ACCEPTED MANUSCRIPT concentrations of CuPF6{(S)-BINAP} and PF6- in the cascade are high at both ends and low in the middle of the cascade, but in the flow direction view, their tendencies are opposite. The concentrations of L-PGL enantiomers in the aqueous phase and organic phase are low at both ends
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and high in the middle. For D-PGL enantiomers, the concentrations are low between 1 stage and 5
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stage and high between 6 stage and 10 stage. The reason is that CuPF6{(S)-BINAP} has a
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preference for L-PGL enantiomers in the stripping section and PF6- has a preference for CuBAD complex. In the experiments, the aqueous concentration of enantiomers in the of 10 stage, measured after 5 hours at steady-state, HPLC chromatogram is depicted in Figure 7(b) and the
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original sample chromatogram is shown as Figure 7(a).
Figure 6 Concentration profile in the 10 stage cascade at steady state.
(O/F = 2.0, O/W = 1.0, [AD,L] = 2.0×10-3 mol·L-1, [PF6-] = 2.0×10-3 mol·L-1, [CuB] = 1.0×10-3 mol·L-1, pH = 7.0, f = 6 and N = 10)
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(a)
(b)
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Figure 7 HPLC chromatogram of PGL enantiomers in the aqueous phase before (a) and after separation (b).
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It can be concluded from the above that flow ratios, extractant concentration and PF6-
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concentration have great effects on the extraction process. The concentrations of enantiomers in the extract and raffinate change regularly in the process of different extraction conditions. A high
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correlation between model and experiment was shown in the above studies. The model is satisfied for the multi-stage centrifugal fractional extraction process simulation and optimization of
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4-nitrobenzenze glycine enantiomers. It is therefore the aim of below chapter to study with the model which different extraction conditions generate a specified yield and product optical purity in each stream, and the specifications of them are exchanged for „equal yield (yieldeq)‟ and „equal enantiomeric excess (eeeq)‟. We call this operation „symmetric separation‟. The enantiomeric excess and yield are defined in equations as follows. Enantiomer AL predominates in extract stream, its ee is given in equation 5. Note that „AL‟ and „AD‟ encompass L-PGL and D-PGL in all forms (AL, AL-, CuBAL, etc.) in this equation.
ee
all forms all forms [ AL ]org [ AD ]org all forms forms [ AL ]org [ AD ]all org
(5)
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(6)
forms forms [ AD ]all [ AL ]all aq aq
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ee
forms forms [ AD ]all [ AL ]all aq aq
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The yield of the enantiomer AL in extract stream is given in equation 7. Similary, the yield of
total AL extract [mol ] total AL feed [mol ]
(7)
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yield AL , extract
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AD in raffinate stream can be defined.
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4.5 Symmetric separation 4.5.1 Location of feed stage
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The location of feed stage is a degree of freedom in the multi-stage centrifugal fractional
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extraction processing equipment. The amount of stages in the stripping section and the wash
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section will be altered with the location of feed stage, and it will lead to different performance of symmetric separation. It can be seen in figure 8 that the feed stage located in the middle of the
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cascade equipment, a better symmetric separation performance can be obtained than at other locations. In this paper, the single L-PGL and D-PGL enantiomers have different medicinal value, at the same time the concentration of L-PGL and D-PGL enantiomers in the raw material is equal. Therefore, the feed stage located exactly in the middle is the most efficient solution for symmetrical separation of PGL enantiomers.
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1 eeeq
yieldeq
0.95 0.9
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0.8 0.75
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eeeq or yieldeq
0.85
0.7
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0.65 0.6 0.55
2
3
4
5 6 7 Location of feed stage
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9
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0.5
Figure 8 Influence of the location of feed stage on the performance for symmetrical separation of PGL enantiomers.
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(O/F = 2.0, O/W = 1.0, [AD,L] = 2.0×10-3 mol·L-1, [PF6-] = 2.0×10-3 mol·L-1,
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[CuB] = 1.0×10-3 mol·L-1, pH = 7.0, N = 10)
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4.5.2 Concentration level
In the cascade equipment of three solution inlets, concentration level encompasses
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enantiomers concentration of feed inlet ([Ai]), extractant concentration of organic phase inlet ([CuB]) and PF6- concentration of aqueous phase inlet ([PF6-]). In this chapter, the performance for
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symmetrical separation of PGL enantiomers will be simulated under different concentration levels. 4.5.2.1 Enantiomers concentration PGL enantiomers concentration and feed flow get together to determine the production rate. There is no doubt that the bigger the values of enantiomers concentration and feed flow are, the better will be in the industrial production. The enantiomers concentration is limited by the solubility of PGL enantiomers in the feed stream, which can be determined experimentally. Therefore no further simulations were carried out on the enantiomers concentration level. In addition, the feed flow is determined by the flow ratios (O/W = a, O/F = b) and the minimum and maximum liquid throughput (Vmin and Vmax, L·min-1) of the real centrifugal device.
ACCEPTED MANUSCRIPT The three inlet flows must satisfy the restriction on „ Vmin W O ‟ and „ W O F Vmax ‟. Then the value of the feed flow can be deduced to: (8)
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a a Vmin F Vmax ab b ab a b
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Furthermore, for a fixed equal enantiomeric excess of products in the process design (e.g. 0.90 eeeq) the flow ratios are bound up with the selected concentration levels of extractant and PF6-. Thus, it is necessary to investigate the influence of extractant and PF6- concentration level on the
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performance for symmetrical separation of PGL enantiomers.
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4.5.2.2 Extractant concentration
Extractant concentration is an important degree of freedom in the multi-stage extraction
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system. The eeeq is simulated as a function of flow ratios at different extractant concentration
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settings. It can be seen in figure 9a, b, c that eeeq decreases to the minimum with O/W and
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increases to the maximum with O/F at a fixed extractant concentration settings. Furthermore, by comparative analysis, it can be found that extractant concentration level has a significant influence
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on the flow ratios for a desired purity specification (e.g. 0.90 eeeq). With the increasing of extractant concentration, the required flow ratios decrease.
(a)
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(c)
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Figure 9 Influence of extractant concentration on the symmetrical separation of PGL enantiomers. ((a) [CuB] = 0.0001 mol·L-1, (b) [CuB] = 0.001 mol·L-1, (c) [CuB] = 0.001 mol·L-1, [PGL] = 2.0×10-3 mol·L-1, [PF6-] = 2.0×10-3 mol·L-1, pH = 7.0, f = 6 and N = 10)
4.5.2.3 PF6- concentration PF6- concentration as a degree of freedom plays an important role in improving the washing effect of washing section. The eeeq is simulated as a function of flow ratios at different PF6concentration settings in figure 10a, b and figure 9b. The eeeq gets to the minimum with O/W and drops to the maximum with O/F at a fixed PF6- concentration settings. For a desired purity specification (e.g. 0.90 eeeq), with the increasing of PF6- concentration, the required flow ratios increase.
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(b)
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Figure 10 Influence of PF6 concentration on the symmetrical separation of PGL enantiomers.
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((a) [PF6-] = 0.0005 mol·L-1, (b) [PF6-] = 0.004 mol·L-1,
[PGL] = 2.0×10-3 mol·L-1, [CuB] = 1.0×10-3 mol·L-1, pH = 7.0, f = 6 and N = 10)
It can be seen from the above investigations the mutual influences of concentration levels and flow ratios conclude that there are many combinations of them to obtain desired production purity. Thus, without a detailed economical analysis, it cannot be decided which way is most efficient. However, the simulation can provide a scientific method for comparative analysis in the real industrial production.
4.5.3 Number of stages In industrial production, it is necessary to operate not only at higher enantiomers
ACCEPTED MANUSCRIPT concentration but also at minimal extractant concentration and number of stages to obtain higher purity and higher yield and to cut down the production cost. The concentrations of extractant and
F [ AD , L ] feed
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O[CuB]org ,0
(9)
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extractant excess
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enantiomers are expressed as „extractant excess‟ (eq.9).
The eeeq is simulated as a function of number of stages at different extractant excess via
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changing extractant. It can be seen in figure 11 that the eeeq increases with the increasing of number of stages and then finally reaches a plateau. It was also observed in the simulation results
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that at lower extractant excess, no matter how many stages increases to, a full separation can never
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be obtained in the multi-stage centrifugal fractional extraction process. In these conditions, the
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extractant will become fully loaded, and increasing the number of stages will not increase the optical purity any further. Therefore, in order to make good use of the centrifugal contactors, a
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reasonable extractant excess is necessary. As shown in figure 11, when the number of stages is 18 stages at extractant excess of 1.0 or 14 stages at extractant excess of 2.0, the eeeq can reach to 99%.
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The settings for the two cases are listed in table 2.
Figure 11 Influence of number of stages on the symmetrical separation of PGL enantiomers at different extractant excess by increased [CuB]. (O/F = 2.0, [AD,L] = 2.0×10-3 mol·L-1, [PF6-] = 2.0×10-3 mol·L-1, pH = 7.0, f = 2/N+1)
ACCEPTED MANUSCRIPT Table 2 Settings for symmetrical separations with extractant excess = 1.0 or 2.0, [AR,S] = 2.0×10-3 mol·L-1, pH = 7.0. Production purity ＞99% eeeq
extractant excess = 2.0
N
18
IP
f
10
O/F
2.0
O/W
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8
0.2
1.0×10-3
2.0×10-3
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2.0
2.0×10-3
D
2.0×10-3
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5 CONCLUSIONS
14
0.7
[CuB] (mol·L-1) [NaPF6] (mol·L-1)
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extractant excess = 1.0
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Variable
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The multi-stage ELLE (enantioselective liquid-liquid extraction) model has been successfully developed to simulate and analysis of multi-stage centrifugal fractional extraction process of 4-nitrobenzenze glycine enantiomers. The objective laws of process parameters such as phase
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ratio, extractant concentration and PF6- concentration on the concentrations of enantiomers in the extract and raffinate are revealed by a series of experiments and simulations. Furthermore, by simulation and analysis on the symmetric separation performance, many important conclusions have been made to instruct process design. When the number of stages is 18 stages at extractant excess of 1.0 or 14 stages at extractant excess of 2.0, the eeeq (equal enantiomeric excess) can reach to 99%.
NOMENCLATURE CuB
CuPF6{(S)-BINAP}
ee
enantiomeric excess
Ka
amino acid dissociation constant, mol/L
ACCEPTED MANUSCRIPT complexation constants
PGL
4-nitrobenzene glycine
P0
physical partition coefficient for molecular PGL
Pi
physical partition coefficient for ionic PGL
Vmax
maximum liquid throughput
Vmin
minimum liquid throughput
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K
eq
equal value
i
index for D,L stage index
0
initial value
org
organic phase
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j
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aqueous phase
D
aq
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Subscripts
REFERENCES
1 Eliel, E.L., Wilen, S.H., Stereochemistry of Organic Compounds; John Wiley & Sons Inc, 1994.
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2 Sheldon, R.A., Chirotechnology: Industrial Synthesis of Optically Active Compounds; Marcel Dekker, Inc.: New York, 1993.
3 Crosby, J., “Synthesis of optically active compounds: A large scale perspective”, Tetrahedron, 47 (27), 4789−4846 (1991). 4 Rouhi, A.M., “Fine chemicals companies are jockeying for position to deliver the increasingly complicated chiral small molecules of the future”, Chem. Eng. News, 81 (18), 45−61 (2003). 5 Gourlay, M.D., Kendrick, J., Leusen, F.J.J., “Predicting the spontaneous chiral resolution by crystallization of a pair of flexible nitroxide radicals”, Cryst. Growth. Des., 8 (8), 2899−2905 (2008). 6 Zenoni, G., Quattrini, F., Mazzotti, M., Fuganti, C., Morbidelli, M., “Scale-up of analytical chromatography to the simulated moving bed separation of the enantiomers of the flavour norterpenoids alphaionone and alpha-damascone. Flavour Fragrance J., 17 (3), 195−202 (2002). 7 Francotte, E., Leutert, T., La Vecchia, L., Ossola, F., Richert, P., Schmidt, A., “Preparative resolution of the
ACCEPTED MANUSCRIPT enantiomers of tert-leucine derivatives by simulated moving bed chromatography”, Chirality, 14 (4), 313−317 (2002). 8 Seidel-Morgenstern, A., Kessler, L. C., Kaspereit, M., “New developments in simulated moving BED
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chromatography”. Chem. Eng. Technol., 31 (6), 826−837 (2008).
9 Lu, J.G., “A Non-linear Model of Simulated Moving Bed Chromatography for Chiral Separations”, Chin. J.
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Chem. Eng., 11 (2), 234−239 (2003).
10 Lu, J.G., “Numerical Simulation of Asynchronous Simulated Moving Bed Chromatography”, Chin. J. Chem. Eng., 12(3), 415−420 (2004).
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11 Hungerhoff, B., Sonnenschein, H., Theil, F., “Separation of enantiomers by extraction based on lipase-catalyzed enantiomerselective fluorous-phase labeling”, Angew. Chem. Int. Ed., 40 (13), 2492−2494 (2001).
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12 Okudomi, M., Shimojo, M., Matsumoto, K., “Easy separation of optically active products by enzymatic hydrolysis of soluble polymer-supported substrates”, Tetrahedron Lett., 48 (48), 8540−8543 (2007).
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13 Mei, T.X., Ya,Y.H., Jing, Y., Yang, H.G., “Study on the kinetic characteristics of the asymmetric production of
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R-(-)-mandelic acid with immobilized Saccharomyces cerevisiae FD11b”, Biochem. Eng. J., 39 (2), 311−318 (2008).
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14 Huo, X.J., Zhi, Q.L., Zhong, C.H., Yu, G.Z., “Production of (R)-epichlorohydrin from 1,3-dichloro-2-propanol by two-step biocatalysis using haloalcohol dehalogenase and epoxide hydrolase in two-phase system”, Biochem. Eng. J., 74 (15), 1−7 (2013).
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15 Afonso, C.A.M., Crespo, J.G., “Recent advances in chiral resolution through membrane-based approaches”, Angew. Chem. Int. Ed., 43(40), 5293−5295 (2004). 16 Keurentjes, J.T.F., Nabuurs, L.J.W.M., Vegter, E.A., “Liquid membrane technology for the separation of racemic mixtures”, J. Membr. Sci., 113(2), 351−360 (1996). 17 Maximini, A., Chmiel, H., Holdik, H., Maier, N.W., “Development of a supported liquid membrane process for separating enantiomers of Nprotected amino acid derivatives”, J. Membr. Sci., 276 (1-2), 221−231 (2006). 18 Sunsandee, N., Leepipatpiboon, N., Ramakul, P., Pancharoen, U., “The selective separation of (S)-amlodipine via a hollow fiber supported liquid membrane: Modeling and experimental verification”, Chem. Eng. J., 180 (15), 299−308 (2012). 19 Li, L.H., Li, F.F., “Chiral separation of α-cyclohexyl-mandelic-acid by aqueous two phase system combined with Cu2-β-cyclodextrin complex”, Chem. Eng. J., 211–212, 240−245 (2012). 20 Lacour, J., Goujon-Ginglinger, C., Torche-Haldimann, S., Jodry, J.J., “Efficient enantioselective extraction of
ACCEPTED MANUSCRIPT tris (diimine) ruthenium(II) complexes by chiral, lipophilic TRISPHAT anions”, Angew. Chem. Int. Ed., 39 (20), 3695−3697 (2000). 21 Colera, M., Costero, A.M., Gavina, P., Gil, S., “Synthesis of chiral 18-crown-6 ethers containing lipophilic
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chains and their enantiomeric recognition of chiral ammonium picrates”, Tetrahedron: Asymmetry, 16 (15), 2673−2679 (2005).
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22 Viegas, R.M.C., Afonso, C.A.M., Crespo, J.G., Coelhoso, I.M., “Modelling of the enantio-selective extraction of propranolol in a biphasic system”, Sep. Purif. Technol., 53 (3), 224−234 (2007). 23 Tan, B., Luo, G.S., Wang, J.D., “Extractive separation of amino acid enantiomers with co-extractants of tartaric
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acid derivative and Aliquat-336”, Sep. Purif. Technol., 53 (3), 330−336 (2007).
24 Tang, K.W., Yi, J.M., Liu, Y.B., Jiang, X.Y., Pan, Y., “Enantioselective separation of R,S-phenylsuccinic acid by
MA
biphasic recognition chiral extraction”, Chem. Eng. Sci., 64 (18), 4081−4088 (2009). 25 Tang, K.W., Song, L.T., Liu, Y.B., Jiang, X.Y., Pan, Y., “Separation of flurbiprofen enantiomers by biphasic
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recognition chiral extraction”, Chem. Eng. J., 158 (3), 411−417 (2010).
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26 Verkuijl, B.J.V., Minnaard, A.J., de Vries, J.G., Feringa, B.L., “Chiral separation of underivatized amino acids by reactive extraction with palladium-BINAP complexes”, J. Org. Chem., 74 (17) 6526−6533 (2009).
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27 Donze, C., Coleman, A.W., “β-CD inclusion complexes: relative selectivity of terpene and aromatic guest molecules studied by competitive inclusion experiments”, J. Incl. Phenom. Macrocycl Chem., 16 (1), 1−15 (1993).
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28 Steensma, M., Kuipers, N.J.M., de Haan, A.B., Kwant, G., “Identification of enantioselective extractants for chiral separation of amines and aminoalcohols”, Chirality, 18 (5), 314−328 (2006). 29 Tang, K.W., Zhang, P.L., Pan, C.Y., Li, H.J., “Equilibrium studies on enantioselective extraction of oxybutynin enantiomers by hydrophilic bcyclodextrin derivatives”, AIChE. J., 57 (11), 3027−3036 (2011). 30 Schuur, B., Winkelmam, J.G.M., Heeres, H.J., “Equilibrium studies on enantioselective liquid-liquid amino acid extraction using a cinchona alkaloid extractant”, Ind. Eng. Chem. Res., 47 (24), 10027−10033 (2008). 31 Koska, J., Haynes, C.A., “Modelling multiple chemical equilbria in chiral partition systems”, Chem. Eng. Sci., 56 (20), 5853−5864( 2001). 32 Steensma, M., Kuipers, N.J.M., de Haan, A.B., Kwant, G., “Modelling and experimental evaluation of reaction kinetics in reactive extraction for chiral separation of amines, amino acids and aminoalcohols”, Chem. Eng. Sci., 62 (5), 1395−1407 (2007). 33 Steensma, M., Kuipers, N.J.M., de Haan, A.B., Kwant, G., “Analysis and optimization of enantioselective
ACCEPTED MANUSCRIPT extraction in a multi-product environment with a multistage equilibrium model”, Chem. Eng. Proc., 46 (10), 996−1005 (2007). 34 Tang, K.W., Zhang, P.L., “Experimental and modeling studies on the enantioselective extraction of hydrophobic
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pranoprofen enantiomers with hydrophilic β-cyclodextrin as selectors”, J. Chem. Eng. Data, 56 (10), 3902−3909 (2011).
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35 Tang, K.W., Miao, J.B., Zhou, T., Liu, Y.B., “Equilibrium Studies on Liquid-Liquid Reactive Extraction of Phenylsuccinic Acid Enantiomers Using Hydrophilic β-CD Derivatives Extractants”, Chin. J. Chem. Eng., 19 (3), 397−403 (2011).
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36 Schuur, B., Jansma, W.J., Winkelman, J.G.M., Heeres, H.J., “Determination of the interfacial area of a
Proce., 47 (9-10), 1484−1491 (2008).
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continuous integrated mixer/separator (CINC) using a chemical reaction method”, Chemical Engineering and
37 Tang, K.W., Zhang, H., Liu, Y.B., “Experimental and Simulation on Enantioselective Extraction in Centrifugal
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Contactor Separators”, AIChE. J., 59 (7), 2594−2602 (2011).
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38 Tang, K.W., Zhang, H., Zhang, P.L., “Continuous Separation of α-Cyclohexyl-mandelic Acid Enantiomers by Enantioselective Liquid-Liquid Extraction in Centrifugal Contactor Separators: Experiments and Modeling”, Ind.
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Eng. Chem. Res., 52(10), 3893−3902 (2013). 39 Zhang, P.L, Liu, C., Tang, K.W., Liu, J.J., Zhou, C.S., Yang, C.A., “Studies on Enantioselective Liquid-Liquid Extraction of Amino-(4-nitro-phenyl)-acetic Acid Enantiomers: Modeling and Optimization”, Chirality, 26(2),
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79−87 (2014).
S1004-9541(15)00291-8 doi: 10.1016/j.cjche.2015.08.015 CJCHE 370
To appear in: Received date: Revised date: Accepted date:
15 January 2014 20 April 2014 17 June 2014
Please cite this article as: Ping Wen, Tang Jicheng, Zhou, Panliang Zhang, Simulation and analysis of multi-stage centrifugal fractional extraction process of 4-nitrobenzenze glycine enantiomers, (2015), doi: 10.1016/j.cjche.2015.08.015
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ACCEPTED MANUSCRIPT 2014-0058
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多级离心分级萃取分离 4－硝基苯甘氨酸对映体过程模拟和分析
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Graphic Abstract
AD,L F
N
N-1
f+1
D
Slovent O
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Stripping section
Raffinate W+F
Organic feed
f
f-1
Wash feed W
Wash section 2
1 Extract O
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Based on the interfacial ligand exchange model and the law of conservation of mass, the multi-stage enantioselective liquid-liquid extraction model has been established to analyze and discuss on multi-stage
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centrifugal fractional extraction process of 4-nitrobenzenze glycine (PGL) enantiomers. The influence of phase ratio, extractant concentration and PF6- concentration on the concentrations of enantiomers in the extract and raffinate was investigated by experiment and simulation. When the number of stages is 18 stages at extractant
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excess of 1.0 or 14 stages at extractant excess of 2.0, the eeeq (equal enantiomeric excess) can reach to 99%.
ACCEPTED MANUSCRIPT Separation Science and Engineering
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Simulation and analysis of multi-stage centrifugal fractional
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extraction process of 4-nitrobenzenze glycine enantiomers*
Ping Wen(文平)1, Kewen Tang(唐课文)2,, Jicheng Zhou(周继承)1,**, Panliang Zhang(张盼良)2,** 1
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Department of Chemical Engineering, Xiang Tan University, Xiangtan 411105, Hunan, China
2
Department of Chemistry and Chemical Engineering, Hunan Institute of Science and Technology, Yueyang
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414006, Hunan, China
Received 15 January 2014
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Article history:
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Received in revised form 20 April 2014
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Accepted 17 June 2014
*Supported by the Natural Science Foundation of China (No.21176062), Hunan Provincial Natural Science Foundation of China (No. 12JJ2007), Scientific Research Fund of Hunan Provincial Education Department (12B053), Science and Technology Planning Project of Hunan Province (2012GK3107) and Aid program for Science and Technology Innovative Research Team in Higher Educational Institutions of Hunan Province. ** To whom correspondence should be addressed. E-mail: [email protected] (P. L. Zhang), [email protected] (J. C. Zhou)
Abstract Based on the interfacial ligand exchange model and the law of conservation of mass, the multi-stage
enantioselective liquid-liquid extraction model has been established to analyze and discuss on multi-stage
centrifugal fractional extraction process of 4-nitrobenzenze glycine (PGL) enantiomers. The influence of phase ratio, extractant concentration and PF6- concentration on the concentrations of enantiomers in the extract and raffinate was investigated by experiment and simulation. A good agreement between model and experiment was
ACCEPTED MANUSCRIPT obtained. On this basis, the influence of many parameters such as location of stage, concentration levels, extractant
excess and number of stages on the symmetric separation performance was simulated. The optimal location of feed
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stage is the middle of fractional extraction equipment. The feed flow must satisfy a restricted relationship on flow
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ratios and the liquid throughout of centrifugal device. For desired purity specification, the required flow ratios decreases with extractant concentration and increases with PF6- concentration. When the number of stages is 18 stages at extractant excess of 1.0 or 14 stages at extractant excess of 2.0, the eeeq (equal enantiomeric excess)
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can reach to 99%.
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Keywords fractional extraction, multistage model, interfacial ligand exchange, chiral separation
1 INTRODUCTION
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Chirality is important in chemical research and chemical industry[1]. When a molecule is
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chiral, the pharmacological activity and toxicity of the different enantiomers may be largely
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different[2]. For example, (S),(S)-ethambutol is tuberculostatic, while (R),(R)-ethambutol causes blindness[3]. The demand for enantiopure compounds is growing rapidly[4]. The most common
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technique to obtain enantiopure compounds is the racemic resolution through crystallization[5]. However, this technique is not always applicable because of excessive solid handling. With the development of separation technology, other techniques, such as simulated moving bed chromatography technique[6-10], enzymatic resolution or biocatalysis[11-14], liquid membrane technology[15-17], and enantioselective liquid-liquid extraction (ELLE)[18-35], have been developed. However, the high cost of SMB, the limitation of enzyme specifity and activity, and the limited transport rates in membrane technology, have impeded their industrial application, while ELLE has circumvented these imperfections and seems to be the most promising technology to separate the enantiomers, such as amino acid, amino alcohol, and aromatic acids.
ACCEPTED MANUSCRIPT Process intensification is a powerful concept to use smaller equipments that combine multiple operations in single highly integrated devices to replace large, energy intensive equipment or
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processes[36]. The Centrifugal contactor separator (CCS) is a very attractive device to integrate
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dispersion of two immiscible liquids, chemical reaction and subsequent phase separation of liquid-liquid systems, which is beneficial not only to energy and investments saving but also to improvement of the efficiency and the selectivity of the extraction processes. Therefore, the CCS
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is perfectly fit for PI on ELLE and bridges the gap between the typical ELLE laboratory
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experiments in batch to larger scale continuous operation.
In recent years, aromatic acid enantiomers have been successfully separated in CCS
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equipment in the operation conditions optimized by the multi-stage ELLE model on homogeneous
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reaction in our works[37, 38]. 4-Nitrobenzene glycine (PGL) is an important pharmaceutical
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chemicals and can be used as D-serine transporter inhibitor for the treatment of nervous system disorders. Separation of PGL enantiomers is of much importance in its analysis and use. On this
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basis, the multi-stage ELLE model on interfacial reaction was established to investigate the multi-stage centrifugal fractional extraction process of 4-nitrobenzenze glycine enantiomers in this paper.
2 MATERIAL AND METHODS 2.1 Material Tetrakis(acetonitrile)copper(I) hexafluorophosphate ([(CH3CN)4Cu]PF6, purity > 99% (w/w)) was
supplied
by
Hewei
Chemical
Co.,
Ltd.
(Guangzhou,
China).
(S)-(−)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthalene ((S)-BINAP) (purity > 99% (w/w)) was
ACCEPTED MANUSCRIPT obtained from Shengjia Chemical Co., Ltd. (Hebei, China). 4-nitrobenzenze glycine (purity > 98% (w/w)) was purchased from HanHong Biochemical Co., Ltd. (Jiangsu, China). Solvent for
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chromatography was of HPLC (High-performance liquid chromatography ) grade. Purified water
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was obtained by reverse osmosis followed by distillation. All other chemicals were of analytical-reagent grade and supplied by different suppliers.
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2.2 Analytical method
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The quantification of the PGL enantiomers in raffinate was performed by HPLC with a UV detector (Merck, Hitachi, Japan) operated at the UV wavelength 260 nm. The column was
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Lichrospher C18 (250×4.6 mm i.d., 5 μm of the packing materials) (Hanbon Science &
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Technology, China). The mobile phase was a mixture of 30 mmol·L-1 sodium acetate aqueous
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solution and methanol (80:20, V/V) containing 2.0×10-3 mol·L-1 L-phenylalanine and 0.5×10-3 mol·L-1 copper sulfate at pH = 4.8 (pH was measured with a pH electrode and a pH meter (Orion,
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model 720A)). The flow rate was set at 1 mL·min-1, and the column temperature was set at 27 oC.
2.3 Extraction experimental method The aqueous phase was prepared by dissolving NaPF6 in 0.1 mol·L-1 NaH2PO4/H3PO4 buffer solution, and racemic PGL was dissolved in 0.1 mol·L-1 NaH2PO4/H3PO4 buffer solution to prepare the feeding phase. The organic phase was prepared by dissolving BINAP-Cu in 1,2-dichloroethane. Extraction experiment was performed by starting the engines of all CCSs and starting the extract (organic phase) pump. After starting the extract pump, the CCSs were filled up in the order from Stage 10 to Stage 1. After the organic phase outflow from Stage 1, the wash
ACCEPTED MANUSCRIPT streams (aqueous phase) were started. When the aqueous phase ran from Stage 10, the feed pump was started. As soon as the feed pump started running, samples of 0.5 mL were taken every 15 min
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from raffinate. The concentrations of AD and AL (represent the enantiomers of D-PGL and L-PGL
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respectively) in raffinate were analyzed using HPLC.
3 Multi-stage equilibrium ELLE model formulations
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A typical flow scheme of a cascade for the separation of AD,L (represent the 4-nitrobenzenze
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glycine raceme) into the enantiomers AD and AL is depicted in figure 1. The fractional extractor consists of two sections, a stripping section and a wash section. The feed is entered at the feed
D
stage and is mixed instantaneously with the aqueous phase that exits the wash section. The stage
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relations in the cascade follow figure 2, in which a single stage from the cascade is displayed. The
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definition of parameters is listed in Table 1. The model parameter values were determined by the thermodynamic studies on the single-stage extraction of 4-nitrobenzene glycine enantiomers in
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our previous work[39].
Raffinate W+F
N Slovent O
AD,L Stripping section N-1
f+1
Organic feed
F
f
f-1
Wash feed W
Wash section 2
1 Extract O
Figure 1 Flow scheme of the multi-stage centrifugal fractional extraction of PGL enantiomers.
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[Ai] j-1 [Ai
-]
j-1
O
Wj-1 [PF 6-]j-1
aqueous phase
[Ai] j
[CuB]j
[Ai-]j
[CuBAi] j
P0
Ai
Ai
organic phase
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Ka Pi
A i-
[A i]j
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H+ Ai -
Fj
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CuPF6{(S)-BINAP} Ki PF6
[PF 6-]j
[Ai] j [Ai-] j
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Table 1 Parameters of the equilibrium model
definitiona
parameter
[ Ai ]aq, j [ H ]aq, j
D
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[ Ai ]aq, j
[ Ai ]org, j
P0
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[ Ai ]org, j
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Pi
[ Ai ]aq, j
KD
KL
[ Ai ]aq, j
[CuBAD ]org, j [ PF6 ]aq, j [ AD ]aq, j [CuB]org, j [CuBAL ]org, j [ PF6 ]aq, j [ AL ]aq, j [CuB]org, j
Cu{(S)-BINAP}A i
[Ai]j+1
[CuBAi]j+1
[Ai-]j+1
[CuB] j+1
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Wj
Figure 2 Single extraction stage. i = D, L.
Ka
-
O
value
dimensions
1.0×10-5.6
mol·L-1
0.01074
dimensionless
0.08095
dimensionless
4.46
dimensionless
18.90
dimensionless
a
The definitions of the parameters P0, Pi and Ka are valid for both enantiomers.
The component balances for Ai (i = D, L) and PF6- for each of the stages (j = 1 … N) are defined as forms forms forms forms Fj [ Ai ]allj forms Wj 1[ Ai ]all O[ Ai ]all Wj [ Ai ]all O[ Ai ]all aq , j 1 org , j 1 aq , j org , j
W j 1[ PF6 ]aq, j
1
O[CuB]org , j 1 W j [ PF6 ]aq, j O[CuB]org , j
(1) (2)
If j < f, then Fj = 0 and Wj-1 = Wj = W. If j = f, then Fj = F, Wj-1 = W and Wj =.W+F. If j > f, then Fj
ACCEPTED MANUSCRIPT = 0 and Wj-1 = Wj = W+F. The overall component mass balances for CuB (represent CuPF6{(S)-BINAP}) and the
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enantiomers Ai are defined as
forms F[ Ai ]all f
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[CuB]0 [CuB]org , j [CuBAD ]org , j [CuBAL ]org , j forms all forms (W F )[ Ai ]all O[ Ai ]org aq , N ,1
(3) (4)
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4 RESULTS AND DISCUSSION
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The model was solved using the software package Matlab.
The fractional extraction of 4-nitrobenzenze glycine enantiomers is an extremely complicated process, which is mainly influenced by various process parameters, such as phase ratio (O/W),
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extractant concentration and PF6- concentration of aqueous phase. In this paragraph, a series of
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experiments and simulations are performed to reveal the objective laws of these process
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parameters on the concentrations of enantiomers in the extract and raffinate.
4.1 Influence of O/W ratio
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The influence of phase ratio on enantiomers concentration in the extract and raffinate was investigated at constant setting for concentration of each component, pH value, O/F ratio and feed flow (F). The results are given in Figure 3. At O/W ratio below 1.0, with the increase of organic phase flow, the L-PGL concentration in the raffinate decreases quickly and increases in the extract. But the D-PGL concentration in the raffinate and in the extract change marginally. After O/W ratio of 1.0, only a few L-PGL exists in aqueous phase, and the L-PGL concentration in the extract decreases with the increase of organic phase flow. The reason for these may be that, L-PGL is preferentially distinguished by the extractant CuPF6{(S)-BINAP}. When O/W ratio is of 1.0 to 2.0, the extractant is present in excess with respect to L-PGL, most of D-PGL are distinguished and
ACCEPTED MANUSCRIPT extracted into the organic phase, and it leads to D-PGL concentration in the raffinate decrease and increase quickly in the extract. After O/W ratio is higher than 2.0, nearly all of D-PGL and L-PGL
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have been extracted into organic phase, D-PGL concentration in the extract is equal to it of L-PGL
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and both of them decrease continuously with O/W. Thus, to get a better separation effect a suitable phase ratio is required. From figure 3 O/W of 1.0 is applicable for separation of PGL enantiomers. all forms
The mean relative error is 1.72% of [A D ]aq , respectively.
all forms
, 2.53% of [A D ]org
and
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D
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all forms
3.08% of [A L ]org
all forms
, 2.24% of [A L ]aq
Figure 3 Influence of O/W ratio on the equilibrium concentrations of PGL enantiomers in the raffinate and extract.
(Lines: model prediction. Symbols: experimental data. Conditions: O/F = 2.0, [AD,L] = 2.0×10-3 mol·L-1, [PF6-] = 2.0×10-3 mol·L-1, [CuB] = 1.0×10-3 mol·L-1, pH = 7.0, f = 6 and N = 10)
4.2 Influence of extractant concentration In the stripping section, the ionic PGL enantiomers in the aqueous phase react with CuPF6{(S)-BINAP} on two-phase boundary and the complexes transfer into the organic stream. To gain insights on the influence of extractant concentration on enantiomers concentration in the extract and raffinate, a series of experiments and simulations were carried out. As shown in figure 4, the simulation results have a good agreement with the experimental data. Both enantiomers are extracted with a preference for L-PGL enantiomer, enantiomers concentration in the raffinate
ACCEPTED MANUSCRIPT decrease with extractant concentration. At extractant concentration higher than 0.001 mol·L-1, D-PGL enantiomers begin to be largely extracted into the organic phase. After CuPF6{(S)-BINAP} concentration higher than 0.0025 mol·L-1, all enantiomers in the aqueous phase are occupied by
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CuPF6{(S)-BINAP} and are extracted into the organic phase. Thus, enantiomers concentration in
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the raffinate drop to be zero and as a result both D-PGL and L-PGL enantiomers concentration in all forms
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the extract change to be constant. The mean relative error is 1.22% of [A D ]aq
, 0.73% of
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D
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all forms all forms all forms [A L ]aq , 1.62% of [A D ]org and 1.14% of [A L ]org , respectively.
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Figure 4 Influence of extractant concentration on the equilibrium concentrations of PGL enantiomers in the raffinate and extract.
(Lines: model prediction. Symbols: experimental data. Conditions: O/F = 2.0, O/W = 1.0, [AD,L] = 2.0×10-3 mol·L-1, [PF6-] = 2.0×10-3 mol·L-1, pH = 7.0, f = 6 and N = 10)
4.3 Influence of PF6- concentration In the wash section, the molecular and ionic PGL enantiomers in the organic stream are redistributed over the aqueous and organic phase, a small percentage of them are washed back to the aqueous stream and then flow into the stripping section. Part of complex enantiomers (CuBAD and CuBAL) from the stripping section are compelled to be decomposed at the interface with a precedence for CuBAD because of the presence of PF6- in the aqueous stream, which will lead to a significant influence on the equilibrium concentrations of PGL enantiomers in the raffinate and extract. It can be seen in figure 5 that the concentrations of PGL enantiomers in the extract
ACCEPTED MANUSCRIPT decrease and the concentrations of PGL enantiomers in the raffinate increase at increasing PF6concentration. Furthermore, in the PF6- concentration region between 0.0 and 0.002 mol·L-1, the influence of increasing PF6- concentration on D-PGL enantiomers concentrations is far more
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significant than on L-PGL enantiomers concentrations. However, after PF6- concentration more
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than 0.002 mol·L-1, most CuBAL complexes begin to be decomposed and it leads to the decrease
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of L-PGL enantiomers concentration in the extract and increase in the raffinate, whereas, D-PGL enantiomers concentration just changes slightly, which will largely cut down the separation performance. Thus, for a better separation performance, a proper PF6- concentration in wash feed all forms
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is needed. The mean relative error is 0.64% of [A D ]aq
all forms
, 1.03% of [A L ]aq
, 2.14% of
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D
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all forms all forms [A D ]org and 2.21% of [A L ]org , respectively.
Figure 5 Influence of PF6- concentration on the equilibrium concentrations of PGL enantiomers in the raffinate and extract. (Lines: model prediction. Symbols: experimental data. Conditions: O/F = 2.0, O/W = 1.0, [AD,L] = 2.0×10-3 mol·L-1, [CuB] = 1.0×10-3 mol·L-1, pH = 7.0, f = 6 and N = 10)
4.4 Concentration profile For the in-depth knowledge on the multi-stage centrifugal fractional extraction process of PGL enantiomers, concentration profile of each component at steady state is given in figure 6 through simulation. Note that the flow direction for the aqueous stream is from 1 stage to 10 stage, and for the organic stream counter-currently from 10 stage to 1 stage. Figure 6 shows that the
ACCEPTED MANUSCRIPT concentrations of CuPF6{(S)-BINAP} and PF6- in the cascade are high at both ends and low in the middle of the cascade, but in the flow direction view, their tendencies are opposite. The concentrations of L-PGL enantiomers in the aqueous phase and organic phase are low at both ends
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and high in the middle. For D-PGL enantiomers, the concentrations are low between 1 stage and 5
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stage and high between 6 stage and 10 stage. The reason is that CuPF6{(S)-BINAP} has a
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preference for L-PGL enantiomers in the stripping section and PF6- has a preference for CuBAD complex. In the experiments, the aqueous concentration of enantiomers in the of 10 stage, measured after 5 hours at steady-state, HPLC chromatogram is depicted in Figure 7(b) and the
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original sample chromatogram is shown as Figure 7(a).
Figure 6 Concentration profile in the 10 stage cascade at steady state.
(O/F = 2.0, O/W = 1.0, [AD,L] = 2.0×10-3 mol·L-1, [PF6-] = 2.0×10-3 mol·L-1, [CuB] = 1.0×10-3 mol·L-1, pH = 7.0, f = 6 and N = 10)
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ACCEPTED MANUSCRIPT
(a)
(b)
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Figure 7 HPLC chromatogram of PGL enantiomers in the aqueous phase before (a) and after separation (b).
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It can be concluded from the above that flow ratios, extractant concentration and PF6-
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concentration have great effects on the extraction process. The concentrations of enantiomers in the extract and raffinate change regularly in the process of different extraction conditions. A high
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correlation between model and experiment was shown in the above studies. The model is satisfied for the multi-stage centrifugal fractional extraction process simulation and optimization of
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4-nitrobenzenze glycine enantiomers. It is therefore the aim of below chapter to study with the model which different extraction conditions generate a specified yield and product optical purity in each stream, and the specifications of them are exchanged for „equal yield (yieldeq)‟ and „equal enantiomeric excess (eeeq)‟. We call this operation „symmetric separation‟. The enantiomeric excess and yield are defined in equations as follows. Enantiomer AL predominates in extract stream, its ee is given in equation 5. Note that „AL‟ and „AD‟ encompass L-PGL and D-PGL in all forms (AL, AL-, CuBAL, etc.) in this equation.
ee
all forms all forms [ AL ]org [ AD ]org all forms forms [ AL ]org [ AD ]all org
(5)
ACCEPTED MANUSCRIPT Enantiomer AD predominates in raffinate stream, its ee is defined by equation 6:
(6)
forms forms [ AD ]all [ AL ]all aq aq
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ee
forms forms [ AD ]all [ AL ]all aq aq
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The yield of the enantiomer AL in extract stream is given in equation 7. Similary, the yield of
total AL extract [mol ] total AL feed [mol ]
(7)
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yield AL , extract
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AD in raffinate stream can be defined.
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4.5 Symmetric separation 4.5.1 Location of feed stage
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The location of feed stage is a degree of freedom in the multi-stage centrifugal fractional
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extraction processing equipment. The amount of stages in the stripping section and the wash
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section will be altered with the location of feed stage, and it will lead to different performance of symmetric separation. It can be seen in figure 8 that the feed stage located in the middle of the
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cascade equipment, a better symmetric separation performance can be obtained than at other locations. In this paper, the single L-PGL and D-PGL enantiomers have different medicinal value, at the same time the concentration of L-PGL and D-PGL enantiomers in the raw material is equal. Therefore, the feed stage located exactly in the middle is the most efficient solution for symmetrical separation of PGL enantiomers.
ACCEPTED MANUSCRIPT
1 eeeq
yieldeq
0.95 0.9
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0.8 0.75
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eeeq or yieldeq
0.85
0.7
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0.65 0.6 0.55
2
3
4
5 6 7 Location of feed stage
8
9
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0.5
Figure 8 Influence of the location of feed stage on the performance for symmetrical separation of PGL enantiomers.
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(O/F = 2.0, O/W = 1.0, [AD,L] = 2.0×10-3 mol·L-1, [PF6-] = 2.0×10-3 mol·L-1,
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[CuB] = 1.0×10-3 mol·L-1, pH = 7.0, N = 10)
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4.5.2 Concentration level
In the cascade equipment of three solution inlets, concentration level encompasses
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enantiomers concentration of feed inlet ([Ai]), extractant concentration of organic phase inlet ([CuB]) and PF6- concentration of aqueous phase inlet ([PF6-]). In this chapter, the performance for
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symmetrical separation of PGL enantiomers will be simulated under different concentration levels. 4.5.2.1 Enantiomers concentration PGL enantiomers concentration and feed flow get together to determine the production rate. There is no doubt that the bigger the values of enantiomers concentration and feed flow are, the better will be in the industrial production. The enantiomers concentration is limited by the solubility of PGL enantiomers in the feed stream, which can be determined experimentally. Therefore no further simulations were carried out on the enantiomers concentration level. In addition, the feed flow is determined by the flow ratios (O/W = a, O/F = b) and the minimum and maximum liquid throughput (Vmin and Vmax, L·min-1) of the real centrifugal device.
ACCEPTED MANUSCRIPT The three inlet flows must satisfy the restriction on „ Vmin W O ‟ and „ W O F Vmax ‟. Then the value of the feed flow can be deduced to: (8)
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a a Vmin F Vmax ab b ab a b
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Furthermore, for a fixed equal enantiomeric excess of products in the process design (e.g. 0.90 eeeq) the flow ratios are bound up with the selected concentration levels of extractant and PF6-. Thus, it is necessary to investigate the influence of extractant and PF6- concentration level on the
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performance for symmetrical separation of PGL enantiomers.
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4.5.2.2 Extractant concentration
Extractant concentration is an important degree of freedom in the multi-stage extraction
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system. The eeeq is simulated as a function of flow ratios at different extractant concentration
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settings. It can be seen in figure 9a, b, c that eeeq decreases to the minimum with O/W and
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increases to the maximum with O/F at a fixed extractant concentration settings. Furthermore, by comparative analysis, it can be found that extractant concentration level has a significant influence
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on the flow ratios for a desired purity specification (e.g. 0.90 eeeq). With the increasing of extractant concentration, the required flow ratios decrease.
(a)
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(b)
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ACCEPTED MANUSCRIPT
(c)
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Figure 9 Influence of extractant concentration on the symmetrical separation of PGL enantiomers. ((a) [CuB] = 0.0001 mol·L-1, (b) [CuB] = 0.001 mol·L-1, (c) [CuB] = 0.001 mol·L-1, [PGL] = 2.0×10-3 mol·L-1, [PF6-] = 2.0×10-3 mol·L-1, pH = 7.0, f = 6 and N = 10)
4.5.2.3 PF6- concentration PF6- concentration as a degree of freedom plays an important role in improving the washing effect of washing section. The eeeq is simulated as a function of flow ratios at different PF6concentration settings in figure 10a, b and figure 9b. The eeeq gets to the minimum with O/W and drops to the maximum with O/F at a fixed PF6- concentration settings. For a desired purity specification (e.g. 0.90 eeeq), with the increasing of PF6- concentration, the required flow ratios increase.
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(a)
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ACCEPTED MANUSCRIPT
(b)
-
Figure 10 Influence of PF6 concentration on the symmetrical separation of PGL enantiomers.
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((a) [PF6-] = 0.0005 mol·L-1, (b) [PF6-] = 0.004 mol·L-1,
[PGL] = 2.0×10-3 mol·L-1, [CuB] = 1.0×10-3 mol·L-1, pH = 7.0, f = 6 and N = 10)
It can be seen from the above investigations the mutual influences of concentration levels and flow ratios conclude that there are many combinations of them to obtain desired production purity. Thus, without a detailed economical analysis, it cannot be decided which way is most efficient. However, the simulation can provide a scientific method for comparative analysis in the real industrial production.
4.5.3 Number of stages In industrial production, it is necessary to operate not only at higher enantiomers
ACCEPTED MANUSCRIPT concentration but also at minimal extractant concentration and number of stages to obtain higher purity and higher yield and to cut down the production cost. The concentrations of extractant and
F [ AD , L ] feed
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O[CuB]org ,0
(9)
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extractant excess
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enantiomers are expressed as „extractant excess‟ (eq.9).
The eeeq is simulated as a function of number of stages at different extractant excess via
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changing extractant. It can be seen in figure 11 that the eeeq increases with the increasing of number of stages and then finally reaches a plateau. It was also observed in the simulation results
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that at lower extractant excess, no matter how many stages increases to, a full separation can never
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be obtained in the multi-stage centrifugal fractional extraction process. In these conditions, the
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extractant will become fully loaded, and increasing the number of stages will not increase the optical purity any further. Therefore, in order to make good use of the centrifugal contactors, a
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reasonable extractant excess is necessary. As shown in figure 11, when the number of stages is 18 stages at extractant excess of 1.0 or 14 stages at extractant excess of 2.0, the eeeq can reach to 99%.
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The settings for the two cases are listed in table 2.
Figure 11 Influence of number of stages on the symmetrical separation of PGL enantiomers at different extractant excess by increased [CuB]. (O/F = 2.0, [AD,L] = 2.0×10-3 mol·L-1, [PF6-] = 2.0×10-3 mol·L-1, pH = 7.0, f = 2/N+1)
ACCEPTED MANUSCRIPT Table 2 Settings for symmetrical separations with extractant excess = 1.0 or 2.0, [AR,S] = 2.0×10-3 mol·L-1, pH = 7.0. Production purity ＞99% eeeq
extractant excess = 2.0
N
18
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f
10
O/F
2.0
O/W
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8
0.2
1.0×10-3
2.0×10-3
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2.0
2.0×10-3
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2.0×10-3
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5 CONCLUSIONS
14
0.7
[CuB] (mol·L-1) [NaPF6] (mol·L-1)
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extractant excess = 1.0
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Variable
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The multi-stage ELLE (enantioselective liquid-liquid extraction) model has been successfully developed to simulate and analysis of multi-stage centrifugal fractional extraction process of 4-nitrobenzenze glycine enantiomers. The objective laws of process parameters such as phase
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ratio, extractant concentration and PF6- concentration on the concentrations of enantiomers in the extract and raffinate are revealed by a series of experiments and simulations. Furthermore, by simulation and analysis on the symmetric separation performance, many important conclusions have been made to instruct process design. When the number of stages is 18 stages at extractant excess of 1.0 or 14 stages at extractant excess of 2.0, the eeeq (equal enantiomeric excess) can reach to 99%.
NOMENCLATURE CuB
CuPF6{(S)-BINAP}
ee
enantiomeric excess
Ka
amino acid dissociation constant, mol/L
ACCEPTED MANUSCRIPT complexation constants
PGL
4-nitrobenzene glycine
P0
physical partition coefficient for molecular PGL
Pi
physical partition coefficient for ionic PGL
Vmax
maximum liquid throughput
Vmin
minimum liquid throughput
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K
eq
equal value
i
index for D,L stage index
0
initial value
org
organic phase
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j
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aqueous phase
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aq
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Subscripts
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