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Chiral separation by enantioselective inclusion complexation-organic solvent nanofiltration
Desalination 199 (2006) 398–400
Chiral separation by enantioselective inclusion complexation-organic solvent nanofiltration Nazlee F. Ghazalia, Frederico C. Ferreiraa, Andrew J.P. Whiteb, Andrew G. Livingstona* a
Department of Chemical Engineering, Imperial College London, South Kensington Campus SW7 2AZ. UK email: [email protected] b Department of Chemistry Imperial College London, South Kensington Campus SW7 2AZ. UK Received 25 October 2005; accepted 6 March 2006
1. Introduction Enantioselective inclusion complexation (EIC) is a promising technique for chiral resolutions which, since it is not restricted to proton transfer interactions, can in principle be used to resolve compounds with almost any functional group. However, an outstanding difficulty with EIC is the separation of enantiomer from the enantioenriched solid complex, typically performed by distillation. This limits EIC to enantiomers with appreciable volatility, and even for these it would be difficult to operate at large-scale due to high temperature distillation, with concomitant problematic heat transfer and vacuum conditions. Here we report for the first time a novel enantioseparation process which combines the highly enantioselective nature of inclusion complexation with the subsequent separation of enantiomers from a chiral host using solvent decomplexation and organic solvent nanofiltration (OSN). In our proposed process (Fig. 1), a racemate is added to a chiral host suspended in a resolution solvent. The S-enantiomer enantioselectively *Corresponding author.
co-crystallizes with the chiral host while the R-enantiomer remains in the liquid (Step A). Nanofiltration of the resulting resolution suspension elutes the R-enantiomer (Step B), retaining the solid chiral host and the solid chiral host-Senantiomer complex. A decomplexation solvent is then added to dissolve and dissociate the complex into S-enantiomer and host (Step C). This solution is then nanofiltered to elute the S-enantiomer, while the soluble host is retained by the membrane (Step D). The dissolved host is then returned as a suspension in resolution solvent to the next cycle of resolution. This is achieved by exchanging the decomplexation solvent for the resolution solvent via diafiltration (Step E). Since chiral hosts are used in stoichiometric quantities, their recovery and multiple reuse is a further key advantage of separation by OSN. 2. Results and discussion To demonstrate this process, we used a chiral host with a large Mw to resolve a racemic of a smaller racemic alcohol. Starmem™ 122 (Starmem™ is a trademark of W. R. Grace & Co., US) with a nominal molecular weight cutoff
Presented at EUROMEMBRANE 2006, 24–28 September 2006, Giardini Naxos, Italy. 0011-9164/06/$– See front matter © 2006 Published by Elsevier B.V. doi:10.1016/j.desal.2006.03.208
N.F. Ghazali et al. / Desalination 199 (2006) 398–400
399
Host H in resolution solvent returned to subsequent cycle R, S
Resolution solvent
Decomplexation solvent
Decomplexation Resolution solvent solvent Decomplexation
R CS
CS
OSN membrane
R
C
C
C S
S
S
R
Step A: Resolution
Step B: Elution of R
Step C: Decomplexation
Step D: Elution of S
Host C is suspended in resolution solvent and a racemate (R and S) is added. S preferentially complexes with C, leaving the liquid phase enriched in R.
The suspension is nanofiltered using OSN. R permeates the membrane, while the solid CS complex is retained. Further resolution solvent is added to elute R.
Decomplexation solvent is added to the suspension containing the solid complex thereby dissociating the S enantiomer from CS complex.
The solution containing S and host is nanofiltered. S permeates the membrane, while the soluble host C is retained. Further decomplexation solvent is added to elute S.
Step E: Host precipitation Resolution solvent is added to precipitate the host C. Decomplexation solvent is removed by diafiltration with resolution solvent.
Fig. 1. Process schematic of enantioselective inclusion complexation-solvent decomplexation-organic solvent nanofiltration.
(MWCO) of 220 g mol–1 was used for OSN. The alcohol was highly permeable in the OSN membrane, and had zero rejection in both resolution and decomplexation solvents. The chiral host was retained efficiently by the OSN membrane (>99% rejection in both solvents). The molecular recognition of the S alcohol enantiomer by the chiral host employed was investigated by resolving the X-ray crystal structure of the complex formed. We show in independent experiments that it is possible to run the resolution in the presence of 0–20 vol% decomplexation solvent without sacrificing the enantiomeric excess (ee), and so is not required to revert to pure resolution solvent at the end of each cycle (Step E in Fig. 1). Similarly, the complete dissociation of complex into free enantiomers and host happens for solvent mixtures enriched above 60 vol% in
decomplexation solvent. Therefore, from the process point of view, it is not necessary to use either pure resolution solvent (Step A), or pure decomplexation solvent (Step D in Fig. 1), avoiding extensive diafiltration. The feasibility of the process was tested throughout two resolution-filtration cycles. Each filtration step was carried out in several successive batches in a dead-end nanofiltration cell. Elution profile of resolution-filtration process and ee of the permeate stream in each filtration are shown in Fig. 1 and ee and yields for the combined streams are resumed in Table 1. 3. Conclusions A novel enantioseparation process using the combination of EIC and OSN has been
400
N.F. Ghazali et al. / Desalination 199 (2006) 398–400
80 0.60 FIRST CYCLE
SECOND CYCLE
0.50
60 R S ee
0.40
20 0
0.30
Step B
Step D
Step B
Step D
–20 –40
0.20
Combined streams
1st Cycle (%)
2nd Cycle (%)
Step B
–46 89 80 31
–34 80 95 51
40 ee of S / %
R and S enantiomers in the permeate / mmol
Table 1 ee and the yield of permeates
100
0.70
Step D
ee (of R) Yield (of R) ee (of S) Yield (of S)
–60 0.10 –80 0.00
–100 1B1 1B2 1B3 1D1 1D2 2B1 2B2 2B3 2D1 2D2 2D3 Filtration numbers
Fig. 2. Elution profile of resolution-filtration process and ee of the permeate stream in each filtration (indicated in Fig. 1) in two cycles. Step B is the elution of R and Step D is the elution of S. Positive ee indicates S-rich permeate. Negative ee indicates R-rich permeate.
demonstrated, showing for the first time that the use of solvent decomplexation with OSN
allows enantiomer recycling of the chiral host. The strength of this process is the direct use of chiral host (without derivatization or immobilization), relatively high operating concentrations, and ambient temperature processing. We regard the method presented here as having potential as an alternative technique for preparative-scale chiral separations, which could extend the scope of EIC from lab to pilot and industrial scale.
Chiral separation by enantioselective inclusion complexation-organic solvent nanofiltration Nazlee F. Ghazalia, Frederico C. Ferreiraa, Andrew J.P. Whiteb, Andrew G. Livingstona* a
Department of Chemical Engineering, Imperial College London, South Kensington Campus SW7 2AZ. UK email: [email protected] b Department of Chemistry Imperial College London, South Kensington Campus SW7 2AZ. UK Received 25 October 2005; accepted 6 March 2006
1. Introduction Enantioselective inclusion complexation (EIC) is a promising technique for chiral resolutions which, since it is not restricted to proton transfer interactions, can in principle be used to resolve compounds with almost any functional group. However, an outstanding difficulty with EIC is the separation of enantiomer from the enantioenriched solid complex, typically performed by distillation. This limits EIC to enantiomers with appreciable volatility, and even for these it would be difficult to operate at large-scale due to high temperature distillation, with concomitant problematic heat transfer and vacuum conditions. Here we report for the first time a novel enantioseparation process which combines the highly enantioselective nature of inclusion complexation with the subsequent separation of enantiomers from a chiral host using solvent decomplexation and organic solvent nanofiltration (OSN). In our proposed process (Fig. 1), a racemate is added to a chiral host suspended in a resolution solvent. The S-enantiomer enantioselectively *Corresponding author.
co-crystallizes with the chiral host while the R-enantiomer remains in the liquid (Step A). Nanofiltration of the resulting resolution suspension elutes the R-enantiomer (Step B), retaining the solid chiral host and the solid chiral host-Senantiomer complex. A decomplexation solvent is then added to dissolve and dissociate the complex into S-enantiomer and host (Step C). This solution is then nanofiltered to elute the S-enantiomer, while the soluble host is retained by the membrane (Step D). The dissolved host is then returned as a suspension in resolution solvent to the next cycle of resolution. This is achieved by exchanging the decomplexation solvent for the resolution solvent via diafiltration (Step E). Since chiral hosts are used in stoichiometric quantities, their recovery and multiple reuse is a further key advantage of separation by OSN. 2. Results and discussion To demonstrate this process, we used a chiral host with a large Mw to resolve a racemic of a smaller racemic alcohol. Starmem™ 122 (Starmem™ is a trademark of W. R. Grace & Co., US) with a nominal molecular weight cutoff
Presented at EUROMEMBRANE 2006, 24–28 September 2006, Giardini Naxos, Italy. 0011-9164/06/$– See front matter © 2006 Published by Elsevier B.V. doi:10.1016/j.desal.2006.03.208
N.F. Ghazali et al. / Desalination 199 (2006) 398–400
399
Host H in resolution solvent returned to subsequent cycle R, S
Resolution solvent
Decomplexation solvent
Decomplexation Resolution solvent solvent Decomplexation
R CS
CS
OSN membrane
R
C
C
C S
S
S
R
Step A: Resolution
Step B: Elution of R
Step C: Decomplexation
Step D: Elution of S
Host C is suspended in resolution solvent and a racemate (R and S) is added. S preferentially complexes with C, leaving the liquid phase enriched in R.
The suspension is nanofiltered using OSN. R permeates the membrane, while the solid CS complex is retained. Further resolution solvent is added to elute R.
Decomplexation solvent is added to the suspension containing the solid complex thereby dissociating the S enantiomer from CS complex.
The solution containing S and host is nanofiltered. S permeates the membrane, while the soluble host C is retained. Further decomplexation solvent is added to elute S.
Step E: Host precipitation Resolution solvent is added to precipitate the host C. Decomplexation solvent is removed by diafiltration with resolution solvent.
Fig. 1. Process schematic of enantioselective inclusion complexation-solvent decomplexation-organic solvent nanofiltration.
(MWCO) of 220 g mol–1 was used for OSN. The alcohol was highly permeable in the OSN membrane, and had zero rejection in both resolution and decomplexation solvents. The chiral host was retained efficiently by the OSN membrane (>99% rejection in both solvents). The molecular recognition of the S alcohol enantiomer by the chiral host employed was investigated by resolving the X-ray crystal structure of the complex formed. We show in independent experiments that it is possible to run the resolution in the presence of 0–20 vol% decomplexation solvent without sacrificing the enantiomeric excess (ee), and so is not required to revert to pure resolution solvent at the end of each cycle (Step E in Fig. 1). Similarly, the complete dissociation of complex into free enantiomers and host happens for solvent mixtures enriched above 60 vol% in
decomplexation solvent. Therefore, from the process point of view, it is not necessary to use either pure resolution solvent (Step A), or pure decomplexation solvent (Step D in Fig. 1), avoiding extensive diafiltration. The feasibility of the process was tested throughout two resolution-filtration cycles. Each filtration step was carried out in several successive batches in a dead-end nanofiltration cell. Elution profile of resolution-filtration process and ee of the permeate stream in each filtration are shown in Fig. 1 and ee and yields for the combined streams are resumed in Table 1. 3. Conclusions A novel enantioseparation process using the combination of EIC and OSN has been
400
N.F. Ghazali et al. / Desalination 199 (2006) 398–400
80 0.60 FIRST CYCLE
SECOND CYCLE
0.50
60 R S ee
0.40
20 0
0.30
Step B
Step D
Step B
Step D
–20 –40
0.20
Combined streams
1st Cycle (%)
2nd Cycle (%)
Step B
–46 89 80 31
–34 80 95 51
40 ee of S / %
R and S enantiomers in the permeate / mmol
Table 1 ee and the yield of permeates
100
0.70
Step D
ee (of R) Yield (of R) ee (of S) Yield (of S)
–60 0.10 –80 0.00
–100 1B1 1B2 1B3 1D1 1D2 2B1 2B2 2B3 2D1 2D2 2D3 Filtration numbers
Fig. 2. Elution profile of resolution-filtration process and ee of the permeate stream in each filtration (indicated in Fig. 1) in two cycles. Step B is the elution of R and Step D is the elution of S. Positive ee indicates S-rich permeate. Negative ee indicates R-rich permeate.
demonstrated, showing for the first time that the use of solvent decomplexation with OSN
allows enantiomer recycling of the chiral host. The strength of this process is the direct use of chiral host (without derivatization or immobilization), relatively high operating concentrations, and ambient temperature processing. We regard the method presented here as having potential as an alternative technique for preparative-scale chiral separations, which could extend the scope of EIC from lab to pilot and industrial scale.