Resolution of Enantiomers Using Enantioselective Micelles in

Chapter 9

Resolution of Enantiomers Using Enantioselective Micelles in Ultrafiltration Systems

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Overdevest , Jos T. F. Keurentjes , A . van der Padt , and K . van 't Riet

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Downloaded by TUFTS UNIV on December 1, 2015 | http://pubs.acs.org Publication Date: November 16, 1999 | doi: 10.1021/bk-2000-0740.ch009

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Department of Food Science, Food and Bioprocess Engineering Group, Wageningen Agricultural University, P. O. Box 8129, 6700 EV Wageningen, Netherlands Department of Chemical Engineering, Process Development Group, Eindhoven University of Technology, P.O. Box 513, 5600 MB Eindhoven, Netherlands

Since it has been recognized that the demand for enantiopure compounds will increase, more and more effort is put in the development of resolution technology. The traditional route to obtain homochiral products is enantiomer separation using diastereoisomer crystallization. Disadvantages of this resolution processes are costly scale-up and a high energy requirement. An alternative is ultrafiltration of enantioselective micelles, which is an easily scalable process with a low energy requirement. In this system, the enantioselective micelles preferentially form a complex with one of the enantiomers. Only free enantiomers can pass the membrane. The objective of this research is to describe the complexation of phenylalanine enantiomers by enantioselective micelles (cholesteryl-L-glutamate anchored in nonionic micelles). It is concluded that straightforward multicomponent Langmuir isotherms can describe the enantiomer complexation by these micelles. The applied science of enantiomer separation, chirotechnology, is a fast developing research field with applications in the pharmaceutical, agrochemical and food industries. The main reasons for the increasing demand for enantiomerically pure compounds are (7): • enantiomers can have different biological activities; • enantiomers can counteract one another's effect, so-called antagonism; • the unwanted enantiomer is seen as an impurity as a consequence of registration constraints in certain countries; and • production costs can decrease significantly as a consequence of an increased production capacity or a decreased use of other expensive achiral intermediates. Since not all optically pure products are available from the chiral pool (2), enantiomers have to be produced from (a)chiral substrates or have to be separated

© 2000 American Chemical Society

In Surfactant-Based Separations; Scamehorn, J., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1999.

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124 from their racemic mixture (equimolar mixture of the two enantiomers). Diastereoisomer crystallization, the conventional separation method, is often a batchwise operation (3) and requires relatively inflexible multi-step processing (7). In many cases a low product yield is observed in one single batch operation, due to a generally low selectivity. The use of membranes for the resolution of racemates can result in a continuous and energy efficient multi-stage separation process at an industrial scale. Chiral discrimination is the basis of enantiomer separation (4). This chiral discrimination can take place in the membrane matrix itself or in the liquid phases separated by the membrane. Selective membranes have been applied as an enantioselective barrier retaining one enantiomer more than the other. Examples thereof are membrane matrices made of chiral polymers (5-7), molecular imprinted membranes (3,8,9), supported liquid membranes (10-12), emulsion liquid membranes (13,14) and membranes containing proteins (15,16). Non-selective membranes have been used to separate two (im)miscible phases of which at least one is chiral, similar to liquid/liquid extraction where two immiscible phases are used to separate enantiomers (17-19). The performance of conventional liquid/liquid extraction equipment is often limited by backmixing and flooding (20). These limitations are eliminated in hollow-fiber membrane extraction, where non-selective membranes separate both phases (21,22). For an efficient process design, it is mandatory that the chiral selector molecules from one phase are insoluble in the other phase. Moreover, if there is a demand for both enantiomers in their optically pure form, the partition of the enantiomers over both phases should not be too farfromunity, since at a high partition coefficient one of the enantiomers will become extremely diluted. This results in losses of valuable product (23). Alternatively, membranes are used to separate a miscible enantioselective microheterogeneous phase from the aqueous bulk. Membrane rejection of the enantioselective phase is guaranteed by using molecules or colloidal particles larger than the pore size of the membrane, e.g. BSA (24,25) or enantioselective micelles as demonstrated by our group (26). Micellarenhanced ultrafiltration (MEUF) has proven its potential to preconcentrate heavy metals and organic compoundsfromaqueous streams (27-29). In addition, micelles are used in micellar electrokinetic capillary chromatography (MEKC) to separate enantiomers on an analytical scale (30-32). Figure 1 shows the investigated MEUF system in which a chiral selector molecule (cholesteryl-L-glutamate) preferentially forms a ternary complex with one of the enantiomers (phenylalanine, Phe) using a Cu(II) ion. The D,L notation is used to distinguish between both phenylalanine enantiomers. The chiral selector molecules (CS) are anchored in micelles of the nonionic surfactant, nonyl-phenyl polyoxyethylene [E10] ether. Nonionic surfactants are used to eliminate undesired electrostatic interactions between enantiomers, Cu(II) ions and micelles (33,34). The MEUF system results in enantiomer separation as a consequence of: • selective complexation of enantiomers by chiral selectors; • rejection of micelles by the membrane and consequently of complexed enantiomers; and • permeation of uncomplexed enantiomers.



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Figure 1. Experimental set-up of the Amicon cell and an impression of the enantiomer separation at the membrane.


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The objective of this study is to describe the complexation of enantioselective micelles and Phe enantiomers in an ultrafiltration system. These complexation isotherms are required to design a system based upon MEUF for the complete resolution of a racemic mixture. Theory

Analogous to Langmuir adsorption isotherms, the binding of enantiomers by chiral selector molecules can be described assuming reversible one-to-one complexations.


Single- and Multicomponent Langmuir Complexation Isotherms. Langmuir has

derived the classical equilibrium isotherm for localized nonlinear monolayer adsorption, considering equilibrium at equal adsorption and desorption rates (35). It is proposed for single gas adsorption and based on the following assumptions (36): • adsorbate molecules are held at a defined number of sites; • each site can accommodate one single adsorbate molecule; • the adsorption energy is equal for all sites; and • neighboring adsorbate-adsorbate interactions do not occur. The Langmuir isotherm has been adapted to describe multicomponent solute adsorption from dilute solutions by simple replacement of the adsorbate pressure by the solute concentration (37). Competitive adsorption takes place, since two enantiomers strive for complexation with the same site. Both single- and multicomponent Langmuir isotherms are used to describe enantiomer complexation (25,38,39). The single-component isotherms are given by equations 1 and 2, respectively: K

c

Resolution of Enantiomers Using Enantioselective Micelles in

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