ARTICLE pubs.acs.org/IECR
Chiral Resolution of Ionic Compounds by Thin Layer Extraction Ram Lavie Department of Chemical Engineering, Technion - Israel Institute of Technology, Haifa, Israel 32000 ABSTRACT: The increasing demand for enantiomer intermediates has attracted in recent years attention to liquidliquid extraction as a scalable chiral resolution method. Thin layer extraction, a simple and effective form of liquidliquid extraction that uses little extractant, promises economic utilization of the most selective chiral hosts. The role played by various parameters when applying thin layer extraction to the resolution of an ionic racemic mixture into its enantiomer components is analyzed. This analysis provides a critical insight that facilitates the design of a successful separation scheme. It transpires that, given a suitable host, certain conditions concerning the host concentration and the pH and rate of the feed and strip solutions must be balanced to obtain optimum enantioseparation or even to obtain any separation at all. A calculated example that is based on experimental data from the published literature indicates that a simple thin layer extractor, using a crown ether host, is capable of separating an ionic racemic mixture into substantially pure enantiomer products at a high yield. It appears that thin layer extraction has some promising features to become an interesting alternative for other extraction-based techniques.
1. INTRODUCTION Chiral resolution is a process for the separation of racemic compounds into their enantiomers. Enantiomers are influential in biology1—a majority of bioorganic molecules are chiral. Enantiomers play an important role in the pharmaceutical industry because enantiomers of a racemic drug may have different pharmacological activities. Enantiomers also play an increasing role in the flavors and fragrances, agrochemicals, food, and polymer industries. Enantiomers are difficult to separate because they have identical physical properties, except for the optical rotation that may be used to sense their distribution but can not serve as a driving force for separation. The separation of enantiomers relies on chiral hosts that bind preferentially to one or the other enantiomer through a mechanism of molecular recognition.2 Chiral hosts are expensive. Highly selective chiral hosts are particularly expensive. Presently, enantiomers are obtained on an industrial scale either directly through asymmetric synthesis or through the separation of a racemic mixture into its enantiomer components by crystallization3 or by chromatography.4 Separation by crystallization is not always applicable. Separation by chromatography, mostly in simulated moving beds, is complicated, expensive, difficult to scale-up, and is associated with waste. The limitations of the presently prevailing separation methods have attracted in recent years a renewed1 interest in chiral resolution by liquid liquid extraction.518 In a liquidliquid extraction (LLX) process, an aqueous solution of the racemate is contacted with an organic phase (the extractant) that consists of a solvent containing an organic chiral host. Some of each enantiomer transfers to the extractant where it reacts reversibly with the host. The selectivity of the host causes an unequal distribution of the free enantiomers in the organic phase. The latter is then contacted with an aqueous strip solution, removing from the organic phase the free enantiomers that are present there in unequal amounts. Multistage operation amplifies the separation. The application of traditional LLX to difficult separations of high value products has r 2011 American Chemical Society
its own flaws. The numerous stages of extraction and stripping are bulky and expensive. They are also associated with substantial, costly inventories of the extractant and processed solutions. Those cause lengthy startup times during which off-spec products are generated—a waste of time and valuable materials. Related methods such as supported liquid membranes19 (SLM) and solvent impregnated resins20 (SIR), that address those impediments confront limited mass transfer rates and stability problems. Centrifugal extractors811,18 have demonstrated successful results while mitigating, up to a limit, the inventory problem. But a chain of numerous centrifugal extractors is expensive and difficult to control. Thin layer extraction21,27 (TLX), a relatively new, simple version of liquidliquid extraction reduces inventories and waste to the minimum. It uses the chiral host effectively and may in some cases do without any solvent at all. It therefore has advantages as a liquidliquid extraction method that is fit for difficult separations of high value products. Much work has been invested in exploring potential hosts for the resolution of various racemate families in both the contexts of chromatography4,22 on a chiral stationary phase (CSP) and for liquidliquid extraction, in a solvent.10,23,24 To this day, fitting a host to a new chiral application remains a bit of an art. Data from chromatography can be useful when searching for an extraction host. The evaluation of a potential host as a selector for a particular racemate passes through the thermodynamic evaluation of its reaction with the enantiomers, that defines a selectivity. Steensma24 discusses the influence of various process parameters on extraction equilibrium in the context of continuous LLX and deals specifically with the complex formation constants, the solvent, and the concentration of the host in the solvent. In what concerns the solvent itself, there are indications that, in some cases, a same host in a different solvent may perform somewhat Received: July 23, 2011 Accepted: October 3, 2011 Revised: October 2, 2011 Published: October 03, 2011 12750
dx.doi.org/10.1021/ie201596n | Ind. Eng. Chem. Res. 2011, 50, 12750–12756
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Scheme 1. Equilibrium Model
Figure 1. Thin layer extraction scheme.
differently.24,25 This has not been fully elucidated and it is sufficient to say that this factor merits consideration when selecting a solvent. Chiral hosts manifest mostly a selectivity in the order of αint = 1.11.7. Some crown ethers and ionic liquids may manifest αint >10. In the following, the application of TLX to the resolution of chiral ionic compounds is studied, analyzed, and simulated, on the basis of a widely accepted model for the transport and separation of the enantiomers.1015 Conditions pertaining to the performance of the chiral host, the solvent, and the boundary conditions are identified. Finally, a simulated example of the separation of an ionic racemic mixture into its components, based on relevant published experimental data20, is developed. The development of a separation process for a new case is generally a time-consuming and costly undertaking.26 It is hoped that the following may also facilitate this task.
2. THIN LAYER EXTRACTION TLX is an intensive, periodic reactive liquidliquid extraction method21,27,28 that implements a compact extraction/back-extraction cycle using little extractant. TLX uses an open, solid macroporous matrix made of a microporous material. A thin layer of the liquid extractant, which is immiscible with the feed and strip liquids, attaches permanently to the microporous material by capillary forces. Then, two feeds, one a donor liquid and the other a strip liquid, alternate at contacting, as thin layers, the thin layer of extractant in a frequent periodic cycle. The species of interest in the donor liquid react with the host in the extractant to form a complex and are then released later in the cycle into the strip liquid at appropriate conditions (pH and/or temperature) that favor such release. In comparison to the traditional LLX structure, the modular counter-current multistage TLX process (Figure 1) is particularly simple and linearly scalable. The extractant need not be dilute beyond what is prescribed by the host solubility. This structure and the frequent cycle that also permits a minimum extractant inventory result in simplicity of operation, compactness, and controllability. In TLX, mass transfer resistance is negligible: with a molecular diffusivity in the order of 109 m2/s, the characteristic time for diffusion through a 20-μm thick layer is of the order of 0.4 s. This is what permits the frequent cycling between the donor and the strip liquids. Unlike resin-based processes, which are usually limited to the processing of dilute feeds because of bed saturation, TLX productivity is independent of saturation values. Process parameters that are ordinarily fixed in traditional LLX, such as the organic to aqueous ratio or, in one version even the number of stages, may be manipulated in TLX, in situ. TLX requires significantly fewer stages, as compared to traditional LLX, to reach a specified reduction ratio.21 At startup, TLX reaches a (periodic) steady state quickly, thereby limiting the generation of off-spec products during the transient. The extractant in TLX must be
particularly insoluble in water such as not to be washed away. The processed solutions must be clean to prevent clogging spray nozzles. The qualities of TLX make of it an attractive tool for difficult separations of high value products to high purity specifications, such as is the case in chiral resolution.
3. MATHEMATICAL MODEL The advantageous mass transfer conditions prevailing in TLX together with the typically fast complex formation rate justify an equilibrium model. The model in Scheme 1 is an adaptation of a widely accepted1015,20 model of the periodic conditions prevailing in each stage of TLX. The enantiomers dissociate in the aqueous phases with only the neutral form distributing between the aqueous and the organic phases according to a distribution coefficient m. In the organic phase, the enantiomers AR, AS, react with the host C to form complexes ARC and ASC. The different equilibrium constants 6 KcS are responsible for the separation. The extraction and KcR ¼ the stripping aqueous phases are maintained at different pH, driving the enantiomers from extraction to stripping. In the following, we shall assume for convenience that the R enantiomer is the one that binds preferentially to the host and that the aqueous solutions are dilute in the enantiomer species. The model also presumes that the initial host concentration is sufficient and is never depleted. According to this model, six subprocesses take place within a cycle of TLX operation: extraction, complex formation, and stripping for each of AR and AS. The parameters that are relevant to the six subprocesses are the four distribution coefficients: Kij ¼
½Aij orgðallformsÞ ½Aij aqðallformsÞ
¼ mð1 þ Kci ½CÞηj , 12751
ðmM=LÞorg ðmM=LÞaq
ð1Þ
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Figure 2 represents a solution to eq 6 for an arbitrary value of Die. β relates the relative strength of the sink to that of the source driving the transfer of the species from donor to strip. A deep sink and/or a strong source cause better transfer. Also, the relative amounts of donor and strip impact β whose value increases with more donor and decreases with more strip. A small β leads to substantial extraction. The intrinsic selectivity of the host is defined as αint ¼
Figure 2. Effect of β on the reduction ratio.
½Aij aqðneutralÞ ½Aij aqðallformsÞ
¼
1 ð1 þ 10ðpHj pKa Þ Þ
,
αop ¼
j ¼ R, S
! S Kij Fj
i ¼ R, S; j ¼ e, s
½Ai C ¼ Kci , ½Ai ½C
i ¼ R, S
ð3Þ
It is convenient to define a complex formation capacity λi that represents the ratio of an enantiomer that is in complex form to that in free form in the organic phase: ½Ai C ¼ Kci ½C ½Ai
ð4Þ
A stripping to extraction factor ratio (5) controls the amount of the enantiomers residing in the organic phase: Dis η Fe β¼ ¼ s Die ηe Fs
yip ¼ yif
ð1 βÞ , Die þ 1 n β βDie þ 1
Die
for n > 1
and Ri ¼
yip βDie þ 1 , ¼ ðβ þ 1ÞDie þ 1 yif
when n ¼ 1
1 þ KcR ½C 1 þ λR 1 þ λS αint ¼ ¼ e αint 1 þ KcS ½C 1 þ λS 1 þ λS
ð8Þ
ð6Þ
Ri is the reduction ratio for component i, and yif and yip are, respectively, the composition of component i in the feed and in the raffinate product. Equation 6 permits the evaluation of the compositions in the raffinate and the strip products, relative to the donor feed composition, as a function of the extraction factors Die, the stripping to extraction factor β, and the number of stages n.
ð1 Ri ÞFe yef Fs
ð9Þ
4. DEVELOPMENT OF A CHIRAL RESOLUTION SCHEME The objective of the separation is to obtain a high product purity and yield, if possible, for both enantiomers. The purity is expressed in terms of an enantiomer excess yRp ySp RR RS ¼ eeR ¼ yRp þ ySp RR þ RS ð10Þ ySp yRp RS RR eeS ¼ ¼ yRp þ ySp RR þ RS where p represents the raffinate product for one enantiomer and the strip product for the other enantiomer. The yield is the fraction of an enantiomer in the feed that ends up in the respective product. YR ¼
ð5Þ
A material balance over the entire extraction scheme yields21 the following for dissolved component i in the donor feed and a solute-free strip feed: Ri ¼
yisn ¼
ð2Þ
Fj/S is the aqueous to organic ratio or service ratio in step j. It is determined by the size, Fj, of the aqueous batches of the donor or the strip that are brought into contact within each cycle of operation with a constant amount S of the extractant. The complex formation equilibrium is defined as
λi ¼
ð7Þ
When λi .1, then αop ≈ αint ≈ α. The composition of the strip product derives from a material balance:
and the four extraction/stripping factors:
Dij ¼
αint > 1
The operational selectivity is
where ηj ¼
KcR ; KcS
PyRp PySp and Ys ¼ FyRf FySf
ð11Þ
4.1. Choosing the Extractant. If the host is a liquid, one may possibly do without a solvent. A high selectivity of the host is clearly desirable. However, other properties of the host and the solvent (if used) must also be considered: (a) mutual solubility of the host, solvent, water, enantiomers, and complex formation products, (b) distribution of the enantiomers between the aqueous and organic phases, (c) complex formation equilibrium. The solvent and the host—together the extractant—must be hydrophobic for compatibility with the microporous substrate, must be insoluble in water to prevent the extractant layer from being washed away, and should not be volatile. Substantial solubility of the host in the solvent (if used) represents an advantage. The enantiomers (in neutral form) and the complex must be soluble in the solvent. 4.2. Role of the Design and Operation Parameters. The design parameters are related to the choice of an extractant and to 12752
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Figure 3a. Detail of Figure 3 for n = 8.
Figure 4. Influence of host concentration.
Figure 3. Influence of selectivity on product purity for m*ηe = 0.002, β = 0.05, S/Fe = 0.1; α = 1.2, 1.7, 10.
the equipment. They include the complex formation equilibrium constants KcR, KcS, the host concentration [C] in the solvent (if used), the distribution coefficient m relating the enantiomers compositions in the organic phase to those in the aqueous phases, and the number n of separation stages. KcR and KcS, represent the values of KcR and KcS evaluated at standard conditions. As hosts are normally characterized by their selectivity, we prefer to represent the design parameter set by αint, KcS, [C], m, and n. The extractant components are selected, within the limitations listed in Section 4.1, such that they will provide high purity products in a minimum number of separation stages. With the complex formation being the mechanism of differentiation between the enantiomers, one would intuitively tend to select a selective host that also exhibits a high complex formation equilibrium constant together with a high host concentration [C],
resulting in a high complex formation capacity λS = KcS[C]. As it turns out, this is not necessarily advantageous. Figures 3 and 3a—which plot, on the basis of eqs 6 and 10 and arbitrary operating conditions, the enantiomer excess in the raffinate as a function of the complex formation capacity λ and the number of TLX stages n, for several values of selectivity— expose a narrow ridge of relative purity that rises over a plain of zero separation. Obviously, too much complex formation can be detrimental. The ridge in Figure 3 gets steeper for a higher selectivity, indicating that it will then require fewer stages to provide a high purity raffinate. Also, when high purity is attained, the ridge widens into a plateau of maximum purity. Figure 4 indicates that the host concentration influences the location of the ridge along the KcS axis. Low complex formation equilibrium constants can be compensated by increasing the concentration [C]. The operation parameters include pHe, pHs, and Fs/Fe. We chose to represent the set of operation parameters by ηe, β, and S/Fe (the extractant batch S is constant). Figures 5 and 6 explore the influence of the operation parameters on the process outcome. Varying the value of an operational parameter will move the ridge up or down the KcS axis, as demonstrated in Figure 5 and may also affect the purity that will be obtained within a given number of stages, as demonstrated in Figure 6. Any one of the operation parameters can be adjusted to move the ridge watershed in Figure 3 up or down the KcS axis until it coincides with the standard value KcS. It should be mentioned that the simulations depicted in Figures 3, 4, 5, and 6 assume that the concentration [C] always 12753
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Table 1. Effect of the Parameters on the Location and Elevation of the Watershed parameter, x
∂log(KcS)/∂x
∂(ee)/∂x
m
