TSINGHUA SCIENCE AND TECHNOLOGY I S S N 1 0 0 7 - 0 2 1 4 0 5 / 1 8 p p 1 7 1 -180 Volume 11, Number 2, April 2006

Affinity Solvents for Intensified Organics Extraction: Development Challenges and Prospects
Andr B. de Haan**
University of Twente, Enschede, The Netherlands Abstract: In most organics extraction processes, the commonly used solvents employ solely physical interactions. Therefore, for the recovery and purification of products from complex mixtures, the selectivity and/or capacity of classical solvents towards the desired solutes is usually insufficient, enforcing the need for complex and thus expensive separation schemes. Significant simplification and cost-reduction can be achieved when affinity solvents would be available that are able to recognize the solutes of interest by their molecular structure. The main development challenges to establish such affinity solvents are: Selection and incorporation of molecular recognition and complexation capabilities; Evaluation of extraction capabilities; Efficient recovery and recycling of the affinity solvents; Implementation in industrial extraction equipment. This paper presents how these development challenges are addressed at the University of Twente, going all the way from affinity solvent design and synthesis, via high throughput screening and characterization up to pilot plant evaluation. Essential in the successful development of affinity solvents are structural cooperations with molecular chemists and custom synthesis companies for their design and synthesis. The various aspects are illustrated by several examples where newly developed environmentally benign affinity solvents appeared able to create major breakthroughs. The applications addressed involve oxygenates, sugars, and pharmaceutical ingredients, such as optical isomers and biomolecules. Key words: affinity solvent; organics extraction; molecular recognition; complexation reaction

Introduction
In contrast to inorganics and metals processing, most organics extraction processes use classical organic solvents that utilize physical interactions with the solutes of interest to achieve the desired separation[1]. Clear examples are the extraction of caprolactam, organic acids, phenol, and penicillin from aqueous solutions where nonpolar solvents such as benzene, toluene, ethylacetate, butylacetate, and isopropyl ether are commonly applied. The major drawbacks of these solvents are their lack of molecular specificity (selectivReceived: 2005-10-09

E-mail: A. B. deHaan@utwente.nl

ity), unfavorable capacity, and their relatively high loss to the feed solution. As a result, many additional operations are often required to recover the used solvents and for the final purification of the desired product. Furthermore, the lack of molecular specificity imposes strong limitations on the use of solvent extraction for the selective recovery of target solutes from complex often dilute mixtures such as petrochemicals, food processing liquids, liquefied biomass, pharmaceuticals, and fermentation liquors. In these applications, tremendous process intensification would be possible if affinity solvents (extractants) capable of highly selective molecular recognition of the desired solute or solute class would be available. As a result, many additional separation and purification operations could be

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omitted and the remaining operations will reduce considerably in size, thereby requiring a much smaller solvent inventory. Affinity extractants (liquid ion exchangers) are already used for many decades in the hydrometallurgical and nuclear industry to recover and refine metals[1]. Within this industry, a long history of affinity extractant design and development to achieve the desired capacity and selecitivity properties exists. More recently, many of the metal affinity extractants have been used to recover primary and secondary metabolites from fermentation liquors[2]. For some solutes, such as organic acids and amino acids, promising new processing concepts incorporating high capacities and selectivities have been obtained. However, the main obstacle for wide application of affinity extractants in organics extraction lies in the fact that mainly acidbase interacting extractants are used that were developed for other applications, mainly metals extraction. Unfortunately, many organic solutes are not able to interact through these acid-base mechanisms, thereby severely restricting the solutes for which high capacities and/or selectivities can be achieved. For this reason, we started a research program with the objective to develop affinity extractants for intensified organics extraction. For this purpose, it is essential to design affinity extractants that can provide strong, specific, yet reversible complexing reactions with the organic solutes of interest. Frequently, the complexing agent is dissolved in a diluent that can improve the equilibrium and kinetics through solvation of the complex. In order for the reaction to be reversible in an economically attractive process, it must have a relatively low bond energy. Such reactions are known as complexation or association reactions. Figure 1 shows some important examples of such reactions with the bond energies typically involved. Generally, complexation reactions with bond energies less than 10 kJ/mol are too weak to be of interest, while reactions with bond energies above 50 kJ/mol tend to be too difficult to reverse. In many cases, multiple types of interactions can be incorporated into affinity extractants to obtain the desired properties with respect to capacity, selectivity, and reversibility. From this, it is clear that an indefinite amount of options exist to design and develop affinity extractants for organics extraction. One of the main

challenges is therefore to structure this development process in such a way that systems are established that can be applied with sufficient confidence on industrial scale. This paper aims to present an overview on how affinity extractant development for organics extraction can be addressed. First, the identification, selection, design, synthesis, and high throughput screening of new affinity extractants are discussed. Absolute key in successful affinity extractant development is structural cooperations with molecular chemists and custom synthesis companies for their design and synthesis. Subsequently, attention will be paid to conceptual process design, pilot plant evaluation, and affinity extractant recovery and recycling. All these aspects will be illustrated by a variety of examples where newly developed affinity extractants appeared able to create major breakthroughs.

Fig. 1 Bond energies most suited for affinity extractants[3].

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1.1

Selection/Identification of Affinity Extractants

Initial interaction/extractant identification

There are several strategies to identify potential affinity extractants. The most common strategy used by chemists is empirical design and synthesis of new extractants based on former experience or as a variation on an existing extractant. This approach works fine as long as the interactions that need to be exploited

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are known and initial extractants to start from are available. In the last decade, molecular modelling capabilities have increased tremendously, allowing a much more fundamental approach to affinity extractant design. The main problem associated with molecular modelling, however, is still the fact that incorporating all criteria (see below) simultaneously into the model is very tedious and time-consuming, whereas the reliability of the molecular models is still not sufficient to make trustworthy predictions without experimental validation. In spite of these limitations, molecular modelling is gaining increasing importance to direct the design, and synthesis of optimal affinity extractants, since predicted trends are usually reasonably accurate. Both techniques, empirical design, and molecular modelling are perfectly suited to improve affinity extractant behaviour when the solute-extractant interactions to be exploited are known. For organics extraction, however, often no suitable affinity extractants are known a priori and efforts have to be made to identify which interactions are promising enough to be exploited during further development. An excellent starting point is then usually established by evaluating the synthetic organic and analytical chemistry literature. In this literature, often many different interactions and reversible complexation reactions are described that can provide very promising affinity extractants for organic solutes once their functionalities are incorporated into suitable extractant structures. Using this strategy, we have identified many different complexation reactions that may be exploited for aldehydes, ketones, alcohols, acids[4,5], sugars[6], olefin isomers[7], and chiral amino alcohols[8] and incorporated them into suitable extractants. Once identified all potential reactions/ interactions should be evaluated on their ability to meet the design criteria for the specific application area. It is clear that for each application the relative weight of the selection criteria will differ. Therefore, below only the selection criteria that must be additionally included relative to regular solvent extraction are summarized. 1.2 Selection criteria

main difference between affinity extractants and regular solvents is that by applying reversible solutespecific reactions, one is able to combine high selectivities with high capacities while with regular solvents high selectivity is nearly always obtained at the expense of low capacity and vice versa. An illustrative example of this is shown in Fig. 2, where the distribution coefficients for the extraction of 1.5 wt.% benzaldehyde from toluene with an aqueous sodium taurinate solution are plotted. Due to a Schiff base formation reaction (Fig. 3), the sodium taurinate increases the benzaldehyde distribution coefficient by about 30 times while the toluene distribution coefficient is even slightly reduced due to salting out effects. As a result, the selectivity of extraction is increased over 50 times.

Fig. 2 Distribution coefficient of benzaldehyde and toluene as function of initial sodium taurinate concentration in water at 25.

The initial selection criteria for affinity extractants are more or less similar to the criteria for regular solvent extraction. Most important is a combination of a high distribution coefficient with a high selectivity. The

Fig. 3 Schematic of reversible Schiff base and tetrahedral diol-boronic acid complex formation.

Other important criteria that must be met by the affinity extractant are related to the design of the affinity extraction operation and recovery/recyling of

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the affinity extractant. In most cases, the affinity extractant will be considerable more expensive as regular solvents, thereby increasing the required efficiency of their recovery. Therefore, it is extremely important to allow full regeneration of the extractant by reversing the complexation reaction, preferably by only moderate changes in process conditions such as temperature or pH. Furthermore, care should be taken to avoid extractant losses from the solvent to the feed phase and already incorporate the ease of solute recovery from the loaded affinity solvent during the selection/identification stage. Figure 4 illustrates that sometimes the solute (i.e., fructose) can play a detrimental role by extracting the affinity extractant (i.e., PBA) from the solvent into the feed phase. This is a frequently encountered problem and needs to be solved by anchoring the affinity extractant through an optimal design. In this example, the extractant leaching problem was solved by connecting the boronate group to a hexadecyl tail, after which excellent extraction results of glucose and fructose were obtained without any detectable extractant loss (Fig. 5) in the form of a tetrahedral sugar boronic acid complex (Fig. 3).

Fig. 5 Distribution coefficient of glucose and fructose between water and 2-ethyl-1-hexanol with TOMA+HBA (trioctylmethylammonium+-hexadecylboronic acid) at 45.

solute and extractant. This means that the applied complexation reaction should have sufficiently fast kinetics in order to avoid the need of excessive residence times during extraction. From the above, it is clear that during the development of suitable affinity extractants many different, often counteracting criteria need to be fulfilled. For regular solvent extraction, many of these criteria can be evaluated from computer calculations by using predictive models such as Unifac, Cosmo-RS, etc. Unfortunately, accurate and reliable prediction of reversible complexation reactions is still not possible, making experimental evaluation one of the main pillars supporting affinity extractant development. For this purpose, the classical experimental techniques proved to be laborious, time-consuming, and costly, which prompted us to develop a high throughput extractant evaluation methodology.

2
Fig. 4 Distribution of phenylboronic acid (PBA) between 2-ethylhexanol and 0.25 mol/L aqueous fructose solution.

High Throughput Affinity Solvent Evaluation

For the design of the affinity extraction process, the common selection criteria such as sufficient density difference, not too high viscosity, and favorable interfacial tension also apply. Furthermore, issues such as availability, cost, toxicity, compatibility, flammability, stability, and environmental impact should be taken into account. The main difference with regular solvents is the reversible complexation reaction involved in the extraction process in addition to the mass transfer of

The use of jacketed glass cells operated manually is the most commonly applied procedure for liquid-liquid equilibrium measurements. However, this procedure involves laborious work, thereby limiting the number of experiments that can be performed per day and introducing unnecessary experimental errors that may reduce the accuracy of the results. Therefore, we have developed a fully automated workstation for high throughput determination of liquid-liquid equilibria. The workstation includes a CombiPal advanced autoinjector station (CTC Analytics, Switzerland), a

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Fig. 6 Scheme (a) and photo (b) of the automated workstation for high throughput affinity solvent evaluation: A1, xcrossrail; A2, y-crossrail; A3, z-crossrail; A4, vertical holders; B, 2-mL vial tray holder with tray; C, 20-mL vial tray holder with tray; D, 100-mL vial holder with three vials; E, orbital shaker; F, washing station; F1, waste disposal tank; F2 and F3, washing solvent storage tanks; G, dilutor syringe; G1, diluting fluid storage bottle; H, remote HPLC injector; I, GC injector.

gas chromatograph (GC) CP-3800 (Varian, USA), a high-pressure liquid chromatograph (HPLC) ProStar (Varian), a heating/cooling bath with external temperature control (Julabo Labortechnik, Germany), and a personal computer (Fig. 6). A more detailed description can be found in Ref. [9]. All operations, from preparation of aqueous and organic solutions, liquid transfer into a vial, agitation, phase sampling, to sample preparation for analysis and chemical analysis itself, are done automatically. The liquid-liquid equilibrium is established in 2-mL glass vials closed by a metal crimp seal with a septum. Seals made of metal enable picking-up and moving of a vial

by the magnetised end of the vial lifter and placing them automatically in the shaker for mixing. In the configuration described in this work, up to 65 equilibria can be measured continuously with no necessity for human interference. Depending on the system, studying up to 36 equilibrium experiments per day are possible, which is 5 to 10 times more than can be achieved by using a glass cell. Important additional advantages of using 2-mL vials are that minimal amounts of the sometimes expensive affinity extractants are consumed and not more than 4 mL of liquid waste per experiment is produced. To demonstrate its applicability and reliability,

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Fig. 7 shows a comparison between the distribution coefficient of caprolactam between benzene and water determined with the fully automated workstation and literature data. The measured values of the distribution ratio of caprolactam are all exactly within the cloud of the literature data, demonstrating that sufficient accuracy for high throughput affinity extractant evaluation is obtained. For the affinity extraction of benzaldehyde from toluene with an aqueous sodium glycinate solution, a comparison between the fully automated workstation and jacketed glass vessels is depicted in Fig. 8. The agreement of the experimental results illustrates clearly the suitability of the fully automated workstation for high throughput affinity solvent evaluation.

This high throughput experimentation is especially important since the additional degrees of freedom in the structural design of affinity solvents (functional group+support+diluent) and establishment of optimal process conditions require large amounts of potential combinations to be evaluated.

Extractant Recovery/Recycling

Fig. 7 Comparison of the distribution coefficient of caprolactam KD at 20 between benzene and workstation water as a function of the aqueous mass a fraction of caprolactam w3 obtained by the automated workstation() with literature data (symbols)[9].

After extraction, it is essential to recover the extracted solute from the affinity extractant. For this purpose, it is essential that the used complexation reaction is easily reversed by a moderate change in process conditions. It is clear that a temperature shift is the simplest condition to be changed. Figures 9 and 10 illustrate for two different systems that indeed a change in temperature is often sufficient to reverse the complexation and recover the extracted solute. However, when the complexation interaction is too strong, as with sodium hydrogen sulphite in Fig. 9, the resulting distribution coefficient will remain unfavourable for back extraction even after a substantial temperature increase. In that case, one might think of using other options such as salt gradients or pH-shift to reverse the complexation reaction. The main disadvantage of course is the production of salt wastes when additional components are used. This problem can be overcome by using volatile acids or bases such as carbon dioxide or ammonia to impose a pH shift. Examples of what can be attained are shown in Figs. 11 and 12. During the recovery, the dissolved solute exceeds its solubility limit such that a second liquid phase appears which consists of nearly pure solute. Exploiting this

Fig. 8 Comparison of jacketed glass vessels() and the automated () to determine the benzaldehyde distribution coefficient between toluene and aqueous sodium glycinate at 25.

Fig. 9 Distribution coefficient of benzaldehyde between aqueous salt solution containing sodium taurinate(, ) or sodium hydrogen sulphite (, ) and toluene at 25 (solid) and 70 (open).

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Fig. 10 Distribution ratio for recovery of S() and R() phenylglycinol from chiral crown ether in toluene by back extraction with water.

Fig. 12 New liquid layer (II) formation of hexanoic acid during recovery by CO2.

Fig. 11 Measured and predicted recovery of hexanoic acid by new liquid phase formation as a function of the CO2 pressure at 5.

phenomenon allows dramatic concentration of the solute, thereby strongly decreasing the energy demands for further concentration and purification.

Next to solute recovery, the recycling of affinity extractant itself is a major issue because most extractants will be reasonably expensive. Therefore, losses during back extraction or in the raffinate should be minimized. The common way to do this is either anchoring the affinity extractant in the solvent solution. For organic solvents, this is commonly done by connecting the affinity ligand to a large hydrocarbon moiety for which especially macrocycles and supramolecular structures seem to provide interesting opportunities, as illustrated by the chiral crown ether and calyx[6]arene in Fig. 13. In aqueous solutions, the easiest way to prevent dissolution in an organic phase is to connect the affinity ligand to an ionic group, such as in the case of organic salts.

Fig. 13 Structures of solvent anchored chiral crown ether (a), calyx[6]arene (b) and water anchored amine in the form of the sodium salt of taurine (c).

Industrial Implementation

Absolutely essential for future industrial utilization of affinity extractants is their implementation into

extraction equipment. For most industrial extractors, extensive knowledge exists on their operation, design, and scale-up as long as physical extraction is concerned[10]. In contrast to reactive distillation, hardly

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any knowledge exists on how to operate, design, and scale-up extractors that utilize affinity extractants employing reversible complexation reactions for selective organics extraction. Most knowledge on reactive extraction is restricted to mixer-settler operations for metals extraction[11] and research studies on organic acids extraction with various contacting devices[2]. Therefore, it is essential that bench-scale and pilot-plant studies are included in the development of affinity solvents for organics extraction. As an example, the recovery of 1.5 wt.% benzaldehyde from toluene with an aqueous solution of sodium hydrogen sulphite is investigated in a pulsed disk and donut column (ID=40 mm, active height = 4 m) (Fig. 14). Extraction with pure water as the solvent is also included to demonstrate the difference between reactive and physical extraction. The results are presented in Fig. 15 by the normalised concentration profile as a function of the normalised column height at a solvent to feed ratio (S/F) of 2 and 4. As expected, virtually no benzaldehyde is extracted into pure water due to the highly unfavourable distribution coefficient. On the other hand, by using the aqueous solution of sodium hydrogen sulphite, benzaldehyde recovery of up to 99.96% is achieved for the applied conditions. The lines in Fig. 15 represent the concentration profiles if the extraction would be limited by mass transfer alone, considering the minimum and maximum numbers of transfer units present during the extraction with pure

Fig. 15 Concentration profile of benzaldehyde in the dispersed toluene phase as a function of the column height (H) during extraction with water (, ) and an aqueous sodium hydrogen sulphite (, ).

Fig. 14 Schematic presentation of the pulsed disc and donut column pilot with the aqueous phase (1) and the affinity solvent phase (2).

water. As expected, the reactive extraction experimental results are lying outside the physical extraction region and less solute is extracted than would be in a pure physical extraction. This is suggesting that the reaction kinetics adversely affect the extraction and need to be included during scale-up and design. To investigate the effects of complexation kinetics on the efficiency of extraction, we have performed various studies in which we attempted to isolate the kinetics from the mass transfer effects. As with metals extraction, our first studies used a modified Lewis cell (Fig. 16) for various solutes. An example is shown in Fig. 17, where the chiral extraction of racemic leucine with Cu(II)-n-dodecyl-L-hydroxyproline is plotted at different stirrer speeds. Due to the ligand exchange nature of this complexation reaction, the kinetics is rather slow compared to mass transfer, which is confirmed by the absence stirred speed effects on the rate of extraction. However, we also encountered many systems in which the mass transfer rate was of the same order of magnitude as the complexation rate. Under these circumstances, measurements with the Lewis cell become very complicated because no distinct regime where only the kinetics are limiting can be obtained. Another factor complicating the determination of intrinsic complexation reaction kinetics is the fact that many solutes are soluble in the organic phase to some extend. This means that it is very difficult to distinguish between mass transfer and reaction kinetics limitation because part of the reaction can take place in the bulk of the affinity solvent and improved measuring techniques are required. A Lewis cell can only provide reliable results when the physical solubility of solutes is very low and

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reactions are slow compared to mass transfer.

equilibrium experiments needed. Industrial application requires the development of reliable design and scaleup models for affinity extraction processes and their experimental validation on pilot scale. Once the risk in the design of these processes is significantly reduced and more dedicated affinity solvents have been established, dramatic intensification of organics extraction processes will be possible due to the high capacity and selectivity of affinity solvents. These applications will not be limited to organics, but may also extend into the field of biotechnology where the right affinity solvent is even able to dissolve complete biomolecules, as illustrated by Fig. 18.

Fig. 16

Schematic of Lewis cell.

Fig. 18 Extraction of myoglobin with a calix[6]arene in butyl acetate as a function of pH.

Fig. 17 Affinity extraction of racemic leucine with Cu(II)-n-dodecyl-L-hydroxyproline at 25 in Lewis cell.

References
[1] [2] [3] Lo T C, Baird M H I, Hanson C. Handbook of Solvent Extraction. New York: John Wiley & Sons, 1983. Schgerl K. Solvent Extraction in Biotechnology. Berlin: Springer Verlag, 1994. King C J. Separation processes based on reversible chemical complexation. In: Rousseau R W, ed. Handbook of Separation Process Technology. New York: John Wiley & Sons, 1987: 760-774. [4] Kuzmanovi B, Kuipers N J M, de Haan A B, Kwant G. Reactive extraction of carbonyl compounds from apolar hydrocarbon using aqueous salt solutions. Ind. Eng. Chem. Res., 2003, 42(13): 2885-2896. [5] Kuzmanovic B. Reactive extraction of oxygenates with aqueous salt solutions. [Ph. D. Dissertation]. University of Twente, the Netherlands, 2003. [6] Vente J. Adsorbent functionality in relation to selectivity and capacity in oligosaccharide separations [Ph. D. Dissertation]. University of Twente, the Netherlands, 2004.

Conclusions, Challenges, and Prospects

Affinity solvents offer interesting properties for the intensification of organics extraction processes due to the dramatic increase in capacity as well as selectivity that can be achieved by incorporating reversible complexation reactions in these solvent. Initially, the main development challenges are the identification of suitable complexation reactions for the solute of interest and design/synthesis of affinity solvent systems that do not only show excellent extraction performance but at the same time are easy to regenerate and do not leach from the solvent phase. High throughput experimentation is essential to be able to perform the large amount of

180 [7] Wentink A E. Functionalized solvents for isomer purification by reactive extractive distillation [Ph. D. Dissertation]. University of Twente, the Netherlands, 2004. [8] Steensma M. Chiral separations of amino-alcohols and amines by fractional reactive extraction [Ph. D. Dissertation]. University of Twente, the Netherlands, 2005. [9] Kuzmanovi B, van Delden M L, Kuipers N J M, de Haan A B. Fully automated workstation for liquid-liquid

Tsinghua Science and Technology, April 2006, 11(2): 171-180 equilibrium measurements. J. Chem. Eng. Data, 2003, 48(5): 1237-1244. [10] Godfrey J C, Slater M J. Liquid-Liquid Extraction Equipment. New York: John Wiley & Sons, 1994. [11] Bart H J. Reactive Extraction. Berlin: Springer-Verlag, 2001.

MOU Signed Between Tsinghua and Ecole Polytechnique

Tsinghua Vice President Xie Weihe visited Ecole Polytechnique recently and signed a Memorandum of Understanding between the two institutions. Ecole Polytechnique, established in 1794, plays an important role in France and enjoys world-wide prestige. Its graduates have been top leaders and researchers in politics, industry, and education circles. Only 400 French students and 100 international students are admitted annually into Ecole Polytechnique. The MOU covers the cooperation areas of the exchange of information and academic materials, exchange of faculty and students, joint masters programs and joint supervision of Ph.D. students, and joint research projects. The institutions hope to enhance the exchange and coordination to explore other cooperation possibilities. (From http://news.tsinghua.edu.cn)