University of Groningen
Enantioselective liquid-liquid extraction in microreactors
Susanti, Susanti
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Susanti, S. (2018). Enantioselective liquid-liquid extraction in microreactors. University of Groningen.
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Summary
Samenvatting
Acknowledgement
List of publications and attended
conferences
Summary
Summary
Most of the molecules of importance to living system like amino acids, sugars, proteins and nucleic acids are chiral. Chiral molecules exist in two forms (enantiomers) which have the same chemical structure but are mirror images of each other and cannot be superimposed (Figure S1). The demand of single enantiomer (enantiopure) compounds is increasing
since the realization that the two enantiomers of a chiral compound have different biological activity. Chiral separation of the racemate is one of the possible ways to obtain enantiopure compounds.
Figure S1. Enantiomers of glyceraldehyde.
Enantioselective liquid-liquid extraction (ELLE) is a promising method for chiral separation of racemic mixtures. ELLE typically involves con-tacting a racemate dissolved in water with an immiscible organic solution containing the chiral host (Figure S2). The enantiomers are transferred
C CHO
HO C OH
CHO
L-glyceraldehyde Mirror D-glyceraldehyde
CH2OH CH2OH
Figure S2. Schematic representation of enantioselective liquid-liquid extraction
144
Summary
from the aqueous phase to the organic phase where complexation with the host occurs. The complexation constants for both enantiomers differ and this is the basis for enantio-separation. Reverse ELLE, i.e. host in the water phase and the racemate in the organic phase has also been investi-gated, though to a by far lesser extent.
The use of micro devices (reactors, solvent extractors) in fine chemical synthesis has been investigated in great details the last two decades and has many advantages compared to conventional batch systems. These in-clude higher heat- and mass transfer rates, high surface to volume ratio, reduced inventories of reactants and products, and lower reagent con-sumption. Microdevices for solvent extraction should in principle also be suitable for reactive extraction including chiral separations (ELLE). To the best of our knowledge, the use of microdevices for chiral extraction in the slug flow regime has never been reported in the literature.
The principle of ELLE in the slug flow regime in a microdevice is sche-matically depicted in Figure S3. When using hydrophobic microchannels or microtubes, aqueous droplets and organic slugs are formed and en-antiomers are transferred from the aqueous droplet to the organic slug. Potential advantages when operating in the slug flow regime compared ELLE in conventional devices are high mass transfer rates, reduced use of expensive hosts (in case an efficient back extraction step is included) and organic solvents.
In this thesis experimental and modeling studies on the application of slug flow capillary microdevices for ELLE will be reported. The overall objective was to provide the proof of principle for ELLE in micro de-vices on laboratory scale. The experimental studies were carried out in capillary microreactors operated in the slug flow regime. A systematic approach was used involving three discrete research phases with in-creasing complexity (Figure S4).
In the first part of this thesis (Chapter 2) experimental studies on (re-active) achiral extraction systems are reported to gain insight in mass transfer characteristics of slug flow operated capillary microdevices. It involves physical extraction studies of acetanilide from a water phase
Summary
to an organic phase (1-octanol). Based on the experimental data, a mass transfer model was developed. Subsequently, an example of reactive extraction i.e. lactic acid extraction from an aqueous phase using tri-oc-tylamine (TOA) as the extractant in 1-octanol was investigated in the microdevice. Equilibrium extraction performance was obtained after 90 s runtime without noticeable emulsion formation. The experimental results were modeled using a mass transfer model assuming an instan-taneous irreversible complexation reaction between lactic acid and TOA. In Chapter 3, experimental studies on the use of capillary microre-actors for ELLE are reported. The experiments involved the chiral ex-traction of an amino acid derivative (3,5-dinitrobenzoyl-(R,S)-leucine (DNB-Leu)) by a chiral cinchona alkaloid (CA) as a host using two or-ganic solvents (1,2-dichloroethane and 1-octanol). The extraction perfor-mance was investigated using a phase ratio of one, a temperature of Ca. 23°C and different residence times. Of high interest is the observation that the enantiomeric excess (ee) is higher in the kinetic regime than in the equilibrium regime, particularly when using 1-octanol as the sol-vent. These findings suggest that non-equilibrium ELLE may have high potential.
In Chapter 4, a modeling study is provided on ELLE of 3,5-dinitro-benzoyl-(R,S)-leucine (DNB-Leu)) by the chiral cinchona alkaloid (CA) in 1-octanol based on the experimental data given in Chapter 3. Mass transfer characteristics of the micro device were taken from the exper-imental findings reported in Chapter 2. The experexper-imentally observed higher ee values in the kinetic regime at short residence times com-pared to the equilibrium values is likely due to differences in reaction rates for the complexation reaction between the host and the individual enantiomers, the (S)-enantiomer being more reactive. As such, the in-stantaneous regime was considered for the (S)-enantiomer, whereas an intermediate regime with a finite reaction rate for complexation was
Figure S4. Research approach.
Chapter 1
22
Figure 1.12. Schematic representation of ELLE in the slug flow regime.
In this thesis experimental and modeling studies on the application of slug flow capillary microdevices for ELLE will be reported. The overall objective was to provide the proof of principle for ELLE in microdevices on laboratory scale. A systematic approach was used with three different research phases with increasing complexity (Figure 1.13).
In the first part of this thesis (Chapter 2) a simple extraction system (without chiral recognition) is investigated to gain insight in mass transfer characteristic of slug flow operated capillary microdevices. It involves physical extraction studies of acetanilide from a water phase to an organic phase (1-octanol). Based on the experimental data, a mass transfer model was developed. Subsequently, an example of reactive extraction i.e. lactic acid extraction from an aqueous phase using tri-octylamine (TOA) as the extractant in octanol was investigated in the microdevice. A reactor model was developed using the penetration theory for mass transfer.
Figure 1.13. Research approach.
Physical extraction studies
Reactive extraction studies
Chiral separation studies incr
146
Summary
taken for the (R)-enantiomer. The reactor model was used to determine guidelines for multi-stage operation in microreactors to increase yield and enantiopurity.
In Chapter 5, an experimental study on a new ELLE system is de-scribed involving tryptophan (Trp) and a chiral Pd complex Pd(PF6)2
((S)-XylBINAP)2 as the host and 1-octanol as the solvent. The kinetic profiles
show that the complexation reaction between the host and Trp is slow and the time to reach equilibrium typically exceeds 6 h. In addition, the kinetic profiles are complex and actually show two regimes, a fast pro-cess in the timescale of minutes and a slower propro-cess ultimately reaching equilibrium. The fast-initial stage is attributed to the reactive extraction of Trp by Pd nanoparticles, which act as (non enantio-selective) hosts, the second stage involves the chiral reactive extraction of Trp with the chiral organometallic complex. The operational selectivity was indepen-dent of the host-substrate molar ratio with a maximum selectivity of 1.8. Surprisingly and unprecedented, separate experiments with enantiopure Trp did not results in enantio-separation, indicating that the presence of both Trp enantiomers is required for the ELLE process. Possibly the formation of 2 to 1 complexes plays a role, though this could not be sub-stantiated by MS studies. Irreversible reactions also do not play a role as was shown by sequential extraction experiments.
Samenvatting
Samenvatting
De meeste moleculen die belangrijk zijn voor levende systemen zoals aminozuren, suikers, eiwitten en nucleïnezuren zijn chiraal. Chirale mo-leculen komen voor in twee vormen (enantiomeren) die dezelfde chemi-sche structuur hebben, maar spiegelbeelden van elkaar zijn (Figuur S1). De vraag naar enantiomeer zuivere producten is groeiende, met name als gevolg van het feit dat de beide enantiomeren verschillende biologische activiteit kunnen hebben. Chirale scheiding is een van de mogelijke ma-nieren om enantiomeer zuivere producten te maken.
Figuur S1. Enantiomeren van glyceraldehyde.
Enantioselectieve vloeistof-vloeistof extractie (EVVE) is een veelbe-lovende methode voor de scheiding van enantiomeren. Tijdens EVVE wordt een racemaat opgelost in water en in contact gebracht met een organische oplosmiddel met een chirale extractant (host, zie Figuur S2).
C CHO
HO C OH
CHO
L-glyceraldehyde Mirror D-glyceraldehyde
CH2OH CH2OH
Figuur S2. Schematische weergave van enantioselectieve vloeistof-vloeistof
148
Samenvatting
De enantiomeren worden getransporteerd van de water laag naar de organische laag, alwaar complex vorming met de host plaatsvindt. De complexatie constanten zijn verschillende voor beide enantiomeren en dit is de basis is voor EVVE.
Het gebruik van microapparatuur (reactoren, extractoren) voor de syn-these van fijnchemicaliën is de laatste twintig jaar uitgebreid bestudeerd en heeft voordelen ten opzichte van conventionele batch systemen. Zo zijn in microapparatuur warmte en massa transport snelheden hoger dan in batch, is de oppervlakte/ volume verhouding gunstiger en kan het verbruik van dure hulpstoffen gereduceerd worden. Het gebruik van mi-croapparatuur voor vloeistof-vloeistof extractie zou in principe ook ge-schikt moeten zijn voor reactieve extracties inclusief EVVE. Voor zover ons bekend is het gebruik van microapparatuur voor chirale scheidingen nog niet eerder bestudeerd en beschreven.
Het principe van EVVE in het zogenaamde “slug flow” regiem in een microapparaat is schematisch weergegeven in Figuur S3. Bij gebruik van hydrofobe microkanalen of microbuisjes vormen zich waterdruppels en organische “slugs” in de kanalen. Tijdens EVVE worden de enantiome-ren overgedragen van de waterdruppels naar de organische slugs.
In dit proefschrift worden zowel experimentele als model studies naar de toepassing van microapparaten voor EVVE beschreven. Het uiteinde-lijke doel was om op laboratorium schaal EVVE aan te tonen. De experi-mentele studies zijn uitgevoerd in cappilaire micro reactoren in het slug flow regiem. In het onderzoek zijn drie discrete onderzoeksfasen met oplopende complexiteit toegepast (Figuur S4).
In het eerste gedeelte van dit proefschrift (hoofdstuk 2) worden ex-perimentele studies naar (reactieve) achirale extracties beschreven om een beter inzicht te krijgen in de massa overdracht eigenschappen van de gebruikte microreactoren. De nadruk lag hierbij op de extractie van acetanilide van een waterfase naar een organische fase (1-octanol). Op basis van de experimentele data is een massa transport model opgesteld. Daarna is de extractie van melkzuur uit een waterige fase met behulp van tri-octylamine (TOA) als extractant in 1-octanol bestudeerd, een
Samenvatting
voorbeeld van een reactief extractie proces. De experimentele resultaten zijn succesvol gemodelleerd onder de aannames dat de complexatie reac-tie tussen melkzuur en TOA erg snel en onomkeerbaar is.
In hoofdstuk 3 worden experimentele EVVE studies in microreacto-ren beschreven. Hierbij is gebruik gemaakt van een aminozuur derivaat (3,5-dinitrobenzoyl-(R,S)-leucine (DNB-Leu)) opgelost in water en een host in de vorm van een chinchona alkaloïd (CA) opgelost in twee ver-schillende organische oplosmiddelen (1,2-dichloroethane en 1-octanol). De extracties zijn uitgevoerd bij een fase verhouding van 1, 23°C en ver-schillende verblijftijden. Er is aangetoond dat de enantiomere overmaat hoger is in het kinetische regiem dan bij evenwicht, met name als 1-oc-tanol als oplosmiddel gebruikt werd. Deze bevindingen suggereren dat EVVE in het kinetische regiem voordelen kan hebben ten opzichte van het thermodynamisch regiem.
In hoofdstuk 4 is een model ontwikkeld voor de EVVE van (DNB-Leu)) met (CA) als host in 1-octanol op basis van de experimentele data beschreven in hoofdstuk 3. De observatie dat hogere enantiomere over-maten mogelijk zijn in het kinetische regiem bij korte verblijftijden in vergelijking met de evenwichts waarden wordt waarschijnlijk veroor-zaakt door het verschil in reactiesnelheden voor de complexatie reactie van de beide enantiomeren. De (S)-enantiomeer is reactiever en als ge-volg hiervan vindt de EVVE voor dit enantiomeer plaats in het instan-tane extractie regiem. Het model is gebruikt om meerdere extracties te simuleren om zo de opbrengsten en enantiozuiverheid te verhogen.
In hoofdstuk 5 wordt een experimentele studie aan een nieuw EVVE systeem beschreven. Het betreft studies met tryptophan (Trp) opgelost in water en een chiraal Pd complex (Pd(PF6)2((S)-XylBINAP)) als host in
1-octanol. De kinetische profielen laten zien dat de complexatie reactie tussen de host en Trp langzaam is en de tijd waarin evenwicht wordt be-reikt is typisch in de orde van 6 h. Bovendien laten de kinetische profielen
Figuur S4. Onderzoek aanpak.
Chapter 1
22
Figure 1.12. Schematic representation of ELLE in the slug flow regime.
In this thesis experimental and modeling studies on the application of slug flow capillary microdevices for ELLE will be reported. The overall objective was to provide the proof of principle for ELLE in microdevices on laboratory scale. A systematic approach was used with three different research phases with increasing complexity (Figure 1.13).
In the first part of this thesis (Chapter 2) a simple extraction system (without chiral recognition) is investigated to gain insight in mass transfer characteristic of slug flow operated capillary microdevices. It involves physical extraction studies of acetanilide from a water phase to an organic phase (1-octanol). Based on the experimental data, a mass transfer model was developed. Subsequently, an example of reactive extraction i.e. lactic acid extraction from an aqueous phase using tri-octylamine (TOA) as the extractant in octanol was investigated in the microdevice. A reactor model was developed using the penetration theory for mass transfer.
Figure 1.13. Research approach.
Physical extraction studies
Reactive extraction studies
Chiral separation studies incr
150
Samenvatting
twee regimes zien, een snel proces met een tijdschaal van minuten en een langzamer proces dat uiteindelijk evenwicht bereikt. De snelle begin fase wordt toegeschreven aan de niet selectieve reactieve extractie van Trp door Pd nanodeeltjes, de langzamere fase door de gewenste EVVE tussen Trp en de chirale Pd host. De selectiviteit was onafhankelijk van host-substraat verhouding en was ongeveer 1.8. Experimenten met zuivere enantiomeren van Trp in plaats van het racemaat gaven verge-lijkbare profielen. Dit duidt erop dat de aanwezigheid van beide enan-tiomeren noodzakelijk is voor het EVVE proces. De vorming van 2 op 1 complexen speelt mogelijk een rol, alhoewel dit niet bewezen kon wor-den met MS studies. Onomkeerbare reacties spelen ook geen rol, zoals aangetoond met meerdere extractie experimenten.
Acknowledgement
Acknowledgement
Here, I would like to take the opportunity to express my sincere grati-tude to all those who gave support and contributed to finish my PhD life.
First of all, I would like to express my sincere thanks to my supervisor Prof. Erik Heeres. Erik thank you for kindly giving me the opportunity to be a PhD researcher in your group. Often, I lost my confidence in this PhD journey, but you were always understanding and kindly encouraged me to keep on going. Thank you for your great guidance, help, input, corrections and encouragement, it all gave me the confidence to continue till the end. Also, thanks for the discussions about many other things, not only about research. I learned a lot from you.
I would also like to thank my co-supervisors, Dr. Jun Yue, Dr. Jos Winkelman and Dr. Boelo Schuur. Jun, thanks for your help, particu-larly on the modeling studies, advice and your patience. Possibly I was the student who most often knocked on your office door. Jos, you also helped me a lot with the modeling studies, thanks for your help, support, interest and valuable hints. I have to apologize, in a reference to one of our papers, your initials have been put in front of my name. I have never seen you with a tired look on your face, and ever heard you told your students that “I am happy if my students are happy”. Now I am “happy” Jos!. Boelo, although we did not meet very frequently, you gave a lot of input on my research and thesis. Thank you for your fast response to my emails. I learned a lot from you about chiral separation in general and ELLE in particular.
Next, I would like to thank the members of the reading committee; Prof. Picchioni, Prof. Versteeg, and Prof. Hessel, for spending their valu-able time to read and evaluate my PhD thesis. I also would like to address a special thanks to Qingqing and B’Frita for being my paranymphs and helping me in the preparation of my PhD defense. I wish you success with your PhD research.
This study was supported by a grant from STW through project no. 11404 (Chiral Separations by Kinetic Extractive Resolution in Microfluidic Devices). I thank STW for this financial support and all committee mem-bers for the valuable input during regular progress meeting. I also would like to express my sincere thanks to all collaborator in this project, espe-cially to Prof. de Vries, Prof. Feringa, and Erik P., thanks for the interesting discussions especially on organic synthesis and molecular interactions. Erik P., thank you also for your help during my PhD research. I wish you great success with your career. Michal and Sandra, thanks for the interest-ing discussions and for beinterest-ing a nice host when I visited the UT in Enschede.
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Acknowledgement
During my PhD time, I had the opportunity to work with some fan-tastic colleagues. To those who worked in similar research areas, Tim Meinds, Jorn, Martijn H., and Yanyan, thank you for the nice discussions. I also would like to thank all support staff of the Chemical Engineering cluster, Anne, Marcel, Erwin, Jan Henk, Leon, Marya, Kim and Geraldine, for the excellent research services and the organization of many enjoy-able lab activities (especially the labuitje and the kerstlunch). Also thanks to all my office mates: Jan-Willem, Anna, Bu Ima (who often had to listen to my complaints, and gave valuable input), Henk (always help-ful), Ionela (always actively participated in any discussion), Xi, Fatemeh, Zhiwen, Qingqing and my labmates: Bilal, Laurens, Esteban and Arne. I also would like to thank all current and former members of Chemical Engineering cluster, especially Ria, B’Frita & Fam., Angela (for help and all gifts for Anika), Pa Henky, Yusuf & Fam., Mas Ilmi, Mas Fachri, Dian, Louis, CB, Teddy, B’Agnes, Yifei, Arjan & Zheng, Yin, Diego W., Maria Jesus, Valeriya, Monique, Bhawan, Zhenchen, Nicola, Zara, Frank, Arjen, Martijn B., Songbo, Inge, Peter, Idoia, Shilva, Jessi, Li He, Patrizio, Rodrigo, Paolo, Ranjita and Prof. Broekhuis. Alphons Navest, thank you for all the administrative arrangements. Thanks also for the members of the ana-lytical department of the Stratingh Institute: Monique S., Hans van der Velde, and Theodora. To the Bernoulli board and members, thanks for or-ganizing several events, I enjoyed it (especially the Bernoulli symposia).
Thanks to all current and former members of PPIG and De Gromiest. Special thanks to: Iqbal & Eryth (for the information regarding the PhD vacancy in Erik group and other help), Alia & Fam. (for hosting me and for cooking delicious food before I rented my own apartment, and other help), Bude Nunung (for all your help and care for Anika), Desti & Fam., B’Yuni & Fam., Nna & Fam., Bu Rini & Fam. (for the delicious foods and taking care (for free) for Anika), Lia & Robby, Astri, Rachma, Faizah & Fam., Nizar, Wahono, T’Sella & Kang Zaky, Bu Rohmah & Fam., B’Rosel & Fam., Umi Fitri & Fam., B’Ayu & Fam., B’Icha & Fam., Liany & Fam., B’Irma & Fam., Monik & Fam., Reren, B’Nieke & Fam., Neily & Fam. Teh Puti & Fam., Liza & Fam., B’Laksmi & Fam., B’Awalia & Fam., B’Erna & Fam., B’Ratna & Fam., B’Tiur, B’Nur Q., B’Irawaty, Inda, Anis & Didin, B’Arum & Fam., Mba Uci & Fam., Yas & Fam, Bude Arie & Om Herman, Uwak Asiyah & Fam, Widy, Bintoro, Sofie, Adel, Doti, Putri, May & Dina. I also give my gratitude to my best friends in Indonesia, especially the Sugar spices Ki’02 group, alumni kimia ITB’02, and alumni PPI-UTM (period 2007-2010) who often cheered me up via a chat group.
I express my deepest gratitude to my family. Mas Bino and Anika, thank you for your unconditional love, understanding and all your prayers. Mas Bino thanks for your care, and for being the best partner I
Acknowledgement
could wish for. Anika, who always asked me “when will you finish your thesis?”. Now dear, it is done! Ema sareng Apa, nuhun pisan kana sagala dukungan salami ieu utamina pidu’ana. T’Aning & fam., and my little brother Witana, thank you for your love, support, prayers, and taking care of our parents. To my Mother in-law, Cakra, and Mas Adjie & fam., thank you for your support and prayers. Uwak, paman sareng bibi sa-dayana, nuhun pidu’ana.
Finally, thanks to all people who are interested in this work and read my thesis.
Alhamdulillaahi rabbil’aalamiin Groningen, 2018
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List of publications
List of publications
(1) Susanti; Winkelman, J. G. M.; Schuur, B.; Heeres, H. J.; Yue, J. Lactic Acid Extraction and Mass Transfer Characteristics in Slug Flow Capillary Microreactors. Ind. Eng. Chem. Res. 2016, 55, 4691.
(2) Susanti; Meinds, T. G.; Pinxterhuis, E. B.; Schuur, B.; Vries, J. G. de; Feringa, B. L.; Winkelman, J. G. M.; Yue, J.; Heeres, H. J. Proof of Concept for Continuous Enantioselective Liquid-Liquid Extraction in Capillary Microreactors Using 1-Octanol as a Sustainable Solvent. Green Chem. 2017, 19, 4334.
(3) Susanti,; Schuur, B.; Winkelman, J. G. M.; Heeres, H. J.; Yue, J. Modelling Studies of Enantioselective Extraction of an Amino Acid Derivative in Slug Flow Capillary Microreactors. Chem. Eng. J. 2018, 354, 378
List of attended conferences
(1) Susanti; Meinds, T. G.; Schuur, B.; Heeres, H. J. Reactive Extraction of Lactic Acid in Microdevice (Poster Presentation), Smart Separation Day, The Netherlands, 2014.
(2) Susanti; Winkelman, J. G. M.; Schuur, B.; Heeres, H. J.; Yue, J. Slug Flow Capillary Microreactors for Lactic Acid Extraction (Oral Presentation), Netherland Proces Technology Symposium 14, The Netherlands, 2014.
(3) Susanti; Winkelman, J. G. M.; Schuur, B.; Heeres, H. J.; Yue, J. Slug flow capillary microreactors for lactic acid extraction: Experimental study and mass transfer modelling (Oral Presentation), 10th European Congress of Chemical Engineering, France, 2015.
(4) Susanti; Meinds, T. G.; Schuur, B.; Winkelman, J. G. M.; Yue, J.; Heeres, H. J. Continuous Chiral Separation in Microreactors (Oral Presentation), ENTEG Meeting, The Netherlands, 2015.
(5) Susanti; Winkelman, J. G. M.; Schuur, B.; Heeres, H. J.; Yue, J. Capillary microreactors for lactic acid extraction: experimental and modelling study (Oral Presentation), CHAINS, The Netherlands, 2015.
(6) Susanti; Meinds, T. G.; Pinxterhuis, E. B.; Schuur, B.; Vries, J. G. de; Feringa, B. L.; Winkelman, J. G. M.; Yue, J.; Heeres, H. J.. Continuous Chiral Separation in Microreactors (Oral Presentation), CHAINS, The Netherlands, 2016.
(7) Susanti; Meinds, T. G.; Pinxterhuis, E. B.; Schuur, B.; Vries, J. G. de; Feringa, B. L.; Winkelman, J. G. M.; Yue, J.; Heeres, H. J. Experimental and Modelling Study of Chiral Separations in Slug Flow Microreactors (Oral Presentation), 10th World Congress of Chemical Engineering, Barcelona, 2017.
