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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Enantioselective
liquid-liquid extraction
in microreactors
Cover design by Susanti
Layout by Susanti and Lovebird design.
www.lovebird-design.com
Printed by Eikon +
The research described in this thesis was carried out in Chemical Engineering clus-ter, Engineering and Technology institute Groningen (ENTEG), Faculty of Science Enginering, University of Groningen.
The work described in this thesis was financially supported by STW, The Netherlands, through project no. 11404 (Chiral Separations by Kinetic Extractive Resolution in Microfluidic Devices).
ISBN: 978-94-034-0943-6 (print ) ISBN: 978-94-034-0942-9 (electronic)
Enantioselective liquid-liquid
extraction in microreactors
PhD thesis
to obtain the degree of PhD at the University of Groningen
on the authority of the Rector Magnificus Prof. E. Sterken
and in accordance with the decision by the College of Deans This thesis will be defended in public on Tuesday 11 September 2018 at 09.00 hours
by
Susanti
born on 12 September 1983 in Solokanjeruk, Indonesia
Supervisor Prof. H.J. Heeres Co-supervisors Dr. Jun Yue Dr. J.G.M. Winkelman Dr. B. Schuur Assessment committee Prof. F. Picchioni Prof. G.F. Versteeg Prof. V. Hessel
Contents
Chapter 1 Introduction 1
1.1. Background 3
1.2. Chirality and its implication for life 3
1.3. Chiral separation techniques 5
1.4. Chiral separation by ELLE 6
1.4.1. Principles of ELLE 6
1.4.2. Extractants/hosts for ELLE 7
1.4.3. Equipment for ELLE 12
U and W-Tube devices 12
Configurations for larger scale operation 13
Centrifugal contactor separators 15
1.5. Microdevices for liquid-liquid extraction 16 1.5.1. Microscale liquid-liquid extractions 16
1.5.2. ELLE in microdevices 20
1.6. Aim of this thesis and thesis outline 20 References 22
Chapter 2 Lactic acid extraction and mass transfer characteristics in
slug flow capillary microreactor 31
Abstract 32 2.1. Introduction 33 2.2. Experimental details 35 2.2.1. Materials 35 2.2.1. Experimental setup 35 2.2.2. Experimental procedures 36 2.2.3.1. Physical extraction 37 2.2.3.2. Reactive extraction 38
2.2.3.3. Slug flow pattern visualization 38
2.2.3.4. Analytical procedures 39
2.3. Results and discussion 39
2.3.1. Mass transfer in physical extraction 39 2.3.2. Mass transfer in reactive extraction 48
2.4. Conclusions 56
References 57 Appendices 60
Appendix 2A. Extraction efficiency as a function of the residence time in
physical extraction 60
Appendix 2B. Dissociation of lactic acid in the aqueous phase 61 Appendix 2C. Extraction efficiency as a function of the residence time and inlet lactic acid concentration in reactive extraction 62 Appendix 2D. (Kova)Chem as a function of the residence time and inlet lactic
Chapter 3 Proof of concept for continuous enantioselective liquid– liquid extraction in capillary microreactors using 1-octanol as a
sustainable solvent 65
Abstract 66
3.1. Introduction 67
3.2. Materials and methods 69
3.2.1. Materials 69
3.2.2. Experimental setup 69
3.2.3. Experimental procedures 70
3.2.3.1. ELLE experiments in the capillary microreactors 70 3.2.3.2. ELLE experiments with DNB-(R,S)-Leu and CA3 in a batch set-up 71
3.2.3.3. Analytical procedures 71
3.3. Theory and definitions 72
3.4. Results and discussions 74
3.4.1. Equilibrium experiments in batch with 1,2-DCE and 1-octanol 74 3.4.2. Experiments in the continuous microreactor set-up 74 3.4.2.1. Continuous experiments in 1,2-DCE 74 3.4.2.2. Continuous experiments in 1-octanol 77
3.5. Conclusions 80
References 81 Appendices 84
Chapter 4 Modelling studies on enantioselective extraction of an amino acid derivative in slug flow capillary microreactors 89
Abstract 90
4.1. Introduction 91
4.2. Experimental method 92
4.2.1. Materials 92
4.2.2. ELLE in capillary microreactors 93 4.2.3. Determination of ELLE equilibrium constants in batch reactors 94
4.2.4. Analytical procedures 94
4.3. Model development 95
4.3.1. Calculation of the molar fluxes 96
4.3.2. Bulk phase concentrations 98
4.3.3. Physico-chemical parameters 99
Interfacial area 99
Overall mass transfer coefficient 99
Enhancement factor 100
Activity coefficient 101
Physical properties of the system 101
4.3.4. Numerical solution method 102
4.4. Results and discussions 103
4.4.1. Equilibrium extractions 103
4.4.2.1. Model I: instantaneous complexation rate for both the (S)- and
(R)-enantiomers 104
4.4.2.2. Model II: instantaneous complexation rate for the (S)-enantiomer and finite complexation rate for the (R)-enantiomer 106 4.4.3. Process simulation for multi-stage ELLE operation 109
4.5. Conclusions 114
Nomenclature 115 References 116 Appendices 120 Appendix 4A. Extraction performance as a function of the residence time 120 Appendix 4B. Enhancement factor in the aqueous phase in the presence of
dissociation reaction 121
Appendix 4C. Number of segments along the microreactor and its effect on
the model convergence 123
Chapter 5 Enantioselective liquid-liquid extraction studies on
(D,L)-tryptophan using a cationic Pd-XylBINAP complex as chiral host
in 1-octanol 125
Abstract 126
5.1. Introduction 127
5.2. Experimental section 128
5.2.1. Materials 128
In situ preparation of Pd(PF6)2((S)-XylBINAP) 128 5.2.2. Enantioselective liquid-liquid extraction of DL-Tryptophan with
Pd(PF6)2((S)-XylBINAP) 129
5.2.2.1. Extraction set-up 129
5.2.2.2. Experimental procedures 129
5.2.3. Analytical procedures 130
5.3. Theory and definitions 130
5.4. Results and discussions 131
ELLE of racemic Trp using different concentrations of the
Pd(PF6)2((S)-XylBINAP) complex. 133 Reactive extraction of enantiopure tryptophan 134
5.5. Conclusions 137 References 138 Appendix 5A 140 Summary 143 Samenvatting 147 Acknowledgement 151 List of publications 154
CHAPTER 1
1
3
Introduction1.1. Background
The demand of enantiopure compounds is increasing since the realization that the two enantiomers of a chiral compound can sometimes have dif-ferent biological activities. Several methodologies have been developed
to obtain enantiopure compounds.1 Examples are the direct synthesis2,3
by for example asymmetric catalysis or the separation of a racemic mix-ture. Direct synthesis is preferred, but separation of a racemic mixture is often the most cost-effective option.2
Enantioselective liquid-liquid extraction (ELLE) is a promising method for chiral separation of racemic mixtures. ELLE has been studied in detail and reported in several papers.4 However, due to the relatively low enan-tioselectivities, many equilibrium stages are required to obtain both
en-antiomers in high-enantiopurity.1,4 The intensification of ELLE has been
demonstrated using a countercurrent cascade of multiple CCS devices5,6
and intensified columns.7 Another possible alternative to intensify ELLE is the use of microreactors. Such devices have been used already to in-tensify conventional solvent extractions.8–11
The use of microreactors has become an important methodology in fine chemical synthesis, as they offer many advantages, such as enhanced heat- and mass transfer rates, high surface to volume ratio, reduced
in-ventories of reactants and products, and lower reagent consumption.8–11
In this thesis, the use of the ELLE concept in microreactors is explored to determine its potential for chiral separations.
This introduction will start with the concept of chirality and its im-plication for many aspects of life. The importance of enantiopure com-pound will be highlighted and synthetic methodology to obtain enantio-pure compounds will be discussed, including available methods for chiral separation. Subsequently, the use of liquid-liquid extraction for chiral separations will be discussed in detail, both from a chemistry and more applied point of view.
1.2. Chirality and its implication for life
“Chirality” was observed for the first time in the 1840’s when Louis Pasteur found that crystals of tartaric acid are present in two forms, which were later identified as mirror images of each other.12,13 Fifty years
later, the term chirality was introduced by Lord Kelvin in the second Robert Boyle Lecture at the Oxford University Junior Scientific Club.14
Chiral originally comes from the Greek word kheir, meaning hand.15,16 To
explain the concept of chirality, the idea of right- and left-handedness is often used. Like hands, chiral objects are non-superimposable on their mirror images (Figure 1.1).
4
Chapter 1
In chemistry, a compound is chiral when exists in two forms (enantio-mers) which have the same chemical structure but are mirror images of each other and cannot be superimposed.17 An example is tetrahedrally- bonded carbon with four different substituents e.g. the two enantiomers of glyceraldehyde (Figure 1.2).
Most of the molecules of importance to living system like amino acids, sugars, proteins and nucleic acids are chiral. As a result of chirality, en-antiomers can have different interactions on a molecular level, including differences in protein binding and transport, mechanism of action, rates of metabolism, changes in activity due to metabolism, clearances rates, and persistence in the environment.13
Chirality play an important role in the pharmaceutical, agrochemical,
flavor and fragrance industry.2–4 The enantiomers of a racemic drug may
Can be superimposed Mirror Cannot be superimposed Mirror a) Chiral objects b) Achiral objects
Figure 1.1. Chiral and achiral objects. Chapter 1
4
Figure 1.1. Chiral and achiral objects.
Most of the molecules of importance to living system like amino acids, sugars, proteins and nucleic acids are chiral. As a result of chirality, enantiomers can have different interactions on a molecular level, including differences in protein binding and transport, mechanism of action, rates of metabolism, changes in activity due to
metabolism, clearances rates, and persistence in the environment.13
Figure 1.2. The two enantiomers of glyceraldehyde.
Chirality play an important role in the pharmaceutical, agrochemical, flavor and
fragrance industry.2–4 The enantiomers of a racemic drug may have different
pharmacological activities, as well as different pharmacokinetic and pharmacodynamic
effects.18–20 The human body, a chiral environment, will interact differently with each
enantiomer of a drug and as such different metabolic pathways may be followed, giving differences in pharmacological activity. In the worst case, only one of the two enantiomers is active and the other even toxic.20
Can be superimposed Mirror Cannot be superimposed Mirror a) Chiral objects b) Achiral objects C CHO HO C OH CHO
L-glyceraldehyde Mirror D-glyceraldehyde
CH2OH CH2OH
1
5
Introductionhave different pharmacological activities, as well as different
pharma-cokinetic and pharmacodynamic effects.18–20 The human body, a chiral
environment, will interact differently with each enantiomer of a drug and as such different metabolic pathways may be followed, giving differ-ences in pharmacological activity. In the worst case, only one of the two enantiomers is active and the other even toxic.20
Many chemical products used for pest-control are used as racemates. Pesticides in agriculture have shown to be hazardous for the environ-ment and have created a potential danger to both aquatic- and human hife.21,22 Therefore, the use of enantiomers instead of racemates for
agri-cultural purposes can have a positive effect.22
Chirality also has an import role in the flavor and fragrance industry.
Two enantiomers may show different odor character.23–25 Moreover, the
taste is also depending on whether a racemate or chiral compound is used.12,26-28
Thus, it is clear that the availability of enantiopure compounds is of high importance. In general, enantiopure compounds can be obtained from natural sources (chiral pool), separation of a racemic mixture or by
chiral synthesis.2,29 From a viewpoint of economic efficiency,
enantiose-lective synthesis is more attractive than the separation of a racemic mix-ture, the latter one producing intrinsically half of the product as waste. However, relatively few catalytic conversions with enantioselectivities higher than 95% have been reported and the application of the enanti-oselective catalyst often is often substrate specific and thus not broadly applicable for a wide range of substrates.30 As such, many of the devel-oped stereoselective synthesis routes require a final purification step to remove the undesired enantiomer from the final product. Because of this limitation of stereoselective synthesis, chiral separation methods are cur-rently the most often used for the production of the majority of single enantiomers.29
Chiral separation techniques use the competitive advantage of the ease of synthesis of a racemic mixture instead of a chiral compound. The time-to-market for this strategy is potentially shorter than for asymmet-ric catalysis, provided that the separation of the enantiomers can be done with a technique that is broadly applicable to structurally very diverse substrates.29,31
1.3. Chiral separation techniques
The separation of racemates is of great importance to obtain enantiopure compounds. On industrial scale, resolution by crystallization is the most
commonly used technology.32–34 The main drawbacks of this method are
6
Chapter 1
A large number of laboratory techniques have been developed for en-antioseparation,37–42 examples are chromatography41 and capillary
electro-phoresis.42 Typically, high capital investments are required for scale up.43,44
Nevertheless, for the separation of small amounts of racemates to obtain single enantiomers required in early development stages, the high separa-tion costs by chromatographic techniques are still small compared to the total drug development costs.45 Recent examples of preparative chiral sep-aration techniques are centrifugal partition chromatography,46 and simu-lated moving bed chromatography.33,34,47 Another strategy for chiral
sepa-ration is based on the use of membrane-based approaches.1,48–51 Here, the
amount of selector can be reduced considerably, as they are immobilized in (liquid) membranes. Limitations of this technology are the relatively low transport rates through the membranes and the risk of fouling.
Liquid-liquid extraction (LLE) is considered a promising technology for chiral separation.4,52,53 Several studies have been reported on chiral
separations using LLE for amino acids, amines, and amino alcohols. This technique, also known as enantioselective liquid-liquid extraction (ELLE), is potentially attractive for chiral separation at different scales.53 Scale up of the technology is relatively easy and continuous processing mode is advantageous to eliminate batch-to-batch variations.53
1.4. Chiral separation by ELLE
Chiral separation by ELLE was first reported in 1959 followed by reports in the 1970’s for the separation of amino ester salts by Nobel laureate Donald Cram.54 This technique never really made it beyond the explor-atory research state because of limited selectivity of the extractants.54 In the 2000’s, interest in ELLE intensified and scale-up studies.7,52,55,56
as well as screening studies on the development of improved selectors were reported.56,57
1.4.1. Principles of ELLE
ELLE combines solvent extraction58 and chiral recognition.59 ELLE in-volves contacting two liquid phases, commonly an aqueous solution with the racemic mixture to be separated, with an organic solution containing a chiral host with a higher affinity for one of the enantiomers. However, the opposite is also possible, viz. the racemic mixture is dissolved in the organic phase and the chiral host is present in the aqueous phase.6,60–67
For the case the racemic mixture is dissolved in the aqueous phase, the process principle of ELLE is schematically represented in Figure 1.3. The enantiomers are transferred 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 enantioseparation.
1
7
IntroductionThe choice of the organic solvent is critical and of high importance is a low solubility of the organic phase in the water phase and vice versa. Chlorinated and long chain hydrocarbon solvent have been reported to be beneficial for ELLE.7,53,66,68 In addition, it is also of high importance that the
solubility of the extractant/host in the water phase is limited in order to re-duce the loss of (expensive) host.1 Widely used host-racemate combinations and solvent selection will be reviewed in the next subsection, followed by an overview of available laboratory and process equipment for ELLE. 1.4.2. Extractants/hosts for ELLE
Several classes of extractants (hosts) have been reported for the separa-tion of racemates. A summary of extractants for ELLE and their perfor-mance is provided in Table 1.1. Perforperfor-mance indicators for the case where the racemate to be separated is present in liquid phase one (L1) and the extractant in L2 is given in Eqs 1.1-1.5.
Operational selectivity (αop): R op S D D α = , if D R > DS (1.1)
Here, D is the distribution of the enantiomers between the two liquid phases (L1 and L2), which is defined as:
Figure 1.3. Representation of enantioselective liquid-liquid extraction (ELLE) for a
8
Chapter 1[ ]
[ ]
L12 R L R D R = ;[ ]
[ ]
2 1 L S L S D S = (1.2)where [R] and [S] represent the concentration of the (R)- and (S)-enantiomer.
Intrinsic selectivity (αint): int R
S K K
α = , if KR > KS (1.3)
Here, KR and KS are the equilibrium constant for the complexation of the
enantiomers and host. For the case of 1 to 1 complex formation, these are defined as: [ ] [ ][ ] R CR K C R = ; [ ] [ ][ ] S CS K C S = (1.4)
Here [CR] and [CS] represent the concentration of the complex between the (R)- and (S)-enantiomer with the host C, respectively and [C] is the concentration of host C.
Enantiomeric excess (ee):
[ ] [ ]
[ ] [ ]
R S 100% ee R S − = × + (1.5)Crown ether-based systems are among the most selective extractants known.69 For instance, Cram’s BINOL crown ether system for the ex-traction of α-amino acid ester salts showed an operational selectivity up to 31, making them the most versatile extractants in the field. For extract-ants with lower selectivity, multistage extraction is required.6,52,70 Most
examples involve a host dissolved in the organic phase and a racemic mixture in the aqueous phase. To date, only a limited number of systems have been reported for the reverse situation, an example is the extraction of hydrophobic compounds in the organic phase with hydrophilic B-cyclodextrin (CD) and derivatives in the water phase.6,60–67
1
9
Introduction Table 1.1. Hosts/ extr actants f or chir al separ ation in biphasic sy st em Extractant phaseSubstrate (in aque
ous phase) Performance: αop (-), or α int (-), or ee (%) Ref. Host solv ent Cr own ethers Cram’s BINOL cr
own ether system and derivativ
es
Chlor
oform
Amine and amino ester salts
αint = 1.5-5 71 Chlor oform
α-amino acid ester salts
αop
up to 31
72
Chlor
oform
Amino salts and amine esters
αop
for amine salts <2, up to 12 for amino esters
73 Chlor oform α-amino acids αop range of 5.1-19.2 74 Chiral cr
own ether base
d hosts with
only one chiral element
Chlor
oform and or mixtur
es
of A
CN and chlor
oform
α-amino acids and
α-amino
acid methyl esters
Maximum α op of 23.4, using a mix -tur e of organic solv ents 74 Guanidinium-cr
own ether tether
ed systems DCE α-amino acids ee up to 98% 75 DCM α-amino acids Up to 79% e e 76 Substitute d p yridine-18-cr own-6 ethers Chlor oform
Picrates and Orange 2
αint < 3 77 18-cr own-6 ethers Chlor oform Picrates αint < 3.23 78 Azophenolic cr own ether Various solv ent
Amines and amino alcohols
αint = 1.5 -12 2 Metal comple xes Cu(II)N-do de cyl-(L)-hy dr oxypr oline n-BuOH α-amino acids αint =1.8-4.5 79 Cu(II)( N -(n-do de cyl)-L-hy dr oxypr oline) Octanol Leucine αop <2.1 80 Cu(II)( C12Pr o)2 n-BuOH Mandelic acid αop =1.46-1.85 81 Zinc comple x of a strapp ed N -alkylp orphyrin Chlor oform Pr ote cte d amino acids Highest sele ctivity up to 23.4 for e xtraction of N-(3,5-DNB)phenylgly cinate 82
Lantanide(III) tris(β -diketonates
DCM Amino acids ee values b etw een 3-49% 83 Cu(II)(N-de cyl-( l)-hy dr oxypr oline)2 He xanol/de cane Amino acids αint <2.4 84 ,85 Co(III)( salen)( O A c) DCM Pr ote cte d amino acids ee values b etw een 38.9-93% 86 Cu(II)( C12Hyp) 2 or Cu(II)( OH-C12Hyp) 2
n-BuOH and or Mixtur
e
of n-BuOH:He
xane
Amine and amino alcohols
Maximum α op of 1.8 using mixtur e organic solv ent 2 Cu(II) N-de cyl-(L)-hy dr oxypr oline he xanol:de cane (1:1) Amino acids SLM, αint ~ 1. 6 87 Pd(II)-tBuBOX; 2,2’-isopr op ylidenebis((4s)-4-tert-bu -tyl-2-o xazoline) and [2, 6-bis((4 R )-4-phenyl-2-oxazolinyl)p yridinePd(II)Cl]+ SbF 6 –(Pd-p yBOX)
Various organic solv
ents Amino acids Maximum sele ctivity , αop of 2.3 obtaine d using Pd-p yBOX dissolv ed in chlor ob enzene 88
10
Chapter 1
Extractant phase
Substrate (in aque
ous phase) Performance: αop (-), or α int (-), or ee (%) Ref. Host solv ent BINAP-metal comple xes (S
)-BINAP in combination with (
A CN) 2 PdCl 2 Various solv ent Amino acids αop
<2.8 using DCE as organic solv
ent 45 (S )-BINAP or derivativ es in com -bination with ( A CN) 2 PdCl 2 Various solv ent
Amino acids and phenyl alanine analogues
High sele
ctivity using Pd(
Cl2
)-(
S)-XylBINAP as hosts with α
op
= 3.2-7
.0
49
(S
)-BINAP in combination with
((A CN) 2 PdCl 2 [(A CN) 4 Cu]PF 6 , [(P h)3 P]NiCl 2
Various organic solv
ent
Amino acids and chlor
ophenylgly cine αint < 4.2 36 ,89 –91 (S
)-BINAP in combination with [(
A CN) 4 Cu]PF 6 DCM Amino acids αint = 2.15 92 (S
)-BINAP in combination with (
A CN) 2 PdCl 2 DCE Amino acids 90% e e obtaine
d using 10 stages using a CCS,
mo del pr edicte d 99% e e using 16 stages 70 Di(2-ethylhe
xyl) phosphoric acid (D2EPHA
)
or Aliquat 336 and a tartaric acid de
-rivativ es (i.e . DBT A and D T TA ): D2EHP A and DBT A or D TT A n-Octanol Mandelic acid αop b etw een 1.3 and 1. 6 93 D2EHP A and DBT A n-Octanol Amino acids αop < 5.3 94 Aliquat 336 DBT A or D TT A n-Octanol Amino acids αop b etw een 1.4 and 4 95 D2EHP A and DBT A n-Octanol Mandelic acid αop < 2.74 96 D2EHP A and DBT A n-Octanol Oflo xacin αop b etw een 1.3 and 5. 6 97 Alkyl tartrates, p ossibly in combination with β-cy clo de xtrin ( β-CD ): D- or L-dib enzo yltartaric acid n-Octanol RS-oflo xacin αint b etw een 1.13 and 3.86 98 L-Dip entyl T artrate and β-CD De canol Mandelic acid αop =2.1 99
D(L)-isobutyl tartrate and β-CD
DCE
Derivatize
d mandelic
acid and napr
oxen αop <2.49 100 101 (R)- and (S)-di-n-do de cyltartrate Chlor oform Amino alcohols αint = 2.77 102
D(L)-isobutyl tartrate and derivatize
d β-CD DCE Zopiclone 1.2-1.5 103 D-( +)-D TT A and derivatize d β-CD Various solv ents Mandelic acid αop < 1.53, the b
est for HP-B-CD and o
ctanol
44
D(L)-isobutyl tartrate and derivatize
d β-CD
Various solv
ents
Ibupr
ofen and or flurbipr
ofen
αint
<1.24, with DCE as the b
est organic solv
ent
104
,105
L-Iso-p
entyl-tartrate and various derivatize
d B-CD He xanol Keto conazole αint <1.3, membrane assiste d 106
Various tartaric acid derivativ
es and derivatize d B-CD Various solv ents Amines αint < 2. 62, the b est in H-B-CD as sele ctor in the aque
ous phase and de
canol as the organic solv
ent
1
11
IntroductionExtractant phase
Substrate (in aque
ous phase) Performance: αop (-), or α int (-), or ee (%) Ref. Host solv ent
D-iso-butyl tartrate (D-IBT
A
) and SDS
Various solv
ents
Mandelic acid derivativ
es
αop
<4.5, b
est organic solv
ent is n-o ctanol 108 D- or L-dib enzo yltartaric acid 1-De canol Amines SLM, α op = 1. 0-1.7 109
L-tartaric acid dihe
xyl ester Various solv ents Ibupr ofen Lo w sele ctivity , αop <1.2 110
isobutyl tartrate and derivatize
d β-CD Various solv ents Amines αop <1.2, the b
est was obtaine
d us
-ing DCE as organic solv
ent
111
Cinchona alkaloid Lipophilic carbamo
ylate d quinine Various solv ents Pr ote cte d Amino A cids ee up to 95% 112 Cinchona-base d chiral host DCE Pr ote cte d Amino A cids ee of 34% in single stage ee of 98% after 6 stages 5 ,32 ,52 ,113 ee up to 98. 6% 7 Various cinchona-base d chiral hosts Various solv ents Pr ote cte d Amino A cids ee up to 96% after cr ystallization fr om heptane . ee 59% without cr ystallization 68 Ster
oidal guanidinium hosts
Ster
oidal guanidinium cations
Chlor oform N-acyl pr ote cte d α-amino acids ee up to 81% 114 , 115 Lip ophilic ster oidal guanidinium r eceptor Various solv ents N-acyl pr ote cte d α-amino acids ee ar ound 7
0%, when using DCM as organic solv
ent 116 Other chiral e xtractants: Diphosphonium salt b earing binaphthyl gr oups Mixtur e of DCE: CCl 4 (1:1) di-o-b enzo yl-tartrate αop < 1.36 117
Dialkyl tartrates and b
oric acid Chlor oform Amino alcohols αop < 2.9 118 ,119 De oxyguanosine derivativ es Chlor oform 2,4-DNB-α-amino acids ee up to 29% 120 Tris-(tetrachlor ob enendiolato-phosphate(V) (TRISP AT) Chlor oform Rac ruthenium comple xes ee b etw een 78 and 94% 121 Hy dr ogen-b ond assiste d BINOL-aldehy de hosts Chlor oform 1,2-amino alcohols αint b etw een 3.1 and 15 122
Ionic liquids: copp
er acetate dis -solv ed in [ Cnmim][ l-Pr o] Ethylacetate a-amino acids ee up to 50. 6% 123 Derivatize d B-CD [bmim][PF 6 ] ionic liquid Mandelic acid αint b etw een 1.3 and 1.7 124 Binol-base d phosphoric acids Various solv ents Benzylic primar y amines αop < 2.3 57 (S)-3-A cetyl-2,2-dihy dr oxy-1,1-binaphthyl- ketone Chlor oform Amino acid High ee in e xtractant phase of 73-85% 125
Mandelic acid esters
Various organic solv
ents Zoplicone Maximum sele ctivity of 1.46 in cy clohe xane 126 A
CN = acetonitrille; DCE = 1,2-dichlor
oethane; DCM= dichlor omethane; DBT A = O ,O’-dib enzo yl-(2R,3R)-tartaric acid; D TT A = O ,O’-dib enzo yl-(2S,3S)-4-toluo yl-tartaric aci
12
Chapter 1
1.4.3. Equipment for ELLE
Equipment for liquid-liquid extraction is available on lab- and com-mercial scale. Selection of the most suitable configuration is depending among others on process conditions. For instance, when short contact times are required to prevent product degradation, a centrifugal contac-tor separacontac-tor is a suitable device. Proper selection of extraction equip-ment may be performed using the selection chart given by Laddha et al.127 Chiral extractions have been performed in laboratory equipment and at industrial scale. Lab scale equipment is often used to provide the proof of principle for a host-racemate system and is characterized by single stage extraction at small scale and in most cases in batch mode. Scale-up is typically performed in dedicated equipment, and often using continuous operation.
U and W-Tube devices
Typical examples of a small-scale devices used for screening ELLE exper-iments are U- and W-tubes.73 The U-tube (Figure 1.4) is typically applied using a chiral host.45,73,76,128,129 A typical arrangement of the phases in the
U-tube is given in Figure 1.4. Dissolved host in transport phase (usually in organic phase) is placed at the bottom of the U tube. The racemate mixture (usually in the aqueous phase) is placed on top of the transport phase in the left tube. The right tube is filled with water as receiving phase. Stirring is started at non-turbulent rate and the enantiomer will be transported from the aqueous phase to the organic phase. Due to pref-erential complexation with the host, the transport phase is enriched with one of the enantiomers. Subsequently, the complexed enantiomer in the transport phase is transferred to the receiving phase.45,57,73,76 Besides for
ELLE experiments, it has been reported that U tube having potential to be used for fast screening of the best candidates for chiral recognition.69,73,76
Introduction
13
1.4.3. Equipment for ELLE
Equipment for liquid-liquid extraction is available on lab- and commercial scale.
Selection of the most suitable configuration is depending among others on process
conditions. For instance, when short contact times are required to prevent product
degradation, a centrifugal contactor separator is a suitable device. Proper selection of
extraction equipment may be performed using the selection chart given by Laddha et
al.
127Chiral extractions have been performed in laboratory equipment and at industrial
scale. Lab scale equipment is often used to provide the proof of principle for a
host-racemate system and is characterized by single stage extraction at small scale and in
most cases in batch mode. Scale-up is typically performed in dedicated equipment, and
often using continuous operation.
U and W-Tube devices
Typical examples of a small-scale devices used for screening ELLE experiments are U-
and W-tubes.
73The U-tube (Figure 1.4) is typically applied using a chiral
host.
45,73,76,128,129A typical arrangement of the phases in the U-tube is given in Figure 1.4.
Dissolved host in transport phase (usually in organic phase) is placed at the bottom of
the U tube. The racemate mixture (usually in the aqueous phase) is placed on top of the
transport phase in the left tube. The right tube is filled with water as receiving phase.
Stirring is started at non-turbulent rate and the enantiomer will be transported from the
aqueous phase to the organic phase. Due to preferential complexation with the host, the
transport phase is enriched with one of the enantiomers. Subsequently, the complexed
enantiomer in the transport phase is transferred to the receiving phase.
45,57,73,76Besides
for ELLE experiments, it has been reported that U tube having potential to be used for
fast screening of the best candidates for chiral recognition.
69,73,76Figure 1.4. Schematic representation of the U-tube device. Reprinted from Ref. no. 45 with
permission, Copyright © 2009 American Chemical Society.
The W-tube consists of two connected U tubes (Figure 1.5) and is applied for the
separation of a racemate. The racemate to be separated in a water phase is placed in the
Figure 1.4. Schematic representation of the U-tube device. Reprinted from Ref. no.
1
13
IntroductionThe W-tube consists of two connected U tubes (Figure 1.5) and is applied for the separation of a racemate. The racemate to be separated in a water phase is placed in the center part of the device. The heavier organic phase is placed at the bottom of the two tubes, one containing the (R)- and the other containing the (S)- enantiomer. Finally, water is placed in both the right and left tube. Extraction is initiated by stirring and the system is stirred till equi-librium is attained. The device was successfully applied for ELLE of amino salts and amine esters using a dilocular crown ether as the host.73
Configurations for larger scale operation
In general, three basic types of equipment are used for industrial- scale continuous solvent extractions viz. mixer-settlers, columns and centrif-ugal contactors.29 In a mixer-settler, contacting and separation are
per-formed in two discrete stages.58 Extraction columns are widely used81,130
and are applicable for small and large-scale operation. The extraction efficiency is increased by contacting the two liquid phases in a counter-current mode.29 Several ELLE studies in countercounter-current column set-ups have been reported. For example, Takeuchi et al.130 reported extensive studies in the column set-up schematically given in Figure 1.6.
Recently, the use of a process intensified extraction column (PIEC) was demonstrated for ELLE, see Figure 1.7 for a schematic representation. The column (inner diameter of 15 mm) consist of five modular sections
consisting each of 10 stirred cells.7,131 A racemic mixture is fed into the
middle of the extraction column, the second phase (in this case is a heavy phase) which contains the host is fed into the top of the column, while the receiving solvent (i.e. a light phase) for back extraction, enters the bottom of the column.
The PIEC concept has been successfully demonstrated for two ELLE systems. It was used for the separation of racemic phenylsuccinic acid in an organic solvent (n-decanol) using L-hydroxypropyl-β-cyclodextrin (HP-β-CD) in a buffered aqueous phase as the host solution.131 An
Chapter 1
14
center part of the device. The heavier organic phase is placed at the bottom of the two
tubes, one containing the (R)- and the other containing the (S)- enantiomer. Finally,
water is placed in both the right and left tube. Extraction is initiated by stirring and the
system is stirred till equilibrium is attained. The device was successfully applied for
ELLE of amino salts and amine esters using a dilocular crown ether as the host.
73Figure 1.5. Schematic representation of the double U-tube.
Configurations for larger scale operation
In general, three basic types of equipment are used for industrial-scale continuous
solvent extractions viz. mixer-settlers, columns and centrifugal contactors.
29In a
mixer-settler, contacting and separation are performed in two discrete stages.
58Extraction
columns are widely used
81,130and
are applicable for small and large-scale operation. The
extraction efficiency is increased by contacting the two liquid phases in a countercurrent
mode.
29Several ELLE studies in countercurrent column set-ups have been reported. For
example, Takeuchi et al.
29reported extensive studies in the column set-up schematically
given in Figure 1.6.
Figure 1.6. Column set-up for ELLE used by Takeuchi et al.130 Reproduced with permission from Taylor & Francis.
14
Chapter 1
heavy phase outlet
Figure 1.7. Schematic representation of the process intensified extraction column
(PIEC). Reprinted from Ref. 7 with permission, Copyright © 2015 American Chemical Society.
Chapter 1
14
center part of the device. The heavier organic phase is placed at the bottom of the two
tubes, one containing the (R)- and the other containing the (S)- enantiomer. Finally,
water is placed in both the right and left tube. Extraction is initiated by stirring and the
system is stirred till equilibrium is attained. The device was successfully applied for
ELLE of amino salts and amine esters using a dilocular crown ether as the host.
73Figure 1.5. Schematic representation of the double U-tube.
Configurations for larger scale operation
In general, three basic types of equipment are used for industrial-scale continuous
solvent extractions viz. mixer-settlers, columns and centrifugal contactors.
29In a
mixer-settler, contacting and separation are performed in two discrete stages.
58Extraction
columns are widely used
81,130and
are applicable for small and large-scale operation. The
extraction efficiency is increased by contacting the two liquid phases in a countercurrent
mode.
29Several ELLE studies in countercurrent column set-ups have been reported. For
example, Takeuchi et al.
29reported extensive studies in the column set-up schematically
given in Figure 1.6.
Figure 1.6. Column set-up for ELLE used by Takeuchi et al.130 Reproduced with permission
from Taylor & Francis.
Figure 1.6. Column set-up for ELLE used by Takeuchi et al.130 Reproduced with
1
15
Introductionenantiomeric excess of 60% and yields of 80% for both enantiomers were obtained.131 Holbach et al.7 investigated ELLE using the PIEC concept for an amino acid derivative (3,5-DNB-(R,S)-leucine) and a cinchona alkaloid as the host. Impressive ee’s of up to 98.6% were obtained for the (R)-enantiomer in the aqueous phase at high yields (93.7%).
Centrifugal contactor separators
A centrifugal contactor separator (CCS) is a continuously operated de-vice that integrates mixing and separation (Figure 1.8). It consists of a rotating centrifuge in a static house. Two liquid phases enter the CCS from different inlets and are mixed intensively in the annular zone and subsequently transferred to the centrifuge via a small hole in the bot-tom of the centrifuge. Here, the dispersion is separated in two separate phases by centrifugal forces. The CCS is well suited for ELLE because it has a low liquid hold-up, is easy to scale up and is compact.1 Schuur
et al. have demonstrated the application of the CCS device for
continu-ous ELLE.52,68,132
A number of CCS devices in series allow for multistage extraction and this concept has been applied successfully for ELLE.6,52,70 For instance,
Heeres et al. have demonstrated ELLE for six CINC devices in combi-nation with one device for the back-extraction (shown in Figure 1.9). It proved possibility to obtain one of the DNB-(S)-leucine enantiomers with an average enantiomeric excess (ee) of 98% and a yield of 55% us-ing a chiral chincona alkaloid as the host.5 Model predictions reveal that
Figure 1.8. Schematic overview of a CCS device (darker gray: heavy phase; lighter
gray: light phase; hatched: dispersion). Reprinted from Ref. 52 with permission, Copyright © 2008 American Chemical Society.
16
Chapter 1
17.7 kg of racemate can be separated with 99% ee by using a cascade of twelve CCS devices with an extractant hold-up of 60 g in one week.113
1.5. Microdevices for liquid-liquid extraction
In the last decades, continuous flow devices ranging from microscale9,133–139
to milli-scale have been studied extensively.140–144 A microdevice has
char-acteristic dimensions far below conventional equipment, typically below the sub-millimeter range.145 Several review papers have been published on the use of microreactors/devices for chemical synthesis,9,146 multiphase
re-actions,10,147 and liquid−liquid extraction.8,148–152 The use of microextractors
for liquid-liquid extractions will be reviewed in the next sub section. 1.5.1. Microscale liquid-liquid extractions
Liquid-liquid extraction has been successfully demonstrated in various microdevices.8,148–150,153–157 Three major types of devices for this purpose
can be discriminated150 viz. i) chip based microextractors, ii) capillary based microextractors and iii) high capacity mini extractors (Table 1.2). The use of microdevices for liquid−liquid extractions is a promising alter-native for macroscale counterparts.8,148,153–157 This is mainly due to a
sig-nificantly enhanced extraction efficiency by the higher interfacial areas, the results of smaller droplets of the dispersed phase150,158 and/or higher
mass transfer coefficients.
In addition, the use of such microdevices enables precise control of important process parameters such as residence times and the interface between the two liquid phases. In contrast to conventional extraction
Figure 1.9. Experimental setup consisting of six CCS devices and a back-extraction
unit for ELLE (F = feed; BE = back-extraction). Reprinted from Ref. 5 with permission, Copyright © 2009 American Chemical Society.
1
17
Introductionprocesses, the phase ratio mainly determines which of the phases is the dispersed and which is the continuous phase.150 Several flow patterns are attainable in microchannels.149,150,159 The most important ones are
sche-matically represented in Figure 1.10.
After extraction in a microdevice, the two liquids need to be separated efficiently. Phase separation by gravity is difficult to implement and other options have been developed.152 These include the use of physical
supports such as membranes,160 guided structures,161,162 and partitioned
walls.8 Moreover, phase separation based on preferential wettability by using a Y-splitter consisting of two different materials has also been explored.8,154
Table 1.2. Microdevices for liquid-liquid extraction
Example Remarks
a) Chip based microdevices
The devices are usually prepared from polydimethylsiloxane (PDMS). Other polymers used for microchips are po-ly-methylmethacrylate (PMMA),163 poly-carbonate (PC),168 and polyvinylidene flu-oride (PVDF).165 A major issue is solvent resistance, which is low for most solvents and leads to excessive swelling, partic-ularly at eleveated temperatures.150 For extreme conditions such as used for super-critical CO2 extractions166 the extractor is
typically made from silicon or Pyrex glass. Slug flow capillary microdevice
b) Capillary based microdevices
These devices are generally made from fluorine containing polymers such as per-fluoroalkoxy alkanes (PFA), polytetraflu-oroethylene (PTFE), ethylene tetrafluoro-ethylene (ETFE) and fluorinated tetrafluoro-ethylene propylene (FEP), which are relatively cheap and solvent resistant. Other exam-ples are the use of silica and polyether ether ketone (PEEK). Commercial fittings are available to connect these tubes with the micromixer and the flow control systems.167,168
Slug flow capillary microdevice c) high capacity mini extractors
Advantages of these devices are higher in-terfacial areas compared with microtubes and chips. Various configurations such as the slit interdigital micromixer,169 the micro-sieve dispersion mixer170,171with a
maximum treatment capacity of 100 mL/ min, and the Corning advanced-flow de-vice with a maximum treatment capacity of 200 mL/min have been developed.172
18
Chapter 1
The two most commonly used flow patterns for liquid-liquid extraction in microchannels are parallel and slug flow. Parallel flow is character-ized by a side-by-side flow of immiscible fluids (see Figure 1.10).8,161 Here,
mass transfer direction is perpendicular to the flow direction of the two phases. Due to laminar flow in the channel, it is governed mainly by mo-lecular diffusion. A potential advantage in parallel flow operation is that the separation between immiscible liquids at the microchannel outlet is relatively easy.
Higher mass transfer rates can be obtained when increasing the su-perficial velocity of the liquids i.e. operating at higher flow rates and/ or the use of smaller microchannels.158 With proper selection, slug flow regime, characterized by alternating segments of immiscible fluids may be obtained (Figure 1.10). Slug flow operation is characterized by high in-terfacial areas154 and high mass transfer rates due to internal circulation inside a slug/segment.8,173,174 However, phase separation in the slug flow
regime is not as straightforward as for parallel flow.
Microdevice extractions in the slug flow regime has also shown to lead to higher mass transfer rates when compared with other conventional
system.154,175 A comparison of the volumetric mass transfer coefficients
(kLa) for slug flow operation compared to data obtained in stirred vessels
(CSTR) is provided in Table 1.3. For microdevices, kLa values between
0.07 and 8.83 s-1 have been found, which is considerably higher than Ȁ
Ȍ
Ȍ
Ȍ
Ǧ Ȍ
1
19
Introduction Table 1.3. V olume tric mass tr ansf er c oefficients (k La ) in slug flo w oper at ed micr ode vic es and CSTRs. Contactor (shap e of the mixer , de vice)Chemical system (feed solv
ent – solute – e xtracting solv ent) kL a [s -1] a a [m 2∙m -3] Ref. CSTR 1.6 x 10 -5 – 0. 017 154 Y-shap e, capillar y i.d. = 0.50 mm b W ater – io dine – ker osene 0.31 – 0.98 4500 – 4800 c 154 Y-shap e, capillar y i.d. = 0.75 mm b W ater – io dine – ker osene 0.29 – 0. 64 2980 – 3190 c 154 Y-shap e, capillar y i.d. = 1. 00 mm b W ater – io dine – ker osene 0.13 – 0.32 2510 – 27 60 c 154 Y-shap e, capillar y i.d. = 0.50 mm b Ker osene – acetic acid – water 0.42 – 1.47 n.a. 154 Y-shap e, capillar y i.d. = 0.75 mm b Ker osene – acetic acid – water 0.42 – 1.11 n.a. 154 Y-shap e, capillar y i.d. = 1. 00 mm b Ker osene – acetic acid – water 0.42 – 1. 02 n.a. 154 Y-shap e, capillar y i.d. = 0.50 mm b Ker osene – Butyl formate – water + NaOH 0.90 – 1. 67 1600 – 3200 c 177 Y-shap e, capillar y i.d. = 0.75 mm b Ker osene – Butyl formate – water + NaOH 0.91 – 1.46 1075 – 277 0c 177 Y-shap e, capillar y i.d. = 1. 00 mm b Ker osene – Butyl formate – water + NaOH 0.88 – 1.29 830 – 2480 c 177 Y-shap e, r ectangular micr ochannel i.d. = 0.40 mm b He xane – trichlor oacetic acid – water + NaOH 0.2 – 0.5 ~ 11000 161 T-shap e, squar e micr ochannel i.d. = 0.21 mm b Toluene – acetone – water 1.61 – 8.44 6090 – 13400 178 T-shap e, squar e micr ochannel i.d. = 0.30 mm b Toluene – acetone – water 0.72 – 2. 65 4540 – 9600 178 T shap
e mixer (i.d.= 1.5 mm), capillar
y (i.d. = 1. 0 mm) Do de cane – phenol – water 0.23 – 0.96 n.a. 179 T-shap e, capillar y i.d. = 1. 00 mm b n-heptane – acetic acid
– Ionic liquid EMIM EtSO4
0. 004 – 0. 014 n.a. 180 T-shap e, r ectangular micr ochannel i.d. = 0.30 mm b Toluene – N,N-dimethylformamide – water < 5.3 20000 181 T-shap e, capillar y i.d. = 1. 0 mm b n-butyl acetate – acetone – water 0.577 – 0.356 n.a. 182 T-shap e, micr ostructur ed helically coile d tub e (MHCT), i.d. = 1. 00 mm b n-butyl acetate – acetone – water 1.128– 0.534 n.a. 182 T-shap e, micr ostructur ed coile d flo w inv
erter (MCFI) i.d. = 1.
00 mm b n-butyl acetate – acetone – water 1.026– 0.483 n.a. 183 T-shap e, capillar y i.d. = 0.5 -2 mm)
Nitric acid solution –
UO2 2+ – TBP Ionic liquid 0. 049-0.29 n.a. 182 T-shap e, capillar y i.d. = 0. 2 mm Toluene – acetic acid – water 0. 01 – 0.1 n.a. 184 T-junction, r ound micr ochannel i.d. = 0. 3 mm water – (Zn)D2EHP A – Do de cane 0.1 n.a. 185 a sp ecific interfacial ar ea (m 2∙m -3 r eactor v olume)
b the internal diameter of the Y
-junction is e
qual to the inner diameter of the capillar
y micr
or
eactor
.
c with wall film include
d (
without wall film values ar
e r oughly 2 to 3 times lo w er ). d not available .
20
Chapter 1
values found for a CSTR. The kLa values become higher when
decreas-ing the inner diameter of the microtube. This is mainly due to the fact that the slug becomes smaller and thus the specific interfacial area is higher when the inner diameter is reduced.154 Besides that, internal con-vection in the slug is intensified, resulting in an enhanced convective mass transfer rate.154 Furthermore it has been reported that the use of a liquid- liquid slug flow capillary microdevice requires a lower power input (0.2-20 kJ/m3) to obtain such large interfacial areas compared to a CSTR (150-250 kJ/m3).176 As such, there is also an incentive to apply microdevices in the slug flow regime for ELLE.
1.5.2. ELLE in microdevices
Microdevices for solvent extraction should in principle be also suitable for reactive extraction including chiral separations (ELLE). However, the use of micro- or milli-scale ELLE so far is limited. To the best of our knowledge, there is only one report on continuous chiral separation in
a microdevice186 for the separation of racemic Ibuprofen. It involves the use of three liquid phase, two with the host and racemate separated by an ionic liquid membrane (Figure 1.11). Enantiomeric excesses above 97.6% were reported for a single stage extraction.
Figure 1.11. Microfluidic contactor used for chiral separation. Reprinted from Ref.
1
21
Introduction1.6. Aim of this thesis and thesis outline
As is evident from the literature overview provided above, the use of microdevices for chiral separation has received limited attention. To the best of our knowledge the use of microdevices for chiral extraction in the slug flow regime has never been reported. The principle of ELLE in the slug flow regime in a microdevice is schematically depicted in Figure 1.12. When using hydrophobic microchannels or microtubes in combination with an aqueous and an organic phase, aqueous droplets and organic slugs are formed. Thus, ELLE involves the transfer of enantiomers from the aqueous droplet to the organic slug. Possible advantages when oper-ating in the slug flow regime 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
Figure 1.12. Schematic representation of ELLE in the slug flow regime.
Figure 1.13. 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
ease in complexity
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
22
Chapter 1
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 trans-fer characteristic of slug flow operated capillary microdevices. It involves physical extraction studies of acetanilide from a water phase to an or-ganic 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.
In Chapter 3, the use of ELLE in a slug flow capillary microdevice for the chiral extraction of 3,5-dinitrobenzoyl-(R,S)-leucine (DNB-Leu) by a cinchona alkaloid was investigated. The extraction performance in two organic solvents e.g. 1,2-dichloroethane and 1-octanol at different resi-dence times was determined. The experimental data of Chapter 3 were the input for an extensive reactor modeling study described in Chapter 4, with the objective to explain the observed experimental trends and particularly the extraction efficiencies as a function of the residence time. As mentioned in the introduction, BINAP-metal complexes show a good selectivity for several classes of substrates.45,49,187 In the last part of
this thesis (Chapter 5), the use of such metal complexes for the ELLE of amino acid was explored and involved the separation of tryptophan en-antiomers with Pd(PF6)2((S)-XylBINAP)2 as the host in a water/1-octanol
system. The research includes both equilibrium studies with racemates and individual enantiomers and reactions in ELLE.
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