Selector screening for enantioseparation of DL-α-methyl phenylglycine amide by liquid-liquid extraction

Article abstract of DOI:10.1002/chir.22400

Enantioseparation through liquid extraction technology is an emerging field, e.g., enantioseparations of amino acids (and derivatives thereof), amino alcohols, amines, and carboxylic acids have been reported. Often, when a new selector is developed, the versatility of substrate scope is investigated. From an industrial point of view, the problem is typically approached the other way around, and for a target racemate, a selector needs to be found in order to accomplish the desired enantioseparation. This study presents such a screening approach for the separation of the enantiomers of DL-α-methyl phenylglycine amide (DL-α-MPGA), a model amide racemate with high industrial relevance. Chiral selectors that were reported for other classes of racemates were investigated, i.e., several macrocyclic selectors and Pd-BINAP complexes. It appeared very challenging to obtain both high extraction yields and good enantioselectivity for most selectors, but Pd-BINAP-based selectors performed well, with enantioselectivities up to 7.4 with an extraction yield of the desired enantiomer of 95.8%. These high enantioselectivities were obtained using dichloromethane as solvent. Using less volatile chlorobenzene or 1-chloropentane, reasonable selectivities of up to 1.7 were measured, making these the best alternative solvents for dichloromethane.

Full text of DOI:10.1002/chir.22400

CHIRALITY (2014)
Selector Screening for Enantioseparation of DL-α-Methyl Phenylglycine
Amide by Liquid–Liquid Extraction
1
1
2
1
3
BOELO SCHUUR, MAREK BLAHUŠIAK, CAECILIA R. VITASARI, MICHAL GRAMBLIČKA, ANDRÉ B. DE HAAN, AND TON J. VISSER4
*
1University of Twente, Faculty of Science and Technology, Sustainable Process Technology Group, Enschede, The Netherlands
2Institute for Sustainable Process Technology, Amersfoort, The Netherlands
3Delft University of Technology, (Biobased) Process Technology, Transport Phenomena, Department of Chemical Engineering, Delft, The Netherlands
4Syncom B.V., Groningen, The Netherlands
ABSTRACT
Enantioseparation through liquid extraction technology is an emerging field,
e.g., enantioseparations of amino acids (and derivatives thereof), amino alcohols, amines, and
carboxylic acids have been reported. Often, when a new selector is developed, the versatility
of substrate scope is investigated. From an industrial point of view, the problem is typically
approached the other way around, and for a target racemate, a selector needs to be found in
order to accomplish the desired enantioseparation. This study presents such a screening approach
for the separation of the enantiomers of DL-α-methyl phenylglycine amide (DL-α-MPGA), a model
amide racemate with high industrial relevance. Chiral selectors that were reported for other classes
of racemates were investigated, i.e., several macrocyclic selectors and Pd-BINAP complexes. It
appeared very challenging to obtain both high extraction yields and good enantioselectivity for
most selectors, but Pd-BINAP-based selectors performed well, with enantioselectivities up to 7.4
with an extraction yield of the desired enantiomer of 95.8%. These high enantioselectivities were
obtained using dichloromethane as solvent. Using less volatile chlorobenzene or 1-chloropentane,
reasonable selectivities of up to 1.7 were measured, making these the best alternative solvents for
dichloromethane. Chirality 00:000–000, 2014. © 2014 Wiley Periodicals, Inc.
KEY WORDS: enantioselective liquid–liquid extraction; amides; crown ethers; calixarenes;
heterocycles; Pd-BINAP
INTRODUCTION
amino alcohols and amines,32–35 and carboxylic acids.36–39 A re-
view of enantioselective liquid–liquid extraction recently
Over the past three decades the development and application
of enantioseparation technology has become of major impor-
tance for the pharmaceutical industry.1–4 Active pharmaceutical
ingredients and key intermediates should be enantiomerically
pure due to differences in the pharmacological effects of enantio-
mers.2 Although routes through chiral feedstock,5 asymmetrical
catalysis,6 and dynamic kinetic resolution7 are sometimes avail-
able and favorable for their theoretical 100% yield, obtaining
enantiopure compounds is industrially mainly done by the sepa-
ration of enantiomers, usually through crystallization tech-
niques.2,8,9 Crystallization, however, is not always possible,10
and alternatives are needed. On a laboratory scale, many alter-
native technologies are available, but most techniques are diffi-
cult to scale-up, or not economic at commercial scale.3
Simulated Moving Bed chromatography11–13 is an example of
a scale-up strategy for laboratory chiral separation technologies.
The efficiencies compared to the original laboratory separations
have been highly improved; nevertheless, the solvent use and
expensive stationary phases remain limiting factors for applica-
tion on an industrial production scale.
Alternative approaches such as horizontal reactive distilla-
tion,14 enantioselective liquid–liquid extraction (ELLE),15 the
closely related chiral liquid membrane (CLM),16,17 membrane-
assisted ELLE systems,18 or centrifugal partitioning chromatog-
raphy technologies (CPC)19 may be applied for the
enantioseparation of racemates. These technologies have been
demonstrated to be scalable, and the development of new chiral
selectors for ELLE and CLM technology is ongoing. Over the
years, efficient selectors have been developed and applied for
enantioseparation of amino acids and derivatives thereof,20–31
appeared.3
One of the drawbacks of the ELLE technology is that a
moderate selectivity (typically >1.5)40 is required to avoid
an excessive number of stages. Many selectors used in sta-
tionary phases in chromatography are thus not suitable for
the traditional liquid–liquid extraction approach. Approaches
to overcome this limitation in versatility include the applica-
tion of biphasic recognition to increase the selectivity of the
system,35,36,38 or to use thin-layer extraction41,42 to enable
large numbers of stages while keeping the equipment size
small. Several hybrid processes have been published, trying
to advance benefits from multiple unit operations in a single
operation or in a sequence of operations. E.g., in cases where
preferential crystallization is possible from enantioenriched
solutions, hybrid processing may be a solution to improve
processing efficiency, e.g., by enriching racemic solutions to
moderate enantiomeric excess through a CLM process,
followed by preferential crystallization,43 or involving chiral
nanoparticles in the extraction process.44 Another, rather ge-
nerically applicable hybrid approach, is to apply the ELLE
concept in a chromatographic mode. This can be done by im-
pregnating the extract phase (the chiral selectors in a
Contract grant sponsor: Institute for Sustainable Process Technology (ISPT);
Contract grant number: PH-00-01.
*Correspondence to: Boelo Schuur, University of Twente, Faculty of Science
and Technology, Sustainable Process Technology Group, P.O. Box 217,
7500 AE Enschede, The Netherlands. E-mail: b.schuur@utwente.nl
Received for publication 30 July 2014; Accepted 8 September 2014
DOI: 10.1002/chir.22400
Published online in Wiley Online Library
(wileyonlinelibrary.com).
© 2014 Wiley Periodicals, Inc.

SCHUUR ET AL.
solvent) in the pores of a resin to increase the capacity of a
a single selector or a class of selectors (also known as
hosts) for a range of substrates is investigated, industrial
challenges would typically call for a selector screening for
a specific racemate. We report here a screening study for
the ELLE of DL-α-methyl phenylglycine amide (DL-α-
MPGA), an industrially relevant amino acid amide. Based
on the literature on ELLE for amino acid derivatives and
chiral HPLC,46 we decided to study macrocyclic chiral
hosts from the crown ether, calix[4]arenes and heterocycle
classes, as well as binol derivatives such as binol phospho-
ric acids and Pd-BINAP. The model racemate DL-α-MPGA
as well as all chiral selectors used in this study are
displayed in Figure 1.
fixed bed chromatographic process.45 For such a hybrid pro-
cess (extraction and chromatography), the maximum num-
ber of economically realistic stages is much higher than in
extraction. Therefore, we estimate that the selectivity con-
straint of 1.5 for ELLE40 may be reduced to about 1.2–1.3.
Whether applied in ELLE, CLM, or any of the novel hy-
brids, the first stage in the development of a new chiral sep-
aration process remains finding a suitable chiral selector.
Although many selectors have been reported for amino
acids, amino alcohols and amines, and carboxylic acids,3
enantioseparation of amide containing racemates is a spe-
cific challenge. Whereas in the literature often the use of
Fig. 1. Structures of DL-α-MPGA and the chiral selectors that were applied in this study.
Chirality DOI 10.1002/chir

AMIDE ENANTIOSEPARATION BY LIQUID–LIQUID EXTRACTION
MATERIALS AND METHODS
Definitions and Extraction Mechanisms
Equilibrium Enantioselective Liquid–Liquid Extraction
Experiments
In the ELLE literature, two types of mechanisms have been reported,
the interfacial ligand exchange mechanism, and the homogeneous ligand
addition mechanism.29,47–49 The most important difference between the
two mechanisms is when the homogeneous ligand addition mechanism
applies. In that case the enantiomers physically distribute towards the or-
ganic phase in which they form a complex with the chiral host. Because
the solubility of ionic species into apolar solvents is typically low, distribu-
tions of ionizable (through protonation or deprotonation) enantiomers
into the organic phase can be manipulated by changing the pH. The enan-
tiomers of DL-α-MPGA are bases and may be protonated. The protonation
equilibrium is by definition the same for both enantiomers and the rela-
tion for the Kb is given in Eq. 1.
ELLE experiments were carried out in jacketed 50 mL glass vessels
connected to a Julabo F-32 thermostat bath to control the temperature,
or in 20 mL glass vials in a thermostated shaking bath (in all experiments
the temperature was 25 °C). Two mM aqueous DL-α-MPGA solutions
were mixed with organic phase solutions of the chiral selectors
(extractants). The initial concentration of DL-α-MPGA was 2 mM, and ex-
tractant concentrations ranging from 1 to 5 mM were applied. After mag-
netically stirring at 600 rpm for at least 2 h (or alternatively, shaken
overnight at 150 min-1), the phases were allowed to settle. Samples were
taken from the aqueous phase to measure the pH and to determine the
concentration of DL-α-MPGA by high-performance liquid chromatography
(HPLC). The concentration of DL-α-MPGA in the organic phase was deter-
mined by mass balance. Experiments to determine physical partitioning
ratios were carried out without a host present.
Â
Ã
MPGAHþ þ ½OHꢀꢁ
Kb
¼
(1)
½MPGAꢁ
Analytical Method
The distributions of the enantiomers are affected by the solubility of
the neutral α-MPGA in the applied organic solvent, by the availability of
the neutral form (i.e., the applied pH during the extraction), and by the in-
teraction between the host and the enantiomers. The distribution coeffi-
cients are defined as:
The concentrations of the individual enantiomers of DL-α-MPGA in the
aqueous phase were determined with an accuracy of 3% by chiral HPLC
analysis making use of either a Varian (Palo Alto, CA) Pro Star HPLC set-
up or an Agilent (Palo Alto, CA) 1100 series, equipped with a Chiralpak IB
(+) chiral column (250 X 4.6 mm ID). Detection was done at 220 nm using
an UV detector. The flow rate of the eluent, a 90:10 v:v mixture of 100 mM
KPF6 in water: acetonitrile, was 0.6 mL/min, the injection volume was
20 μL. The column was kept at 20 °C using a thermostated column oven.
½D ꢀ α ꢀ MPGAꢁorg;tot
DD
DL
¼
(2a)
(2b)
½D ꢀ α ꢀ MPGAꢁaq;tot
½L ꢀ α ꢀ MPGAꢁorg;tot
½L ꢀ α ꢀ MPGAꢁaq;tot
¼
RESULTS AND DISCUSSION
Estimation of pKb and Physical Partitioning
In Eqs. 2a and 2b, the subscripts tot indicate all forms in which the
solutes can possibly exist in that phase, i.e., in the aqueous phase the
α-MPGA enantiomers may be present in the neutral form and in the pro-
tonated form, while in the organic phase, the neutral α-MPGA might be
present as well as complexes of the α-MPGA enantiomers with a chiral
host. The operational enantioselectivity, αop is defined as the ratio of
the two distribution coefficients:
In order to understand the effect of pH on the extraction
behavior of DL-α-MPGA, the pKb was determined by measur-
ing the pH of DL-α-MPGA solutions and DL-α-MPGA solutions
to which HCl was added. By measuring the pH, the concen-
trations of [H+] and [OH-] are known, and [Cl-] was given
by the added amount of HCl, from which the last unknown,
the [MPGAH+], could be calculated as well as the ratio of
[MPGAH+] / [MPGA]. Fitting Eq. 1 to the experimental data
resulted in pKb = 6.90 (and, hence, pKa = 7.10). The physical
distribution as a function of the pH was expected to exhibit
an s-curve with negligible distribution at low pH and attaining
the maximum distribution at pH > pKa. The maximum distri-
bution coefficients (Dmax) were determined experimentally
to be 0.84 for octanol, and 0.41 for DCE. In Figure 2a the par-
ity plot is shown for the fitting of the pKb, and in Figure 2b the
validation is displayed, showing DDL/DDL,max for both sol-
vents octanol and DCE.
DL
DD
αop
¼
(3)
Another measure for the extraction efficiency is the yield,
which is defined as the fraction of the enantiomers that is ex-
tracted to the organic phase:
ꢀ
ꢁ
½D ꢀ α ꢀ MPGAꢁaq;tot;in ꢀ ½D ꢀ α ꢀ MPGAꢁaq;tot
½D ꢀ α ꢀ MPGAꢁaq;tot;in
Y D
Y L
¼
¼
(4a)
(4b)
ꢀ
ꢁ
½L ꢀ α ꢀ MPGAꢁaq;tot;in ꢀ ½L ꢀ α ꢀ MPGAꢁaq;tot
½L ꢀ α ꢀ MPGAꢁaq;tot;in
From Figure 2 it can be concluded that the measured pH
and the calculated pH for pKb = 6.90 are in good agreement.
From the validation experiments it can also be concluded that
the neutral form of MPGA is partitioning over the two phases,
whereas the protonated MPGAH+ does not. The transition
from negligible partitioning at low pH to the maximum value
at high pH corresponds very well with the calculated fraction
of MPGA that is in the neutral form.
Materials
DL-α-MPGA was provided by DSM (Geleen, The Netherlands). PdCl2
((S)-xylyl-BINAP) was obtained from Strem Chemicals (Bisscheim,
France). PdCl2((S)-BINAP) was prepared in situ using PdCl2 and (S)-
BINAP. All other chiral selectors were custom synthesized at Syncom
(Groningen, The Netherlands) using known procedures. All solvents
were of analytical grade and used as supplied.
Screening Chiral Selectors for the Enantioselective
Extraction of DL-α-MPGA
pKb – Determination and Validation
The chiral selectors that were studied for the
enantioseparation of DL-α-MPGA can be classified as macro-
cyclic hosts and binol derivatives. The selectors 1 to 9 are
macrocylic hosts, 10, 11, and 12 are binol derivatives.
Because high selectivities were observed in the past for chi-
ral separations of amino acid derivatives using crown ethers
as host,23–25,33 a series of chiral crown ethers (structures 1
Chirality DOI 10.1002/chir
To determine the pKb, pure water and 3 mM HCl solution in varying
proportions ranging from 0–5 mL were added to aliquots of 1–3 mL of a
3.3 mM aqueous DL-α-MPGA solution. After mixing several minutes the
pH was measured. Validation of the pKb was done by contacting 2 mM
aqueous DL-α-MPGA solutions with a set pH ranging from 5–11.5 with
1,2-dichloroethane (DCE) and with octanol (phase ratio 1 mL organic
phase / 1 mL aqueous phase) in the absence of any chiral selector.

SCHUUR ET AL.
Fig. 2. (a) Parity plot of measured and calculated pH in the pKb-estimation; circles and squares correspond to two different series of measurements. (b) Valida-
tion experiments comparing the measured distributions with the maximum distribution at high pH (all α-MPGA in the neutral form). Line: calculated fraction of α-
MPGA in the neutral form, open symbols: using DCE as solvent, closed symbols: using octanol as solvent.
through 6 in Fig. 1) were studied for the enantioseparation of
DL-α-MPGA. Furthermore, some calix[4]arenes and a hetero-
cycle were studied (selectors 7–9), as they are known for
their use in stationary phases in chiral HPLC.46 Because
macrocycles, and in particular crown ethers, are not only able
to extract neutral species, but can also form complexes with
ion pairs with the cations inside the cavity,50 next to the effect
of the organic solvent, also the effect of the pH on the extrac-
tion was studied. An overview of the ELLE results obtained
with the investigated hosts is presented in Table 1.
dropped below the detection limit of the HPLC. Therefore,
the extraction conditions were modified so that the experi-
ments could be analyzed. Experiments 29 and 30 show very
high selectivities of 7.4 and 6.2, indicating that both PdCl2-
(S)-BINAP and PdCl2-xylyl-(S)-BINAP are suitable hosts for
ELLE of DL-α-MPGA. This finding shows once more the
TABLE 1. ELLE selector screening results
Experiment
Host
Solvent
pH
DL
DD
αop
In experiments 1–4 (host 1), 11, 12, 15, 16 (host 3), 18–21
(host 5), 26–28 (host 9), the effect of the organic solvent was
investigated at pH 8.8. Under these conditions MPGA is
predominantly in the neutral form (the pKb was determined by
acid-base titration at 6.90). The general trend in the distribution
for both enantiomers is octanol> DCE > 3-pentanone > toluene.
However, for none of the solvents was a reasonably high selectiv-
ity observed, except for some cases where the distribution
coefficient was very low (e.g., in experiment 10). Experimental
selectivities obtained at very low distributions should be valued
with caution due to the experimental inaccuracy, which has a
large effect on the calculated selectivity under these conditions.
Experiments 3, 5, 6 with host 1 in 3-pentanone were per-
formed to study the effect of the pH. If there was a host–guest
interaction, the distribution of the DL-α-MPGA would improve
as compared to the physical distribution in the absence of the
host. The physical distribution in 3-pentanone at pH 8.8 was
determined to be 0.5, and it can be concluded that the pH-
dependent distribution in the presence of host 1 approaches
a maximum value that resembles the physical distribution.
It can thus be concluded that host 1 is not a suitable host
for DL-α-MPGA. The trend in experiments 13–15 is identical,
hence also host 3 in 3-pentanone appears not to complex with
DL-α-MPGA. In the case of host 2 in toluene, it can be ob-
served that the distribution at pH 5–7 exceeds the physical
distribution (which is 0.04), and is much higher than the dis-
tribution at pH 8.8. It thus appears that there is a host–guest
complexation between protonated amine functionality in α-
MPGA and host 2; however, there is hardly any selectivity,
and the distribution is still rather low. Considering both the
variations in solvent and in pH, unfortunately it must be con-
cluded that for α-MPGA none of the hosts 1–9 show enough
enantioselectivity at reasonable distribution ratios to be ap-
plied in a liquid–liquid-based enantioseparating process.
When applying the standard conditions (5 mM host in sol-
vent, 2 mM aqueous DL-α-MPGA, Vaq/Vorg = 1, T = 25 °C) for
hosts 10 and 11, it was found that the distribution coeffi-
cients were so high that the aqueous phase concentrations
Chirality DOI 10.1002/chir
1
2
3
4
5
6
7
8
1
Octanol
DCE
8.8
8.8
8.8
8.8
7.0
5.0
3.0
5.0
7.0
8.8
8.8
8.8
5.0
7.0
8.8
8.8
8.8
8.8
8.8
8.8
8.8
3.0
7.0
8.8
8.8
8.8
8.8
8.8
6.9
6.9
7.0
4.9
7.0
7.0
7.0
0.80
0.40
0.48
0.16
0.12
0.16
0.11
0.17
0.15
0.04
0.74
0.53
0.09
0.16
0.43
0.12
0.25
0.84
0.54
0.46
0.24
0.28
0.24
0.04
0.03
0.74
0.38
0.46
95.8
72.2
0.84
4.27
0.96
0.54
0.82
0.77
0.41
0.51
0.14
0.12
0.14
0.10
0.17
0.16
0.02
0.75
0.57
0.11
0.19
0.47
0.10
0.25
0.81
0.53
0.50
0.24
0.26
0.22
0.03
0.02
0.77
0.41
0.50
12.9
11.7
0.88
4.05
0.88
0.51
0.89
1.0
1.0a
1.1a
1.1
1.0
1.1
1.1
1.0
1.1a
2.0
1.0a
1.1a
1.2a
1.2a
1.1a
1.2
1.0
1.0
1.0
1.1a
1.0
1.1
1.1
1.3
1.5
1.0
1.1
1.1
7.4
6.2
1.0a
1.1
1.1
1.1
1.1a
1
1
3-pentanone
Toluene
3-pentanone
3-pentanone
Toluene
Toluene
Toluene
Toluene
Octanol
DCE
3-pentanone
3-pentanone
3-pentanone
Toluene
Toluene
Octanol
DCE
3-pentanone
Toluene
Toluene
toluene
Toluene
Toluene
Octanol
3-pentanone
DCE
1
1
1
2
2
9
2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29b
30b
31c
32d
33d
34c
35c
2
3
3
3
3
3
3
4
5
5
5
5
6
6
7
8
9
9
9
10
11
12
12
12
13
14
DCM
DCM
DCM
Octanol
Octanol
DCM
DCM
Conditions: 5 mM host in solvent, 2 mM aqueous DL-α-MPGA, Vaq/Vorg = 1,
T = 25 °C.
aSelectivity towards D-enantiomer.
bConditions: Vaq/Vorg = 2.75, [host] = 2.93 mM, [DL-α-MPGA]in = 1.84 mM.
cThe concentration host was here 1 mM.
dConditions: Vaq/Vorg = 2.5, [host] = 2 mM, [DL-α-MPGA]in = 0.72 mM.

AMIDE ENANTIOSEPARATION BY LIQUID–LIQUID EXTRACTION
versatility of these hosts, as recently metal-BINAP-based
increasing the host concentration will result in an increasing
operational selectivity with increasing host excess.33 It can be
concluded from Figure 3. that both PdCl2-(S)-BINAP and
PdCl2-(S)-xylyl-BINAP dissolved in DCM are highly selective
towards L-α-MPGA. By manipulating the conditions, the extrac-
tion yields can easily be tuned to be applied in a multistage ex-
traction process with a limited number of equilibrium stages
where a full enantioseparation will be possible.
The results displayed in Figure 3 were obtained using the
solvent DCM, which is from a processing point of view not
an ideal solvent because of its high volatility. When
enantioseparation processes are envisioned making use of
immobilized liquids, the solubility of DCM in water (13 g/L)
requires the eluting aqueous phase to be presaturated with
DCM, which is not ideal either. Hence, if DCM can be re-
placed by another solvent that is less volatile and less soluble
in water, that would be a big improvement. Therefore, for
both host 10 and 11, a series of solvents were studied, in-
cluding 1-octanol, 1,2-dichloropropane, chlorobenzene, 2-
chlorotoluene, 1-chloropentane, and 1-chlorooctane.
hosts were found applicable in ELLE for a wide range of sub-
strates.27,29,51–55 Similar to the BINAP-based hosts, binol-
based phosphoric acids have recently been demonstrated to
be selective for a range of benzylic amines. Therefore, these
were also applied in this study. In contrast to our expectations
on the basis of the work by Feringa and coworkers,34,47 none
of the hosts 12–14 displayed a selectivity above 1.1 under
the applied conditions.
Based on the results from the screening study, it was de-
cided to study the extraction of DL-α-MPGA with PdCl2-(S)-
BINAP and PdCl2-xylyl-(S)-BINAP in more detail.
ELLE Studies With PdCl2-(S)-BINAP and PdCl2-xylyl-(S)-
BINAP Hosts
Because the distributions in experiments 29 and 30 in Table 1
were very high, the hosts 10 and 11 were studied with a lower
host concentration of 2 mM in the organic phase, and with
V
aq =5.5mL, and Vorg =2 mL. In Figure 3 the extraction yields
and selectivities are presented using DCM as solvent.
In Figure 3 it can be seen that the yield increases with
increasing pH, which is in line with the results presented in
Figure 2 for pure physical extraction without the host present.
Furthermore, it can be seen that going from pH 5.5 to pH 7.0,
the operational selectivity is increasing, while further increas-
ing the pH to 7.7 results in such an increase in the extracted
amount of both enantiomers that the operational selectivity is
dropping again. When comparing the yields and selectivities
in Figure 3a,b with those in Figure 3c,d, it can be observed
that both the yields and the selectivities are higher at a lower
initial racemate concentration. The higher operational selec-
tivity at lower racemate concentration (and thus a larger
excess of host) is an indication that the complexation constants
are relatively small. When the complexation is very strong
instead, increasing the host excess leads typically to lower
operational selectivity due to excessive coextraction of the un-
desired enantiomer.48 In the case of less strong complexation,
Solutions of 10 in 1-octanol were found to be unstable, and
the PdCl2-(S)-BINAP precipitated from the solution (X-ray
analysis of the crystals confirmed that the precipitated matter
was indeed PdCl2-(S)-BINAP). For that reason the solvent 1-
octanol was considered not suitable for further studies.
Nonchlorinated and otherwise nonfunctionalized aliphatic
and aromatic hydrocarbons do not normally work well for
ELLE, because of precipitation and interference in the π–π in-
teractions, respectively.21 Therefore, chlorinated versions were
investigated. The experimental results using PdCl2-(S)-BINAP
in 1,2-dichloropropane, chlorobenzene and 4-chlorotoluene are
displayed in Figure 4. Results obtained with PdCl2-(S)-xylyl-
BINAP in 1,2-dichloropropane, chlorobenzene, 4-chlorotoluene,
1-chloropentane, and 1-chlorooctane are displayed in Figure 5.
From Figures 4 and 5 it follows that for the aliphatic solvents
the extraction yields follow the same trend that was observed in
DCM (Fig. 3) for both 10 and 11, but in none of the solvents
Fig. 3. Extraction yields YL (open symbols) and YD (closed symbols) for experiments with (a) 0.724 mM DL-α-MPGA, and (c) 1.50 mM DL-α-MPGA. Vaq = 5.5 mL
and Vorg = 2 mL, organic phase: 2 mM 10 and 11 in DCM. Panels (b) and (d) display the operational selectivities corresponding to the yields in panels (a) and (c).
Squares represent results for 10, circles for 11.
Chirality DOI 10.1002/chir

SCHUUR ET AL.
Fig. 4. (a) Extraction yields YL (open symbols) and YD (closed symbols) for experiments with 1.62 mM DL-α-MPGA, Vaq = 5.5 mL and Vorg = 2 mL, organic phase:
2 mM 10 in solvents 1,2-dichloropropane (squares), chlorobenzene (triangles) and 4-chlorotoluene (circles). (b) operational selectivities corresponding to results
displayed in (a).
Fig. 5. (a) Extraction yields YL (open symbols) and YD (closed symbols) for experiments with 1.62 mM DL-α-MPGA, Vaq = 5.5 mL and Vorg = 2 mL, organic phase:
2 mM 11 in solvents 1,2-dichloropropane (squares), chlorobenzene (triangles), 4-chlorotoluene (circles), 1-chloropentane (stars), and 1-chlorooctanea (diamonds).
(b) operational selectivities corresponding to results displayed in (a). aRacemate concentration 1.50 mM.
did the selectivity approach that of DCM. The highest selectivity
was observed using the dichlorinated 1,2-dichloropropane, while
the observed operational selectivity (1.5) with a reasonable yield
of 0.39 for L-α-MPGA using 11 in 1-chloropentane is still high
enough to achieve a full enantioseparation within a reasonable
number of stages. With 11 in 1-chlorooctane, however, no sig-
nificant selectivity was observed. With regard to volatility and
therewith related solvent losses, the solvent 1-chloropentane ap-
pears to be the best aliphatic solvent for 11.
Because chlorobenzene and 4-chlorotoluene show relatively
environmentally benign and low toxic characteristics compared
to other chlorinated solvents, the aromatic solvents chloroben-
zene and 4-chlorotoluene were also investigated. From both
Figures 4 and 5 it follows that at the lower pH investigated
(pH 5.5) the selectivity seems to be towards D-α-MPGA, rather
than towards L-α-MPGA. The results at pH 5.5 need to be viewed
with care, however, because of the low yields. At higher pH, it
appears that both the yield and the selectivity are good for
chlorobenzene, which in combination with the relatively mild
character with respect to the environment and toxicity makes
this an interesting solvent. The two most promising solvents to
replace DCM are 1-chloropentane and chlorobenzene.
highly selective. Operational selectivities towards L-α-MPGA
higher than 7 were observed.. This shows that a dedicated
selector search for a given racemate can yield selectivities high
enough to develop an enantioselective liquid–liquid extraction
process. The system was further examined in various solvents,
and a less volatile alternative for DCM was found in 1-
chloropentane, still exhibiting selectivities up to 1.5. The
BINAP and xylyl-BINAP complexes have been reported several
times recently in enantioselective liquid–liquid extraction stud-
ies,27,29,51–55 and also here they were the selectors with the
highest selectivity (by far). Therefore, the development of
metal-BINAP-complexes appears promising to further broaden
the library of hosts for enantioselective liquid–liquid extraction.
ACKNOWLEDGMENTS
Marek Blahušiak received a scholarship from the Slovak
Scholarship programme of MŠVVaŠ SR to study abroad.
NOMENCLATURE
Symbols
D
V
distribution [(mol/L) / (mol/L)]
volume [mL]
Kb
Y
basicity constant [-]
extraction yield [-]
CONCLUSIONS
From the primary screening study, it was found that many
hosts that have been successful in enantioselective extrac-
tions of structurally related racemates were not able to com-
bine reasonable distributions with a significant selectivity
for the enantioselective liquid–liquid extraction of DL-α-
MPGA. Apparently, the amide functionality brought in a sig-
nificant disturbance of the enantiorecognition mechanism
for these chiral selectors. Among the screened selector classes,
PdCl2-(S)-BINAP and PdCl2-xylyl-(S)-BINAP were found to be
Chirality DOI 10.1002/chir
Superscripts and Subscripts
aq
D
DL
in
aqueous phase
D-α-MPGA
DL-α-MPGA
initial
L
L-α-MPGA
maximum
organic phase
total
max
org
tot

AMIDE ENANTIOSEPARATION BY LIQUID–LIQUID EXTRACTION
25. Peacock SC, Domeier LA, Gaeta FCA, Helgeson RC, Timko JM, Cram DJ. Host-
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