Highly efficient enantioselective liquid-liquid extraction of 1,2-amino-alcohols using SPINOL based phosphoric acid hosts

Article abstract of DOI:10.1039/c7sc02783d

Access to enantiopure compounds on large scale in an environmentally friendly and cost-efficient manner remains one of the greatest challenges in chemistry. Resolution of racemates using enantioselective liquid-liquid extraction has great potential to meet that challenge. However, a relatively feeble understanding of the chemical principles and physical properties behind this technique has hampered the development of hosts possessing sufficient resolving power for their application to large scale processes. Herein we present, employing the previously untested SPINOL based phosphoric acids host family, an in depths study of the parameters affecting the efficiency of the resolution of amino-alcohols in the optic of further understanding the core principles behind ELLE. We have systematically investigated the dependencies of the enantioselection by parameters such as the choice of solvent, the temperature, as well as the pH and bring to light many previously unsuspected and highly intriguing interactions. Furthermore, utilizing these new insights to our advantage, we developed novel, highly efficient, extraction and resolving protocols which provide remarkable levels of enantioselectivity. It was shown that the extraction is catalytic in host by demonstrating transport in a U-tube and finally it was demonstrated how the solvent dependency could be exploited in an unprecedented triphasic resolution system.

Full text of DOI:10.1039/c7sc02783d

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Highly efficient enantioselective liquid–liquid
extraction of 1,2-amino-alcohols using SPINOL
Cite this: DOI: 10.1039/c7sc02783d
based phosphoric acid hosts†
Erik B. Pinxterhuis,‡a Jean-Baptiste Gualtierotti,‡a Hero J. Heeres, b Johannes G. de
ac
a
*
*
Vries
and Ben L. Feringa
Access to enantiopure compounds on large scale in an environmentally friendly and cost-efficient manner
remains one of the greatest challenges in chemistry. Resolution of racemates using enantioselective liquid–
liquid extraction has great potential to meet that challenge. However, a relatively feeble understanding of
the chemical principles and physical properties behind this technique has hampered the development of
hosts possessing sufficient resolving power for their application to large scale processes. Herein we
present, employing the previously untested SPINOL based phosphoric acids host family, an in depths study
of the parameters affecting the efficiency of the resolution of amino-alcohols in the optic of further
understanding the core principles behind ELLE. We have systematically investigated the dependencies of
the enantioselection by parameters such as the choice of solvent, the temperature, as well as the pH and
bring to light many previously unsuspected and highly intriguing interactions. Furthermore, utilizing these
new insights to our advantage, we developed novel, highly efficient, extraction and resolving protocols
which provide remarkable levels of enantioselectivity. It was shown that the extraction is catalytic in host by
demonstrating transport in a U-tube and finally it was demonstrated how the solvent dependency could be
exploited in an unprecedented triphasic resolution system.
Received 22nd June 2017
Accepted 13th July 2017
DOI: 10.1039/c7sc02783d
rsc.li/chemical-science
catalysts or the differentiation of one of the enantiomers via
kinetic resolution.7 The separatory approach relies on selec-
Introduction
tively removing one enantiomer from a racemate via crystal-
lisation or chromatography.8,9 While asymmetric synthesis has
clearly shown to be incredibly powerful in answering the need
for chiral molecular diversity, it needs longer development
times and thus struggles to achieve the requirements dened by
time to market pressure, although this problem can largely be
abated by the use of high throughput experimentation.10,11 In
addition, many reported catalytic procedures are too slow to be
cost-effective and require extensive development to increase the
turnover frequency. In contrast, resolution of racemates is still
a preferred method as oen the cost of the racemate is rather
low and the processes are easy to develop. One example of this is
the production of enantiopure BINOL via entrainment crystal-
lisation.12 Although these crystallisation methods t better with
the time to market demands, there is only a limited number of
low-cost resolving agents available. In addition, these processes
oen suffer from solids handling issues in the plant.13–17 Other
resolution techniques such as chromatography, electropho-
resis, or the use of membranes are either too slow or require
high cost systems hindering large sale applications.18–34
There is a large demand for enantiopure compounds, not only
for the pharmaceutical and ne chemical industries,1,2 but also
for the fragrance & avour, agrochemical and food & feed
industries.3 Some chiral molecules can be obtained from agri-
culture or fermentation, in the past referred to as the “chiral
pool”, however, the number of chiral compounds obtained in
this way is rather limited.3–6 Therefore the development of effi-
cient methods to obtain chiral compounds in enantiopure form
has been the centre of much attention over the past decades.
This occurred via two distinctive pathways. The synthetic
approach relies on the asymmetric transformation to create
enantiopure compounds via such methods as the reaction of
prochiral compounds to single enantiomers using chiral
aStratingh Institute for Chemistry, Faculty of Mathematics and Natural Sciences,
University of Groningen, Nijenborgh 4, 9747AG Groningen, The Netherlands. E-mail:
b.l.feringa@rug.nl
bDepartment of Chemical Engineering, ENTEG, University of Groningen, Nijenborgh 4,
9747AG Groningen, The Netherlands
c
¨
¨
Leibniz Institut fur Katalyse e. V. an der Universitat Rostock, Albert-Einstein-Strasse
29a, 18059 Rostock, Germany. E-mail: johannes.devries@catalysis.de
† Electronic supplementary information (ESI) available: Experimental data
regarding the synthesis the hosts as well as procedures and raw data and for
ELLE experiments. See DOI: 10.1039/c7sc02783d
Enantioselective Liquid–Liquid Extraction (ELLE) has been
well studied as an answer to these issues and many reports as to
the potential efficiency, scalability and costs have been pub-
lished.25,35–43 Since this method relies on the catalytic use of
‡ Both authors contributed equally.
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a chiral host and since mixing and separation of the two phases
are the two major unit operations used it has a much reduced
operational cost. In addition, the method can be scaled up quite
easily as was shown earlier by us, for instance through the use of
existing centrifugal contactor-separators.44,45 This means that it
has the potential to be even more viable, both economically and
environmentally, than crystallisation. However, despite all the
potential advantages of ELLE, it has, to the best of our knowl-
edge, never been applied in large-scale production due to the
fact that few developed chiral hosts are sufficiently selective (aop
> 3; for an explanation of how this value is obtained see below),46
to allow a reduction of the number of extractions (stages).2,43
Most of the reported host structures,43 such as crown ethers,
BINOL derivatives, metal complexes (Pd, Cu, Ln, Zn, Co, Ru),
tartrates, Cinchona alkaloids or guanidinium derivatives or our
own BINOL based phosphoric acid system, though promising,47
function only at a proof of concept level with extraction values
falling just short of applicability. Another underlying issue
within these systems is that the fundamental chemical princi-
ples (kinetics, interactions, active complexes.) that drive them
are poorly understood making further optimisation and devel-
opments difficult. As a direct result the developments in the
eld of ELLE has slowed signicantly with only a few recent
results appearing such as the work of Schuur48 and Tang.49
Therefore a more detailed understanding of these systems is of
paramount importance for the development of new, highly
selective, hosts.
With the recent advancements in the eld of organocatalysis,
numerous new selector candidates have emerged. Their identi-
cation and study may provide the required insight into the core
principles behind ELLE to bridge the gap between concept and
application and explain the dependencies of the enantioselection
on different parameters. Herein, we describe the results of an in
depths study, from a fundamental point of view, of the interac-
tions and parameters determining the efficiency of the resolution
of amino-alcohols by several new selector candidates. These
hosts are capable of separating aminoalcohols with sufficient
operational selectivity (vide infra) to reach the required level of
efficiency to become industrially viable.
Fig. 1 Relationship between number of stages and aop according to
eqn (1c) for ee ¼ 99%.
shown in eqn (1a). The distribution is dened as the ratio
between the concentration of one enantiomer in the organic
phase and the concentration of the same enantiomer in the
aqueous phase (eqn (1b)). To achieve full resolution of racemates
a complete selectivity is not required since, once a minimum
amount of selectivity is reached, multistage extraction processes
can be used to achieve complete enantioseparation.43–45 The
threshold at which a process has a sufficient operational selec-
tivity for application depends on the amount of process steps
required to achieve full resolution of the racemate (Nmin) which
has to remain as low as possible. The relationship between the
operational selectivity and the minimal number of fractional
extraction steps to achieve this is given by the Fenske equation
(eqn (1c)) and is displayed graphically in Fig. 1 for ee ¼ 99%. It is
commonly accepted that an aop of 1.5, which represents 25 steps
is the minimum to remain within feasibility. However, due to the
exponential drop of Nmin as aop increases, processes with an aop
signicantly above this value are much preferred. At an aop > 3
(Nmin < 10 steps) the decrease in number of steps verses rise of aop
diminishes notably with an optimum at 7 where the Nmin no
longer shows a signicant decrease upon a further rise of aop and
therefore can be considered ideal.
In addition to the operational selectivity another parameter
is important as to the scalability and application of the ELLE
process. The ability to recover the guest from the host is a key
factor which has to be measured via back-extraction experi-
ments. This is tested on laboratory levels via the use of a U-tube
extractor where a release phase is added to the system. This
system, based on the developments of Cram, allows a quanta-
tive measurement of the release of the guest by the host and its
applicability to large scale processes.
Results and discussion
Principles of enantioselective liquid liquid extraction
For a better understanding of the results we here give a short
description of the methodology used and the meaning of the
units. Enantioselective Liquid Liquid Extraction (ELLE) is based
on the principles of host–guest chemistry and extraction. An
ELLE system is, composed of two immiscible (or partially
immiscible) liquid phases with the racemate soluble only in one
of the phases and the chiral host only in the other. Enantiose-
lective extraction occurs via chiral recognition in the form of
preferred binding of one of the two enantiomers to the host in the
other phase, as described by Lehn50 and Cram,51 followed by back
extraction in a third phase (usually the same solvent as the
feeding phase). The efficiency of this process is expressed as its
operational selectivity (aop) which represents the ratio of the
distributions of the enantiomers between the two phases as
Host family studied
SPINOL derived ligands have been used for highly enantiose-
lective metal-catalyzed catalytic transformations, outclassing in
many cases the more traditional BINOL and H8-BINOL derived
alternatives, in terms of enantio-discrimination.52,53
½iꢀ
DR
org
aÞ aop
¼
¼
bÞ Di ¼
ði ¼ R; SÞ
DS
½iꢀ
aq
ꢀ
ꢁ
xR=ð1 ꢁ xRÞ
xS=ð1 ꢁ xSÞ
ln aop
ln
cÞ Nmin
(1)
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Nevertheless, SPINOL-based hosts could be highly suited for
ELLE as long as they are stable under the conditions of the
extraction and if sufficient turnovers can be obtained. For this
study we have selected four well-described SPINOL based
phosphoric acids as potential hosts, (Fig. 2) which we obtained
via known synthetic routes (see ESI† for more information).
Evaluation of the capacity towards the enantioselective liquid
liquid extraction of various racemates by hosts
These chiral hosts were tested in the two-phase enantioselective
extraction of a range of chiral compounds that are oen used in
enantiopure form as building blocks in organic synthesis (Fig. 3)
and highly promising initial results were obtained. 6,60-Unsub-
stituted SPINOL phosphoric acid (SPA 1) gave racemic extraction
for all families whereas 6,60-phenyl substituted SPA 2 showed
modest enantio-discrimination for phenylglycine (7, 6% ee) and
1,2-diphenylethan-1-amine (15, 10% ee) and good to excellent
selectivites in the cases of 1-amino-2,3-dihydro-1H-inden-2-ol (10,
18% ee) and phenylglycinol (11, 40% ee). 6,60-(3,5-diCF3) Phenyl
substituted SPA 3 showed a similar trend though, overall, with
slightly lower selectivities, while 6,60-(5-anthracyl) substituted
SPA 4 proved selective only for phenylglycinol (11, 37%). Highly
encouraged by these results we next measured the aop for the
most selective guest–host pairs. We obtained in the case of trans-
inden-2-ol (10) an aop of 3.8 when using SPA 2, while for phe-
nylglycinol (11) we obtained, respectively, 5.1 and 3.6 for SPA 2,
SPA 3 as well as and an exceptional aop of 34.8 for SPA 4. These
results are signicantly better than anything previously re-
ported47 and open the way towards industrial application. The
result obtained with SPA 4 in the resolution of 11 is particularly
striking as its efficiency is, to the best of our knowledge, higher
than any previously reported system including the pioneering
work of Cram who obtained with his best system an aop of 31 for
phenylglycine methyl ester.54 In all cases the (R)-enantiomer of
the SPINOL based hosts preferentially extracts the (R)-enan-
tiomer of the corresponding amino acid or amino alcohol.
Fig. 2 Chiral host for ELLE.
However, these ligands require
synthetic effort to obtain compared to the other backbones and
are therefore underused in elds outside asymmetric catalysis.
a signicantly greater
Study and optimisation of the ELLE of amino-alcohols by
hosts
In view of these exceptional results we further examined the
parameters affecting the ELLE of phenylglycinol (11) using SPA 2
and SPA 4 to gain insight into the mode of action of these hosts.
The temperature of the extraction usually strongly affects the
operational selectivity; prior experience has taught us that
a delicate balance between solubility and selectivity exists with
ꢂ
an optimum oen at around 6 C and that small changes can
Fig. 3 Screening of compound classes. Conditions: all extraction
experiments were conducted in 2 ml auto-sampler vials with crimp
cap seals equipped with stirrbars. A solution of the racemic guest
(0.4 ml, 2 mM) dissolved in a phosphate buffer solution (buffer strength
0.1 M, pH 5.0) was carefully added to a solution of the corresponding
strongly impact the process. We therefore studied the variation
of ELLE over a 2–40 ꢂC range using the two best hosts (Fig. 4a).
Interestingly, both revealed unexpected differences in behav-
ꢂ
iour. With SPA 2 the highest ee and aop were obtained at 2 C
host in chloroform (0.4 ml, 1.0 mM). The two-phasic system was then (48% ee, aop ¼ 15.3) with diminishing results at increasing
cooled to 6 ꢂC and stirred at 900 rpm for 16 h. The phases were then
allowed to separate over a period of 2 min. The aqueous phase was
then removed and an aliquot injected into a reverse phase HPLC for
determination of the ee, distribution and aop. All extraction experi-
temperatures although it retained much of its exceptional
selectivity even at 40 ꢂC (33% ee, aop ¼ 3.5). At 6 ꢂC, a maximum
in the amount extracted was observed, however at lower ee's.
SPA 4 showed a far greater sensitivity towards temperature. The
highest ee's and aop's are obtained in a very small window
ments were carried out in triplo and with a simultaneous blank reaction
(concentration of host ¼ 0.0 mM). aSee ref. 43. bSee ref. 50.
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Fig. 4 Tꢂ and G/H screenings. Conditions: all extraction experiments were conducted in 2 ml auto-sampler vials with crimp cap seals equipped
with stir bars. (a) A solution of racemic 11 (0.4 ml, 2 mM) dissolved in a phosphate buffer solution (buffer strength 0.1 M, pH 5.0) was carefully
added to a solution of the corresponding host in chloroform (0.4 ml, 1.0 mM). The two-phasic system was immediately cooled to the indicated
temperature and stirred at 900 rpm for 16 h. (b) A solution of racemic 11 (0.4 ml, indicated concentration) dissolved in a phosphate buffer solution
(buffer strength 0.1 M, pH 5.0) was carefully added to a solution of the corresponding host in chloroform (0.4 ml, 1.0 mM). The two-phasic system
was then immediately cooled to 6 ꢂC and stirred at 900 rpm for 16 h. In all cases, the phases were then allowed to separate over a period of 2 min.
The aqueous phase was removed and an aliquot injected into a reverse phase HPLC equipped with chiral columns for determination of the ee,
distribution and aop. All extraction experiments were carried out in triplo and with a simultaneous blank reaction (concentration of host ¼ 0.0
mM). For numerical values and entire pH distribution graphs see ESI.†
around 6 ꢂC (37% ee, aop ¼ 34.8). Much lower enantioselection the total amount of guest. Nevertheless, in each separatory stage
was observed at both lower and higher temperatures even the concentrations of host and racemate can be varied to ach-
though these results remain exceptionally high for ELLE (aop
¼
ieve the optimum result. This could even include a situation
3.6–4.3). Interestingly, this exceptionally high aop is due to where the concentration of host is higher than that of the
a reduction in the overall amounts extracted at 6 ꢂC which racemate. We thus measured the effectiveness of the ELLE
results in near perfect selectivity for one enantiomer rather than process with SPA 2 and SPA 4 over a G/H range of 0.25 to 3.0
any enhancement of extraction of the desired enantiomer, this (Fig. 4b). We observe that when an excess of guest over host is
therefore results in fewer steps needed to achieve high ee's and used (G/H > 2) a progressive erosion of ee and alpha is observed
therefore an overall increase in efficiency. A similar behaviour is as expected due to a decreasing proportion of guest which can
observed with SPA 2 at 2 ꢂC. Initially all measurements were be extracted which mathematically leads to lower distribution
performed in a two to one guest to host (G/H) ratio for there to values and therefore ee's and aop. When a sub-stoichiometric
be an equivalent of each enantiomer to the catalyst. However, amount of total guest to host is used (G/H < 1) the host
we were also interested in the effect the G/H ratio had on our extracts more guest regardless of conguration and an erosion
system. To put this in perspective: in a continuous extractive of ee and alpha can be observed.
separation, the host is used in catalytic amounts with respect to
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Fig. 5 pH screenings. Conditions: all extraction experiments were conducted in 2 ml auto-sampler vials with crimp cap seals equipped with stir
bars. A solution of racemic 11 (0.4 ml, 2 mM) dissolved in a phosphate buffer solution (buffer strength 0.1 M, indicated pH) was carefully added to
a solution of the corresponding host in chloroform (0.4 ml, 1.0 mM). The two-phasic system was then immediately cooled to 6 ꢂC and stirred at
900 rpm for 16 h. In all cases, the phases were then allowed to separate over a period of 2 min. The aqueous phase was removed and an aliquot
injected into a reverse phase HPLC equipped with chiral columns for determination of the ee, distribution and aop. All extraction experiments
were carried out in triplo and with a simultaneous blank reaction (concentration of host ¼ 0.0 mM). For numerical values and entire pH
distribution graphs see ESI.†
The more interesting behaviour of these systems appears in selectivity, this is, however, due to some solubility of the neutral
the 1–2 G/H range (excess of total guest, substoichiometric guest into the organic phase,57 though the effect of the catalyst
amount of each enantiomer) were loss in selectivity is less than remains visible. Below pH ¼ 7, where the amounts extracted is
expected. This may indicate that the extraction is not solely determined by the catalyst, both SPA 2 and SPA 4 show inter-
determined by a competition between enantiomers for the host esting behaviours. SPA 2 has a maximum in extraction at pH 5
which, one would expect, would give a linear erosion of selec- while SPA 4 is in a local minimum with the amount of undesired
tivity as observed when G/H < 1 but appears to also be deter- enantiomer extracted dropping to almost zero. In both cases
mined by the two association constants between each these local variations result in optimal aop values despite their
enantiomer and host.
opposite trends, making any attempts at determining struc-
We next determined the effect of the pH on the enantiose- ture–activity relationships difficult.
lectivity of the extraction. As the recognition between host and
One hypothesis towards explaining this high pH dependency
guest relies on acid–base interactions, we reasoned that pH would be that the changing ionic strength of the media affects
could prove a crucial parameter for enantio-discrimination. the ion-pairing distance of the G/H complex, altering the chiral
While surprisingly little pH dependency was noted when recognition between guest and host. At a pH close to both the
BINOL derived phosphoric acids were used47 (estimated pKa pKa of the host and pKb of the guest, the complex might tighter
3.5–3.9),55 SPINOL based phosphoric acids have predicted pKa's ion pairs with stronger interactions which would explain the ee
(around 4.9)55 far closer to the pKb of phenylglycinol (around optimum at pH 5. As a control to check the inuence of the
5.5)56 which could have a positive effect as to the selectivity. We buffer on the system, an extraction without buffer was per-
therefore studied the effect of the pH over a range of pH ¼ 2–12 formed and we obtained an ee of 37% and an aop of 5.6 which
(Fig. 5). Both SPA 2 and SPA 4 showed similar behaviours in showed that the buffer was not key to the extraction mechanism
terms of ee of the extraction with two signicant maxima for but important for maintaining an optimal pH as it varied
each, a rst one at pH 5 (40 and 37% ee respectively) and strongly over the course of the extraction.
a second one at respectively pH 9.6 (44% ee) and pH 8.4 (52%
Finally we turned our attention to the solvent effect on the
ee), respectively. From the measured distributions it is clear ELLE with these hosts. Due to limitations in solvent miscibility
that above pH 7 the amounts extracted are too high for good and the requirement that the guest must only be soluble in one
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Fig. 6 Solvent screenings. Conditions: all extraction experiments were conducted in 2 ml auto-sampler vials with crimp cap seals equipped with
stir bars. A solution racemic 11 (0.4 ml, 2 mM) dissolved in a phosphate buffer solution (buffer strength 0.1 M, pH 5.0) was carefully added to
a solution of the corresponding host in the indicated solvent (0.4 ml, 1.0 mM). The two-phasic system was then immediately cooled to 6 ꢂC and
stirred at 900 rpm for 16 h. In all cases, the phases were then allowed to separate over a period of 2 min. The aqueous phase was removed and an
aliquot injected into a reverse phase HPLC equipped with chiral columns for determination of the ee, distribution and aop. All extraction
experiments were carried out in triplo and with a simultaneous blank reaction (concentration of host ¼ 0.0 mM). For numerical values and entire
pH distribution graphs see ESI.†
phase, we limited our study to various halogenated and believe that a key p–p interaction exits between the guest and
aromatic solvents (Fig. 6). Both SPA 2 and SPA 4 show similar the host backbone. In the absence of toluene, one enantiomer
trends with chloroform, which was the optimal solvent in both can interact favourably with the backbone whereas the other
cases (40% ee, aop ¼ 5.1; 37% ee, aop ¼ 34.8, respectively). When cannot, determining the selectivity of the extraction. When
switching to DCM or tetrachloromethane, a loss of ee and lower toluene is present it can act as a p–p interaction relay allowing
extraction efficacy is observed. Most astonishingly, when for the second enantiomer to also interact with the backbone.
switching from chlorinated solvents to toluene with both hosts This, in addition to being the less sterically hindered of the pair
we observed a reversal in selectivity, with near perfect retention results in an inversion of selectivity. Further investigations into
of aop in the case of SPA 4 (ꢁ8% ee, aop ¼ 3.8; ꢁ39% ee, aop
¼
these host–guest complexes are underway and will be reported
at a later date.
35.0, respectively).
In order to further investigate this behaviour we tested
It has oen been observed in ELLE that the interactions
halogenated aromatic solvents such as chlorobenzene or tri- between host and guest are so specic that even slight changes
chlorotoluene but did not see any signicant effect, with aop in guest structure signicantly alter the outcome of the extrac-
values remaining in the same range as with DCM. Mechanistic tion making generalisation of a method over a family of
investigations were attempted to better understand the pecu- compounds highly difficult. However, in view of the efficiency of
liarities observed with this system. However, attempts at DFT our system we were curious as to the behaviour of these hosts
modelling of the system, crystal growth of the host–guest towards other amino alcohols. We therefore selected a family of
complex or its NMR characterisation proved unsuccessful. similar amino-alcohols and tested their resolution via ELLE
Nevertheless, observation of a basic physical model leads us to using SPA 2 and SPA 4 under the optimized conditions (Fig. 7).
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derivatives 27 and 28 could be extracted with lower but still
signicant selectivities (SPA 2, aop ¼ 2.8 and SPA 2, aop ¼ 3.3).
Overall this conrmed that p-stacking was signicantly
involved in determining the guest–host affinity.
In view of the extraordinary sensitivity of the extraction of 11
towards the pH of the aqueous phase, we decided to further
optimise the pH for the extraction of 28 (Fig. 8). This resulted in
a pH dependency which had a similar prole to that of 11 with
local maxima and minima arranged around the estimated pKb/
pKa ranges of the host–guest system with the highest ee at pH 5
(57% and 60% ee for SPA2 and SPA 4, respectively). However,
the distribution of the preferred enantiomer showed a drop in
extraction at that pH whereas extraction of the other enan-
tiomer remained at the same level unlike in the case of 11. This
caused the operational selectivity to be at a minimum at pH 5.
The optimum pH for the extraction of 28 was 3.5 with aop's
nearly doubling, reaching 6.4 for SPA 2 and 5.3 for SPA 4. While
this shows how hard it is to predict what the optimal extraction
pH will be for each individual compound as no trend can be
observed, it also demonstrates that these hosts can be efficiently
applied to a number of amino alcohols.
Fig. 7 Amino-alcohol screening. Conditions: all extraction experi-
ments were conducted in 2 ml auto-sampler vials with crimp cap seals
equipped with stir bars. In a standard experiment, a solution of the
racemic guest (0.4 ml, 2 mM) dissolved in a phosphate buffer solution
(buffer strength 0.1 M, pH ¼ 5.0) was carefully added to a solution of
the corresponding host in chloroform (0.4 ml, 1.0 mM). The two-
phasic system was then immediately cooled to 6 ꢂC and stirred at
900 rpm for 16 h. The phases were then allowed to separate over
a period of 2 min. The aqueous phase was removed and an aliquot
injected into a reverse phase HPLC equipped with chiral columns for
determination of the ee, distribution and aop. All extraction experi-
ments were carried out in triplo and with a simultaneous blank reaction
(concentration of host ¼ 0.0 mM).
Applicability and scalability
With this highly efficient, optimized system in hand we turned
our attention to the scalability of the process toward multistage
reactors, running a U-tube experiment which serves as a useful
test to judge the capacity of a host to deliver a guest from
a feeding to a release phase in a catalytic manner (Fig. 9a).44
A
blank run showed that at pH 5 there was no leaching of guest
into the second aqueous phase over 24 h so any transfer
observed can solely be attributed to the host.
When a 2 mM guest solution was used as feeding phase an ee
of 41% could be measured in the receiving phase aer an hour.
However, further aliquots aer two and three hours showed
a slow erosion of ee occured over time. This is due to a depletion
of the desired enantiomer of the guest in the feeding phase and
subsequent transport of the other enantiomer as was observed
earlier by us,56 indicating as well that the host was undergoing
multiple transport release cycles. When a 20 mM feeding phase
was used to overcome this issue, a 50% ee could be observed in
the receiving phase aer just 10 minutes with the ee staying
globally constant over several hours while the amount of guest
accumulated in the receiving phase rose steadily. Only aer 24
hours was a notable loss in ee observed (29%) due, again, to
depletion of the feeding phase. This showed that this system
could be adapted to multistage reactors with high efficiency,
potentially reaching 99% ee in under ve steps if a cascade of
centrifugal contactor separators is employed as was shown by
our group in 2009 for 3,5-dinitrobenzoyl-(R),(S)-leucine45 and
that a catalytic process was achieved with multiple turnovers,
the rst turnover being achieved in approximatively 40 min. In
the centrifugal contactor separators these extractions are ach-
ieved in a matter of seconds.
We rst studied the importance of the 1,2-amino-alcohol
moiety. When cyclic trans-1-hydroxy-2-amino compound 10
was used only SPA 2 retained some selectivity (aop ¼ 3.8), 1,3-
aminoalcohol 20, N-isopropyl phenylglycinol 21 and O-methyl
phenylglycinol 22 were extracted as a racemate by both hosts. 1-
Amino-2-hydroxy compound 23 was extracted with moderate
selectivity (SPA 4, aop ¼ 1.5). We also tested a similar norepi-
nephrine metabolite, normetanephrine (24), which is cheaply
available in the racemic version but only available in the
enantiopure form by total synthesis. With this compound we
obtained an aop of above 3 with SPA 2, which is sufficient for
efficient large scale resolution of this biologically relevant
molecule.58 Overall this shows how important the 1,2-amino-
alcohol motif is and how specic its interactions with the
phosphoric acid via H-bonding are. Altering the chain length
between moieties, increasing the steric bulk around these
positions or removing H-bond donor or acceptor positions
results in a total loss of selectivity.
We then studied the importance of the aromatic ring of the
guest in terms of selectivity. When phenylalaninol (25) was used
only minor selectivity could be observed (SPA 4, aop ¼ 1.24) in
its extraction, naphthyl substituted aminoalcohol 26 was too
insoluble in water for ELLE whereas substituted phenylglycinol
In addition, the unique solvent dependency of this system
can also be exploited in a novel fashion via simultaneous
extraction of both enantiomers with a single catalyst in
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Fig. 8 pH dependency of 28. Conditions: all extraction experiments were conducted in 2 ml auto-sampler vials with crimp cap seals equipped
with stir bars. In a standard experiment, a solution of racemic 28 (0.4 ml, 2 mM) dissolved in a phosphate buffer solution (buffer strength 0.1 M, pH
¼ 5.0) was carefully added to a solution of the corresponding host in chloroform (0.4 ml, 1.0 mM). The two-phasic system was then immediately
cooled to 6 ꢂC and stirred at 900 rpm for 16 h. The phases were then allowed to separate over a period of 2 min. The aqueous phase was removed
and an aliquot injected into a reverse phase HPLC equipped with chiral columns for determination of the ee, distribution and aop. All extraction
experiments were carried out in triplo and with a simultaneous blank reaction (concentration of host ¼ 0.0 mM). For numerical values see ESI.†
a vertical variation of the W-tube rst suggested by Cram.59
When a triphasic system is set-up as shown below (Fig. 9b) with
the bottom phase containing the host in chloroform ((R)-host
phase 1), the middle phase containing the aqueous racemic
guest solution (2 mM, feeding phase) and the top phase con-
taining the host in toluene ((R)-host phase 2) extraction of the
guest occurs from the feeding phase into both host phases
which respectively yield, aer back-extraction,60 an ee of 41% for
the chloroform phase and an ee of 48% of the opposite enan-
tiomer for the toluene phase.
The triphasic system therefore allows for the simultaneous
extraction of both enantiomers with a single host is, to the best
of our knowledge, unique and opens many new possibilities for
ELLE extraction.
Fig. 9 U-tube and tri-phasic reactor. Internal diameters: 1.0 cm,
0.9 cm, respectively. Stirring: for both 900 rpm, temperature: for both:
6 ꢂC initial set-up: (a) (R)-host phase: SPA 4 in chloroform (10 ml, 0.5
mM). Feeding phase: 5 ml of a 2 or 20.0 mM solution of racemic
phenylglycinol dissolved in
a phosphate buffer solution (buffer
strength 0.1 M) pH ¼ 5.0. Receiving phase: 5 ml of a HCl solution in
doubly distilled water such as pH ¼ 2.0. At regular intervals an aliquot
of the receiving phase was injected into a reverse phase HPLC
equipped with a chiral column for determination of the ee, distribution
and aop. (b) (R)-host phase 1: SPA 4 in chloroform (3 ml, 1.0 mM)
feeding phase: 5 ml of a 2.0 mM solution of racemic phenylglycinol
dissolved in a phosphate buffer solution (buffer strength 0.1 M) pH ¼
5.0. (R)-Host phase 2: SPA 4 in toluene (3 ml, 1.0 mM). All extraction
experiments were carried out in triplo and with a simultaneous blank
reaction (concentration of host ¼ 0.0 mM). For numerical values see
ESI.†
Conclusions
In summary, we have studied the efficiency of a previously
unexplored family of chiral hosts towards the enantioselective
liquid–liquid extraction of
including biologically relevant ones. These chiral 3,30-
substituted SPINOL phosphoric acids were shown to be highly
efficient at the resolution of this type of substrates reaching
unprecedented levels of selectivity. The operational selectivity of
the extractions is highly dependent on the solvent, the pH and
a range of 1,2-aminoalcohols
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the temperature. We have also validated these systems towards 17 M. Leeman, G. Brasile, E. Gelens, T. Vries, B. Kaptein and
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21 G. Guebitz and M. G. Schmid, Chiral Separations, Humana
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22 S. Ahuja, Chiral Separations: Application and Technology, ACS,
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Conflicts of interest
There are no conicts of interest to declare.
¨
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24 V. A. Davankov, J. Chromatogr. A, 1994, 666, 55–76.
Acknowledgements
Financial support from STW through project no. 11404 (Chiral 25 M. Steensma, N. J. M. Kuipers, A. B. De Haan and G. Kwant,
Separations by Kinetic Extractive Resolution in Microuidic Chirality, 2006, 18, 314–328.
Devices), from the Swiss National Science Foundation (SNSF) 26 G. B. Cox, Preparative Enantioselective Chromatography,
and from the Ministry of Education, Culture and Science
Blackwell Publishing Ltd, 2007.
(Gravitation Program 024.001.035 to BLF) are all gratefully 27 E. Gavioli, N. M. Maier, C. Minguillon and W. Lindner, Anal.
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>98% extraction of guest into aquous phase.
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