Enantiomeric enrichments via the self-disproportionation of enantiomers (SDE) by achiral, gravity-driven column chromatography: A case study using N-(1-phenylethyl)acetamide for optimizing the enantiomerically pure yield and magnitude of the SDE

Article abstract of DOI:10.1002/hlca.201500041

This work explores the self-disproportionation of enantiomers (SDE) via achiral, gravity-driven column chromatography as typically used in laboratory settings for the purpose of enantiomeric enrichment using N-(1-phenylethyl)acetamide (PEA) as a case stud

Full text of DOI:10.1002/hlca.201500041

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Enantiomeric Enrichments via the Self-Disproportionation of Enantiomers
(SDE) by Achiral, Gravity-Driven Column Chromatography: a Case Study
Using N-(1-Phenylethyl)acetamide for Optimizing the Enantiomerically Pure
Yield and Magnitude of the SDE
by Alicja Wzorek*a), Azusa Satob), Józef Drabowiczc)d), Vadim A. Soloshonoke)f), and
Karel D. Klika*g)
a
´
) Institute of Chemistry, Jan Kochanowski University in Kielce, Swie˛tokrzyska 15G, PL-25-406 Kielce
(e-mail: alicja.wzorek@ujk.edu.pl)
b) Department of Chemistry, Tokyo Womenꢀs Medical University, 8-1 Kawada-cho, Shinjuku-ku,
162-8666 Tokyo, Japan
c) Department of Heteroorganic Chemistry, Center of Molecular and Macromolecular Studies,
´
Polish Academy of Sciences, Sienkiewicza 112, PL-90-363 Łódz
d) Institute of Chemistry, Environmental Protection and Biotechnology, Jan Długosz University in
Czestochowa, Armii Krajowej 13/15, PL-42-201 Cze˛stochowa
e) Department of Organic Chemistry I, Faculty of Chemistry, University of the Basque Country
UPV/EHU, ES-20018 San Sebastiµn
f) IKERBASQUE, Basque Foundation for Science, ES-48011 Bilbao
g) Molecular Structure Analysis, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280,
DE-69009 Heidelberg (phone: þ 49-6221-424515; e-mail: klikakd@yahoo.co.uk)
This work explores the self-disproportionation of enantiomers (SDE) via achiral, gravity-driven
column chromatography as typically used in laboratory settings for the purpose of enantiomeric enrich-
ment using N-(1-phenylethyl)acetamide (PEA) as a case study. The major finding of this work is the very
large magnitude of the SDE for PEA across a variety of conditions and broad range of starting ee values,
thereby facilitating a simple, reliable, and predictable means of obtaining enantiomerically pure samples.
For example, starting with a sample of PEA of ee as low as 28%, a single column run yielded an
enantiomerically pure sample (> 99.9% ee) from the first fractions and a significantly enantiomerically
depleted sample (<17% ee) from the final fractions. An assessment of SDE via achiral, gravity-driven
column chromatography was also rendered with regard to the differing objectives that workers might
target – a large magnitude of the SDE, obtaining an optimum sample of desired ee, or preparative-scale
separation of the excess enantiomer. Overall, it can be considered that the SDE phenomenon via achiral,
gravity-driven column chromatography – readily applicable in the usual laboratory settings – is a simple
and convenient method for enantiomeric enrichment with a high degree of proficiency. Advantages of
SDE via achiral, gravity-driven column chromatography over conventional fractional recrystallization
for the enantiomeric enrichment of amides/amines, and applicable also to many other classes of com-
pounds as well, are discussed.
Introduction. – The self-disproportionation of enantiomers (SDE)1) [1] describes
any process under achiral conditions which transforms a nonracemic sample of a chiral
compound into fractions containing varying – enriched and depleted – proportions of
1
)
The applied terminology has been much discussed and debated and is used herein as recommended
by Klika and Soloshonok [1].
ꢁ 2015 Verlag Helvetica Chimica Acta AG, Zürich

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the enantiomers in comparison with the enantiomeric composition of the original
sample [2]. Since the initial observations of SDE via sublimation [3] and achiral
chromatography [4], numerous papers have reported this phenomenon to occur via
sublimation [5], achiral chromatography [6], and even by distillation [6a][7]. In
addition to general reviews [8][9] on the SDE phenomenon, there are also two specific
reviews [10][11] focused on achiral chromatography. The acronym ESDAC (enan-
tiomer self-disproportionation over achiral chromatography) is sometimes used for the
SDE phenomenon when referring explicitly to SDE via chromatography [12 – 14]. The
underlying premise for the process in effect is that the transient formation of dimeric
homo- or heterochiral associations or other higher-order aggregates are responsible for
the phenomenon [2][12][15]. While the vast majority of cases appear to involve the
formation of homo- and heterochiral associates based on H-bonding [8][11][12][16],
other cases based on p-stacking [4][17] or dipoleÀdipole interactions [18][19] have also
been described. Of note, it has been shown that enantiomeric enrichment based on the
SDE phenomenon can rival conventional recrystallization in performance and practical
application for some compounds [6a][6c][6d].
It is worth reiterating [19][20] the predictions resulting from mathematical
modeling [14][21] that have been made for the SDE phenomenon in idealized cases
where only a single intermolecular interaction is present and only one structural entity
is formed, e.g., dimer formation. Firstly, baseline separation between the first eluting
component (e.g., the excess enantiomer) and the second eluting component (e.g., the
racemic portion) is not possible. Secondly, due to the lack of baseline separation and
the asymptotic convergence of the first eluting component, it is not possible to isolate
completely the first eluting component, i.e., obtain all of the excess enantiomer from
the racemic portion if the excess enantiomer is the first eluting component, but it is
possible nevertheless to obtain a large proportion of it. Thirdly, it is not possible at all to
obtain the second eluting component completely free of the first eluting component
due to the asymptotic convergence of the first eluting component, though in practice
this can be inconsequential since the level of ꢂcontaminationꢀ becomes negligible as the
content of the first eluting component, along with the second component, converges to
zero. However, it is possible to obtain fractions containing the first eluting component
completely free of the second eluting component, and this is not wholly dependent on a
high starting ee value [19]. It is also worth noting that there are large deviations from
this idealized behavior in many real-world examples.
As part of our ongoing, comprehensive investigation into the processes and
interactions leading to SDE via achiral, gravity-driven column chromatography
[19][20], we had examined [20] a set of amides in detail with respect to various
parameters, e.g., amide structure, sample ee, eluent polarity, and other chromato-
graphic parameters such as column geometry, ratio of analyte to stationary phase, type
of stationary phase and pore size, etc., to gauge the sensitivity of the SDE phenomenon
to the prevailing conditions. As a result, we were able to demonstrate the generality and
persistence of the SDE phenomenon for the examined compounds. Since chiral amides
are one of the most prevalent classes of organic compounds and are some of the most
commonly used intermediates in asymmetric synthesis (and duly, also amines), it was of
considerable importance to prove that a sizeable, and therefore concerning, magnitude
of the SDE (Dee values, defined as the difference in ee between the fractions of lowest

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Fig. 1. Structures of (R)- and (S)-N-(1-phenylethyl)acetamide
(PEA)
and highest ee, ostensibly the first and final fractions) can readily occur [20] under the
routine conditions of achiral chromatography as chiral amides are usually purified
using this technique as part of common laboratory practice. In addition to noting the
generality of the SDE phenomenon via achiral, gravity-driven column chromatography
for a range of chiral amides, we also demonstrated [20] that it was expressed over a
broad range of starting ee values.
Having previously examined the SDE phenomenon with regard to various aspects,
we herein focus on N-(1-phenylethyl)acetamide (PEA, Fig. 1) as a case study to
ascertain the conditions for obtaining a high yield of enantiomerically pure samples and
how this relates to just enantiomeric purity per se.
The aims of the present work are thus to i) gain a deeper appreciation of the SDE
phenomenon via achiral, gravity-driven column chromatography and ascertain the
requirements for obtaining a large Dee value, ii) ascertain the requirements for
obtaining fractions of high enantiomeric purity, and iii) ascertain the requirements for
obtaining a high, amounting to preparative scale, yield of enantiomerically pure
sample. Counter to intuitive expectations, these objectives are not necessarily mutually
inclusive.
Results and Discussion. – This present investigation of the SDE phenomenon via
achiral, gravity-driven column chromatography utilized N-(1-phenylethyl)acetamide
(PEA), synthesized from (1-phenylethyl)amine by acetylation with AcCl, and
centered on examining a range of PEA samples of varying ee under assorted
conditions. Samples were constituted from the (R)- and (S)-enantiomers of PEA that
had each been prepared separately from enantiomerically pure samples of (R)- and
(S)-N-(1-phenylethyl)acetamide, respectively, with the ee of the resulting PEA
mixtures determined by chiral HPLC analysis. Altogether, thirteen gravity-driven
column chromatographic runs were performed with the details of each presented in the
Table. Gravity-driven chromatography columns were eluted with target flows of 3 –
5 min/10 ml, amounting to total elution times ranging from 4 – 11 h. The first aliquots
collected (denoted as ꢂearlyꢀ) were 10 ml in volume, followed by 50-ml volumes
(denoted as ꢂmiddleꢀ), then finally by 100-ml volumes (denoted as ꢂfinalꢀ). As noted
previously [19], it is important for reproducibility and application transfer to other
systems to describe the chromatographic conditions adequately with respect to flow
rates, elution times and volumes, etc., as the SDE process is heavily dependent on such
parameters, probably more than otherwise, since the dynamic equilibrium between free
molecules and homo- and heterochiral dimers is strongly influenced by the prevailing
conditions.
Using tBuOMe/cyclohexane 2 :1 as eluent, chromatography of half-a-dozen
samples of PEA over achiral silica gel were performed for a range of sample ee

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values, from 13.8 – 90.4% (runs 1 – 6, Table). A graphical representation of the
chromatographic profile for run 4 is depicted in Fig. 2. The profile of run 4 is considered
to represent a typical elution profile akin to that of an idealized system. Although the
occurrence of the SDE phenomenon does depend to a degree on the starting ee of a
sample, previous investigations have implied [2][22] that, to simply obtain a sample
with high enantiomeric purity using SDE via chromatography, it was necessary to
utilize a sample of high ee, but this need not be the case. Nevertheless, it may be the
case in some instances that only a small range of ee values lead to a large Dee value and
therefore potentially to the obtainment of enantiomerically pure fractions [2], this only
adding to the mistaken belief that a high initial ee was required to obtain an
enantiomerically pure fraction. Here, a strong dependency on sample ee was not
evident and in all cases, a large Dee value resulted (41.4 – 83.7%), and, except for run 6
where a sample of 13.8% ee was used, an enantiomerically pure sample (> 99.9% ee)
of PEA was always obtained in the early fractions. This latter aspect is generally
considered unusual but may, in fact, be a much more common occurrence as
demonstrated, in line with theory, here for samples of only modest ee (<28%). Thus,
the results confirm previous observations [20] that SDE via achiral, gravity-driven
column chromatography does neither require a high ee of the starting sample nor is it
necessarily restricted to a limited range of ee values to attain a large resultant Dee value
or to attain an enantiomerically pure sample.
An observable trend in runs 1 – 6 is that while runs 1 – 3 are appropriate for
obtaining samples highly enriched in the first eluting component, i.e., the excess
enantiomer in this instance, runs 4 and 5 are also useful for obtaining samples highly
ꢂenrichedꢀ in the second eluting component, i.e., the racemic portion in this instance,
while run 6 is useful only for obtaining a sample highly ꢂenrichedꢀ in the second-eluting,
racemic portion. It is also conceivable, albeit likely to be only occasional, that
Fig. 2. Graphical representation of chromatography run 4 (see Table) showing the % ee of each fraction
vs. the weight percent of each fraction. The starting ee (50.2%) is indicated. Run 4 represents a typical
elution profile akin to that of an idealized system. tBuOMe/cyclohexane (2 :1) was used as eluent and the
ratio of PEA to silica gel was ca. 1 mmol :30 g. The column flow rate was targeted to 5.0 min/10 ml and
altogether 22 fractions were collected consisting of 15 Â 10 ml early aliquots, 5 Â 50 ml middle aliquots,
and then two final aliquots of 100 ml to give a total elution volume of 600 ml.

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circumstances can arise where the racemic portion as well as the excess enantiomer, or
even the former in lieu of the latter, is desired. Thus, perceivable, and competing,
objectives could be for obtaining the first, the second, or even both components
depending on elution order and/or the desired component.
Further consideration of the graphical representations for runs 1 – 6 reveals that
they are not ideal and aberrant SDE behavior can be observed in that the ee did not
always fall smoothly during the course of the chromatography, as is predicted by
mathematical modeling [14][21] assuming a single intermolecular interaction and the
formation of only one type of transitory aggregate structure [11][12]. Even rises in ee
are evident in some of the graphical representations, particularly for runs 2, 3, and 5. A
graphical representation of the chromatographic profile for run 2 is depicted in Fig. 3.
These latter aberrations have previously been described [19] as ꢂkinksꢀ and allude to the
complex nature of the processes leading to the SDE phenomenon or to drastic changes
in the local concentrations as well as the shortfall of describing the system in simple
terms such as the formation only of homo- and heterochiral dimers based on a single
interaction. Such kinks have been observed to occur at the front end of the elution
profile [6b][17][19][23], but they may also occur in the middle [19] as well as the tail
[19] and even occur multiple times during the course of the elution [19]. By far, the
most dramatic example, so extreme in fact it has been dubbed [13] ꢂdouble ESDACꢀ,
was observed during the chromatography of spirobrassinins [24]. Thus, oligomer
formation, in addition to dimer formation, or alternative binding modes must be
occurring whenever aberrant behavior is observed. The latter explanation has been
proposed [13][25], with some legitimacy, to account for the dramatic behavior of the
spirobrassinins [24]. For PEA, only the intermolecular H-bonding-based interactions
are considered to be sufficiently effectual for SDE purposes, thus leaving oligomer
formation by default as the cause of the anomalous behavior observed in this instance.
Fig. 3. Graphical representation of chromatography run 2 (see Table) showing the % ee of each fraction
vs. the weight percent of each fraction. The starting ee (78.9%) is indicated. The pronounced kink towards
the end of the run is discussed in the text. tBuOMe/Cyclohexane (2 :1) was used as eluent and the ratio of
PEA to silica gel was ca. 1 mmol :30 g. The column flow rate was targeted to 5.0 min/10 ml, and
altogether 22 fractions were collected consisting of 15 Â 10 ml early aliquots, 5 Â 50 ml middle aliquots,
and then two final aliquots of 100 ml to give a total elution volume of 600 ml.

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Using Et2O/cyclohexane in a 4 :1 ratio as eluent, very similar results in comparison
to runs 3 – 5, in terms of Dee values, obtaining an enantiomerically pure sample, and
obtaining the second-eluting, racemic portion, were obtained for the three comparable
runs (runs 7 – 9, resp., Table) using this solvent with sample ee values in the range 29.6 –
69.9%. The persistence of the SDE phenomenon for PEAusing different eluents is thus
notable.
As previously noted [19], the SDE phenomenon is dependent on the ratio of
analyte to stationary phase. Reducing the amount of silica gel used for the
chromatography at a set sample ee, viz., run 10 relative to run 7, revealed some
surprising results (Table). While Dee values, in accord with expectations, increased
from 50.7 to 65.5%, and both runs were able to furnish initial fractions containing
enantiomerically pure PEA, the amount of enantiomerically pure material that could
be obtained from the chromatography, whether of 99.9, 99, or 95% ee, was
considerably reduced in the case of run 10. Run 10 was also more amenable to
obtaining both the first and second eluting components in comparison to run 7.
Thus, while a higher concentration of analyte generally favors expression of the
SDE phenomenon, sufficient chromatographic exposure is still necessitated, and
clearly for run 10, this is suboptimal. In addition, the kink appearing near the end
of the chromatographic run is much more pronounced in run 10 (see Fig. 4) in
comparison to run 7, suggesting that, in line with proposed suppositions, kinks are
concentration dependent and infer that drastic changes in local concentration leading
to the formation of higher aggregates might be responsible for their occurrence. Thus,
while a greater analyte to stationary phase ratio may improve overall Dee values,
it may not necessarily facilitate improved isolation of a preparative-scale enantiomeri-
cally pure sample and, in addition, may exacerbate any aberrant effects that are
present.
Fig. 4. Graphical representation of chromatography run 10 (see Table) showing the % ee of each fraction
vs. the weight percent of each fraction. The starting ee (69.4%) is indicated. The kink towards the end of
the run is more pronounced in comparison with run 7 where a lesser analyte to stationary phase ratio was
used. Et2O/Cyclohexane (4 :1) was used as eluent and the ratio of PEA to silica gel was ca. 1 mmol :20 g.
The column flow rate was targeted to 3.0 min/10 ml, and altogether 22 fractions were collected consisting
of 15 Â 10 ml early aliquots and 7 Â 50 ml middle aliquots to give a total elution volume of 500 ml.

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Runs 11 and 12 tested a general change in solvent by using AcOEt in place of
tBuOMe/Et2O as the polar component of the eluent, and wherein the SDE
phenomenon was found to still persist strongly though the Dee value was reduced
(Table). The graphical representations for runs 11 and 12 looked very different to
previous runs 3 and 7, and while run 11 was adequate for furnishing an enantiomerically
pure sample (but not for the racemic portion), run 12 was good for neither. The amount
of enantiomerically pure sample that could be realized in the case of run 11 was also
markedly reduced. Clearly, the higher polarity of AcOEt in the eluent system is, not
unexpectedly, debilitating for the SDE phenomenon since it is, in this case, based on
intermolecular H-bonding. Runs 11 and 12 also compare the result of a subtle change in
the eluent, specifically comparing the substitution of cyclohexane (run 11, Table) with
hexane (run 12). Although the differences in terms of Dee values are modest between
runs 11 and 12 with the graphical profiles nominally similar, they are noticeable and are
in concert with the premise of Klika et al. [13] who maintain that the SDE phenomenon
is very sensitive to the applied conditions. Thus, while Dee values for runs 11 and 12
were comparable (44.4 and 42.6%, resp.), only run 11 was able to furnish a fraction
containing enantiomerically pure PEA.
Even with the use of a very polar eluent system, CH2Cl2/AcOEt in a ratio of 10 :1
(run 13, Table), the SDE phenomenon was still in effect despite the H-bonding-based
mode of intermolecular interaction. However, the Dee value was greatly reduced and
the system was unable to furnish a fraction that was enantioenriched or -depleted.
Nevertheless, overall the SDE phenomenon for PEA is generally persistent across all of
the conditions applied here and previously [20] and is not restricted to a limited range
of ee values for the sample applied. Thus, in terms of providing an enantiomerically
pure sample of 99.9% ee, all of the chromatographic runs provided such with the
exception of runs 6 (ee of the applied sample 13.8%), 12, and 13 (wherein a highly polar
eluent was used). Even run 11 using AcOEt/cyclohexane in a ratio of 1:1 was able to
furnish an enantiomerically pure sample. Clearly though, strongly polar eluents are
prohibitive towards the SDE phenomenon in this case and to obtain a large Dee value,
whether for the purposes of furnishing an enantiomerically pure sample, both
enantioenriched or -depleted samples, or a practical amount of an enantiomerically
pure sample, ethereal-based eluents, or at least eluents that are not highly polar, are
required. However, in terms of isolating the excess enantiomer, chromatographic runs
t
that utilized BuOMe as the polar component in the eluent were much more efficient
than comparable runs using Et2O. Indeed, in terms of extraction of the excess
enantiomer, the yields relative to the available amount of excess enantiomer correlated
strongly with the ee of the original sample. So although large Dee values and the
ability to obtain an enantiomerically pure fraction were possible for almost all of the
runs conducted here, high yielding extractions of the excess enantiomer at the
preparative scale were obtained only for runs conducted with a high ee for the original
sample.
Although the SDE for PEA can be explained by the formation of homo- and
heterochiral dimers via H-bonding with the differing chromatographic behavior of the
entities the underlying mechanism responsible for the SDE phenomenon, it has been
intimated previously [12] that a large energy differential between the dimer types is not
required in principle for observation of SDE via achiral chromatography. That is, there

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need not be a large, overwhelming, almost exclusive, bias towards the formation of one
aggregate type over the other to account for the observations of SDE via achiral
chromatography. Indeed, it already has been proven that the domination of one dimer
type over the other cannot be the sole determining factor, since the elution order –
excess enantiomer or racemate first – can be dependent on the very stationary phase in
use [19]. That observation substantiates the premise of Klika et al. [13] whereby they
assert that the SDE phenomenon is not just a question of a preference between homo-
and heterochiral dimers, but the relative stability of these homo- and heterochiral
dimers as the environment changes, e.g., from solution in the eluent in the interstitial
spaces to the pores of the stationary phase. That is, a perturbation in aggregation
behavior between the free molecules and the homo- and heterochiral dimers can arise
from the different environments of different stationary phases.
Since PEA provides such a large Dee value, it represents a good example to test the
assertion regarding energy differentials. Thus, quantum-chemical molecular modeling
was conducted to confirm the premise using DFT calculations at the M06-2X/tzvp level
of theory. This level of theory with respect to both the functional and the basis set was
considered adequate to account for the H-bonding present in the constructs [12][26].
In Fig. 5 are presented the homochiral and heterochiral dimeric associates of PEA
wherein it was found that the difference in Gibbsꢀ free energies, DG, was only 0.06 kcal/
mol in favor of the heterochiral construct. This negligible value thereby was in full
support of the postulation.
Fig. 5. The DFT-optimized model structures at the M06-2X/tzvp level of theory of the homochiral (upper)
and heterochiral (lower) dimeric associates of PEA. The calculated difference in Gibbsꢀ free energies,
DG, indicated the heterochiral construct to be favored by 0.06 kcal/mol.

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Conclusions. – In this work, we have described the results of an investigation into
the SDE phenomenon via gravity-driven chromatography over achiral silica gel using
N-(1-phenylethyl)acetamide (PEA) as a case study. We demonstrated that it is possible
to obtain in a practical and useful manner enantiomerically pure PEA starting from a
sample of only modest ee. Indeed, it was observed that PEA exhibited the SDE
phenomenon under all applied conditions, including a broad range of starting ee values.
These results can thus be useful for practical applications to obtain enantiomerically
pure samples from a nonracemic sample of a chiral compound. While strongly polar
eluents are clearly prohibitive towards the SDE phenomenon in this case and to obtain
a large Dee value, whether for the purposes of simply furnishing an enantiomerically
pure sample, both enantioenriched or -depleted samples, or a practical amount of an
enantiomerically pure sample, ethereal-based eluents, or at least eluents that are not
highly polar, are required. However, in terms of isolating the excess enantiomer,
chromatographic runs that utilized tBuOMe as the polar component in the eluent were
much more efficient than comparable runs using Et2O. Indeed, in terms of extraction of
the excess enantiomer, the yields relative to the available amount of excess enantiomer
correlated strongly with the ee of the original sample. So although large Dee values and
the ability to obtain an enantiomerically pure fraction were possible for almost all of
the runs conducted here, high yielding extractions of the excess enantiomer at the
preparative scale were found only for runs conducted with a high ee for the original
sample. Nevertheless, it could well be that enantiomeric enrichment based on the SDE
phenomenon via gravity-driven chromatography represents a simple, reliable, and
predictable method with a high degree of proficiency for this class of compounds.
The conventional means to obtain an enantiomerically pure sample from a
nonracemic sample of a chiral compound without recourse to, for example, chiral
chromatography, is fractional recrystallization. There are, however, some limitations to
this time-honored technique. For one, fractional recrystallization becomes increasingly
difficult and generally less efficient with a reduction in ee and is limited to ee values
above the eutectic point of the system. Secondly, fractional recrystallization is
problematic on a practical level with small sample sizes. Finally, there are often
problems with controlling the solvent and the amount of the racemic portion that is
kept in solution while depositing the excess enantiomer when performing fractional
recrystallization. By comparison, the SDE phenomenon via chromatography can
readily persist to low ee values, small sample sizes are easily handled by chromatog-
raphy, and with chromatography one can readily select quite easily the amount of the
sample to fractionate or to combine fractions accordingly. Thus, in many respects, SDE
via chromatography represents a complementary, alternative technique to fractional
recrystallization for the purposes of extracting the excess enantiomer from a
nonracemic sample to obtain an enantiomerically pure sample. Since it is possible to
control precisely how much of the sample is collected during chromatography and SDE
via chromatography performs so well at high ee values, SDE via chromatography might
even be superior to fractional recrystallization for preparative-scale isolations in
particular cases.
The authors gratefully acknowledge generous financial support from IKERBASQUE, the Basque
Foundation for Science (Spain) (V. A. S.), the Basque Government (V. A. S. ), Hamari Chemicals (Osaka,

Helvetica Chimica Acta – Vol. 98 (2015)
1157
´
Japan) (V. A. S. ), and for studies conducted in Łódz, the National Science Center (Poland) (Grant no.
UMO-2012/06/A/ST5/00227) (J. D.). The CSC – IT Center for Science Ltd. (Finland) is also gratefully
acknowledged for providing computational resources (K. D. K.).
Experimental Part
General. AcCl, (R)-, and (S)-(1-phenylethyl)amine were purchased from Aldrich. Column
chromatography solvents, CH2Cl2, cyclohexane, hexane, AcOEt, and Et2O were purchased from
Chempur (Poland) while tBuOMe was purchased from POCh (Poland); all solvents were used without
further purification. HPLC Solvents, hexane and i-PrOH, and silica gel (230 – 400 mesh) for column
chromatography were purchased from Merck.
HPLC Chromatographic analysis was performed on a Varian ProStar instrument equipped with a
UV/VIS detector and a Vertex Plus Eurocel 01 chiral column (5 mm, 250 Â 4.6 mm; Knauer, Germany)
using hexane/i-PrOH 90 :10 as the mobile phase at a flow rate of 0.8 ml/min.
Gravity-driven column chromatography with the various eluents given in the text was performed
using a column of diameter 20 mm and height 600 mm. The ratio of PEA to silica gel was 1 mmol:30 g
unless otherwise stated. Samples of PEA of various ee were prepared by mixing appropriate amounts of
the (R)- and (S)-enantiomers of PEA and loaded onto the column as a soln. in CH2Cl2. Columns were
eluted with target flows of 3 – 5 min/10 ml amounting to total elution times of ca. 4 – 11 h.
DFT Quantum chemical calculations were performed following previous methodology [12][27]
using Gaussian09 [28] (version D.01) and analyzed using GaussView [29] (version 4.1.2). Geometry
optimization of the structures in the gas phase were performed using the M06-2X hybrid meta density
functional [30] with the tzvp basis set in tandem with vibrational analyses and thermochemistry
calculations at the same level of theory. Geometry optimization was conducted with tight criteria by
invoking the keyword opt ¼ tight and fine intervals by invoking the keyword int ¼ ultrafine. Vibrational
analyses by invoking the keyword freq ¼ noraman were conducted to confirm that optimized structures
were true minima on the potential energy surface by not providing imaginary frequencies and to obtain
the thermodynamic contributions at 298.15 K and 1 atm wherein frequencies were left unscaled.
(R)- and (S)-N-(1-Phenylethyl)acetamide (PEA). The (R)- and (S)-enantiomers of PEA were
synthesized according to literature [6d][31]. To a soln. of (R)- or (S)-(1-phenylethyl)amine (2 g,
16.5 mmol) in anh. THF was added Et3N (3.5 ml, 24.8 mmol) followed by, after cooling to 08, AcCl
(1.2 ml, 16.5 mmol), and then, the soln. was left to be stirred. After 5 h at r.t., the mixture was poured into
an aq. sat. NH4Cl soln. and extracted with AcOEt (3 Â 20 ml). The combined org. extracts were washed
with brine, dried (MgSO4), and then evaporated to dryness. The crude product was purified by
recrystallization from Et2O. The physical and spectral data of the products (R)- and (S)-PEA were
consistent with those in [31b].
REFERENCES
[1] V. A. Soloshonok, K. D. Klika, Helv. Chim. Acta 2014, 97, 1583.
[2] V. A. Soloshonok, Angew. Chem., Int. Ed. 2006, 45, 766.
[3] G. Pracejus, Liebigs Ann. Chem. 1959, 622, 10.
[4] K. C. Cundy, P. A. Crooks, J. Chromatogr. A 1983, 281, 17.
[5] J. Han, D. J. Nelson, A. E. Sorochinsky, V. A. Soloshonok, Curr. Org. Synth. 2011, 8, 310; V. A.
Basiuk, T. Y. Gromovoy, A. A. Chuiko, V. A. Soloshonok, V. P. Kukhar, Synthesis 1992, 449; V. A.
Soloshonok, H. Ueki, M. Yasumoto, S. Mekala, J. S. Hirschi, D. A. Singleton, J. Am. Chem. Soc.
2007, 129, 12112; M. Yasumoto, H. Ueki, T. Ono, T. Katagiri, V. A. Soloshonok, J. Fluorine Chem.
2010, 131, 535; M. Albrecht, V. A. Soloshonok, L. Schrader, M. Yasumoto, M. A. Suhm, J. Fluorine
Chem. 2010, 131, 495; M. Yasumoto, H. Ueki, V. A. Soloshonok, J. Fluorine Chem. 2010, 131, 266; M.
Yasumoto, H. Ueki, V. A. Soloshonok, J. Fluorine Chem. 2010, 131, 540; H. Ueki, M. Yasumoto,
V. A. Soloshonok, Tetrahedron: Asymmetry 2010, 21, 1396; A. V. Tarasevych, A. E. Sorochinsky,
V. P. Kukhar, A. Chollet, R. Daniellou, J.-C. Guillemin, J. Org. Chem. 2013, 78, 10530; A. Bellec, J.-

1158
Helvetica Chimica Acta – Vol. 98 (2015)
C. Guillemin, Chem. Commun. 2010, 46, 1482; A. Bellec, J.-C. Guillemin, J. Fluorine Chem. 2010,
131, 545.
[6] a) J. L. AceÇa, A. E. Sorochinsky, T. Katagiri, V. A. Soloshonok, Chem. Commun. 2013, 49, 373;
b) S. Ogawa, T. Nishimine, E. Tokunaga, S. Nakamura, N. Shibata, J. Fluorine Chem. 2010, 131, 521;
c) A. E. Sorochinsky, T. Katagiri, T. Ono, A. Wzorek, J. L. AceÇa, V. A. Soloshonok, Chirality 2013,
25, 365; d) T. Nakamura, K. Tateishi, S. Tsukagoshi, S. Hasimoto, S. Watanabe, V. A. Soloshonok,
J. L. AceÇa, O. Kitagawa, Tetrahedron 2012, 68, 4013; e) R. M. Carman, K. D. Klika, Aust. J. Chem.
1991, 44, 895.
[7] B. Koppenhoefer, U. Trettin, Fresen. Z. Anal. Chem. 1989, 333, 750; T. Katagiri, C. Yoda, K.
Furuhashi, K. Ueki, T. Kubota, Chem. Lett. 1996, 25, 115.
[8] J. Martens, R. Bhushan, Helv. Chim. Acta 2014, 97, 161.
[9] A. E. Sorochinsky, V. A. Soloshonok, Top. Curr. Chem. 2013, 341, 301.
[10] J. Martens, R. Bhushan, J. Liq. Chromatogr. Relat. Technol. 1992, 15, 1.
[11] V. A. Soloshonok, C. Roussel, O. Kitagawa, A. E. Sorochinsky, Chem. Soc. Rev. 2012, 41, 4180.
[12] V. Nieminen, D. Y. Murzin, K. D. Klika, Org. Biomol. Chem. 2009, 7, 537.
[13] K. D. Klika, M. Budovskµ, P. Kutschy, J. Fluorine Chem. 2010, 131, 467.
[14] V. Schurig, J. Chromatogr. A 2009, 1216, 1723.
[15] V. A. Soloshonok, D. O. Berbasov, Chim. Oggi/Chem. Today 2006, 24, 44.
[16] A. E. Sorochinsky, J. L. AceÇa, V. A. Soloshonok, Synthesis 2013, 45, 141.
[17] V. J. Mayani, S. H. R. Abdi, R. I. Kureshy, N. H. Khan, S. Agrawal, R. V. Jasra, Chirality 2009, 21,
255.
[18] W.-L. Tsai, K. Hermann, E. Hug, B. Rohde, A. S. Dreiding, Helv. Chim. Acta 1985, 68, 2238.
[19] A. Wzorek, K. D. Klika, J. Drabowicz, A. Sato, J. L. AceÇa, V. A. Soloshonok, Org. Biomol. Chem.
2014, 12, 4738.
[20] Y. Suzuki, J. Han, O. Kitagawa, J. L. AceÇa, K. D. Klika, V. A. Soloshonok, RSC Adv. 2015, 5,
2988.
[21] E. Gil-Av, V. Schurig, J. Chromatogr. A 1994, 666, 519; R. Baciocchi, G. Zenoni, M. Mazzotti, M.
Morbidelli, J. Chromatogr. A 2002, 944, 225; R. Baciocchi, M. Mazzotti, M. Morbidelli, J.
Chromatogr. A 2004, 1024, 15; R.-M. Nicoud, J.-N. Jaubert, I. Rupprecht, J. Kinkel, Chirality 1996, 8,
234; M. Jung, V. Schurig, J. Chromatogr. A 1992, 605, 161; O. Trapp, V. Schurig, Tetrahedron:
Asymmetry 2010, 21, 1334.
[22] W. Song, Y. Zhou, Y. Fu, W. Xu, Tetrahedron: Asymmetry 2013, 24, 909.
[23] V. A. Soloshonok, D. O. Berbasov, J. Fluorine Chem. 2006, 127, 597.
´
[24] M. Suchy, P. Kutschy, K. Monde, H. Goto, N. Harada, M. Takasugi, M. Dzurilla, E. Balentovµ, J. Org.
´
Chem. 2001, 66, 3940; K. Monde, N. Harada, M. Takasugi, P. Kutschy, M. Suchy, M. Dzurilla, J. Nat.
Prod. 2000, 63, 1312.
[25] K. D. Klika, M. Budovskµ, P. Kutschy, Tetrahedron: Asymmetry 2010, 21, 647.
´
´
´
[26] M. K. Dudek (Jamróz), S. Kazmierski, K. Stefaniak, V. B. Glinski, J. A. Glinski, Org. Biomol. Chem.
2014, 12, 9837.
[27] P. Tähtinen, A. Bagno, K. D. Klika, K. Pihlaja, J. Am. Chem. Soc. 2003, 125, 4609; K. D. Klika, I.
Ricarte, M. T. Salles Trevisan, M. Goretti de Vasconcelos Silva, R. W. Owen, Tetrahedron:
Asymmetry 2015, 26, 247.
[28] M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, G. Scalmani,
V. Barone, B. Mennucci, G. A. Petersson, H. Nakatsuji, M. Caricato, X. Li, H. P. Hratchian, A. F.
Izmaylov, J. Bloino, G. Zheng, J. L. Sonnenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J.
Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven, J. A. Montgomery Jr.,
J. E. Peralta, F. Ogliaro, M. Bearpark, J. J. Heyd, E. Brothers, K. N. Kudin, V. N. Staroverov, T.
Keith, R. Kobayashi, J. Normand, K. Raghavachari, A. Rendell, J. C. Burant, S. S. Iyengar, J. Tomasi,
M. Cossi, N. Rega, J. M. Millam, M. Klene, J. E. Knox, J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo,
R. Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski, R. L.
Martin, K. Morokuma, V. G. Zakrzewski, G. A. Voth, P. Salvador, J. J. Dannenberg, S. Dapprich,
A. D. Daniels, O. Farkas, J. B. Foresman, J. V. Ortiz, J. Cioslowski, D. J. Fox, Gaussian09, Revision
D.01, Gaussian, Inc., Wallingford, CT, USA, 2009.

Helvetica Chimica Acta – Vol. 98 (2015)
1159
[29] R. Dennington II, T. Keith, J. Millam, GaussView, Revision 4.1.2; Semichem: Shawnee Mission, KS,
USA, 2009.
[30] Y. Zhao, D. G. Truhlar, Theor. Chem. Acc. 2008, 120, 215; Y. Zhao, D. G. Truhlar, Acc. Chem. Res.
2008, 41, 157.
[31] a) G. Li, J. C. Antilla, Org. Lett. 2009, 11, 1075; b) M. L. Leathen, E. A. Peterson, Tetrahedron Lett.
2010, 51, 2888.
Received February 14, 2015