Asymmetric hydrogenation catalysis via ion-pairing in chiral ionic liquids

Article abstract of DOI:10.1016/j.molliq.2013.10.025

The relevant interactions between the organic ions of ionic liquids (ILs) include van der Waals forces, hydrogen bonding and coulombic interactions. In solutions these interactions lead to the formation of aggregates. Depending on the strength of the inte

Full text of DOI:10.1016/j.molliq.2013.10.025

Journal of Molecular Liquids 192 (2014) 177–184
Contents lists available at ScienceDirect
Journal of Molecular Liquids
journal homepage: www.elsevier.com/locate/molliq
Asymmetric hydrogenation catalysis via ion-pairing in chiral ionic liquids
⁎
Valentin Wagner, Peter S. Schulz, Peter Wasserscheid
Lehrstuhl für Chemische Reaktionstechnik, Universität Erlangen-Nürnberg, D-91058 Erlangen, Germany
a r t i c l e i n f o
a b s t r a c t
Available online 8 November 2013
The relevant interactions between the organic ions of ionic liquids (ILs) include van der Waals forces, hydrogen
bonding and coulombic interactions. In solutions these interactions lead to the formation of aggregates. Depending
on the strength of the interactions and the concentration of the IL in the solvent, different aggregates are formed
with ion-pairs being the dominant species at low concentrations. A probe for investigating these interactions is
the enantioselectivity of a reaction carried out on a prochiral ion in presence of its chiral counter-ion. As asymmet-
ric induction requires structurally well-defined interactions, the induced enantioselectivity can be correlated
to ion aggregate formation. The first proof of this concept was provided by the asymmetric hydrogenation of
[N-(3′-oxobutyl)-N-methylimidazolium]-[(R)-camphorsulfonate] and -[(S)-camphorsulfonate] using a hetero-
geneous Ru on C contact. Depending on the substrate IL concentration an enantioselectivity of up to 94% could
be realized. The catalytic results were linked to the probability of the ion pair formation as evidenced by
DOSY-NMR measurements and dielectric relaxation spectroscopy. The expansion of this principle to chiral
ionic liquids that can be easily decomposed to chiral building blocks of synthetic relevance led us to the
development of two approaches: a) the application of an IL substrate consisting of a chiral cation and a keto-
functionalized, prochiral carboxylate counter-ion allowing for the synthesis of chiral esters in the sequence of
IL hydrogenation and esterification; and b) reversible binding of a prochiral substrate to the cation of an IL
with a chiral, enantiopure anion allowing the synthesis of neutral chiral building blocks in a sequence
of binding, hydrogenation and splitting. The latter approach was tested for two ILs based on the hydroxyl-
functionalized cation cholinium to which a prochiral keto functionalized carboxylic acids was reversibly attached
via esterification. The hydrogenation of such prochiral ester cation in the presence of enantiopure anions resulted
in ees of up to 63%.
Keywords:
Chiral ionic liquid
Ion-pairing
Hydrogenation
Asymmetric syntheses
© 2013 Elsevier B.V. All rights reserved.
1. Introduction
proved to provide interesting information is optical Kerr effect spectros-
copy [38].
The properties of ionic liquids are dominated by interionic forces
that result from a combination of coulombic, hydrogen-bonding and
van der Waals interactions. The nature and strength of those interac-
tions is influenced by the structure and functionalization of the ions.
Many theoretical studies have been published dealing with molecular
modeling of ion interactions [1–18]. Related experimental investiga-
tions have focused on the physico-chemical properties of ionic liquid
mixtures [19] or solutions of polar molecules in ionic liquids [20].
Analytical techniques used successfully to probe ionic interactions are
mass spectrometric analysis [21,22], NMR-spectroscopy [23–27],
fluorescence-spectroscopy [28], FT-IR and Raman spectroscopy
[29–31], and a combination of osmotic coefficient, conductivity, volu-
metric and acoustic properties [32]. In addition, dielectric relaxation
spectroscopy (DRS) has received much attention in the last years as it
offers a direct measurement of the ion pairing effects and degree of
organization within the ionic liquid [33–37]. Another technique that
Besides these analytical methods cation–anion interactions and
ionic liquid-transition state interactions can also be studied by using
the selectivity of a reaction as the probe. This approach was published
by Chiappe et al. who demonstrated in the bromination of alkynes
that the structure of the ionic liquid under investigation had a strong
influence on the transition state, the reaction order and therefore the
rate of syn- and anti-addition products [39]. Similar investigations
were carried out to study the ionic liquid's influence on the reaction
selectivity of the C- vs. O-alkylation of sodium β-naphthoxide with
benzyl halides [40] and for Diels–Alder reactions [41]. Two publications
describe the degree of ion-pair interaction in camphorsulfonate ionic
liquids and both link this interaction to the endo/exo stereoselectivity
of a Diels–Alder reaction [42,43].
The interest in chiral ionic liquids (CILs) has increased significantly in
recent years. The first ionic liquid with a chiral anion (lactate) was report-
ed in 1999 by Seddon's group [44]. Further ionic liquids with chiral anions
were prepared later by the groups of Ohno (19 natural amino acids) [45],
Machado ((S)-10-camphorsulfonate and (R)-1,10-binaphtylphosphate)
[46], and Leitner (L-(-)-malic acid) [47]. Chiral cations are rarer, as their
synthesis from substances of the chiral pool usually requires multi-step
⁎
Corresponding author at: Egerlandstrasse 3, D-91058 Erlangen, Germany.
E-mail address: wasserscheid@crt.cbi.uni-erlangen.de (P. Wasserscheid).
0167-7322/$ – see front matter © 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.molliq.2013.10.025

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V. Wagner et al. / Journal of Molecular Liquids 192 (2014) 177–184
syntheses [48,49]. Common starting materials are aminoacids and
aminoalkohols [50], alkaloids, terpenes, hydroxyacids or carbohy-
drates. More chiral cations are accessible via alkylation of imidazole
or imidazoline with chiral alkylation agents [51]. Bulky anions based
on a binaphtyl backbone bearing axial chirality have been synthesized
by the groups of Leitner [52] and Giernoth [53]. Ionic liquids with chi-
rality in both ions are very rare to date. Machado's Group published
the first “doubly chiral” ionic liquid in 2005 [54].
Chiral ionic liquids have found applications in chiral analytics and
asymmetric chemical reactions. In chiral analytics they are used as addi-
tives to the mobile phases, as stationary phases in chiral chromatogra-
phy [55–64] or as chiral NMR shift reagents [65–69]. Another main
field of research is influencing asymmetric reactions by CILs. There are
two main approaches for utilizing CILs in asymmetric reactions. The
first applies the CIL as part of the catalyst, the second as reaction solvent.
Incorporating CILs as part of the catalytic system was realized in sev-
eral different ways and demonstrated for many reactions. Some of the
most relevant examples deal with the application of a CIL as ligand in
the asymmetric Diels–Alder reaction [70] and as proline-based organo-
catalysts in asymmetric Michael-addition [71] and aldol reactions [72–75].
Francio et al. used a rhodium complex with a tropoisomeric ligand
in the presence of a CIL for homogeneously catalyzed hydrogenation
reactions and realized in this way good enantioselectivities [52].
Furthermore, they were able to show that a CIL can lead to a selective
poisoning of one of the possible enantiomers of a catalyst complex.
This can enable asymmetric catalysis despite the use of a racemic mix-
ture of the applied chiral ligand [76].
Asymmetric induction by the solvent throughout a chemical reac-
tion is possible but the enantioselectivities achieved in this way are
usually small to moderate [77]. It was shown that the strong inter-
ionic interactions in ionic liquids hinder the transfer of chirality to
uncharged molecules and transition states, which are common in
most organic reactions [78]. However, it has been also found that
the chiral anion of a CIL does strongly interact with an appropriate
counter-ion and that the degree of such interaction is solvent and
concentration dependent [65,79]. These ion-pair interactions could
be verified by 19F-NMR-spectroscopy using a racemic mixture of
methoxy-α-trifluoromethylphenylacetate (deprotonated Mosher's
acid) sodium salt as substrate in an enantiomeric pure ephedrinium
bis(trifluoromethylsulfonyl)imide ionic liquid. Consequently, the
first results of solvent induced chirality transfer with high enantio-
selectivities were obtained by Leitner et al. for the aza-Baylis–Hillman
reaction [47] and by Schulz et al. for the hydrogenation of the prochiral
keto-functionalized cation of (R)-camphorsulfonate ionic liquids [80].
For the aza-Baylis–Hillman reaction an ionic transition state was postu-
lated in which the Brønsted acidic, chiral anion is incorporated as a kind
of organocatalyst.
Chirality transfer in ionic liquids via ion-pairing effects is a very
young field of research. But the basic principle of chiral recognition
was reported first in 1931, when it was found that diastereoselective in-
teractions between a configurationally labile charged metal complex
and a chiral counter-ion can induce stereoselectivity at the metal center
(Pfeiffer effect) [85]. In the field of homogeneous metal catalyzed
reactions many recent publications picked up on this effect and utilized
it remarkably successfully [86–91]. Asymmetric counter-ion directed
catalysis (ACDC) evolved as a new term for this concept. In the last
years a number of papers have been published in high-ranked journals
that make successful use of these chiral recognition effects in organo-
catalysis, [92] Brønsted acid catalysis, [93] and phase transfer catalysis
[94]. Chiral recognition has been also proven by 1D and 2D-NMR studies
with chiral ions and racemic counter ions [95].
As stated before, chirality transfer between the ions of an IL has been
demonstrated for the hydrogenation of prochiral cations in the presence
of their enantiomeric pure counter-ion camphorsulfonate. As an asym-
metric induction requires structurally well-defined interactions, it is
expected that the induced enantioselectivity should correlate with the
probability of ion pairing. First evidence for this hypothesis was found
in the heterogeneously catalyzed (Ru/C), asymmetric hydrogenation
of [N-(3′-oxobutyl)-N-methylimidazolium]-[(R)-camphorsulfonate] in
ethanol (Scheme 1) [80].
The induced enantioselectivity showed a strong dependence on
the IL concentration in the applied organic solvent with a maximum at
medium concentrations of up to 94% ee. This behavior was linked to
the degree of ion pair formation. The latter was determined by DOSY-
NMR measurements and dielectric relaxation spectroscopy. These
analytical techniques provided indeed evidence that the highest degree
of ion pairing and the highest enantioselectivity correlate well for differ-
ent IL-solvent combinations. Further experiments varying the structure
of the IL cation showed that the cation's H-bonding ability has a strong
influence on ion-pairing and thus also on the effectiveness of asymmet-
ric induction [80–84].
In all previous studies dealing with the asymmetric hydrogenation
of prochiral IL cations in the presence of an enantiopure counter-ion,
imidazolium-based ionic liquids were applied as substrates and thus
doubly chiral imidazolium salts were obtained. As neutral chiral build-
ing blocks are of much higher synthetic relevance than chiral salts we
were interested to convert these newly formed chiral ions into neutral
substances. However, in the case of imidazolium salts, such a transfor-
mation would require high temperatures and/or reaction with strong
nucleophiles. These experimental conditions would result in many
side reactions and very likely in racemization of the chiral group of the
ion.
In this contribution we report on our on-going attempts to use
asymmetric induction via ion-pair interactions for the preparation of
neutral, enantiomeric enriched organic molecules that form interesting
building blocks for organic synthesis. Still we are interested in gaining
more insight into the nature of ion pairing in ionic liquid solutions and
the degree of asymmetric induction that can be realized in this way.
2. Synthesis of chiral esters through asymmetric hydrogenation of
prochiral carboxylate salts
Our first synthetic approach towards this goal was the hydrogena-
tion of [(1R,2S)-dimethylephedrinium] salts carrying a prochiral keto-
functionalized carboxylate counter-ion (Scheme 3 and 4). In this “re-
verse” approach to our previous studies, the cation is derived from the
chiral pool and has shown successful application in chiral recognition
[65]. The hydrogenation product, a chiral carboxylate with enantiomeric
excess can be easily converted to a neutral molecule by an esterification
reaction. Also the isolation of the chiral ester should be straight forward
by extraction with organic solvents from the remaining salt.
We tested this concept using the same heterogeneous catalyst as
used in our previous work and applying DOSY-NMR spectroscopy to
gain further understanding for the influence of ion-pairing in this type
of asymmetric reaction (see Section 2.1.1). In a separate set of experi-
ments, the homogeneous Wilkinson catalyst was applied in the same
hydrogenation reaction in combination with racemic and enantiopure
BINAP ligands. In this way we aimed to probe whether ion pairing
Scheme 1. Enantioselective hydrogenation of a keto-functionalized imidazolium camphorsulfonate ionic liquid.

V. Wagner et al. / Journal of Molecular Liquids 192 (2014) 177–184
179
within the CIL is also influencing the selectivity of the homogenously
catalyzed hydrogenation reaction (see Chapter 2.1.2). As the first step,
however, we had to synthesize the substrate salt for these studies.
the degree of dissociation αdiss of ionic liquid ions can calculated from
the modified Stokes–Einstein Eq. (1) [96].
Ne2
kT
À
Á
2.1. Synthesis of CILs with optical pure cation and prochiral anion
σD ¼ αdiss
D− þ Dþ
;
ð1Þ
As prochiral anions the keto-functionalized carboxylates phenyl-
glyoxylate and levulinate were chosen. The corresponding ionic liquids
were synthesized using an anion-exchange resin yielding the CILs
[(1R,2S)-dimethylephedrinium][phenylglyoxylate] IL1 and -[levulinate]
IL2 in quantitative yield (Scheme 2).
with σD = conductivity, N = cations per volume, e = electric charge
and D−/D+ = self-diffusion coefficients of the anion and cation.
The degree of dissociation represents the degree of order in the sys-
tem and gives an insight into the aggregation behavior of the ions of an
IL. Measurements for similar IL/solvent systems have shown, that the
minima of the degree of dissociation and the probability of ion pairing
correlate well [81,84].
2.1.1. Heterogeneously catalyzed hydrogenation of ILs based on
keto-functionalized carboxylic acids
Hydrogenations were carried out in batch autoclaves using the same
achiral ruthenium on charcoal catalyst as used in the previous work
(40 bar H2, 10 wt.% Ru/C (5% Ru), T = 60 °C, t = 5d) [80]. After
hydrogenation the anions were further converted to the methyl ester
by reaction with methanol in presence of the acidic cation exchange
resin H-Amberlite. The obtained esters were analyzed via chiral gas
chromatography. The overall reaction for IL2 is depicted in Scheme 3.
The enantioselectivity obtained in the hydrogenations of IL1 and IL2
are shown in Table 1, the reactions were carried out in methanolic solu-
tions at different concentrations.
The overall enantioselectivities are much lower than in the case
of the hydrogenation of keto-functionalized imidazolium camphor-
sulfonates. This probably reflects the differences in the structure of the
ions, especially of the cation, compared to the imidazole based ILs. A
successful asymmetric induction requires structurally defined ion-pairs
with a close contact of the chiral center and the prochiral keto-
functionality. The overall values are therefore difficult to compare.
However, the observed small ee demonstrates a certain generality of
the concept.
For IL1 the ee induced is almost constant, with a minor maximum at
a concentration of 0.2 mol/L. Note that the enantioselectivity found for
the hydrogenation of ([N-(5′-oxohexyl)-N-methylimidazolium][(S)-
mandelate], in which the comparable (S)-mandelate acts as the source
of the chirality, also showed little concentration dependence [83].
Although the cations are difficult to compare it can be assumed, that
those very similar anions might have a tendency for ion-pairing by hy-
drogen bonding and π-stacking over a relatively broad concentration
range.
For IL2 a slightly stronger dependency of ee on concentration is
found, with a maximum at 0.2 mol/L. In order to correlate the observed
enantioselectivities to ion-pairing, DOSY-NMR spectroscopy measure-
ments have been carried out. In accordance with the existing literature
a bpp-led (bipolar pulsed pairs longitudinal echo current delay) se-
quence was used for the measurements [81]. DOSY-NMR is a very
versatile and powerful method to investigate transport properties of
diffusing ions in solution. It allows for the independent calculation of
the self-diffusion coefficients of the cation and anion of an ionic liquid
[81,96–101]. By a combination of conductivity measurements and the
determination of the self-diffusion coefficients of anions and cations,
Unfortunately, IL1 has no 1H-NMR signals that can be analyzed by
this method as the method requires separated signals of cation and
anion whereas in this case the protons on the cation overlap with the
aromatic protons of the anion. The results for IL2 are shown in Fig. 1.
Indeed, the minimum of the degree of dissociation and the maxi-
mum of the induced ee are found in good agreement. This indicates
asymmetric induction via ion-pairing. Unfortunately the formation of
ion-pairs does not lead to a high degree of asymmetric induction for
this specific system compared to the imidazolium-based ILs. But still
the small induction shows that the concept of asymmetric induction
via ion-pairing is also applicable for the synthesis of enantiomeric
enriched esters.
2.1.2. Homogeneously catalyzed hydrogenation of keto-functionalized
carboxylate ionic liquids
With the influence of ion-pairing on the heterogeneously catalyzed
asymmetric hydrogenation clearly proven, we were interested to inves-
tigate whether inter-ionic induction would also influence the homoge-
neously catalyzed hydrogenation of prochiral ionic liquids. Whereas
chiral poisoning could be excluded by test reactions with non-ionic sub-
strates in the case of heterogeneous catalysts, [80] chiral poisoning of
homogeneous catalysts can be excluded by using a chiral cation togeth-
er with a neutral catalyst complex. Note that poisoning by a chiral
counter-ion or metal complexation would require the use of a chiral
anion together with the cationic transition metal complex. IL1 is a suit-
able substrate for homogeneously catalyzed hydrogenation and also
carries its chiral center at the cation. As a catalyst, the standard Wilkin-
son complex Rh(PPh3)3Cl was used as a pure compound and with an
added PPh3 ligand in an IL/catalyst/ligand ratio of 250:1:4. To avoid ad-
ditional influences by the temperature dependency of the IL aggregation
behavior, hydrogenations were carried out under the same reaction
conditions as previously used in the heterogeneous hydrogenation.
THF was used as solvent.
In addition, the influence of a chiral counter-ion on the hydrogena-
tion was investigated. Chiral ligands were applied to test the possibility
for chiral enhancement. For this purpose the corresponding complexes
with racemic and enantiopure (S)-BINAP-ligand were also tested.
All homogeneously catalyzed hydrogenations of the phenylglyoxylate
anion were carried out under the same conditions (p(H2) = 40 bar,
T = 60 °C, reaction time = 5d).
The reaction mixture was worked up analogously to the heteroge-
neously catalyzed reaction by converting the chiral anion into the corre-
sponding methyl ester. The latter was analyzed by chiral GC. Note that
the reaction rate was very slow – independent of the ligand used –
with a degree of conversion below 10% after five days of reaction time.
The results are shown in Table 2.
The hydrogenation using the standard Wilkinson catalyst yielded no
ee, independent on the addition of more PPh3 ligand. Therefore, the in-
fluence of the chiral cation on the catalyst complex seems not strong
enough to influence the enantioselectivity of the catalyst. This also
shows that the chiral cation does not interact strongly with the catalyst
complex in a manner that leads to a chiral poisoning effect.
Scheme 2. Synthesis of ILs 1 and 2 based on the chiral cation [(1R,2S)-dimethylephedrinium]
and prochiral carboxylate ions.

180
V. Wagner et al. / Journal of Molecular Liquids 192 (2014) 177–184
Scheme 3. Heterogeneously catalyzed hydrogenation of IL1 followed by an esterification yielding a neutral product.
A small degree of enantioselectivity was found, however, with a
Completion of the reaction was checked by NMR-spectroscopy and
the reaction in all cases gave quantitative yields after drying the product
salt under high vacuum.
racemic mixture of the BINAP ligand for the hydrogenation of IL1.
31P-NMR spectroscopy showed that the catalyst is not altered by addi-
tion of the IL, as neither the chemical shift of the ligand changed nor
was a diastereomeric splitting observed. As the catalyst is not charged
the induction is not a variant of asymmetric counter-ion directed catal-
ysis, but is attributed to ion pairing within the IL. The results of the
hydrogenation using enantiopure BINAP gives further indication that
the chiral cation can lead to chiral enhancement in combination with
a chiral ligand. This shows the strong influence of ion–ion interactions
within solutions of ionic liquids and can be used for asymmetric synthe-
sis. Obviously, further understanding of concentration effects and struc-
tural optimization of the salt/ligand combination e.g. using a Noyori-
type catalyst are required to obtain ee-values of preparative interest.
As prochiral substrates for the creation of the new chiral center by
this method we selected again keto-functionalized carboxylic acids.
These can be bound to the cholinium ion by esterification and liberated
after the hydrogenation reaction by ester cleavage. For an easier separa-
tion of the carboxylic acid out of the IL medium after reaction, the acid
can again be converted to the ester by using an acidic cation exchange
resin and methanol as solvent and substrate. The overall product of
the reaction sequence (Scheme 6) is a chiral acid or methyl ester,
respectively. The enantiomeric excess of these neutral products can be
analyzed via chiral GC.
The first step of the reaction sequence of Scheme 6 is the esterifica-
tion of the carboxylic acid and the cholinium ion of the IL. The esterifica-
tion is an acid or base catalyzed equilibrium reaction, in which the water
has to be removed from the system to achieve high conversions. The
usual esterification protocol [104] involves refluxing the acid and the
alcohol in toluene in presence of an acid catalyst. Water is removed by
either a drying agent or a water-separator. By applying this method to
the esterification of the cholinium cation with the prochiral substrates
phenylglyoxylic acid (S1) and levulinic acid (S2) only moderate degrees
of conversion were obtained. We assume that this observation is linked
to the highly hydrophilic nature of IL3.
Higher yields could be achieved by using Steglich conditions [102].
This method of esterification is very elegant as the main reagent
dicyclohexylcarbodiimide enhances the reaction by activation of the
acid and also binds the by-product water and therefore pushes the
equilibrium in favor of the ester product. In order to suppress possible
side reactions, a small amount of dimethylaminopyridine was added
(DMAP) (Scheme 7).
In contrast to the esterification of IL3, conversion of the IL4 with the
prochiral acids phenylglyoxylic acid (S1) and levulinic acid (S2) in tolu-
ene led directly to high yields in the desired esters, probably due to the
strongly hydrophobic nature of IL4. Details on the synthetic procedures
are given in the Section 4, the degrees of esterification for all substrates-
IL reactions are shown in Table 3.
2.2. Synthesis of neutral chiral building blocks by reversible attachment of a
prochiral substrate to a CIL
In another attempt to utilize the asymmetric induction between the
ions of a CIL for asymmetric synthesis we adapted a method used in
peptide chemistry [103]. Here, the substrate is bound reversibly to a
support, the reaction proceeds while the substrate is bound to the sup-
port, and finally the product is liberated from the support. In our case
the support is an ionic liquid composed of a hydroxyl-functionalized
cation and a chiral enantiopure counter-ion. The hydroxyl functional
group enables the reversible binding of carboxylic acids to the cation.
In order to test the influence of the anion's structure on the chiral
induction, two different enantiopure anions were tested. As the first
candidate [cholinium][(S)-camphorsulfonate] IL3 was synthesized
and applied. This IL candidate was selected due to the fact that in our
previous work [80–84] the best ee values were obtained with [S-
camphorsulfonate] salts. As the second candidate, a hydrophobic chiral
anion was selected as the hydrophobic nature of the salt leads to advan-
tages in the workup procedure. Consequently, [cholinium][((R)-1,1′-
Binaphtyl-2,2′-sulfonimid] ([cholinium][BINBAM]) IL4, based on a
bulky anion with axial chirality, was synthesized and applied. Both
salt syntheses were achieved in a straightforward manner by neutraliz-
ing [cholinium][OH] with the respective chiral acid. [Cholinium][OH] is
commercially available and cheap, but has to be cleaned from the re-
maining amine before use. (S)-camphorsulfonic acid is derived from
the chiral pool and therefore inexpensive. [BINBAM]- is not commercial
and was synthesized in cooperation with the Giernoth group, following
the previously published procedure [53]. Scheme 5 shows the synthesis
of IL3 and IL4.
The second reaction step is the asymmetric hydrogenation of the so-
formed ester. Tetrahydrofurane (THF) was applied as the solvent for the
hydrogenation of the acids bound to IL3. For the hydrogenation of the
acids bound to IL4 only DMF was viable, due to the poor solubility of
the IL in all the other solvents suitable for hydrogenation. In order to cal-
culate the correct concentration of IL for the hydrogenations the average
molecular weight was calculated taken into account for the achieved
degree of esterification. All the samples were hydrogenated under the
Table 1
Asymmetric hydrogenation of the [(1R,2S)-dimethylephedrinium]-based ionic liquids IL1
and IL2 in methanolic solution.
Concentration
[mol/L]
ee in anion after
hydrogenation of IL1 [%]
ee in anion after
hydrogenation of IL2 [%]
0.1
0.2
0.3
0.5
9
4
14
9
14
12
11
Scheme 4. Homogeneously catalyzed hydrogenation of [(1R,2S)-dimethylephedrinium]
[phenylglyoxylate] (IL1).
n. d.

V. Wagner et al. / Journal of Molecular Liquids 192 (2014) 177–184
181
indeed observed in all cases where the prochiral substrate was attached
to a high degree to the ionic liquid. An enantiomeric excess of up to 63%
could be realized for the hydrogenation of IL4 in DMF (c = 0.05 mol/L).
After the hydrogenation reaction the enriched acid was liberated from
the IL by ester cleavage or esterification. In principle, this method
enables the use of the CIL as a chiral auxiliary, as the latter may be re-
used in a next reaction cycle.
4. Experimental section
All the syntheses were carried out under argon unless otherwise
specified. Solvents for the hydrogenation reactions were of spectroscop-
ic grade. Methylimidazole was distilled und kept under argon at −18 °C
prior to use. [Cholinium][OH] solution (Aldrich, 46 wt.%) was diluted
to double of its volume with water, filtered over activated charcoal.
Afterwards its concentration was determined by titration. All other
chemicals were purchased at Aldrich and used as received. Ruthenium
on charcoal (5% Ru) was purchased from Fluka.
Fig. 1. Degree of dissociation of IL2 at different concentrations in methanol.
The conductivity of solutions was determined using a conductivity
cell (LTA 1, WTW, cell constant K = 1, platinized platinum electrode).
NMR experiments were carried out using a Jeol ECX 400 MHz spec-
trometer with a 2-channel (HF, LF)-probe. Spectra were referenced to
the solvent. The procedure of DOSY-NMR followed published proce-
dures using a bpp-led sequence [81,100,101,105,106] All GC chromato-
grams were recorded using a Varian 3900 equipped with a Varian CD
8410 auto-sampler and a flame-ionization detector. As a chiral column,
a Varian CP Chirasil-Dex was used (25 m × 0.32 mm).
same reaction conditions (p(H2) = 40 bar, T = 60 °C, 10 wt.% Ru/C
(5% Ru), RT = 5d) using 20 mL batch autoclaves.
After the hydrogenation the chiral acids were liberated from the IL
by acidic ester cleavage followed by extraction and chiral gas chroma-
tography. The results are shown in Table 3.
A challenge within the reaction system is the incomplete esterifica-
tion and its negative influence on the chirality transfer from the IL
anion to the prochiral center of the reaction. Consequently, for low
degrees of esterification no ee was found for both substrates bound
to IL3. With higher degrees of esterification, ee induced during the
hydrogenation of the prochiral center was clearly visible. Remarkably,
for almost quantitative esterification (Entry 5, Table 3) the ee during
hydrogenation was highest and reached 63%. The very clear
dependence of the induced ee on the degree of esterification is a very
strong indication that the chirality transfer does indeed proceed via
ion pairing effects. It is evident that the here presented concepts need
further elaboration to explore the scope of substrates and optimal
concentration ranges. However, we present here the first successful
example of the synthesis of a chiral ester using reversible binding to a
chiral ionic liquid.
4.1. [(1R,2S)-N,N-dimethylephedrinium][phenylglyoxylate] (IL1)
A 0.1 molar solution of [(1R,2S)-N,N-dimethylephedrinium][iodide]
was eluted slowly over a Dowex 1 × 8-column, which was presaturated
with [phenylglyoxylate]. The eluent was intermittently tested to be io-
dide free by Ag[NO3]. Afterwards, the column was rinsed with water
and the combined solutions were dried using a rotary evaporator and
HV. The product was obtained as a white solid in near quantitative yield.
1H−NMR ðDMSO−d6; 400 MHz; ppmÞ : δ ¼ 1:08 ðd; 3H;3 J ¼ 6:6 HzÞ;
3:22 ðs; 9HÞ; 3:65 ðq; 1H; 3 J ¼ 6:5 HzÞ; 5:56 ðs; 1HÞ; 6:82 ðs; 1HÞ;
7:23−7:80 ðm; 5HÞ:
3. Conclusion
13C−NMR ðDMSO−d6; 100; 4 MHz; ppmÞ : δ ¼ 6:44; 52:06; 69:51;
74:70; 125:58; 128:12; 128:78; 129:18; 129:62; 132:16; 135:05; 140:45;
172:76; 182:52:
We have explored two basic methods to apply ion pair interactions
within chiral ionic liquids for the asymmetric synthesis of neutral com-
pounds. The first applied ion pair interactions between a chiral cation
and a prochiral keto-functionalized anion in heterogeneously and ho-
mogeneously catalyzed hydrogenation. In the heterogeneous version
of the reaction the obtained ees were low but could be linked to inter-
ionic interactions by DOSY-NMR measurements. For the homogenous
version of the reaction we found chiral enhancement when racemic or
enantiopure chiral ligands were applied together with the prochiral
ionic liquid.
4.2. [(1R,2S)-N,N-dimethylephedrinium][levulinate] (IL2)
A 0.1 molar solution of [(1R,2S)-N,N-dimethylephedrinium][iodide]
was eluted slowly over a Dowex 1 × 8-column, which was presaturated
with [levulinate]. The eluent was intermittently tested to be iodide free
by Ag[NO3]. Afterwards, the column was rinsed with water and the
combined solutions were dried using a rotary evaporator and HV. The
product was obtained as a white solid in near quantitative yield.
As a second method we attached prochiral, keto-functionalized
carboxylic acids to a hydroxyl functionalized cation of a chiral ionic
liquid. During hydrogenation of the resulting salt, chiral induction was
1H−NMR ðDMSO−d6; 400 MHz; ppmÞ : δ ¼ 1:08 ðd; 3H;3 J ¼ 6:6 HzÞ;
2:00 ðs; 3HÞ; 2:08 ðt; 2H; 3 J ¼ 7:2 HzÞ; 2:42 ðt; 2H; 3 J ¼ 7:1 HzÞ;
3:22 ðs; 9HÞ; 3:57 ðq; 1H; 3 J ¼ 6:9 HzÞ; 5:63 ðs; 1HÞ; 6:82 ðs; 1HÞ;
7:10−7:46 ðm; 5HÞ:
Table 2
Homogeneous hydrogenation of IL1 and phenylglyoxylic acid using PPh3, racemic and
enantiopure S-BINAP.
PPh3
rac-BINAP
S-BINAP
ee in cation after hydrogenation [%]
13C−NMR ðDMSO−d6; 100; 4 MHz; ppmÞ : δ ¼ 7:25; 32:02; 51:05;
67:80; 74; 45; 126:31; 126:44; 127:47; 128:48; 129:0; 136:6; 143:77;
175:35; 203:17:
Phenylglyoxylic acid
IL1
0
0
0
14
7
34

182
V. Wagner et al. / Journal of Molecular Liquids 192 (2014) 177–184
Scheme 5. Synthesis of the chiral cholinium salts ILs IL3 and IL4.
Scheme 6. Asymmetric hydrogenation of a keto-functionalized carboxylic acid reversibly attached to a chiral carrier IL (IL3).
4.3. Column preparation
4.5. [Cholinium][(R)-1,1′-binaphtyl-2,2′-sulfonimid] (IL4)
A Dowex 1 × 8 column (Cl-form, capacity = 1.2 mmol/mL) was
washed with 2 M NaOH until no chloride could be detected when
adding a silver nitrate solution. After washing to neutral pH with
water, the column was charged with 0.1 M solution of the acid corre-
sponding to the desired anion. The column was washed to neutrality
again.
To one equivalent of the pretreated [cholinium][OH] solution, one
volume equivalent of DMF and afterwards one equivalent of [H][((R)-
1,1′-Binaphtyl-2,2′-sulfonimid] was added. After stirring for 1 h, the
solvent was removed using a rotary evaporator and HV. The product
was obtained as a brown–white solid in near quantitative yield.
1H−NMR ðDMSO−d6; 400 MHz; ppmÞ : δ ¼ 3:03 ðs; 9HÞ;
3:34 ðm; 2HÞ; 3:78 ðs; 2HÞ; 6:97 ðd; 2H; 3 J ¼ 8:8 HzÞ;
7:28 ðm; 2HÞ; 7:54 ðm; 2HÞ; 7:90−8:14 ðm; 6HÞ
4.4. [Cholinium][(S)-camphorsulfonate] (IL3)
To one equivalent of the pretreated [cholinium][OH] solution, one
equivalent of (S)-camphorsulfonic acid was added. After stirring for
1 h, the solvent was removed under reduced pressure (rotary evapora-
tor and HV). The product was obtained as a white solid in quantitative
yield.
13C−NMR ðDMSO−d6; 100:4 MHz; ppmÞ : δ ¼ 25:66;
53:68; 55:68; 67:46; 123:22; 127:29; 127:62;
127:96; 132:10; 132:98; 134:44; 140:86:
4.6. Acidic esterification in toluene
1H−NMR ðDMSO−d6; 400 MHz; ppmÞ : d ¼ 0:70 ðs; 3HÞ;
1:01 ðs; 3HÞ; 1:20−1:28 ðm; 2HÞ; 1:74−1:91 ðm; 3HÞ;
One equivalent of IL and one equivalent of the acid was dissolved in
toluene. After addition of a 0.05 equivalent of H2SO4 and 10 wt.% of an-
hydrous Mg[SO4] the reaction mixture was refluxed at 130 °C for 24 h.
The mixture was then filtered. For IL3 as substrate the solvent was re-
moved in HV at 75 °C, afterwards the mixture was dissolved in water
and extracted with ether. The aqueous phase was dried under reduced
pressure yielding the product as yellow oil. For IL4 as substrate the or-
ganic phase was washed with water and afterwards dried in HV yielding
the product as a brown solid.
2:20 ðm; 1HÞ; 2:33 ðd; 1H; 3 J ¼ 14:8 HzÞ; 2:65 ðm; 1HÞ;
2:83 ðd; 1H; 3 J ¼ 14:8 HzÞ; 3:07 ðs; 9HÞ;
3; 37 ðt; 2H;3 J ¼ 5:2 Hz Þ 3; 80 ðm; 2HÞ; 5:30 ðbrs; 1HÞ
13C−NMR ðDMSO−d6; 100:4 MHz; ppmÞ : δ ¼ 19:37; 19:94;
23:91; 26:20; 42:32;
46:71; 47:13; 53:13; 55:24; 58:29; 66:93:
Scheme 7. Esterification of IL3 and levulinic acid using Steglich reagents.

V. Wagner et al. / Journal of Molecular Liquids 192 (2014) 177–184
183
Table 3
Asymmetric hydrogenation of carboxylic acids bound to a chiral carrier ILs.
4.11. Analysis by chiral GC of IL3 and IL4
After hydrogenation, the reaction mixture was dried in HV. A sample
was taken and dissolved in water. After the addition of sulfuric acid and
stirring for 30 min, the liberated acid was extracted three times with
diethyl ether. Afterwards, methanol and H-Amberlite were added
to the combined organic phases in order to yield the corresponding
methyl ester. The organic phase was afterwards analyzed using chiral
gas chromatography.
Entry Ionic Substrate Degree of
Solvent Concentration ee in product after
liquid
esterification
[mol/L]
hydrogenation [%]
[%]
1
2
3
4
5
IL3
IL3
IL3
IL3
IL4
S1
S1
S2
S2
S2
56
33
74
40
97
THF
THF
THF
THF
DMF
0.1
0.1
0.1
0.1
0.05
37
0
30
0
63
Acknowledgments
4.7. Esterification using Steglich reagents
The authors wish to thank the German Science Foundation (DFG) for
funding this work within its priority program SPP1191 “Ionic Liquids”.
Furthermore the authors want to thank the Giernoth Group, Marcel
Treskow in particular, for the synthesis of [H][(R)-1,1′-Binaphtyl-2,2′-
sulfonimid].
One equivalent of the acid was dissolved in dichloromethane and
1.05 equivalents of dicyclohexylcarbodiimide were added. After stirring
for 10 min one equivalent of the IL and 0.05 equivalents of N,N-
dimethylaminopyridine were added. The reaction mixture was stirred
for 16 h. Afterwards it was heated to 60° for one hour. The so formed
white precipitate was filtered of. For IL3 the organic phase was extract-
ed three times with water. Drying the aqueous phase under reduced
pressure yielded the product as yellow oil. For IL4 the organic phase
was washed with water. Drying the aqueous phase yielded the product
as a brown solid.
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IL3
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IL4
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